eMJA: Ziegler and Ffrench, XIII International AIDS Conference, Durban, 9-14 July, 2000

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
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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

©MJA 2000
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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].)

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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.)

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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.)

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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.)

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