Hepatitis: Sydney

Anonymous00371, McCaughan GW, Omata M, Amarapurkar D, Bowden S, Chow WC, Chutaputti A, Dore G, Gane E, Guan R, Hamid SS, Hardikar W, Hui CK, Jafri W, Jia JD, Lai MY, Wei L, Leung N, Piratvisuth T, Sarin S, Sollano J, Tateishi R. · Centenary Research Institute, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, University of Sydney, NSW 2006, Australia. · J Gastroenterol Hepatol. · Pubmed #17444847 No free full text.

This publication has no abstract.

Farrell GC, Liaw YF. · Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, New South Wales, Australia. · J Gastroenterol Hepatol. · Pubmed #10921372 No free full text.

This publication has no abstract.

McCaughan GW, Shackel NA, Bertolino P, Bowen DG. · AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and Sydney University, Sydney, Australia. · Transplantation. · Pubmed #19384153 No free full text.

Abstract: Hepatitis C virus (HCV)-related liver disease postliver transplantation is associated with an accelerated course in comparison with that observed in the nonimmunosuppressed individual. Outcomes in transplantation for this indication have, therefore, been a major area of clinical interest in the field of liver transplantation. The factors underlying the rapid progression of HCV-related liver disease posttransplantation are complex and multifactorial. Nevertheless, recent data indicate a range of parameters assessable early posttransplantation that may be useful in the prediction of outcome of transplantation for this condition. This overview, therefore, concentrates on the early events occurring postliver transplantation in the HCV-infected patient, and the implications of these recent observations for the pathogenesis of the various forms of HCV-related allograft injury.

Post J, Ratnarajah S, Lloyd AR. · Department of Infectious Diseases, Prince of Wales Hospital, Randwick, NSW 2031, Australia. · Cell Mol Life Sci. · Pubmed #19011759 No free full text.

Abstract: Individuals infected with hepatitis C virus (HCV) have two possible outcomes of infection, clearance or persistent infection, determined by a complex set of virus-host interactions. The focus of this review is the host mechanisms that facilitate clearance. Strong evidence points to characteristics of the cellular immune response as the key determinants of outcome, with evidence for the coordinated effects of the timing, magnitude, and breadth, as well as the intra-hepatic localisation of CD4+ and CD8+ T cell responses being critical. The recent discovery of viral evasion strategies targeting innate immunity suggests that interferon-stimulated gene products are also important. A growing body of evidence has implicated polymorphisms in both innate and adaptive immune response genes as determinants of viral clearance in individuals with acute HCV.

van der Poorten D, George J. · Storr Liver Unit, Westmead Millennium Institute, Westmead NSW, Australia. · Clin Liver Dis. · Pubmed #18984468 No free full text.

Abstract: Our mechanistic understanding of liver fibrosis has increased dramatically in recent years for all liver diseases and for hepatitis C and nonalcoholic steatohepatitis (NASH) in particular. Hepatitis C causes liver injury and fibrosis through direct cytopathic means, direct and indirect interactions with hepatic stellate cells, and activation of the immune system. Steatosis and insulin resistance, which are intrinsic deficits in NASH, are also of great importance in hepatitis C and may be induced by viral or host metabolic factors. For NASH, the key mediators of damage include oxidative stress, fat compartmentalization, visceral fat, apoptosis, and adipokine derangement. This article explores in depth the disease-specific mechanisms of fibrosis in hepatitis C and NASH, with a focus on recent developments.

Huynh W, Cordato DJ, Kehdi E, Masters LT, Dedousis C. · Department of Neurology, Liverpool Hospital, Liverpool, New South Wales, Australia. · J Clin Neurosci. · Pubmed #18976924 No free full text.

Abstract: Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system that is usually considered a monophasic disease. ADEM forms one of several categories of primary inflammatory demyelinating disorders of the central nervous system including multiple sclerosis, optic neuropathy, acute transverse myelitis, and neuromyelitis optica (Devic's disease). Post-infectious and post-immunisation encephalomyelitis make up about three-quarters of cases, where the timing of a febrile event is associated with the onset of neurological disease. Post-vaccination ADEM has been associated with several vaccines such as rabies, diphtheria-tetanus-polio, smallpox, measles, mumps, rubella, Japanese B encephalitis, pertussis, influenza, hepatitis B, and the Hog vaccine. We review ADEM with particular emphasis on vaccination as the precipitating factor. We performed a literature search using Medline (1976-2007) with search terms including "ADEM", "acute disseminated encephalomyelitis", "encephalomyelitis", "vaccination", and "immunisation". A patient presenting with bilateral optic neuropathies within 3 weeks of "inactivated" influenza vaccination followed by delayed onset of ADEM 3 months post-vaccination is described.

Matthews GV, Dore GJ. · Viral Hepatitis Program, National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, New South Wales, Australia. · J Gastroenterol Hepatol. · Pubmed #18707597 No free full text.

Abstract: The significant burden of HIV/hepatitis C virus (HCV) coinfection is increasingly recognized worldwide, and in particular within the Asia-Pacific region. Individuals who are coinfected with both viruses are at risk from accelerated liver disease and consequently cirrhosis, liver failure, and hepatocellular carcinoma. In addition, coinfected individuals may have altered immunological responses to HAART and are at increased risk of highly active antiretroviral therapy (HAART)-related hepatotoxicity. Treatment for HCV infection in HIV-infected individuals is with standard pegylated interferon and ribavirin therapy, and all HIV/HCV coinfected subjects should undergo suitability for HCV treatment assessment. Response rates to HCV therapy are generally 10-15% lower than in HCV monoinfection, and therapy may be complicated by issues of drug interactions and significant toxicity. However, greater understanding of baseline factors can contribute to better prediction of treatment outcome, and monitoring of on-treatment virological responses increasingly allows individualization of therapy. Where possible, treatment of HCV is often advisable before HAART is required to avoid the issues of drug interactions on HCV therapy and the risk of HAART-related hepatotoxicity. Early diagnosis of both HIV and HCV infection is essential to most effectively manage HIV-HCV-coinfected individuals. New therapies, including HCV protease and polymerase inhibitors, are in development and may widen therapeutic options for HIV-HCV-coinfected individuals into the future.

Danta M, Dusheiko GM. · St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Australia. · Curr Pharm Des. · Pubmed #18673193 No free full text.

Abstract: HCV/HIV co-infection is a major public health problem with between 10-25% of HIV-positive individuals infected with HCV. Following the introduction of effective HIV therapies, HCV has become a leading cause of morbidity and mortality in the HIV population. Since the early 2000s, there has been a marked rise in the diagnosis of acute HCV in HIV-positive populations. Cohorts have been reported in Europe, USA and Australia. Molecular studies have revealed multiple HCV variants circulating within the HIV-positive men who have sex with men (MSM) population. There is also evidence of a large international transmission network, particularly in Europe. Significantly, permucosal rather than percutaneous risk factors related to high-risk traumatic sexual and drug factors have been associated with transmission. This has important implications for public health interventions aimed at mitigating the spread of HCV. HIV also impacts the early cell-mediated immunological responses to HCV, leading to higher rates of persistence. Data now exists supporting early treatment of these individuals with combination pegylated interferon and ribavirin. This epidemic has come about as a result of significant change in patient behavioural risk factors and these factors need to be the focus of a concerted effort on the part of public health specialist, clinicians and HIV-positive individuals themselves at a national and international level. Acute HCV in HIV-positive individuals differs significantly from acute HCV mono-infection in its epidemiology, natural history, immunology and virology and is becoming an increasingly significant problem in the HIV community. This will be the focus of this review article.

London RM, George J. · Westmead Millennium Institute, Storr Liver Unit, Westmead, NSW 2145, Australia. · Clin Liver Dis. · Pubmed #17544972 No free full text.

Abstract: The incidence of non-alcoholic steatohepatitis, a disorder linked to visceral adiposity, insulin resistance, dyslipidemia, and type 2 diabetes mellitus, is increasing with the rise in the prevalence of the metabolic syndrome. This review focuses on animal models of steatohepatitis currently used to study (1) the mechanisms regulating hepatic lipid, glucose, and cholesterol homeostasis and (2) inflammatory recruitment and fibrogenesis in the steatotic liver. The ultimate aim of this research is to gain insights into the role of hepatic lipid, inflammation, and fibrosis in human non-alcoholic fatty liver disease.

Matthews G. · Viral Hepatitis Clinical Research Program, National Centre in HIV Epidemiology and Clinical Research, Sydney, New South Wales, Australia. · Curr Opin Infect Dis. · Pubmed #17197877 No free full text.

Abstract: PURPOSE OF REVIEW: Coinfection with HIV and hepatitis B virus has a significant impact on the natural history of hepatitis B disease with faster rates of progression to cirrhosis and end stage liver disease. An increasing number of hepatitis B virus active drugs are now available, many of which have dual anti-HIV activity. This review highlights the most important recent developments in the management of HIV and hepatitis B virus coinfection. RECENT FINDINGS: Natural history studies continue to confirm the increased rate of liver-related mortality in coinfected individuals and the importance of hepatocellular carcinoma in this population. The most recent studies of adefovir and tenofovir in open label use in coinfected individuals are discussed and new data on the activity of emtricitabine, entecavir and pegylated interferon are presented. Strategies for use of these new options for anti-hepatitis B virus therapy in coinfected individuals are discussed. SUMMARY: Prevention of end stage liver disease and hepatocellular carcinoma in the coinfected population is vital and the increasing availability of drugs with potent anti-hepatitis B activity is encouraging. Appropriate diagnosis and monitoring of hepatitis B, coupled with better understanding of the mechanisms of drug resistance, will enable clinicians to manage coinfection more effectively.

Lloyd AR, Jagger E, Post JJ, Crooks LA, Rawlinson WD, Hahn YS, Ffrench RA. · Centre for Infection and Inflammation Research, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia. · Immunol Cell Biol. · Pubmed #17130897 No free full text.

Abstract: Individuals infected with hepatitis C virus (HCV) have two possible outcomes of infection, clearance or persistent infection. The focus of this review is the host mechanisms that facilitate clearance. The interaction between HCV viral components and the immune system ultimately determines the balance between the virus and host. Strong evidence points to the aspects of cellular immune response as the key determinants of outcome. The recent discovery of viral evasion strategies targeting innate immunity suggests that the interferon-alpha/beta induction pathways are also critical. A growing body of evidence has implicated polymorphisms in both innate and adaptive immune response genes as determinants of viral clearance in individuals infected with HCV.

Menzies R, McIntyre P. · The National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, Sydney, New South Wales, Australia. · Epidemiol Rev. · Pubmed #16763071 No free full text.

Abstract: Compared with nonindigenous people, indigenous people in first-world countries have experienced much higher rates of many vaccine preventable diseases. This systematic review of published scientific literature, government reports, and immunization guidelines from Australia, Canada, New Zealand, and the United States compares pre- and postvaccination disease rates and vaccination policy for indigenous people in these four countries. Nationally funded universal vaccination programs are clearly the most effective way of reducing disease in indigenous populations. Most successful have been programs for viral diseases in which strain variations are not important and herd immunity is high, such as measles and hepatitis B. For bacterial infections, strain variations (pneumococcal disease), heavy nasopharyngeal colonization of young infants (pneumococcal and Haemophilus influenzae type b disease), low vaccine effectiveness in adults with a high prevalence of risk factors (polysaccharide pneumococcal vaccine), and waning immunity (pertussis) have been associated with continuing or widening disparities between indigenous and nonindigenous populations. However, universal vaccination programs are not always possible. Geographic targeting of all persons in certain regions with high disease rates has been successful, as has targeting of indigenous populations in regions where they constitute larger proportions of the population. In national programs targeting only indigenous people, it has been difficult to achieve high coverage, particularly in urban areas. Innovative program approaches are particularly needed in these situations.

Elliot LN, Lloyd AR, Ziegler JB, Ffrench RA. · School of Women's and Children's Health, The University of New South Wales, Sydney, New South Wales, Australia. · Immunol Cell Biol. · Pubmed #16509830 No free full text.

Abstract: There is increasing evidence that a small percentage of individuals exposed to the hepatitis C virus have the capacity to generate a strong cellular immune response against the virus and avoid persistent infection, and perhaps do so repeatedly after re-exposure. This article reviews the evidence that the responses identified in this unique group of individuals represent the protective immunity that will need to be elicited by hepatitis C virus vaccines.

Micallef JM, Kaldor JM, Dore GJ. · National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Darlinghurst, Sydney, NSW, Australia. · J Viral Hepat. · Pubmed #16364080 No free full text.

Abstract: A large number of studies have reported on spontaneous viral clearance rates in acute hepatitis C infection, however most have been small, and reported rates have varied quite widely. To improve the precision of the estimated rate of spontaneous viral clearance, a systematic review was conducted of longitudinal studies. Factors associated with viral clearance were also examined. Inclusion criteria for studies were: longitudinal assessment from time of acute hepatitis C; hepatitis C virus RNA analysis as determinant of viral clearance; untreated for acute hepatitis C. Information on study population, and factors that may influence viral clearance were extracted from each study. Viral clearance was defined among individuals with at least 6 months follow-up following acute hepatitis C. The number of subjects with viral clearance was expressed as a proportion for each study and a weighted mean for proportion was calculated. A total of 31 studies were examined. Study populations included nine studies of post-transfusion hepatitis, 19 of acute clinical hepatitis, and three of sero-incident cases. In total, data was available for 675 subjects and the mean study population was 22 (range 4-67). The proportion with viral clearance ranged from 0.0 to 0.8, with a weighted mean of 0.26 (95% CI 0.22-0.29). Factors associated with viral clearance were female gender and acute clinical hepatitis C study population. Further studies are required to more clearly define predictors of clearance and guide therapeutic intervention strategies.

Saksena NK, Wang B, Steain M, Yang RG, Zhang LQ. · Centre for Virus Research, Westmead Millennium Institute, The University of Sydney, Westmead NSW 2145 Sydney, Australia. · Cell Res. · Pubmed #16354574 links to  free full text

Abstract: Several reviews have focused on the nature of HIV infection and its spread in various geographical regions of China. In contrast, this review provides a comprehensive update on the prevalence of multiple HIV-1 subtypes, consequent emergence of recombinant and novel forms of HIV-1 in China, and the implications this may have on HIV diversity and the development of effective vaccines. In addition it also examines the dissemination of primary drug resistance in therapy naïve patients, as well as co-infections with two other important viruses-hepatitis B and C. The main purpose of this review is to provide a current snapshot of HIV-1 pathogenesis in China and possibly shed some light on the future of HIV evolution, and potential challenges for future vaccine and anti-retroviral therapeutics against HIV strains in this area.

Wood N, Backhouse J, Gidding HF, Gilbert GL, Lum G, McIntyre PB. · National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, Westmead, New South Wales. · Commun Dis Intell. · Pubmed #16220866 No free full text.

This publication has no abstract.

Matthews G, Kronborg IJ, Dore GJ. · Viral Hepatitis Program, National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Darlinghurst, Australia. · Clin Infect Dis. · Pubmed #15768342 No free full text.

Abstract: An estimated 210,000 people were living with hepatitis C virus (HCV) infection in Australia at the end of 2001, and the number of people developing cirrhosis was projected to increase 4-fold by 2020. Eighty percent of prevalent and 90% of incident HCV infections are related to injection drug use. Current injection drug use was an exclusion criterion for access to government-funded treatment for HCV infection until May 2001. Despite the removal of this barrier to treatment access for current injection drug users (IDUs), the number of IDUs receiving treatment remains extremely low. Treatment outcomes among IDUs with chronic HCV infection treated at 2 public hospital-based hepatitis clinics are presented. These data demonstrate that IDUs who continue to inject infrequently during treatment for HCV infection can achieve a sustained virological response. Further studies are under way to examine outcomes of treatment for HCV among clients undergoing treatment for drug dependency who have chronic HCV infection and among current IDUs with acute and newly acquired HCV infection.

Graham GG, Scott KF, Day RO. · Department of Clinical Pharmacology, St Vincent's Hospital, School of Medical Sciences, Sydney, Australia. · Drug Saf. · Pubmed #15733027 No free full text.

Abstract: The excellent tolerability of therapeutic doses of paracetamol (acetaminophen) is a major factor in the very wide use of the drug. The major problem in the use of paracetamol is its hepatotoxicity after an overdose. Hepatotoxicity has also been reported after therapeutic doses, but critical analysis indicates that most patients with alleged toxicity from therapeutic doses have taken overdoses. Importantly, prospective studies indicate that therapeutic doses of paracetamol are an unlikely cause of hepatotoxicity in patients who ingest moderate to large amounts of alcohol. Controlled clinical trials have found that paracetamol is very well tolerated by the gastrointestinal tract. While variable results have been found in case control studies, most studies have shown no change or a small increase in the relative risk of perforations, ulcer or bleeding in the upper gastrointestinal tract. However, associations between the use of paracetamol and gastrointestinal toxicity, as well as with chronic renal disease and asthma, are very likely to reflect biases in some case control studies. In particular, such biases may be caused by the perceived high tolerability of paracetamol in these diseases. The consequent use of paracetamol in these diseases states then leads to an apparent association between paracetamol and the disease. Despite metabolism of paracetamol to reactive compounds, hypersensitivity reactions are rare, although urticaria occurs in occasional patients. Paracetamol appears to be well tolerated during pregnancy although prospective studies are required.

Dore GJ, Thomas DL. · National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales, Sydney, Australia. · Semin Liver Dis. · Pubmed #15731995 No free full text.

Abstract: Injection drug use is the major mode of hepatitis C virus (HCV) transmission in developed countries. Despite this, relatively few current and recovering injection drug users (IDUs) have received HCV treatment. Studies among individuals with a recent history of injection drug use or those receiving drug dependency treatment have provided evidence that these groups can be successfully treated for chronic HCV infection. These studies have provided the impetus to change guidelines for treatment of current and recovering IDUs, with a move toward individualized HCV treatment assessment and the removal of defined periods of illicit drug use abstinence. Strategies to improve access to HCV treatment for current and recovering IDUs include drug dependency treatment education and training for hepatologists and other HCV treatment physicians, HCV treatment education and training for addiction medicine physicians, development of multidisciplinary clinics, and peer-based eduction and support for individuals considering and receiving HCV treatment.

McCaughan GW, Koorey DJ, Strasser SI. · AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown NSW 2050, Australia. · Hosp Med. · Pubmed #15686159 No free full text.

Abstract: Viral hepatitis is associated with two forms of liver failure that may require liver transplantation: fulminant hepatic failure associated with all forms of acute viral hepatitis and chronic liver failure as a result of chronic hepatitis B and C infection (or both). This review briefly discusses liver transplantation for fulminant hepatitis but focuses on transplantation for hepatitis B- and hepatitis C-associated cirrhosis.

Braet F. · Australian Key Centre for Microscopy and Microanalysis, Electron Microscope Unit, University of Sydney, Sydney, NSW 2006, Australia. · Liver Int. · Pubmed #15566501 No free full text.

Abstract: This review discusses the current state of knowledge about the ultrastructure of hepatic endothelial fenestrae. The application of different high-resolution correlative microscopic methods during the past decade facilitated the accumulation of new insights in the morpho-functional and structural organization of the liver sieve. The data gathered unambiguously show the involvement of special domains in de novo formation and disappearance of fenestrae, and focuses future research into the (supra)molecular structure of the fenestrae-forming center, defenestration center and fenestrae-associated cytoskeleton ring by using cryo-electron microscopic tomography.

Henwood A. · Histopathology Department, The Children's Hospital at Westmead, Westmead, NSW, 2145, Australia. · Biotech Histochem. · Pubmed #15473577 No free full text.

Abstract: Current uses of orcein to demonstrate elastic fibers and, following permanganate oxidation (Shikata's modification), hepatitis B surface antigen, copper associated protein, and sulfated mucins, are reviewed. Variations in staining performance with batch of dye and age of dye solution is also discussed. Additional experimental findings support the view that the orcein stain for elastic tissue and Shikata's modification produces consistent, high quality results as long as appropriate controls and suitable dye batches, e.g., Biological Stain Commission certified dyes, are used.

Menzies R, McIntyre P, Beard F. · National Centre for Immunisation Research and Surveillance, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145. · Commun Dis Intell. · Pubmed #15460950 No free full text.

Abstract: This report complements the Vaccine Preventable Diseases and Vaccination Coverage reports produced biannually since 2000 by the National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases in association with the Australian Institute of Health and Welfare. It integrates the available sources of routinely collected data relevant to the current status of vaccine preventable diseases and vaccine coverage in Aboriginal and Torres Strait Islander people in Australia. It aims to better inform Indigenous communities, Indigenous health care providers and planners of immunisation services of the current status and future needs for vaccine prevention in Indigenous people. The data presented here demonstrate that vaccination programs have had a significant impact on the health of Aboriginal and Torres Strait Islander people. Several areas are highlighted for further development of vaccination policy recommendations, in particular high rates of preventable hepatitis A and B, influenza and pneumococcal disease. Areas where more research is needed include means to more accurately monitor vaccination status, the applicability of meningococcal serogroup B vaccines when available, and effective ways of increasing vaccination coverage and timeliness of vaccination. Such issues need to be considered and implemented in full cooperation with Aboriginal and Torres Strait Islander people.

Teoh NC, Farrell GC. · Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, New South Wales, Australia. · Intern Med J. · Pubmed #15228394 No free full text.

Abstract: The management of chronic viral hepatitis has changed significantly with the availability of effective antiviral agents. There is now a high probability that timely intervention can arrest development of cirrhosis, thereby preventing mortality from portal hypertension, liver failure and liver cancer. This two-part review discusses the implications of this new era of antiviral therapy for physicians. The present review is about chronic hepatitis C virus (HCV); a similar review that considers the treatment of hepatitis B virus will be published in a later issue of the Internal Medicine Journal. Chronic HCV infection is common, but fibrotic progression of liver disease is slow and variable; many infected persons never develop cirrhosis. Case selection for antiviral therapy is crucial. The most effective therapy is a pegylated (long-acting) interferon with ribavirin. Sustained viral response (SVR) (absent viraemia 6 months after completing treatment) can be obtained in 40-60% of individuals infected with genotype 1 and in approximately 67% with genotype 4 after 12 months of treatment. Response rates are higher (75-85%) with genotypes 2 and 3 after only 6 months of treatment. Late relapse is negligible after SVR. This viral cure reverses hepatic fibrosis, reduces the risk of liver failure and of hepato-cellular carcinoma. Combination therapy requires a supportive setting to minimize the impact of side-effects and maximize therapeutic effectiveness. Overall management of HCV-infected persons must also embrace measures to improve quality of life by preventing or dealing with psychosocial issues and advocating lifestyle changes to counter comorbidity from alcohol, central obesity and insulin resistance. These latter factors favour fibrotic disease progression, complications of cirrhosis (such as hepatocellular carcinoma) and development of type 2 diabetes mellitus, as well as eroding the chances of SVR with antiviral therapy.

Nowak AK, Chow PK, Findlay M. · NHMRC Clinical Trials Centre, University of Sydney, Locked Bag 77 Camperdown, NSW 1450, Australia. · Eur J Cancer. · Pubmed #15196530 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is a common cause of cancer mortality worldwide. Whilst local treatments are useful in selected patients, they are not suitable for many with advanced disease. Here, we review phase II and III trials for systemic therapy of advanced disease, finding no strong evidence that any chemotherapy, hormonal therapy, or immunotherapy regimen trialled to date benefits survival in this setting. Many trials were inadequately powered, single centre, and enrolled highly selected patients. From this review, we cannot recommend any therapeutic approach in these patients outside of a clinical trial setting. Including an untreated control arm in clinical trials in HCC is still justified. Every effort should be made to enroll these patients into adequately powered trials, and promising phase II results must be tested in a multicentre phase III setting, preferably against a placebo control arm. Prevention of hepatitis B and C remains vital to decrease deaths from HCC.