Infectious diseases

Conference Report XIII International AIDS Conference, Durban, 9-14 July, 2000 Nelson Mandela argues for urgent action against HIV in Africa John B Ziegler and Rosemary A Ffrench Let us not equivocate: a tragedy of unprecedented proportions is unfolding in Africa. AIDS today in Africa is claiming more lives than the sum total of all wars, famines and floods, and the ravages of such deadly diseases as malaria . . . Economic growth is being undermined and scarce development resources have to be diverted to deal with the consequences of the pandemic . . . Decades have been chopped from life expectancy and young child mortality is expected to more than double in the most severely affected countries of Africa. AIDS is clearly a disaster, effectively wiping out the development gains of the past decades and sabotaging the future. Earlier this week we were shocked to learn that within South Africa one in two, that is half, of our young people will die of AIDS. The most frightening thing is that all of these infections, which statistics tell us about, and the attendant human suffering, could have been, can be, prevented. Something must be done as a matter of the greatest urgency. And with nearly two decades of dealing with the epidemic, we now do have some experience of what works.-- Nelson Mandela1 MJA 2000; 173: 572-574 Prevention - Mother-to-child transmission - Vaccines - Treatment strategies - Hope - References - Authors' details Box 1: HIV in African countries, 1999 Box 2: Trends in mortality among children under five Nelson Mandela's closing address to the conference1 was a welcome contrast to the opening address by Thabo Mbeki, President of South Africa, who disappointed delegates by failing to resolve their concerns about his view that HIV does not cause AIDS. In his plenary address, David Ho (Director, Aaron Diamond AIDS Research Center, New York) noted that Mbeki would be judged harshly by history. Judge Ed Cameron, a gay white South African living with HIV, in a moving address, pointed out that his government had consistently mismanaged the epidemic, and that he was only alive because his income allowed him to purchase antiviral drugs not available to most South Africans with AIDS. Prevention Box 3: Probability of a Zimbabwean boy aged 15 dying before age 50 Box 4: Projected population structure, Botswana 2020 While news of the explosive spread of HIV in the Republic of South Africa highlighted the urgency of effective preventive strategies, there was relatively good news from some countries where decisive action by pragmatic governments was paying off: the HIV infection rate has stabilised at a relatively low level in Senegal; Uganda has brought its estimated prevalence rate down to about 8% from a peak of close to 14% in the early 1990s; Thailand's "100% condom use" campaign among female sex workers has contributed to falling prevalence in military recruits and antenatal clinic patients.2 In the opening plenary session, Professor Roy Anderson (Director, Centre for the Epidemiology of Infectious Disease, Oxford) explained that interventions to interrupt the spread of HIV in populations would have relatively little impact once prevalence was high. Targeting individuals engaging in high risk behaviours was only effective early in an epidemic; unfortunately, few governments have been prepared to invest resources in the early stages, when such efforts are most cost-effective. There was hope that relatively inexpensive strategies to prevent heterosexual transmission of HIV might emerge from the conference. Unfortunately, the results of a study of a vaginal microbicide containing nonoxynol-9 among sex workers in Côte d'Ivoire showed a higher infection rate in the experimental arm. This suggests that the microbicide's detergent action caused ulceration that enhanced HIV transmissibility. Mother-to-child transmission Amid the gloom of the inexorable spread of HIV in Africa and emerging epidemics in Eastern Europe, delegates were virtually unanimous that there should be no delay in implementing cost-effective measures to prevent mother-to-child transmission of HIV, especially with some drug companies offering to provide free drugs in less developed countries. Data from a prospective observational study in the USA showed that, with optimal maternal combination antiretroviral treatment, the risk of mother-to-child transmission falls to as low as 1%. In breast feeding populations treated with only one drug the gains were less dramatic, but nevertheless very impressive, with the potential to prevent the infection of 25 000 infants a year in South Africa alone. Data presented at the conference reinforced concern that the benefit of perinatal antiviral therapy would be lost when mother-to-child transmission occurred during subsequent breast feeding. However, analysis of the HIVNET 012 trial (mother and infant each received a single dose of nevirapine in labour and by Day 3, respectively) at 18 months showed that an absolute 8% reduction persisted despite prolonged breast-feeding.3 These interventions prevent only about a third of mother-to-child transmission, but they point to cost-effective strategies relevant in resource-poor settings. Implementation will be challenging; it was clear that many women attending African antenatal clinics do not accept HIV screening, do not return for results or do not accept antiretrovirals if HIV positive; attrition rates of 80% were reported. The role of breast feeding in perinatal transmission of HIV was firmly established by a randomised, controlled trial in Nairobi, Kenya.4 While observational data suggested that exclusive breast feeding may be safer than mixed feeding, bottle feeding provides the best protection against HIV infection. The Nairobi investigators reported that the mode of feeding did not affect survival to 24 months, either in the infected or uninfected infants. Surprisingly, breast feeding was associated with three times as much maternal mortality at two years as formula feeding. Vaccines New candidate HIV vaccines presented at the conference provided some hope for the future control of the pandemic. After the disappointing immunogenicity of the recombinant protein vaccines, which were designed to elicit antibody responses, it was thought that strategies for eliciting cellular immunity, particularly cytotoxic T lymphocyte (CTL) activity, may be more successful. The trials of vCP205 (a canarypox virus expressing HIV genes), both alone or with a recombinant protein boost, showed very few vaccine recipients with detectable CTL activity, and these few responses were not sustained. However, it was shown that responses were detected more frequently when vaccine recipients received higher doses of vCP205, so more antigen expresssion may be necessary to achieve the desired levels of immunity. Results of a Phase II trial of the whole, killed HIV vaccine, Remune, in HIV-positive individuals in Thailand were presented. The subjects who received the therapeutic vaccine had a small but significant increase in the CD4+ cell count (P = 0.05) of about 46 cells/µL, with increased antibody levels but no change in viral load. Probably the most controversial decision relating to HIV vaccines in the past few years was to take the AIDSVAX recombinant envelope protein into Phase III clinical trials (in Phase I/II trials the vaccine did not induce antibodies that would neutralise circulating strains of HIV). It was reported in Durban that enrolment in the Phase III trials had been completed in Thailand (n = 2100) and the USA (n = 5400). Efficacy data will not be available until early 2003. There are many new vaccine concepts currently undergoing preclinical testing and some impressive data were presented on experiments in mice and macaques. Stephen Kent (Principal Research Fellow, HIV Vaccines Laboratory, University of Melbourne) presented further evidence that a prime-boost vaccine strategy using DNA vectors, followed by fowlpox virus recombinant for gag and pol simian immunodeficiency virus genes, produced very high levels of cellular immunity in macaques, and that these responses could be increased by the co-expression of the cytokine gene IFN-g. This candidate vaccination strategy, for which the University of New South Wales was recently awarded $27 million by the US National Institutes of Health (NIH), will be tested in Phase I/II human clinical trials in Australia within two years. Another vaccine that has generated considerable interest was presented by Dr Robert Johnson (Director, Alphavax, Professor of Virology, University of North Carolina). The vector for the vaccine, a Venezuelan equine encephalitis replicon, was shown to target dendritic cells, one of the most powerful inducers of cellular immune responses. Testing of this vaccine will begin in South Africa early next year. Dr B. Ensoli (Virologist, Instituto Superiore di Sanità, Rome) also presented some convincing data on preclinical macaque studies of a vaccine targeting immune responses to the tat gene of HIV. She found that five of seven macaques were protected from infection with pathogenic simian/human immunodeficiency virus challenge, and that these monkeys had developed good cellular immune responses to tat protein. Clinical trials are due to begin with this vaccine in Italy and Africa. Thus, although HIV vaccines tested to date have produced somewhat disappointing results, there was optimism at Durban that the next generation of vaccines are promising. Treatment strategies Clinicians and patients have recently become excited by the concept of structured treatment interruptions, which have been suggested to enhance immune responses to HIV while providing relief from the cost, inconvenience and toxicity of complex antiretroviral regimens. Dr Tony Fauci (Director, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland) presented a pilot study of five patients selected because they had achieved undetectable viral levels with potent therapy. They then interrupted therapy for one week in two. During seven such interruption cycles the patients' viral levels remained undetectable and their immune function was preserved. However, because the cohort was small, the subjects highly selected (with extremely well controlled viral replication) and the period of observation was too short, the results did not provide reassurance that such a strategy would not be associated with the risk of induction of drug-resistant variants. It is thus much too early to recommend this strategy in clinical practice. Hope Overall, the conference was hugely successful. Despite talk of boycotts because of Mbeki's views, the conference was well attended. The colourful national costumes of delegates, signage, art and craft displays and street theatre all provided a celebratory atmosphere. There was a mood of optimism that the problems of access to treatments in resource-poor countries were at last beginning to be addressed. Simple, cost-effective, population-based prevention strategies are working in those countries which have implemented them. The hope is that an affordable preventive vaccine that is active against strains of HIV in areas of high prevalence is not too far off. References Closing address by former President Nelson Mandela at the 13th International AIDS Conference, 14 July 2000, Durban. <http://www.aids2000.com/> Accessed 1 November 2000. UNAIDS. Report on the global HIV/AIDS epidemic, June 2000.<http://www.unaids.org/epidemic_update/report/index.html> Accessed 1 November 2000. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999; 354: 795-802. Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000; 283: 1167-1174. Authors' details Department of Immunology, Sydney Children's Hospital, Sydney, NSW. John B Ziegler, MD, FRACP, Associate Professor. Rosemary A Ffrench, PhD, Senior Scientist, Research Laboratory. Reprints will not be available from the authors. Correspondence: Associate Professor J B Ziegler, Department of Immunology, Sydney Children's Hospital, High Street, Randwick, NSW 2031. j.zieglerATunsw.edu.au 1: Seroprevalence of HIV in African countries in 1999 Over the last decade HIV has spread dramatically in sub-Saharan Africa, the fastest increases in prevalence occurring in Eastern and Southern Africa. (Reproduced by kind permission of the Joint United Nations Progamme on HIV [UNAIDS].) Back to text 2: Trends in mortality among children under five years old, with reference to adult HIV prevalence rate at the end of 1999 During the 1980s there were impressive improvements in child mortality attributable at least in part to improved immunisation rates, better management of diarrhoeal and respiratory disease and economic development. However, those gains are being lost and the increased child mortality rates are attributable to increasing incidence of perinatally acquired HIV. (Source: Demographic and Health Surveys, Macro Intenational, USA.) Back to text 3: Probability of a Zimbabwean boy aged 15 years dying before age 50 Trends are shown according to data from various national surveys. In high prevalance countries, a teenager has a greater than 50% chance of dying of AIDS before age 50. (Source: Feeney G, unpublished data, 1999.) Back to text 4: Projected population structure with and without the AIDS epidemic, Botswana 2020 The population chimney graph shows the dramatic impact that AIDS is predicted to have on the structure of the population of Botswana, where over a third of the 775 000 adults are now infected with HIV. The red pyramid shows the population structure as it would be in the absence of an AIDS epidemic. More children would be born (because more mothers would survive and remain fertile throughout their reproductive years) and fewer would have died because they acquired the virus from their mothers. Far fewer young adults would die before old age. The yellow areas show that the burden of AIDS will be greatest in children and in the most economically productive years of adult life. The implications of this change in population structure are shocking. The United States Census Bureau projects that in 20 years' time there will be more adults in their 60s and 70s in Botswana than in their 40s and 50s. This is based on the assumption that patterns of new infection will not change greatly over the next decade; however, as changes in future infection rates will principally affect men and women under 40 in 2020, the demographic chimney pattern for older adults is hardly affected by this assumption. The "missing adults" -- men and women who should have reached their 40s and 50s in 2020 -- are now in their 20s and 30s, although some have already died. Many more are already infected with HIV and will die before they reach their 50s.2 (Source: US Census Bureau, World Population Profile 2000.) Back to text

John B Ziegler · Rosemary A Ffrench

Responding to Crisis Malaria in the Australian Defence Force during and after participation in the International Force in East Timor (INTERFET) Scott J Kitchener, Alyson M Auliff and Karl H Rieckmann Malaria in Australian Defence Force members has been far more common in East Timor than in other recent overseas deployments. By six months after all 5500 members of the International Force in East Timor had returned to Australia, 267 malaria infections had been reported to the Army Malaria Institute. Only 64 of those affected had their first clinical episode during their 4-5 months in East Timor, and about two-thirds of these infections were caused by Plasmodium falciparum. The remaining 212 soldiers developed their first symptoms after returning to Australia, and all but two infections were caused by P. vivax. After treatment, 44 soldiers had relapses of their vivax infections; 11 had a second relapse and two had a third relapse. These findings raise several issues about prevention and management of malaria in the ADF. MJA 2000; 173: 583-585 Antimalarial measures - High malaria rates in two battalions - Notification of malaria infections - Malaria infections with onset in East Timor - Malaria infections with onset in Australia - Parasite resistance to drugs? - References - Authors' details - - More articles on Infectious diseases and parasitology On 12 September 1999, President Habibie of Indonesia invited an international peace-keeping force to help restore peace in East Timor after significant civil unrest. The United Nations Security Council Recommendation 1264 (15 September 1999) directed the formation of an International Force in East Timor (INTERFET). On 20 September, lead elements of INTERFET from the Australian Defence Force (ADF) landed in Dili and were soon followed by approximately 5500 ADF personnel assigned to serve in different parts of East Timor. INTERFET concluded on 23 February 2000, when most ADF personnel came under the command of the Peace Keeping Force of the United Nations Transition Administration for East Timor (UNTAET). Antimalarial measures ADF personnel used various personal protection measures against mosquitoes, including insect repellents and permethrin-treated mosquito-nets. Preventive medicine units also carried out mosquito control measures. Personnel were given doxycycline (100 mg daily) for prophylaxis, starting one or two days before departure for East Timor and continuing for two weeks after return to Australia. Weekly doses of mefloquine (250 mg) were used as an alternative if doxycycline prophylaxis was not tolerated or contraindicated. In addition, terminal prophylaxis with primaquine (7.5 mg three times daily) was given for two weeks after return to Australia. In general, chemoprophylaxis was not taken under supervision. High malaria rates in two battalions On 23 October 1999 -- approximately one month after deployment -- the first malaria infection was diagnosed in a soldier serving with the Second Battalion, Royal Australian Regiment (2RAR). During the four months of the battalion's deployment on the northern border region, mainly during the wet season, 17 members of the battalion developed malaria (monthly rate, 0.71%). Most of these cases were traced to exposures in Batugade (see Box 1). The Third Battalion (3RAR), deployed to the Oecussi (Ambino) enclave for five months, reported 24 cases of malaria (monthly rate, 0.73%). These malaria attack rates were the highest observed during the ADF involvement in INTERFET. Based on data from ADF units deployed to other areas of East Timor, other high risk areas were the mouth of the Komoro River in Dili (near the international airport) and the southern border regions near Suai. Within 7-8 months after returning to Australia, a further 127 soldiers from 2RAR and 3RAR had developed malaria. Combined with the 41 cases with onset overseas, this equates to nearly three (2.96) of every 100 soldiers from these two battalions acquiring malaria for every month's deployment to East Timor. This rate is higher than that experienced by Australian military forces deployed recently to Southeast Asia and Africa1 and Bougainville (unpublished), but lower than that observed during some military deployments to Papua New Guinea.2 Notification of malaria infections That malaria was a health problem was obvious during the five-month duration of INTERFET, and this became even more noticeable after the return of troops to Australia. Clinical episodes of malaria were reported to the Central Malaria Register of the ADF, which is managed by the Army Malaria Institute (AMI). The AMI records clinical and epidemiological data, and, whenever possible, confirms the diagnosis by microscopic examination of blood films or polymerase chain reaction (PCR). Malaria infections with onset in East Timor During deployment of the entire Australian contribution to INTERFET, 64 ADF members developed malaria while in East Timor (Box 2a). About two-thirds of these infections were caused by Plasmodium falciparum and the remainder by P. vivax. This 2:1 ratio reflects the relative prevalence of these two species in the local communities,3 and suggests that there was inadequate compliance with doxycycline prophylaxis or that there were other factors resulting in lower drug concentrations, such as drug deterioration under adverse environmental conditions or reduced bioavailability. The falciparum infections were treated with either a one-day course of mefloquine, or quinine (3 days) combined with doxycycline (10 days). One patient tolerated mefloquine poorly and received atovaquone and proguanil (3 days). None of the patients had a recurrence of clinical symptoms and were presumably cured of their infections. The vivax infections were treated with a combination of chloroquine (3 days) and primaquine (14 days). All affected patients responded well to treatment, but a few had a recurrence of clinical symptoms and parasitaemia (relapse) a few weeks to months later (Box 2b). Malaria infections with onset in Australia Many more malaria infections had their onset after soldiers had left East Timor, with the first clinical episode of malaria occurring in 212 ADF members after their return to Australia (Box 2a). They all had vivax malaria, except for two soldiers who developed falciparum malaria within two weeks of their return. This indicates that doxycycline prophylaxis effectively prevented the development of the blood stages of P. vivax, but that dormant parasites (hypnozoites) in the liver reactivated, entered the bloodstream, and initiated acute attacks of malaria after doxycycline prophylaxis was discontinued. Such initial episodes of vivax malaria could occur many months after return to Australia, with most ADF personnel involved in INTERFET leaving East Timor between December and March 2000 (Box 2b). A few more initial infections will undoubtedly emerge up to 12 months or longer after return from East Timor. It was obvious that terminal prophylaxis with primaquine had not been successful in eradicating all the residual hepatic parasites. As primaquine is the only drug capable of eliminating such parasites, the 210 patients hospitalised with vivax malaria received primaquine again (22.5 mg or 30 mg daily) in addition to a standard course of chloroquine (3 days). Compliance with treatment courses was undoubtedly better than with terminal prophylaxis. Forty-four soldiers had relapses 22-180 days (median, 77 days) after treatment. Although most soldiers were cured after a second course of chloroquine and primaquine, 11 had a second relapse 28 to 157 days (median, 82 days) after treatment and two had a third relapse 145 to 159 days after the third course of treatment. Apart from the distress caused by these recurrent acute episodes of malaria, the overall effect on operational capability was quite substantial. Clearly, there is an urgent need for more effective malaria prophylaxis. Parasite resistance to drugs? Doxycycline has proven to be very effective in the past for prophylaxis of both falciparum and vivax malaria. In combination with any rapid-acting drug, it also cures falciparum infections provided it is taken for 7-10 days. All the falciparum infections in East Timor were cured after treatment with doxycycline, indicating that the parasites had not developed resistance to doxycycline. Primaquine tolerance is a well-recognised phenomenon in Papua New Guinea2 and other Melanesian countries, but it has not been well documented in East Timor. The surprisingly large number of soldiers who developed vivax malaria after returning to Australia obviously had their infections suppressed effectively by doxycycline while they were in East Timor. Their delayed malaria attacks after their return were the result of either deteriorating drug compliance or primaquine-tolerant hepatic parasites. The fact that 44 (21%) of the 210 patients with vivax malaria had a relapse of their infections (a quarter on more than one occasion), under more closely supervised drug administration, indicates that primaquine-tolerant parasites are present in East Timor. Efforts currently being made to reduce the many malaria casualties in East Timor are summarised in Box 3. References Shanks GD, Roessler P, Edstein MD, Rieckmann KH. Doxycycline for malaria prophylaxis in Australian soldiers deployed to United Nations Missions in Somalia and Cambodia. Milit Med 1995; 160: 443-445. Rieckmann KH, Yeo AET, Davis DR, et al. Recent military experience with malaria chemoprophylaxis. Med J Aust 1993; 158: 446-449. World Health Organization. East Timor epidemiological profile, September 1999 <http://www.who.ch/eha/> (accessed November 2000). Authors' details Army Malaria Institute, Gallipoli Barracks, QLD. Scott J Kitchener, FAFPHM FACTM, Officer Commanding Clinical Field Section; Alyson M Auliff, BSc(Hons), Scientific Officer, Clinical Field Section; Karl H Rieckmann, MD, Director. Reprints: Major S Kitchener, AMI, Gallipoli Barracks, Milpo, QLD 4152. scott.kitchenerATdefence.gov.au Make a comment 1: East TimorMap showing Batugade and the Oecussi (Ambino) enclave, identified as sources of infection for the Secound and Third Battalions, Royal Australian Regiment. Back to text 2: Pattern of malaria infections during the deployment of the International Force in East Timor (INTERFET) (a) Distribution of malaria type and place of onset for the 267 infections among INTERFET peronnel deployed from September 1999 to March 2000. (Data collected up to September 2000). (b) Time of onset of 210 initial vivax malaria infections and 57 relapses after return to Australia (between December 1999 and March 2000). Back to text 3: Improvement of malaria control measures Increased vigilance for malaria in the border areas of East Timor, and continued surveillance of malaria infections after redeployment to Australia; Assessment of the effectiveness of personal protection measures and remedial measures to improve compliance; Evaluation of higher doses of primaquine for eradicating parasites from the liver; and Appraisal of the effectiveness of alternative control measures, including new prophylactic drug regimens. Back to text Plasmodium falciparum Plasmodium vivax

Scott J Kitchener · Alyson M Auliff · Karl H Rieckmann

For Debate Should we conduct a trial of distributing naloxone to heroin users for peer administration to prevent fatal overdose? Simon R Lenton and Kim M Hargreaves MJA 2000; 173: 260-263 Abstract - Should there be a trial - Suggested trial design - Conclusion - References - Authors' details - - More articles on Drugs and alcohol Abstract Heroin overdose is a major cause of death among heroin users, and often occurs in the company of other users. However, sudden death after injection is rare, giving ample opportunity for intervention. Naloxone hydrochloride, an injectable opioid antagonist which reverses the respiratory depression, sedation and hypotension associated with opioids, has long been used to treat opioid overdose. Experts have suggested that, as part of a comprehensive overdose prevention strategy, naloxone should be provided to heroin users for peer administration after an overdose. A trial could be conducted to determine whether this intervention improves the management of overdose or results in a net increase in harm (by undermining existing prevention strategies, precipitating naloxone-related complications, or resulting in riskier heroin use). The rate of fatal heroin overdose in Australia has risen from 10.7 per million in 1979 to 67.0 per million in 1995; similar increases have been reported in other developed countries.1 Heroin users have an excess mortality about 13 times that of their age-matched peers,2 with annual mortality rates of between 1% and 3%.3 Although non-fatal overdoses are common among heroin users, overdose remains a major cause of death among this group,4 even in countries with high rates of HIV among injecting drug users.5 The central nervous system (CNS) depressants benzodiazepines and/or alcohol are often also present in the blood of people who died of heroin-related overdose.3,6In many fatal heroin overdoses there is ample opportunity for intervention: approximately 60% of deaths occur in the company of others,3,4,6-8 mostly other users, and sudden death after injecting is rare (about 15% of deaths).6,9 Death occurs more than three hours after injection in 22%-52% of cases.3 Furthermore, most overdoses occur in a home or other dwelling.9 Witnesses to fatal overdoses only call an ambulance in about 10% of cases,6 and there is no intervention before death in 79% of cases.3 Reasons for not calling an ambulance include fear of police involvement,8,10 ambulance costs,7 and previous negative experiences with hospital staff.10 Since the early 1990s, experts have suggested that naloxone hydrochloride, an opioid antagonist (Box), which has long been used to treat opioid overdose, should be provided to heroin users for administration by their peers in an overdose situation.8,24,38-40 This is one of a range of interventions aimed at reducing the incidence of fatal overdose, including: overdose prevention (eg, educating heroin users about risk factors for overdose and ways of reducing the risks, and increasing numbers in methadone maintenance treatment); and overdose management (eg, providing basic first aid training to heroin users, with emphasis on the need to call an ambulance).41 Naloxone has been available over-the-counter from pharmacies in Italy since 1995 and therefore available for peer administration. There are unpublished reports of authorised distribution for peer administration in Jersey (UK) and Berlin (Germany), and underground distribution through needle exchanges in San Francisco and Chicago, USA. However, to our knowledge, its use by heroin users and their peers has not yet been evaluated. In July 1998, the Health Department of Western Australia (HDWA) commissioned the National Drug Research Institute to explore the feasibility of conducting a trial of naloxone provision for peer administration. We discuss the issues to be considered in deciding whether or not a trial should proceed. The views expressed here are ours and not necessarily those of the HDWA. Should there be a trial of naloxone for peer administration? Distribution of naloxone for peer administration is clearly an intervention with potential to reduce the number of fatal heroin overdoses. However, from a public health perspective, questions remain regarding the impact of naloxone on the uptake and effectiveness of other overdose prevention strategies. Additionally, there is a risk of subsequent morbidity or mortality if no medical follow-up occurs after naloxone administration. These concerns can best be addressed by a multisite longitudinal study of naloxone provision within a carefully monitored group. Below, we summarise the issues to be considered in recommending such a trial. Method of administration The preferred route for peer administration would be intramuscular (see Box). Shelf life and stability Naloxone has a shelf life of 18 months to 2 years, depending on the product form and preparation. Because of this short shelf life, a trial would attempt to determine whether drug users replace expired stock. Furthermore, there are concerns about naloxone's stability and susceptibility to environmental factors. If it is made available for peer administration, it is likely to be left in the glove box of cars or carried in pockets or bags for extended periods of time. Although it is preferable that naloxone be stored in accordance with the manufacturers' recommendations, one manufacturer reports it has been stored at 40ºC for six months, and frozen for up to a month, without compromising its chemical stability (Brenda Fox, Medical Affairs Pharmacist, Fauldings Ltd, 1998, personal communication). Half-life and recurrent overdose Another major concern about the wider availability of naloxone relates to its short duration of effect: its elimination half-life is estimated to be 30-90 minutes, with individual differences due to variations in metabolism.12 Although evidence to date suggests that recurrent overdose is rare,18,23,42 there is the potential for resedation to occur, particularly when longer-acting opioids such as methadone have been used, or additional drugs have been consumed after naloxone administration. Thus, it will often be necessary to administer subsequent doses of naloxone. Research in Victoria suggests that, when ambulance staff administer an intramuscular dose of up to 1.6 mg total dose, few, if any, problems arise, with 90% of patients regaining consciousness (Dr Paul Dietze, Senior Research Fellow, Turning Point Drug and Alcohol Centre Inc, 1999, personal communication). As part of a trial, it may be appropriate to supply two 0.8 mg/2 mL prefilled syringes of naloxone for intramuscular administration (to allow a subsequent dose if necessary), accompanied by appropriate instructions on administration, polydrug intoxication, and the need for medical review. Airway management and first aid In many overdose situations all that is necessary to improve an individual's condition is to provide ventilatory support.27 Even after naloxone is administered, ventilatory support is required until it takes effect. The ability to administer first aid, in particular expired air resuscitation, should therefore be viewed as an integral part of any education provided for peer-administered naloxone. Information about possible complications and how to identify them should also be included. Polydrug use The use of other CNS depressants, particularly alcohol and benzodiazepines, is common in overdoses involving heroin,3,6,8,43,44 but should not preclude a trial of naloxone. Removal of the opioid effect with naloxone could prevent a fatality,40 minimise associated morbidity, and provide time in which to use other interventions. If CNS stimulants are used in conjunction with opioids, naloxone has the potential to unmask their associated toxicity and produce aggression, hypertension, acute pulmonary oedema, cardiac arrhythmia, or seizures.45,46 This may be more of a concern where cocaine use, particularly "speedballs" (heroin mixed with cocaine), is increasingly common among heroin users.47 Overdose prevention strategies should continue to warn users about polydrug use. Solitary heroin users Using heroin alone is a significant risk factor for overdose, as is using heroin in the company of others and then being left to "sleep it off". One of the arguments against the distribution of naloxone for peer administration is that it will have no impact on the death rate among solitary injecting drug users. The dangers of using drugs alone or failing to monitor sleeping drug users should be emphasised in a trial of naloxone. Naloxone administration by intoxicated peers Concern has been expressed that peers available to administer naloxone may be intoxicated, but this is also likely with other overdose management strategies. Some current strategies are quite complex and require vigilance, such as expired air resuscitation, monitoring, checking the pulse, and so on. Naloxone administration, particularly with a prefilled syringe, seems no more complicated, and its use should not be precluded because the person administering it may be affected by drugs. Undermining other overdose strategies Availability of naloxone for peer administration may undermine existing overdose prevention and management strategies, notably calling an ambulance. Research supports this, with many heroin users believing that peer administration of naloxone would negate the need to call an ambulance.8,40,48 Thus, some non-fatal overdose victims may not be transported to hospital.48 This is similar to what occurs in many Australian States after naloxone administration -- overdose patients refuse to be transported to hospital or, alternatively, leave hospital against medical advice. In these situations, wherever possible, the individual is placed in the care of a "responsible person", and in several States ambulance staff provide a pamphlet which outlines potential risks and gives basic first aid information. A similar intervention should be included in any trial of naloxone provision, with users encouraged to seek medical review after peer-administration of naloxone. Impact on heroin use among current users It has been suggested that some heroin users, if they believe that their peers can revive them with naloxone, might take more risks with their use of heroin.38 It is unlikely that this behaviour would become widespread, not least because of the unpleasant effect of naloxone in precipitating withdrawal in opioid-dependent people.8,24,39 According to heroin users, factors other than the likelihood of overdose or strategies available to prevent it influence drug use.48 Removing barriers to first use Naloxone provision could make heroin use appear safer and therefore encourage its uptake by novices. However, similar concerns were raised about the wider availability of needles and syringes, and there is no evidence that these measures have encouraged injecting among those previously not using needles.49 Rapid detoxification There is anecdotal evidence to suggest that some people take opioid antagonists to lower their tolerance and reduce the amount of heroin needed to achieve their desired level of intoxication. This has the potential to increase the individual's risk of overdose. Naltrexone, an oral opioid antagonist, is now more readily available for the treatment of opioid dependence and therefore people are more likely to use this treatment to lower their opioid tolerance than naloxone. However, the extent to which naloxone is used to reduce dependence should be assessed as part of a trial. Suggested trial design As peer administration of naloxone would take place within drug-using networks, a network sampling strategy is appropriate. This would recruit heroin users (and their peers) who have experienced and/or witnessed multiple overdose events. The trial could compare "first aid plus naloxone access and training" with "first aid only" across three Australian States over a 12-month period. An initial intake of 450 heroin users should produce a final sample of 250 individuals at 12 months, and about 180 overdose events for investigation.48 Power calculations for logistic regression analyses on a final sample of 250 would produce a power of 97% for events with a probability of 0.2, and 88% for events with a probability of 0.1, with an odds ratio of 2.0 with variables correlated at 0.4. Contamination between the intervention and control groups is a potential problem. In States with large populations of users in regional centres, geographical distance could be used to counteract this. It may also be possible to have a larger control group and place control respondents who gain access to naloxone into a third group. This would maintain the integrity of the control group, while allowing some analysis of the diffusion of the "naloxone training and access" intervention into other groups. Economic cost We estimate the cost of running a trial at three sites to be about $300 000, of which the cost of naloxone would be about $25 000 (1250 doses) at full retail price. Trial results could contribute to an economic modelling of the potential cost effectiveness of naloxone distribution. Dietze et al50 have estimated the cost of ambulance attendance for heroin overdoses in Victoria at over $1 million per annum, which they regard as cost effective in terms of preventing serious injury and death. If naloxone is recommended for more widespread distribution in the future, research suggests that many heroin users (75%) would be willing to pay for their own naloxone,51 which would further reduce the cost of the intervention. Legal issues A number of legal issues are raised by the possibility of conducting a trial of peer-administered naloxone. Central to this is the mechanism of providing naloxone to trial participants. If provided on prescription under Schedule 4, both the patient and the prescriber would be legally compromised when, as is likely, a third person administers the drug. Trial participants could be issued with a permit to access the drug, but this would compromise confidentiality. The drug could be rescheduled from Schedule 4 to Schedule 3 (dispensed by pharmacists only and stored out of public access) for the purposes of the trial, although the requirement for supervised dispensing could not be guaranteed given that the drug is likely to be passed to a third person. The drug could be removed from scheduling for persons involved in a possible future trial under an agreement between the research consortium and the relevant statutory body. While, to our knowledge, this has not been done before, it would enable the identity of trial participants to remain confidential. This would simplify the issue of naloxone provision and/or administration by a third person, and may also limit the exposure of participating agencies to civil action. Conclusion Faced with increasing heroin overdose deaths, the provision of naloxone to heroin users for peer administration is one of a range of interventions worth trialling. However, questions remain as to whether it can appropriately be used by peers as part of a comprehensive first aid intervention, and whether it improves outcomes, or results in net increases in harm. Net harm could increase as a result of undermining existing strategies, naloxone-related complications, or riskier heroin use. Many of these questions could be answered by a multisite longitudinal study of naloxone provision within a carefully monitored group. References Darke S, Ross J. Fatal heroin overdoses resulting from non-injecting routes of administration, NSW, Australia, 1992-1996. Addiction 2000; 95: 569-573. English DR, Holman CDJ, Milne E, et al. The quantification of drug caused morbidity and mortality in Australia. 1995 edition. Canberra: Commonwealth Department of Human Services and Health, 1995. Darke S, Zador D. Fatal heroin "overdose": a review. Addiction 1996; 91: 1765-1772. Darke S, Ross J, Hall W. Overdose among heroin users in Sydney Australia. 1. Prevalence and correlates of non-fatal overdose. Addiction 1996; 91: 405-411. Davoli M, Perucci CA, Rapiti E, et al. A persistent rise in mortality among injection drug users in Rome, 1980 through 1992. Am J Public Health 1997; 87: 851-853. Zador D, Sunjic S, Darke S. Heroin-related deaths in New South Wales, 1992: toxicological findings and circumstances. Med J Aust 1996; 164: 204-207. Loxley W, Davidson P. Forgetting to breathe: opioid overdose and young injecting drug users in Perth. Perth: Curtin University of Technology, National Centre for Research into the Prevention of Drug Abuse, 1998. McGregor C, Darke S, Ali R, Christie P. Experience of non-fatal overdose among heroin users in Adelaide, Australia: circumstances and risk perceptions. Addiction 1998; 93: 701-711. Darke S, Ross J. Heroin-related deaths in South Western Sydney: 1992-1996. Sydney: The University of New South Wales, National Drug and Alcohol Research Centre; 1998. Gore C. Report of the Pilot Heroin Overdose Peer Education project -- March 1997. NSW: Centre for Education and Information on Drugs and Alcohol, 1997. MIMS (Australia). 1998 MIMS Annual. Sydney, NSW: Intercontinental Medical Statistics (Australasia), 1998: 1176-1177. Chamberlain JM, Klein BL. A comprehensive review of naloxone for the emergency physician. Am J Emerg Med 1994; 12: 650-660. David Bull Laboratories (Australia). Naloxone hydrochloride injection. USP product information. Melbourne Vic: David Bull Laboratories; 1992. Boots Pharmaceuticals (Australia). Narcan injection and Narcan Neonatal injection. Product information. Sydney, NSW: The Boots Company (Australia) Pty Ltd, 1993. Moore RA, Rumack BH, Conner CS, Peterson RG. Naloxone: underdosage after narcotic poisoning. Am J Dis Child 1980; 134: 156-158. Jasinski DR, Martin WR, Haertzen CA. The human pharmacology and abuse potential of N-allylnoroxymorphone (naloxone). J Pharmacol Exp Ther 1967; 157: 420-426. Barsan WG, Olinger CP, Adams HP, et al. Use of high dose naloxone in acute stroke: Possible side-effects. Crit Care Med 1989; 17: 762-767. Jacobs I, Oxer H. The use of naloxone in the pre-hospital management of narcotic overdose. Perth: Western Australian Pre-Hospital Care Research Unit; 1998. Bernard S, Barger W. An audit of two different doses of intramuscular naloxone in prehospital narcotic overdose. Melbourne: Melbourne Ambulance Service, 1995. Sporer KA, Firestone J, Isaacs SM. Out-of-hospital treatment of opioid overdoses in an urban setting. Acad Emerg Med 1996; 3: 660-667. Schwartz JA, Koenigsberg MD. Naloxone-induced pulmonary edema. Ann Emerg Med 1987; 16: 1294-1296. Osterwalder JJ. Naloxone -- for intoxications with intravenous heroin and heroin mixtures: harmless or hazardous? A prospective clinical study. Clin Toxicol 1996; 34: 409-416. Seidler D, Sthülinger GH, Fischer G, et al. After antagonization of acute opiate overdose: a survey at hospitals in Vienna. Addiction 1996; 91: 1479-1487. Strang J, Darke S, Hall W, et al. Heroin overdose: the case for take-home naloxone. BMJ 1996; 312: 1435. Kanof PD, Handelsman L, Aronson MJ, et al. Clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects. J Pharmacol Exp Ther 1992; 260: 355-363. Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, Molinoff PB, et al, editors. Goodman & Gilman's the pharmacological basis of therapeutics. 9th edition. New York: McGraw Hill, 1996: 549-551. Moss J. Ambulances say "no" to Narcan. Connexions 1997; 17: 29. Gaddis GM, Watson WA. Naloxone-associated patient violence: an overlooked toxicity? Ann Pharmacother 1992; 26: 196-198. Judson BA, Himmelberger DU, Goldstein A. The naloxone test for opiate dependence. Clin Pharmacol Ther 1980; 27: 492-501. Neal JM. Complications of naloxone. Ann Emerg Med 1988; 17: 765-766. Ward S, Corall IM. Hypertension after naloxone. Anaesthesia 1983; 38: 1000-1001. Andree RA. Sudden death following naloxone administration. Anesth Analg 1980; 59: 782-784. Azar I, Turndorf H. Severe hypertension and multiple atrial premature contractions following naloxone administration. Anesth Analg 1979; 58: 524-525. Flacke JW, Flacke WE, Williams GD. Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 1977; 47: 376-378. Brimacombe J, Archdeacon J, Newell S, Martin J. Two cases of naloxone-induced pulmonary oedema -- the possible use of phentolamine in management. Anaesth Intensive Care 1991; 19: 578-580. Harrington LW. Acute pulmonary edema following use of naloxone: a case study. Crit Care Nurse 1988; 8: 69-73. Yealy DM, Paris PM, Kaplan RM, et al. The safety of prehospital naloxone administration by paramedics. Ann Emerg Med 1990; 19: 902-905. Darke S, Hall W. The distribution of naloxone to heroin users. Addiction 1997; 92: 1195-1199. Strang J, Farrell M. Harm minimisation for drug misusers: when second best may be best first. BMJ 1992; 304: 1127-1128. Strang J, Powis B, Best D, et al. Preventing opiate overdose fatalities with take-home naloxone: pre-launch study of possible impact and acceptability. Addiction 1999; 94: 199-204. Hall W. Reducing the toll of opioid overdose deaths in Australia. Drug Alcohol Rev 1999; 18: 213-220. Vilke GM, Buchanan J, Dunford JV, Chan TC. Are heroin overdose deaths related to patient release after prehospital treatment with naloxone? Prehosp Emerg Care 1999; 3: 183-186. Bammer G, Sengoz A. Non-fatal heroin overdoses. Med J Aust 1994; 161: 572-573. Coleridge J, Cameron PA, Drummer OH, McNeil JJ. Survey of drug-related deaths in Victoria. Med J Aust 1992; 157: 459-462. Hsu W, Rao RB, Nelson LS. Naloxone hazards overstated. Clin Toxicol 1997; 35: 215-217. Buchwald A. Naloxone use: side effects may occur. Ann Emerg Med 1988; 17: 765. Hando J, Darke S. NSW Drug Trends 1997. Findings from the Illicit Drug Reporting System (IDRS). Sydney: The University of New South Wales, National Drug and Alcohol Research Centre, 1998. Hargreaves K, Lenton S. The Naloxone Feasibility Study. Perth, Western Australia: National Drug Research Institute, Curtin University of Technology, 2000. In press. Des Jarlais DC, Friedman SR. AIDS and the use of injected drugs. Sci Am 1994; February: 56-62. Dietze PM, Cvetkovksi S, Rumbold G, Miller P. Ambulance attendance at heroin overdose in Melbourne: the establishment of a database of Ambulance Service records. Drug Alcohol Rev 2000; 19: 27-33. Darke S, Ross J, Cohen J, Hall W. Context and correlates of non-fatal overdose among heroin users in Sydney. Sydney: The University of New South Wales, National Drug and Alcohol Research Centre, 1994. Authors' details National Drug Research Institute, Curtin University, Perth, WA. Simon R Lenton, MPsych(Clin), Research Fellow. Kim M Hargreaves, BA, Research Associate. Reprints: Mr S R Lenton, National Drug Research Institute, GPO Box U1987, Perth, WA 6845. simonATndri.curtin.edu.au Make a comment Naloxone hydrochloride NALOXONE HYDROCHLORIDE is an opioid antagonist that competitively binds to µ-opiate receptors to reverse the respiratory depression, sedation and hypotension associated with opioids. It does not reduce the respiratory depression caused by non-opioid central nervous system (CNS) depressants, such as alcohol and benzodiazepines, and lacks pharmacological activity in the absence of opioids.11 Naloxone is classified under Schedule 4 of the Poisons Schedule (prescription only) and is available either as ampoules or prefilled syringes (Min-I-Jet [CSL Ltd]). It is effective when given by intravenous, intramuscular or subcutaneous injection,12 being rapidly distributed to the brain and other body tissues. Effects are observed within 1-2 minutes of intravenous administration and 2-5 minutes of intramuscular or subcutaneous administration.13,14 Naloxone has been administered millions of times in emergency departments for opioid overdose;12 in very large doses (eg, 20 times the recommended dose in a 30-month-old15 and up to 24mg/70kg in adults16); and over a number of weeks to evaluate efficacy and toxicity in patients with acute stroke,17 without major complications. Naloxone in the prehospital setting When used to treat opioid overdose, naloxone has been reported to improve consciousness and alertness in 64%-80% of patients within 10 minutes of administration,18,19 and in other patients it improved respiration. As long as blood pressure can still be recorded, its administration can be beneficial.20 Naloxone-related complications have been reported after treatment of opioid overdose.20-22 However, many of the apparent drug reactions observed could also have resulted from the overdose itself.22,23 Treatment of heroin overdose in the United Kingdom and Australia suggests that such reactions are rare, with no significant problems reported after hundreds of administrations.24 Naloxone does have the potential to precipitate opioid withdrawal symptoms when administered to opioid-dependent people,25,26 and may result in generalised convulsions.11,22 Those in acute withdrawal can become aggressive and endanger themselves and others.27,28 Withdrawal symptoms are typically less severe after intramuscular than intravenous administration.29 With the correct equipment (eg, prefilled syringes), intramuscular administration is also easier to perform and has a longer duration of action. The disadvantage of intramuscular administration is the delayed onset of action. Naloxone in the postoperative setting Naloxone is used after surgery to reverse the CNS depression caused by opioids administered during the procedure. Naloxone complications have been documented in this setting,30 with an increased risk when pre-existing hypertension and cardiovascular disease are present.31 Many of the complications reported - hypertension, atrial and ventricular tachycardia, fibrillation, left ventricular failure, pulmonary oedema, and sudden death12,32-34 - occurred in patients with underlying cardiac or pulmonary disease. Pulmonary oedema attributed to naloxone administration has also been reported among individuals with no underlying medical conditions.21,34-36 Many patients who experience adverse effects do so after an operation when multiple medications have been administered, so the causal role of naloxone is uncertain.12,37 Back to text

Simon R Lenton · Kim M Hargreaves

In December 1998, a 37-year-old Queensland woman died from a rabies-like illness, 27 months after being bitten by a flying fox (fruit bat). Molecular techniques enabled diagnosis of infection with Australian bat lyssavirus (ABL), the second human case to be recognised and the first to be acquired from a flying fox. It must be assumed that any bat in Australia could transmit ABL; anyone bitten or scratched by a bat should immediately wash the wounds thoroughly with soap and water and promptly seek medical advice. The Australian bat lyssavirus (ABL) was first recognised in June 1996.1 It was subsequently shown not only to belong to a new genotype within the Lyssavirus genus, but also to be more closely related to classic rabies virus than any of the other five genotypes of lyssavirus.2 The first recognised human infection with ABL was in November 19961,3 (Box 1). The patient died from a rabies-like illness 20 days after first becoming unwell. She had apparently been bitten by a yellow-bellied sheathtail bat (Saccolaimus flaviventris; an insectivorous bat) about 4.5 weeks before onset of the illness (R Taylor, Public Health Physician, Rockhampton, QLD, personal communication). We describe here the features of the second recognised human infection with ABL, which had a much longer incubation period and was transmitted by a flying fox (fruit bat; Pteropus sp.). Clinical record A 37-year-old woman was admitted to Mackay Base Hospital in late November 1998 with a five-day history of fever, vomiting, anorexia, pain about the left shoulder girdle, paraesthesiae about the dorsum of her left hand and sore throat with difficulty swallowing. On examination she was acutely ill but well oriented. She was unable to fully open her mouth, was drooling saliva and had difficulty speaking. She was febrile (38 degrees C) but normotensive. Muscle tone was increased, and examination occasionally provoked painful spasms. Examination of the throat provoked spasmodic attempts to swallow. Apart from neutrophilia (12.0 x 109/L; reference range, 2.0-8.0 x 109/L), routine haematological and biochemical tests gave normal results. Twelve hours later her condition had deteriorated considerably, with increased agitation, dysphagia and dysphonia, and the muscular spasms had become more frequent and severe. She was paralysed and ventilated. At about this time, a history of a bat bite was elicited, and a diagnosis of ABL infection was considered. Cerebrospinal fluid (CSF), serum and saliva were submitted for testing. An attempt on Day 2 of hospitalisation to cease artificial ventilation was unsuccessful; when the sedative dose was reduced, she was no longer able to communicate and did not appear to understand verbal commands. Thereafter, she remained ventilator-dependent; whenever the dose of muscle relaxants was reduced, purposeless movements, such as facial grimacing and rolling eye movements, and muscular spasms, such as arching of the back, became evident. Another prominent feature of the illness was marked fluctuations of body temperature and blood pressure. On Day 4 of hospitalisation, the reference laboratory reported that a polymerase chain reaction (PCR) had detected what appeared to be a specific ABL product in the saliva. Nursing and medical staff were informed of the probable diagnosis of ABL infection, and appropriate precautions were implemented.4 The diagnosis of ABL infection was confirmed four days later. On Day 14 of hospitalisation, the patient ceased spontaneous movements and respiratory effort. Ventilator support was withdrawn; she died 19 days after onset of the illness. Post-exposure treatment (PET) was provided to seven healthcare workers because of possible percutaneous or mucous membrane exposure to the patient's saliva.4,5 The patient had attended an evening barbecue in late August 1996, 27 months before onset of the illness (Box 1). At the function, a flying fox had suddenly landed on the back of a young child. In the course of removing it, the patient was bitten at the base of her fifth left finger. Two days later, she presented to her general practitioner and was given tetanus toxoid and appropriate antibiotics. Six months later, in early March, she returned to the GP, asking about a blood test for the "bat virus". She was advised that she should instead receive PET because of a potential exposure to ABL, but decided against this. As soon as the diagnosis of ABL infection was confirmed, PET was administered to the child and to four other people exposed to the flying fox at the barbecue. Diagnostic studies No antibodies to Japanese encephalitis (JE), Murray Valley encephalitis, Kunjin or rabies viruses were detected by enzyme immunoassay tests of serum and CSF collected on Day 2 of hospitalisation. Attempts were made to culture virus by inoculating serum, CSF and saliva onto monolayers of C636, BHK-21, Vero and mouse neuroblastoma cells, but no viruses were isolated. Serum, CSF and saliva were examined for RNA of JE virus, Hendra virus (formerly known as equine morbillivirus) by in-house reverse transcriptase PCR, and for RNA of ABL by heminested reverse transcriptase PCR.6 No viral RNA was detected in serum or CSF, and neither JE nor Hendra virus RNA was detected in saliva. However, the heminested PCR for ABL in saliva produced amplicons of the expected size6 in both first- and second-round reactions (600 and 586 base pairs, respectively). Nucleotide sequencing showed that the amplicon was a lyssavirus-specific product that differed from any other ABL held at the reference laboratory. Concurrently, products from the amplification were separated electrophoretically, transferred onto a nylon membrane7 and hybridised with a digoxigenin-labelled ABL-specific probe. The probe hybridised with the control virus and with amplicons generated from the saliva, indicating that the amplicons were indeed lyssavirus-specific products. Postmortem studies Light microscopy revealed widespread and severe encephalitis affecting all parts of the brain other than the cerebellum. Inflammation and necrosis were particularly severe in the brainstem and hippocampi, where most neurones had either completely disappeared or were necrotic. There was perivascular cuffing by lymphocytes and diffuse infiltration of grey matter neuropile by microglia and lipid-laden macrophages. Occasional neurones showed neuronophagia. A few cytoplasmic inclusion bodies were seen, particularly in the hypothalamus. Light microscopy also revealed diffuse pancarditis with focal myocyte destruction and infiltration of epicardial nerve branches with mononuclear cells. There was no evidence of viral inclusions in acinar or ductal epithelial cells of the parotid and submandibular glands, but nerve bundles in each were infiltrated by mononuclear cells. Spinal cord, brainstem, cerebellum, midbrain and both cerebral hemispheres were examined by immunofluorescent antibody staining. Intense fluorescence was observed in all impression smears, indicating the widespread presence of ABL (Box 2). RNA extracted from these brain samples, as well as salivary and adrenal glands, was tested for ABL by heminested PCR; all samples were strongly positive. Portions of each tissue section were cultured with mouse neuroblastoma cells. PCR indicated successful virus isolation from brain and spinal cord after the first blind passage (Day 7 after inoculation), while specific immunofluorescent antibody staining of cells, indicating presence of ABL, was evident after the second blind passage (Day 14). Sequencing of the PCR product from the cell cultures confirmed that the isolate was the flying-fox variant of ABL. Public health responses As soon as the patient's diagnosis was announced in the media, requests for PET increased markedly throughout Queensland. Many requests were for exposures that had occurred many months, sometimes years, previously. Five hundred and eighteen courses were requested between December 1998 and February 1999 (inclusive), compared with 24 courses in the same three months the previous year, and 59 courses in the preceding three months (Box 3). Discussion The clinical presentation, duration and course of the patient's illness were virtually indistinguishable from those seen in rabies. A short, non-specific prodrome was followed by inexorable progression through distinct stages, culminating, after a relatively short illness, in coma and death. Pain and paraesthesiae about the site of the bite and signs of autonomic instability, such as hypersalivation and labile blood pressure, are also commonly seen in rabies.8 The histological features in the brain were similar to those seen in rabies, including the pathognomonic Negri-like inclusion bodies.8 Findings similar to those seen in the heart and salivary glands have been described in patients who died of rabies.9 Monoclonal antibody and molecular sequencing studies have shown distinct variants of rabies virus, each associated with a dominant mammalian reservoir.10 The first reported patient with ABL infection was infected with the virus variant associated with yellow-bellied sheathtail bats (A Gould, Senior Principal Research Officer, Australian Animal Health Laboratory, Geelong, Vic, personal communication), and, as expected, our patient was infected with the flying-fox variant. ABL has been found in all four Australian flying fox species, and, to date, all ABL-infected bats have been either unwell or dead at the time of collection.11 An extraordinary feature of the patient's illness was the very long (27 months) incubation period. The usual incubation period for rabies is 20-90 days, and 95% of cases occur within a year of exposure.8 Although rare, prolonged incubation periods have been reported,12,13 but the reason for the prolongation has not been established. Even if the patient had accepted the recommended PET, it is uncertain whether the illness would have been prevented. This is because the guidelines at the time recommended vaccine only, without rabies immunoglobulin, as treatment after a bat exposure more than three months previously.5 Rabies that occurred because PET was either delayed or did not include rabies immunoglobulin has been reported.14 The guidelines were subsequently changed to recommend rabies immunoglobulin for all bat exposures,15 but most public health authorities do not include this immunoglobulin if the potential exposure to ABL was more than 12 months previously. Media reporting of the patient's diagnosis was initially restrained but changed on her death, with some reports becoming blatantly alarmist. This media attention and the inherent concern about rabies contributed to intense public demand for PET from Queensland public health units. Although the cost of this PET was considerable, it was predominantly for "catch-up" treatments for those with historical exposures and therefore probably represents a "one-off" expense. This case reminds that ABL infection, although rare, is lethal. Any bat in Australia must be assumed to have the potential to transmit the virus, and members of the public should therefore avoid handling bats. Anyone either bitten or scratched by a bat should immediately wash the wounds thoroughly with soap and water and promptly seek medical advice, regardless of the site or severity of the exposure. Acknowledgements Many people were involved in the management of the patient and in the public health responses. We wish to thank the nursing staff of the Intensive Care Unit, Mackay Base Hospital, and the Public Health Nurses, in particular Mrs Dorothy Symons, of the Tropical Public Health Unit Network. We also thank Ms Judy Northill and Mr Alan Westacott (Queensland Health Scientific Services) and Mr David Gould (Communicable Diseases Unit, Queensland Health). References

Jeffrey N Hanna · Ian K Carney · Greg A Smith · Joseph E Deverill · John A Botha · Ina L Serafin · Bruce J Harrower · Peter F Fitzpatrick · Jeffrey W Searle

Abstract Objective: To describe the epidemiological pattern of newly diagnosed HIV infection and AIDS among Indigenous Australians. Design and setting: National surveillance for newly diagnosed HIV infection and AIDS in Australia. Information on Indigenous status was sought at HIV/AIDS notification in all State/Territory health jurisdictions, except the Australian Capital Territory, and Victoria before June 1998. Main outcome measures: Number of people with newly diagnosed HIV per year and population rate of HIV diagnosis; demographic characteristics of people with HIV and AIDS diagnoses by Indigenous status. Results: From 1992 to 1998, 127 Indigenous Australians were newly diagnosed with HIV infection and 55 were diagnosed with AIDS. The population rate of HIV diagnosis among Indigenous Australians (5.23/100 000 per year) was similar to that among non-Indigenous Australians (5.51/100 000 per year). The annual number of HIV diagnoses among Indigenous people was relatively stable, but among non-Indigenous people it declined steadily over time. A higher proportion of Indigenous people diagnosed with HIV were women (26.8% v 8.9%; P < 0.001). Although male homosexual contact was the predominant source of exposure for both Indigenous (46.7%) and non-Indigenous (75.0%) people with HIV infection, exposure by heterosexual contact (36.7% v 15.3%; P < 0.001) was reported more frequently among Indigenous people. Conclusion: Although HIV incidence was similar among Indigenous and non-Indigenous Australians, the lack of a recent decline in incidence and the higher proportion of Indigenous people exposed to HIV by heterosexual contact indicate the need to intensify interventions to prevent HIV transmission among Indigenous people. Introduction The epidemic of HIV transmission peaked in Australia in the mid 1980s, and there was a subsequent peak in AIDS incidence of nearly 1000 cases in 1994.1 The estimated number of people diagnosed with HIV infection in Australia to the end of 1998 was 16 714, with an estimated 11 800 living with HIV infection. Although the peaks of both the HIV and AIDS epidemics in Australia have passed, HIV infection continues to be transmitted, predominantly through male homosexual contact, at an estimated level of 450 cases per year.1 Despite evidence of a relatively well-controlled HIV epidemic in Australia, evaluation of the Third National HIV/AIDS Strategy noted an increase in the reported number of Indigenous Australians diagnosed with HIV infection in the early 1990s.1 Furthermore, high rates of other sexually transmissible infections in some Indigenous communities indicate the potential for HIV transmission.1 To define the pattern of HIV infection among Indigenous Australians, and to assess time trends in new diagnoses of HIV infection and AIDS, we examined national HIV and AIDS notification data by Indigenous status for the years 1992-1998. National Health and Medical Research Council guidelines on ethical matters in Aboriginal and Torres Strait Islander health research were followed.2 Methods National surveillance procedures Surveillance procedures for newly diagnosed HIV infection and AIDS have been described previously.3,4 Briefly, newly diagnosed HIV infection and AIDS are notifiable conditions in each State or Territory health jurisdiction in Australia. Information sought at national notification of newly diagnosed HIV infection includes the State or Territory of diagnosis, postcode of residence, namecode (based on the first two letters of the family name and the first two letters of the first given name), sex, date of birth, Indigenous status, date of HIV diagnosis, CD4 cell count at HIV diagnosis, evidence of newly acquired HIV infection, and patient-reported source of exposure to HIV. Information sought at AIDS notifications also includes the date of AIDS diagnosis, AIDS-defining illnesses, and use of antiretroviral therapy before AIDS diagnosis. People with newly diagnosed HIV infection with evidence of newly acquired HIV infection (ie, a negative or indeterminate HIV antibody test result or a diagnosis of HIV seroconversion illness within 12 months of HIV diagnosis) were defined as having "newly acquired HIV infection". People with AIDS were classified as having "late HIV diagnosis" if HIV infection was newly diagnosed within three months of AIDS diagnosis. Indigenous status From 1985, information on Indigenous status, obtained through self-identification as Aboriginal or Torres Strait Islander, was routinely sought at notification of HIV infection and AIDS for people newly diagnosed in the Northern Territory, Queensland, South Australia, Tasmania and Western Australia. In New South Wales, Indigenous status has been sought for newly diagnosed cases of HIV infection and AIDS since 1992. Indigenous status was not available for people with HIV infection or AIDS diagnosed in the Australian Capital Territory, or from Victoria before June 1998. Information on Indigenous status has been sought nationally from 1995; available information on Indigenous status for cases diagnosed before 1995 was obtained retrospectively through State or Territory health authorities. Exposure category HIV exposure was classified as male homosexual contact, male homosexual contact plus injecting drug use, injecting drug use, heterosexual contact only, haemophilia/coagulation disorder, receipt of blood or tissue, mother with or at risk for HIV infection, and other or undetermined exposure. Statistical analysis A χ2 or Fisher's exact test and odds ratios were used to test for differences between Indigenous and non-Indigenous cases with respect to demographic characteristics (sex, residence), newly acquired HIV 1infection, late HIV diagnosis, HIV exposure category, and individual AIDS-defining illnesses. Residence was divided into "metropolitan" and "non-metropolitan" on the basis of postcode. "Metropolitan" was defined as capital city (including Canberra), and "non-metropolitan" was defined as other than capital city. In the analyses, cases without information on Indigenous status were grouped with non-Indigenous cases. The population-based rate of HIV diagnosis was calculated by Indigenous status and year (for States and Territories other than Victoria and the ACT) using Australian Bureau of Statistics (ABS) census data for 1996.5 Results Information on Indigenous status was available for 91% of people with newly diagnosed HIV infection. For the period 1992-1998, 5313 cases of newly diagnosed HIV infection were notified to the national HIV surveillance centre, of which 127 (2.4%) were Indigenous cases. For the same period, 3638 AIDS cases were notified, of which 55 (1.5%) were Indigenous cases. The annual number of HIV diagnoses among Indigenous people was relatively stable over this period (Box 1). In contrast, the annual number of HIV diagnoses among non-Indigenous people gradually declined over the years 1992-1998. During this period, the annual HIV diagnosis rate per 100 000 population among Indigenous people (diagnosed in States and Territories other than Victoria and the ACT) (5.23) was similar to that among non-Indigenous people (5.51) (Box 1). A higher proportion of Indigenous people with HIV were female (26.8% v 8.9%; P < 0.001) (Box 2). The median age at HIV diagnosis (30 years v 33 years; P < 0.001) and AIDS diagnosis (32 v 37 years; P < 0.001) was lower among Indigenous cases. The pattern of exposure to HIV reported by Indigenous people was different from that reported by non-Indigenous people both for newly diagnosed HIV infection and AIDS (Box 2). Although male homosexual contact was the predominant source of exposure to HIV for both Indigenous (46.7%) and non-Indigenous (75.0%) people, a history of heterosexual contact only was reported more frequently by Indigenous people (36.7% v 15.3%; P < 0.001). The proportion of Indigenous and non-Indigenous people with AIDS with "late HIV diagnosis" was similar (23.6% and 18.3%; P = 0.42), as was the proportion reporting antiretroviral therapy before AIDS diagnosis (56.4% and 62.2%; P = 0.5). No difference between Indigenous and non-Indigenous cases was observed in the median CD4 cell count at diagnosis of HIV and of AIDS. The spectrum of AIDS-defining illnesses for Indigenous and non-Indigenous people with AIDS is shown in Box 3. Cryptococcal disease (odds ratio [OR], 3.3; 95% CI, 1.4-7.6; P = 0.004), oesophageal candidiasis (OR, 1.8; 95% CI, 0.95-3.38; P = 0.05), and atypical mycobacterium (OR 8.3; 95% CI, 2.4- 25.42; P = 0.002) were more frequent among Indigenous AIDS cases, whereas Kaposi's sarcoma was less frequent (OR, 0.12; 95% CI, 0.01-0.80; P = 0.01). Among people with HIV, there were more Indigenous than non-Indigenous cases in non-metropolitan locations (36% v 16%) (P < 0.01). Similarly, among people with AIDS, there were more Indigenous than non-Indigenous cases in non-metropolitan locations (37% v 19%) (P = 0.002). Discussion The HIV epidemic among Indigenous Australians has been relatively limited to date, with an overall rate of HIV diagnosis comparable with that for non-Indigenous Australians over the years 1992-1998. However, there have been contrasting trends in these rates, with a declining rate of HIV diagnosis among the non-Indigenous population, but a relatively stable rate among Indigenous people. Features that distinguish the Indigenous from the non-Indigenous HIV epidemic are a higher proportion of women affected, a higher proportion with heterosexual exposure to HIV, a younger age at HIV and AIDS diagnosis, and a higher proportion of people with HIV in rural areas. The low proportion of people with "late HIV diagnosis" among both Indigenous and non-Indigenous AIDS cases would suggest that a large pool of undiagnosed HIV infection is not present in Australia. The very low HIV prevalence among prison entrants in all States and Territories, including those where Indigenous Australians constitute a large proportion of prison inmates, is further confirmation that HIV prevalence among Indigenous Australians remains low.6 Our findings also extend those of an earlier study that showed comparable rates of HIV infection in both the Indigenous and the non-Indigenous population in Queensland.7 In interpreting our findings, several limitations to the study methods need to be considered. Firstly, the lack of a uniform reporting system for Indigenous status in all States and Territories may result in under-reporting in some jurisdictions. However, there is evidence that in recent years Indigenous status has been more completely reported, with 91% of HIV notifications in those States/Territories other than the ACT and Victoria currently reporting Indigenous status.1 Secondly, reporting of Indigenous status was based on "self-identification", which may either not be reported correctly by the patient, or not requested by the clinician. If identifying as Indigenous is more likely in a census setting than in clinical practice, our rates of Indigenous HIV diagnosis may be underestimates. Thirdly, reported rates of HIV and AIDS diagnoses are dependent on the level and extent of HIV testing. Poor access to and uptake of confidential testing by some Indigenous people, and fear of possible stigmatisation arising from positive test results, may influence the extent of HIV testing among Indigenous people. The explanation for the apparently limited HIV epidemic among Indigenous Australians is almost certainly multifaceted. The drop in HIV transmission from the mid 1980s has meant that the extent of the Australian HIV epidemic has been limited compared with many other countries.1 Behaviour change among homosexual men was largely responsible for the initial reduction in HIV transmission from the mid 1980s,1 with other measures such as the widespread introduction of harm minimisation programs for injecting drug users,8 and high condom use and low rates of sexually transmissible infections among most sex workers9 contributing to the ongoing relatively low level of HIV transmission. The absence of substantial levels of HIV infection among injecting drug users and female sex workers1 may have limited the spread of HIV into the heterosexual population. Despite the fact that the proportion of HIV diagnoses attributed to heterosexual contact has increased in recent years, homosexual contact remains the exposure category for about 85% of new HIV diagnoses.1 Australia's Indigenous people are not a homogeneous group. There are many hundreds of language groups and a wide diversity of cultural, social, economic and geographical settings within and between Indigenous Australian communities. Most Indigenous Australians suffer a higher burden of illness and die at a younger age than non-Indigenous Australians for almost every type of disease or condition for which information is available.10 Indigenous Australians are more likely to have lower annual incomes, are less likely to have qualifications beyond secondary school,11 and are 15 times more likely to be imprisoned than non-Indigenous Australians.11 These factors, combined with the remote locations in which many Indigenous Australians live and the resulting poor access to health services, contribute to their vulnerability to sexually transmissible infections.12 Associations in other industrialised countries between socioeconomic disadvantage and HIV transmission from heterosexual exposure and injecting drug use13 highlight the need to provide HIV prevention services which reach all sectors of society. The higher proportion of Indigenous people with HIV in rural areas should alert policymakers to the need for access to culturally appropriate health services in these locations. Likewise, the higher proportion of Indigenous people with HIV infection who are women, who report heterosexual exposure only and who inject drugs shows a need for broadly focused HIV prevention programs. This demographic pattern, the relatively stable level of HIV diagnoses in Indigenous people, and the continuing high rates of other sexually transmissible infections among some Indigenous communities,1 highlight the need to strengthen both sexual health and harm-minimisation strategies for Indigenous Australians. Following the recommendations of the Evaluation of the Third National HIV/AIDS Strategy, several measures have been implemented in an attempt to reduce the higher rates of sexually transmissible infections among Indigenous Australians and the associated risk of HIV infection. These include the establishment of an Indigenous Australians' Sexual Health Working Party and the subsequent implementation of the National Indigenous Australians' Sexual Health Strategy 1996-97 to 1998-99, which proposed a comprehensive approach to HIV prevention through a range of strategies considering treatment and care, partnership agreements and a properly resourced workforce.14 In particular, the Strategy emphasises the need for access to primary care services for communities without adequate facilities for diagnosing and treating sexually transmissible infections and the provision of information on reducing the risk of acquisition. Strategies aimed at the underlying causes of low socioeconomic status, low levels of education and low levels of employment must also be employed in order to reduce the risk of transmission of HIV and other sexually transmissible infections in Indigenous Australians. Acknowledgements The National Centre in HIV Epidemiology and Clinical Research (NCHECR) is funded by the Commonwealth Department of Health and Aged Care. We would like to acknowledge the valuable input and feedback received from the National Australian Indigenous Sexual Health Working Party during the drafting of this article. We also thank Ms Yueming Li for statistical analyses, Ms Patty Correll (NCHECR) for her assistance in extracting data, and Ms Suzanne Blogg (National Centre for Epidemiology and Population Health [NCEPH]) for her guidance and assistance. We thank the doctors who reported cases of newly diagnosed HIV infection and AIDS under national surveillance procedures, and the National HIV Surveillance Committee for their collaboration. The National HIV Surveillance Committee comprises Ms Irene Passaris (ACT), Mr Robert Menzies (NSW), Dr Jan Savage (NT), Dr Hugo Ree (QLD), Ms Therese Davey (SA), Mr Neil Cremasco (TAS), Ms Cathy Keenan (VIC), Dr Gary Dowse (WA), Professor John Kaldor (NCHECR), and Ms Ann McDonald (NCHECR). References Commonwealth Department of Human Services and Health. Valuing the past -- investing in the future. Evaluation of the National HIV/AIDS Strategy 1993-94 to 1995-96. Canberra: AIDS/Communicable Diseases Branch, CDHSH, 1995. National Health and medical Research Council. Guidelines on ethical matters in Aboriginal and Torres Strait Islander health research. Canberra: NHMRC, 1991. McDonald AM, Crofts N, Blumer CE, et al. The pattern of diagnosed HIV infection in Australia, 1984-1992. AIDS 1994; 8: 513-519. Kaldor J, McDonald AM, Blumer CE, et al. The acquired immunodeficiency syndrome in Australia: incidence 1982-1992. Med J Aust 1993; 158: 10-17. Australian Bureau of Statistics. Population distribution, Indigenous Australians. Canberra: ABS 1997. (Catalogue No. 4705.0.) McDonald AM, Ryan J, Brown PR, et al. HIV prevalence at reception into Australian prisons, 1991-1997. Med J Aust 1999; 171: 18-21. Neilson G, Hill PS. Human immunodeficiency virus notifications for Aborigines and Torres Strait Islanders in Queensland. Med J Aust 1993; 158: 155-157. MacDonald M, Wodak A, Ali R, et al. HIV prevalence and risk behaviour in needle exchange attenders: a national study. Med J Aust 1997; 166: 237-240. O'Connor CC, Berry G, Rohrsheim R, et al. Sexual health and use of condoms among local and international sex workers in Sydney. Genitourin Med 1996; 72(1): 4-51. Australian Bureau of Statistics. The health and welfare of Australia's Aboriginal and Torres Strait Islander peoples, 1997. Canberra: ABS, 1997. (Catalogue No. 4704.0.) Office of the Aboriginal and Torres Strait Islander Social Justice Commissioner. Indigenous deaths in custody 1989 to 1996. Sydney: Human Rights and Equal Opportunity Commission, October 1996. Fairley CK, Bowden FJ, Gay NJ, et al. Sexually transmitted diseases in disadvantaged Australian communities. JAMA 1997; 278: 117-118. Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report 1998; 10 (No. 2): 1-43. ANCARD Working Party on Indigenous Australians' Sexual Health, Commonwealth Department of Health and Family Services. The National Indigenous Australians' Sexual Health Strategy, 1996-1997 to 1998-1999. Canberra: CDHFS, 1997. Authors' details National Centre in HIV Epidemiology and Clinical Research, Sydney, NSW. Jillian A Guthrie, BA, MAE (Indigenous Health) also at National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT. Gregory J Dore, FRACP, MPH, Lecturer. Ann M McDonald, MPH, Coordinator, National HIV/AIDS Surveillance. John M Kaldor, PhD, Professor; and Head, Epidemiology Unit. Reprints will not be available from the authors. Correspondence: Professor J M Kaldor, National Centre in HIV Epidemiology and Clinical Research, Level 2, 376 Victoria Street, Darlinghurst, NSW 2010. jkaldorATnchecr.unsw.edu.au 2: Newly diagnosed HIV infection and AIDS, 1992-1998, by Indigenous status and selected characteristicsHIV diagnoses IndigenousNon-IndigenousP Odds ratio (95% CI)Total casesn=127n=5186Males93 (73.2%)4726 (91.1%)<0.0010.27 (0.17-0.41)Median age (years)3033Median CD4 cell count4844000.10Newly acquired HIV*24 (18.9%) 930 (17.9%)0.79Late HIV diagnosis?---HIV exposure categoryn=120?n=4507?Male homosexual contact56 (46.7%)3382 (75.0%) <0.0010.29 (0.20-0.43)Male homosexual contact and injecting drug use 12 (10.0%)191 (4.2%)0.0022.51 (1.29-4.78)Injecting drug use6 (5.0%)176 (3.9%)0.3Heterosexual contact only44 (36.7%)689 (15.3%)<0.0013.21 (2.16-4.77)Receipt of blood/tissue0 (0.0)34 (0.8%)0.4Mother-to-child transmission2 (1.7%)35 (0.8%)0.2Other/Undetermined7679 AIDS diagnoses IndigenousNon-IndigenousPOdds ratio (95% CI)Total casesn=55n=3583Males43 (78.2%)3411 (95.2%)<0.0010.18 (0.09-0.37)Median age (years)3237<0.001Median CD4 cell count90600.71Newly acquired HIV*---Late HIV diagnosis?13 (23.6%)675 (18.8%)0.42HIV exposure catergoryn=52?n=3405?Male homosexual contact26 (50.0%)2783 (81.7%)<0.0010.22 (0.12-0.38)Male homosexual contact and injecting drug use7 (13.5%)167 (4.9%)0.0162.95 (1.20-6.93)Injecting drug use1 (1.9%)127 (3.7%)0.4Heterosexual contact only17 (32.7%)238 (7.0%)<0.0016.28 (3.33-11.75)Receipt of blood/tissues0 (0.0)76 (2.2)0.3Mother-to-child transmission1 (1.9%)15 (0.4%)0.2Other/Undetermined3178 *A negative or indeterminate HIV antibody test result or a diagnosis of HIV seroconversion illness within 12 months of HIV diagnosis. ?HIV infection newly diagnosed within three months of AIDS diagnosis. ?The "other/undetermined" category was excluded from the calculation of the percentage of cases attributed to each HIV exposure category.

Jillian A Guthrie · Gregory J Dore · Ann M McDonald · John M Kaldor

Editorials Measles in an era of measles control As measles becomes rare in Australia, clinical diagnosis becomes increasingly inaccurate MJA 2000; 172: 103-104 It has been a long road to the control of measles in Australia. Live attenuated measles vaccine was licensed in 1968, and included in childhood vaccination schedules in 1971. Even after the first national measles campaign, in 1988, coverage remained too low (85%)1 to achieve herd immunity, as evidenced by major measles outbreaks in many areas in 1993-1994. In 1994, a second dose of measles-mumps-rubella (MMR) vaccine was introduced for all children aged 10-16 years. Although the incidence of measles declined, seroprevalence studies2 indicated that further measles outbreaks were likely. In response to these findings, the Australian Measles Control Campaign (MCC) was launched in July 1998. The centrepiece of this campaign was administration of a dose of MMR vaccine to all primary school children in the second half of 1998. This "catch-up" dose was needed before lowering the recommended age for the second dose of MMR vaccine to four years in 1999. After the MCC, an estimated 96% of children aged five to 12 years had received two doses of MMR vaccine.3 As a result of this campaign and the continuing efforts to eradicate measles, it is hoped that Australia will soon be shown to have joined other countries, such as the United States,4 the United Kingdom5 and Finland,6 where indigenous measles transmission has been interrupted. The better the control of measles, the lower the probability that someone presenting with fever and rash will have measles, and the poorer the positive predictive value (PPV) of a clinical diagnosis. Even in 1990-1993, before any major measles control measures, a study of 58 people notified with measles in eastern Sydney found that only 49% of cases were serologically confirmed.7 A case definition of morbilliform rash, cough and fever at rash onset had a PPV of 69%.7 In this issue of the Journal, there is a report of a larger study of enhanced measles surveillance in Victoria from July 1997 to December 1998 (ie, primarily conducted before the MCC) which showed a much lower level of confirmation.8 Only 8% of the 248 notified cases that could be classified on the basis of serological results were confirmed as measles. The PPV of the National Health and Medical Research Council (NHMRC) clinical case definition for considering public health action9 was as low as 5% when secondary cases from clusters were excluded.8 Since the MCC, the proportion of serologically confirmed cases is likely to have fallen even further. In the UK, after a similar school-based MMR program in 1994,5 and in Finland 12 years after high coverage with a two-dose MMR schedule,6 only about 1% of suspected cases were shown to be measles. These developments necessitate major changes in the approach of medical practitioners to suspected measles, especially in general practice where most cases will be seen. The latest draft of the revised NHMRC guidelines for measles control emphasise that confirmation by detection of measles IgM in a serum specimen is essential when measles is clinically suspected.10 This policy is also recommended by the authors of the Victorian study and by the National Measles Surveillance Strategy.11 Confirmation is particularly important in sporadic cases, where the prior probability of measles is especially low, and should also be obtained from at least two cases during an outbreak. The high level of laboratory testing achieved in Victoria is encouraging. However, overall, only 44% of the 428 cases accepted as measles notifications in Australia between January 1998 and June 1999 were laboratory confirmed (personal communications from State and Territory health departments). It may be possible to improve this percentage -- although teams of venepuncturists are impractical for many areas of Australia, arrangements to bleed patients can usually be made in consultation with local public health authorities. Considerable interest has also focused on non-invasive diagnostic methods, such as salivary testing. This method has been used in the UK but has technical difficulties,11 making timely testing more difficult than for serological testing. Even when serological testing is done, as measles becomes rare the likelihood of a falsely positive measles IgM will rise, as found in Victoria and elsewhere.4 A positive measles IgM test should therefore be confirmed by a reference laboratory, especially in sporadic cases. Clinicians should be aware that many viral infections in children may resemble measles clinically, and that measles is more likely in older children and young adults than in infants. After control of measles in Finland,6 37% of 993 children with suspected measles had serological evidence of infection caused by parvovirus, enteroviruses, adenovirus or human herpesvirus type 6 (HHV-6).12 The most common serological diagnoses were parvovirus infection, in children aged four to 15 years, and enterovirus and HHV-6 infection, in children aged under four years. In Sydney, in 1990-1993, the mean age of patients with confirmed measles was 11.3 years,7 and, in Victoria in 1997-1998, more than half (53%) the patients with confirmed measles were aged at least 10 years.8 An outbreak of measles in Victoria in 1999, after the MCC, indicates the likely future pattern of measles in Australia -- 84% of patients were aged 18-30 years and all patients aged one to eight years were unvaccinated.13 Sustained measles control will require further efforts in young adults as well as continued high coverage with two doses of measles vaccine in children. Young adults, especially those attending tertiary institutions or planning travel to areas where measles remains endemic, should be encouraged to have a second dose of MMR or serological confirmation of measles immunity. Peter B McIntyre Deputy Director Heather F Gidding Epidemiologist National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, Royal Alexandra Hospital for Children and University of Sydney, Sydney, NSW Gwendolyn L Gilbert Director, Centre for Infectious Diseases and Microbiology and University of Sydney, Sydney, NSW Australian Bureau of Statistics. National health survey. Children's immunisation, Australia, 1989-90. Canberra: ABS, 1992. (Catalogue no. 4379.0.) Gilbert GL, Chan S-W, Escott R, et al. Seroepidemiology of measles in New South Wales, 1997. Report to the National Centre for Disease Control, Commonwealth Department of Health and Aged Care, 1998 (available from the Department). National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases. Australian measles control campaign 1998. Evaluation report. Sydney: University of Sydney, Royal Alexandra Hospital for Children, 1999. Watson JC, Redd SC, Rhodes PH, Hadler SC. The interruption of transmission of indigenous measles in the United States during 1993. Pediatr Infect Dis J 1998; 17: 363-366. Gay N, Ramsay M, Cohen B, et al. The epidemiology of measles in England and Wales since the 1994 vaccination campaign. Commun Dis Rep CDR Rev 1997; 7: R17-R21. Peltola H, Hienonen OP, Valle M, et al. The elimination of indigenous measles, mumps, and rubella from Finland by a 12-year, two-dose vaccination program. N Engl J Med 1994; 331: 1397-1402. Ferson MJ, Young LC, Robertson PW, Whybin LR. Difficulties in clinical diagnosis of measles: proposal for modified clinical case definition. Med J Aust 1995; 163: 364-366. Lambert SB, Kelly HA, Andrews RM, et al. Enhanced measles surveillance during an interepidemic period in Victoria. Med J Aust 2000; 172: 114-118. National Health and Medical Research Council. Measles: guidelines for the control of outbreaks in Australia. Canberra: NHMRC, 1996. National Health and Medical Research Council. Measles: guidelines for the control of outbreaks in Australia [draft]. Canberra: NHMRC, 2000. Heath T, Burgess M, McIntyre P, Catton M. The national measles surveillance strategy. Commun Dis Intell 1999; 23: 41-49. Davidkin I, Valle M, Peltola H, et al. Etiology of measles and rubella-like illness in measles, mumps, and rubella-vaccinated children. J Infect Dis 1998; 178: 1567-1570. Lambert S, Lynch P, Morgan M, Gercovich D. Measles outbreak -- young adults at high risk. Victorian Infect Dis Bull 1999; 2: 21-22. Make a comment

Peter B McIntyre · Heather F Gidding · Gwendolyn L Gilbert

Public Health Enhanced measles surveillance during an interepidemic period in Victoria Stephen B Lambert, Heath A Kelly, Ross M Andrews, Mike C Catton, Pauline A Lynch, Jennie A Leydon, Debbie K Gercovich, Geoffrey G Hogg, Melissa L Morgan and Rosemary A Lester MJA 2000; 172: 114-118 For related article see McIntyre et al Abstract - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Infectious diseases and parasitology Abstract Objective: To describe results of the first two years of enhanced measles surveillance in Victoria. Design: Case series identified through enhanced measles surveillance. Participants and setting: All measles cases notified to the Disease Control Section, Department of Human Services, Victoria, in 1997 and 1998. Main outcome measures: Proportion of notified cases laboratory confirmed as measles, rubella, or human parvovirus infection; identification of clusters (two or more linked cases of measles); and utility of the National Health and Medical Research Council clinical case definition for suspected measles. Results: Rates of laboratory testing of notified cases improved after introduction of a paediatric phlebotomy service in July 1997, from 21 of 90 notified patients (23%) in the preceding six months, to 258 of 317 notified patients (81%) between July 1997 and December 1998. Of the 317, only 19 (6%) were laboratory confirmed with measles, while a further 26 (8%) were laboratory confirmed with human parvovirus infection (18) or rubella (8). Three clusters of measles, involving 11 cases, were identified during 1998. Use of the NHMRC case definition did not greatly improve the positive predictive value for diagnosis of measles above that of notification alone (14% versus 8%). Conclusions: Circulation of measles virus in Victoria in 1997 and 1998 appeared minimal. In this interepidemic period most notified cases of measles were not measles; to identify true cases, surveillance during an interepidemic period must include laboratory testing of notified cases. Cases of classical measles are uncommon in countries with successful measles control programs, making clincal diagnosis less reliable. To ensure the validity of clinical notifications, it is increasingly important to confirm the diagnosis in every sporadic case of measles and in at least one case in every chain of transmission in such countries.1 Australia suffered a nationwide outbreak of measles in 1993-1994.2 Since 1994, a two-dose measles-mumps-rubella (MMR) vaccination program has been implemented,3 and in 1998 a national campaign targeting primary school-aged children was conducted.4 The country was free of any substantial outbreak until early 1999, when importation of the disease from Bali resulted in measles cases, mainly among young adults in Victoria.5 To monitor the success of the measles control program, the State of Victoria began a state-based enhanced surveillance program in 1997. This program concentrates on confirming the diagnosis of measles for all notifications received by the Disease Control Section of the Victorian Department of Human Services.6 We report the results of the first two (interepidemic) years of this enhanced measles surveillance program and make recommendations for the investigation of notified cases of measles. Methods The enhanced measles surveillance strategy adopted by Victoria has been reported elsewhere.6 In brief, all notifications to the Department of Human Services in 1997 and 1998 were followed up by a structured telephone interview with the patient or, if the patient was a child, with the parent or guardian. Demographic data, clinical symptoms, and measles vaccination history were recorded. The parent/guardian was asked to read the date of vaccination from the personal vaccination record when available. We attempted to identify a possible source of infection, as well as contacts who required advice about immunoglobulin or MMR vaccination. Suspected preceding or subsequent cases were followed up in a similar manner to identify clusters of infection (defined as two or more epidemiologically linked cases7). A sporadic case was one that could not be linked to another case. Serological testing A serum specimen was sought from each notified patient for laboratory confirmation of the clinical diagnosis. From July 1997, this specimen was obtained by a paediatric phlebotomist in the patient's home. Some patients provided a combined throat and nose swab and a urine specimen for viral culture or isolation of genetic material by polymerase chain reaction, and subsequent virus genotyping.8Sera were tested for measles IgM and IgG at the Victorian Infectious Diseases Reference Laboratory (VIDRL) or, if original testing was performed elsewhere, the testing laboratory was asked to forward remaining sera from measles IgM-positive specimens to VIDRL for confirmatory testing. Testing at VIDRL used a commercial enzyme immunoassay (Dade Behring Enzygnost, Marburg, Germany). The manufacturer reports the measles IgM assay as having a sensitivity of 100% and specificity of 98%. Sera that were negative for measles IgM at VIDRL were assayed for human parvovirus IgM and IgG (Biotrin Parvovirus B19 Enzyme Immunoassay, Dublin, Ireland), rubella IgM (DiaSorin ETI-RUBEK-M reverse PLUS, Saluggia, Italy) and rubella IgG (Panbio Rubella IgG ELISA Test, Brisbane, Australia). Analyses Using a defined algorithm,6 each notified case was classified as confirmed measles or otherwise according to the criteria in Box 1. These included serological and other results, as well as concordance with the clinical case definition for suspected measles11 recommended by the National Health and Medical Research Council (NHMRC) -- morbilliform rash, fever present at rash onset, and cough.12Analysis was performed using Epi Info version 6.04.13 Significance of differences between categorical data was tested by the Fisher's exact or χ2 test. Results In the first six months of surveillance (January to June 1997), sera were collected from 21 of 90 notified patients (23%). After employment of a paediatric phlebotomist to collect samples in the patient's home, collection rates improved progressively -- sera were collected from 258 of 317 notified patients (81%) between July 1997 and December 1998, including from 107/120 (89%) in the second half of 1998.6Because of the lower rate of specimen collection in the first six months of surveillance, we analysed data for July 1997 to December 1998 only. In this period, only 19/317 notifications (6%) were classified as laboratory confirmed (Box 2). The remainder were laboratory rejected (229; 72%), clinically compatible (12; 4%), not clinically compatible (41; 13%) and not classifiable (16; 5%). All epidemiologically linked cases were able to be laboratory confirmed. Of the 229 cases that were laboratory rejected as measles, 18 had human parvovirus infection (8%), and eight had rubella (3%). Box 3 shows serological results by age group. Serum collection rates did not differ significantly between age groups (P = 0.4), but laboratory confirmation was significantly more likely among patients aged 10 years or over than among younger children (P = 0.0002). Clusters of measles Three clusters of measles, involving 11 patients, were identified, all in 1998. The first, involving four people, began in January 1998. A 19-year-old man from New South Wales visited Melbourne soon after illness onset on 10 January. Three other people were infected: his 22-year-old brother (onset, 18 January), six-month-old nephew (onset, 1 February), and a 23-year-old male household contact (onset, 3 February). None of the Victorian patients in this cluster reported previous measles vaccination; all required hospital admission. In the second cluster, the index patient was a two-year-old girl (onset, 1 February). Although she lived within a kilometre of the household of the first cluster, no clear epidemiological link could be established with any of the earlier cases. Three other children, aged 10 months to three years, and an 18-year-old woman were infected (onset, 12 February-13 March); all attended the same small church group as the index patient. The index patient's parent reported she had been vaccinated against measles in New Zealand at the age of one year, but did not have a record to confirm this. No other patients in the cluster had been vaccinated against measles. In the third cluster, the index patient was an 18-year-old woman who had returned from Bali on 4 December and became ill seven days later. Her brother developed prodromal symptoms 12 days later. Neither had been vaccinated against measles. Measles vaccination history Vaccination histories of the 317 notified patients are shown in Box 4. More than half those notified (55%) reported having been vaccinated, more than half of whom provided a vaccination date from a personal vaccination record. Reported measles vaccination status was compared with the presence of measles IgG for those with serological results available. Only 7% of those who reported prior vaccination lacked measles IgG. In contrast, 67% of patients who were aged over one year (and therefore eligible for vaccination) and did not report being vaccinated lacked measles IgG (P < 0.001). Among patients who reported vaccination, those who provided a vaccination date were no more likely to have measles IgG detected than those who did not provide a date (P = 0.76). Prior measles vaccination was reported by 141 patients (62%) who were classified as laboratory rejected, compared with six (32%) who were classified as laboratory confirmed (P = 0.01). Among patients with laboratory-confirmed measles, sporadic cases were more likely to give a history of vaccination (5/8) than those who were part of a cluster (1/11) (Fisher's exact test, P = 0.04). Reference laboratory testing Of the 19 patients classified with laboratory-confirmed measles, 16 were positive for measles IgM on testing at VIDRL, two after initial positive results elsewhere. The 16 comprised all 11 cluster cases and five sporadic cases. Another three sporadic cases were positive for measles IgM on testing at other laboratories but had insufficient serum available for retesting at VIDRL. These cases were still classified as "laboratory confirmed". A further three patients were positive for measles IgM on testing at other laboratories but were negative on retesting at VIDRL and were classified as "laboratory rejected". Evaluation of NHMRC clinical case definition for suspected measles There was sufficient clinical information to classify 275 notified patients (87%) according to the NHMRC clinical case definition for suspected measles: 92 (33%) met the definition, and 183 (67%) did not. To examine the utility of the NHMRC case definition, we analysed cases that were able to be classified both in this way and according to serological results -- either laboratory confirmed (18) or rejected (202) as measles. Results are shown in Box 5. Sensitivity of the NHMRC case definition was 61% and specificity was 66%, while positive and negative predictive values were 14% and 95%, respectively. When non-index cases from clusters were excluded (to test the utility of the definition in identifying cases with no epidemiological link to a confirmed measles case), sensitivity and positive predictive value fell to 40% and 5%, respectively, while specificity and negative predictive value remained almost unchanged. Cases from clusters were more likely than sporadic cases to satisfy the NHMRC case definition (10/11 [91%] versus 1/7 [14%]; Fisher's exact test, P = 0.002). The relationship between notification and laboratory measles diagnosis was also examined: the positive predictive value of notification was 8% (18/220), dropping to 5% (10/212) when non-index cases were excluded. Discussion We found that, during the interepidemic period of July 1997 to December 1998 in Victoria, a clinical diagnosis of measles had a low positive predictive value. Despite an 81% rate of serological testing, only 6% of all measles notifications were laboratory confirmed (8% of those that could be classified on the basis of serological results). Laboratory diagnoses of human parvovirus or rubella infections accounted for a further 8% of measles notifications, similar to experience in other countries that have conducted enhanced surveillance.14These results highlight the critical importance of laboratory confirmation as part of enhanced measles surveillance. They also highlight the low utility of the NHMRC clinical case definition for suspected measles. As only 33% of notified cases met this definition, it does not seem widely used as the basis for notification. Furthermore, it was neither sensitive (40%) nor highly predictive of true measles (5%) during this interepidemic period. Therefore, rather than the NHMRC clinical case definition for suspected measles, we advocate a definition similar to that used by the Pan American Health Organization of all cases in which a health worker suspects measles.15 Our findings do not mean that those responsible for measles surveillance, investigation and control can ignore measles notifications. The Disease Control Section now relies on urgent serological testing performed by VIDRL to inform public health action and improve the quality of the surveillance dataset. In Victoria, clinical specimens can often be collected within 24 hours of notification, with a laboratory result available on the next testing day.6 During the interepidemic period, when measles was rare, if public health action were to involve excluding contacts of a notified case from a school or childcare centre, we attempted to arrange urgent serological testing. No action was taken until the result was available. If serological testing was not possible, we treated the case as though it were measles regardless of whether it met the NHMRC case definition. Based on our experience, and drawing on elements from the National Measles Surveillance Strategy,7 we have refined recommendations for follow-up of measles notifications in a region with good disease control during an interepidemic period (Box 6). We believe these recommendations will allow identification of clusters of disease and minimise unnecessary public health action. We have maximised the sensitivity of the passive surveillance system by following up notifications from any source. By using laboratory testing to identify cases that are not measles, we have minimised the likelihood that our surveillance dataset will consist largely of false-positive notifications. Because no IgM antibody test is 100% specific, even laboratory-confirmed cases may not be measles. We found that three of five laboratory diagnoses of measles made in non-reference laboratories could not be confirmed at VIDRL. Sporadic cases were less likely to be confirmed at VIDRL than cluster cases and were also less likely to meet the NHMRC case definition, but were more likely to report prior measles vaccination. As prior measles vaccination correlates well with measles immunity, we believe that at least some of the sporadic cases classified as laboratory confirmed were not true measles. This reinforces the important role of reference laboratories as we approach national measles elimination and global eradication.7 We suggest that local transmission of measles within Victoria during this interepidemic period was minimal. We base this belief on the small number of sporadic cases identified, along with the possibility that some of these cases were not true measles, and the fact that identified clusters of infection involved few people and were self-limiting. Specimen collection for genotyping is already under way and will provide further evidence of the interruption of indigenous transmission in Victoria.16,17 The findings of the enhanced surveillance program, along with those from investigation of the 1999 measles outbreak in Victoria,5 lead us to believe that the two-dose MMR vaccination policy and the 1998 measles control campaign have dramatically reduced circulation of measles virus in the targeted age groups. We have demonstrated that, when measles is rare, enhanced surveillance relying on laboratory confirmation is essential to identify true cases of measles promptly and to ensure that surveillance datasets do not largely comprise false positive notifications. Acknowledgements The Victorian Enhanced Measles Surveillance Working Party appreciates the cooperation of the patients who agreed to be interviewed and provided serum samples for enhanced surveillance. We also gratefully acknowledge the nursing staff, clinicians, and pathology collection centres who collected serum specimens during the study period. Enhanced surveillance and public health intervention would not be possible without notification of cases by clinicians and laboratories. References World Health Organization. Expanded programme on immunization (EPI). Meeting on advances in measles elimination: conclusions and recommendations. Wkly Epidemiol Rec 1996; 71: 305-309. Lambert S. Measles in Victoria 1992 to 1996: the importance of laboratory confirmation. Comm Dis Intell 1998; 22: 17-22. National Health and Medical Research Council. The Australian immunisation handbook. Canberra: AGPS, 1997. National Centre for Disease Control. Immunise Australia program: measles control campaign. Comm Dis Intell 1998; 22: 156. Lambert S, Lynch P, Morgan M, et al. Measles outbreak -- young adults at high risk. Victorian Infectious Diseases Bulletin 1999; 2: 21-22. The Enhanced Measles Surveillance Working Party. Implementing a system of enhanced surveillance for measles in Victoria. Commun Dis Intell 1999; 23: 51-54. Heath T, Burgess M, McIntyre P, Catton M. A national measles surveillance strategy. Commun Dis Intell 1999; 23: 41-49. Jenkin GA, Chibo D, Kelly HA, et al. What is the cause of a rash after measles-mumps-rubella vaccination? Med J Aust 1999; 171: 194-195. Centers for Disease Control and Prevention. Measles, mumps, and rubella -- vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunisation Practices (ACIP). MMWR Morb Mortal Wkly Rep 1998; 47 (RR-8): 1-58. Helfand R, Heath J, Anderson L, et al. Diagnosis of measles with an IgM capture EIA: the optimal timing of specimen collection after rash onset. J Infect Dis 1997; 175: 195-199. Ferson M, Young L, Robertson P, Whybin L. Difficulties in clinical diagnosis of measles: proposal for modified clinical case definition. Med J Aust 1995; 163: 364-366. National Health and Medical Research Council. Measles: guidelines for the control of outbreaks in Australia. Canberra: AGPS, 1996. Dean A, Dean J, Coulombier D, et al. Epi Info, version 6: a word processing database, and statistics program for public health on IBM-compatible microcomputers. Atlanta, Ga: Centers for Disease Control and Prevention, 1995. Brown D, Ramsay M, Richards A, Miller E. Salivary diagnosis of measles: a study of notified cases in the United Kingdom, 1991-3. BMJ 1994; 308: 1015-1017. Centers for Disease Control and Prevention. Measles eradication: recommendations from a meeting cosponsored by the World Health Organization, the Pan American Health Organization, and CDC. MMWR Morb Mortal Wkly Rep 1997; 46 (RR-11): 1-20. Rota JS, Heath JL, Rota PA, et al. Molecular epidemiology of measles virus: identification of pathways of transmission and implications for measles elimination. J Infect Dis 1996; 173: 32-37. Chibo D, Birch C, Rota P, Catton M. Genetic characterisation of measles viruses isolated in Victoria, Australia 1973-1998. Immunisation beyond 2000. 6th National Public Health Association Immunisation Conference; 1998 Nov 4-5; Melbourne. Canberra: Public Health Association of Australia, 1998. (Received 30 Jun, accepted 27 Oct, 1999) Authors' details Department of Human Services, Melbourne, VIC Stephen B Lambert, FAFPHM, Public Health Physician; Ross M Andrews, MPH, MAppEpid, Epidemiologist; Pauline A Lynch, Public Health Nurse; Debbie K Gercovich, Paediatric Phlebotomist; Melissa A Morgan, MB BS, Immunisation Coordinator; Rosemary A Lester, FAFPHM, Public Health Physician. Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC Heath A Kelly, FAFPHM, Head, Epidemiology Division; Mike C Catton, FRCPA, Head, Virology Division; Jennie A Leydon, BAppSci, Senior Scientist. Microbiological Diagnostic Unit, University of Melbourne, Melbourne, VIC. Geoffrey G Hogg, FRACP, FRCPA, Director. Reprints will not be available from the authors. Correspondence: Dr H A Kelly, Victorian Infectious Diseases Reference Laboratory, Locked Bag 815, Carlton South, VIC 3053. heath.kellyATnwhcn.org.au Make a comment Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> 1: Classification of notified measles cases by the Victorian Enhanced Measles Surveillance Program 1. Laboratory confirmed Serum is positive for measles IgM,* and patient had not received the first dose of a measles vaccine within 45 days of specimen collection9 OR Diagnostic rise in measles antibody titres in paired sera OR Wild-type measles virus isolated from a clinical specimen OR A clinical specimen is PCR-positive for wild-type measles virus 2. Laboratory rejected Serum is negative for measles IgM with sample collected at least three days after rash onset10 OR Serum is negative for measles IgM but positive for measles IgG OR Serum is positive for rubella IgM OR Serum is positive for human parvovirus IgM 3. Epidemiologically linked to a laboratory-confirmed case Neither 1 nor 2 above AND An epidemiologic link to a laboratory-confirmed case has been established7 4. Clinically compatible Neither 1, 2 nor 3 AND The case satisfies the NHMRC clinical case definition † for suspected measles 5. Not clinically compatible Neither 1, 2 nor 3 AND The case does not satisfy the NHMRC clinical case definition for suspected measles 6. Not classifiable Neither 1, 2 nor 3 AND There are insufficient clinical data available to allow classification as clinically compatible (4) or not clinically compatible (5). NHMRC=National Health and Medical Research Council. PCR=polymerase chain reaction. *Sera that gave IgM-positive results at laboratories other than the Victorian Infectious Diseases Reference Laboratory (VIDRL) were retested at VIDRL and classified accordingly. If serum was not available for retesting, then the case was classified as laboratory confirmed to maximise sensitivity, rather than positive predictive value, of the system. †Morbilliform rash, fever present at rash onset, and cough. Back to text Back to text 3: Serological results for patients notified with measles in Victoria, July 1997 to December 1998 Age group (years)Number (% of notifications) Serologically tested (% of age group) Serologically confirmed (% of tested)<190 (28%)69 (77%)2 (3%)1-4122 (38%)100 (82%)7 (7%)5-963 (20%)55 (87%)010-1927 (9%)22 (81%)5 (23%)>2015 (5%)12 (80%)5 (42%)Total317258 (81%)19 (7%) Back to text 4: Measles vaccination and immunity for 317 notified cases in Victoria, July 1997 to December 1998 Reported vaccination statusNumber (% of notifications)Serologically tested (% of vaccination group)IgG-negative (% of tested)Vaccinated174 (55%)152 (87%)11 (7%)Date provided9987 (88%)7 (8%)No date provided7565 (87%)4 (6%)Not vaccinated124 (39%)92 (74%)83 (90%)Age <1 year9068 (76%)67 (99%)Age ≥1 year3424 (71%)16 (67%)No information19 (6%)14 (74%)2 (14%) Back to text 5: Utility of the National Health and Medical Research Council clinical case definition for suspected measles in Victoria, July 1997 to December 1998 Predictive value SensitivitySpecificityPositiveNegativeAll cases11/18 (61%)133/202 (66%)11/80 (14%)133/140 (95%)Excluding non-index cases4/10 (40%)133/202 (66%)4/73 (5%)133/139 (96%)Back to text 6: Recommendations for follow-up of measles notifications in an interepidemic period Cases of measles should be notified on suspicion, regardless of whether they satisfy the NHMRC clinical case definition for suspected measles. A serum specimen should be obtained for all sporadic notified cases of measles, and from at least two cases in an outbreak. All IgM positive serological results should be confirmed at a reference laboratory. If public health action during an interepidemic period is to involve excluding contacts, this action should be postponed if rapid serological testing is available. If a serum specimen cannot be obtained from a notified case, or rapid serological testing is not available, it should be assumed the case is measles, regardless of whether the case meets the NHMRC clinical case definition for suspected measles, and public health action should be taken immediately. Back to text

Stephen B Lambert · Heath A Kelly · Ross M Andrews · Mike C Catton · Pauline A Lynch · Jennie A Leydon · Debbie K Gercovich · Geoffrey G Hogg · Melissa L Morgan · Rosemary A Lester

Research Hepatitis C virus antibody prevalence among injecting drug users at selected needle and syringe programs in Australia, 1995-1997 Margaret A MacDonald, Alex D Wodak, Kate A Dolan, Ingrid van Beek, Philip H Cunningham, and John M Kaldor, for the Collaboration of Australian NSPs* MJA 2000; 172: 57-61 For editorial comment see Watson Abstract - Introduction - Method - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Infectious diseases and parasitology Abstract Objectives: To describe point prevalence of HCV antibody and relevant risk behaviour among people who inject drugs and who attended selected needle and syringe programs throughout Australia in 1995, 1996 and 1997. Design and setting: Repeated cross-sectional surveys of one week's duration were carried out in 21, 20 and 23 needle and syringe program sites throughout Australia in 1995, 1996 and 1997, respectively. Participants: All clients attending participating sites during the designated survey week were asked to complete a self-administered questionnaire and provide a finger-prick blood sample for HCV antibody testing. Main outcome measures: Prevalence of HCV antibody. Results:Survey response was 41% (n = 979) in 1995, 51% (n = 1463) in 1996 and 48% (n = 1699) in 1997. HCV prevalence declined significantly from 63% in 1995 to 51% in 1996 and 50% in 1997 (P < 0.001). Among respondents who reported injecting for less than three years, prevalence declined from 22% in 1995 to 13% in 1996 and 1997 (P < 0.001). Reported use of needles and syringes after someone else in the previous month declined from 31% in 1995 and 28% in 1996 to 15% in 1997 (P < 0.001). Conclusions: Despite an apparent decline in HCV prevalence, carriage rates of HCV antibody remain high. Introduction Hepatitis C virus (HCV) infection is predominantly spread through blood contact.1 In most First World countries, most prevalent and incident cases of HCV infection involve people who have, at some time, illicitly injected drugs. In such people, transmission is believed to occur predominantly through sharing of injecting equipment.2 HCV infection is a public health concern because of its serious complications, such as cirrhosis of the liver and hepatocellular carcinoma,3 as well as its high prevalence, long latent period and high probability of long-term carriage and infectiousness. Australia adopted a harm reduction approach as part of its national drug strategy in 1985.4 An extensive network of needle and syringe programs (NSPs) has been established in Australia; in the financial year 1994-95, around 700 NSPs distributed six million syringes nationally and an additional four million were distributed through pharmacies.5 Early and vigorous implementation of harm reduction measures, such as methadone maintenance, peer-based education and NSPs, has successfully maintained low seroprevalence of HIV infection among people who inject drugs in Australia.6 In contrast, prevalence and incidence of HCV infection among this population remain high.2,7 To assess the impact of prevention activities on HIV and HCV infection, a monitoring system was established at selected NSPs throughout Australia.6 Cross-sectional surveys at NSPs among people who inject drugs offer a practical and repeatable mechanism for recruiting large samples of injecting drug users. This provides a basis for systematic monitoring of HCV and HIV infection, and of injecting behaviours associated with transmission of these viruses. We report the results of the first three years of national HCV monitoring among NSP attenders in Australia. Methods The survey methods have been described in detail previously.6 Briefly, trained staff at participating NSPs asked all clients attending during one-week periods in March 1995, June 1996 and October 1997 to complete a brief, self-administered questionnaire and provide a finger-prick blood sample. Participating NSP sites were selected for number of attendances and coverage of all Australian States and Territories (see Box 1). Those selected in 1995 distributed approximately 40% of the syringes distributed nationally through NSPs. There was some change in sites over the three years because the number of NSPs increased, but a core group of 16 sites was maintained. Sex and age group were recorded for all clients who attended participating sites during the survey week. As some clients attended more than once, a record was kept as to whether the attendance was the first for that week to measure survey response rate. Participants completed a brief questionnaire on basic demographic characteristics and injecting and sexual behaviour. Capillary blood was collected on blotting paper by finger prick with single-use lancets. Venous blood was not obtained, as few NSPs had appropriate facilities for collecting and storing large amounts of blood. Specimens were tested for HCV antibody by a modified third-generation enzyme immunoassay (Abbott HCV 3.0, Chicago, USA). A modified cutoff value for optical density was calculated to capture more than 95% of the seronegative population. Specimens were considered positive for HCV antibody if the optical density to cutoff ratio was greater than or equal to one on initial and subsequent testing. In 1998, as a quality control measure, 60 samples were randomly selected from each year's survey and retested for HCV antibody as described. Retest results were 100% concordant for the 1995 and 1997 surveys but only 88% for 1996. Subsequently, all available stored 1996 samples (83%) were retested. Ethical approval for this study was obtained from relevant ethics committees associated with the investigators and with participating sites. Statstical analysis Data were analysed with the Stata computer package.8 We assessed change in demographic, behavioural or serological variables using the χ2 test for categorical variables and the Kruskal-Wallis or Mann-Whitney tests for discrete variables. To control for changes in sample characteristics between surveys, we assessed change in HCV prevalence from 1995 to 1997 for all participants, and, for participants who reported only one or two years of drug injection, by multivariate logistic regression analysis. We also used multivariate logistic regression analysis, restricted to sites that participated in all surveys, to assess change in HCV prevalence. Associations between HCV prevalence and participants' characteristics were evaluated by the χ2 test and χ2 test for linear trend. To control for intralaboratory variation with HCV antibody tests, we calculated HCV prevalence for 1996 participants using retested results where available. In addition, for participants with insufficient stored sera for retesting, the original estimates of HCV prevalence were adjusted for each category of variables used in the analysis, by the overall difference between original and retest test results. Associations between HCV prevalence and participants' characteristics in 1997 were also assessed using multivariate logistic regression. Factors significantly associated with HCV infection on univariate analysis (with an inclusion criterion of P ≤ 0.05) or factors that were considered a priori to be predictors of HCV risk were included in the logistic regression model. Results Characteristics of respondents As shown in Box 1, 979 clients in 1995, 1463 in 1996 and 1699 in 1997 completed a questionnaire and provided a blood sample suitable for HCV antibody testing, giving overall response rates of 41%, 51% and 48%, respectively. There was a higher response rate among clients aged less than 25 years compared with those aged 25 years or more in 1996 (56% v. 49%), but no difference in 1995 and 1997. There was a higher response rate among females than males in 1995 (46% v. 39%) and 1997 (63% v. 39%). The age ranges for respondents in the three years were 14-54 years in 1995, 13-53 years in 1996 and 15-58 years in 1997. The median age of respondents was significantly higher in 1995 than in 1996 (29 years v. 28 years; P = 0.009) and 1997 (29 years v. 27 years; P < 0.001). Median age at commencement of injecting drug use was 18 years in the three surveys. Consequently, the median number of years that respondents had injected drugs was significantly higher in 1995 than in 1996 (10 years v. 8 years; P = 0.001) and 1997 (10 years v. 7 years; P < 0.001). Similar proportions of males (65%, 67% and 66%), respondents reporting being heterosexual (79%, 78% and 79%), and those reporting having been imprisoned in the past year (15%, 13% and 14%) participated in the 1995, 1996 and 1997 surveys. Almost a third of respondents in each year reported no contact with health services such as counselling, detoxification or methadone maintenance treatment. The proportion of respondents on methadone treatment, however, was significantly lower in 1997 (33%) than in 1995 (40%; P = 0.001) or 1996 (36%; P = 0.02). More respondents reported that heroin was the last drug they injected in 1996 and 1997 than in 1995 (53% and 56% v. 44%) and fewer reported last injecting amphetamines (19% and 18% v. 21%) and methadone (12% and 11% v. 19%; P < 0.001). Daily or more frequent injection increased from 41% of respondents in 1995 and 1996 to 51% in 1997 (P = <0.001). Syringe use after someone else Reported use of a needle and syringe after someone else in the preceding month declined significantly from 1995 and 1996 to 1997 (31%, 28%, and 15%, respectively; P < 0.001). This practice was significantly more common among females than males in 1995 and 1997 (35% v. 28% and 17% v. 14%; P = 0.04). In 1997, respondents aged less than 25 years were more likely than older respondents to report syringe use after someone else in the past month (19% v. 12%; P = 0.001). HCV antibody prevalence Box 2 shows that HCV antibody prevalence was significantly lower in 1996 and 1997 than in 1995 (51% and 50% v. 63%; P < 0.001). This difference remained significant after adjustment for differences in sample characteristics between surveys (adjusted odds ratio, 0.5; 95% CI, 0.4-0.7). Sex, age, duration of drug injecting, last drug injected, frequency of drug injection and health service contact were included in the model. A similar pattern was found when analysis was restricted to the 16 sites that participated in all three surveys (63% in 1995 v. 50% in 1996 and 51% in 1997; P < 0.001) and when respondents who reported participation in more than one survey were excluded from the analysis (63% v. 49% and 47%; P < 0.001). HCV antibody prevalence was also significantly lower in 1996 and 1997 (13%) than in 1995 (22%) among respondents who reported less than three years of drug injection (P = 0.03). This difference also remained significant after adjustment for sex, age, last drug injected, frequency of drug injection and health service contact (adjusted odds ratio, 0.4; 95% CI, 0.2-0.7). HCV antibody prevalence was lower in 1996 and 1997 than in 1995 among respondents aged less than 25 years, regardless of whether the last drug injected was heroin (trend test, P = 0.03) or amphetamine (trend test, P = 0.002; Box 3a). Box 3b shows that, when respondents were grouped according to the year they started injecting, HCV antibody prevalence was higher among those reporting most recent injection of methadone or heroin than among those reporting most recent injection of amphetamine. HCV antibody prevalence was also significantly higher among respondents from New South Wales and Victoria than those from Queensland, and remained higher when the analysis was restricted to respondents reporting heroin as the last drug injected and stratified according to the year drug injection started (Box 3c). Multivariate logistic regression analysis showed that other factors significantly associated with presence of HCV antibody in 1997 included being female, having been imprisoned in the past year, having a history of methadone treatment, being aged 25 years or more, having injected drugs for more than five years, and daily or more frequent injection (see Box 2). Discussion Our findings indicate that HCV antibody prevalence, although high, is declining, particularly among participants new to injecting. While all cases of HCV infection among respondents who reported having injected for only one or two years cannot be classified as new infections, it is highly likely that the vast majority reflect recent transmission. Variation in the populations surveyed in the three years of the study cannot be excluded as an explanation for our observations. Respondents in 1997 were younger and newer to injecting than in 1995. Nonetheless, the decline in HCV antibody prevalence remained statistically significant when multivariate logistic regression analysis was used to control for differences in demographic characteristics, when analysis was restricted to respondents who reported less than three years of drug injection, and when analysis was restricted to sites that participated in all three surveys. It is also conceivable that HCV infection status influenced participation in the survey. For example, people infected with HCV might be more likely to participate than those not infected because of the services provided by NSPs or because they have an interest in blood-borne infections by virtue of having one. Alternatively, people with HCV infection might be reluctant to provide a blood sample in a non-clinical setting because of concerns about inadvertent spread of infection. It is not possible to determine whether people with HCV infection were more or less likely than those without infection to participate in the surveys. If such bias occurred it is unlikely that the direction changed from 1995 to 1996 and 1997. However, the extent to which the magnitude of such bias may have changed over the three surveys is not known. Comparison of our data with those of other Australian studies reporting HCV antibody prevalence according to type of drug injected and duration of injecting supports our observation that HCV antibody prevalence is declining among people who inject drugs. Among opiate injectors who had been injecting for less than three years, HCV antibody prevalence was 70% in the late 1980s9 and almost 50% in the early 1990s,10 compared with 20% in our study. Declining HCV antibody prevalence has also been reported from other cities that implemented HIV prevention measures in the mid-1980s, namely Geneva11 and Glasgow.12 We also found that the proportion of respondents who reported using a syringe after someone else was significantly lower in 1997 than in 1995 and 1996. There has been a marked decline in reported sharing of syringes in Australia since 1984, when more than 90% of respondents reported having done so in the month before interview.13 Of concern was the higher rate of sharing reported among respondents aged less than 25 years than among older respondents in 1997. Younger injecting drug users are probably more recent initiates to injecting; this is a subpopulation previously identified as being at extremely high risk of acquiring HCV infection.14 An extremely high incidence of HCV infection has also been reported recently among young people with a history of drug injecting in Sydney.7 It is difficult to explain the marked geographic variation in HCV antibody prevalence detected in our study. The sample recruited from Queensland was significantly different from other States and Territories with regard to known correlates of HCV infection such as duration of injecting and type of drug injected. Nonetheless, significantly lower prevalence persisted among respondents from Queensland compared with those from New South Wales and Victoria when the sample was stratified according to these factors. Despite our finding of declining HCV antibody prevalence among people who inject drugs in Australia, and even though an epidemic of HIV infection has so far been prevented, the prevalence and incidence of HCV infection in this group remain high.2,7 Percutaneous transmission is more efficient for HCV than for HIV infection.1 More importantly, the carriage rate of HCV among injecting drug users was already considerably higher than that for HIV when harm reduction policies were first introduced.9 It is likely that occasional instances of shared injection equipment and other blood contact during injection have been sufficient to maintain high levels of HCV transmission without an increase in HIV transmission. It can not be assumed that the results of our surveys are generalisable to all people who inject drugs in Australia. However, NSP clients represent a heterogeneous population of injecting drug users who are readily accessible for targeted prevention initiatives. Prevention efforts encompassing education, drug treatment and needle exchange need to be enhanced to improve consistency and coverage so that transmission of HCV infection is reduced further and the current low prevalence of HIV infection is sustained. * The Collaboration of Australian NSPs: ACT Drug Referral and Information Centre (Maureen Cane); AIDS Council of Central Australia (Sue Fielding); Australian IV League (Judith Byrne); Biala Alcohol & Drug Services (Margaret Holtham); Centre for Immunology, St Vincent's Hospital Sydney (Phillip Cunningham & Claire Temby); Clovelly Park, Norlunga, SAVIVE and Salisbury NSP, Adelaide; Drug Intervention Services Cabramatta (Sue Heard & Lisa Maher); GAIN (Richard Beckman & Diane Flint); Gold Coast Hospital (Dr Lynn Hawken); HIV and Sexual Health Services Cairns (Chris Barron & Mark Mills); Kirketon Road Centre & K2 (Dr Ingrid van Beek & Damian Hull); Macfarlane Burnet Centre for Medical Research (Dr Nick Crofts); Melbourne Inner Needle Exchange (Craig Mercer); Northern Rivers Health Service (Wendy Evans); Northern Territory AIDS Council (Charles Roberts); Resource & Education Program (IDU): Redfern & Canterbury (Julie Dixon & Anna Miraglia); St George NSP (Richard Sulovsky); St Kilda NSP (Simon Kroes); Sexual Health Services, Toowoomba (Bill Rutkin); SHARPS Melbourne (Sean Swift & Melissa Virtue); South Australian Drug and Alcohol Services Council (Dr Robert Ali & Bob Braithwaite); Tasmanian Council on AIDS and Related Diseases (Melinda Tonks); Tasmanian Users Health Support League (Stuart Williams); Wentworth NSP (Elizabeth O'Neil & Andy Hart); West Australian AIDS Council Inc. (Katrina Roberts & Samantha Nicholson); Western Australia Substance Users' Assoc. Inc. (Tamara Speed); Western Region AIDS and Hepatitis Prevention (Sandra Fox); Western Sydney AIDS Prevention Services: Harris Park & Blacktown (Anton Evers). Acknowledgements We acknowledge the contribution of survey participants, needle and syringe program staff and site coordinators who facilitated the surveys. We also thank Dr Greg Dore for his comments on earlier drafts. Surveys were funded by the Commonwealth Department of Health and Aged Care. The National Centre in HIV Epidemiology and Clinical Research is supported by the Commonwealth Department of Health and Aged Care through the Australian National Council on AIDS and Related Diseases and its Research Advisory Committee. References MacDonald M, Crofts N, Kaldor J. Transmission of hepatitis C virus: rates, routes and cofactors. Epidemiol Rev 1996; 18: 137-148. Crofts N, Jolley D, Kaldor J, et al. Epidemiology of hepatitis C virus infection among injecting drug users in Australia. J Epidemiol Community Health 1997; 51: 692-697. Seeff LB. Natural history of hepatitis C. Hepatol 1997; 3 Suppl: 21S-28S. Blewett N. National Campaign against drug abuse: Assumptions, arguments, and aspiration. Canberra: AGPS, 1987. (NCADA Monograph No. 1.) Wodak A, Lurie P. A tale of two countries: Attempts to control HIV among injecting drug users in Australia and the United States. J Drug Issues 1996; 27: 117-134. MacDonald M, Wodak A, Ali R, et al, on behalf of the Collaboration of Australian Needle Exchanges. HIV prevalence and risk behaviour in needle exchange attenders: a national study. Med J Aust 1997; 166: 237-240. van Beek I, Dwyer R, Dore GJ, et al. Infection with HIV and hepatitis C among injecting drug users in a prevention setting: retrospective cohort study. BMJ 1998; 317: 433-437. Stata Statistics/Data Analysis [computer program]. Version 5.0. Texas: Stata Corporation, 1997. Bell J, Batey RG, Farrell GC, et al. Hepatitis C virus in intravenous drug users. Med J Aust 1990; 153: 217-273. Crofts N, Hopper JL, Milner R, et al. Blood-borne virus infections among Australian injecting drug users: Implications for spread of HIV. European J Epidemiol 1994; 10: 687-694. Broers B, Junet C, Bourquin M, et al. Prevalence and incidence rate of HIV, hepatitis B and C among drug users on methadone maintenance treatment in Geneva between 1988 and 1995. AIDS 1998; 12: 2509-2066. Goldberg D, Cameron S, McMenamin J. Hepatitis C antibody prevalence among injecting drug users in Glasgow has fallen but remains high. Commun Dis Public Health 1998; 1: 95-97. Crofts N, Webb-Pullman J, Dolan K. An analysis of trends over time in social and behavioural factors related to the transmission of HIV among injecting drug users and prison inmates. Evaluation of the National HIV/AIDS Strategy 1993-94 to 1995-96. Technical Appendix 4. Canberra: AGPS, 1996. Garfein RS, Vlahov D, Galai N, et al. Viral infections in short-term injection drug users: the prevalence of hepatitis C, hepatitis B, human immunodeficiency, and human t-lymphotropic viruses. Am J Public Health 1996; 86: 655-661. (Received 1 Jun, accepted 16 Sep, 1999) Authors' details National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, NSW. Margaret A MacDonald, BSocSci, DipEpidemiol, Senior Research Assistant. John M Kaldor, PhD, Deputy Director. Alcohol and Drug Services, St Vincent's Hospital, Sydney, NSW. Alex D Wodak, FRACP, FAFPHM, Director. National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW. Kate A Dolan, PhD, Senior Lecturer. Kirketon Road Centre, Sydney, NSW. Ingrid van Beek, MBA, FAFPHM, Director. Centre for Immunology, St Vincent's Hospital, Sydney, NSW. Philip H Cunningham, BAppSc, Senior Hospital Scientist. Reprints: Ms M A MacDonald, National Centre in HIV Epidemiology and Clinical Research, Level 2, 376 Victoria Street, Darlinghurst, NSW 2010. mmacdATnchecr.unsw.edu.au Make a comment Back to text 2: Hepatitis C virus antibody prevalence according to demographic and injecting characteristics (1995-1997), and multivariate logistic regression analysis (1997) 1995 1996 1997 CharacteristicNo. tested% with HCVNo. tested% with HCVNo. tested% with HCVAdjusted odds ratio (95% CI)Total979631463 51169950-Sex Male63963981 49‡111947*1 Female32764467 56574552 (1.5-2.7*)Imprisonment in previous year No82160*122448*145947*1 Yes14678190 71234702.3 (1.6-3.5*)Health service contact NSP only30032*483 17*53220*1 Detoxification, counselling12552 18338276351.4 (0.9-2.2) Past methadone maintenance15779 2657132570 3 (1.9-4.6*) Current methadone maintenance39584524 77563743.8 (2.5-5.8*) 1995 1996 1997 CharacteristicNo. tested% with HCVNo. tested% with HCVNo. tested% with HCVAdjusted odds ratio (95% CI)Age at survey (years) <206528*138 18*18419*1 20-2422639363 22440231.1 (0.6-1.9) 25-2919863308 50368471.9 (1.0-3.4‡) 30-3423775282 68290642 (1.0-3.8‡) 35+246 8436381414 845.7 (2.9-11.0*)Years of drug use <3131 22*24013*308 13*1 3-5165 3528521345 261.3 (0.8-2.1) 6-1020962309 51362442 (1.2-3.3†) >104568658081642 837.5 (4.4-13.0*)Last drug injected Amphetamine20635*274 22*31218*1 Heroin43167780 54951542.3 (1.4-3.7*) Combined drugs8572126 63104591.7 (0.8-3.5) Methadone18987169 82180783 (1.5-5.9†) Other6546109 45142462.1 (1.1-4.1‡) 1995 1996 1997 CharacteristicNo. tested% with HCVNo. tested% with HCVNo. tested% with HCVAdjusted odds ratio (95% CI)Frequency of drug injecting Less than daily50761†745 49†70741*1 Daily or more39968609 56867582 (1.5-2.7*) Not in last month704798 4111845-Syringe use after someone else in the last month No624 62†96850*1284491 Yes27971382 58220531.3 (0.9-2.0)State or Territory Queensland30940*490 33*47929*1 Victoria11853191 48436512.4 (1.6-3.5*) New South Wales41284497 71523702.2 (1.4-3.3*) Other14059285 50261461.6 (1.0-2.6‡)NSP=needle and syringe program. *P<0.001; †P<0.01 and >0.001; ‡P<0.05 and >0.01. Back to text 3: HCV antibody prevalence in relation to age, injecting habits and State or Territory. Back to text Back to text Back to text

Margaret A MacDonald · Alex D Wodak · Kate A Dolan · Philip H Cunningham

The Research Enterprise Nature, nurture and my experience with smallpox eradication A career influenced by chance events Frank Fenner MJA 1999; 171: 638-641 Introduction - Family and education - Infectious diseases - Myxomatosis - The Intensified Smallpox Eradication Programme - References - Career outline - Why smallpox could be eradicated - Remaining problems with smallpox - Subsequent eradication programs - Authors' details - - More articles on Infectious diseases and parasitology

Frank Fenner

Viewpoint Cryptosporidiosis in the immunocompromised: weighing up the risk Current evidence does not support a permanent "boil water" alert for all immunocompromised groups Paul M Byleveld, Amanda Hunt and Jeremy M McAnulty MJA 1999; 171: 426-428 See also Fairley et al Synopsis - Introduction - Transmission risks - Recommendations - Conclusion - References - Authors' details - - More articles on Public and environmental health Synopsis Cryptosporidiosis has been increasingly recognised as a cause of diarrhoeal illness in both immunocompetent and immunocompromised people. Massive outbreaks have been linked to municipal drinking water supplies in North America and Europe, but so far none have been reported in Australia. There is evidence that modes of transmission other than drinking water are more important. There can be no guarantee that infective Cryptosporidium oocysts will not contaminate an Australian water supply. Therefore, a permanent "boil water" warning may be warranted on medical advice in severely immunocompromised people, for whom cryptosporidiosis could be persistent and life threatening. Introduction Between July and September 1998, drinking water in Sydney was contaminated with the protozoan parasites Cryptosporidium and Giardia. Human illness with cryptosporidiosis had been notifiable by laboratories in New South Wales since 1996, but giardiasis was not. In response to the contamination, surveillance for diarrhoeal disease was enhanced and residents in affected areas were advised to boil all drinking water. To determine whether the incidence of diarrhoeal illness had increased, NSW Health's six public health units in Sydney regularly contacted laboratories, general practitioners, emergency departments, pharmacies and nursing homes. In addition, NSW Health conducted telephone surveys of households to determine the residents' disease experience and compliance with warnings. At times during the contamination events, a proportion of the population was exposed to drinking water containing apparently high concentrations of Cryptosporidium and Giardia, because the water reached houses before the contamination was identified and because of poor compliance with the "boil water" alert. Despite this, there was no outbreak of disease attributable to drinking water, as indicated by increases in cases of diarrhoeal disease presenting to emergency departments, sentinel general practices or nursing homes, or laboratory reports of cryptosporidiosis.1The Sydney Water Inquiry was established in August 1998 to investigate the causes of contamination and management of the incidents and to make recommendations about the control and prevention of such events. The Inquiry recommended that a permanent warning be issued to immunocompromised persons to boil all tap water before use, and that advice be provided on the risks of contracting cryptosporidiosis from water and other sources.2 The permanent "boil water" recommendation is a very cautious reaction to a threat that may be small, but is consistent with advice offered in the United Kingdom.3 The implementation of such advice would have a serious effect on the operation and costs for healthcare facilities and the food industry, if required to buy in treated water or provide additional treatments for water used for drinking or as ingredients. In contrast to the recent Sydney experience of high oocyst counts but no detectable disease, large community-wide outbreaks of cryptosporidiosis have occurred in Britain and the United States following contamination of drinking water with concentrations of Cryptosporidium oocysts that were apparently much lower than those in Sydney.4,5 In Britain and the US, several outbreaks of waterborne cryptosporidiosis have resulted in significant morbidity and mortality in people infected with HIV (Box 1).6-8 Other classes of severely immunocompromised persons, including transplant recipients and patients receiving chemotherapy, may also be at greater risk from water contaminated with Cryptosporidium. While the available data are limited, the attack rate in these groups does not appear to be as high as that in those with HIV.6,7 The identification of waterborne disease is more likely in the immunocompromised, as these people may have prolonged illness and receive closer medical surveillance. Compared with Cryptosporidium, the risk posed by Giardia and viral and bacterial pathogens to immunocompromised people from municipal water supplies is thought to be lower, because conventional water treatment processes (including chlorination) more easily control them.14 Transmission risks The public and many clinicians poorly understand the relative importance of transmission of Cryptosporidium by drinking water compared with other modes of transmission (Box 2). Recent evidence shows that contaminated swimming pools are likely to pose a greater risk than a public water supply for the waterborne transmission of human infective forms of C. parvum.18,19There have been no documented outbreaks of cryptosporidiosis or giardiasis associated with municipal water supplies in Australia. For waterborne transmission to occur, viable human-infective forms of C. parvum must be present in sufficient (albeit small) numbers. Available data to date suggest that parasites found in Sydney drinking water and originating from the catchments may not have been infectious to humans.1 However, the potential for transmission of Cryptosporidium and Giardia by drinking water in Australia was demonstrated at a campsite in Victoria, when guests developed cryptosporidiosis and giardiasis after an inground water tank was contaminated by effluent from a septic tank.20 In regional areas, the risk of waterborne cryptosporidiosis and giardiasis may vary from town to town. While the data are scarce, there is currently no evidence to suggest that immunocompromised persons who reside in these areas and receive an appropriately treated drinking water supply are at greater risk. Precautions should be taken with untreated water supplies, particularly those obtained from surface sources (rivers, creeks and dams). In New South Wales, a number of water suppliers have collaborated with health authorities to evaluate the risk of contamination from "catchment to tap". This process -- which involves assessments of (i) the risks to the water catchment area from sources including septic tanks, sewage overflows and agricultural activities, (ii) the integrity of the water treatment processes, and (iii) the distribution system -- better equips water suppliers and health authorities to provide information on local drinking water quality to clinicians and the public. Recommendations Since well before the recent contamination incidents, NSW Health has stated that people living with HIV and AIDS, those receiving treatment for some types of cancer and transplant recipients may (after consulting with their doctor) choose to avoid unboiled drinking water.21 Although evidence to date suggests that appropriately treated drinking water in New South Wales does not place anyone at risk of cryptosporidiosis, this advice is offered as a precautionary measure and is consistent with that offered by the US Centers for Disease Control and Prevention.22Particular care should be taken with drinking water and food at remote accommodation facilities. Boiling is the most effective way to kill Cryptosporidium (and other pathogens) in drinking water, while many, but not all, filters and bottled water meet satisfactory standards. Consumers should carefully examine the labels on filters and bottled water and seek an assurance from manufacturers that their products will protect against waterborne cryptosporidiosis and giardiasis. Water treatment units that incorporate boiling, distillation or reverse osmosis processes are satisfactory. Suitable filters include those labelled "absolute 1 micron" (or smaller) and certified to meet the relevant standard for cyst removal (either ANSI/NSF5323 or AS/NZS434824), but require an additional disinfection unit to inactivate bacterial and viral pathogens. Filters are likely to fail if not maintained in accordance with manufacturer's instructions. Because filters may accumulate pathogens, it is advisable to wear gloves and wash hands after changing filters. It should not be assumed that all bottled water, beverages reconstituted with tap water and ice products are free from contamination. Mineral (or spring) water obtained from well-protected sources should not contain Cryptosporidium and Giardia. Other packaged water and ice products that are treated by distillation, reverse osmosis, or filtering through an absolute 1 micron (or smaller) filter should be free of Cryptosporidium and Giardia. Data available to date have not provided evidence of local drinking water borne cryptosporidiosis and do not support a permanent "boil water" warning for all immunocompromised persons in New South Wales. Although the risk is likely to remain low, there can be no guarantee that infective Cryptosporidium oocysts will not contaminate an Australian water supply. Therefore, a permanent "boil water" warning may be warranted on medical advice in severely immunocompromised people, for whom cryptosporidiosis could be persistent and life threatening. Such people should also be advised to take great care with all other potential risk factors. Given the broad range and dynamic nature of these conditions, it is impossible for health authorities to list all classes of people who should receive this warning. Individual advice can only be provided by a doctor after considering the patient's status and case history. The potential effect of a permanent boil water advice on quality of life for immunocompromised persons should be weighed up against benefits that may be gained. Factors to consider include the need to avoid a range of foods and beverages that may contain tap water, the risk of burns and scalds, and ongoing costs where filters or bottled water are used. Conclusion Health departments rely on the diagnosis and timely notification of diarrhoeal disease and monitoring of water quality to protect the public from waterborne disease outbreaks. Where a reasonable threat to public health is likely to exist, the public is advised to boil drinking water. The recent events suggest that the risk of transmission of cryptosporidiosis by drinking water in Sydney may be very low, and highlight the limitations of water-testing techniques that do not define viability or human infectivity. But more is to be learnt about Cryptosporidium and the risk that it poses to the community. It is essential that health agencies continue to monitor and investigate clusters of cryptosporidiosis cases to learn more about modes of transmission and risk factors. Sound public health decisions can only be made on such evidence. References NSW Department of Health. The Sydney Water Incident: July-September 1998. NSW Public Health Bulletin 1998; 9: 91-94. McClellan P. Sydney Water Inquiry. Final Report. Sydney: NSW Premier's Department, 1998. Bouchier IAD. Cryptosporidium in water supplies. 8. Advice to the immunocompromised individual. <http://www.dwi.detr.gov.uk/crypto/bou008.htm>. UK Drinking Water Inspectorate, Department of the Environment, Transport and Regions, 1998. Accessed 16 September 1999. Atherton F, Newman CPS, Casemore DP. An outbreak of waterborne cryptosporidiosis associated with a public water supply in the UK. Epidemiol Infect 1995; 115: 123-131. MacKenzie WR, Hoxie NJ, Proctor ME, et al. A massive outbreak in Milwaukee of Cryptosporidium infection transmitted through the public water supply. N Engl J Med 1994; 331: 161-167. Clifford CP, Crook DW, Conlon CP, et al. Impact of waterborne outbreak of cryptosporidiosis on AIDS and renal transplant patients. Lancet 1990; 335: 1455-1456. Goldstein ST, Juranek DD, Ravenholt O, et al. Cryptosporidiosis: an outbreak associated with drinking water despite state-of-the-art water treatment. Ann Intern Med 1996; 124: 459-468. Hoxie NJ, Davis JP, Vergeront JM, et al. Cryptosporidiosis-associated mortality following a massive waterborne outbreak in Milwaukee, Wisconsin. Am J Public Health 1997; 87: 2032-2035. National Centre in HIV Epidemiology and Clinical Research. HIV/AIDS and related diseases in Australia: Annual Surveillance Report 1998. Sydney: National Centre in HIV Epidemiology and Clinical Research, 1998. Available at <http://www.med.unsw.edu.au/nchecr>. Detels R, Munoz A, McFarlane G, et al. Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators. JAMA 1998; 280: 1497-1503. Correll PK, Law MG, McDonald AM, et al. HIV disease progression in Australia in the time of combination antiretroviral therapies. Med J Aust 1998; 169: 469-472. Carr A, Marriot D, Field A, et al. Treatment of HIV-1-associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy. Lancet 1998; 351: 256-261. Foudraine NA, Weverling GJ, van Gool T, et al. Improvement of chronic diarrhoea in patients with advanced HIV-1 infection during potent antiretroviral therapy. AIDS 1998; 12: 35-41. National Health and Medical Research Council, and Agriculture and Resource Management Council of Australia and New Zealand. Australian Drinking Water Guidelines 1996. Sorvillo F, Lieb LE, Nahlen B, et al. Municipal drinking water and cryptosporidiosis among persons with AIDS in Los Angeles County. Epidemiol Infect 1994; 113: 313-320. Kim LS, Stansell J, Cello JP, et al. Discrepancy between sex- and water-associated risk behaviours for cryptosporidiosis among HIV-infected patients in San Francisco. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 19: 44-49. Caputo CS, Forbes A, Frost F, et al. Determinants of antibodies to Cryptosporidium infection among gay and bisexual men with HIV infection. Epidemiol Infect 1999; 122: 291-297. Lemmon JM, McAnulty JM, Bawden-Smith J. Outbreak of cryptosporidiosis linked to an indoor swimming pool. Med J Aust 1996; 165: 613-616. NSW Department of Health. Infectious diseases -- January-February 1998. NSW Public Health Bulletin 1998; 9: 24. Lester R. A mixed outbreak of cryptosporidiosis and giardiasis. Update. Quarterly Bull Infect Dis Health Department Victoria 1992; 1: 14-15. NSW Health. Preventing cryptosporidiosis. A guide for persons with HIV, AIDS and immunosuppressed systems. April 1998. United States Environmental Protection Agency Office of Water and Centers for Disease Control and Prevention. Safe drinking water. Guidance for people with severely weakened immune systems. <http://www.epa.gov/safewater/crypto.html>. Revised 18 June 1998. Accessed 15 September 1999. American National Standard/NSF International Standard. Drinking water treatment units -- health effects. ANSI/NSF 53. Ann Arbor MI: NSF International, 1997. Australian/New Zealand Standard. Water supply -- domestic type water treatment appliances. Performance requirements. AS/NZS 4348. Sydney: Standards Australia, 1995. Authors' details New South Wales Department of Health, Sydney, NSW. Paul M Byleveld, PhD, Senior Policy Advisor, Water Unit; Amanda Hunt, BHB, MPhil(Env Sc), Policy Advisor, Water Unit; Jeremy M McAnulty, MB BS, MPH, Medical Epidemiologist, Communicable Diseases Surveillance and Control Unit. Reprints: Dr J M McAnulty, NSW Department of Health, Locked Mail Bag 961, North Sydney, NSW 2059. jmcanATdoh.health.nsw.gov.au 1: Cryptosporidiosis and HIV/AIDS During the 1994 cryptosporidiosis outbreak in Nevada, most of the 78 confirmed cases were in HIV-infected adults (61 people, most of whom had CD4+ lymphocyte counts less than 100 cells/µL).7 The remainder of those infected included 11 immunocompetent children, four adults without HIV infection, two HIV-infected children, a renal transplant recipient receiving corticosteroid therapy, and a patient with testicular cancer receiving chemotherapy. In Australia, there has been a marked decline in the incidence of cryptosporidiosis as the initial AIDS-defining illness since 19949 (Dr G Dore, Lecturer in Epidemiology, National Centre in HIV Epidemiology and Clinical Research, personal communication), and there is little evidence that other classes of immunocompromised persons are currently at greater risk of developing cryptosporidiosis. In Australia and other countries, the prognosis for those with HIV infection has improved dramatically with the introduction of highly active antiretroviral treatments, which extend the time to development of AIDS and survival time, and arrest the decline in CD4+ lymphocyte counts.9-11 The administration of antiretroviral therapy that includes a protease inhibitor in HIV-positive individuals appears to restore immunity to C. parvum, relieves cryptosporidial diarrhoea and, in some cases, helps eradicate the parasite.12,13 It is possible that, if an outbreak of waterborne cryptosporidiosis were to occur tomorrow, it would have a less severe impact on the HIV-positive community than outbreaks that occurred in the first half of this decade.7,8 Back to text 2: Modes of transmission Cryptosporidium is transmitted by: faecal-oral contact with infected persons (particularly in childcare centres, by not washing hands after going to the toilet, after changing nappies, or from sexual activity that involves exposure to faecal matter); bathing in contaminated water or swimming pools; handling young livestock; contact with animals that have diarrhoea; and consumption of contaminated foods and drinking water (including water supplies when camping or travelling). A study conducted in Los Angeles concluded that modes of transmission other than drinking water were more important risk factors for the development of cryptosporidiosis in people with AIDS.15 Similarly, a study in persons with HIV in San Francisco revealed that high-risk sexual behaviours were prevalent even among those who were concerned enough about exposures to consume only boiled or bottled water.16 A recent study conducted in persons with HIV in Melbourne suggested that a number of sexual practices, but not CD4+ cell count or tap water consumption, were significant risk factors for prior Cryptosporidium infection.17 Back to text

Paul M Byleveld · Amanda Hunt · Jeremy M McAnulty

Research Vancomycin and teicoplanin use in Victorian hospitals Marion B Robertson, Jonathan G A Dartnell and Tony M Korman, on behalf of the Victorian Drug Usage Evaluation Group MJA 1999; 171: 127-131 See also Ferguson, Grayson et al & Collignon Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Pharmacology Abstract Objective: To determine patterns of prescribing of glycopeptide antibiotics (vancomycin and teicoplanin) in Victorian hospitals and identify areas for targeted intervention. Design: A concurrent, observational, multisite evaluation of drug use. Setting: Thirty-five Victorian hospitals, 1-14 September 1997. Study population: Patients commencing a glycopeptide antibiotic course. Main outcome measures: Rate of glycopeptide antibiotic use; indications; duration of use; main hospitals using glycopeptide antibiotics. Results: 293 patients (269 adults and 24 neonates) commenced on 302 glycopeptide antibiotic courses: 296 intravenous (IV) vancomycin courses and three each of oral vancomycin and parenteral teicoplanin. The overall rate of use was 10.3 courses per 1000 inpatient separations. Of 271 IV vancomycin courses for adults, 176 (65%) were for treatment -- 120 empirically. The median duration of treatment courses was 4.7 days (interquartile range, 2.0-8.2 days). A flucloxacillin-resistant organism was confirmed for 44% of treatment courses. Ninety-five IV vancomycin courses were for prophylaxis, including for cardiac (54%) and vascular surgery (21%); 82% of prophylactic courses were administered for less than 24 hours. Of all the glycopeptide antibiotic courses, 69% were administered at five major metropolitan hospitals. Conclusions: Glycopeptide antibiotic use in Victoria is concentrated in the major metropolitan hospitals. Prolonged durations of vancomycin therapy, including for surgical prophylaxis and empirical therapy not subsequently confirmed by microbiology findings, would be suitable targets for interventional strategies. Introduction The emergence of resistant strains of Staphylococcus aureus and coagulase-negative staphylococci has resulted in increased use of the glycopeptide antibiotics vancomycin and teicoplanin.1 These antibiotics are the only effective treatments for infections with these pathogens, but the emergence of vancomycin-resistant enterococci (VRE) threatens their utility.1,2 VRE can cause serious life-threatening infections, and can transfer their resistance in vitro to other pathogens, such as Staphylococcus, rendering the bacteria resistant to currently available antimicrobials.3,4The emergence of VRE has been linked to both overuse and inappropriate use of antibiotics such as vancomycin, teicoplanin and extended-spectrum cephalosporins.2,4 There is also a strong relationship with the use of glycopeptide antibiotics in animals.5 Australian studies have reported inappropriate use of vancomycin ranging from 42% to 65% in individual hospitals.6,7 Responding to these concerns, consensus guidelines have been disseminated to all Victorian hospitals.8 The aim of this study was to examine patterns of prescribing vancomycin and teicoplanin in Victorian hospitals in order to identify potential areas for targeted intervention to improve use of these antibiotics. Methods This study was conducted by the Victorian Drug Usage Evaluation Group, a multidisciplinary group that aims to promote and improve coordination of drug use evaluation activities as a means to improve drug use. All Victorian public and private hospital pharmacy departments listed in the Society of Hospital Pharmacists of Australia directory9 were invited to participate. All patients at participating hospitals who commenced a course (Box 1) of oral or intravenous (IV) vancomycin or teicoplanin between 1-14 September 1997 inclusive were enrolled. Pharmacists at each hospital collected data concerning: demographic details, the indication for antibiotic therapy as determined from the medical record or by consultation with the prescriber, site and source of infection, beta-lactam hypersensitivity, and past history of methicillin-resistant S. aureus (MRSA) or methicillin-resistant S. epidermidis (MRSE), microbiology results of specimens taken up to seven days before or concurrent with vancomycin or teicoplanin therapy, administration of antibiotics before, during and immediately after vancomycin or teicoplanin therapy, and specialist consultation and advice. Prescription data were collected until the end of the course, until the day of discharge or death, or until 28 September 1997. Each hospital provided details of the number of inpatient separations between 1-14 September 1997. This was used to estimate the number of glycopeptide antibiotic courses commenced per 1000 inpatient separations. Data were evaluated by the Mann-Whitney rank sum test of the equivalence of medians of samples not drawn from a normally distributed population. Proportions were compared using the χ2 test. Data are presented as proportions, medians and interquartile ranges. Results Hospitals: Thirty-five hospitals participated in the study: 33 of 58 public and two of 14 private hospitals invited to participate. Twenty hospitals were in the Melbourne metropolitan area and 15 in regional areas. Patients: In the study period, 293 patients (mean age, 54 years; range, 0-90 years; 112 females) commenced a course of vancomycin or teicoplanin. The 293 patients received 302 courses of glycopeptide antibiotics -- three teicoplanin, three oral vancomycin, and 296 intravenous vancomycin (Box 2). Five of Melbourne's six major metropolitan hospitals participated and administered 209 (69%) of the 302 courses. Twenty hospitals enrolled between one and 11 patients and contributed the remaining 93 courses. Glycopeptide antibiotic use in neonates: Four hospitals enrolled 24 neonates who were prescribed 25 courses of IV vancomycin, with a median duration of 2.3 days (interquartile range, 2.0-4.6 days). One course was for prophylaxis for abdominal surgery; the other 24 courses were for empirical treatment. One treatment course was for respiratory infection and the others were for an unknown site of infection. Flucloxacillin-resistant organisms were isolated for six courses (two MRSA, four coagulase-negative staphylococci). Glycopeptide antibiotic use in adults: Twenty-five hospitals enrolled 269 adults who commenced 277 glycopeptide antibiotic courses; 143 (53%) patients were treated by a medical unit and 126 (47%) by a surgical unit; 73 (27%) of the patients were in an intensive care unit at some stage during the glycopeptide antibiotic course. Of the 269 patients, 235 (87%) were discharged, 30 (11%) died, and 4 (1%) were still in hospital three months after the study. For 94 courses (34%), specialist consultation for the use of vancomycin and teicoplanin was noted in the records. More than 80% of these consultations were with infectious disease/microbiology specialists. There were 263 patients who received 271 courses of IV vancomycin -- 176 (65%) for treatment and 95 for prophylaxis (Box 3). Of the 176 IV vancomycin treatment courses, 120 (68%) were for empirical treatment and 56 (32%) as specific treatment. Empirical courses were shorter than specific courses (P < 0.02). Patients being treated empirically had been in hospital for fewer days before the course commenced than patients receiving specific treatment (P < 0.001). The duration of empirical courses for which a flucloxacillin-resistant organism was subsequently identified was significantly greater than that of the unconfirmed courses (P < 0.05). Of the other six patients, three received a course of oral vancomycin for the treatment of confirmed (two cases) or suspected (one case) Clostridium difficile diarrhoea, and three received IV teicoplanin for treatment of wound infections (2 patients) or cellulitis (1 patient), commenced on the advice of infectious diseases clinicians. Other antibiotic use in adults: In the seven days before IV vancomycin treatment courses, the most frequently prescribed antibiotics were ceftriaxone and cefotaxime (28% of courses), metronidazole (16%), flucloxacillin (15%), and gentamicin (15%). The most frequently prescribed concurrent antibiotics were ceftriaxone and cefotaxime (11% of vancomycin courses), gentamicin (11%), ceftazidime (9%), imipenem (7%), ciprofloxacin (6%) and metronidazole (6%). For 14 treatment courses, vancomycin was continued beyond the close of the study. Immediately following the 162 completed courses (in 162 patients), other antibiotic therapy was commenced for 57 patients (35%), concurrent antibiotic therapy continued for 35 patients (22%), and there was no antibiotic therapy for 50 patients (31%). On-going therapy was not recorded for nine patients (6%), and the remaining 11 patients (7%) died. The antibiotics most frequently commenced immediately after vancomycin were oral flucloxacillin (12 courses), oral fusidic acid and oral rifampicin (12 courses), and oral ciprofloxacin (eight courses). For the 95 IV vancomycin prophylaxis courses, other antibiotics were given concurrently for 46 (48%) courses, most frequently gentamicin (14% of vancomycin courses), ceftriaxone (14%), cephazolin (6%) and ticarcillin/clavulanate (5%). Comparison of five main vancomycin users: The five hospitals that used most vancomycin were major metropolitan university teaching hospitals where use was restricted by protocols and consultations. Use by number of courses was greatest in Hospital 1 but the total quantity used was less than half that used at Hospital 2 (Box 4). Rate of use was significantly lower in Hospital 4 than in the other four hospitals. Surgical use of vancomycin predominated in Hospital 1, while medical use predominated in Hospital 4. Hospitals 2, 3 and 5 had a significantly smaller proportion of single doses for prophylaxis than Hospitals 1 and 4. Discussion We have examined the pattern of use of vancomycin in a large sample of Victorian hospitals. We found that use of teicoplanin and oral vancomycin was low, and that intravenous vancomycin was used predominantly for empirical treatment or prophylaxis. Our study is the first to capture a statewide picture of hospital drug use linked to indication, and we are not aware of any published comparable multihospital pharmacoepidemiological data. Based on the number of inpatient separations for Victorian public hospitals in 1996-97 (about 890 000),10 we reviewed an estimated 82% of public hospital inpatient separations in the two-week study period. We estimated the overall rate of glycopeptide antibiotic use to be 10.3 courses per 1000 inpatient separations, which suggests about 9160 courses are used annually in Victorian public hospitals. The main limitation of our study was that vancomycin courses were not individually compared against explicit criteria to determine the proportion of appropriate use on the basis of indication, dosage and duration. We chose not to compare against criteria because of the variety of prescribing restrictions in participating hospitals. The most frequent indications for empirical IV vancomycin were febrile neutropenia, pneumonia and wound infections. The indications for and duration of empirical therapy could be targets for intervention. For pneumonia, IV vancomycin use may be reasonable for hospital-acquired infections in institutions with a high prevalence of MRSA. For febrile neutropenia, IV vancomycin may be best restricted to patients with suspected associated IV line sepsis. For wound infections, unless there is a high prevalence of MRSA, IV vancomycin treatment should wait until after microbiological confirmation. Oral vancomycin should be restricted to the treatment of antibiotic-associated colitis due to toxigenic C. difficile unresponsive to or relapsing after an adequate course of metronidazole (or bacitracin), or for patients with severe colitis.11 Clinicians should be encouraged to regularly review the need for ongoing drug therapy; however, to improve the current situation, we need effective decision support tools to facilitate timely attention to important test findings.12 Almost half the treatment courses were sanctioned or recommended by infectious diseases/microbiology specialists, who should be familiar with relevant guidelines for vancomycin use. Surgical prophylaxis consumed 35% of IV vancomycin courses, with cardiac and vascular surgery accounting for 75% of prophylactic courses. The duration of vancomycin prophylaxis was generally according to recommendations, with 72% of courses given as single doses and 82% of courses given for less than 24 hours. However, there was considerable interhospital variation in the duration of surgical prophylaxis. The implementation of hospital policies on duration of surgical prophylaxis would be an important target for intervention. Glycopeptide antibiotic use was concentrated in five major metropolitan teaching hospitals. Although these five hospitals all had policies in place, vancomycin use varied substantially. It is of critical importance for patient care and resource management that there is a conscious effort to preserve the utility of vancomycin and teicoplanin. This should be founded on good infection control practice, but there is also a need for all hospitals to implement effective interventional strategies to improve the use of the glycopeptide antibiotics. Acknowledgements Financial support for the employment of the Project Coordinator was provided by the Victorian Drug Usage Advisory Committee and the Victorian Standing Committee on Infection Control. The project was also reliant on the voluntary work of pharmacists at the participating hospitals who undertook all the data collection. We acknowledge the assistance of the other members of the Victorian Drug Usage Evaluation Group in the planning and execution of the study and the preparation of this manuscript: Stephanie J Alvarez, Drug Utilisation Evaluation Pharmacist, Monash Medical Centre; Dr Jo-anne Brien, Senior Lecturer, Department of Pharmacy Practice, Monash University (Parkville Campus); Dr Lisa L Ioannides-Demos, Senior Research Fellow, Department of Epidemiology and Preventative Medicine, Monash University, and Senior Research Officer, Victorian Centre for Ambulatory Care Innovation, Alfred Hospital; Sam Koroneos, Senior Drug Utilisation Pharmacist, Pharmacy Department, Austin and Repatriation Medical Centre; Anne Leversha, Senior Lecturer, Monash University, Faculty of Medicine, and Victorian College of Pharmacy, and Deputy Manager Pharmacy Services, Latrobe Regional Hospital, Traralgon West; Julie A V Lord, Senior Drug Information and Clinical Research Pharmacist, St Vincent's Hospital, Melbourne; Heather J Lyall, Deputy Director of Pharmacy, Geelong Hospital; Roslyn I McKinnon, Executive Officer, Victorian Drug Usage Advisory Committee; Associate Professor R Moulds, Director, Department of Clinical Pharmacology and Therapeutics, Royal Melbourne Hospital; Susan G Poole, Deputy Director, Peter MacCallum Cancer Institute; Dr Gail J Ware, Drug Usage Evaluation Pharmacist, Alfred Hospital. References Ena J, Dick RW, Jones RN, Wenzel RP. The epidemiology of intravenous vancomycin usage in a university hospital: a 10 year study. JAMA 1993; 269: 598-602. Heath CH, Blackmore TK, Gordon DL. Emerging resistance in Enterococcus spp. Med J Aust 1996; 164: 116-120. Reduced susceptibility of Staphylococcus aureus to vancomycin -- Japan, 1996. MMWR Morb Mortal Wkly Rep 1997; 46: 624-626. Quale J, Landman D, Atwood E, et al. Experience with a hospital-wide outbreak of vancomycin-resistant enterococci. Am J Infect Control 1996; 24: 372-379. Witte W. Medical consequences of antibiotic use in agriculture. Science 1998; 279: 996-997. Misan GMH, Martin ED, Smith ER, et al. Drug utilisation review in a teaching hospital: experience with vancomycin. Eur J Clin Pharmacol 1990; 39: 457-461. Radford JM, Whitby RM, Looke DFM, Coombes JA. Vancomycin usage review in the era of vancomycin-resistant enterococci (VRE). Aust J Hosp Pharm 1997; 27: 1410-1413. Guidelines for preventing emergence of vancomycin-resistant enterococci. Melbourne: Victorian Drug Usage Advisory Committee and the Standing Committee on Infection Control in collaboration with the Writing Group for the Therapeutic Guidelines: Antibiotic, 1997. Vernon G, Thomson W, editors. Directory of hospital pharmacy and pharmaceutical organisations. Melbourne: Society of Hospital Pharmacists of Australia, 1996. Department of Human Services Annual Report 1996-97. Melbourne: Department of Human Services, Victoria, 1997. Therapeutic Guidelines: Antibiotic, 10th ed. Melbourne: Therapeutic Guidelines Limited, 1998. Schiff GD, Rucker D. Computerized prescribing. Building the electronic infrastructure for better medication usage. JAMA 1998; 279: 1024-1029. (Received 21 Dec 1998, accepted 17 May 1999) Authors' details Victorian Drug Usage Evaluation Group, Melbourne, VIC. Marion B Robertson, BPharm, MSc, Project Coordinator. Royal Melbourne Hospital, Melbourne, VIC. Jonathan G A Dartnell, BPharm, MPS, Senior Pharmacist, Department of Clinical Pharmacology and Therapeutics. Monash Medical Centre, Melbourne, VIC. Tony M Korman, FRACP, Infectious Diseases Physician. Reprints will not be available from the authors. Correspondence: Mr J G A Dartnell, Department of Clinical Pharmacology and Therapeutics, c/- Post Office, Royal Melbourne Hospital, VIC 3050. Email: Jonathan. DartnellATnwhcn.org.au 1: Definitions Course: The administration to a patient of at least one dose of vancomycin or teicoplanin. If a dose was administered more than 24 hours after a previous dose (and the drug was re-prescribed), this was considered a new course. Patients with renal impairment on regimens with dosing intervals longer than 24 hours were considered to have received a continuous course. Prophylaxis: Antibiotic administration commenced perioperatively to prevent postoperative infection. Empirical treatment: Antibiotic administration commenced before or without identification of flucloxacillin-resistant bacterial pathogens. Specific treatment: Antibiotic administration commenced after identification of flucloxacillin-resistant bacterial pathogens. Duration: Durations of courses were calculated by subtracting the date and time of the first dose from the date and time of the last dose. The duration of a single dose was considered to be 0 hours. Back to text 2: Glycopeptide antibiotic courses commenced in participating hospitals during study period*Hospital locationNumber of courses † (patients)Number of inpatient separationsCourses per 1000 separationsMelbourne52 (51)‡235622.0Melbourne49 (48)245520.0Melbourne38 (37)194319.6Melbourne37 (37)299712.3Melbourne33 (30)§141623.3Regional11 (11)14777.4Melbourne10 (9)53818.6Melbourne10 (10)14776.7Melbourne9 (9)10718.4Melbourne8 (8)10897.3Melbourne8 (7)13575.9Melbourne7 (7)42316.5Regional5 (5)8086.2Melbourne5 (5)10554.7Melbourne3 (3)15002.0Melbourne3 (2)27111.1Regional3 (3)3748.0Regional2 (2)§14613.7Melbourne2 (2)8772.3Melbourne2 (2)4694.3Melbourne1 (1)6681.5Regional1 (1)7251.4Regional1 (1)§2663.8Melbourne1 (1)6361.6Melbourne1 (1)5102.0Overall*302 (293)2944510.3*Another 9 regional and 1 Melbourne hospital accounted for 2785 inpatient separations but did not use glycopeptide antibiotics during the study period. †Intravenous vancomycin except where indicated. ‡Includes 3 courses of teicoplanin. §Includes 1 course of oral vancomycin. Private hospital. Back to text 3: Intravenous vancomycin courses commenced in adultsAll treatment courses 176 treatment courses median duration, 4.7 days (interquartile range, 2.0-8.2 days) indications: wound infections33 (18.8%)pneumonia29 (16.5%)febrile neutropenia21 (11.9%)septicaemia12 (6.8%)intravenous catheter-associated sepsis11 (6.3%)cellulitis9 (5.1%)infected prosthesis9 (5.1%)peritonitis/CAPD8 (4.5%)meningitis3 (1.7%)other16 (9.1%)not recorded25 (14.2%)Gram-positive bacteria, including Staphylococcus, Streptococcus, Enterococcus and Bacillus species isolated for 113 (64%) courses Isolated organism confirmed flucloxacillin-resistant in 78 courses; organism was MRSA in 67 coursesEmpirical treatment courses 120 empirical treatment courses (68% of all treatment courses) median duration, 4.4 days (interquartile range, 1.5-8.0 days) patients in hospital for median 4.0 days (interquartile range, 1-12 days) before course commenced most frequent indications: febrile neutropenia (18%), pneumonia (16%) and wound infections (12%) 32 (26%) of patients had history of beta-lactam antibiotic hypersensitivity or a previous infection with MRSA or MRSE. Two patients had a history of severe hypersensitivity that may have necessitated use of vancomycin rather than beta-lactam antibiotics. flucloxacillin-resistant organism subsequently identified in 24 (20%) empirical courses duration of courses with confirmed resistant organism was 6.9 days (interquartile range, 2.0-13.8 days) compared with 3.9 days (interquartile range, 1.3-6.7 days) for unconfirmed courses (P<0.05) Specific treatment courses 56 specific treatment courses (32% of all treatment courses) median duration, 6.1 days (interquartile range, 3.0-11.6 days) patients in hospital for median 12 days (interquartile range, 4-22 days) before course commenced Surgical prophylaxis courses95 surgical prophylaxis courses 68 (72%) single-dose courses, 78 (82%) less than one day, 12 (12%) one to three days, 5 (5%) more than three days 12 (13%) were for patients with history of beta-lactam hypersensitivity, including four severe cases, and 5 (5%) were for patients with history of MRSA or MRSE infection 51 (54%) used in cardiac surgery; 31 single doses, 12 (24%) lasted more than 36 hours 20 (21%) used in vascular surgery; all were single dosesCAPD=chronic ambulatory peritoneal dialysis. MRSA=methicillin-resistant Staphylococcus aureus. MRSE=methicillin-resistant S. epidermidis. Back to text 4: Comparison of intravenous vancomycin in adults in the major teaching hospitalsHospital 1Hospital 2Hospital 3Number of courses494938Number of patients484837Courses per 1000 separations*20.820.019.6Vancomycin used (g)177371280Median length of stay (days)121816Courses given in intensive care9 (18%)9 (18%) 17 (45%)Courses prescribed by medical unit12 (24%)28 (57%)20 (53%)Indication: prophylaxisNumber of courses (%)28 (57%)15 (31%)15 (39%)Number (%) as single doses †28 (100%)7 (47%)9 (60%)Surgery type (number of courses) cardiac2476 vascular241 other248Indication: treatmentNumber (%) empirical13 (62%)30 (88%) 19 (83%)Median duration of courses (days) empirical3.73.64.8 specific3.04.511.0Indications (number of courses) pneumonia724 wound infection436 febrile neutropenia181 other92112 Hospital 4Hospital 5Number of courses3332Number of patients3229Courses per 1000 separations*12.322.6Vancomycin used (g)299118Median length of stay (days)209Courses given in intensive care6 (18%)9 (28%)Courses prescribed bymedical unit30 (91%)17 (53%)Indication: prophylaxisNumber of courses (%)8 (24%) 16 (50%)Number (%) as single doses †8 (100%)11 (69%)Surgery type (number of courses) cardiac18 vascular63 other15Indication: treatmentNumber (%) empirical18 (72%)10 (62%)Median duration of courses (days) empirical5.51.5 specific3.02.0Indications (number of courses) pneumonia60 wound infection33 febrile neutropenia24 other149* Hospital 4 significantly less than Hospitals 1, 2, 3 and 5 (P<0.02). †Hospitals 2, 3, and 5 significantly less than Hospital 1 (P<0.01) and Hospital 4 (P<0.1). Back to text

Marion B Robertson

The vilest deeds, like poison weeds, Bloom well in prison air; Oscar Wilde, "The Ballad of Reading Gaol", 1896 More than two years ago, an editorial in this Journal stated: "Prison authorities and governments must realise that the responsibility for the infection of a prisoner with a bloodborne virus, because means for prevention were not available within the prison, rests with them."1 Sadly, there is little improvement to report. Bleach, for cleaning injecting equipment, has been made available since 1995 in most custodial systems. Condoms and dental dams were first introduced into New South Wales prisons in 1997, but are currently provided to prison inmates in only three jurisdictions. The methadone maintenance program began in New South Wales in 1986 and will soon expand through trials in Queensland and South Australian prisons. Methadone withdrawal regimens are provided in Victorian prisons. Three articles in this issue of the Journal highlight some of the continuing health risks faced by inmates in Australian prisons.2-4 These reports raise concerns that inmates are still placed at unnecessary risk by not being offered opportunities to minimise infection with bloodborne viruses, and complement reports of transmission of a wide range of contagious diseases from custodial systems in other countries.5,6 McDonald et al report that control of HIV transmission in the community has protected prisoners, with sustained low levels of identified HIV-antibody-positive individuals entering Australian prisons.2 The evidence for transmission in prison of HIV presented by Dolan and Wodak3 and of hepatitis C by Haber et al4 indicate that custodial authorities' commitment to zero tolerance would be better applied to the transmission of these viruses rather than to illicit drugs and injecting equipment within prison. Despite universal support for zero tolerance among Australian custodial authorities, drug use continues after reception into prison. In New South Wales, in 1996, 21% of men and 32% of women reported that they had injected drugs in prison; 18% of men and 11% of women did so in the week before interview. Of those who had injected in prison, 69% of men and 64% of women reported that they had shared needles.7 Zero tolerance is not protecting the lives of prison inmates. Between 1980 and 1998, there were 86 deaths in custody in Australian prisons that were classified as accidents -- overwhelmingly drug related.8 The fear of having illicit drugs confiscated leads to "binge" use. Irregular use and inexperience in assessing dosage and drug purity readily lead to overdosing. Needles and syringes have a higher probability of being infectious in the prison environment, as the prevalence of bloodborne viruses is so high. An environment that inadvertently encourages sharing of equipment actually promotes transmission of bloodborne viruses. Consider the ability of zero tolerance in providing prison workers with a safe work environment. It might be argued that the restrictions on needles and syringes make prisons a safer workplace, but the evidence for this is not compelling. The malicious stabbing of a prison officer with a syringe filled with HIV-contaminated blood in 1990 occurred when needles and syringes were prohibited items. The principle of harm minimisation guides public health efforts to control bloodborne viruses in the community. Why should this not also be applied in the prison environment? No measures should be spared to provide a safer environment for prison inmates, and health and custodial staff. A full range of options need to be available for custodial and health authorities to offer inmates, including drug-free prisons, methadone maintenance and consideration of therapeutic prescription of injectable drugs. With controlled heroin prescribing and provision of syringes and needles, the trafficking of contaminated equipment should decrease. In Switzerland and Germany, programs for therapeutic heroin prescription in a few prisons are currently being evaluated.9 These initiatives will require strong advocates for the health of prison inmates and the general community. For this to occur, prison health services must be brought into the mainstream of clinical medicine and public health.10 This can be accomplished by granting autonomy to prison health authorities, by fostering ties between correctional health programs and academic and public health departments, and by funding research that addresses public policy questions peculiar to the prison environment.11 To accelerate the uniform introduction of health protective measures throughout Australian prison systems, correctional health programs need standards against which their performance can be monitored. Australian prison authorities have devised uniform guidelines of operation, but they are not health standards, and they are not enforceable.12 There are currently over 19 000 inmates in Australian prisons, and the number is increasing by more than 7% each year.13 The importance of the health of prisoners and its impact on the general community can only grow. Since March 1999, the Australian Red Cross has identified imprisonment in the previous 12 months as an unacceptable risk factor for blood donation.14 Two years have been squandered. The evidence mounts that prisons pose a health risk to inmates, to workers within prisons, and to the general community. The statement by Crofts bears repeating: "Prison authorities and governments must realise that the responsibility . . . rests with them."1 Michael H Levy Director, Population Health, Corrections Health Service Matraville, NSW, and Department of Public Health and Community Medicine University of Sydney Crofts N. A cruel and unusual punishment. Med J Aust 1997; 166: 116. McDonald AM, Ryan J, Brown PR, et al. HIV prevalence at reception into Australian prisons, 1991-1997. Med J Aust 1999; 171: 18-21. Dolan K, Wodak A. HIV transmission in a prison system in an Australian State. Med J Aust 1999; 171: 14-17. Haber PS, Parsons SJ, Harper SE, et al. Transmission of hepatitis C within Australian prisons. Med J Aust 1999; 171: 31-33. Taylor A, Goldberg D, Emslie J, et al. Outbreak of HIV infection in a Scottish prison. BMJ 1995; 310: 289-292. Valway SE, Richards SB, Kovacovich J, et al. Outbreak of multi-drug-resistant tuberculosis in a New York State prison, 1991. Am J Epidemiol 1994; 140: 113-122. Preliminary findings of the Inmate Health Survey. Sydney: Corrections Health Service, 1997. Dalton V. Prison homicide in Australia: 1980 to 1998. Trends and issues in crime and criminal justice. No. 103. Canberra: Australian Institute of Criminology, 1999. Vumbuca G. Finding a better way. Canberra: The Winston Churchill Memorial Trust of Australia, 1999. Prisoners: an end to second class health care? BMJ 1999; 318: 954-955. Correction of attitudes to prison medicine [editorial]. Lancet 1998; 351: 1371. Standard Guidelines for Corrections in Australia 1996. The Corrective Services Ministers' Conference. 1995. Australian Bureau of Statistics. Corrective Services, Australia. Canberra: ABS, 1998. (Catalogue no. 4512.0.) Australian Red Cross Blood Service. Donor Questionnaire. March 1999.

Michael H Levy

Abstract Objective: To investigate possible HIV transmission among prison inmates. Setting: A prison system in an Australian State. Participants: 13 ex-prisoners and their prison contacts. Methods: Ex-prisoners who claimed to have been infected with HIV in prison and their prison contacts were interviewed about HIV risk behaviour. Entries in prison and community medical records were used by a three-member expert panel to establish the likelihood of primary HIV infection and its possible timing and location. Main outcome measures: Determination of whether HIV infection probably occurred in prison. Results: There was a very high probability that at least four of 13 ex-prisoners investigated acquired HIV in prison from shared injection equipment. Another two ex-prisoners most probably acquired HIV infection outside prison. The location of infection for the remaining seven could not be determined. Conclusions: HIV transmission in prison has substantial public health implications as most drug-using prisoners soon return to the community. HIV prevention strategies known to be effective in community settings, such as methadone maintenance treatment and syringe exchange schemes, should be considered for prisoners. Introduction HIV transmission in prison has been reported in the United States,1 Scotland2 and Australia.3 The infrequency of these reports has led to a belief that HIV transmission occurs rarely among inmates. A more likely explanation is that confirmation of HIV transmission is more difficult in prisons than community settings.4 Multiple and powerful factors conducive to high HIV incidence are found in prisons. These include that: HIV prevalence is generally several times higher in prisons than in surrounding communities because of the considerable over-representation of injecting drug users (IDUs) among prisoners;5 reports of syringe sharing with multiple injectors are still common in prisons but now rare in community settings;6 HIV infection has been associated with imprisonment in France7 and Spain;8 and incidence of hepatitis C among IDUs incarcerated twice within a 12-month period was double that among IDUs who remained at liberty.9 Furthermore, HIV prevention measures, such as provision of sterile injecting equipment, condoms and methadone maintenance, are uncommon in prisons.10 Although several estimates of HIV prevalence have been conducted in correctional institutions,1,11,12 assessing the incidence of HIV transmission within a prison system poses considerably greater challenges.4 Most drug users serve short, repeated sentences. This hampers the investigation of infection outbreaks and identification of transmission location. In an earlier Australian study,13 several IDUs claimed to have become infected with HIV in prison. Some reported symptoms indicative of primary HIV infection while incarcerated. The aim of this study was to assess, using epidemiological data, whether these IDUs or their contacts had become infected in prison. A similar approach has been used to investigate an HIV outbreak in a Scottish prison.2 Methods Index cases The investigation took place between 1993 and 1994. Seven IDUs from an earlier study13 who claimed to have acquired HIV infection in prison were recontacted. In the earlier study, respondents who had injected drugs and had recently been released from prison were recruited from methadone units, hostels for ex-prisoners or drug injectors, probation offices, syringe exchange schemes, local media advertisements, AIDS organisations and via street networking.13 Prison contacts We traced prison contacts nominated by these seven people through the state methadone registry, AIDS services, drug users' organisations, HIV physicians and the State Registry of Deaths. The contacts were inmates with whom the seven index inmates had engaged in syringe sharing, anal sex or tattooing while in prison. Assessment of HIV infection HIV infection was assessed by an expert panel of three HIV physicians. The experts were provided with dates of entry to and exit from prison, HIV test results, symptoms recorded at the time the prisoner believed infection occurred, self-reported symptoms and self-reported risk behaviour. All dates were referenced in months from the year before the first detected case had last tested HIV negative. Each expert independently assessed whether the recorded symptoms indicated an HIV seroconversion illness and whether the infection occurred in prison, in the community, or if the location was indeterminate. We then accepted the majority decision in each assessment. Ethical approval Relevant ethics committees approved the study on condition that study participants' contacts in the community following their release from prison were not traced. We were also required to alert potential study participants to the possibility of legal or other consequences of admitting drug use in prison or transmitting HIV to another person. Participation in the study required signed, informed consent. Information which would identify the exact time and location of these possible infections has not been included, in accordance with requirements of one ethics committee. Results Contact tracing Between 1993 and 1994, seven male IDUs described in a previous study13 were recontacted (subjects A, B, C, D, E, F, G). They identified 20 prison contacts: six of these contacts could not be located, six had died of AIDS (according to death certificates), and two declined to participate for fear of repercussions for transmitting HIV. The six remaining contacts (H, I, J, K, L, M) plus the seven index cases made a total of 13 ex-prisoners available for investigation (Figure). Prison clusters Prison records revealed two clusters (C1, C2) of six subjects in one or two prison wings. Subjects B, E, I, K and M were held in Prison 1 (population about 250 inmates) in months 22 and 23, during which time index subject B seroconverted. Subjects B, D, I, K and M were held in Prison 2 (population about 300 inmates) in months 29 and 30, during which time contact subject K seroconverted. Index participant A was not part of either cluster, but another participant reported sharing syringes with him. Of the six deceased potential respondents, two had been part of C1 and another two had been part of C2. According to death certificates, two deceased potential respondents became infected with HIV in the year when they were held with the clusters. Cluster analysis was not possible because of the lack of records being kept on the total number of inmates held in the prison wings during the crucial times. Self-reported risk behaviour Eleven participants (A, B, C, E, I, K, M, D, F, G, L) reported syringe sharing in prison, with the first seven nominating another person in this series as a sharing partner. Contact participants I and M also reported receiving a tattoo in prison, and index subject C reported unprotected anal sex. All six deceased prison contacts wereidentified by one or more participants as having shared syringes with them around the crucial periods of months 22 and 23 and months 29 and 30. Assessment of HIV infection Medical file entries for 10 subjects (A, B, C, E, F, G, I, K, L, M) were reviewed by the expert panel. The experts concluded that five participants (A, B, C, G, K) had experienced primary HIV infection and that the most likely location of transmission for individuals A, B and C was in prison (Box 1). Overall, it was concluded that infection occurred in prison for four subjects and in the community for two (Box 2). Discussion The epidemiological evidence that individual A was infected in prison is beyond doubt: he tested negative and then positive for HIV infection after years of confinement in prison. There was strong epidemiological evidence that individuals B, C and J were also infected in prison. Individuals D and G were infected with HIV in the community. The location of infection for the remaining seven subjects (and the six deceased potential respondents) could not be determined. Thus, on epidemiological grounds, at least four of the 13 people investigated were infected with HIV while in an Australian prison system. The most likely route of HIV transmission was shared injection equipment. These are both conservative and probabilistic assessments. It is likely that a prospective investigation of these 13 people, or even a retrospective investigation closer to the events, would have yielded a larger number of confirmed HIV transmissions in prison. However, the strength of evidence for this network and the multitude of factors conducive to HIV infection in prisons suggest that the extent of HIV transmission occurring in prisons through shared injection equipment is underestimated. A mathematical model of HIV transmission in an Australian prison system14 using values derived from empirical studies also suggests that transmission is occurring within correctional centres. This study illustrates some of the difficulties of confirming HIV transmission in prison. We became aware of a possible outbreak by chance. Obtaining ethical approval for the study was an extremely protracted process requiring the assistance of a legal expert. Inmates were understandably wary of admitting risk behaviour because of the potentially serious consequences (as outlined in the consent form). Apart from the logistical and ethical problems of this type of research, the incubation period for HIV infection is almost as long as the average duration of a prison sentence served for drug-related offences in Australia. Consequently, many HIV infections occurring in prisons will not be detected by conventional surveillance. These factors may help to explain why so few cases of HIV transmission among inmates have been reported. Our study differed from previous reports10 in the extent of transmission detected and the type of prisoners studied. Previous studies have investigated long term, high security prisoners, who have less opportunity to associate with other inmates and visitors to obtain drugs and consequently become infected with HIV.15 Our study found a relatively large number of incident cases considering the small sample size, the extremely low prevalence of HIV infection in the Australian prison population16 and the rapid turnover of inmates. All these factors militate against detection of HIV transmission in prison. A limitation of the study was reliance on self-reported risk behaviour. However, we accepted self-reported data only if corroborated by another external source. Moreover, symptoms reported by informants coincided closely with medical records, supporting the validity of self-reported data. We were precluded by ethics committee requirements from determining whether any sexual partners (and their children) were infected with HIV by participants following release from prison. This restriction prevented investigation of possible HIV transmission beyond prison to the community. However, medical files indicated that four subjects had each had an HIV-positive female sexual partner following release from prison. Two of these women, and an additional HIV-negative partner, became pregnant, with at least two pregnancies reaching full term. Medical files also indicated that at the time of the investigation two former inmates had been engaging in unprotected sex with two HIV-negative women, against the advice of their counsellors. Existing evidence of HIV transmission among prisoners has persuaded prison authorities in few countries to implement effective prevention strategies for inmates. Confirmation of HIV infection from prison to the community may be more persuasive for authorities. Syringe exchange, methadone and bleach programs reduce the spread of HIV in community settings,16-18 and preliminary results from these programs in prison appear promising.19-21 The paucity of data confirming HIV transmission in prison should not be regarded as adequate justification for the lack of effective HIV prevention measures within prisons. There is already sufficient information on HIV transmission between prisoners to justify rapid implementation in correctional institutions of prevention measures shown to be effective in community settings. Improved methods of monitoring the spread of HIV within prisons and from inmates to community members following release are required urgently. Acknowledgements We are grateful to the NSW Department of Health for funding this study. We also wish to thank David Buchanan, Andrew Carr, Ying Chun Ge, David Cooper, Anthony Cunningham, Basil Donovan, John Dwyer, Tania Sorrell and Dominic Dwyer. Results of tracing 20 prison contacts of seven index cases for recruitment into the study. References Brewer TF, Vlahov D, Taylor E, et al. Transmission of HIV-1 within a statewide prison system. AIDS 1988; 2: 363-367. Taylor A, Goldberg D, Emslie J, et al. Outbreak of HIV infection in a Scottish prison. BMJ 1995; 310: 289-292. Dolan K. AIDS, drugs and risk behaviour in prison: state of the art. Int J Drug Policy 1997; 8: 5-17. Dolan K. Why is there conflicting evidence of HIV transmission in prison? In: O'Brien O, editor. Report of the 3rd European Conference on Drug and HIV/AIDS Services in Prison. London: Cranstoun Drug Services, 1997; 19-21. Gaughwin MD, Douglas RM, Wodak AD. Behind bars -- risk behaviours for HIV transmission in prisons, a review. In: Norberry J, Gerull SA, Gaughwin MD, editors. HIV/AIDS and prisons conference proceedings. Canberra: Australian Institute of Criminology, 1991; 89-107. Crofts N, Webb-Pullman J, Dolan K. An analysis of trends over time in social and behavioural factors related to the transmission of HIV among IDUs and prison inmates. Evaluation of the National HIV/AIDS Strategy. Technical Appendix 4. Canberra: AGPS, 1996. Richardson C, Ancelle-Park R, Papaevangelou G. Factors associated with HIV seropositivity in European injecting drug users. AIDS 1993; 7: 1485-1491. Granados A, Miranda MJ, Martin L. HIV seropositivity in Spanish prisons. Presented at the VIth International AIDS Conference, San Francisco. Abstract no Th. D.116, 1990. Crofts N, Stewart T, Hearne P, et al. Spread of blood-borne viruses among Australian prison entrants. BMJ 1995; 310: 285-288. Dolan K, Wodak A, Penny R. AIDS behind bars: preventing HIV spread among incarcerated drug injectors. AIDS 1995; 9: 825-832. Vlahov D, Brewer TF, Castro KG, et al. Prevalence of antibody to HIV-1 among entrants to US correctional facilities. JAMA 1991; 265: 1129-1132. Bird AG, Gore SM, Jolliffe DW, Burns SM. Anonymous HIV surveillance in Saughton Prison, Edinburgh. AIDS 1992; 6: 725-733. Dolan K, Wodak A, Hall W, et al. Risk behaviour of IDUs before, during and after imprisonment. Addict Res 1996; 4: 151-160. Dolan K, Wodak A, Hall W, Kaplan E. A mathematical model of HIV transmission in NSW prisons. Drug Alcohol Depend 1998; 50: 197-202. Dye S, Isaacs C. Intravenous drug misuse among prison inmates: implications for spread of HIV. BMJ 1991; 302: 1506. Feachem R. Valuing the past . . . investing in the future. Evaluation of the National HIV/AIDS Strategy. 1993-94 to 1995-96. Canberra: AGPS, 1996. Ward J, Mattick R, Hall W. Methadone maintenance treatment and other opioid replacement therapies. Amsterdam: Harwood Academic Publishers, 1998. Normand J, Vlahov D, Moses LE. Preventing HIV transmission: the role of sterile needles and bleach. Washington: National Academy Press, 1995. Nelles J, Harding T. Preventing HIV transmission in prison: a tale of medical disobedience and Swiss pragmatism. Lancet 1995; 346: 1507-1508. Dolan K, Wodak A, Hall W. Methadone maintenance treatment reduces heroin injection in NSW prisons. Drug Alcohol Rev 1998; 17: 153-158. Dolan K, Wodak A, Hall W. A bleach program for inmates in NSW: an HIV prevention strategy. Aust N Z J Public Health 1998; 22: 838-840. Authors' details National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW. Kate A Dolan, BSc, PhD, Research Fellow. Alcohol and Drug Services, St Vincent's Hospital, Sydney, NSW. Alex Wodak, FRACP, FAFPHM, Director. Reprints: Dr K A Dolan, Research Fellow, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW 2052. Email: ndarc8@unsw.edu.au

Kate A Dolan · Alex Wodak

Transmission of hepatitis C within Australian prisons Transmission of hepatitis C virus (HCV) within prisons has long been suspected but has not been satisfactorily documented. We present four cases of HCV infection occurring during periods of continuous imprisonment. Each subject was HCV seronegative on entering prison and on repeat testing after 4-52 months in prison, but subsequently became seropositive. Two subjects gave a history of injecting drug use, and the most likely means of infection in the other two subjects were lacerations from barbers shears and lacerations arising from physical assault. There is an urgent need for detailed study of the incidence of HCV infection and the modes of transmission in prisons. Introduction The prevalence of hepatitis C (HCV) infection in voluntary screening among entrants to Australian and North American prisons is as high as 40%.1-3 It is therefore surprising that HCV transmission within prisons has not been well documented, although it is known that a history of incarceration is an independent risk factor for HCV seroconversion4 and uninfected prisoners are at high risk of seroconversion by the time of a second prison entry.1,3 These observations provide only indirect evidence of transmission within prisons, as infection could have occurred either during the first period of imprisonment or outside prison between release and re-incarceration. This report describes the first published series of well-documented cases of transmission of HCV within a prison. The Research Ethics Committee of the Corrections Health Service of New South Wales approved reporting of these cases. Clinical records Between April 1994 and October 1997, four male prisoners presented with HCV infection appearing a minimum of 11 months after entry to prison (Table). All had had negative HCV antibody tests on entry to prison and again after 4-52 months of continuous incarceration (anti-HCV ELISA version III, Murex Diagnostics, Kyalamani, South Africa; confirmation by Innotest HCV Ab III assay, Innogenetics, Zwijnaarde, Belgium). All bore tattoos, but all four stated that no tattoos had been applied within two years of the last negative HCV antibody test. None had received blood products, or undergone medical or dental procedures, including vaccination, in the year before acquisition of HCV. All four denied any body piercings within two years of the last negative HCV antibody test, or sexual intercourse with another person since entering prison. Case 1 A 23-year-old inmate requested an HCV antibody test after receiving a scalp laceration during a close-shave haircut (performed with electric shears without a plastic guard) in June 1997. There was minimal bleeding and the wound did not require suturing. The patient denied having injected drugs at any time, but admitted to smoking marijuana and snorting cocaine in the past. Indeed, he regarded any injection with abhorrence and feared bloodborne infection. As a result, he had requested HCV antibody tests after numerous low risk events in prison and was repeatedly seronegative. After this latest incident, the patient again requested serological tests for HCV, and seroconversion was documented six weeks later. The patient stated that several of the four preceding inmates on whom the barbers shears were used on the same day were HCV antibody positive and had also received minor lacerations during their haircuts. He also claimed that the electric shears were not disinfected in any way between uses. No further details are available of the barber's list for that day, as no permanent records of these lists are kept. Sterilisation of shears before reuse was not normal practice at the time. One of the other inmates on whom the shears were used was confirmed to be positive for HCV antibody and HCV-RNA by polymerase chain reaction (PCR) analysis (Amplicor HCV detection kit, Roche Diagnostic Systems, Branchburg, NJ, USA). Case 2 A 35-year-old inmate suffering from lassitude and anorexia presented for examination. He had started using intravenous drugs for the first time after being in prison for several years. For a period of six months, he had injected two to three times per week, frequently sharing needles with known HCV-seropositive inmates, but routinely sterilising the injecting apparatus using a recommended bleaching protocol with 5.25% hypochlorite solution.4 Six weeks after ending drug use, he developed the symptoms described, which, in association with raised alanine aminotransferase (ALT) levels, were consistent with viral hepatitis. HCV seroconversion was found to have taken place since his last negative test one year previously. Case 3 A 27-year-old inmate presenting with lassitude was found to have abnormal liver function tests typical of acute viral hepatitis. The patient was an infrequent injecting drug user who had continued his habit intermittently during imprisonment. As he was aware of the risk of transmission of bloodborne pathogens, he used a bleached injecting apparatus for each episode, but shared the mixing spoon in which the drug suspension was prepared. HCV seroconversion was confirmed. Case 4 A 25-year-old inmate presented for examination after being involved in a physical assault with another inmate, during which blood-to-blood contact occurred from abrasions and lacerations. He had sustained no serious injury. The other inmate was a known HCV-positive injecting drug user who later left prison and was lost to follow-up. Blood taken soon after the assault was negative for HCV antibodies, but seroconversion, associated with mild symptoms of hepatitis, was documented three months later. The patient denied injecting drug use. Discussion These cases provide strong evidence that transmission of HCV occurs in prison. Infection during injecting drug use is likely to be a leading mode of HCV transmission in prisoners. Inmates report that injecting apparatus is scarce in the prison system, whereas heroin is readily obtained. These circumstances favour repeated use of a limited number of needles and syringes by many prisoners. The recommended bleach cleansing of the injecting equipment appears ineffective, as our report corroborates previously documented transmission of HCV, but not HIV, after sharing of cleaned injecting apparatus.5 In two of the cases, HCV may have been transmitted by means unrelated to injecting drug use. The high prevalence of HCV among those entering prison, together with the strong likelihood of blood-to-blood contact in the prison environment, may increase the chance of HCV transmission by barbers shears, during physical assault or by other mechanisms.6 However, a limitation of our study is the reliance on self-reporting of risk factors by prison inmates. Inmates' self-reporting is relatively accurate if their status is unlikely to be affected by the content of the report, but may be biased if they perceive that harm or benefit may result.7 Our study provides the strongest evidence to date that transmission of HCV infection occurs within prisons. Two cases of HCV seroconversion among prisoners in Maryland (USA) have been reported:2 of 164 prisoners who tested negative for HCV on entry to prison, two tested positive 18 months later. However, there was not unequivocal evidence that HCV transmission occurred within prison, as the initial negative HCV test may have been carried out during the window phase between infection and seroconversion if viral transmission occurred outside prison shortly before incarceration. In our study, all four subjects were seronegative for HCV after 4-52 months' continuous imprisonment, and remained in continuous full-time custody until seroconversion was documented (Table). Approximately 10 500 imprisonments occur annually in New South Wales, which has a population of 6 300 000. At any one time, the NSW prison population is about 6000. The average sentence is seven months, and there are more than 25 000 transfers between prisons each year. Thus, the prison population has a high turnover and is not isolated from the general community. The extent of HCV transmission may be significant because of the prevalence of high-risk behaviours in prison, and the fact that some harm-reduction measures, such as needle exchange programs, are not available in Australian prisons. Thus, the prison community is a population at significant risk of HCV infection and a potentially important source of subsequent transmission of HCV into the general community. The cases presented here probably represent only a small fraction of inmates acquiring new HCV infection in prison. Firstly, our cases were detected clinically (whereas most primary HCV infections are subclinical) and, secondly, our study did not attempt a systematic search for HCV transmission among inmates. Moreover, there are rare occurrences of HCV infection without detectable HCV antibodies, and such cases depend on HCV-PCR testing for diagnosis.8 This report confirms that HCV is currently being transmitted within NSW prisons. The circumstances for acquisition of serious bloodborne infections during imprisonment should be identified and opportunities for transmission minimised where possible. Accordingly, detailed studies of the incidence of and risk factors for HCV transmission within prisons are urgently needed, followed by development and implementation of control measures. References Crofts N, Stewart T, Hearne P, et al. Spread of bloodborne viruses among Australian prison entrants. BMJ 1995; 310: 285-288. Vlahov D, Nelson KE, Quinn TC, Kendig N. Prevalence and incidence of hepatitis C infection among male prison inmates in Maryland. Eur J Epidemiol 1993; 9: 566-569. Butler TG, Dolan KA, Ferson MJ, et al. Hepatitis B and C in New South Wales prisons: prevalence and risk factors. Med J Aust 1997; 166: 127-130. van Beek I, Dwyer R, Dore GJ, et al. Infection with HIV and hepatitis C virus among injecting drug users in a prevention setting: retrospective cohort study. BMJ 1998, 317: 433-437. Bodsworth NJ, Robertson M, Kaldor J. Transmission of hepatitis C but not human immunodeficiency virus type 1 following sharing of injecting equipment. Genitourin Med 1994; 70: 206-207. Gill ON, Noone A, Heptonstall J. Imprisonment, injecting drug use, and bloodborne viruses: a threat of transmission but an opportunity for prevention. BMJ 1995; 310: 275-276. Darke S. Self-report among injecting drug users: a review. Drug Alcohol Depend 1998; 51: 253-263. Gretch DR. Diagnostic tests for hepatitis C. Hepatology 1997; 26 Suppl 1: 43S-47S. Authors' details Drug and Alcohol Services, Royal Prince Alfred Hospital, Sydney, NSW. Paul S Haber, MD, FRACP, Staff Specialist. Public Health Nursing Unit, Corrections Health Service, Sydney, NSW. Sandra J Parsons, RN, Clinical Nurse Consultant; Susan E Harper, RN, Public Health Nurse. Virology Division, Department of Microbiology, South Eastern Sydney Area Laboratory Services, Sydney, NSW. William D Rawlinson, PhD, FRACP, FRCPA, Division Head. Peter A White, PhD, Research Fellow. School of Pathology, University of New South Wales, Sydney, NSW. Andrew R Lloyd, MD, FRACP, Associate Professor, Inflammation Research Unit.

Paul S Haber · Sandra J Parsons · Susan E Harper · Peter A White · William D Rawlinson · Andrew R Lloyd

"You've gotta have HAART"* Highly active antiretroviral therapies have changed the prospects for people living with HIV MJA 1998; 169: 456-457 The past two years have seen extraordinary advances in the practice of HIV medicine. In Australia, this is reflected in a dramatic drop in morbidity and mortality associated with the introduction of highly active antiretroviral therapy (HAART), as reported by Correll and colleagues in this issue of the MJA .1 The advent in 1996 of the very potent protease inhibitors and the growing list of reverse transcriptase inhibitors enabled the development of combination therapy with three or four drugs aimed at durable suppression of viral replication. Durability is a critical aspect of treatment, as HIV is capable of rapidly developing resistance to single agents. Fortunately, in 1997 the measurement of HIV plasma RNA concentration (viral load) became routine practice, allowing physicians and patients to monitor the effectiveness and durability of combination therapy. Publications on the efficacy of HAART have mostly reported its effects on the important surrogate markers (viral load and CD4+ T-cell count), although there are already clinical endpoint data showing a reduction in progression to AIDS and death.2,3 Clinical trials, however, do not always reflect clinical practice. How effective have these drugs been in the real world? In this regard, the report in this issue from the National Centre for HIV Epidemiology and Clinical Research (NCHECR)1 is of particular importance. In the years 1994-1997 there were 80% fewer deaths and 43% fewer AIDS cases among a cohort of people with advanced HIV infection (CD4+ T-cell count below 200/µL) than in a matched patient cohort from 1990-1993.1 These findings are similar to those reported from Switzerland4 and the United States.5 Although such studies have methodological difficulties, the emerging pattern is very clear. Moreover, the benefits escalate each year.5 This is not surprising as the change in prescribing has been stepwise: the first phase, sequential monotherapy, ended with the publication in 1996 of the definite but modest advantage of combining two reverse transcriptase inhibitors (eg, zidovudine-didanosine).6 In the same year, protease inhibitors became accessible, and the practice of multiple drug regimens including a protease inhibitor became widespread during 1997. It is likely that the analyses for 1998 will show even greater benefits. "What you really need is HEART"* The highly active regimens become highly effective antiretroviral therapy (HEART) by slowing the damage to the immune system and, in part, by restoring lost function. HAART leads to an immediate rise in the CD4+ T-cell count, due initially to a redistribution and expansion of memory T-cells followed by a very gradual replenishment of naive T-cells, the latter filling in gaps in the T-cell repertoire and providing the host with the ability to respond to a broader range of invaders.7,8 While the goal for HAART is to reduce the viral load to an undetectable level, a rise in CD4+ T-cell count occurs in patients in which this is not achieved.9 Moreover, the elevated CD4 cell count and clinical benefit from HAART may persist long after virological failure (rising viral load) in some patients. Yet much remains to be learned. For HAART to remain HEART in 1999 and beyond, three major problems must be overcome: drug resistance, long term side effects, and compliance with difficult regimens that may be taken for many years. A sizeable proportion of patients have developed some resistance to each of the current drug combinations. Many agents are available (see Table, below), but a high rate of cross-resistance exists within members of each class of antiretroviral drugs. Second generation protease inhibitors are in development, as are nucleotide analogues and inhibitors of viral integrase. However, the use of the powerful protease inhibitors is limited in some patients by metabolic toxicity, involving lipodystrophy, hyperlipidaemia and insulin resistance, the mechanisms for which are still a matter of hypothesis.10 Poor compliance encourages drug resistance; a strong commitment to HAART is necessary before starting treatment. Simple, easily tolerated regimens are still years away. These issues are driving the need for new approaches. In this regard, the past two years have brought remarkable advances in HIV science with the discovery of the major co-receptors used by HIV (with CD4) to infect and damage the cells of the immune system. Mutations in the genes encoding these receptors are associated with protection against HIV infection in homozygotes (about 1% of Caucasians are all but uninfectable with HIV-1) and a slower rate of progression to AIDS and death in heterozygotes.11 These discoveries are underpinning a frenzy of commercial activity12 aimed at developing a range of antireceptor agents, several of which have reached phase I/II clinical trials.13 The future looks promising for those early in the course of their HIV infection; for those whose infections are already overcoming HAART, it is a major challenge to find the best approach to "salvage therapy" while awaiting new drugs. A HAART-less world In Australia, HIV physicians have the option of prescribing HAART, despite its expense, for all appropriate patients. But there is no access to HAART for the vast majority of the world's 30-40 million people living with HIV, mostly in Africa and Asia. In a US study, Medicaid patients were less likely to receive a protease inhibitor and had a higher mortality rate than privately insured patients.5 The remarkable success of HAART has brought into focus the disparity in healthcare between rich and poor and between the developed and developing countries -- gaps to be bridged in the new millennium. Critical research question In addition to the benefits for patients, the positive effect on HIV doctors has been considerable, both through relief from sadness and through the affirmation of the scientific paradigm under which we practice. The viagra-like change in therapeutic potency carries, however, the danger of assuming that because we have a proud new tool we know exactly how to use it. In reality, it is still not known when to start HAART, which agents to start with, when to change and to what. National treatment guidelines depend, by necessity, on the lowest level of evidence: consensus opinion of experts.14 There is high biological plausibility to justify striving for an undetectable viral load from early in infection, but there are no data to support the long term benefits of "going early and going hard", nor long term data on side effects. There are few data on whether virological failure (rising viral load) equals clinical failure, or on what best to do for patients who have "failed" all available drugs. It is essential that clinical trials continue to address these questions, but the benefits of HAART and the licensing of many drugs makes this more difficult. Future prospects While there are strong grounds for expecting that simple, well-tolerated, effective and durable conbination regimens will emerge from current science, the real therapeutic hope is that HAART might eventually eradicate the virus in HIV-infected individuals. This outcome requires effective viral suppression beyond the life span of the long-lived cells that form a reservoir of latent virus. Initial enthusiasm15 has been tempered by a gradual realisation of the difficulties,16 but it is not an unrealistic hope given the extraordinary pace of discovery in HIV science and medicine. Graeme J Stewart Chairman, Research Advisory Committee Australian National Council on AIDS and Related Diseases Westmead Hospital, Sydney NSW Correll PK, Law MG, McDonald AM, et al. HIV disease progression in the time of combination antiretroviral therapies. Med J Aust 1998; 169: 469-472. Cameron DW, Heath-Chiozzi M, Danner S, et al. Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Lancet 1998; 351: 543-549. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337: 725-733. Egger M, Hirschell B, Francioli P, et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. BMJ 1997; 315: 1194-1199. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853-860. Sherer R. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283-291. Roederer M. Getting to the HAART of T cell dynamics. Nature Med 1998; 4: 145-146. Li TS, Tubiana R, Katlama C, et al. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 1998; 351: 1682-1686. Kaufmann D, Pantaleo G, Sudre P, et al. CD4-cell count in HIV-1 infected individuals remaining viraemic with highly active antiretroviral therapy (HAART). Lancet 1998; 351: 723-724. Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia and insulin resistance. Lancet 1998; 351: 1881-1883. Stewart G. Chemokine genes - beating the odds. Nature Med 1998; 4: 275-277. Cohen J. Exploiting the HIV-chemokine nexus. Science 1997; 275: 1261-1264. Cairns JS, D'Souza MP. Chemokine and HIV-1 second receptors: the therapeutic connection. Nature Med 1998; 4: 563-568. Gazzard B, Moyle G. 1998 revision to the British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 1998; 352: 314-316. Wain-Hobson S. Down or out in blood and lymph. Nature 1997; 387: 123-124. Balter M. HIV survives drug onslaught by hiding out in T cells. Science 1997; 278: 1227. * With apologies to Ross and Adler's 'Heart' from Damn Yankees (1954), and to readers too young to know this high point in American immediate postwar culture. - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Graeme J Stewart

HIV disease progression in Australia in the time of combination antiretroviral therapies Patricia K Correll, Matthew G Law, Ann M McDonald, David A Cooper and John M Kaldor MJA 1998; 169: 469-472 For editorial comment, see Stewart Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Infectious diseases and parasitology - ©MJA1998 Abstract Objective: To examine the effect of recent developments in antiretroviral therapy on HIV disease progression and survival. Design: Retrospective cohort study. Participants and setting: Two cohorts of people with HIV were defined retrospectively from the records of a large immunology laboratory. The first cohort were subjects whose CD4+ T cell counts had dropped to 200 x 106/L during 1990, and the second were subjects whose CD4+ T cell counts had dropped to 200 x 106/L in 1994. Main outcome measures: HIV disease progression and survival was determined over a minimum three years of follow-up for each cohort (ie, 1990-1993; 1994-1997). Results: 346 subjects were included in the analysis (193 subjects from 1990 and 153 from 1994). The relative risk of progression to AIDS in the 1994 cohort compared with the 1990 cohort was 0.57 (95% confidence interval, 0.35-0.91; P = 0.018) and the relative risk of death was 0.20 (95% confidence interval, 0.08-0.49; P < 0.001). Conclusions: There were 43% fewer AIDS cases and 80% fewer deaths in the time following the increased availability of combination antiretroviral therapy in Australia. Introduction In recent years there have been major advances in antiretroviral treatments for people with HIV infection. Evidence from clinical trials (DELTA and ACTG 175)1,2 first defined the superiority of combination therapy over monotherapy in delaying progression to AIDS and prolonging survival. Since that time more potent antiretroviral agents have been approved, including lamivudine (widely available in Australia since early 1995) and protease inhibitors (available since late 1995). In clinical trials, these drugs have demonstrated significant ability to reduce disease progression and improve survival when added to existing regimens of antiretroviral treatments.3,4Although there has been anecdotal evidence in Australia suggesting that these treatments have reduced the overall number of AIDS cases and improved survival following AIDS, their effect has not been systematically studied. We therefore decided to compare the rates of progression to AIDS and survival in two cohorts of people between 1990-1993 and 1994-1997, with CD4+ T cell counts of 200 x 106/L (CD4 cell count 200/µL) at entry to the study, as a basis for assessing the impact of new treatments. Methods Subject identification Two cohorts of subjects in this study with CD4 cell counts of 200/µL were defined retrospectively from records of routine CD4 cell counts undertaken at the Centre for Immunology, St Vincent's Hospital, Sydney. St Vincent's Hospital has been responsible for the care of about 25% of people with AIDS in Australia, and its immunology laboratory is used by St Vincent's Hospital inpatient and outpatient services, and by several general practitioner clinics that specialise in managing people with HIV infection. Subjects whose CD4 cell counts fell below 200/µL in 1990 would not have had access to combination therapies, whereas the 1994 cohort was under follow-up when combination therapies with more potent drugs were becoming available in Australia. A CD4 cell count of 200/µL was used as the starting point for follow-up because at this point individuals have not usually developed AIDS-defining illnesses,5 but are considered to be at a point of immune decline where the probability of developing AIDS in the near future has greatly increased.6,7 Subjects included were HIV-positive but without AIDS at entry to the study, with CD4 cell counts declining through 200/µL in the index year (1990 or 1994) or with a single CD4 cell count in the range 180-220/µL. All eligible subjects were included, except subjects from two large clinics which had used the Centre for Immunology laboratory in 1990 but not in 1994. Where available, two or more CD4 cell count results from the period beginning in the middle of the year before the index year and ending at the middle of the following year were recorded so that the rate of CD4 cell change could be estimated. Subjects with multiple CD4 cell counts entered the study on the date of the first test in the index year that was below 200/µL. For subjects with a single CD4 cell count only, entry to the study was on the date of this test, provided the result fell between 180-220/µL. Follow-up Analysis was based on a minimum of three (up to four) years' follow-up of both cohorts through linkage to the National AIDS Registry, which records AIDS diagnoses and deaths following AIDS in Australia. Testing records were linked to Registry data by matching name codes (first two letters of the surname and given name) and dates of birth from the reference laboratory database with the Registry. Because reporting of AIDS diagnoses and deaths to the Registry is subject to delay, subjects from the 1994 cohort who did not appear on the Registry were followed up through their referring doctors. The doctor was also contacted for follow-up information if a name code was not available with the CD4 count records. Information sought included name code, date of birth, whether the subject had progressed to AIDS or died with AIDS, and date of the doctor's most recent contact with the subject. Statistical methods All statistical analyses were performed using SAS.8 Decline of CD4 cells was estimated for subjects with two or more CD4 cell counts by linear regression. Baseline characteristics in the two cohorts were compared by means of Fisher's exact test for categorical variables and the Mann-Whitney rank sum test for continuous variables. We calculated AIDS-free survival and overall survival curves using Kaplan- Meier methods, and assessed the statistical significance of the difference in survival between the two cohorts by the log rank test. Proportional hazards regression was used to assess the effect of age, CD4 cell count at entry, and decline of CD4 counts on AIDS incidence and survival. In survival analysis, subjects without an AIDS diagnosis or death reported to the National AIDS Registry were assumed to be AIDS-free and alive at the end of follow-up. Secondary analyses were also performed based on confirmed AIDS-free and survival times by censoring at the date of last confirmed contact on the National AIDS Registry or with the referring doctor. Results After excluding 109 subjects in 1990 who had been referred from two clinics which did not use the Centre for Immunology laboratory in 1994, the database search identified 214 eligible subjects from 1990 and 169 from 1994, of whom 193 and 153, respectively, could be traced for follow-up and were included in the analysis (Box 1). As shown in Box 1, 60% of subjects who were followed up during 1990-1993 progressed to AIDS and 38% died, compared with 37% who progressed to AIDS and 13% who died during follow-up between 1994-1997. This corresponds to a 43% decrease in AIDS and an 80% reduction in death. As shown in Box 2, the median age at entry of the 1994 cohort was older than in the 1990 cohort, but sex, CD4 cell count at entry and CD4 cell decline were similar. The median age and sex of excluded subjects who came from the two clinics which did not use the Centre for Immunology laboratory in 1994 (age 37.5 years, 96% male) were similar to those included in the 1990 cohort (age 35 years, 98% male). Box 3 shows that progression to AIDS was slower and survival longer in the 1994 cohort than in the 1990 cohort, and that the improvement in both indices appeared to emerge after about one year of follow-up. Adjustment for age, CD4 count and CD4 slope at entry did not materially affect the differences between the two cohorts in progression time to AIDS and survival (Box 4). There were 52 subjects for whom only one CD4 cell count was recorded and rate of CD4 cell decline could not be estimated. A sensitivity analysis excluding these subjects gave very similar results to those for the full cohort (relative risk of AIDS and death in the 1994 group, 0.51 [P = 0.02] and 0.21 [P < 0.01], respectively). When follow-up was censored at the date of last confirmed contact, there remained a 28% decrease in progression to AIDS (P = 0.04) and a 45% reduction in death (P = 0.021). Discussion In this study, progression to AIDS was nearly halved and deaths fell by 80% among people with HIV infection whose CD4 cell count fell below 200/µL in 1994 compared with the corresponding 1990 cohort. The difference between the two groups emerged after about one year of follow-up, which in the 1994 cohort corresponded roughly to the introduction of lamivudine in early 1995, followed by protease inhibitors later in the same year. Although other differences between the cohorts cannot be entirely ruled out, the most likely explanation for the improved outcomes is advances in treatment strategies for people with HIV, including combination antiretroviral therapies. The benefit of combination therapy and new antiretroviral agents has been demonstrated so far largely through randomised controlled trials.9 Only recently has information started to emerge of the effectiveness of new therapies in a community-wide setting. The results of this study concur with recent cohort studies overseas, where substantial decreases in AIDS and deaths have been identified in patients followed up after the introduction of combination therapies compared with those under follow-up in earlier times.10,11 Although information on antiretroviral treatment was unavailable for the individuals in our cohorts, recent evidence suggests a dramatic change in the use of antiretroviral therapies in Australia over the time in which the two cohorts reported in our study were followed up. HIV-infected participants in the Sydney Men and Sexual Health Study (a prospective study of homosexually active men in Sydney) increased their uptake of combination antiretroviral therapy from about 2% in 1993 to more than 70% in 1997.12 Our study relied on the National AIDS Registry, which is subject to both reporting delay and underreporting. It is believed that about 70% of HIV diagnoses are reported to the Registry within six months (the minimum reporting time available in this study) and that nearly 100% are reported within three years.13 It is possible that incomplete reporting of AIDS and AIDS-related deaths to the National AIDS Registry may have resulted in underestimates of AIDS incidence or mortality in the later cohort. Results were similar, however, when analyses were censored at the date of last contact, suggesting that underreporting to the Registry was not in fact an important source of bias. One other potential source of bias is that changes in the natural history of the HIV epidemic may have resulted in a lower proportion of rapid progressors in more recent years, so that patients with CD4 counts of 200/µL in 1990 progressed more rapidly than those in 1994.14 In our analysis, there was little difference between the cohorts in CD4 cell decline (Box 2), and survival analysis adjusted for this gave very similar results. Furthermore, a sensitivity analysis excluding those subjects with only a single CD4 cell count also did not significantly affect the results. This analysis was based on CD4 cell counts collected over two years (mid year before the index year to mid year after), and is robust enough to suggest that both cohorts were subject to similar rates of progression. As the subjects were identified at two different times, it is possible that there were unidentifiable differences between the cohorts that may have influenced the outcomes in this study. However, the possibility of bias was substantially reduced by identifying all subjects from the same laboratory. This study contributes evidence to suggest that the rate of progression of HIV disease has decreased in Australia at the same time as new, more potent combination antiretroviral treatments have become available. It would be useful to study similar cohorts in the future to monitor the evolving pattern of the epidemic at a population level. Acknowledgements The National Centre in HIV Epidemiology and Clinical Research is funded by the Commonwealth Department of Health and Family Services through the Australian National Council on AIDS and Related Diseases. The help of the following medical practitioners in study follow-up is gratefully acknowledged: B Anderson, P Brooke, K Brown, A Carr, B Donovan, N Doong, C Duncombe, W Genn, J Kidd, A Mackie, M McMurchie, A McNulty, R Penny, A Pethebridge, M Robertson. We also thank John Zaunders at the St Vincent's Hospital Centre for Immunology for assistance in identifying the study sample. References Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283-291. Hammer SM, Katzenstein DA, Hughes MD, et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4+ cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996; 335: 1081-1090. CAESAR Coordinating Committee. Randomised trial of addition of lamivudine or lamivudine plus loviride-zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 1997; 349: 1413-1421. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4+ cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337: 725-733. Centers for Disease Control. Conditions included in the 1993 AIDS surveillance case definition. MMWR Morb Mortal Wkly Rep 1992; 41: RR-17. Hoover DR, Rinaldo C, Yanhua H, et al. Long-term survival without clinical AIDS after CD4+ cell counts fall below 200 x 106/L. AIDS 1995; 9: 145-151. Tindall B, Swanson CE, Cooper DA. Development of AIDS in a cohort of HIV-seropositive homosexual men in Australia. Med J Aust 1990; 153: 260-265. SAS statistical software version 6.12. Carey, NC: SAS Institute Incorporated, 1994. HIV/AIDS Clinical Trials and Treatments Advisory Committee of the Australian National Council on AIDS and Related Diseases. Antiretroviral therapy for HIV infection: principles of use. Standard of care guidelines; October 1997. Sydney: HIV/AIDS Clinical Trials and Treatments Advisory Committee, 1997. Egger M, Hirschel B, Francioli P, et al. Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study. BMJ 1997; 315: 1194-1199. Palella F, Delaney K, Moorman A, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. New Engl J Med 1998, 338: 853-860. National Centre in HIV Epidemiology and Clinical Research. HIV/AIDS and related diseases in Australia: Annual Surveillance Report 1998. Sydney: National Centre in HIV Epidemiology and Clinical Research, 1998. National Centre in HIV Epidemiology and Clinical Research. An epidemiological assessment of the HIV epidemic in Australia. Evaluation of the National HIV/AIDS Strategy 1993-1994 to 1995-1996. Canberra: Commonwealth Department of Health and Family Services, 1996. Ioannidis JPA, Cappelleri JC, Schmid CH, Lau J. Impact of epidemic and individual heterogeneity on the population distribution of disease progression rates. Am J Epidemiol 1996; 144: 1074-1085. (Received 13 Jan, accepted 30 Apr, 1998) Authors' details National Centre in HIV Epidemiology and Clinical Research, Sydney, NSW. Patricia K Correll, BN, MPH, Research Assistant; Matthew G Law, MA, MSc, Statistician; Ann M McDonald, BSc, MPH, Senior Research Assistant; David A Cooper, DSc, MD, FRACP, Director; John M Kaldor, PhD, Deputy Director. Reprints will not be available from the authors. Correspondence: Patricia Correll, National Centre in HIV Epidemiology and Clinical Research, Level 2, 376 Victoria Street, Sydney, NSW 2010. Email: pcorrellATnchecr.unsw.edu.au - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Patricia K Correll · Matthew G Law · Ann M McDonald · David A Cooper · John M Kaldor

The prevalence of hepatitis C in patients admitted with acute hepatitis to Fairfield Infectious Diseases Hospital, 1971-1975 Jennifer A Thomson, Alison J Rodger, Sandra C Thompson, Damien Jolley, Amanda Byrne, Susan J Best and Nick Crofts MJA 1998; 169: 360-363 Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Infectious diseases and parasitology - ©MJA1998 Abstract Objective: To identify and determine trends in the prevalence of hepatitis C virus (HCV) antibody in stored sera from 1971 to 1975 and to determine associations with HCV seropositivity, including markers for other hepatitis infections and possible routes of transmission. Design: A retrospective cross-sectional study. Patients and setting: 1511 adults admitted to Fairfield Infectious Diseases Hospital, Victoria, with a clinical and biochemical diagnosis of hepatitis between 1 January 1971 and 31 December 1975. Main outcome measures: Prevalence over study period of hepatitis A virus antibody (anti-HAV) IgM, hepatitis B core antibody (anti-HBc), hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV) in stored sera; sociodemographic data and risk factors for blood-borne viruses documented in original medical records. Results: Anti-HCV was detected in 17% of adults admitted with hepatitis from 1971 through 1975. Prevalence increased significantly over this period. Most cases were in young men who had a history of injecting drug use. HCV seropositivity was also significantly associated with markers for hepatitis B infection. Conclusions: Given the 20-30-year period between infection with hepatitis and the development of liver disease, our findings predict significant liver-related morbidity in Australia in the next decade. The increase in prevalence over the five years studied suggests rapid spread of HCV through susceptible populations, principally injecting drug users. Introduction Hepatitis C is an important public health problem in Australia. Approximately 150 000 people in this country are currently infected with the virus, predominantly as a result of injecting drug use.1,2 Acute hepatitis C virus (HCV) infection is generally benign; less than 25% are estimated to be icteric.3 The main significance of HCV infection is that it is strongly associated with the development of chronic liver disease. After 20 to 30 years a significant proportion of those infected will have chronic hepatitis, cirrhosis, liver failure and primary hepatocellular carcinoma.4 In view of this 20-30-year latency period, estimating the prevalence of HCV in the Australian community during the early 1970s may give an indication of the morbidity to be expected from this infection over the next decade. We thus aimed to determine the prevalence of hepatitis C antibody in stored sera from people with acute viral hepatitis admitted to Fairfield Infectious Diseases Hospital (FIDH), Victoria, from 1971 to 1975, to identify possible associations with HCV seropositivity and to detect trends in HCV prevalence over that time. Methods Ethical approval for the study was obtained from the ethics committees at FIDH and the Australian Institute of Health and Welfare. We chose the period 1971 to 1975 because systematic storage of sera began in 1971, the same year diagnostic coding was standardised at FIDH (with the introduction of International classification of diseases, ninth revision coding), and because a previous study had identified HCV antibody in stored sera from that time.5We included all patients admitted to FIDH with biochemical and clinical evidence of hepatitis between 1 January 1971 and 31 December 1975. Those for whom there was no original serum sample for testing and those for whom medical records could not be found were excluded. Patients aged under 16 years at the time of admission were also excluded as they were generally admitted for hepatitis A infection, which was endemic at that time.6 Multiple serum samples had been stored for many patients. For each individual, we tested the last available serum sample associated with their final hepatitis admission and which was adequate for testing. Sera were tested for all hepatitis markers at the Victorian Infectious Diseases Reference Laboratory and the National Serology Reference Laboratory, Australia by the following commercially available immunoassays: hepatitis A virus antibody (anti-HAV) IgM, IMX assay and HAVAB M enzyme immunoassay; hepatitis B core antibody (HBcAb), CORAB radioimmunoassay; hepatitis B surface antigen (HBsAg), AUSRIA II radioimmunoassay; and hepatitis C antibody (HCVAb), second generation enzyme immunoassay (all assays manufactured by Abbott Diagnostics, Abbott Park, Illinois, USA). Results were designated reactive or non-reactive by the laboratories. As previous studies of frozen sera stored for long periods suggested a stringent classification was required to avoid overestimating the prevalence of antibody to HCV,7,8 we used twice the manufacturer's recommended cutoff (as recommended in the literature7) to further increase the specificity of the HCV antibody test. Individuals with weakly positive results (ie, a ratio of 1-2 of sample optical density determined by enzyme-linked immunosorbent assay [ELISA] to cutoff optical density) were recorded as equivocal and excluded to minimise misclassification bias. Medical records were located and information collected on sociodemographics and risk factors for hepatitis. For patients with multiple admissions over the study period, information on risk factors was summarised from all admissions preceding the date of the last available serum sample. We compared our test results for the stored serum samples with the original results recorded for HBsAg at the time the samples were taken using K 9 to measure agreement. In addition, we traced a subset of patients in 1996 and 1997 and obtained information on risk factors before their FIDH admission. Traced patients were also retested for hepatitis B and C markers in 1996 and 1997. The results of tests on their original stored serum samples were compared with these follow-up results for hepatitis C virus antibody (anti-HCV) and hepatitis B core antibody (anti-HBc). Statistical analysis We used the Statistical Package for Social Sciences (SPSS)10 for data analysis, which included descriptive statistics, unpaired t test, chi-squared test, Fisher's exact test, chi-squared test for trend, and measures of risk and agreement. Results Patients aged over 16 and admitted to FIDH with hepatitis during the study period numbered 1798. Medical records were found for 1737 (97%) and 5% were noted to have been admitted with hepatitis more than once over the study period. Serum specimens were found for 1559 of these patients (90%) and testing for all the measured hepatitis markers was completed for 1511 (87%). We were able to trace a subset of 161 patients for follow-up in 1996 and 1997. The distribution of optical density ratios indicating anti-HCV status for the 1511 patients in the study is shown in Box 1. Seven per cent (99) had equivocal anti-HCV results and were excluded. Of the remaining 1412, 17% (238) were anti-HCV positive. Only 15% (37) of those who were anti-HCV positive had no evidence of other hepatitis markers. Those who were anti-HCV positive were significantly more likely to have markers for hepatitis B virus (Box 2), and the sensitivity and specificity of anti-HBc as a surrogate marker for HCV infection were 77% and 57%, respectively. The trends in prevalence of each of the measured hepatitis markers were significant (P < 0.05). The prevalence of anti-HCV increased fourfold, with the biggest increase between 1974 and 1975. The prevalence of anti-HBc and HBsAg also increased, while the prevalence of anti-HAV IgM declined (Box 3). In patients who were HCV seropositive, the prevalence of markers of hepatitis A and B did not change significantly over the study period. Validation of serological tests For the 161 patients we traced, comparing the results of serological testing of their stored sera for anti-HBc and anti-HCV with those of follow-up tests in 1997 showed good overall agreement, with complete agreement for anti-HBc of 91% (K, 0.79; 95% CI, 0.67-0.91) and, for anti-HCV, of 88% (K, 0.74; 95% CI, 0.66-0.82). For all patients, there was moderate agreement between HBsAg results recorded at the time of original admission and our results for the stored sera, with complete agreement for 65% (K, 0.58; 95%CI, 0.43-0.72). Sociodemographic data and risk behaviours Sociodemographic data were available from medical case records for all patients. The 238 individuals who were positive for anti-HCV were significantly younger than those who were anti-HCV negative (mean age at time of original admission, 22 years; SD, 5.3 years v. 29.5 years; SD, 12 years; P < 0.001). Anti-HCV-positive individuals were also significantly more likely to have been born in Australia (80% v. 69%; RR, 1.5; 95% CI, 1.4-1.8; P < 0.001) and to be male (62% v. 52%; RR, 1.4; 95% CI, 1.1-1.9; P < 0.001). Information on risk factors was incompletely recorded in medical records. Only 40% had information recorded for injecting drug use, 69% for contact with someone with hepatitis, 36% for transfusion, 15% for tattooing and 11% for travel. A history of injecting drug use and of contact with someone with hepatitis were the only risk factors significantly associated with HCV seropositivity (Box 2). There was good agreement between original records of injecting drug use in case records on admission and follow-up information obtained from the 161 patients traced in 1996 and 1997 (k, 0.83; 95% CI, 0.74-0.92). Discussion Our findings confirm the presence of anti-HCV among adults admitted with acute hepatitis to FIDH in Victoria in the early 1970s and also that its prevalence increased markedly from 1971 through 1975. Most cases were in young men who had a history of injecting drug use. Most individuals with HCV appear to have been admitted because of subsequent infection with hepatitis A or B. While the actual proportion is unclear, it is likely to be significant as only 16% of HCV-seropositive individuals had no evidence of other acute hepatitis markers. As this implies that individuals with subclinical acute HCV infection were admitted and therefore included in the study, the HCV seropositive group would appear to be reasonably representative of community-acquired HCV infection in Melbourne in the 1970s. The significant association between the presence of HCV antibody and documented contact with a person with clinical hepatitis infection probably results from a spurious association with the hepatitis A or hepatitis B infection that precipitated admission. This also suggests that those infected with HCV were likely to have risk behaviours that exposed them to other hepatitis viruses, in particular to hepatitis B. Significant misclassification of hepatitis status appears unlikely as there was moderate to good agreement between original results for hepatitis A and B with our results. In addition, we used a more stringent cutoff to classify anti-HCV status, to increase specificity and reduce misclassification bias. Another source of potential bias in our study was loss of samples as a result of our exclusion criteria, but given the large sample size this should not have significantly affected our findings. The risk factor information in the original case records was also incomplete and may have been subject to bias. However, the results of follow-up assessment of risk factors in patients we were able to trace equate well with risk factor information documented at the time of original admissions, in particular the presence or absence of a history of injecting drug use. In addition, the association between injecting drug use and HCV seropositivity -- documented in many other studies in the 1990s1,2,11-14 -- was very clear. We did not identify the presence of tattoos and a history of blood transfusion as significant risk factors for HCV seropositivity, and this probably reflects the low prevalence of HCV in the general population in the 1970s. The significant increase in the prevalence of HCV seropositivity over the five-year study period suggests that infection became firmly established within the Australian community, particularly the injecting drug user population, as early as the mid 1970s. Most of the estimated 150 000 people in Australia currently infected with HCV are thought to have become infected in the past two decades, implying that the population of injecting drug users expanded dramatically in the late 1970s and early 1980s.1 Our finding of a twofold increase in the recording of injecting drug use among patients admitted with viral hepatitis from 1971 through 1975 supports this. Given the 20-30-year latency period before the development of liver-related complications, it is likely that the rapid increase in prevalence of HCV infection from the mid 1970s will translate into a rapid increase in HCV-positive individuals presenting with liver disease over the next decade. Health service planning and resource allocation should take this into account. Further research is now urgently required on the natural history of community-acquired, as opposed to transfusion-acquired, HCV infection in the Australian population and on factors that predict the development of hepatic sequelae. Acknowledgements We thank Anna Lanigan (MBCMR), Dr Alan Breschkin, Dr Mike Catton and Associate Professor Steven Locarnini (Victorian Infectious Diseases Reference Laboratory) and Dr Elizabeth M Dax (National Serology Reference Laboratory, Australia). The National Health and Medical Research Council (NHMRC) Public Health and Development Committee provided funding for the study, and Dr J Thomson was an NHMRC PHRDC Research Fellow. Dr Nick Crofts was funded from the Research Fund of the Macfarlane Burnet Centre and Dr Alison Rodger partly funded by the Victorian Health Promotion Foundation. References Crofts N, Jolley D, Kaldor J, et al. Epidemiology of hepatitis C virus infection among injecting drug users in Australia. J Epidemiol Community Health 1997; 51: 692-697. MacDonald M, Crofts N, Kaldor J. Transmission of hepatitis C virus rates, routes, and cofactors. Epidemiol Rev 1996; 18: 137-148. Alter HJ. To C or not to C? These are the questions. Blood 1995; 85: 1681-1695. Seeff L. Natural history of Hepatitis C. Hepatology 1997; 26: 21-28. Moaven L, Crofts N, Locarnini SA. Hepatitis C virus infection in Victorian injecting drug users in 1971. Med J Aust 1993; 158: 574. Lehmann NI, Gust ID. The prevalence of antibody to hepatitis A virus in two populations in Victoria. Med J Aust 1977; 2: 731-732. Lok AS, Ma OC, Chan TM, et al. Overestimation of the prevalence of antibody to hepatitis C virus in retrospective studies on stored sera. Hepatology 1991; 14: 756-762. Moaven L, Cunningham T. Hepatitis C serology. Aust Microbiologist 1994; 12: 321-323. Fleiss J. Statistical methods for rates and proportions. 2nd ed. London: Wiley; 1981. SPSS [computer program]. Version 8. Chicago, Ill.: SPSS Inc, 1998. Van Beek I, Buckley R, Stewart M, et al. Risk factors for hepatitis C virus infection among injecting drug users in Sydney. Genitourin Med 1994; 70: 321-324. Crofts N, Aitken, CK. Incidence of and risk behaviours for blood-borne viruses in a cohort of injecting drug users in Victoria, 1990-1995. Med J Aust 1997; 167: 17-20. Galeazzi B, Tufano A, Barbierato E, et al. Hepatitis C virus infection in Italian intravenous drug users: epidemiological and clinical aspects. Liver 1995; 15: 209-212. Van den Hoek JA, van Haastrecht HJ, Goudsmit J, et al. Prevalence, incidence, and risk factors of hepatitis C virus infection among drug users in Amsterdam. J Infect Dis 1990; 162: 823-826. (Received 3 Feb, accepted 3 Aug, 1998) Authors' details Epidemiology and Social Research Unit, The Macfarlane Burnet Centre for Medical Research, Melbourne, VIC. Jennifer A Thomson, PhD, FAFPHM, Research Fellow; Alison J Rodger, MRCP(UK), MFPHM(UK), Research Fellow; Sandra C Thompson, PhD, FAFPHM, Research Associate; Amanda Byrne, BSc(Hons), MSc, Research Assistant; Nick Crofts, MPH, FAFPHM, Head. Department of Public Health & Community Medicine, The University of Melbourne, Melbourne, VIC. Damien Jolley, MSc(Epidemiol), MSc(Stats), Senior Lecturer in Epidemiology and Biostatistics. National Serology Reference Laboratory, Australia, Melbourne, VIC. Susan J Best, DipMedTech, Senior Scientist. Reprints will not be available from the authors. Correspondence: Dr A J Rodger, The Macfarlane Burnet Centre for Medical Research, PO Box 254, Fairfield, VIC 3078. E-mail: rodgerATburnet.edu.au - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Jennifer A Thomson · Alison J Rodger · Sandra C Thompson · Amanda Byrne · Susan J Best · Nick Crofts

Tuberculosis in the young: focusing on those at risk Recognition and workable strategies for children at risk are needed MJA 1998; 168: 100-101 Tuberculosis (TB) is curable and preventable, yet causes more deaths worldwide than any other infectious disease -- three million yearly, with 450 000 involving children. Australia has one of the lowest rates of TB in the world, and multidrug-resistant TB has not emerged as a problem here.1,2 None the less, people born overseas, Aboriginal people, those infected with HIV, the elderly (especially men over 65), and the homeless experience much higher than average rates of disease. Children up to the age of 14 years account for only 3%-6% of all Australian notifications. Children are also much less likely to transmit infection than adults. However, they have a high risk of developing active disease -- 23%-43% for those infected in the first year of life, 8%-25% for those infected between one and 10 years of age, and 16% for those infected when aged 11-15 years.3 Thus, it is important to identify infected children for preventive therapy (i.e., usually isoniazid for six months) to prevent progression to disease. Children born overseas, child contacts of infectious (usually adult) patients and Aboriginal children have much higher than average rates of infection and disease and deserve specific TB control strategies. The primary strategy for TB control is to stop transmission by timely diagnosis and curative treatment of infectious patients. The next priority, especially in children, is to identify by Mantoux testing those infected and to initiate preventive therapy where appropriate. Screening of at-risk groups and contact tracing of cases are important for both these strategies. It is also important that the skills and resources for diagnosing and curing TB are available to health care providers serving those at risk, such as general practitioners working in high risk migrant communities, Aboriginal medical services and regional chest clinics or public health units. The overall age-specific rates in Australia in 1995 were highest in overseas-born children aged 0-4 years (approximately 44, compared with 1 per 100 000 in Australian-born children of the same age).4 By contrast, 5-14-year-olds, whether born in Australia or overseas, have the lowest specific rates of any age groups, a finding that is consistent worldwide. In this issue of the Journal, the Consensus Statement5 on strategies for TB control in children in Australia from two paediatric special interest groups recommends Mantoux screening of immigrant children from high prevalence countries. This recommendation is long overdue, but needs a workable strategy. Issuing a Tuberculosis Undertaking (as is done for any adult migrant considered to be at increased risk of TB) to all children under five years of age emigrating from countries of high TB prevalence (> 25 per 100,000) would obligate a parent or guardian to contact the Health Assessment Service of the Department of Immigration and Multicultural Affairs within a specific period for direction to the nearest centre for Mantoux testing. The Health Assessment Service is currently investigating the feasibility of such a proposal. Findings from the Melbourne study by Johnson and colleagues6 on the prevalence of asymptomatic Mycobacterium tuberculosis infection in secondary school students add to earlier studies from Sydney,7,8 the Northern Territory9 (NT) and South Australia10 (SA) in supporting targeted school screening. Clearly, there is no current evidence to support mass school screening, and efforts should be directed towards students from countries of high TB prevalence to identify those at risk of developing active, contagious TB in adulthood and to offer them preventive therapy. TB is detected in around 1% of contacts of active cases. While contact tracing finds up to 10% of notified cases of TB overall, this percentage is much higher in children. In 0-14-year-olds, 65% of all cases11 and 78% of intrathoracic cases12 were identified by contact tracing. TB in a child which is not found by contact tracing usually signals recent transmission within the family, providing an opportunity to diagnose adult TB and stop further transmission. Alternatively, it may indicate inadequacies in current control methods, such as failure to trace contacts or to promote successful preventive therapy in identified infected children. The forthcoming National Health and Medical Research Council (NHMRC) publication Towards elimination of tuberculosis II emphasises the importance of contact tracing and provides detailed guidelines for contact screening.3 Limited national data are available on TB in Aboriginal children, but reports from Queensland, SA and the NT confirm they are at increased risk of infection and disease. In the NT from 1989 to 1997, Aboriginal children represented 25 of the 28 notified TB cases aged 0-14 years. Twelve of these 25 cases were nodal TB, consistent with the high rate of extrapulmonary disease seen in children; in contrast, only two cases of non-tuberculous (atypical mycobacteria) nodal disease were found. Suspected mycobacterial disease of lymph nodes always requires culture and susceptibility testing, and in Aboriginal as in migrant children should be considered as TB until proved otherwise. This is in contrast to the 1989 NHMRC statement "that in children born in Australia, mycobacterial disease of lymph nodes is almost invariably due to atypical mycobacterial disease".13 Strategies for TB control among Aboriginal children include diligent contact tracing, which may extend to community screening due to sociocultural interactions and overcrowded housing,3 and targeted school Mantoux testing, education and preventive therapy in regions of high TB incidence.9 The Consensus Statement lists BCG vaccination as an important control strategy, and recommends extending this beyond Aboriginal and Torres Strait Islander neonates in regions of high incidence, neonates born to parents with leprosy, and children under the age of five years living or travelling in countries of high TB prevalence for more than three months, as recommended by the NHMRC TB Working Party.3 While BCG vaccination protects against disseminated TB in the young, it has not played a large role in reducing transmission and controlling TB worldwide. Children born in Australia with one or both parents born overseas are at no higher risk of infection than those with Australian-born parents.6,7,8,9,10 Present evidence therefore supports continuing BCG vaccination according to the three recommendations above. Comprehensive information about the actual TB cases notified in all Australian-born children would be useful to further evaluate this issue. The recommendation that specialised State and Territory TB control programs be maintained in a climate of economic rationalism for a disease with low national rates and low rates in children5 is appropriate. However, an international focus is also required. To this end, it is encouraging that TB has been recognised as a priority issue by the Advisory Group on International Health of AusAID. With 75% of cases being in the migrant population, and Australia's location between two regions which the World Health Organization estimates account for two-thirds of the world's 8-9 million cases, we can not work alone towards eliminating TB. Australia needs to be a partner in the region as well as a contributor to global TB-control strategies. Vicki L Krause Director, Centre for Disease Control Territory Health Services, Casuarina, NT Dawson DJ, Cheah DF, Chew WK, et al. Tuberculosis in Australia 1989-1992. Bacteriologically confirmed cases and drug resistance. Med J Aust 1995; 162: 287-290. Dawson D. Tuberculosis in Australia: bacteriologically confirmed cases and drug resistance, 1994 and 1995. Commun Dis Intell 1997; 21: 245. Towards elimination of tuberculosis II -- guidelines and protocols for controlling tuberculosis in Australia. Draft prepared by NHMRC Tuberculosis Working Party -- 2nd stage public consultation. Canberra: NHMRC, June 1996. Oliver G, Harvey B. Tuberculosis notifications in Australia, 1995. Commun Dis Intell 1997; 21: 261-269. Isaacs D, Mellis CM. Tuberculosis in children in Australia: strategies for control. Med J Aust 1998; 168: 121-124. Johnson PDR, Carlin JB, Bennett CM, et al. The prevalence of asymptomatic tuberculosis infection in Melbourne secondary school students. Med J Aust 1998; 168: 106-110. Alperstein G, Fett MJ, Reznik R, et al. The prevalence of tuberculosis infections among Year 8 school children in inner Sydney in 1992. Med J Aust 1994; 160: 197-201. Alperstein G, Morgan K, Fett MJ, et al. Prevalence of tuberculosis infection among primary school entry children in Sydney. Aust J Pub Health 1996; 20: 123-128 . Wright J, Krause V. Outcomes of the NT School Mantoux Program 1991-1994 [abstract]. Program and abstracts. The 2nd National Tuberculosis Conference: Australia's regional role in tuberculosis control. 1997 Nov 17-18: 38. Sydney: The Public Health Association of Australia, 1997. Broomell K, Antic R, Stapledon R. A decade of tuberculosis control in SA. Abst. Program and Abstracts. The 2nd National Tuberculosis Conference: Australia's regional role in tuberculosis control. 1997 Nov 17-18: 38. Sydney: The Public Health Association of Australia, 1997. Goldman JM, Teale C, Cundall DB, Pearson SB. Childhood tuberculosis in Leeds, 1982-90: social and ethnic factors and the role of the contact clinic in diagnosis. Thorax 1994; 49: 184-185. Pineda PR, Leung A, Muller NL, et al. Intrathoracic paediatric tuberculosis: a report of 202 cases. Tubercl Lung Dis 1993; 74: 261-266. National Health and Medical Research Council. Tuberculosis in Australia and New Zealand into the 1990s. Canberra: AGPS, 1989. Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Vicki L Krause

Prevalence of tuberculosis infection in Melbourne secondary school students Paul D R Johnson, John B Carlin, Catherine M Bennett, Peter D Phelan Michael Starr, Jane Hulls and Terry M Nolan MJA 1998; 168: 106-110 Abstract - Introduction - Methods - Statistical analysis - Results - Discussion - Acknowledgements - References - Authors' details - - ©MJA1998 Abstract Objective: To estimate the prevalence of asymptomatic Mycobacterium tuberculosis infection in Melbourne secondary school students. Design: Cross-sectional Mantoux testing of a partly random and partly targeted sample of secondary school students, designed to enable estimation of prevalence by region of birth. Setting: Fifty-one State and Catholic secondary schools in metropolitan Melbourne during 1995. Participants: Australian and overseas-born students in Years 9 and 10. Outcome measures: Proportions of students with positive Mantoux reactions (defined as induration at 48 hours of ≥5 mm with a history of recent exposure; ≥10 mm and no prior BCG vaccination; ≥15 mm and prior BCG vaccination). Results: Of 2586 students potentially eligible for testing, evaluable results were obtained from 1274 (49%). The overall prevalence of infection for Melbourne students in Years 9 and 10 was 2.5% (95% CI, 1.1-3.9%). Main predictors of a positive test were birth overseas and number of years residing overseas. Prevalence varied considerably by region of birth, and was very low in students born in Australia (0.7%), "other developed countries" (0.7%), and Southern Europe (0). The highest rates were observed in students born in Indochina (15.9%), other countries in South East Asia (10.2%), and Eastern Europe (10.2%). Conclusions: The risk of a young person becoming infected with M. tuberculosis while living in Melbourne is very low. Our results do not indicate a need for the reintroduction of mass screening in Victorian schools. If targeted screening were to be considered, the group most likely to benefit would be recently arrived migrants from Indochina. Introduction Human infection with Mycobacterium tuberculosis is usually clinically silent, and may then only be detectable by a positive Mantoux skin test. A minority of infected individuals develop active tuberculosis (TB), and those with pulmonary disease are the major source of new human infections. For M. tuberculosis to persist within a community over time, each person with pulmonary TB must infect an average of 20 others.1,2 In developed countries, the transmission rate is much lower than this, and the incidence of tuberculosis has declined steadily for many years.2 In the United States, a 32-year trend of declining TB notifications was reversed in the mid 1980s.3 This resurgence is thought to have resulted in at least 51 000 unexpected cases of the disease, and has been attributed to the impact of AIDS, urban decay, homelessness and high levels of migration from regions where TB is endemic.4 Recent increases in incidence have also been reported from other developed countries, including Denmark, Italy, the Netherlands, Spain, Switzerland, France and the United Kingdom.5 In Australia, the incidence of TB has remained constant during the 1990s (rates per 100 000 population of 5.95 in 1990 and 5.75 in 1995).6 In Victoria, the annual incidence of TB per 100 000 declined from 47 in 1954 to 6.2 in 1992;7 it was 6.35 in 1995.6 In 1970 40% of new cases of active tuberculosis in Victoria were in people born overseas, but by 1990 this figure had risen to 80%. Currently, most new TB patients are migrants from Indochina and South East Asia.7 Although intending adult migrants are screened by chest x-ray before their arrival in Australia, migrant children are generally not screened, partly because childhood tuberculosis is not normally transmissible. In a recent inner-Sydney study, 27% of foreign-born Year 8 students (159 of 580), compared with 2% of those born in Australia (20 of 1221), had positive Mantoux reactions.8 As adolescents appear to have an increased risk (compared with children over three years and adults) of developing active tuberculosis,9 this group may become a source of new, locally acquired infection. During 1995, we conducted a Mantoux survey of healthy metropolitan Melbourne secondary students in Years 9 and 10. Our aim was to estimate the prevalence of asymptomatic TB infection, and to identify specific groups of students by region of birth who may benefit from future targeted screening and intervention programs. Methods The study was a cross-sectional survey of secondary school students in the metropolitan region of Melbourne (population, 3.1 million, with people aged 12 to 17 years comprising approximately 8% [Australian Bureau of Statistics, 1996 Census]). To recruit enough overseas-born students for estimating prevalence by region of birth, we used a combination of targeted and random sampling, aiming to include schools where at least 4% of students were born overseas, plus a 5% random sample of all other schools. The Australian Bureau of Statistics (ABS) provided numbers and country of birth of Melbourne residents aged 12 to 17 years from the 1991 national census. The Directorate of School Education and the Catholic Education Office provided numbers of students at each school speaking a language other than English at home. These data were combined and used to select schools with high enrolments of overseas-born students. Independent schools were not included as they comprised only 18% of all Year 9 and Year 10 students (Directorate of School Education, personal communication), and we assumed that they would have a low proportion of recently arrived overseas-born students. Of 50 purposely selected and seven randomly selected schools approached, six and one, respectively, declined. The randomly selected school was replaced by a neighbouring school, so that 51 schools participated. Parents of all students in Years 9 and 10 at each participating school were provided with an explanatory letter and a short survey (in English and, if appropriate, one of 12 translations). The survey was part of a separate study on asthma, but included a question on country of birth and sought permission to approach students a second time for the TB study. The initial (asthma) survey was distributed to all 13 020 Year 9 and Year 10 students at the 51 schools; 9794 usable responses were obtained (75%). Respondents comprised 85% from purposely selected and 15% from randomly selected schools. From the returned surveys we created 12 notional region-of-birth groups, based partly on geography and partly on numbers of respondents to the first survey, and an additional group comprising Australian-born students with both parents born in Asia (Box 1). We aimed to enrol approximately 200 students from each group to allow us to estimate prevalence within each with a 95% confidence interval of ± 1.9% if the true prevalence were 2%, and ± 6.4% if the true prevalence were 30%. Selection for Mantoux testing was random, except when the number of respondents in a category was less than 200, in which case all respondents from that region were included. Parents of students selected for Mantoux testing were sent information letters, consent forms and a TB survey (in English and one of 14 translations). This survey sought parental consent for Mantoux testing and included questions on parents' country of birth, date of arrival in Australia and history of BCG vaccination. Mantoux testing (by two experienced nurses, with two assistants from the Victorian Tuberculosis Program) was performed at school. Responses on each TB survey were checked for completeness and each student's deltoids, forearms and scapulas inspected for the presence of BCG vaccination scars before testing, which involved intradermal injection of 0.1 mL of a 100 IU/mL solution of purified protein derivative (PPD; CSL Limited, Parkville, Vic.) to the volar aspect of the student's left forearm. A single batch of PPD was used throughout. At between 48 and 72 hours, the extent of transverse palpable induration was measured by ruler and recorded in millimetres. The study was approved by the Ethics in Human Research Committee of the Royal Children's Hospital. Statistical analysis We used the exact binomial method for confidence intervals and the chi-squared test for comparisons between groups. Logistic regression was used to estimate prevalences, adjusted for differences in duration of residence in Australia. As we had deliberately selected schools with high concentrations of foreign-born students, we estimated overall prevalence of infection by direct standardisation to the population distribution of region of birth in students aged 12 to 17 years in metropolitan Melbourne (1991 Census data, ABS). Results Of 2586 students (the results of our efforts to create the 13 groups) sent the TB survey, 620 (24.0%) did not return it, and 692 (27%) returned completed surveys but declined to be tested or were away on the day of testing. Test results were therefore available for 1274 students (49%). To explore the potential for response bias, survey response rates and acceptance of testing were compared between subgroups defined by age, sex and time since arrival in Australia (Box 2). Younger students and females were statistically more likely to return their surveys than older students and males (data not shown), but refusal to be tested did not vary between these subgroups. Proportions of students with Mantoux reactions that were positive by National Health and Medical Research Council criteria (≥5 mm with a history of recent exposure; ≥10 mm and no prior BCG vaccination; ≥15 mm and prior BCG vaccination8,10 ) were compared by region-of-birth group (Box 3). Birth overseas, number of years resident outside Australia (Box 4) and past BCG vaccination were predictors of a positive result. The crude prevalence was 5.3%. After standardisation by region of birth, we estimated that 2.5% of all students in Years 9 and 10 in metropolitan Melbourne had positive Mantoux results (95% CI, 1.1-3.9%). Students born in Australia, "other developed countries" and Southern Europe had the lowest rates (0.7%, 0.7% and 0, respectively). The highest rates were observed in students born in Indochina (15.9%), other countries in South East Asia (10.2%), and Eastern Europe (10.2%) (Box 3). Differences in mean number of years resident overseas between the groups prevented direct statistical comparison, so logistic regression was used to estimate the odds ratio for increase of risk for each year lived overseas (odds ratio per year, 1.15; 95% CI, 1.08-1.24), and to standardise rates by region so they could be compared directly. After this adjustment, statistically significant differences in prevalence by region persisted, but the ranking of some regions, most notably Eastern Europe, was altered (Box 3). Prevalence of TB in the group of Australian-born students with Asian-born parents was 3.6%. None of these students had received a prior BCG vaccination. This prevalence was fivefold higher than the background rate of 0.7% for other students born in Australia, but this difference did not reach statistical significance (P = 0.17, two-tailed Fisher's exact test). The 244 students with a result ≥10 mm and the two with a result ≥5 mm plus a history of exposure to someone known to have TB were referred to a special clinic at the Royal Children's Hospital for chest x-ray and clinical review. However, 10 students with indurations ≥10 mm declined to attend the clinic, five of whom had positive Mantoux reactions. Of the 236 students who attended the clinic, 174 had at least one BCG vaccination scar and/or documentary evidence of BCG vaccination and a Mantoux reaction < 15 mm; these were therefore considered to have negative results. Students with results positive by NHMRC criteria8,10 were offered isoniazid preventive therapy, provided there was no evidence of active disease and they had not been previously treated. Sixty-two students had positive Mantoux reactions. Of these, seven had previously been prescribed isoniazid preventive therapy, two had previously been treated for TB disease, and one (a recently arrived refugee from East Timor) had active pulmonary TB. Five students refused isoniazid therapy, and five were not offered therapy as they were considered to have a reduced risk (recent BCG). Forty-two students with positive Mantoux reactions were offered isoniazid preventive therapy; 38 (90%) completed six months of treatment. Multiple BCG scars (evidence of previous vaccinations) were common in students from Eastern Europe (mean number, 1.6; 33% of students with ≥2 scars) and the Middle East, whereas those from Indochina generally had only one (mean number, 0.9; 11% of students with ≥2 scars). Discussion The risk of a young person becoming infected with M. tuberculosis while living in Melbourne appears to be very low. The major determinant of the size of the Mantoux reaction in this study was birth overseas. However, most students with reactions to testing had also received at least one prior BCG vaccination, which complicates interpretation. Most Australian-born students had not been vaccinated, and the prevalence of infection in this group was very low (0.7%, giving a calculated annual risk of infection of 0.04% per year). The higher prevalence in Australian-born students with Asian-born parents may be the result of low-level transmission within migrant communities, although the apparent difference could have been due to chance. For those born overseas, the number of years spent outside Australia correlated positively with Mantoux results, indicating that the risk of infection increases with duration of residence in an endemic region. The prevalence of infection in Year 9 and Year 10 students in metropolitan Melbourne appeared to be approximately half that identified in a recent survey in Year 8 students in inner Sydney, both overall and within specific migrant subgroups.8 The authors of the Sydney study commented that the prevalence they identified was higher than previously reported in Australia and have since found a slightly lower prevalence in a further survey of younger students.11 Our lower rate may be the result of differing patterns of migration between Melbourne and Sydney, or the selection of our sample from the whole metropolitan region instead of just the inner city. Although only half of eligible students in our study were tested, we do not believe that our results are systematically biased in a way that would have led us to grossly underestimate prevalence. In particular, we found no association between recent arrival in Australia and the likelihood of refusing to be tested, and the group with the lowest participation rate (Eastern Europe) showed the second-highest prevalence. In retrospect, acceptance of testing may have been improved by selecting whole classes rather than individuals within a class for testing, and our two-stage study design allowed ample opportunity for students to withdraw. However, any future targeted screening program would need to select individuals from within a larger group, and part of our study rationale was to investigate the acceptability of such programs. Even if it were assumed that non-participants had twice the prevalence of those tested, the true prevalence would only be 50% greater than our estimates. There is controversy about the influence of BCG vaccination on the results of subsequent Mantoux testing. In countries with a high prevalence of TB infection, a single BCG vaccination is often given shortly after birth, but this is unlikely to influence the result of a Mantoux test 15 years later.12 By contrast, BCG given to older children or given several times during childhood probably does influence Mantoux reaction size.13 Although the current NHMRC guidelines make some allowance for past BCG vaccination, they could be further refined.13 For example, for recently arrived migrants who have received a single BCG vaccination early in life and who have lived for many years in a region of high prevalence it may be appropriate to use ≥10 mm to indicate a positive reaction, while for migrants from countries that routinely give three BCG vaccinations in childhood but have a lower prevalence of infection ≥20 mm may be more appropriate.13 Whether or not such refinements are introduced, the distinction between positive and negative reactions will remain somewhat arbitrary; a more reliable test is urgently required. Mass screening of secondary school students by Mantoux test was discontinued in Victoria over 10 years ago. Our results do not suggest that such programs need to be reintroduced, and recent overseas studies suggest that mass screening at school is unlikely to be cost effective.14-16 However, 24% of overseas-born students in our study had Mantoux reactions ≥10 mm, one of whom had active pulmonary disease and one-quarter of whom were considered eligible for isoniazid preventive therapy. If reactions of ≥10 mm for students born in a high-risk region with a history of having received a single BCG vaccination in infancy were considered positive, the number of students eligible for preventive therapy would increase further. If targeted screening were introduced, the group most likely to benefit would be recently arrived students from Indochina. We offered isoniazid therapy to students who tested positive because adolescents have an increased risk of developing active tuberculosis.9,17 However, we were mindful that isoniazid therapy is not entirely without risk even in young people,18-20 and that the risk of infection progressing to disease in an affluent society with a low prevalence of HIV infection may be much lower than the 10% often quoted.21 We cannot therefore be completely confident that wider use of isoniazid in this way would result in a net benefit to the Australian community. Acknowledgements This study was supported by a grant from the John Burge Estate administered by the Victorian Department of Human Services. We gratefully acknowledge the assistance of the principals, coordinators, teachers, students and parents at the participating schools. We also wish to thank the following individuals: Mary Randall, Mary McColl and staff of the Victorian Tuberculosis Program; Marita Dalton, Colin Powell, Department of Thoracic Medicine; and Susan Sawyer, Centre for Adolescent Health, Royal Children's Hospital. References Bates JH, Stead WW. The history of tuberculosis as a global epidemic. Med Clin North Am 1993; 77: 1205-1217. Styblo K. Recent advances in epidemiological research in tuberculosis. Tuberc Res 1980; 20: 1-63. Centers for Disease Control and Prevention. Tuberculosis morbidity -- United States, 1992. MMWR Morb Mortal Wkly Rep 1993; 42: 696-704. Snider DE Jr, Raviglione M, Kochi A. Global burden of tuberculosis. In: Bloom BR, editor. Tuberculosis: pathogenesis, protection and control. Washington DC: ASM Press, 1994: 3-12. Raviglione MC, Sudre P, Rieder HL, et al. Secular trends of tuberculosis in western Europe. Bull World Health Organ 1993; 71: 297-306. Oliver G, Harvey B. Tuberculosis notifications in Australia, 1995. Commun Dis Intell 1997; 21: 261-269. MacIntyre CR, Dwyer B, Streeton JA. The epidemiology of tuberculosis in Victoria. Med J Aust 1993; 159: 672-677. Alperstein G, Fett MJ, Reznik R, et al. The prevalence of tuberculosis infection among year 8 schoolchildren in inner Sydney in 1992. Med J Aust 1994; 160: 197-201. Comstock GW, Livesay VT, Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol 1974; 99: 131-138. National Health and Medical Research Council. Tuberculosis in Australia and New Zealand into the 1990s. Canberra: AGPS, 1990. Alperstein G, Morgan KR, Fett MJ, et al. Prevalence of tuberculosis infection among primary school-entry children in Sydney. A N Z J Pub Health 1996; 20: 123-128. Menzies R, Vissandjee B. Effect of bacille Calmette-Guerin vaccination on tuberculin reactivity. Am Rev Resp Dis 1992; 145: 621-625. Ildirim I, Hacimustafaoglu M, Ediz B. Correlation of tuberculin induration with the number of Bacillus Calmette-GuŽrin vaccines. Ped Infect Dis J 1995; 14: 1060-1063. Driver CR, Valway SE, Cantwell MF, Onorato IM. Tuberculin skin test screening in schoolchildren in the United States. Pediatrics 1996; 98: 97-102. Mohle-Boetani JC, Miller B, Halper M, et al. School-based screening for tuberculous infection: a cost-benefit analysis. JAMA 1995; 274: 613-619. Starke JR. Universal screening for tuberculosis infection: school's out! JAMA 1995; 274: 652-653. Katz J, Kunofsky S. Logistics of chemoprophylaxis of tuberculosis. Chest 1971; 59: 600-605. Gal AA, Klatt EC. Fatal isoniazid hepatitis in a child. Ped Infect Dis J 1986; 5: 490-491. Israel HL, Gottlieb JE, Maddrey WC. Perspective: preventive isoniazid therapy and the liver. Chest 1992; 101: 1298-1301. Millard PS, Wilcosky TC, Reade-Christopher SJ, Weber DJ. Isoniazid-related fatal hepatitis. West J Med 1996; 164: 486-491. Haas DW, Des Prez RM. Mycobacterium tuberculosis . In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone, 1995: 2213-2243. (Received 23 May, accepted 27 Sep, 1997) Authors' details Clinical Epidemiology and Biostatistics Unit, Royal Children's Hospital, Melbourne, VIC. Paul D R Johnson, FRACP, PhD, Research Officer, Royal Children's Hospital Research Institute (also, Infectious Diseases Physician, Department of Infectious Diseases and Clinical Epidemiology, Monash Medical Centre); John B Carlin, BSc(Hons), PhD, Deputy Head (also, Associate Professor, University of Melbourne, Department of Paediatrics); Catherine M Bennett, BSc(Hons), Research Officer; Jane Hulls, RN, Research Nurse; Terry M Nolan, PhD, FRACP, Head (also, Associate Professor, University of Melbourne, Department of Paediatrics). University of Melbourne, Department of Paediatrics, Royal Children's Hospital, Melbourne, VIC. Peter D Phelan, MD, FRACP, Stevenson Professor, and Head (currently, Emeritus Professor of Paediatrics). Department of Microbiology and Infectious Diseases, Royal Children's Hospital, Melbourne, VIC. Michael Starr, MB BS, FRACP, Paediatrician. Reprints: Dr P D R Johnson, Department of Infectious Diseases and Clinical Epidemiology, Monash Medical Centre, Clayton, VIC 3168. E-mail: Paul. Johnson AT med.monash.edu.au Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Paul D R Johnson FRACP, PhD · John B Carlin · Catherine M Bennett · Peter D Phelan · Michael Starr · Jane Hulls · Terry M Nolan

Tuberculosis in children in Australia: strategies for control David Isaacs and Craig M Mellis, on behalf of the Paediatric Special Interest Group of the Australasian Society for Infectious Diseases* and the Australasian Paediatric Respiratory Group** MJA 1998; 168: 121-124 Introduction - Epidemiology - Childhood tuberculosis - Child advocacy - Control of tuberculosis - Acknowledgements - References - Paediatric Special Interest Group of ASID - Australasian Paediatric Respiratory Group - Authors' details - - ©MJA1998 Introduction Globally, tuberculosis (TB) is responsible for more deaths per year than any other infection. The World Health Organization estimated that in 1990 there were 7.5 million new cases of TB; 1.3 million were in children under 15 years of age, of whom 450 000 died.1 TB is relatively rare in Australian children, but, because of the associated high morbidity and mortality and the risk of later reactivation of disease, it should not be neglected. This paper outlines strategies to control paediatric TB. Tuberculosis in childhood is different from that in adults, and requires different expertise. This position paper, a consensus by paediatric infectious disease and respiratory specialists, outlines strategies for managing childhood TB in Australia. A companion paper, in preparation, will address strategies applicable to New Zealand. A further paper will deal with specific details of management of paediatric tuberculosis, including diagnosis and treatment. Epidemiology While the incidence of TB in industrialised countries has fallen to very low levels with improving living conditions, in the United States the steady decline in incidence of TB has halted. From 1985 to 1992 there was a 20% increase in reported cases in both adults and children1-4 (although this situation has now improved5 ). Further, the US has experienced an increase in the prevalence of infection with multidrug-resistant strains of TB.2,4 This increase was the result of an association of HIV infection and TB, increasing poverty, immigration from countries with high TB prevalence, and decreased public health funding.4,5 The re-emergence of TB as a problem in the USA has caused other industrialised countries to re-examine policies for the prevention and management of this disease. Tuberculosis is not presently a major problem in Australia. Its incidence has remained stable since 1986 at 5.5-6.0 cases per 100 000 population per year.6-9 The number of notified cases in children aged 0-14 years has fallen from 70 in 1991, to 45 in 1992, 37 in 1993, and 33 in 1994.7-9 Two childhood deaths from TB were notified in 1992; none have been notified since. While most TB notifications are made from New South Wales and Victoria, the rate of notifications is highest in the Northern Territory. The notification rate is lowest in non-indigenous Australian-born people (1.5-2.0 per 100 000), while Aboriginality is associated with a higher incidence (10-13 per 100 000).8,9 However, being born overseas is associated with an even higher incidence, which has been consistently reported at around 15 per 100 000 for the past three years.7-9 Childhood tuberculosis Starke10 has emphasised the differences between paediatric and adult tuberculosis. Children generally have a much smaller bacterial population and there is less secondary resistance. Cavitary lesions are very rare, but children have a greater propensity for extrapulmonary disease. While children tolerate higher doses of medication relative to body weight, with lower rates of adverse reactions, paediatric formulations (syrups or soluble powders) are not always available. Paediatric tuberculosis is usually acquired from contact with an infected adult, and children with TB are generally at low risk of infecting others. Child advocacy In Australia, children with suspected or proven tuberculosis may be managed by paediatricians, at adult chest clinics, or by specialists in paediatric or adult infectious diseases.9 Given the low incidence of childhood cases, this variety of attending specialists is not surprising and does not necessarily mean that current management of paediatric TB is inappropriate. In large cities there may be enough children with TB or receiving preventive therapy to warrant specialised paediatric TB clinics that combine both paediatric and public health expertise. However, in many parts of Australia, children with TB or TB contact are managed in chest clinics by chest physicians who are expert in tuberculosis, but may lack paediatric knowledge and skills. On the other hand, the regional paediatrician, with experience in examining and managing children, may have little knowledge and experience of childhood tuberculosis. Although paediatric TB is rare, child contacts of adults with TB are much less rare, and preventive therapy of children requires expert knowledge and supervision.3,10 Guidelines on tuberculosis concentrate on adult aspects of TB, and tend to neglect paediatric aspects.11-13 As paediatricians are child advocates and experts in child health, they should be more involved in the care of children with TB,14 not necessarily as sole carers, but at least in consultation. Paediatricians can provide clinical expertise and advice in areas such as compliance with medication, particularly for very young children. Recommendation: Paediatricians should be consulted and involved in the management of TB in children whenever possible. [Consensus view, not addressed by the NHMRC TB Working Party.11] Control of tuberculosis The most critical aspect of control of tuberculosis is the existence of appropriate public health programs. The important strategies in TB control are: BCG vaccination; Screening of children at high risk; Contact tracing; and Appropriate duration of drug therapy. BCG vaccine Bacille Calmette-Guerin (BCG) vaccine was first used in humans in 1921, and few attempts have been made since then to develop improved vaccines against TB. BCG vaccine is moderately effective: a recent meta-analysis15 gave its protective efficacy as 50% against any TB disease, 64% against TB meningitis, and 71% against death from TB. Occasional cases of TB meningitis occur in children in Australia6-9 and might be prevented by BCG vaccination. The NHMRC TB Working Party currently recommends BCG vaccination for three groups of children:11 Aboriginal and Torres Strait Islander neonates in regions of high incidence; Neonates born to patients with leprosy (because of cross-protection by BCG against leprosy); and Children under the age of five years who will be travelling to live in countries of high TB prevalence for long periods. The NHMRC TB Working Party11 states that BCG vaccine should be considered for: Neonates who will be living in a household which includes immigrants or visitors recently arrived from countries of high TB prevalence (and neonates in families who have returned to visit the homes of relatives in countries of high prevalence); and Children and adolescents aged less than 16 years who continue to be exposed to a patient with active TB, and where the child or adolescent cannot be given preventive isoniazid therapy, or the person with active disease has organisms resistant to both rifampicin and isoniazid. We believe these latter two "considerations" should be changed to "recommendations" to prevent occasional, but devastating, cases of tuberculosis in these children. In particular, neonates whose parents are from South-East Asia or the Indian subcontinent should be given BCG at birth. There is currently no information on how many children receive BCG vaccine in Australia each year, either as an absolute number or as a proportion of those eligible. Clearly, such information would be a great advantage in analysing BCG vaccine efficacy, and thus in evaluating the current NHMRC recommendations. The Australian Childhood Immunisation Register, implemented in 1996, monitors compliance with some vaccines, but not with BCG as yet. Studies are needed on the proportion of eligible children who receive BCG vaccine, and on side effects of BCG vaccination. Recommendations: We support the indications for BCG vaccination as recommended by the NHMRC TB Working Party, but feel that BCG should be recommended in all five situations detailed above. [Consensus opinion based on the high rate of TB in children exposed to adults with TB. This recommendation has also been made in the Australian immunisation procedures handbook,16 but not by the NHMRC TB Working Party,11 in 1989.] We strongly urge the Federal Government to put in place mechanisms to audit the number of children vaccinated with BCG vaccine each year. [Consensus opinion.] Mantoux screening In Australia, Mantoux skin testing is usually performed with 10 tuberculin units of purified protein derivative (PPD), although one unit only may be used if there is a high risk of TB.16 In the United States,17 Mantoux skin testing is performed with five tuberculin units of PPD. US authorities' interpretation of a positive Mantoux skin test is shown in the Box; there is currently no recognised Australian interpretation of skin test positivity. At present, the Committee on Infectious Diseases of the American Academy of Pediatrics (the "Red Book" committee)17 recommends annual tuberculin testing of children at high risk, but not of children at low risk. Six months of isoniazid preventive therapy is recommended for children who are Mantoux positive without disease,12 as this is as effective as nine months' duration of therapy18 and has a better risk-benefit analysis.19 While Australian children are not routinely tested with tuberculin, two recent surveys of the Mantoux status of 13-year-old20 and six-year-old21 Sydney schoolchildren showed t hat being born overseas was the major risk factor for being Mantoux-positive. In addition, the later the child left the country of birth, the greater the risk of being Mantoux- positive. Australian-born children with one or both parents born overseas were not at increased risk of being Mantoux- positive compared with Australian-born children of Australian-born parents. As most Mantoux-positive children in Australia were born overseas, it is important to screen children who are migrating to Australia from countries with a high prevalence of TB. Short visits (e.g., holidays) overseas are associated with a low risk of becoming infected with TB. Although short term visitors to Australia occasionally transmit TB, screening them would be extremely difficult, and this is not done routinely. However, screening might be indicated in special circumstances (e.g., a visitor from a high endemic area with chronic respiratory symptoms). Routine annual Mantoux screening is not justified by the available data. Recommendations: Children born overseas who are migrating to Australia from a country with a high prevalence of tuberculosis should be screened by Mantoux testing with or without a chest x-ray on entry into Australia. [Based on evidence,20,21 but not currently recommended by the NHMRC TB Working Party.11] Children born in Australia should not be screened annually by Mantoux testing. [Based on evidence20,21 and consistent with NHMRC TB Working Party recommendations.11] Visitors to Australia from areas of high TB incidence should not be routinely screened, but neonates exposed to such visitors should be vaccinated with BCG. [Consensus opinion, consistent with Australian immunisation procedures handbook.16] Mantoux-positive children with no evidence of TB disease should be given preventive therapy with isoniazid for six months. [Based on evidence18,19 and consistent with NHMRC TB Working Party recommendations.11] Contact tracing Diligent tracing of the adult source of paediatric TB infection through public health networks continues to be an important step in preventing the spread of TB. Appropriate duration of drug therapy The emergence of highly resistant and multiply resistant strains of M. tuberculosis has re-emphasised the importance of good management of TB, and the development of innovative management and control strategies. The emergence of resistant strains is thought to be the result of failure of patients with TB to complete courses of chemotherapy. In New York, this was a consequence of failure to supervise patients' therapy as a result of cuts in health funding in the 1980s.4,5 In Australia, some States supervise all antituberculous therapy, while others use targeted supervision of patients considered to be at risk of being non-compliant. In general, there are insufficient public health staff to ensure supervision of preventive therapy with isoniazid. Continued supervision of therapy (either full or targeted supervision) is important to prevent the emergence of resistant strains in Australia, and requires funding. Recommendation: Specifically funded TB control programs need to be maintained in each State and Territory in Australia. [Consensus opinion.] This document has been discussed by the Writing Panel of the Paediatric Special Interest Group of the Australasian Society for Infectious Diseases (ASID), circulated to all members, and ratified by the ASID Council. It was discussed at the 1996 meeting of the Australasian Paediatric Respiratory Group, and circulated to all members for comment. It was sent to Dr Greg Stewart, Chair of the NHMRC Working Party on Towards elimination of tuberculosis II. Guidelines and protocols for controlling tuberculosis disease in Australia, and to the Public Health Association of Australia. Acknowledgements Helpful comments were received from Dr T Konstantinos, Dr Graeme Oliver, Dr Graham Simpson and Professor Louis Landau. References Raviglione MC, Snider DE, Kochi A. Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. JAMA 1995; 273: 220-226. Report from the Centers for Disease Control and Prevention: tuberculosis morbidity, United States, 1992. JAMA 1993; 270: 1525. Starke JR, Jacobs RF, Jereb J. Resurgence of tuberculosis in children. J Pediatr 1992; 120: 839-855. Drucker E, Alcabes P, Bosworth W, Schell B. Childhood tuberculosis in the Bronx, New York. Lancet 1994; 343: 1482-1485. Frieden TR, Fujiwara PI, Washro RM, Hamburg MA. Tuberculosis in New York City -- turning the tide. N Engl J Med 1995; 333: 229-233. Cheah D. Tuberculosis notification rates, Australia, 1991. Commun Dis Intell 1992; 16: 398-400. Hargreaves J. Tuberculosis notifications in Australia, 1992. Commun Dis Intell 1994; 18: 330-337. Hargreaves J. Tuberculosis notifications in Australia, 1993. Commun Dis Intell 1995; 19: 332-341. Oliver G. Tuberculosis notifications in Australia, 1994. Commun Dis Intell 1996; 20: 108-115. Starke JR. Multidrug therapy for tuberculosis in children. Pediatr Infect Dis J 1990; 9: 785-793. National Health and Medical Research Council. Tuberculosis in Australia and New Zealand into the 1990s. Canberra: AGPS, 1989. Grossman M, Hopewell PC, Jacobs RF, et al. Consensus: management of tuberculin-positive children without evidence of disease. Pediatr Infect Dis J 1988; 7: 243-246. NSW Health Department. Controlling tuberculosis in New South Wales. Sydney: NSW Health, 1993. Forfar JO. Child health in a changing society. Oxford: Oxford University Press, 1988. Colditz GA, Brewer TF, Berkey JCS, et al. Efficacy of BCG vaccine in the prevention of tuberculosis. JAMA 1994; 271: 698-702. National Health and Medical Research Council. The Australian immunisation procedures handbook. 6th ed. Canberra: AGPS, 1997. American Academy of Pediatrics. Report of the Committee on Infectious Diseases. 23rd ed. Illinois: The Academy, 1994. Comstock GW, Baum G, Snider DE Jr. Isoniazid prophylaxis among Alaskan Eskimos. Am Rev Respir Dis 1979; 119: 827-830. International Union Against Tuberculosis, Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis. Five years of follow-up in the IUAT trial. Bull World Health Organ 1982; 60: 555-564. Alperstein G, Fett MJ, Reznik R, et al. The prevalence of tuberculosis infections among Year 8 school children in inner Sydney in 1992. Med J Aust 1994; 160: 197-201. Alperstein G, Morgan K, Fett MJ, et al. Prevalence of tuberculosis infection among primary school entry children in Sydney. Aust J Pub Health 1996; 20: 123-128. *Paediatric Special Interest Group of ASID R Benn, MA Burgess, D Burgner, D Caplan, J Carapetis, P Collignon, R Doherty, G Eagles, J Faoagali, M Ferson, K Forsyth, S Garland, GL Gilbert, D Gordon, K Grimwood, J Hanna, D Hansman, G Hogg, D Holdaway, M Holloway, D Isaacs, H Jeffery, C Jones, A Kakakios, A Kesson, D Lennon, D McCrossin, P McIntyre, A McGregor, D McIntosh, M Nissen, D Roberton, R Robins-Brown, J Robson, J Royle, L Voss, S Wesselingh, J Whitson, B Wild, A Yung. The writing panel of the Paediatric Special Interest Group of ASID comprised GL Gilbert, MA Burgess, M Ferson, S Garland, K Grimwood, G Hogg, D Isaacs, and P McIntyre. **Australasian Paediatric Respiratory Group H Allen, I Asher, P Van Asperen, G Bowes, B Clements, D Cooper, P Cooper, K Dawson, P Field, P Francis, N Freezer, J Gillies, M Haifer, M Harris, R Henry, A Isles, A Kemp, D Kennedy, L Landau, J Martin, CM Mellis, S Sawyer, B Masters, J Morton, T Olinsky, P Pattemore, P Phelan, C Robertson, P Robinson, P Sly, G Smith, P Le Souef, R Staugas, S Stick. Authors' details Australasian Society for Infectious Diseases, Sydney, NSW. David Isaacs, FRACP, Member of the Paediatric Special Interest Group; Craig M Mellis, FRACP, Member of the Australasian Paediatric Respiratory Group. Reprints will not be available from the authors. Correspondence: Associate Professor D Isaacs, Department of Immunology and Infectious Diseases, Royal Alexandra Hospital for Children, Westmead, NSW 2145. E-mail: davidi AT rich.edu.au - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Antibiotic use or misuse? The public, as well as prescribers, need education about appropriate antibiotic use MJA 1997; 167: 116-117 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". - ©MJA1997 Compared with similar developed countries, Australia has a high rate of antibiotic use. This is made clear in this issue of the Journal by McManus et al.,1 who show that retail sales of oral antibiotics in Australia in 1994 were about 25 defined daily doses (DDDs) per 1000 population/day, compared with 24 in the United States, 16 in the United Kingdom and 11 in West Germany. The reasons for these differences are less clear. Indeed, they seem paradoxical, as Australia has most of the conventional prescribing controls in place -- a strict regulatory process for evaluating new drugs, the tightly controlled Pharmaceutical Benefits Scheme (PBS), and prescription-only availability. Australia also has a strong tradition of promoting appropriate prescribing in medical schools, through publications such as Antibiotic guidelines2 and through education of medical and pharmacy practitioners. The MJA has been an educational leader in this area, publishing articles and editorials on rational drug use,3,4 antibiotic guidelines5 and antibiotic prescribing interventions in both hospitals6,7 and general practice.8 Cynics often blame the high rate of antibiotic use on the pharmaceutical industry and its intensive promotional activities. Yet the industry is also bound by the regulatory environment, its own code of ethics, and the very powerful effects of the PBS on market forces. The PBS has ensured that drugs in Australia are among the cheapest in the Western world. But, has it ensured that we use antibiotics wisely? The climate is now right to educate the public about infections and when antibiotics might not help. Antibiotics are a valuable resource that is easily squandered. They are unique in being specifically designed to have no action on the host. This can make them attractive to both prescriber and patient, as they can be taken "just in case" the infection is bacterial. However, adverse reactions are still a risk. In addition, bacteria have the ability to mutate to or acquire resistance at rates sufficient to reduce or negate antibiotic usefulness within one to two decades.9,10 Unnecessary prescribing adds to the selective pressure for antibiotic resistance. This leads in turn to increased costs to the community because of the need for more expensive, broader-spectrum agents, extra visits to medical practitioners, and further prescriptions or hospitalisations for antibiotic failures. Broader-spectrum agents generate further resistance, leading steadily to multidrug resistance. Eliminating unnecessary antibiotic use cannot stop resistance emerging, but can reduce its frequency and prolong the useful life of the older, cheaper antibiotics. It is widely believed among Australian microbiology and infectious diseases practitioners that their colleagues often misuse antibiotics. This view is reinforced by results presented by McManus et al., from the Therapeutics Resource and Educational Network for Doctors (TREND) project of the Royal Australian College of General Practitioners. These show widespread use of antibiotics for respiratory tract infections, which are mostly caused by viruses. Australians are unlikely to suffer more bacterial infections or superinfections than their counterparts in other developed countries. More likely, the long history of unnecessary prescribing has built up a community belief that antibiotics are needed for most infections. We have also learnt that information about adverse reactions has only a modest impact on prescribers. For example, publicity about serious adverse reactions to trimethoprim- sulfamethoxazole, flucloxacillin and amoxycillin-clavulanic acid, through means such as the Drug reactions advisory committee bulletin, letters to general practitioners and via the PBS, had minimal effects on prescribing volumes. Subsequent regulatory interventions by the Therapeutics Goods Administration and the PBS had variable results. Flucloxacillin use declined about 30% between 1994 and 1995, and adverse hepatic reactions declined by 50%. In contrast, over the same period use of amoxycillin-clavulanic acid rose by about 10%, and adverse hepatic reactions by 15%.11 We have spent the past decade haranguing prescribers without the expected dividends. However, they continue to be handicapped by the lack of rapid diagnostic tests for common infections to determine need for an antibiotic before prescribing. Thus, it may well be time to switch our attention from the supply to the demand side -- patients must be empowered with basic knowledge about infections. Last year saw the first small step, with the introduction of National Medicines Week, focusing on antibiotics. Soon after, the public began to take notice of emerging resistance and the impact of indiscriminate antibiotic use, largely through the "doomsday" and "superbug" scenarios promoted by the media with stories about drug-resistant Streptococcus pneumoniae, multidrug-resistant Mycobacterium tuberculosis, vancomycin-resistant enterococci, and, most recently, vancomycin-resistant Staphylococcus aureus. The climate is now right to educate the public about infections and when antibiotics might not help. This will reduce not only antibiotic misuse, but also the number of patient visits to medical practitioners, with major benefits for both the community and government. We need a measured approach to public education. It should be conducted at many levels, including in secondary schools, during patient visits to health professionals and through specifically targeted local and national programs similar to National Medicines Week. On an optimistic note, as McManus et al. show, oral antibiotic use actually declined slightly between 1989 and 1994. We must capitalise on this trend by intensifying efforts to eliminate unnecessary use. Lessons can be learned from the approach to other major public health issues -- a judicious combination of regulation and education is likely to be most successful. A pro-active approach to the regulation of availability, prescribing and access to antibiotics, rather than one that is reactive to the pressures of cost and adverse reactions, will favour rational use. Education is needed for health professionals, at both undergraduate12 and postgraduate level,8,13 and for consumers. Everyone will benefit from a better understanding of the basics of infectious diseases and their management given that infections are the commonest of human ailments. John Turnidge Director, Microbiology and Infectious Diseases Women's and Children's Hospital, Adelaide, SA McManus P, Hammond L, Whicker SD, et al. MJA 1997; 167: 124-127. Victorian Drug Usage Advisory Committee. Antibiotic Guidelines. 9th edition. Melbourne: Victorian Medical Postgraduate Foundation Therapeutics Committee, 1996. Moulds RFW. From knowledge to action: improving drug prescribing. Med J Aust 1996; 165: 299-300. Moulds RFW. Rational therapeutics: the way ahead. Med J Aust 1992; 156: 823-824. McDonald P. Antibiotic guide-lines: do we know where we are? Med J Aust 1989; 150: 610-611. Harvey KJ, Stewart R, Hemming M, et al. Educational antibiotic prescribing. Med J Aust 1986; 145: 28-32. Landgren FT, Harvey KJ, Mashford ML, et al. Changing antibiotic prescribing by educational marketing. Med J Aust 1988; 149: 595-599. DeSantis G, Harvey KJ, Howard D, et al. Improving the quality of antibiotic prescription patterns in general practice. The role of educational intervention. Med J Aust 1994; 160: 502-505. Turnidge J, Nimmo G, Francis G, and the Australian Group on Antimicrobial Resistance. Evolution of resistance in Staphylococcus aureus in Australian teaching hospitals. Med J Aust 1996; 164: 68-71. Collignon PJ, Bell JM, on behalf of the Australian Group on Antimicrobial Resistance (AGAR). Drug-resistant Streptococcus pneumoniae : the beginning of the end for many antibiotics? Med J Aust 1996; 164: 64-67. Adverse Drug Reactions Advisory Committee. Antibiotics of continuing concern. Aust Adverse Drug React Bull 1996; 15: 6-7. Snell BF on behalf of the organising committee of the ASCEPT/CHF Conference. Rational prescribing: the challenge for medical educators. Med J Aust 1992; 156: 352-354. Eckert GM, Ioannides-Demos LL, McLean AJ. Measuring and modifying hospital drug use. Med J Aust 1991; 154: 587-592. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

John Turnidge

Incidence of bloodborne virus infection and risk behaviours in a cohort of injecting drug users in Victoria, 1990-1995 Nick Crofts and Campbell K Aitken Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - ©MJA1997 Abstract Objective: To assess changes in risk behaviours for transmission of bloodborne viruses and incidences and prevalences of these viruses in a field-recruited cohort of injecting drug users. Design: Prospective longitudinal cohort study. Setting: Metropolitan and rural Victoria, June 1990 to December 1995. Subjects: 626 current injecting drug users (i.e., who had injected drugs within the previous 12 months). Main outcome measures: Seroconversion to HIV and hepatitis B and C viruses (HBV and HCV); risk behaviours for infection. Results: HIV incidence was very low (0.2 per 100 person-years). HCV incidence was high (10.7 per 100 person-years), but fell throughout the study, although the downward trend did not reach statistical significance. HBV incidence was moderate (1.8 per 100 person-years) and did not fall. Prevalence of risk behaviours, notably sharing needles and syringes, decreased significantly. Conclusions: Significant change has occurred in the risk behaviours of the cohort, confirming results of cross-sectional studies of injecting drug use. This change may be responsible for the apparent decline in HIV and HCV incidence. Further studies are needed to monitor the incidence of bloodborne viruses in injecting drug users. Efforts to decrease risk of transmission should continue. MJA 1997; 167: 17-20 Introduction Bloodborne viruses, especially the human immunodeficiency virus (HIV) and hepatitis viruses B and C (HBV, HCV), pose major risks to the health of people who inject illicit drugs.1 This is largely because of transfer of blood through sharing of contaminated injecting equipment or of environmental contamination in injecting settings, which in turn depends on the behaviour of injecting drug users (IDUs).2 The Victorian Injecting Drug Users Cohort Study (VICS) is the first longitudinal cohort study of IDUs carried out in Australia. At the inception of VICS in 1989, there was little Australian research into injecting drug use, and most studies were small, cross-sectional and retrospective.3 Information was needed about changes in IDU behaviour and their impact on the incidence of infection with bloodborne viruses among IDUs. The aims of VICS were: To develop methods for follow-up of active, field-recruited IDUs; To measure incidences of HIV, HBV, HCV and other bloodborne and sexually transmitted diseases among IDUs, and to investigate risk factors; To examine risk behaviour, behaviour change and influences on behaviour over time among IDUs; and To describe the natural history of injecting drug use in this cohort. This article describes the incidence of three bloodborne viruses (HIV, HBV and HCV) in the cohort, the prevalences of some important risk behaviours for transmission of these viruses and relationships between the two. Methods Subjects and assessment Subjects were current IDUs (i.e., who had injected drugs in the previous 12 months) and were recruited between June 1990 and March 1995. Because we wished to study a cohort of IDUs not necessarily in treatment and because of the difficulties in recruiting and following up IDUs over any length of time, novel methods were developed. These have been outlined previously.4,5 Subjects were recruited by peer outreach workers (former or continuing IDUs with extensive experience of the IDU "scene"), primarily through their own social networks and, to a lesser extent, from agencies (such as needle exchange programs and prisons). These outreach workers undertook all interviews, blood sampling and follow-up, after training in HIV counselling at the Melbourne Sexual Health Centre. Follow-up continued until December 1995. Interviews and collection of blood samples were initially intended to be at six-month intervals, but difficulties in tracking participants meant that interviews occurred opportunistically. The interview questionnaire included questions on demographics, frequency of drug injection, injecting history, needle-sharing, and other injecting practices. The full questionnaire is available from the authors on request. A blood sample was collected after interview if the situation allowed and the participant was willing. Inevitably, samples were not collected at every interview and fewer IDUs provided samples than were interviewed. Blood was tested for antibodies to HIV, HCV and HBV core antigen. Statistical analyses For calculating incidences, we assumed that seroconversion occurred on the date halfway between a seroconverter's last negative and first positive test. Confidence intervals for incidences were calculated using an exponential-error formula.6 The chi-squared trend statistic (2TR) was used to measure significance of trends in incidences and behaviours over time.7 Ethical approval The original study design and sub sequent modifications (including venepuncture, delivery of serological results, and pre- and post-test counselling by the peer outreach workers) were approved by the Institutional Ethics Committee of Fairfield Hospital, Melbourne, Victoria. Results Cohort description Data were obtained from 716 IDUs, but were insufficient for this analysis for 90. The remaining 626 IDUs provided contact and background data at an initial interview and detailed data at one or more follow-up interviews (maximum, 11). A total of 1663 follow-up interviews were conducted, with 267 IDUs (42.7%) completing only one follow-up questionnaire and 359 (57.3%) completing two or more, at an average interval of 259 days. Subjects were recruited from the community (431; 70%), agencies (134; 22%) and prisons (51; 8%). The prisoners were recruited between May and September 1994. Descriptive information was collected at the first interview. Of the 626 participants, 39% were women and 60% were men (one respondent was transsexual). Median age was 27.7 years (range, 14.9-63.2), and median age of first injection was 18 years (range, 10-60). Of 512 participants who had injected drugs in the previous month, 63.9% specified heroin as the drug most often injected and 33.6% specified amphetamines. For 420 participants who had injected in the previous week, median injection frequency was four times per week (range, 1-210). One hundred and eighty-eight participants (30%) reported injecting with a shared needle or syringe in the previous month. Prevalence of bloodborne viruses Nearly 6000 serological tests were performed on blood samples from 531 participants. Prevalences of HIV, HBV and HCV are shown in Box 1. On their first blood test, almost two-thirds of IDUs (62.4%) were found to have been infected with HCV, almost half (45.2%) with HBV and 3% with HIV. Between 1990 and 1995, the prevalence of HIV antibodies among those tested in each year declined significantly, from 6.3% to 0.7% (2TR = 12.49; P < 0.005). The prevalences of antibodies to HCV and HBV core antigen also varied over this period but with no discernible trend. Incidence of bloodborne viruses Only one person converted from HIV-seronegative to HIV-seropositive during the 599.8 person-years at risk captured by the study, an overall HIV incidence of 0.2 per 100 person-years (95% confidence interval [95% CI], 0.0-1.4). Seroconversions and incidences of HBV and HCV infection are shown in Box 2. Five participants seroconverted to HBV during 276.3 person-years at risk, an overall HBV incidence of 1.8 per 100 person-years (95% CI, 0.8-4.3). However, HBV incidence increased between 1992-1993 and 1994-1995, when four of the seroconversions occurred. However, first-test HBV prevalence did not vary significantly from year to year. Nineteen participants seroconverted to HCV during 177.6 person-years at risk, an overall HCV incidence of 10.7 per 100 person-years (95% CI, 6.8-16.8). One hundred and sixty-five participants remained HCV-seronegative throughout the study. Although there was a downward trend in HCV incidence between 1990-1991 and 1994-1995, comparison of 95% confidence intervals showed it did not reach statistical significance. Prevalence of risk behaviours The Figure shows prevalences of four risk behaviours over the 11 six-month periods of data collection. Bingeing (a period of heavier than usual drug use for the individual which may impair the ability to maintain safe behaviour) was common, with 41% of participants reporting at least one binge; however, the percentage who reported bingeing declined significantly over time (2TR = 4.5; P < 0.03). There were also significant downward trends in the percentage of current IDUs who shared needles and syringes (2TR = 5.5; P < 0.02), shared rinsing or mixing water (2TR = 12.8; P < 0.001) and were sometimes injected by others (2TR = 15.1; P < 0.001). Mean frequency of injecting in the cohort varied over time, ranging from five to nine times per week, without any significant trend. Figure: Prevalences of risk behaviours for transmission of bloodborne viruses in a cohort of Victorian injecting drug users, 1990-1995. Association between risk behaviours and incidence For the 202 participants who completed at least three interviews and reported continuing to inject, an attempt was made to relate the major risk behaviour -- sharing needles and syringes -- to HCV infection status (see Box 3). A gradient in both prevalence and incidence of HCV infection was apparent, related to the frequency that sharing was reported, although 95% confidence intervals for the incidences and a 2 test for the prevalences showed that these gradients were not statistically significant (2TR = 2.5; P = 0.28). However, 43 who were HCV-positive and two who seroconverted never reported sharing needles or syringes. Discussion We found that incidence of HIV among a cohort of Victorian IDUs was very low (0.2 per 100 person-years at risk), while incidence of HCV was high (10.7 per 100 person-years) and incidence of HBV was moderate (1.8 per 100 person-years). There was evidence that HCV incidence has decreased among Victorian IDUs, from 16.6 per 100 person-years in 1990-1991 to 8.1 per 100 person-years in 1994-1995, although the small number of seroconverters meant that the downward trend did not reach statistical significance. We also found significant declines in prevalence of risk behaviours, notably sharing of needles and syringes. There are several possible explanations for this apparent decline in risk behaviours. Firstly, it may be a real decline, as a similar decrease in risk behaviour was seen between the Melbourne arms of two cross-sectional national IDU surveys, in 19898 and 1994,9 respectively. Prevalence of sharing of injecting equipment (in the previous month) fell from 38%8 to 13% 9 of respondents, a statistically significant difference. These surveys had sample groups largely independent of the VICS cohort. Another explanation is that participants became less likely to report risk behaviour with time; this change in social desirability bias might also have been responsible for the difference between the results of the two national surveys.3 However, in our study, participants' increasing trust in their peer workers -- the basis for continued follow-up -- makes this unlikely. It is also possible that the cohort experienced greater attrition over time among IDUs whose behaviour was relatively risky. This might also explain the decreasing HCV incidence, with those most at risk of HCV infection seroconverting first. To evaluate this possibility, the study was kept open to new recruits until March 1995; the rise in HBV incidence in 1994-1995 reflects enrolment of a group at heightened risk of bloodborne viruses, most of whom were already exposed to HCV. Lastly, these results might simply reflect the natural history of injecting drug use (e.g., a move away from being injected by others with longer use) and have nothing to do with changes in the environment (such as educational campaigns). If so, cross-sectional studies would find a higher prevalence of risk behaviour among younger IDUs. However, such a difference was not apparent in a major national cross-sectional study of 812 IDUs.9 If the decline in risk behaviour is real, then it may indicate that information campaigns about modes of HCV transmission are having an effect among Victorian IDUs. As there is evidence that reduced needle-sharing reduces HCV transmission,10 this change in behaviour may be responsible for a decline in HCV incidence. Other studies of Australian IDUs have also found a high incidence of HCV infection, but our study is the first to note a fall in incidence.11 However, a decline in first-test HCV prevalence was seen among IDUs at a major methadone maintenance clinic in Melbourne.12 We have documented a phenomenon which needs further investigation -- new HCV infections in IDUs who report no needle-sharing. This raises the possibility that infection is being spread in other ways. Several key risk behaviours for transmission of bloodborne viruses among IDUs have been documented.13 Sharing needles and/or syringes is thought to offer the greatest potential for transmission of HBV and HCV because of the relatively large volumes of blood which can be exchanged. However, equipment such as mixing spoons and filters, as well as rinsing water and the environment (such as surfaces and hands), can also become contaminated and are potential vehicles for transmission. Alternatively, respondents may have unwittingly shared needles or been reticent about disclosing sharing behaviour. If routes of infection other than needle-sharing are involved in HCV transmission, they are likely to be substantially less efficient, as HCV incidence among IDUs who reported sharing at half or more of their interviews was almost four times greater than among those who reported no sharing. These data confirm that HIV is not spreading among Australian IDUs (in our cohort, HIV prevalence significantly declined) and that rates of risk behaviours for HIV transmission among this group are low.14 This difference in epidemiology of HIV and HCV is probably due to the much higher prevalence of HCV among IDUs and the much smaller volume of blood necessary, on average, to transmit HCV compared with HIV. Nevertheless, we found that risk behaviours for HCV transmission are continuing and that HBV, which is vaccine-preventable, is spreading. While HCV transmission may already be decreasing among IDUs, our results suggest that further and sustained behaviour change is possible and necessary if the spread of HCV among Australian IDUs is to be controlled. The results also indicate yet again the failure of our current policies on hepatitis B vaccination and the need for vaccination targeted to IDUs and prisoners.15,16 Acknowledgements The authors are grateful for the hard work of Jenny Kelsall, Michael Kerger, John Meade, Franz Hernberger, Vicky Hunt and the multitude of others associated with the Victorian Injecting Drug Users Cohort Study. We also gratefully acknowledge the support of the Victorian Health Promotion Foundation, the Drug and Alcohol Research and Education Advisory Council and the Commonwealth Department of Health and Family Services. Nick Crofts was supported by the Research Fund of the Macfarlane Burnet Centre for Medical Research. References Crofts N, Hopper JL, Bowden DS, et al. Hepatitis C infection among a cohort of Victorian injecting drug users. Med J Aust 1993; 159: 237-241. Saxon AJ, Caslyn DA, Jackson TR. Longitudinal changes in injection behaviours in a cohort of injection drug users. Addiction 1994; 89: 191-202. Crofts N, Webb-Pullman J, Dolan K. An analysis of trends over time in social and behavioural factors related to the transmission of HIV among injecting drug users and prison inmates. Canberra: AGPS, 1996. Crofts N, Hopper JL, Bowden DS, et al. Hepatitis C infection among a cohort of Victorian injecting drug users. Med J Aust 1993; 159: 237-241. Aitken CK, Crofts N. Effectiveness of peer interviewers in a cohort study of injecting drug users. In: Gooding R, Whelan G (editors). Proceedings of the Autumn School of Studies on Alcohol and Drugs. 1996 May 9; Melbourne. Melbourne: St Vincent's Hospital, 1996: 15-26. Clayton D, Hills M. Statistical models in epidemiology. Oxford: Oxford Science Publications, 1993: 6. Daly LE, Bourke GJ, McGilvray J. Interpretation and uses of medical statistics. Oxford: Blackwell Scientific Publications, 1991. Monheit B, Mijch A, Lewis V. Australian national AIDS and injecting drug use study: Melbourne 1989. Melbourne: Fairfield Hospital, 1991. Loxley W, Carruthers S, Bevan J. In the same vein: first report of the Australian Study of HIV and injecting drug use (ASHIDU). Perth: National Centre for Research into the Prevention of Drug Abuse, Curtin University of Technology, 1995. Crofts N, Jolley D, Kaldor J, et al. The epidemiology of hepatitis C virus infection among injecting drug users in Australia. J Epidemiol Community Health. In press. Hagan H, Des Jarlais DC, Friedman SR, et al. Reduced risk of hepatitis B and C among injection drug users in the Tacoma syringe exchange program. Am J Public Health 1995; 85: 1531-1537. Crofts N, Nigro L, Oman K, et al. Methadone maintenance and hepatitis C virus infection among injecting drug users. Addiction. In press. Lenaway DD, Guilfoile A, Rebchook G. Multiple HIV-risk behaviors among injection-steroid users. AIDS Public Policy J 1992; 7: 184-186. Crofts N, Ballard J, Chetwynd J, et al. Involving the communities: AIDS in Australia and New Zealand. AIDS 1994; 8 Suppl 2: S45-S53. Thompson SC, Oman K. Why should Australia adopt universal infant hepatitis B vaccination? Aust N Z J Public Health 1996; 20: 436-439. Crofts N, Stewart T, Hearne P, et al. Spread of bloodborne viruses among Australian prison entrants. BMJ 1995; 310: 285-288. (Received 10 Jan, accepted 16 May, 1997) Authors' details Epidemiology and Social Research Unit , Macfarlane Burnet Centre for Medical Research, Melbourne, VIC. Nick Crofts, MPH, FAFPHM, Head; Campbell K Aitken, PhD, Senior Research Officer. Reprints: Dr N Crofts, Epidemiology and Social Research Unit, Macfarlane Burnet Centre for Medical Research, PO Box 254, Fairfield, VIC 3078. E-mail: crofts @ mbcmr.unimelb.edu.au - - To top of article - ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Nick Crofts · Campbell K Aitken

The risk of transmitting HCV, HBV or HIV by blood transfusion in Victoria Gordon S Whyte and Helen F Savoia Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Abstract - Introduction - Methods - Incident rates - Risk estimation - Results - Hepatitis B virus - Hepatitis C virus - HIV - Discussion - Acknowledgements - References - Authors' details - ©MJA1997 Abstract Objective: To report the incidence rate of hepatitis B virus (HBV), hepatitis C virus (HCV) and HIV in Victorian repeat blood donors and to derive the residual risk of transmission of the viruses by screened blood transfusion. Design: The interval from the previous whole blood donation was extracted retrospectively from Victorian Red Cross Blood Bank records for each of the 358 332 repeat donations given between March 1994 and December 1995. Records of repeat donors found positive for the viruses in this period were traced to the previous seronegative donation and accepted if screened by the same test. For each virus, the number of previous donations screened by the same test was calculated and the sum of all donation intervals used to derive the incidence of infection in the repeat donor population. Published intervals after infection (when a donation can be infective although seronegative) were used to calculate the risk of release of a seronegative unit which would be infective. Participants and setting: Homologous blood donors at the Red Cross Blood Bank of Victoria. Main outcome measures: Incidence rate of HBV, HCV and HIV in regular blood donors and risk of infective donations being seronegative. Results: The incidence of infection in repeat donors was: HBV: 1.67 per 100 000 person-years; HCV: 1.89 per 100 000 person-years; and HIV: 1.31 per 100 000 person-years. The risk of a seronegative repeat donation being infective was: HBV: 2.71 per million donations (adjusted to 6.45 to account for viraemias which remain seronegative); HCV: 4.27 per million donations; and HIV: 0.79 per million donations. Conclusion: The risk of transmitting HCV, HBV or HIV by repeat blood donors is low and compares favourably with overseas data. Repeat donors have an incidence rate of HIV and HBV comparable to that of the general population, but the incidence rate of HCV is lower for repeat donors than in the general population. MJA 1997; 166: 584-586 Introduction There are no current Australian estimates of the risks of transmission by blood of hepatitis B virus (HBV) or hepatitis C virus (HCV), although the theoretical risk of HIV transmission has been estimated to be less than 1 in 903 000.1 Accurate estimates of the risk of transfusion-transmitted viral infections are important data for the risk-benefit analysis of homologous blood transfusions and in assessing the cost-effectiveness of new screening tests or methods of donor assessment. Schreiber et al. recently reported estimates of the risk of transfusing blood collected during the infectious "window period" (the time between a non- reactive blood donation and a repeat blood donation confirmed positive by the same test) at five United States blood centres.2 We used a method similar to that of Schreiber et al. to estimate the incidence of HBV, HCV and HIV in repeat Victorian blood donors and the risk of collecting blood infective for the viruses but seronegative by screening tests. Window-period collections are responsible for most transmissions of these three viruses. Methods A glossary of terms is shown in the Box. The donation interval was extracted from Victorian Red Cross Blood Bank records for all repeat whole blood donations given in Victoria in the 22-month period 1 March 1994 to 31 December 1995. This period was chosen because an algorithm was finalised in March 1994 to decide whether a donor reactive to a second generation HCV screening test was truly positive, liable to transmit HCV and liable to the sequelae of infection.3 Patients attending for autologous, directed or therapeutic donations were excluded, as were donors returning for repeat testing or counselling only. Plasma donors were not analysed because they are selected from repeat donors, there are no seroconversions and plasma undergoes virucidal procedures in fractionation. In the study by Schreiber et al., seroconversion intervals all lay within a three-year period.2 In contrast, in our study, seroconversion intervals were not required to commence in the same period, but were taken back to the year of the introduction of the screening test for each virus that was used in 1994-1995 in order to increase the number of seroconversions available for study. Therefore, the study period was different for different tests, but required that the reactive donation was given between March 1994 and December 1995. HBV: Seroconverting donors were identified whose seroconversion interval lay between the introduction of the current HBV surface antigen test (Auszyme Monoclonal, Abbott Laboratories, Illinois, USA) in January 1994 and the end of the study in December 1995. HCV: Seroconverting donors were identified whose initial (negative) donation was given after the introduction of the current second generation screening test (Abbott HCV EIA 2nd generation, Abbott Laboratories, Wiesbaden, Germany) in December 1991 and whose second (reactive) donation was given between March 1994 and December 1995. HIV: Seroconverting donors were identified whose initial (negative) donation was given after the current screening test for HIV antibody (Genelavia MIXT. Screening kit for the detection of antibodies to HIV-1 and HIV-2 in serum/plasma by enzyme immunoassay. Sanofi Pasteur, Marne la Coquette, France) was introduced in July 1992 and whose second (reactive) donation was given between March 1994 and December 1995. The repeat donor population screened by the same test was calculated to match the seroconversion study period for each disease by assuming that all repeat donors in the study period gave blood on 31 January 1995 (midpoint of the study period). For HBV, the number of donors was found whose previous donation was less than 53 weeks before (January 1994); for HCV, the interval was 165 weeks (December 1991); and, for HIV, the interval was 134 weeks (July 1992). Incident rates The incident rate was calculated as the number of incident cases (i.e., the number of seroconversions) divided by the sum of the interdonational intervals, in person-years, as described by Busch et al.,3 of all the donors in the study period. Risk estimation To derive the residual risk of transmission of each virus, the number of seroconversions were multiplied by the reported window periods before seroconversion, expressed in fractions of a year. The product is the probability that a seroconverting donor gave an infectious unit of blood during the window period that was not detected as seropositive by the screening tests currently in use and could therefore have been given in a blood transfusion.2 Results Repeat whole blood donors gave 358 332 donations in which the interdonational interval lay between March 1994 and December 1995. Half of the interdonational intervals were 12-15 weeks, with none less than 12 weeks. Ninety per cent of interdonational intervals were less than 54 weeks. Hepatitis B virus There were two seroconversions in the interval covered by the same screening test. There were 325 534 interdonational intervals after January 1994, calculated as 53 weeks before the end of January 1995, representing 6 221 761 person-weeks. The incidence rate of HBV was therefore 2 in 6 221 761 person-weeks, or 1.67 per 100 000 person-years. Interdonational intervals for the two seroconvertors were 77 and 178 days. The HBV window period is thought to be 59 days (range, 37-87),5 so the previous donation of each of the two seroconvertors could have been falsely negative for a total window period of 118 days (range, 74-174) in 6.22 million person-weeks, or 2.71 per million donations. The risk of giving blood infective for HBV (i.e., in the window period) was therefore 2.71 per million donations (range, 1.70-4.00). Hepatitis C virus There were three seroconverting whole blood repeat donors whose seronegative donation was after December 1991 and whose second (reactive) donation was between March 1994 and December 1995. Interdonational intervals for the three seroconvertors were 96, 651 and 1369 days, respectively. Of the 358 332 repeat donations in the 22 months from March 1994, the first donation of 349 226 interdonational intervals was given after December 1991, calculated as 165 weeks before the end of January 1995. The intervals represent 8 221 189 person-weeks, giving an incidence rate of HCV of 1.89 per 100 000 person-years. The HCV window period for second generation antibody tests is considered to be 82 days (range, 54-192).3,6 The risk of donating blood infective for HCV but seronegative was therefore 246 days (range, 162-576) in 8 221 189 person-weeks, or 4.27 per million donations (range, 2.82-10.01). HIV There were two seroconverting whole blood repeat donors whose seronegative donation was after July 1992 and whose reactive donation was between March 1994 and December 1995. Interdonational intervals for the two seroconvertors were 279 and 223 days. There were 347 076 interdonational intervals after July 1992, calculated as 134 weeks before January 1995. The donations represent 7 951 347 person-weeks, or 152 911 person-years, giving an incidence rate of HIV of 1.31 per 100 000 person-years. The HIV window period for second generation tests is considered to be 22 days (range, 6-38).7 The risk of donating blood infective for HIV but seronegative was therefore 44 days (range, 12-76) in 7 951 341 person-weeks, or 0.79 per million donations (range, 0.22-1.37). Discussion The effect of modifying the model used by Schreiber et al.3 depends on the length of the interdonational intervals of the study population compared with the intervals for seroconvertors. If long interdonational intervals are characteristic of seroconvertors, there will be a progressive overestimation of incidence in our model compared with that of Schreiber et al. This is because the total population of intervals is skewed strongly towards 12-15 weeks, and long intervals are under-represented in this study. HBV: Schreiber et al. argued that the true risk of a seronegative donation which is nevertheless infective is higher than that identified by HBV surface antigen because only 42% of HBV incident infections persist to be detected by the HBV surface antigen assay.2 Application of this adjustment to the risk in Victoria yields a window-period risk of 6.45 per million donations (range, 4.05-9.52). The comparable figure in the United States is 15.83 per million (range, 6.82-31.97)2 and, in France, 8.45 per million (range, 2.8-25.2).8 In our study, the unadjusted incidence of HBV in Victorian repeat volunteer donors was 1.67 per 100 000 person-years, comparable to the unadjusted incidence in the Australian general population of 2.4 per 100 000 person-years.9 The similarity of the two figures suggests that the critical factors for community transmission of HBV have not been identified well enough to assist in donor selection. During the study period, each time they donated blood donors signed a form stating that they had not engaged in male-to-male sex or used intravenous drugs. HCV: A current estimate of the incidence of HCV in Australia is 7.6 per 100 000 person-years.10 The estimate has been considered unreliable because of the unlikeliness that mild cases would be detected, although most of the individuals tested were more likely to be at high risk. Locarnini et al. hypothesised that if the number of incident cases were underestimated by a factor of three, and that 75% were intravenous drug users, then the true rate could be extrapolated to 22.2 per 100 000 per year.11 In our study, the 10-times-lower incident rate of HCV in repeat donors of 1.89 per 100 000 person-years is evidence of the low-risk behaviour of repeat volunteer blood donors. The risk of transmission of HCV by blood transfusion in Victoria in the window period was 246 days in 8 221 189 person-weeks, or 1 in 234 000 donations (range, 100 000-355 000). The comparable United States figure is 1 in 103 0002 and, in France, 1 in 223 000.8 HIV: The incidence of HIV in Australia is thought to be 480 per year from 1993, or 2.7 per 100 000 person-years.12 Our study shows that repeat Victorian blood donors have an incidence of HIV of 1.31 per 100 000 person-years. The limited reduction in the incidence of HIV in repeat volunteer donors is evidence of an increasing proportion of seroconversions caused by activity not identified as high risk. The risk of collecting a seronegative but HIV-infected donation in the window period is 1 in 1.27 million, similar to the calculation by Dax et al.1 The comparable United States figure is 1 in 493 0002 and, in France, 1 in 571 000.8 The incidence rate of HBV and HIV in regular blood donors is comparable to that of the general population. This suggests that donor assessment is ineffective in repeat donors, presumably because those who contract HBV or HIV do not regard themselves as at risk by the criteria applied by the blood bank. The incidence rate of HCV is lower for regular blood donors than the general population. The relative effectiveness of HCV discrimination presumably reflects the lack of experimentation by regular donors with intravenous drugs. The risk of window-period transmission of HBV, HCV and HIV in Victoria is low and compares favourably with overseas figures. The risk is probably overestimated for HIV because of the long seroconversion intervals. Care should be exercised when generalising from these figures because of the small number of seroconversions. However, the medical community and the general public should be reassured by this evidence that the blood supply is very safe. Acknowledgements We wish to thank John Butler, Christine Carroll, Phil Keily and Tony Chan at the Red Cross Blood Bank Victoria for data collation and processing, and John McNeil of Monash University for critical review of the manuscript. References Dax EM, Healey DS, Crofts N. Low risk of HIV-1 infection from blood donation: a test-based estimate. Med J Aust 1992; 157: 69. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. N Engl J Med 1996; 334: 1685-1690. Busch MP, Korelitz JJ, Kleinman SH, et al. Declining value of alanine aminotransferase in screening of blood donors to prevent posttransfusion hepatitis B and C virus infections. Transfusion 1995; 35: 903-910. Strasser SI, Smith BC, Watson KJR, et al. Evaluation of blood donors with equivocal hepatitis C serological results. Med J Aust 1995; 162: 459-461. Mimms LT, Mosely JW, Hollinger FB, et al. Effects of concurrent acute infection with hepatitis C on hepatitis B virus infection. BMJ 1993; 307: 1095-1097. Lelie PN, Cuypers HT, Reesink HW, et al. Patterns of serological markers in transfusion transmitted hepatitis C infection using second generation HCV assays. J Med Virol 1992; 37: 203-209. Busch MP, Lee LL, Satten GA, et al. Time course of detection of viral and serological markers preceding human immunodeficiency virus type 1 seroconversion: implications for screening blood and tissue donors. Transfusion 1995; 35: 91-97. Courouce A-M, Pillonel J. Transfusion transmitted viral infections. N Engl J Med 1996; 335: 1609-1610. Kaldor JM, Plant AJ, Thompson SC, et al. The incidence of hepatitis B infection in Australia: an epidemiological review. Med J Aust 1996; 165: 322-326. Andrews R, Curran M. Enhanced surveillance for incident cases of hepatitis C in Australia, 1995. Communicable Diseases Intelligence 1996; 20: 384-388. Locarnini S, McAnulty. Hepatitis C surveillance [editorial]. Communicable Diseases Intelligence 1996; 20: 388-389. Feachem RGA. Valuing the past -- investing in the future: evaluation of the National HIV/AIDS Strategy 1993-94 to 1995-96. Canberra: Commonwealth Department of Human Services and Health, 1995: 29-40. (Received 5 Dec 1996, accepted 16 April 1997) Authors' details Red Cross Blood Bank, Southbank, VIC. Gordon S Whyte, FRACP, FRCPA, Director; Helen F Savoia, MB BS, Registrar. No reprints will be available from the author. Correspondence: Dr G S Whyte, PO Box 354, South Melbourne, VIC 3205. E-mail: gwhyte @ rcbbv.org.au ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Gordan S Whyte · Helen F Savoia

New guidelines for management and prevention of meningococcal disease in Australia Mahomed S Patel, Peter J Collignon, Charles R Watson, Robert J Condon, Richard R Doherty, Angela Merianos and Gregory J Stewart (on behalf of the Meningococcal Disease Working Party of the National Health and Medical Research Council) The incidence of invasive meningococcal disease in Australia has increased over the past decade, and in April 1997 the National Health and Medical Research Council published guidelines for management of patients with meningococcal disease and their contacts. These guidelines emphasise the need for immediate intravenous antibiotic treatment of patients with suspected meningococcal disease, before transfer to hospital or lumbar puncture. When possible, blood for culture should be collected before antibiotic therapy, if this does not delay treatment. (MJA 1997: 166: 598-601) Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". Introduction - Epidemiology - Vaccines - Patient management - Management of contacts - Identification and management of an outbreak - Acknowledgements - References - Authors' details - ©MJA1997 Introduction The epidemiology of meningococcal disease in the industrialised world is changing, with increases in the incidence of both sporadic disease and outbreaks. These increases have been associated with the spread of virulent clones of meningococci belonging to serogroups B and C,1-6 leading to the suggestion that meningococcal disease should be regarded as an "emerging" infectious disease.4,5 Meningococcal disease affects mainly children under five years of age and adolescents, and can cause death in previously healthy children within several hours of onset. Guidelines for the management of patients with meningococcal disease and their contacts have been developed by the Meningococcal Disease Working Party of the National Health and Medical Research Council (NHMRC). Draft guidelines were distributed for comment in 1995, and the final version was published in April 1997.7 In this article, we summarise the guidelines document with the aim of providing succinct guidance for management of patients and their contacts and for identifying and managing outbreaks (see Box 1). Epidemiology In Australia, incidence of disease caused by meningo- coccus (Neisseria meningitidis) has increased over the past decade.6,8-10 With the decline of invasive disease caused by Haemophilus influenzae type b (Hib) since the introduction of the conjugate Hib vaccine in 1993, meningococcus has become the major cause of childhood meningitis in Australia. The incidence of meningococcal disease varies seasonally, rising in June and peaking in October each year.10 Most cases in the past decade were sporadic, but clusters and outbreaks were also reported.11-16 There are 13 serogroups of N. meningitidis, but serogroups A, B and C account for over 90% of invasive isolates, with serogroup B causing most disease. However, the incidence of disease caused by serogroup C has increased over the past decade. In 1995, 66% of isolates submitted to Australian reference laboratories were serogroup B and 28% were serogroup C.17 Serogroup A is often associated with epidemic disease and was responsible for a prolonged outbreak in Aboriginal communities in central Australia.11 Vaccines No one vaccine is effective against all strains of N. meningitidis. The quadrivalent polysaccharide vaccine against serogroups A, C, Y and W135 is effective in older children and adults, but less so in younger children, particularly those aged under two years.18 A conjugate vaccine against serogroups A and C was highly immunogenic in young infants in Gambia19 and is the subject of further immunogenicity studies in the United Kingdom and the United States. There are plans to start phase III, or clinical, trials, and the United Kingdom has signalled its intention to incorporate this vaccine into the routine childhood vaccination program.20 In contrast, an effective vaccine against serogroup B is not yet widely available, but trials of candidate vaccines against the outer membrane protein of some strains have shown efficacy of 50%-80%.21 In Australia, meningococcal vaccination with the combined A-C-Y-W135 vaccine is recommended for individuals with functional or anatomical asplenia, who are at increased risk of meningococcal, pneumococcal and other infections. They should receive meningococcal and pneumococcal vaccines every five years. About 600 splenectomies are performed each year in Australia; if this procedure is planned electively, the vaccines should be given two weeks before surgery. School- or community-based vaccination programs have also been used in Australia to manage clusters and outbreaks of meningococcal disease.6,11-16 Criteria for vaccination programs are described below. Patient management Effective management of an individual with meningococcal disease requires early intervention with effective antibiotics plus careful attention to associated manifestations, such as shock and coagulopathy. It therefore relies on early diagnosis. Clinical diagnosis The appearance of a petechial rash in association with fever, vomiting and drowsiness is highly suggestive of meningococcal meningitis and an indication for early empirical therapy. However, many patients may have a non-distinctive rash or no rash at all, and not all patients with invasive meningococcal disease have meningitis, many having only bacteraemia. Early recognition of meningococcal disease depends most of all on the clinical suspicion of the physician, and diagnosis can be difficult with sporadic cases unless there is high awareness of the problem in the community and among health care providers. Empirical therapy (before hospital admission) When meningococcal infection is suspected clinically, immediate empirical antibiotic therapy is indicated, before formal diagnosis, transfer to hospital or identification of an organism.22-23 This is particularly important in patients with signs of haemorrhagic disease or actual or incipient shock. However, to confirm the clinical diagnosis, blood for culture should be collected before the antibiotic is given, when this is possible without delaying treatment. The blood specimen should accompany the patient to hospital. At present, nearly all meningococcal isolates are sensitive to penicillin, but as other invasive pathogens may cause meningitis with symptoms similar to those of meningococcal meningitis (including a petechial rash), an antibiotic active against the common causes of meningitis is preferable. These include Streptococcus pneumoniae and H. influenzae type b. The immediate treatment of choice is therefore ceftriaxone, administered intravenously in one dose (see Box 2). Alternatively, intravenous cefotaxime may be used. Neither is available as an emergency ("doctor's bag") drug in Australia. Benzylpenicillin is available as a doctor's bag drug and should be used when ceftriaxone and cefotaxime are unavailable. If benzylpenicillin is not available, ampicillin or amoxycillin may be used, and when penicillin and third generation cephalosporins are contraindicated (e.g., because of hypersensitivity) chloramphenicol is also an alternative. All antibiotics should be given intravenously, unless intravenous access cannot be obtained. While an intravenous cannula is desirable, the dose can be given via a steel or "butterfly" needle. Intramuscular administration is not desirable, as supervening shock and hypotension may impair absorption of the injected antibiotics. Hospital therapy Antibiotic treatment: There should be no delay in starting or continuing treatment after hospital admission. Initial hospital therapy should be with ceftriaxone or cefotaxime, usually with benzylpenicillin.24 Therapy can then be modified depending on culture and sensitivity results. It should be continued for at least five days and, if meningitis is proven or probable, for at least five days after resolution of fever. Preventing transmission: Respiratory isolation of the patient is recommended for 24 hours after starting chemotherapy. The patient should also be given rifampicin before discharge if treatment did not include an antibiotic, such as ceftriaxone, that eradicates nasopharyngeal carriage of N. meningitidis . Diagnostic tests Therapy should not be delayed while awaiting results of diagnostic tests (such as computed tomography). Diagnosis of meningococcal disease is confirmed by isolation of N. meningitidis or detection of gram-negative diplococci or meningococcal antigen in cerebrospinal fluid, blood or another normally sterile site. Therefore, all patients with suspected meningococcal infection should have the following specimens taken and investigations after arrival at hospital: A blood sample taken as soon as possible for culture. A blood sample for neutrophil and platelet counts and, if petechiae or frank bleeding are evident, for formal coagulation studies. Gram-stained smears and culture from purpuric or other skin lesions, which may be helpful in confirming the diagnosis. Cerebrospinal fluid, collected by lumbar puncture, for microscopy and culture. Although once the mainstay of diagnosis, collection of cerebrospinal fluid may need to be deferred because of the association between meningitis and raised intracranial pressure, cerebral oedema, general or focal swelling and mass lesions, such as abscesses. For example, if there is evidence of raised intracranial pressure (e.g., clouded or impaired consciousness, papilloedema, focal neurological signs or vomiting), lumbar puncture should be deferred until therapy and supportive measures have been established and investigations such as computed tomography performed to define intracranial lesions. The patient's coagulation status should also be considered before lumbar puncture owing to the risk of haemorrhage with concomitant coagulopathy. A throat swab for culture. Its value is controversial, but in a patient who has received prior antibiotics this may be the only site from which N. meningitidis can be isolated. Other investigations, such as chest x-rays, electrolyte and acid-base studies, when clinically indicated. With the emphasis on antibiotic therapy before hospital admission, opportunities to prove a diagnosis by culture may decrease, increasing the importance of other diagnostic tests. Urinary antigen tests, while not helpful in diagnosing meningococcal disease because of low sensitivity and specificity, may be helpful if another organism is responsible, such as H. infuenzae type b and group B streptococci. Use of polymerase chain reaction to detect meningococcal DNA in cerebrospinal fluid and, more recently, in peripheral blood can increase the number of proven cases.25 However, this technique is still under development and not widely available. Serological tests of acute and convalescent blood showing a rising antibody titre may be of value in confirming the diagnosis retrospectively. Characterising Neisseria meningitidis Characterising isolates of N. meningitidis is not necessary for clinical management, but is indispensable for identifying and managing clusters and outbreaks of disease, and for following trends in the epidemiology of the disease. Therefore, every isolate of N. meningitidis should be characterised. This should be done urgently when an outbreak is suspected. Otherwise, isolates can be batched together for routine characterisation at about monthly intervals. Laboratories associated with the National Neisseria Network in each State or Territory can arrange testing for the serogroup, serotype and subtype of meningococcal isolates and for antibiotic sensitivities.16 They can also advise on availability of genetic and electrophoretic typing. Management of contacts Close contacts of patients with invasive meningococcal disease are at increased risk, including household members, dormitory contacts, staff and children in childcare facilities and those directly exposed to the patient's oral secretions (e.g., by mouth kissing, sharing food and drinks and performing mouth-to-mouth resuscitation). Health staff who provide clinical care but do not perform mouth-to-mouth resuscitation and are not involved with intubation are not at increased risk of disease, nor are classroom and casual contacts of a sporadic case. The risk of disease among close contacts can be reduced by chemoprophylaxis as soon as possible with rifampicin (10 mg/kg in children, to a maximum of 600 mg; and 600 mg in adults), twelve-hourly for two days.17 Alternative antibiotics include: ceftriaxone as a single intramuscular dose of 5 mg/kg, to a maximum of 250 mg (reduced to 125 mg in children under 15 years of age, and contraindicated in infants below six weeks of age), or ciprofloxacin 500 mg as a single oral dose (contraindicated in children under 12 years of age, people weighing less than 40 kg and pregnant women). Identification and management of an outbreak An outbreak of meningococcal disease is a public health crisis that calls for a rapid, coordinated public health response. Changes that suggest an outbreak is evolving include:6,13,16,26 Clustering of cases within an age or social group; Shift in disease from children under five years to older children and adolescents; and Phenotypic and genetic similarity among the strains causing disease. When an outbreak is caused by a vaccine-preventable strain, vaccination of people at risk should be considered. The decision will usually be complicated by the relatively small number of cases in the community and the high cost of vaccine. The decision-making process should therefore include firm confirmation of the outbreak, identification of the specific population at risk, estimation of the magnitude of risk26 and consideration of the level of community concern. The criteria for considering vaccination are: In a community setting, three or more cases of the same vaccine-preventable strain within three months in a defined population, where the attack rate exceeds 10/100 000 population. In institutions, such as schools or universities, two or more cases of the same vaccine-preventable strain occurring within a three-month period. When determining the number of cases for this purpose, secondary cases should not be included, as they represent the high risk of disease among close contacts rather than population risk.20 In Aboriginal communities, outbreaks of serogroup A and C meningococcal disease are of particular concern,11,13,15,16 and it is advisable to use vaccine earlier in such circumstances. In a remote Aboriginal community, two cases within five days has been used as an indication for a community-wide vaccination program.15 Public concern News of a child with fulminating meningococcal disease, or of outbreaks in schools, other institutions or the community, causes public anxiety and is rapidly taken up by the media. It is important to be proactive in informing the community and general practitioners about the outbreak and planned control measures, particularly if they include a vaccination campaign. The greatest challenge is to have cooperation from the media, so that they support initiatives to control the disease and do not generate unnecessary discord or controversy. Specific guidelines for informing the public and medical profession have been published elsewhere.27 In addition, the NHMRC guidelines describe a communication strategy and provide an information sheet on symptoms of the disease for lay people, sample letters for parents of children who may have been in contact with a patient, bulletins for health professionals and sample media releases.7 During outbreaks, public health units should consider setting up a telephone hotline for enquiries from the public and general practitioners. Politicians at local and State levels should also be kept informed about the course and management of an outbreak. Acknowledgements We acknowledge the excellent assistance provided by the secretariat of the Working Party in developing the guidelines, including Jenny Hargreaves, Barbara Sheppard, Evon Bowler and Leona Seib. Dr Jeff Hanna was a member of the NHMRC Working Party up to the stage it developed the draft guidelines. References Caugant DA, Froholm LO, Bovre K, et al. Intercontinental spread of a genetically distinctive complex of clones of Neisseria meningitidis causing epidemic disease. Proc Natl Acad Sci U S A 1986; 83: 4927-4931. Lystad A, Aasen S. The epidemiology of meningococcal disease in Norway 1975-91. Natl Inst Pub Health (Norway) Ann 1991; 14: 57-65. Whalen CM, Hockin JC, Ryan A, Ashton F. The changing epidemiology of invasive meningococcal disease in Canada, 1985 through 1992. Emergence of a virulent clone of Neisseria meningitidis . JAMA 1995; 273: 390-394. Jackson LA, Schuchat A, Reeves MW, Wenger JD. Serogroup C meningococcal outbreaks in the United States. An emerging threat. JAMA 1995; 273: 383-389. Serogroup B meningococcal disease--Oregon, 1994 [editorial]. MMWR Morb Mortal Wkly Rep 1995; 44: 121-124. Munro R, Kociuba K, Jelfs J, et al. Meningococcal disease in urban south western Sydney, 1990-1994. Aust N Z J Med 1996; 26: 526-532. National Health and Medical Research Council. Guidelines for the control of meningococcal disease in Australia. Canberra: AGPS, 1997. Clements DA, Gilbert GL. Increase in admissions for Neisseria meningitidis infection in Australia [letter]. Lancet 1989; 2: 1464. Levy M, Manning W, Rubin G. Bacterial meningitis makes a comeback. NSW Pub Health Bull 1991; 2: 5,9-10. Hargreaves J. Meningococcal infection -- national notifiable diseases data. Commun Dis Intell 1992; 16: 31-35. Patel MS, Merianos A, Hanna JN, et al. Epidemic meningococcal meningitis in central Australia, 1987-1991. Med J Aust 1993; 158: 336-340. Watson C, Gill J. Further cases of invasive meningococcal infection in the Katanning area of Western Australia. Commun Dis Intell 1990; 20: 12-13. Pearce M, Sheridan J, Jones D, et al. Control of group C meningococcal disease in Australian Aboriginal children by mass rifampicin chemoprophylaxis and vaccination. Lancet 1995; 346: 20-23. Chant K, Stewart G, Brown J, et al. A cluster of meningococcal cases in Campbelltown. NSW Pub Health Bull 1992; 3: 93-94. Hanna J, Alexander D. Invasive meningococcal disease in an Aboriginal community in north Queensland. Commun Dis Intell 1994; 18: 8-9. Hanna J, McCall B, Murphy D. Invasive meningococcal disease in north Queensland, 1990-1994. Commun Dis Intell 1996; 20: 320-324. National Neisseria Network. Meningococcal isolate surveillance, Australia, 1995. Commun Dis Intell 1996; 20: 422-424. National Health and Medical Research Council. The Australian immunisation procedures handbook. 5th ed. Canberra: AGPS, 1994. Twumasi PA, Kumah S, Leach A, et al. A trial of a group A plus group C meningococcal polysaccharide-protein conjugate vaccine in African infants. J Infect Dis 1995; 171: 632-638. Herbert MA, Heath PT, Mayon-White RT. Meningococcal vaccines for the United Kingdom. Commun Dis Rep CDR Rev 1995; 5: R130-R135. Poolman JT. Development of a meningococcal vaccine. Infect Agents Dis 1995; 4: 13-28. Strang JR, Pugh EJ. Meningococcal infections: reducing the case fatality rate by giving penicillin before admission to hospital. BMJ 1992; 305: 141-143. Tunkel AR, Scheld WM. Acute bacterial meningitis. Lancet 1995; 346: 1675-1680. Antibiotic Guidelines Subcommittee of the Victorian Drug Usage Advisory Committee. Antibiotic guidelines. 9th ed. Melbourne: Victoria Medical Postgraduate Foundation Inc., 1996. Kaczmarski EB, Borrow R, Gray SJ, et al. Optimising ascertainment of meningococcal infection in England and Wales. In: Zollinger W, Frasch C, Deal C, editors. Abstracts of the Tenth International Pathogenic Neisseria Conference; 1996 Sep 8-13; Baltimore: 475-476. Wenger JD, Jackson LA, Raj P, Tonelli MJ. Issues in the control of outbreaks of group C meningococcal disease in the United States. Infect Dis Clin Pract 1994; 3: 136-140. Watson C. Public communication during an outbreak of infectious disease. NSW Pub Health Bull 1993; 4: 73-74.(Received 18 Nov 1996, accepted 14 Mar 1997) Authors' details Meningococcal Disease Working Party of the National Health and Medical Research Council, Canberra, ACT. Mahomed S Patel, FRACP, FAFPHM, Fellow, National Centre for Epidemiology and Population Health, Australian National University, Canberra; Peter J Collignon, FRACP, FRCPA, FASM, Infectious Diseases Physician and Microbiologist, Canberra Clinical School, Canberra Hospital, ACT; Charles R Watson, MD, FAFPHM, Chair; and Professor of Public Health and Dean of the Faculty of Health and Behavioural Sciences, University of Wollongong, NSW; Robert J Condon, MApplEpid, FAFPHM, Senior Medical Officer, Royal Flying Doctor Service of Australia, Western Operations, Jandakot, WA; Richard R Doherty, FRACP, Professor of Paediatrics and Head of Paediatric Medicine, Department of Paediatrics, Monash Medical Centre, Melbourne, VIC; Angela Merianos, MApplEpid, FAFPHM, Head, Immunisation and Surveillance Section, Disease Control, Territory Health Services, Darwin, NT; Gregory J Stewart, FRACMA, FAFPHM, Director of Health Services, Central Sydney Area Health Services, Camperdown, NSW. No reprints will be available from the authors. Correspondence: Dr M S Patel, National Centre for Epidemiology and Population Health, Australian National University, Canberra 0200. E-mail: msp868 @ nceph.anu.edu.au ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Mahomed S Patel · Peter J Collignon · Charles R Watson · Robert J Condon · Richard R Doherty · Angela Merianos · Gregory J Stewart

HTLV-I and blood safety: let the community decide Discussion on screening of blood for rare viruses must go beyond the blood transfusion services MJA 1997; 166: 454Subsequently cited in Moaven L. Should we be screening blood donors for hepatitis G virus? The case for screening. MJA 1998; 169: 373-374 Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au/>". - ©MJA1997 Despite the steady reduction over time in the risks associated with blood transfusion, there has been a parallel increase in the community's expectations of the safety standards that must be met by blood and blood products. In the past, the acute complications of transfusion were perhaps viewed by the community as acceptable risks. The contamination of blood products by HIV changed all that; here was a bloodborne infection that produced life-threatening complications years after transfusion. Virtually all patients who received HIV-contaminated blood or blood products became chronically infected and progressed to AIDS and a premature death. Furthermore, in the community, HIV was widely perceived as being associated with society's stigmatised or marginalised groups. Human T-cell lymphotropic virus type I (HTLV-I) was discovered before HIV, but screening of blood for HTLV-I was not implemented with the same degree of urgency as for HIV. In most developed countries, HTLV-I was considered to be an exotic infection which posed a minimal threat to the blood supply. Even in countries endemic for HTLV-I, less than 5% of people with the infection develop serious disease.1,2 There is so little HTLV-I-related morbidity in Australia that single cases still merit case reports.3 Nevertheless, by the mid 1980s HTLV-I screening tests were ready for mass use, and Japan, the only industrialised country with a substantial prevalence of HTLV-I infections, began screening blood for the virus. With litigation arising from HIV infection with transfusion of blood or blood products in full swing in the industrialised world, the American Red Cross in 1988 decided to screen all donations for HTLV-I.4 Can a decision be made to reduce the safety of the blood supply, even if only to a very small degree? In Australia, a response was required. The national peak blood transfusion advisory body, the Red Cross National Blood Transfusion Committee, recommended universal screening of blood donors in 1989 and again in 1991, but the National Health and Medical Research Council did not concur because, it was argued, the costs of universal screening far outweighed any public health benefit.5 Despite these differences in professional judgements, by early 1993 all Australian Red Cross blood banks had introduced HTLV-I screening. In this issue of the Journal, Whyte outlines for the first time in Australia the results of this screening and shows that Australian blood donors have among the lowest HTLV-I prevalence rates ever recorded. He then goes on to implicitly ask whether it is time to review the screening policy. The answer to this question depends very much on the perspective being taken. For blood transfusion services wishing to reduce the risk to the recipients of their products, not to mention their medicolegal vulnerability, the decision to screen all donations for HTLV-I can seem very logical, even if the prevalence of infection is very low. In the United Kingdom, where HTLV-I prevalence in blood donors is some five times higher than in Australia,6 universal screening has not been adopted, but there have been recent calls to review this policy.7 From the point of view of governments and tax-payers, facing ever-increasing demands on health care and escalating health budgets, perhaps health expenditure in other areas may have had a greater impact in value-for-money terms. Screening blood donations for HTLV-I in Australia has an annual cost of two to three million dollars per year in test kits alone, and laboratory staff and handling costs probably account for seven million dollars (E Dax, Director, National Serological Reference Centre, personal communication). The contrasting recommendations of the Australian Red Cross and the National Health and Medical Research Council on HTLV-I screening highlight a deficiency in the decision-making processes on aspects of blood transfusion in Australia. While governments fund State and Territory blood transfusion services and strongly influence their functioning, the Australian Red Cross is the legal entity liable for the blood products. The decisions by the blood transfusion services may inevitably be based on a narrower view of the issues involved than that shared by the community. Is it possible to reconsider the decision to screen blood donations for HTLV-I? Put in another way, can a decision be made to reduce the safety of the blood supply, even if only to a very small degree? If the answer is yes, the process of re-evaluation should take place in a broader context than has been adopted in the past. A framework must be established so that the decision is made by the community as a whole, not just by the blood transfusion services. The recent establishment by the Australian Health Ministers Advisory Council of a Blood and Blood Products Committee, and the national restructuring of the State and Territory Red Cross blood transfusion services into a single corporate entity (see page 453 of this issue of the journal), are valuable steps towards integrated decision-making, but these changes do not go far enough. These two entities need to be brought closer together and utilise expertise in public health, health economics and other areas, as required. A review of HTLV-I screening would ideally be carried out in the context of other infectious agents that can be transmitted by blood. It may be more cost-effective to screen for agents such as parvovirus B19 (which causes pure red cell aplasia), although susceptibility is limited to a very small proportion of the population. Hepatitis G virus and human herpesvirus type 8 (associated with Kaposi's sarcoma and B-cell body cavity lymphoma) are newly discovered viruses that may also require consideration for routine screening once tests become available.8 If deliberations about blood screening are to take place in a broader context, thought must also be given to legal changes that shift the burden of sole liability from the blood transfusion services. The New Zealand "no-fault" compensation model has long been discussed as one possible solution. Another approach may be legislated protection of the blood transfusion services against litigation, provided bloodscreening policies were determined and implemented according to specified guidelines. Although HTLV-I-related disease has been rare in Australia, HTLV-I infection is present at relatively high levels in some populations of indigenous people, and probably also in some migrant groups. If it is decided to reconsider HTLV-I screening of donations, its abandonment is not the only alternative to the status quo. A policy of screening only new donors would have detected all 21 HTLV-I-positive individuals in the time period of Whyte's study and reduced the extent of testing required by over 80%. Therefore, it may be sufficient to screen blood donors only once and thereafter assume that their HTLV-I status remains unchanged, or carry out testing again after five or 10 years. Another approach could be to use the donor interview to identify people who may be at higher risk of HTLV-I. Screening on the basis of country of birth, for example, would have detected a third of the individuals confirmed positive for HTLV-I in Whyte's study. Blood transfusion will never be risk-free. With the risk-benefit balance now many times more favourable than it has ever been, perhaps the time is right to engage the community in a discussion that brings both public health and economic issues into decision-making about blood safety. John M Kaldor Deputy Director and Professor of Epidemiology National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, NSW. Morris JDH, Eddleston ALWF, Crook T. Viral infection and cancer. Lancet 1995; 346: 754-758. Kondo T, Kono H, Miyamoto N, et al. Age- and sex-specific cumulative rate and risk of ATLL for HTLV-I carriers. Int J Cancer 1989; 43: 1061-1064. Kirkland MA, Frasca J, Bastian I. Adult T-cell leukaemia lymphoma in an Aborigine. Aust N Z J Med 1991; 21: 739-741. Centers for Disease Control. Licensure of screening tests for antibody to human T-lymphotropic virus type I. MMWR Morb Mortal Wkly Rep 1988; 37: 736-740, 745-747. National Health and Medical Research Council, Communicable Diseases Standing Committee. HTLV-I screening: outcome of consideration by the Executive. Canberra: NHMRC, 4 December 1992. Brennan M, Runganga J, Barbara JAJ, et al. Prevalence of antibodies to human T cell leukaemia/lymphoma virus in blood donors in north London. BMJ 1993; 307: 1235-1239. Pagliuca A, Pawson R, Mufti GJ. HTLV-I screening in Britain. BMJ 1995; 311: 1313-1314. Allain J-P. Screening blood donors for markers of new viruses. Lancet 1997; 349: 584-585. World Health Organization, International Agency for Research on Cancer. Human Immunodeficiency viruses and human T-cell lytmphotropic viruses. Monographs from the meeting of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; 1996 June 11-18; Lyon. Geneva: WHO, 1996. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

John M Kaldor