Geoff Dusheiko

Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis

BACKGROUND Orthotopic liver transplantation in patients positive for hepatitis B virus (HBV) DNA is associated with a high reinfection rate, even with hepatitis B immunoglobulin (HBIG) prophylaxis. Nucleoside analogues that inhibit hepatitis B replication in patients with chronic hepatitis B could prevent reinfection after transplantation. The aim of this study was to analyse the efficacy and safety of prophylaxis both before and after transplantation with the nucleoside analogue lamivudine, without HBIG, in patients undergoing liver transplantation. METHODS 17 HBsAg-positive patients with decompensated cirrhosis and previous evidence of viral replication were enrolled. 12 were HBV-DNA-positive by a signal amplification assay. Patients were treated with oral lamivudine (100 mg daily) for at least 4 weeks before transplantation and followed up for 18-90 weeks after transplantation. FINDINGS HBV DNA became undetectable in serum before transplantation in all HBV-DNA-positive patients. Four died before transplantation from complications of cirrhosis; one patient was withdrawn from the study because of a cerebrovascular accident. The remaining 12 patients underwent transplantation. Two patients died after transplantation (one at 3 days and one [suicide] at 20 weeks). HBV DNA reappeared in one patient with histological evidence of recurrent hepatitis (72 weeks). By week 24 the nine remaining patients had lost HBsAg and remained negative for HBV DNA. INTERPRETATION Lamivudine treatment may prove useful in preventing recurrence of hepatitis B after liver transplantation. The effect on survival of patients after transplantation remains to be assessed.

The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference*.

Summary.  Worldwide, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause, respectively, 600 000 and 350 000 deaths each year. Viral hepatitis is the leading cause of cirrhosis and liver cancer, which in turn ranks as the third cause of cancer death worldwide. Within the WHO European region, approximately 14 million people are chronically infected with HBV, and nine million people are chronically infected with HCV. Lack of reliable epidemiological data on HBV and HCV is one of the biggest hurdles to advancing policy. Risk groups such as migrants and injecting drug users (IDU) tend to be under‐represented in existing prevalence studies; thus, targeted surveillance is urgently needed to correctly estimate the burden of HBV and HCV. The most effective means of prevention against HBV is vaccination, and most European Union (EU) countries have universal vaccination programmes. For both HBV and HCV, screening of individuals who present a high risk of contracting the virus is critical given the asymptomatic, and thereby silent, nature of disease. Screening of migrants and IDUs has been shown to be effective and potentially cost‐effective. There have been significant advances in the treatment of HCV and HBV in recent years, but health care professionals remain poorly aware of treatment options. Greater professional training is needed on the management of hepatitis including the treatment of liver cancer to encourage adherence to guidelines and offer patients the best possible outcomes. Viral hepatitis knows no borders. EU Member States, guided by the EU, need to work in a concerted manner to implement lasting, effective policies and programmes and make tackling viral hepatitis a public health priority.

Treatment of small hepatocellular carcinomas.

There is growing interest in screening to detect symptomless hepatocellular carcinoma (HCC), which should be easier to treat than symptomatic tumours. Combined alpha-fetoprotein and ultrasound monitoring can detect HCCs of 1 cm, and Lipiodol retention can be detected in tumours smaller than 1 cm. A number of treatment options are available. Surgical resection may be curative in selected patients with a single small tumour, but the cirrhotic patient is left with a diseased liver and the risk of tumour recurrence or death from underlying liver dysfunction. Orthotopic liver transplantation is a rational treatment for patients with decompensating cirrhosis and a small HCC, but it is expensive and necessitates immunosuppression. A variety of targeted or local therapies, either individually or in combination, can be used to treat HCC. These include percutaneous alcohol injection into an HCC, which may be an alternative to surgical resection. Tumour necrosis can be seen after targeted Lipiodol chemotherapy or radiotherapy. Transcatheter arterial embolisation selectively embolises the feeding artery, and can be combined with Lipiodol chemotherapy. Small tumours are thus amenable to treatment, even in patients who cannot have surgery. Screening and treatment for symptomless HCC seems justified, unless controlled trials teach us differently.

A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C.

Summary.  The aim of this study is to review clinical trial data on the newly approved protease inhibitors boceprevir and telaprevir to develop consensus recommendations on the optimal use of these agents for the treatment of patients with chronic hepatitis C virus (HCV) infection. An expert panel of seven leading authorities in viral hepatitis was convened to establish and disseminate a practical guide on best practices for incorporating boceprevir and telaprevir into therapy for HCV infection in both treatment‐naive and treatment‐experienced patients. The topics covered include selecting candidates for boceprevir‐ or telaprevir‐based treatments, predictors of response and early viral kinetics, response‐guided therapy approaches, on‐treatment management strategies to optimize the likelihood of response and minimize the risk of drug resistance, management of adverse effects during therapy and key considerations for special populations. The expert panel incorporated the best available clinical evidence into recommendations on how boceprevir and telaprevir should be used in the clinical setting. They indicated how treatment regimens may differ according to the baseline factors, such as presence of cirrhosis and when therapy may need to be modified or stopped altogether because of adverse events or poor virologic response. This practical guide will serve as a valuable resource for clinicians embarking on the new treatment paradigm of boceprevir or telaprevir in combination with peginterferon/ribavirin for chronic genotype 1 HCV infection.

A Genetic Analysis of Hepatitis C Virus Transmission between Injection Drug Users

Hepatitis C virus (HCV) genotype 1a and 3a partial NS5B gene segment sequences obtained from 154 HCV-infected injection drug users were studied to determine the extent to which HCV transmission occurs between injection drug user communities in London, Edinburgh, Glasgow (United Kingdom), Marseilles (France), and Melbourne. Phylogenetic relationships between sequences were analyzed by conventional methods and by a recently developed method that numerically scores the extent of sequence segregation between groups through calculation of association indices. The association indices revealed that none of the cities sampled support an HCV population that is completely isolated from that circulating in the other cities. Sequences from Melbourne were most isolated, whereas those from London were most dispersed. This suggests that HCV transmission between these cities occurs, with London playing a pivotal role. The degree of city-specific segregation of HCV subtype 1a sequences was linearly related to that of subtype 3a, indicating that these subtypes have spread through similar transmission networks.

Treatment of chronic hepatitis B virus infection in resource-constrained settings: expert panel consensus.

Most of the estimated 350 million people with chronic hepatitis B virus (HBV) infection live in resource‐constrained settings. Up to 25% of those persons will die prematurely of hepatocellular carcinoma (HCC) or cirrhosis. Universal hepatitis B immunization programmes that target infants will have an impact on HBV‐related deaths several decades after their introduction. Antiviral agents active against HBV are available; treatment of HBV infection in those who need it has been shown to reduce the risk of HCC and death. It is estimated that 20–30% of persons with HBV infection could benefit from treatment. However, drugs active against HBV are not widely available or utilized in persons infected with HBV. Currently recommended antiviral agents used for treatment of human immunodeficiency virus (HIV) infection do not adequately suppress HBV, which is of great concern for the estimated 10% of the HIV‐infected persons in Africa who are co‐infected with HBV. Progressive liver disease has been shown to occur in co‐infected persons whose HBV infection is not suppressed. In view of these concerns, an informal World Health Organization consultation of experts concluded that: chronic HBV is a major public health problem in emerging nations; all HIV‐infected persons should be screened for HBV infection; HIV/HBV co‐infected persons should be treated with therapies active against both viruses and that reduce the risk of resistance; standards for the management of chronic HBV infection should be adapted to resource‐constrained settings. In addition, a research agendum was developed focusing on issues related to prevention and treatment of chronic HBV in resource‐constrained settings.

Comparative study of three doses of interferon‐α2a in chronic active hepatitis B

SUMMARY. To determine the efficacy of interferon‐α2a in chronic active hepatitis B, 238 patients were randomly divided, into four groups: three groups received either 2.5 MIU m‐2. 5.0 MIUm‐2 or 10.0 MIU m‐2, three times weekly by intramuscular injection for 12–24 weeks: and a control group received no treatment. Patients were followed for up to 12 months after treatment was discontinued. There was a statistically significant difference in response [clearance of hepatitis B e antigen (HBeAg) and hepatitis B viral DNA (HBV‐DNA)] between treated and untreated patients (3 7 vs 13%) but no statistically significant difference was seen between treatment groups (33% 34% and 43% for the 2.5, 5.0 and 10.0 MIU m‐2 groups, respectively). A transient rise in transaminases (seroconversion hepatitis) was seen in responders, but levels returned to within the normal range after response to treatment. In patients responding to interferon therapy there was a significant reduction in the severity of the hepatitis. Interferon‐α2a was generally well tolerated with respect to vital signs and laboratory parameters.

The natural course of chronic hepatitis C: implications for clinical practice.

Hepatitis C is an important public health problem with high rates of chronic infection ensuing after viral acquisition. The spectrum of the disease ranges from mild to severe chronic hepatitis, cirrhosis and hepatocellular carcinoma. Extra‐hepatic manifestations may occur. The disease is complex and predictions about long‐term prognosis for individual patients remain difficult. It is generally accepted that 10–20% of patients with chronic hepatitis C will develop cirrhosis within 10 years of first infection: identifying the group of patients at greatest risk remains a primary challenge for clinicians. Older age of infection, duration of infection, degree of liver inflammation at first biopsy and cofactors such as alcohol abuse, all appear to be predictors of a poorer prognosis. The following paper aims to identify some of the features of the natural history of hepatitis C most relevant to the clinician.

Cost–Utility Analysis of Tenofovir Disoproxil Fumarate in the Treatment of Chronic Hepatitis B

OBJECTIVE The aim of this study was to assess the cost-effectiveness of tenofovir disoproxil fumarate (TDF) in the treatment of chronic hepatitis B (CHB) versus alternative nucleos(t)ides from a UK National Health Service (NHS) perspective. METHODS A Markov model was used to calculate costs and benefits of nucleos(t)ide strategies in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with hepatitis B virus mono-infection and compensated liver disease. The model included 18 disease states representing CHB progression. Quality-of-life data and costs for severe disease states were based on published studies, while monitoring costs for other disease states were based on expert opinion. Transition probabilities for movements between states were based on a meta-analysis, clinical trials, and natural history studies. RESULTS First-line TDF generated the highest net benefits of all 211 nucleos(t)ide strategies evaluated at a threshold of £ 20,000 per quality-adjusted life-year (QALY) gained. First-line TDF cost £ 19,084/QALY gained compared with giving lamivudine (LAM) first-line and switching to TDF when LAM resistance occurs. First-line TDF was also more effective and less costly than first-line entecavir (ETV), and showed extended dominance over first-line adefovir and strategies reserving adefovir, ETV, or combination therapy until after LAM resistance develops. For patients who have developed LAM resistance, TDF was also the most cost-effective treatment, generating greater net benefits than any other second-line strategy. CONCLUSIONS First-line TDF is the most cost-effective treatment for patients with CHB at a £ 20,000 to £ 30,000/QALY ceiling ratio, costing £ 19,084/QALY gained compared with the next best alternative.

Managing HBV in pregnancy. Prevention, prophylaxis, treatment and follow-up: position paper produced by Australian, UK and New Zealand key opinion leaders

Hepatitis B during pregnancy presents unique management issues for both the mother and fetus. These include the lack of a current cohesive strategy for treatment and follow-up of mothers and their babies; the uncertain risk of postpartum HBV flares; the lack of randomised trial data on the safety and efficacy of antiviral treatment in pregnancy; the lack of head-to-head studies comparing different antivirals in pregnancy; and the lack of epidemiologic information regarding infection across different populations globally. This position paper provides a comprehensive review of the management of women with HBV infection prior to conception, throughout each stage of pregnancy and postpartum, as well as recommendations and clinical approaches for the follow-up of children born to infected mothers, based on available evidence in the literature and recommendations from international experts. Prevention of perinatal transmission is an important component of global efforts to reduce the burden of chronic HBV since vertical transmission is responsible for most of the chronic infection worldwide.