Recommendations and potential future options in the treatment of hepatitis B

The natural history of chronic hepatitis B should be clearly defined before appropriate recommendations for treatment can be advocated. In patients who acquire the disease in early life, the complications of chronic hepatitis B continue to occur as a result of prolonged insidious damage to the liver, even in the low viraemic phase. Treatment that ends with hepatitis B e antigen seroconversion with hepatitis B virus DNA levels just below 10⁵ copies/ml may not be sufficient. Patients with mild elevation of alanine aminotransferase levels are already at considerable risk of developing complications. Treatment strategy should aim at maximal and prolonged viral suppression to the lowest possible hepatitis B virus DNA levels. Nucleotide/nucleoside analogues will become the mainstay of treatment. Future treatment strategic plans should target maximising antiviral potency and minimising the chance of drug resistance.     

Clinical features, biochemical parameters, and virological profiles of patients with hepatocellular carcinoma in Hong Kong

BACKGROUND: Clinical features of hepatocellular carcinoma patients are changing because of screening. AIM: To examine the clinical features of hepatocellular carcinoma patients in Hong Kong and validity of different staging systems. METHODS: A total of 223 Chinese patients with hepatocellular carcinoma were studied. RESULTS: Seventy-eight percent of hepatocellular carcinoma patients had chronic hepatitis B (43% diagnosed by screening). Hepatitis B positivity, weight loss, jaundice, encephalopathy, alpha-fetoprotein level, portal vein thrombosis, extrahepatic metastasis, and treatment were shown to be independent factors affecting survival. Of chronic hepatitis B patients, hepatitis B virus DNA levels (P = 0.001) and portal vein thrombosis (P = 0.008) were independent factors affecting survival. Seventy-six percent of chronic hepatitis B patients with hepatocellular carcinoma were hepatitis B e antigen negative. Screening patients had hepatocellular carcinoma detected at an earlier stage and better survival (median survival: 21 vs. 4 months, P < 0.0001). All staging systems had good stratification of survival. Prognosis and median survival generated were different when compared with the US data. CONCLUSIONS: Chronic hepatitis B was the most common cause of hepatocellular carcinoma in Hong Kong. High-risk chronic hepatitis B patients should be followed irrespective of the hepatitis B e antigen status. Hepatitis B virus DNA levels at the time of diagnosis are an important survival predictor. Screening detected hepatocellular carcinoma at an earlier stage and prolonged survival. Staging systems should be validated in different populations.     

Treating chronic hepatitis B: today and tomorrow

Three hundred and fifty million people worldwide are estimated to be chronically infected with hepatitis B virus. 15-40% of these subjects will develop cirrhosis, liver failure or hepatocellular carcinoma during their life. The treatment of chronic hepatitis B has improved dramatically over the last decade thanks to the advent of nucleoside/nucleotide analogues and the use of pegylated interferons. However, these agents have increased the complexity of the management of hepatitis B. Five drugs have been approved for chronic hepatitis B treatment: standard interferon-alpha 2b, pegylated interferon-alpha 2a, lamivudine, adefovir dipivoxil, and entecavir. A definite course of standard or pegylated interferon is administered to induce hepatitis B virus clearance. Unfortunately, these agents are not effective in all patients and are associated with not negligible side effects. Nucleoside or nucleotide analogues that inhibit hepatitis B virus polymerase induce on-treatment suppression of viral replication but patients tend to relapse after cessation of treatment. Consequently, these analogues, which are well tolerated, should be used for prolonged periods, even indefinitely. However, prolonged treatment is associated with a high rate of resistance. The following anti-hepatitis B virus drugs are currently undergoing clinical testing: telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine and thymosin-+/-1. Here we will examine the mechanism of action, efficacy, safety, tolerability and emergence of resistance of agents used to treat chronic hepatitis B. We shall also examine the potential of drugs now being tested and of combination treatment.     

Lamivudine monotherapy in HBeAg-negative chronic hepatitis B: prediction of response-breakthrough and long-term clinical outcome

BACKGROUND: Factors that predict response and breakthrough phenomenon to lamivudine monotherapy in patients with HBeAg-negative chronic hepatitis B have not been well defined. AIM: To determine pre-treatment and on treatment variables that predict initial response and breakthrough in patients with HBeAg-negative chronic hepatitis B receiving long-term lamivudine. METHODS: Seventy-nine patients, with chronic HBeAg-negative hepatitis B, who received lamivudine for a median of 31 months were included in the study. RESULTS: Initial virologic and biochemical response was observed in 73 (92%) and 70 (89%) patients, respectively, while 34 (47%) and 15 (21%) patients developed virological and biochemical breakthrough, respectively. High levels of necroinflammation in liver biopsy were associated with a higher probability of initial virological and biochemical response. Patients with pre-treatment serum hepatitis B virus DNA concentrations of more than 10(6) copies/mL were three times more likely to develop virologic breakthrough. Two patients died, one with baseline cirrhosis because of liver failure during biochemical breakthrough while the second death was liver and treatment unrelated. CONCLUSIONS: In HBeAg-negative chronic hepatitis B, initial response to lamivudine therapy is associated with necroinflammation, while baseline serum hepatitis B virus DNA exceeding 10(6) copies/mL is a strong predictor for breakthrough because of drug-resistant mutations. Severe complications are uncommon and are associated with biochemical breakthrough and pre-existing cirrhosis.     

Adefovir dipivoxil in chronic hepatitis B infection

Adefovir dipivoxil, an acyclic nucleotide analogue, is effective for the treatment of chronic hepatitis B in both hepatitis B e antigen (HBeAg)-positive and -negative patients, with improvement in liver histology, hepatitis B virus (HBV) DNA levels, alanine aminotransferase levels, and HBeAg seroconversion (for HBeAg-positive patients). It is also effective against lamivudine-resistant strains of hepatitis B mutations. It has been studied in pre- and post-liver transplant patients. Compared to lamivudine, adefovir dipivoxil is associated with a much lower risk of emergence of drug-resistant HBV. Adefovir-associated resistant virus is susceptible to lamivudine therapy. The recommended dose of adefovir dipivoxil 10 mg is associated with low risk of nephrotoxicity. Adefovir dipivoxil can be recommended as a first-line treatment but can also be used in patients with chronic hepatitis B infection who are failing lamivudine therapy.     

Adefovir dipivoxil in chronic hepatitis B infection

Adefovir dipivoxil, an acyclic nucleotide analogue, is effective for the treatment of chronic hepatitis B in both hepatitis B e antigen (HBeAg)-positive and -negative patients, with improvement in liver histology, hepatitis B virus (HBV) DNA levels, alanine aminotransferase levels, and HBeAg seroconversion (for HBeAg-positive patients). It is also effective against lamivudine-resistant strains of hepatitis B mutations. It has been studied in pre- and post-liver transplant patients. Compared to lamivudine, adefovir dipivoxil is associated with a much lower risk of emergence of drug-resistant HBV. Adefovir-associated resistant virus is susceptible to lamivudine therapy. The recommended dose of adefovir dipivoxil 10 mg is associated with low risk of nephrotoxicity. Adefovir dipivoxil can be recommended as a first-line treatment but can also be used in patients with chronic hepatitis B infection who are failing lamivudine therapy.     

Viral hepatitis in elderly haemodialysis patients: current prevention and management strategies

Viral hepatitis continues to be a relevant topic for haemodialysis centres, although the number of infected dialysis patients is declining in most countries. Chronic hepatitis B and C lead to detrimental complications such as liver cirrhosis and hepatocellular carcinoma. These complications can be avoided by successful antiviral treatment. In individuals with normal renal function, drug therapy of chronic hepatitis B is evolving quickly. Today there are several options but no agreed standard therapy. In the absence of renal failure, chronic hepatitis C should be treated with a combination of pegylated interferon-alpha and ribavirin. For both infections, there is no general indication to treat all patients; several criteria can be used to predict benefits and downsides.Chronic renal failure severely alters immune function, particularly activation of T lymphocytes and cytokine production by mononuclear cells. Aging further influences the immune system with deviation of T-lymphocyte differentiation. Both effects seem to act additively, leaving the elderly haemodialysis patient with extensive immune dysfunction. While these effects do not put the patient at risk of opportunistic infection, they do have a relevant effect on the clinical course of viral hepatitis.Haemodialysis patients infected with hepatitis B manifest a subclinical, often anicteric disease, and at least 60% of the infections become chronic. These patients usually do not fulfil the criteria for successful antiviral treatment, since they have normal or slightly elevated liver enzyme levels and few histological signs of liver inflammation. In addition, the prognosis in terms of cirrhosis and hepatocellular carcinoma might be more favourable than in individuals with normal renal function. The former standard treatment of chronic hepatitis B with interferon-alpha or its derivate pegylated interferon was badly tolerated in dialysis patients and associated with low efficacy. Indeed, prior to the advent of nucleoside analogues there was a clear recommendation not to treat chronic hepatitis B infection in all except a few dialysis patients. However, the newer treatment options appear to work well. In particular, there is growing evidence for the effectiveness and tolerability of lamivudine in dialysis patients, including the elderly. Use of adefovir and entecavir has also been reported in a few cases. At present, while we still do not recommend treatment, therapy with nucleoside analogues might be an option in selected patients, for example, those planning renal transplantation. The major effort against hepatitis B should be directed at vaccination and hygienic precautions to prevent the infection.Treatment of hepatitis C in patients undergoing haemodialysis is also limited by the poor tolerability of interferons. Ribavirin is contraindicated because of severe haemolytic anaemia, although a few studies have attempted to manage this with administration of high doses of erythropoetin. Those patients who complete the full course of interferon therapy may expect sustained viral responses comparable with healthy individuals, but in most trials, 30-50% of patients were forced to interrupt treatment because of adverse effects. There is no general indication to treat chronic hepatitis C in haemodialysis patients. Arguments in favour of treatment include elevated liver enzymes, histological signs of relevant liver inflammation, younger age, a virus genotype other than 1 and planned renal transplantation.     

慢性HBV感染患者HBV DNA前C区变异的临床意义

目的:探讨慢性HBV感染患者HBVDNA前C区变异的临床意义。方法:采用ELISA测定99例HBV感染患者血清肝炎病毒标志物,并采用RT-PCR检测HBVDNA前C区变异。结果:99例HBV感染患者中,乙型肝炎病毒携带26例,慢性乙型病毒性肝炎61例,慢性重型病毒性肝炎(乙型)11例和急性乙型病毒性肝炎1例。乙型肝炎病毒携带,慢性乙型病毒性肝炎和慢性重型病毒性肝炎中,变异株组HBVDNA前C区变异发生率与混合株组、野生株组相比,差异均无显著性(P>0.05)。与混合株和野生株两组相比,HBVDNA变异株组肝功能变化差异均无显著性(P>0.05)。结论:HBVDNA前C区变异可发生于HBV感染的不同临床状态。HBVDNA前C区变异可能与肝炎程度和病情进展无明显关系。     

Adefovir dipivoxil added to ongoing lamivudine therapy in patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B

BACKGROUND: Long-term treatment with lamivudine is required to control viral replication in patients with hepatitis B e antigen-negative chronic hepatitis B, but is associated with a high rate of viral resistance. The role of adefovir dipivoxil in these patients has not been definitively evaluated. AIM: To address the role of adefovir in the management of patients with lamivudine-resistant hepatitis B e antigen-negative chronic hepatitis B. METHODS: Patients were assigned to receive adefovir 10 mg once daily plus ongoing lamivudine 100 mg once daily for 52 weeks. The primary end point was reduction in serum hepatitis B virus DNA level (hepatitis B virus DNA response). Secondary end points included the proportion of patients with undetectable hepatitis B virus DNA at week 52 (complete virological response) and the percentage of patients with normalization of alanine transferase level at week 52 (biochemical response). RESULTS: A total of 49 consecutive patients were enrolled in this study. After 52 weeks of treatment, all patients had an hepatitis B virus DNA response and 57.1% had complete virological response. Biochemical response occurred in 75.6% of patients. CONCLUSIONS: Administration of adefovir in patients with lamivudine-resistant chronic hepatitis B results in significant suppression of viral replication. Nevertheless, continuous therapy will probably be needed in order to maintain remission in these patients.     

LB80380: a promising new drug for the treatment of chronic hepatitis B

Hepatitis B virus is a significant cause of liver cirrhosis and hepatocellular carcinoma in patients with chronic infection. Higher levels of viral load are associated with increased risk of developing liver-related complications. The current available oral therapies suppress viral replication through their action on the hepatitis B virus polymerase. As treatment with oral nucleoside/nucleotide analogues is associated with the development of drug-resistant mutations, there is continuing research for newer and more potent antiviral agents to reduce the chance of drug resistance. LB80380, a prodrug, is an oral nucleotide analogue that inhibits viral replication by incorporation into the viral DNA. Antiviral activity against wild-type virus and virus with drug-resistant mutations was demonstrated in Phase II trials, with significant reduction of viral load in patients treated with LB80380. LB80380 was also shown to be safe and well tolerated.     

LB80380: a promising new drug for the treatment of chronic hepatitis B

Hepatitis B virus is a significant cause of liver cirrhosis and hepatocellular carcinoma in patients with chronic infection. Higher levels of viral load are associated with increased risk of developing liver-related complications. The current available oral therapies suppress viral replication through their action on the hepatitis B virus polymerase. As treatment with oral nucleoside/nucleotide analogues is associated with the development of drug-resistant mutations, there is continuing research for newer and more potent antiviral agents to reduce the chance of drug resistance. LB80380, a prodrug, is an oral nucleotide analogue that inhibits viral replication by incorporation into the viral DNA. Antiviral activity against wild-type virus and virus with drug-resistant mutations was demonstrated in Phase II trials, with significant reduction of viral load in patients treated with LB80380. LB80380 was also shown to be safe and well tolerated.     

Lamivudine treatment for fulminant hepatic failure due to acute exacerbation of chronic hepatitis B infection

BACKGROUND: Exacerbation of chronic hepatitis B infection can lead to fulminant hepatic failure with a mortality of up to 90%. AIM: To evaluate the efficacy of lamivudine in the treatment of this subgroup of patients. METHODS: Twenty-four patients with exacerbation of chronic hepatitis B infection and fulminant hepatic failure were treated with lamivudine, 100 mg daily. Hepatitis A, C, D and human immunodeficiency virus co-infections and hepatocellular carcinoma were excluded. RESULTS: The median age was 53 years (range, 24-77 years) with a male predominance of 20:4. Seventeen patients were hepatitis B e antigen positive. Mean hepatitis B virus DNA was 2079 Meq/mL. Eight patients (33%) survived (group A). Thirteen patients died and three patients received liver transplantation (67%) (group B). Baseline laboratory results were comparable between the two groups, including serum albumin, bilirubin, alanine aminotransferase, prothrombin time and creatinine. Group B patients had significantly more comorbid illnesses at baseline and more complications, including sepsis and renal failure, compared with group A patients. Six out of eight survivors (75%) had full hepatitis B e antigen seroconversion, but this was not sustained in four patients. CONCLUSIONS: Lamivudine may be useful in treating patients with fulminant hepatic failure due to exacerbation of chronic hepatitis B. Hepatitis B e antigen seroconversion was less durable in this subgroup of patients and long-term therapy may be required.     

Review article: hepatitis B and liver transplantation

Liver transplantation is an excellent treatment for hepatitis B virus infected patients who have acute or chronic liver failure and/or primary liver cancer. Advances in antiviral prophylaxis prevent clinically significant graft re-infection for the majority of patients. Graft and patient survival has improved significantly during the past decade, and results of transplantation for hepatitis B virus are now superior to those achieved for most other indications. In particular, the availability of lamivudine and adefovir have transformed outcome. The addition of lamivudine to passive immunoprophylaxis with hepatitis B virus immunoglobulin prevents re-infection in most cases. Adefovir should be added to this combination when the patient develops lamivudine resistance before transplantation. The significance of serum hepatitis B virus DNA positivity in the absence of circulating hepatitis B surface antigen is uncertain. Hepatitis B virus infection of the graft can be observed when prophylaxis is inadequate, when the donor liver contains latent hepatitis B virus infection (so-called de novo infection from the hepatitis B virus core antibody positive donor), and when the donor is exposed to third party infection (sexual or nosocomial transmission). Established hepatitis B virus graft infection is a good indication for combination nucleoside analogue therapy. Combination therapy can achieve sustained suppression of viral replication, and hepatitis B e antigen and hepatitis B surface antigen clearance can also be observed.     

Genetic polymorphisms of interleukin-1-beta in association with sustained response to anti-viral treatment in chronic hepatitis B in Chinese

BACKGROUND: Interleukin-1beta is a pro-inflammatory cytokine that may influence host defence against viral infection. AIM: To investigate the impact of interleukin-1beta gene polymorphism on the response to anti-viral treatment. METHOD: Hepatitis B e antigen-positive chronic hepatitis B patients who have completed a randomized study of peginterferon alpha-2b and lamivudine combination vs. lamivudine monotherapy were included. Sustained responders were patients who had persistent hepatitis B e antigen loss and less than two occasions with hepatitis B virus DNA >100 000 copies/mL at any time up to week 76 post-treatment. Polymorphisms at interleukin-1beta-511, -31 and -3954 and interleukin-1 receptor antagonist (RN) were studied. RESULTS: Eighty-eight patients were studied and 18 (20%) patients developed sustained response. Near complete linkage disequilibrium was observed between interleukin-1beta-511 and -31 loci. After adjustment for the potential confounding effects of treatment allocation, hepatitis B virus genotype, pre-treatment alanine aminotransferase and hepatitis B virus DNA levels, genotype C/T at interleukin-1beta-511 was found to be associated with higher sustained response than genotype C/C (adjusted odds ratio 10.4, 95% CI 1.1, 96.9, P = 0.040). The proportion of sustained responders tend to be higher among patients with allele T at interleukin-1beta-511 (83%) than those without (70%) (P = 0.058). CONCLUSION: High interleukin-1beta production genotype at position -511 has a favourable response to anti-viral treatments.     

Review article: chronic hepatitis B – anti‐viral or immunomodulatory therapy?

Aliment Pharmacol Ther 2011; 33: 501–513

Summary

Background First‐line treatment options for chronic hepatitis B (CHB) consist of nucleos(t)ide analogues with a high barrier to resistance (entecavir and tenofovir) or the immunomodulatory agent peginterferon (PEG‐IFN). The optimal choice for individual patients remains controversial. Aim To review treatment options for CHB, with a focus on deciding between prolonged nucleos(t)ide analogue therapy or a finite course of PEG‐IFN. Methods A comprehensive literature search was undertaken. Results Long‐lasting, treatment‐maintained suppression of hepatitis B virus (HBV) DNA without resistance is achievable in most patients by entecavir or tenofovir. A sustained off‐treatment response is, however, unlikely and long‐term therapy must be anticipated. PEG‐IFN offers a higher rate of sustained response in a subgroup of patients, but is frequently complicated by side effects. Pre‐treatment predictors of response, including HBV genotype, alanine aminotransferase and HBV DNA levels, aid in selecting patients for PEG‐IFN therapy. Furthermore, on‐treatment markers such as quantitative hepatitis B surface antigen may be applied to identify nonresponders early during the PEG‐IFN treatment course, thereby preventing unnecessary treatment. Conclusions Both nucleos(t)ide analogues and PEG‐IFN can be prescribed as first‐line treatment options for CHB. However, PEG‐IFN should only be considered for patients with a high chance of response based on pre‐treatment and on‐treatment factors.     

拉米夫定对慢性乙型肝炎孕妇病毒动态的干预效果及安全性观察

目的临床观察拉米夫定干预下慢性乙型肝炎孕妇的病毒动态及安全性。方法对拉米夫定治疗中发现早孕而继续服药的18例慢性乙型肝炎孕妇及发现早孕而停止服药的22例乙型肝炎孕妇,分别观察其病毒动态、妊娠并发症、婴幼儿HBV感染率及发育异常发生率。结果18例继续服用拉米夫定治疗的慢性乙型肝炎孕妇中16例HBV-DNA阴性,18例孕妇所产婴儿HBV感染率为零,妊娠并发症为零,尚未发现婴幼儿发育异常情况。而停止服药的22例慢性乙型肝炎孕妇中,19例HBV-DNA阳性。其婴儿HBV感染率41.9%,有17例发生妊娠并发症。结论拉米夫定可有效降低孕妇HBV-DNA水平,有助于阻断母婴传播,也有助于降低乙型肝炎妊娠并发症。     

影响慢性乙型病毒性重型肝炎预后因素的分析——附120例临床病例分析

目的探讨影响慢性乙型病毒性重型肝炎预后因素。方法将120例慢性乙型病毒性重型肝炎病例分成好转组和死亡组。对两组患者的年龄、性别、初次乙型肝炎病毒载量(HBV DNA)、血清总胆红素、凝血酶原时间、血清白蛋白、营养状况及并发症与预后的关系进行对比分析。结果慢性乙型病毒性重型肝炎与患者的年龄、性别、初次乙型肝炎病毒载量(HBV DNA)、血清总胆红素、凝血酶原时间、血清白蛋白、营养状况及并发症有关。结论年龄、性别、初次乙型肝炎病毒载量(HBV DNA)、血清总胆红素、凝血酶原时间、血清白蛋白、营养状况及并发症是影响慢性乙型病毒性重型肝炎重要因素,对指导临床有一定价值。     

Drug treatment of pediatric chronic hepatitis B

Children with chronic hepatitis B are at risk of developing long-term complications such as cirrhosis and hepatocarcinoma. It is estimated that half to two-thirds of affected children will clear the hepatitis B e antigen (HBeAg) naturally before reaching adulthood. As in adults, treatments in children accelerate the virological response (DNA negativity and HBeAg loss, with anti-HBe seroconversion), which is associated with normalization of transaminase levels. Treatments also favor subsequent loss of hepatitis B surface antigen (HbsAg), the ultimate goal for minimizing long-term consequences. Interferon-alpha was the first approved treatment for pediatric chronic hepatitis B, and was shown to promote DNA negativity and HBeAg loss in 26% of treated patients (6 MU/m(2) body surface area for 6 months) at 1 year and 33% at 18 months (versus 11% in controls). 10% of treated patients also lost HBsAg. Adverse effects mainly included fever, flu-like symptoms and growth impairment during the treatment phase. Nucleotide analogs have now emerged as promising alternatives for the treatment of chronic hepatitis B. Lamivudine dose-ranging studies showed a higher clearance in children, and the optimal dosage was established to be 3 mg/kg once daily in children up to 12 years of age. Efficacy trials showed complete virological response (HBeAg loss and DNA negativity) in 23% of all treated patients after 1 year, and in 34% of patients with initial transaminase levels >2 x the upper limit of normal. Lamivudine resistance due to mutant/variant viruses is observed in 19% of children after 1 year, a figure that may increase by an average of 20% per year. Other nucleotide analogs, such as adefovir, will soon be tested in children, and have shown promising results in adults without so far demonstrating viral resistance. Finally, therapeutic vaccines aiming to induce a cellular immune response towards hepatitis B antigens are being tested in adults, but no clinical benefit has so far been established.     

Clevudine for the treatment of chronic hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection is a major health problem that is responsible for < or = 1 million deaths and 500,000 cases of hepatocellular carcinoma worldwide each year. Drugs that are currently approved by the FDA for the treatment of chronic HBV consist of two groups: the immunomodulators, such as conventional IFN-alpha and pegylated IFN-alpha2a; and nucleoside/nucleotide analogues, such as lamivudine, adefovir dipivoxil and entecavir. However, due to the limitations of these agents, newer agents with improved efficacy are currently being developed. One nucleoside/nucleotide analogue that is drawing a wide range of interest is clevudine, which is an analogue of the unnatural beta-L configuration. In the woodchuck hepatitis virus (WHV), clevudine 10 mg/kg has proven to be effective in suppressing viral replication with < or = 9 log10 decreases in WHV. At this dose, a significant reduction of intrahepatic WHV RNA and covalently closed circular WHV DNA levels can also be observed. Treatment with clevudine 10 mg/kg can confer additional antiviral benefit in the form of a more sustained reduction in WHV replication, serum woodchuck hepatitis surface antigen and intrahepatic woodchuck hepatitis core antigen expression following the withdrawal of clevudine. In humans, clevudine 10, 50, 100 or 200 mg/day for 28 days can reduce the median HBV DNA by -2.5, -2.7, -3 and -2.6 log10, respectively. More importantly, this suppression of antiviral activity is maintained at 12 and 24 weeks post treatment. Based on the early results of clevudine, more large-scale human studies with clevudine monotherapy or combination therapy is eagerly awaited.     

Hepatitis B immunoglobulin: new preparation. Prolongs survival after liver transplantation

The main complication of liver transplantation for hepatitis B is viral re-infection of the graft. It occurs in 50-100% of patients in the absence of prevention, and reduces survival. The clinical evaluation dossier on hepatitis B immunoglobulin contains data from three retrospective studies. Hepatitis B immunoglobulin reduced the rate of graft infections and increased the survival time (measured between 2 and 5 years after grafting) by 15-30% in absolute terms. Treatment should probably be maintained indefinitely with an intravenous injection of 10,000 IU every two to three months, in order to keep anti-HBs antibody titres at adequate levels. In patients with signs of active hepatitis B virus replication, hepatitis B immunoglobulin alone cannot prevent graft infection. Such patients should receive also lamivudine. Hypersensitivity reactions during infusion are the main adverse effects. Hepatitis B immunoglobulin should now be standard treatment for preventing relapse after liver transplantation for hepatitis B.