Volume 169 Issue 7

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

Should we be screening blood donors for hepatitis G virus? The case for screening We should not take the risk that this virus may cause serious disease Len D Moaven MJA 1998; 169: 373-374 For the case against, see Wong et al Introduction - Transfusion transmission of HGV - Effects of HGV - Screening issues - Costs of screening - Conclusion - References - Authors' details - - More articles on Infectious diseases and parasitology - ©MJA1998 Introduction Hepatitis G virus (HGV) and its strain variant, GB virus C, were discovered by workers looking for novel parenterally spread hepatotropic agents.1,2 Currently, the only method of detecting HGV-infected individuals is by using nucleic acid amplification methods, such as the reverse transcription polymerase chain reaction (RT-PCR), to test for HGV RNA. Results from these methods suggest that 1%-4% of volunteer blood donors in developed countries are HGV RNA positive,3-6 and that most of these donors are chronic carriers.6 It is not yet known why there is such a high prevalence of chronic HGV carriage in blood donors. Mother-to-baby7 and sexual transmission8 may be important in the transmission of this virus; however, HGV is known to be transmitted by blood transfusion.9 This has been carefully documented by studying HGV-infected donors and the recipients of their blood and demonstrating a temporal relationship between donation of blood products and acquisition of HGV.3,5,10-12 In some studies, this has been further confirmed by sequencing the HGV isolates and demonstrating a close relationship between viruses in the donor and recipient.5,11,12 Transfusion transmission of HGV Approximately three-quarters of those who acquire HGV by blood transfusion will resolve their infection, and this appears to be associated with a protective immune response.10,12,13 So not all recipients of HGV-infected blood will become chronic carriers of the virus; either they will resolve their infection or they will have been previously exposed and are immune to re-infection. Other host factors also play a role; for example, if the recipient is immunosuppressed it is more likely that viraemia will not resolve.12 Even so, assuming that 15% of recipients are immune or already infected with HGV13 (unpublished data) and that only a quarter of the remainder will become chronic carriers (and that acute resolving infection has no effect on morbidity or mortality), that would still leave about one in five recipients of HGV-infected blood becoming chronic carriers and possibly suffering from the unknown sequelae of chronic HGV infection. Effects of HGV Currently, HGV is only associated with a mild rise in transaminases during acute infection -- not unusual for an acute viral infection.3 Persistent infection is probably not associated with significant liver disease, although some groups disagree.14 There is a contentious association with non-A-E fulminant hepatic failure,15,16 but researchers in Australia, the United Kingdom and Japan have not found a direct causal link with fulminant liver disease.12,17,18 The high prevalence of HGV infection in the general population makes demonstration of disease association particularly difficult. Hence, many researchers have argued that this virus is not currently of concern to transfusion medicine.4,9Although the evidence suggests that HGV is probably not hepatotropic, the virus is replicating somewhere in the infected individual. Many researchers have argued that HGV may be a latent, well adapted virus of low virulence.19 HGV is a positive-strand RNA virus and I would argue that it is unlikely that this type of virus could cause chronic infection and not be associated with a disease syndrome.6 The only other example of a positive-strand RNA virus (which commonly causes chronic infection in man) is hepatitis C virus (HCV). There are examples of so-called latent RNA infections in relatively short-lived animals, but it is difficult to imagine that these accurately reflect infection in man for many years. In any case, during this persistent infection HGV is not quiescent -- individuals have serum viraemias greater than 107 genome equivalents per millilitre.20 This is not indicative of a dormant infection,21 and it can be argued that such a viral burden must eventually have an adverse effect on the target organ of replication. Many HGV carriers appear to be healthy, but the same is true of HCV-infected blood donors and recipients. For example, Seeff et al failed to detect any significant increase in liver disease or mortality in HCV-infected blood recipients followed for almost 20 years.22 It is not until one looks in the gastroenterology or liver transplant clinics that an association between HCV and (liver) disease becomes evident. As the tissue tropism of HGV is yet to be defined, it is not surprising that the HGV syndrome has not yet been discovered. I believe that a significant disease association will be found -- perhaps we should look for it in the medical clinics (for example, the renal, rheumatoid or respiratory clinics) where people with the HGV syndrome may be ending up, rather than following them to see if they get there. Screening issues The RT-PCR test is a relatively expensive, technically demanding and time-consuming assay. It has been argued that this technology precludes mass screening of blood donors,4,9 but these limitations can be overcome. There are now commercially available methods for RNA extraction, reverse transcription and polymerase chain reaction, and detection of RT-PCR products. These systems can overcome the problems of quality control, ease of use and reproducibility of the assay. By pooling serum samples (for example, pools of 10) economies can be made. For a blood transfusion service that processes about 250 000 donations per year, one could assume that this is made up of 125 000 regular blood donors (with 25 000 new donors every year). Assuming that the prevalence of HGV infection is relatively low in Australian blood donors,6,12 that donors need only be screened once, and that 25 000 donations are used for blood products (incorporating sufficient inactivation steps so that HGV screening is not required), then initially only 100 RT-PCR reactions would need to be carried out each day, and this number would dramatically decrease over time. One could process these in "real-time", within 12-24 hours. Costs of screening Each RT-PCR test (including sample preparation and detection) would cost $35 using an automated station (Ms Dianne Young, Product Manager, Roche Diagnostics, personal communication). By adopting the above strategy the cost of reagents for a year would be in the order of $1 million for this service. This figure does not include labour or any other attendant costs. For comparison, the first generation anti-HCV testing would have cost, again for reagents alone, about $1.7 million in 1990 to screen 250 000 donations, using an assay that was only 70% sensitive. Although there is much resistance to nucleic acid testing as a screening method, I believe that it is the "ultimate" screening assay and that it will be introduced for currently screened pathogens within the next 18 months (Dr Peter Simmonds, Senior Lecturer, Edinburgh University, personal communication). Now is the time for blood banks to embrace this technology. Another consideration regarding screening is what to tell individuals, for example blood donors, who are found to be HGV RNA positive. The paucity of information should not be an ethical dilemma. Individuals do not necessarily require "facts"; they need consistent information regarding the current state of knowledge. It is important for individuals to have reliable sources of information or contacts and to be followed up as new information is accrued. Conclusion Decision making under uncertainty is difficult, but we need to learn from the past.23 Historically, many viruses are initially "orphaned" and are often described as latent or non-pathogenic during this period. It is perhaps instructive that this is true of some currently screened viruses -- including hepatitis B virus and HIV. The repercussions of not acting now and waiting for definitive data9 far outweigh the cost-benefits of any current actuarial decision. At the very least this debate should be widened to include the general community.24 I, and others,11 believe that the time has come to screen blood donors for hepatitis G virus. References Linnen J, Wages J Jr, Zhang-Keck ZY, et al. Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent. Science 1996; 271: 505-508. Simons JN, Leary TP, Dawson JG, et al. Isolation of novel virus-like sequences associated with human hepatitis. Nat Med 1995; 1: 564-569. Alter HJ, Nakatsuji Y, Melpolder J, et al. The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease. N Engl J Med 1997; 336: 747-754. Roth WK, Waschk D, Marx S, et al. Prevalence of hepatitis G virus and its strain variant, the GB agent, in blood donations and their transmission to recipients. Transfusion 1997; 37: 651-656. Yoshikawa A, Fukuda S, Itoh K, et al. Infection with hepatitis G virus and its strain variant, the GB agent (GBV-C), among blood donors in Japan. Transfusion 1997; 37: 657-663. Moaven LD, Hyland CA, Young IF, et al. Prevalence of hepatitis G virus in Queensland blood donors. Med J Aust 1996; 165: 369-371. Moaven LD, Tennakoon PS, Bowden DS, Locarnini SA. Mother-to-baby transmission of hepatitis G virus. Med J Aust 1996; 165: 84-85. Stark K, Bienzle U, Hess G, et al. Detection of the hepatitis G virus genome among injecting drug users, homosexual and bisexual men, and blood donors. J Infect Dis 1996; 174: 1320-1323. Alter HJ. G-pers creepers, where'd you get those papers? A reassessment of the literature on the hepatitis G virus. Transfusion 1997; 37: 569-572. Pilot-Matias TJ, Carrick RJ, Coleman PF, et al. Expression of the GB virus C E2 glycoprotein using the Semliki Forest virus vector system and its utility as a serologic marker. Virology 1996; 225: 282-292. Shimizu M, Osada K, Okamoto H. Transfusion-transmitted hepatitis G virus following open heart surgery [letter]. Transfusion 1996; 36: 937. Moaven LD, Locarnini SA, Bowden DS, et al. Hepatitis G virus and fulminant hepatic failure: evidence for transfusion-related infection. J Hepatol 1997; 27: 613-619. Moaven LD, Young IF, Bowden DS, Locarnini SA. Prevalence of hepatitis G virus antibodies in Queensland blood donors [letter]. Med J Aust 1997; 166: 507-509. Colombatto P, Randone A, Civitico G, et al. Hepatitis G virus RNA in the serum of patients with elevated gamma glutamyl transpeptidase and alkaline phosphatase: a specific liver disease? J Viral Hepat 1996; 3: 301-306. Yoshiba M, Okamoto H, Mishiro S. Detection of the GBV-C hepatitis virus genome in serum from patients with fulminant hepatitis of unknown aetiology. Lancet 1995; 346: 1131-1132. Heringlake S, Osterkamp S, Trautwein C, et al. Association between fulminant hepatic failure and a strain of GBV virus C. Lancet 1996; 348: 1626-1629. Kuroki T, Nishiguchi S, Tanaka M, et al. Does GBV-C cause fulminant hepatitis in Japan? [letter]. Lancet 1996; 347: 908. Sallie R, Shaw J, Mutimer D. GBV-C virus and fulminant hepatic failure [letter]. Lancet 1996; 347: 1552. Miyakawa Y, Mayumi M. Hepatitis G virus -- a true hepatitis virus or an accidental tourist? N Engl J Med 1997; 336: 795-796. Hsieh SY, Yang PY, Chen HC, Liaw YF. Cloning and characterization of the extreme 5«-terminal sequences of the RNA genomes of GB virus C/hepatitis G virus. Proc Natl Acad Sci USA 1997; 94: 3206-3210. Perelson AS, Neumann AU, Markowitz M, et al. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 1996; 271: 1582-1586. Seeff LB, Buskell-Bales Z, Wright EC, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med 1992; 327: 1906-1911. Leveton LB, Sox HC Jr, Stoto MA. HIV and the blood supply: an analysis of crisis decision making. Transfusion 1996; 36: 919-927. Kaldor JM. HTLV-I and blood safety: let the community decide. Med J Aust 1997; 166: 454-455. (Received 14 May 1997, accepted 4 Feb 1998) Authors' details St John of God Pathology, Midland, WA. Len D Moaven, FRCPA, Clinical Microbiologist. Reprints: Dr L D Moaven, St John of God Pathology, 243 Great Eastern Highway, Midland, WA 6056. E-mail: profpukATopera.iinet.net.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/>

Len D Moaven

Should we be screening blood donors for hepatitis G virus? The case against screening Given the absence of a disease association, screening is not justified Ping-Yee Wong, Patrick J Coghlan and Peter W Angus MJA 1998; 169: 375-377 For the case against, see Moaven Introduction - Is HGV pathogenic? - How common is the infection among blood donors? - What is the sensitivity and specificity of current tests for HGV? - What are the costs of testing? - What are the risks of not screening? - What is the prevailing expert opinion? - Conclusion - Acknowledgement - References - Authors' details - - More articles on Infectious diseases and parasitology - ©MJA1998 Introduction The availability of a reliable source of safe blood and blood products is essential for medical practice. Currently, blood donors in Australia are screened for syphilis, hepatitis B surface antigen (HBsAg), and antibodies for HIV types 1 and 2, hepatitis C virus (HCV) and human T cell lymphotropic virus (HTLV) types I and II. This screening of blood donors and modern blood product manufacturing techniques have greatly reduced the risk of transmission of serious disease by transfusion.1 In the future, advances in genomic amplification technology may allow routine screening of donor blood for HCV, HBV and HIV genomes, and thus further reduce risks by allowing detection of viraemia during the so-called "window period" of acute infection (the phase of infection before seroconversion). Advances in molecular biological techniques will also enable the development of tests for new potentially pathogenic agents transmitted through blood transfusion, of which the recently discovered hepatitis G virus (HGV) is likely to be but one. These developments will inevitably result in pressure on blood service administrations to expand their screening repertoire. However, the introduction of a new test can be costly "in diminished donor resources, injured donor relationships, and reduced blood supply",2 and financially. Furthermore, experience has shown that blood donor screening tests are difficult to withdraw once introduced,3 even if it can later be shown that the test does not improve outcomes. The decision of Australian blood transfusion services to screen all blood donations for HTLV-I in 1992-1993 is one such example.4 Although there is no consensus regarding the pathogenicity of HGV, there have been calls for the introduction of screening for this newly discovered flavivirus. For this issue the key questions are:ATsubA:Is there evidence that HGV is transmitted through blood transfusion? HGV transmission by blood transfusion has been clearly demonstrated in several studies.5-7 For example, in a retrospective study, Heuft et al traced the donations from two HGV RNA positive blood donors over the previous 18 months.6 Of 23 recipients who received a transfusion from either of the two donors, 15 (65%) tested positive for HGV RNA after six to 11 months. The authors were able to demonstrate by molecular sequencing that three of six (50%) recipients tested were infected by either of the donors, by sequence homology between donor and recipient of more than 99%. Is HGV pathogenic? Transfusion-associated HGV infection is usually not associated with any detectable illness or abnormality of liver function tests.8 A few instances of mild alanine aminotransferase elevation have been documented in recipients of HGV-infected blood, but a cause-and-effect relationship has not been proven.8 Following acute infection HGV RNA may persist in plasma for a decade or more.8 In one study, most individuals were found to have cleared their infection after a period of viraemia of 2-6 months,9 but persistence of HGV RNA is much more likely in immunocompromised subjects.6HGV has been linked with fulminant hepatic failure;10 however, the Australian experience has been that, in patients with fulminant liver failure referred for liver transplantation who were found to be HGV positive, the virus appeared to have been transmitted to the patients after the onset of their illness, as the result of transfusion with HGV-infected blood products.11 There is also no convincing evidence that chronic HGV infection causes liver injury or exacerbates other chronic liver diseases.12 Thus, there is considerable doubt that HGV even qualifies as a "hepatitis virus".13 To date, HGV infection has not been linked with disease of any other organ system. However, vertical transmission of HGV has been demonstrated7,14 and sexual transmission is suspected.15 How common is the infection among blood donors? The prevalence of HGV RNA in various volunteer blood donor populations is summarised in the Box. HGV has been found in all countries where testing has been performed. Its prevalence varies from 1% to 9%; in Australia it is reported to be between 1% and 4%.17,22 Thus, HGV appears to be ubiquitous, and screening for the virus would lead to exclusion of a significant proportion of healthy blood donors. What is the sensitivity and specificity of current tests for HGV? At this time, no serological test has the potential to be used for screening; the recently described anti-E2 antibody to HGV seems to indicate past rather than current infection.23 Most studies use the reverse transcription polymerase chain reaction (RT-PCR) test to detect viraemia. Although this test appears reasonably specific, the actual specificity depends on the primers used.24 As the infected individual may not always be viraemic, the false-negative rate may be unacceptably high.8 Furthermore, none of the PCR approaches that have been used have been subjected to detailed analysis of their sensitivity and specificity. As there is no confirmatory test available, there would be considerable difficulty in dealing with discordant results and in donor counselling. What are the costs of testing? The RT-PCR test is expensive and cumbersome to employ on a large scale. A major investment in equipment and staff training programs is required. The logistical difficulties involved in the transport of PCR-quality samples over long distances and the delay in obtaining results will add to the overall cost. Additionally, Australian blood services can ill-afford the deferral of up to 4% of blood donors as a result of positive test results, because this will occur on top of the steady decline in whole blood donations of 27% since 1981.25 There are likely to be false positive and discordant results, and these will add significantly to the number of deferrals. The test may reduce the rate of transfusion-transmitted HGV infection, but may lead to anxiety and ill-will among HGV-positive donors who will probably have no clinically apparent disease.26 What are the risks of not screening? As outlined above, HGV has not been linked to significant disease. Thus, even if blood is not screened for HGV and the recipient does develop a positive test for the virus, the risk to the patient is minimal. The legal issues which arise concerning screening for HGV are complicated. An NHMRC expert committee, when it considered the legal ramifications related to HTLV-I screening,27 reflected that, whereas it is not easy for people transfused with contaminated blood to claim successfully for compensation, the spectre of large damages does significantly influence a blood transfusion service's decision on whether to screen. Blood services can deal with the perceived risk from adverse public opinion by putting an evidence-based view about the pros and cons of the new screening test on record and encouraging public debate and discussion. What is the prevailing expert opinion? Recent reviews2,28-31 do not support routine screening of donated blood for HGV. The American Association of Blood Banks, in its most recent examination of the issue, concluded that screening was not warranted, but called for ongoing studies to look for "a detectable disease marker for HGV", and "additional searches for hepatic and extrahepatic disease associations" of HGV infection before making a final decision.32 As far as we are aware, no blood service has introduced routine HGV RNA testing of blood donors. Conclusion The development of successful tests for viruses such as HIV and HCV has been a major breakthrough that has greatly reduced the risks associated with blood transfusion. HGV is likely to be the first of a number of new viruses that will be detected in people by studies using the new molecular biological techniques. However, in the absence of evidence of a major ongoing disease risk associated with blood transfusion, blood services need to respond with caution to calls for the introduction of new test strategies. In these situations a rational and transparent process should lead to a reasonable outcome for stakeholders. In the absence of a clear disease association with HGV and with the knowledge that testing would be costly and cause a further diminution in the availability of blood products for no apparent reason, we do not believe that HGV screening can be justified at this time. Acknowledgement The authors would like to thank Dr Anthony Keller, Chairman of the National Donor and Product Safety Committee, Australian Red Cross Blood Service, for his critical comments on a final draft of the manuscript. References Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion- transmitted viral infections. N Engl J Med 1996; 334: 1685-1690. Alter HJ. G-pers, creepers, where'd you get those papers? A reassessment of the literature on the hepatitis G virus [editorial]. Transfusion 1997; 37: 569-572. Holland PV. Viral infections and the blood supply [editorial]. N Engl J Med 1996; 334: 1734-1735. Whyte GS. Is screening of Australian blood donors for HTLV-I necessary? Med J Aust 1997; 166: 478-481. Shimizu M, Osada K, Okamoto H. Transmission of GB virus C by blood transfusions during heart surgery. Vox Sang 1997; 72: 76-78. Heuft HG, Berg T, Schreier E, et al. Epidemiological and clinical aspects of hepatitis G virus infection in blood donors and immunocompromised recipients of HGV-contaminated blood. Vox Sang 1998; 74: 161-167. Roth WK, Waschk D, Marx S, et al. Prevalence of hepatitis G virus and its strain variant, the GB agent, in blood donations and their transmission to recipients. Transfusion 1997; 37: 651-656. Alter HJ, Nakatsuji Y, Melpolder J, et al. The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease. N Engl J Med 1997; 336: 747-754. Simons JN, Desai SM, Mushahwar IK. The GB viruses: isolation, characterization, diagnosis, and epidemiology. Viral Hepatitis Reviews 1996; 2: 229-246. Yoshiba M, Okamoto H, Mishiro S. Detection of the GBV-C hepatitis virus genome in serum from patients with fulminant hepatitis of unknown aetiology. Lancet 1995; 346: 1131-1132. Moaven LD, Locarnini SA, Bowden DS, et al. Hepatitis G virus and fulminant hepatic failure: evidence for transfusion related infection. J Hepatol 1997; 27: 613-619. Goldstein NS, Underhill J, Gordon SC, et al. Comparative histologic features of liver biopsy specimens from patients coinfected with hepatitis G and C viruses with chronic hepatitic C virus alone. An age-, sex-, disease duration-, and transmission-matched controlled study of chronic hepatitis. Am J Clin Pathol 1997; 108: 625-632. Batts KP. Hepatitis G. A virus in search of a disease [editorial]. Am J Clin Pathol 1997; 108: 616-618. Viazov S, Riffelmann M, Sarr S, et al. Transmission of GBV-C/HGV from drug-addicted mothers to their babies. J Hepatol 1997; 27: 85-90. Kao JH, Chen W, Chen PJ, et al. GB virus-C/hepatitis G virus infections in prostitutes: possible role of sexual transmission. J Med Virol 1997; 52: 381-384. Yoshikawa A, Fukuda S, Itoh K, et al. Infection with hepatitis G virus and its strain variant, the GB agent (GBV-C), among blood donors in Japan. Transfusion 1997; 37: 657-663. Coghlan PJ, Wong P-Y, Katsoris J, et al. Hepatitis G -- issues for the blood bank [abstract]. Presentation at the Fourth National Symposium on Hepatitis C and Related Viruses Including Hepatitis G. 23 November 1996, St Vincent's Hospital, Melbourne, Australia. Loiseau P, Mariotti M, Corbi C, et al. Prevalence of hepatitis G virus RNA in French blood donors and recipients. Transfusion 1997; 37: 645-650. Wang Y, Chen H-S, Fan M-H, et al. Infection with GB virus C and hepatitis C virus in hemodialysis patients and blood donors in Beijing. J Med Virol 1997; 52: 26-30. Bassit L, Kleter B, Ribeiro-dos-Santos G, et al. Hepatitis G virus: prevalence and sequence analysis in blood donors of Sao Paulo, Brazil. Vox Sang 1997; 74: 83-87. Jarvis LM, Davidson F, Hanley JP, et al. Infection with hepatitis G virus among recipients of plasma products. Lancet 1996; 348: 1352-1355. Moaven LD, Hyland CA, Young IF, et al. Prevalence of hepatitis G virus in Queensland blood donors. Med J Aust 1996; 165: 369-371. Dille BJ, Surowy TK, Gutierrez RA, et al. An ELISA for detection of antibodies to the E2 protein of GB virus C. J Infect Dis 1997; 175: 458-461. Kao JH, Chen PJ, Chen W, et al. Amplification of GB virus-C/hepatitis G virus RNA with primers from different regions of the viral genome. J Med Virol 1997; 51: 284-289. Whyte G. Quantitating donor behaviour to model the effect of changes in donor management on sufficiency in the blood service. Vox Sang. In press. Busch MP. To thy (reactive) donors be true! Transfusion 1997; 37: 117-120. National Health and Medical Research Council. Case study of screening blood donations for human T-cell lymphotropic virus type I (HTLV-I). Canberra: AGPS, 1993. Di Bisceglie AM. Hepatitis G virus infection: a work in progress. Ann Intern Med 1996; 125: 772-773. Allain J-P. Screening blood donors for markers of new viruses [commentary]. Lancet 1997; 349: 584-585. Karayiannis P, Thomas HC. Current status of hepatitis G virus (GBV-C) in transfusion: is it relevant? Vox Sang 1997; 73: 63-69. Barbara JA. Does GB virus C ('hepatitis G virus') threaten the safety of our blood supply? [editorial]. Transf Med 1997; 7: 75-76. Snyder EL, Lipton KS. Hepatitis G virus: status report and assessment of clinical relevance. AABB Association Bulletin 1998; Bulletin No 98-4, 18 July 1998. (Received 20 May, accepted 12 August, 1998) Authors' details Australian Red Cross Blood Service -- Victoria, South Melbourne, VIC. Ping-Yee Wong, MB BS, MRCP, Senior Medical Officer. Australian Red Cross Blood Service -- National Office, Fitzroy, VIC. Patrick J Coghlan, FRCPA, FRCPath, Director of Intellectual Capital. Gastroenterology and Liver Transplant Units, Austin and Repatriation Hospital, VIC. Peter W Angus, MD, FRACP, Hepatologist. Reprints will not be available from the authors. Correspondence: Dr P-Y Wong, Australian Red Cross Blood Service -- Victoria, PO Box 354, South Melbourne, VIC 3205. E-mail: pwongATrcbbv.org.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/>

Ping-Yee Wong · Patrick J Coghlan · Peter W Angus

Surgery and the randomised controlled trial: past, present and future Michael J Solomon and Robin S McLeod One must attend in medical practice not primarily to plausible theories, but to experience combined with reason -- Hippocrates1 MJA 1998; 169: 380-383 For editorial comment, see Maddern Synopsis - Introduction - How do surgeons assess treatment effectiveness? - Who is performing surgical RCTs and where do they publish? - How good are surgical randomised controlled trials? - Are there problems initiating surgical RCTs? - Where to now? - Conclusion - References - Authors' details - - More articles on Surgery - ©MJA1998 Synopsis Randomised controlled trials (RCTs), with their prospective definition of methods and outcome measures, double-blind assessment of outcomes and unbiased selection of subjects and controls, provide the best possible evidence for deciding the value of a medical or surgical intervention. Few surgical studies are designed as RCTs, and those that are should be of a higher quality. The lack of good surgical RCTs may be a result of surgeons lacking the necessary training, expertise and desire to perform RCTs, inadequate funding from granting agencies, difficulties in securing patient consent or a lack of sufficient patient numbers. If an RCT is not feasible for a particular study, then alternative research designs, such as prospective matched-pair trials, may need to be better developed and used. If RCTs can be performed, other strategies to increase the number and quality of RCTs may be needed: Education of surgeons in clinical research methods Improved funding of surgical RCTs Compulsory evaluation of new techniques and technology before their general adoption is permitted. Introduction Recent decades have brought an increasing awareness of the need for stronger clinical research methods. Statistical and epidemiological principles have been adapted to clinical research, and there has been recognition of a hierarchy of research designs, their individual strengths and weaknesses, and of the clinical situations to which each is suited. Understanding of the attributes and advantages of the controlled clinical trial has grown. In the medical literature, this has led to an increase in the proportion of studies based on comparison of two groups, particularly since the 1980s.2-5 In contrast, the surgical literature has shown no increase in clinical trials or studies with adequate control groups.6-8 Surgeons have been criticised for a lack of adequate scientific assessment of new and old techniques and technology. In response, it has been argued that the problems of surgery lie not with the quality of clinical research but with doctor-patient communication, and that more science and more clinical trials cannot heal the deep rifts in communication between surgeons and their patients.9 Given the general acceptance of the randomised controlled trial (RCT) as the "gold standard" in clinical research, why is it not used more often to research surgical techniques and interventions? Is it the most appropriate research design for clinical research in surgery? What are the barriers to, or arguments against it? How do surgeons assess treatment effectiveness? RCTs comprise only 3%-9% of clinical study designs across all areas of surgery, despite the rapid expansion of new technology in surgery and the linear improvement in adoption of RCTs in other areas of medicine (see Box).5,6,10-12 Several publications have assessed clinical study designs adopted in general surgery. Pollock determined the relative frequency of RCTs in the British Journal of Surgery: in 1965 there were none; in 1975, 7%; and in 1985, 9%.12 A more recent assessment of all clinical studies, published between 1980 and 1990 in three major international surgical journals, has demonstrated little change in the frequency of different clinical study designs.6 Retrospective studies involving only one cohort of patients make up well over 80% of clinical studies in the surgical literature sampled in the past 15 years, with case reports comprising a third of all the clinical studies.6 The frequency of case reports decreased over the 1980s, but they were replaced, not by clinical studies with stronger research designs, but by cross-sectional surveys and case series.6 Surgical specialties show similar patterns. In the 1970s, 45% of abstracts accepted at the annual joint meetings of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery were cross-sectional surveys.10 The proportion of cross-sectional surveys decreased in the 1980s to 30%, while RCTs increased, but from only 1% in the 1970s to 5% in the 1980s.11 Only 5% of articles in the Journal of Neurosurgery between 1973 and 1977 were controlled clinical trials.11 Who is performing surgical RCTs and where do they publish? Given that the surgical literature contains few RCTs in surgery compared with the plethora of case studies, are surgical RCTs published elsewhere, or under a different guise? A search of all RCTs published in general surgery showed that only a third had a surgeon as the principal author, only a quarter were published in surgical journals (the rest being published in medical journals), and (most importantly) less than a quarter actually assessed surgical operations. Most trials looked at medical therapies in surgical patients (eg, adjuvant chemotherapy, or prophylaxis against postoperative infection or deep venous thrombosis).13 How good are surgical randomised controlled trials? The general surgical literature shows an increase in knowledge of trial design during the past decade, with increases in sample sizes, multicentre studies and duration of follow-up, although there has been no increase in the number of prospective trials or cohort studies.6 There are, nevertheless, problems with the standard of the RCTs performed; in particular, the false negative conclusions (Type II errors) that are perceived to be the primary result of so many RCTs in surgery.14 Contrary to this, Gilbert et al found that about 50% of surgical RCTs find in favour of the new therapy, although the authors did not specify the number of RCTs that involved surgical operations, whether surgeons performed the RCTs, or the standard of the RCTs.15Three recent reviews of the strengths and weaknesses of surgical RCTs used qualitative scoring systems to assess the studies in terms of their science rather than their clinical applicability.6,13,16 In more than 90% of trials reviewed, basic issues such as sample size calculation were ignored, so inadequacies in the power of the study to make valid conclusions were not considered. More than a third of trials did not specify exclusion criteria, and an equal proportion made no attempt to eliminate bias by measuring outcomes objectively. In 20% of surgical RCTs, the conclusions were not justified by the data. The most recent review focused on RCTs in laparoscopic surgery and found major errors in sample size assessments and in determining objective outcomes.16 Using a 10-point qualitative score to compare the standard of RCTs, nonrandomised controlled trials and retrospective cohort designs in general surgery since 1980, there was found to be some improvement in all types of comparative studies, including RCTs, but the differences did not reach significance.6 Using the more complex scoring system devised by Chalmers et al for meta-analysis of RCTs, it is possible to compare trials from different specialties in medicine and surgery. Chalmers' group has shown the standard of RCT in medicine increased in a linear fashion through the 1980s.5,17 In surgery, the only study of RCTs using Chalmers' system was performed in general surgery for the year 1990, and the mean quality score for these surgical RCTs was similar to that in other medical disciplines.13 Nevertheless, the quality was shown to be lower if a surgeon was the principal author, and the quality varied depending on whether the trial was published in a medical or surgical journal. The number of centres involved in trials also influenced the quality, and trials involving surgical operations in an arm of the trial were of significantly lower standard than those comparing medical therapies in surgical patients. There were significant differences in the standard of trials across the general surgical specialty subgroups.13 Are there problems initiating surgical RCTs? Despite several successful RCTs of surgical operations in the 1960s, the fall of the surgical RCT has perhaps been more notable than its rise.12,18-22 Why is the RCT not more widely adopted for assessing the effectiveness of surgical operations? Recruitment problems Even when there is indecision among competent experts faced with competing therapies (equipoise),there may be specific methodological and feasibility problems in surgery that make randomisation difficult.23-26 There seem to be important differences in compliance with randomised allocation of treatment, irrespective of patient preferences, when comparing drugs with surgery.27 Perhaps the most poorly understood variable, however, is patient preference.28-30 Whether a patient elects to enter a clinical trial may reflect a principled view of trials themselves, but may also result from differences in the "magnitude" of competing therapies (eg, surgery v. drugs, or major v. minor surgical procedures).31-32 Doctors, when asked to choose from competing therapies as expert "surrogates" for their patients, show a low and variable acceptance of trials (3%-60%), and their preferences for therapies depend on their specialty training and geographical differences (rural v. urban) in their practices.33,34 RCTs have successfully assessed therapies of unequal magnitude in the past: for instance, coronary artery surgery versus medical therapy for ischaemic heart disease, and lumpectomy versus mastectomy for early stage breast cancer, although poor accrual did threaten the latter trial, and the external validity (generalisability) remains in question for the larger group of non-participant breast cancer patients.35 Another major barrier may be that surgeons perceive randomisation of therapies as creating uncertainty, both for themselves and their patients.35,36 One review assessed all the articles in gastrointestinal surgery published in one year, identified the treatment effectiveness hypotheses discussed in each article and determined whether an RCT could have been performed.28 Less than 40% of the published hypotheses involving surgical operations would have been answered successfully by an RCT, even assuming an ideal setting with unlimited resources and availability of all clinical cases. The two most important barriers were, firstly, that the disease incidence was not common enough to perform an RCT even with 100% accrual and, secondly, that patient preference was highly likely to severely limit accrual due to a dramatic inequality in the magnitude of the competing therapies. These two factors alone would have precluded 47% of all treatment evaluation questions involving surgical operations. Methodological issues would have prevented an RCT in only 2% of cases.28 This is clearly only part of the answer. While this review suggests that, even in an ideal clinical research setting, RCTs are applicable to less than 40% of questions involving surgical treatment options, published surgical RCTs account for only 3%-9% of articles.28 Attitudinal problems It may be that surgeons see little need for RCTs. If the proportion of different study designs in the literature is an accurate guide, surgeons appear to accept the results of weaker clinical studies with no comparative groups, no prospective collection of data and no attempt to minimise selection bias.6,10-12 Perhaps clinical research lacks the same esteem that basic research affords in academic surgery; this would explain the abundance of surgical journals weighted heavily towards basic research and the lack of a surgical journal where high quality surgical clinical trials can be found. Funding problems Few surgeons appear to obtain funding for trials, although how many apply is unknown.12 This may reflect a lack of interest in surgical trials among potential funders (industry, community organisations and government bodies), a lack of training on the part of surgeons, or lack of a controlling body like the United States Food and Drug Administration.6,8,37 Good trial design and quality assurance (internal validity) are clearly major issues in surgical RCTs, and it is possible that the qualitative weaknesses of surgical RCTs (which may have a lower standard of research protocol) influences funding allocations from major granting bodies. If so, this may counter criticisms that the lack of funding for surgical RCTs is because physicians and laboratory researchers are overrepresented on granting bodies. Recent experiences in laparoscopically assisted colorectal cancer surgery have highlighted many difficulties in the assessment of new technology and the role of the RCT. Despite initial enthusiasm and widespread adoption in the early 1990s (without adequate trials), the potential to do harm from port-site recurrence (cancer occurring in the laparoscopic port holes) and the additional expense of this surgical technique mean that it is now largely abandoned (without adequate trials).38 Problems with standardisation of therapy and accreditation of surgeons in laparoscopic resection have been major issues in international trials and in planned trials in Australia and New Zealand.39 Multicentre trials in Australia were supported by the Royal Australasian College of Surgeons and the Commonwealth Department of Human Services and Health in 1995, but, despite good trial design involving the NHMRC Clinical Trials Centre, five major colorectal centres, two years of planning and a clinical question with significant ramifications for costs of treatment, quality of life and survival, federal funding was withdrawn before the first patient entered the trial.40 Lack of funding is obviously a major deterrent to large surgical RCTs. Where to now? For the questions that can perhaps be answered by RCTs, the number and standard of RCTs, and thus the quality of evaluation of surgical interventions, may be improved by more economic encouragement from funding agencies and stronger control of new technology by governing bodies (eg, specialist societies, surgical colleges), with a requirement that trials be carried out before, rather than after, widespread adoption of new procedures. It is clear that not all clinical questions can be addressed effectively by an RCT. Rather than continue to assert that the RCT is the only method of evaluating treatment effectiveness and blaming surgeons for not adopting this standard, we need to define better the clinical treatment effectiveness questions that can and should be answered by an RCT. This may involve preference trials (pilot studies of patient and clinician compliance with treatment allocations) before RCTs, as the preferences of both patient and surgeon are probably one of the most significant barriers to the surgical RCT. The development of alternative research designs, both prospective and retrospective, with methods modelled on the rigour of RCT, remains a task for clinical researchers and epidemiologists.28,33-35 For example, matched-pair trials (where preferences are incorporated into the trial design) can still include randomisation for the patients and surgeons, with no strong preferences.28 Internal validity can still be strong, with rigid inclusion and exclusion criteria, prospective data collection, objective outcome measures, and stratified analyses performed to take into account these preferences and the lack of randomisation at inception. While the effects of random error cannot be minimised, systematic error can be reduced with good trial design and analysis. The disadvantages of the effect of random error in these trial designs without randomisation may be minimised by better accrual of the total cohort of eligible patients, avoiding selection biases and improving the generalisability of the results (external validity).41-43 Not only can the lessons learned in minimising bias in RCTs be transferred to other prospective designs, but they can help to improve the quality of retrospective research and database analyses. As with controlled trials, such analyses can adopt inclusion and exclusion criteria, with a log of all eligible and non-eligible patients, emphasis on hard outcomes such as survival, sample size determinants before outcome analysis, attempts at blinding the assessor to treatment groups and stratified and matched-pair analyses to control for systematic error. Conclusion Whether the lack of good surgical RCTs is because surgeons lack the necessary training, expertise and desire to perform RCTs, inadequate funding from granting agencies, or methodological problems is not entirely clear. If there are problems precluding an RCT in a significant proportion of clinical treatment effectiveness questions, then alternative research designs, such as prospective matched-pair trials, may need to be better developed and used. If RCTs can be performed, other strategies to increase the number and quality of RCTs need to be adopted, including continuing education of surgeons in clinical research methods, compulsory evaluation of new techniques and technology by governing bodies and more funding for clinical research. References Jones WHS. Hippocrates (transl). Vol. 1. London: Heinemann, 1923: 313. Fletcher RT, Fletcher SW. Clinical research in general medical journals: a 30 year perspective. N Engl J Med 1979; 301: 180-183. Feinstein AR. Clinical biostatistics. XLIV. A survey of the research architecture used for publications in general medical journals. Clin Pharmacol Ther 1978; 24: 117-125. Kramer MS, Boivin JF. Toward an "unconfounded" classification of epidemiology research design. J Chron Dis 1987; 40: 683-688. Emerson JD, Berdick E, Hoaglin DC, et al. An empirical study of the possible relation of treatment differences to quality scores in controlled randomized clinical trials. Controlled Clin Trials 1990; 11: 339-352. Solomon MJ, McLeod RS. Clinical studies in surgical journals. Have we Improved? Dis Colon Rectum 1993; 36: 43-48. Spodick DH. The surgical mystique and the double standard: controlled trials of medical and surgical therapy for cardiac disease: analysis, hypothesis, proposal. Am Heart J 1973; 85: 579-583. Spodick DH. Numerators without denominators. There is no FDA for the Surgeon. JAMA 1975; 232: 35-38. Little JM. Humane medicine. Cambridge: Cambridge University Press, 1995. Barnes RW. Understanding investigative clinical trials. J Vasc Surg 1989; 9: 609-618. Haines SJ. Randomized clinical trials in the evaluation of surgical innovation. J Neurosurg 1979; 51: 5-11. Pollock AV. The rise and fall of the random controlled trial in surgery. Theor Surg 1989; 4: 163-170. Solomon MJ, McLeod RS, Laxamana A, Devore L. Randomized controlled trials in surgery. Surgery 1994; 115: 707-712. Sacks H, Chalmers TC, Smith H Jr. Randomized versus historical controls for clinical trials. Am J Med 1982; 72: 233-240. Gilbert JP, McPeek B, Mosteller F. Statistics and ethics in surgery and anaesthesia. Science 1977; 198: 684-689. Slim K, Bousquet J, Kwiatkowski F, et al. Analysis of randomized controlled trials in laparoscopic surgery. Br J Surg 1997; 84: 610-614. Chalmers TC, Smith H Jr, Blackburn B, et al. A method for assessing the quality of a randomized control trial. Controlled Clin Trials 1981; 2: 31-49. Goligher JC, Pulvertaft CN, Watkinson G. Controlled trial of vagotomy and gastroenterostomy, vagotomy and antrectomy and subtotal gastrectomy in elective treatment of duodenal ulcer. Br Med J 1964; 1: 455-460. Conn HO, Lindenmuth WW. Prophylactic portacaval anastomosis in cirrhotic patients with esophageal varices: preliminary report of controlled study. N Engl J Med 1962; 266: 743-749. Garceau AJ, Donaldson RM, O'Hara ET, et al. A controlled trial of prophylactic portacaval-shunt surgery. N Engl J Med 1964; 270: 496-500. Oettinger W, Berger HG. Commentary on "the rise and fall of the random controlled trial in surgery". Theor Surg 1989; 4: 170. Russell PS. Commentary on the rise and fall of the random controlled trial in surgery. Theor Surg 1989; 4: 169-170. Fielding LP, Stewart-Brown S, Dudley HAF. Surgeon-related variables and the clinical trial. Lancet 1978; 2: 778-779. Van der Linden W. Pitfalls in randomized surgical trials. Surgery 1980; 87: 258-262. Balch CM, Durant JR, Bartolucci AA. The impact of surgical quality control in multi-institutional group trials involving adjuvant cancer treatments. Ann Surg 1983; 198: 164-167. Neugebauer E, Troidl H, Spangenberger W, et al. Conventional versus laparoscopic cholecystectomy and the randomized controlled trial. Br J Surg 1991; 78: 150-154. Love JW. Drugs and operations; some important differences. JAMA 1975; 232: 37-38. Solomon MJ, McLeod RS. Should we be performing more randomized controlled trials evaluating surgical operations? Surgery 1995; 118: 459-467. Barofsky I, Sugarbaker PH. Determinants of patient non-participation in randomized clinical trials for treatment of sarcomas. Cancer Clin Trials 1979; 2: 237-246. Llewellyn-Thomas HA, McGreal MJ, Thiel EC, et al. Patients' willingness to enter clinical trials: measuring the association with perceived benefit and preference for decision participation. Soc Sci Med 1991; 32: 35-42. Angell M. Patients' preferences in randomized clinical trials. N Engl J Med 1984; 310: 1385-1387. Brewin CR, Bradley L. Patient preferences and randomized clinical trials. Br Med J 1989; 299: 313-315. MacKillop WJ, Ward GK, O'Sullivan B. The use of expert surrogates to evaluate clinical trials in non-small cell lung cancer. Br J Cancer 1986; 54: 661-667. Moore MJ, O'Sullivan B, Tannock IF. How expert physicians would wish to be treated if they had genitourinary cancer. J Clin Oncol 1988; 6: 1736-1745. Taylor KM, Mangolese RG, Soskolne CL. Physicians' reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl J Med 1984; 310: 1363-1367. Hellman S. Randomized clinical trials and the doctor-patient relationship. An ethical dilemma. Cancer Clin Trials 1979; 2: 189-193. Beahrs OH. Clinical trials from a surgeon's view. Cancer 1990; 65 Suppl: 2383-2384. Solomon MJ, Egan M, Roberts R, et al. Incidence of free colorectal cancer cells on the peritoneal surface. Dis Colon Rectum, 1997; 40: 1294-1298. Bagshaw PF, Allardyce RA. NZ national colon cancer trial. Aust N Z J Surg 1997; 66 Suppl 1: 50: A13. Hewett P. The Australian laparoscopic assisted resection for adenocarcinoma of the colon clinical trial. Aust N Z J Surg 1997; 66 Suppl 1: 49: A13. Hamburg D, in "Clinical investigations in the 1980s. Needs and opportunities" (conference summary). Washington, DC: Washington Institute of Medicine, 1981: 2. (Report No.10M-81-007.) Cross design synthesis: a new strategy for medical effectiveness research. Washington, DC: US Government Accounting Office, 1992. (GAO/PEMD-92-18.) Rabenech L, Visioli CM, Horwitz RI. Problems in the conduct and analysis of randomized clinical trials. Are we getting the right answers to the wrong questions? Arch Intern Med 1992; 152: 507-512. Hill AB (Br Med J 1948; 2: 791). Reprinted in Statistical Methods in Clinical and Preventive Medicine. Oxford University Press, New York, 1962. Hill AB. Medical ethics and controlled trials. Br Med J 1963; 1043-1048. Cochrane AL. Effectiveness and efficacy. Random reflections on health services. London: Nuffield Provincial Hospitals Trust, 1972. Sackett DL, Haynes RB, Tugwell, P. Clinical epidemiology. A basic science for clinical medicine. Boston: Little, Brown & Company, 1985. Chalmers TC, Celano P, Sacks HS, Smith HJR. Bias in treatment assignment in controlled clinical trials. N Engl J Med 1983; 309: 1358-1361. Marsoni S, Torri W, Taiana A, et al. Critical review of the quality and development of randomized clinical trials (RCTs) and their influence on the treatment of advanced ovarian cancer. Ann Oncol 1990; 1: 343-350. Authors' details Department of Surgery, University of Sydney, Sydney, NSW. Michael J Solomon, MB BCh(Hons), MSc(ClinEpid), FRACS, Clinical Associate Professor. Department of Surgery, University of Toronto, Toronto, Canada. Robin S McLeod, MD, FRCSC, FACS, Professor of Surgery. Reprints will not be available from the authors. Correspondence: Associate Professor Michael J Solomon, RPAH Medical Centre, Suite 419/100 Carillon Avenue, Newtown, NSW 2042. - 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/>

Michael J Solomon · Robin S McLeod