Lamivudine therapy for chronic hepatitis B in renal transplant recipients

Chronic liver disease due to hepatitis B virus (HBV) infection remains a significant cause of morbidity and mortality after renal transplantation. Administration of immunosuppressive drugs facilitates viral replication and may lead to increased frequency of progressive chronic hepatitis, cirrhosis and hepatocellular carcinoma. Chronic HBV infection adversely affects both patient and graft survival. Because of increased risk of death HBV-seropositive renal graft recipients require prophylaxis and treatment of hepatitis B. Interferon due to its immunomodulating effects, risk of activation of rejection is not recommended for transplant recipients. Lamivudine seems to be efficacious and useful for treating hepatitis B in renal transplant recipients. The main disadvantages of lamivudine are relapse after withdrawal of the agent and emergence of lamivudine resistant strains due to mutations in the YMDD locus of the HBV polymerase gene during prolonged lamivudine therapy. Optimal lamivudine treatment regimen for HBsAg-positive renal transplant recipients should be defined. It seems better to initiate lamivudine therapy before or immediately after transplantation to prevent viral replication. The clinical course of hepatitis in most patients with lamivudine resistant HBV mutants seems relatively benign and long-term resistance was well tolerated. Discontinuation of lamivudine in order to minimize the emergence of drug resistant HBV mutants is safe in selected groups of patients. Lamivudine therapy has become the treatment of choice in HBV positive renal transplant recipients and improves prognosis and outcome of infected patients.     

Spectrum of hepatitis B and renal involvement

Renal involvement in hepatitis B occurs in various spectrums and its knowledge is important for clinicians in management of patients. The renal diseases most commonly associated with hepatitis B virus (HBV) infection include membranous nephropathy, membranoproliferative glomerulonephritis and Polyarteritis nodosa. The widespread use of hepatitis B vaccination has decreased the incidence of HBV‐related renal diseases. The incidence of HBV infection in dialysis patients has significantly decreased over the past few decades because of screening of blood products for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody, implementation of infection control measures and hepatitis B vaccination. The definition of acute kidney injury has been recently modified in cirrhotic population, helping in prognosis and prediction of mortality. The most common etiologies of acute kidney injury in this cirrhotic population, which account for 80% to 90% of all cases, include volume depletion, acute tubular necrosis and hepatorenal syndrome. Treatment with oral nucleoside/tide analogues (NA) brought a new paradigm in the management of HBsAg positive glomerulonephritis, kidney transplant recipients and dialysis patients, resulting in effective viral suppression, reduced hepatic complications and improved patient survival, without compromising renal allograft outcome. NAs are cleared by the kidneys and therefore their dosage has to be adjusted in all patients with impaired renal function. This article reviews the recent knowledge of the pathogenesis and treatment of HBV‐related glomerulonephritis and discusses the management of hepatitis B in patients on dialysis, kidney transplant recipients and cirrhotics, which is continuously evolving.     

Fatal hepatic decompensation in a bone marrow transplant recipient with HBV-related cirrhosis following lamivudine withdrawal

Lamivudine is a nucleoside analogue with a potent antiviral activity used as prophylaxis against hepatitis B virus reactivation in patients with chronic HBV infection receiving chemotherapy. No standard guidelines exist, however, for the duration of lamivudine treatment. We report a clinical case of a 56-year-old patient with HBeAg-negative cirrhosis who developed a multiple myeloma. He was treated with lamivudine for 1 year while receiving chemotherapy and a subsequent bone marrow transplant. Complete remission from multiple myeloma was achieved. Four months after lamivudine was withdrawn, he experienced HBV reactivation with jaundice, though no YMDD mutations were detected. The patient rapidly developed fatal decompensation with septicemia and renal failure. In conclusion, this case shows that physicians should avoid discontinuing nucleoside therapy in patients with HBV infection who undergo immunosuppression for concomitant neoplastic conditions.     

Kidney Transplantation in Patients with Chronic Hepatitis B Virus Infection

The impact of hepatitis B virus (HBV) infection on the long-term outcome of kidney transplant patients is controversial. A total of 34 chronic hepatitis B surface antigen (HBsAg) carriers among 143 renal allograft recipients were identified in this study (mean follow-up period: 5.6 ± 3.3 years; range: 1–13 years). During the follow-up, one HBsAg-positive recipient with preexisting cirrhosis died of liver failure, and seven (21%) others developed serious HBV-related complications (four fulminant hepatitis, two hepatocellular carcinoma, one cirrhosis), and four died. Although HBsAg-positive recipients had a higher rate of liver-related complications and deaths than HBsAg-negative recipients did, there were no significant differences in the long-term graft and patient survival between the two groups. The survival rates, liver-related complications, and deaths in HBsAg-positive allograft recipients and 28 HBsAg-positive uremic patients under dialysis were similar. In conclusion, HBV infection is not a contraindication to kidney transplantation. However, pretransplant candidates should be warned of potentially serious liver-related complications.     

Management of Chronic Hepatitis B in Special Populations: Immunosuppressed Patients and Chronic Kidney Disease

Hepatitis B virus (HBV) infection remains an important cause of liver disease in the population with chronic kidney disease, including patients on long-term dialysis and renal transplant (RT) recipients. Diminished survival due to hepatitis B has been observed after RT. A thorough evaluation, including liver biopsy as well as assessment of serum markers of HBV replication (ie, hepatitis B e antigen and/or HBV DNA) is required before transplantation. Tolerance to interferon is poor both in dialysis patients and after renal transplant. Oral antiviral therapy now permits safe and potent antiviral treatment of HBV-related liver disease in chronic kidney disease patients with prevention of progressive liver disease. Preliminary evidence shows an improved survival of HBsAg positive renal allograft recipients on antiviral therapy. However, numerous issues concerning the treatment of hepatitis B in the population with chronic kidney disease remain unclear and further clinical trials are needed.     

An open-label study of lamivudine for chronic hepatitis B in six patients with chronic renal failure before and after kidney transplantation

OBJECTIVE: The course of hepatitis B virus (HBV) infection after kidney transplantation is aggressive, with a high mortality rate from liver disease mainly in patients who were serum hepatitis B e antigen (HBeAg) or HBV DNA-positive before transplantation. Lamivudine has been shown to be a potent inhibitor of HBV replication. The aim of the study was to examine the efficacy and safety of lamivudine therapy in patients with chronic renal failure and chronic HBV infection. METHODS: The study population consisted of six potential candidates for kidney or combined kidney and liver transplantation aged 25-49 yr (four patients had already undergone a kidney transplantation and developed chronic rejection). All were serum HBeAg and/or HBV DNA-positive and had been maintained on hemodialysis for 3 months to 3 yr. The duration of HBV infection was 7 months to 14 yr. Serum alanine aminotransferase (ALT) levels ranged from 72 to 610 U/L (median, 158 U/L). Liver histological evaluation showed mild to moderate chronic hepatitis (n = 4) or liver cirrhosis (n = 2). None of the patients was infected with hepatitis C or D viruses. In four patients, treatment consisted of 10 mg of oral lamivudine per day. In the other two patients, a virological and biochemical response could be achieved only when the dose was increased to 40 mg/day. RESULTS: Lamivudine treatment was associated with 1) normalization of serum ALT levels and rapid disappearance of serum HBV DNA (by hybridization) (five patients, one of whom died from sepsis); 2) seroconversion: disappearance of HBeAg (three patients) and HBsAg (two patients); 3) minor side effects: abdominal pain and nausea (one patient); 4) clinically asymptomatic lamivudine resistance 8 months after treatment (one patient); and 5) successful combined kidney and liver transplantation with no evidence of recurrent HBV infection at 6-8 months postoperatively (two patients with cirrhosis). CONCLUSIONS: Lamivudine therapy is effective as an HBV replication inhibitor in patients with chronic renal failure and HBV infection. Prospective studies of lamivudine pharmacokinetics and dosing in renal failure are needed to be able to treat patients appropriately. Although our study is small and further follow-up is needed, our data suggest that lamivudine therapy may enable selected patients with chronic hepatitis B to undergo kidney or combined kidney and liver transplantation in patients with established cirrhosis.     

Adefovir dipivoxil therapy in liver transplant recipients for recurrence of hepatitis B virus infection despite lamivudine plus hepatitis B immunoglobulin prophylaxis

BACKGROUND: Treatment of post-transplantation recurrence of hepatitis B virus (HBV) infection despite prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine combination therapy is not easy. Because HBV reinfection has a severe course and could result in graft failure in liver transplant recipients, prompt medication is essential. Herein is reported the authors' experience with adefovir dipivoxil (AD) therapy in 11 liver transplant recipients who had HBV reinfection despite the administration of lamivudine and HBIG. METHOD: Two-hundred and nine patients underwent liver transplantation (100 deceased donor liver transplantations [DDLT], 109 living donor liver transplantation [LDLT]) due to chronic hepatitis B infection between April 1997 and May 2005 in Ege University Medical School, Liver Transplantation Unit. Patients had prophylaxis with lamivudine and low-dose HBIG combination after liver transplantation. Treatment of recurrence consisted of AD 10 mg once a day and lamivudine 300 mg/daily and HBIG was discontinued in those patients. RESULTS: In total there were 11 HBV recurrences: five occurred in DDLT recipients and six in LDLT recipients, at a median follow up of 18 months (range, 6-48 months). In one of 11 patients, pretransplant HBV-DNA and HBeAg were positive. Three patients had a severe course and one patient had fibrosing cholestatic hepatitis. After AD treatment, HBV-DNA level decreased in all patients and became negative in seven patients. Two patients died due to hepatocellular carcinoma recurrence after 12 and 14 months of follow up. Serum creatinine level increased mildly in one patient and no other side-effect was observed, and all patients continued therapy. CONCLUSION: Adefovir dipivoxil is a safe, effective treatment option for post-transplant HBV recurrence even among patients with fibrosing cholestatic hepatitis caused by lamivudine-resistant HBV.     

Hepatitis B and hepatitis C virus and chronic kidney disease

The most common cause of liver disease in patients with chronic kidney disease (CKD) remains infection by hepatitis B virus (HBV) and/or hepatitis C virus (HCV). The adverse effects of HBV and/or HCV infections upon survival in patients with CKD have been repeatedly confirmed. An excess risk of death in HBsAg positive or anti-HCV antibody-positive patients may be at least partially attributed to chronic liver disease with its attendant complications. A negative impact of HCV infection on survival after renal transplantation has been linked to extrahepatic complications, including chronic glomerulonephritis, sepsis, chronic allograft nephropathy, post-transplantation diabetes mellitus, and abnormal metabolism of calcineurin-inhibitors. Transmission of HCV infection by grafts from HCV-infected donors has been unequivocally demonstrated. Registry analyses suggest that recipients of kidneys from anti-HCV antibody positive donors are at increased risk of mortality. Renal grafts from HCV-infected donors should be restricted to viremic anti-HCV positive recipients. Several drugs have been recently licensed for therapy of HBV infection but availabledata in patients with CKD is mostly limited to experience with lamivudine. The standard of care for hepatitis C infection in patients on regular dialysis is monotherapy with conventional interferon, according to recent guidelines. Only dire circumstances justify interferon use after renal transplantation.     

Management of patients with hepatitis B in special populations

The development of effective nucleos(t)ide analogs(NAs)against hepatitis B virus(HBV)has improved the outcome of patients with chronic hepatitis B(CHB).This review updates issues related to the management of CHB patients included in special populations.Entecavir(ETV)and tenofovir(TDF)represent the currently recommended first-line NAs in patients with HBV decompensated cirrhosis.The combination of HBV immunoglobulin(usually for a finite duration)and NA is considered the standard of care for prophylaxis against HBV recurrence after liver transplantation.TDF is the best choice for hemodialysis patients and in patients with chronic kidney disease with nucleoside resistance.ETV and telbivudine are the preferred options in na?ve renal transplant recipients and with low viremia levels,respectively.All hepatitis B surface antigen(HBs Ag)-positive candidates should be treated with NAs before renal transplantation to achieve undetectable HBV DNA at the time of transplantation.Conventional interferon or NAs can also be used in children,on the basis of well-established therapeutic indication.Pregnant women at high risk of perinatal transmission could be treated with lamivudine,telbivudine or TDF in the last trimester of pregnancy.HBs Ag-positive patients under immunosuppression should receive NA preemptively(regardless of HBV DNA levels)up to 12 mo after its cessation.In HBs Ag negative,anti-HBc positive patients under immunosuppression,further studies are needed to form a final conclusion;however,it seems that anti-HBV prophylaxis is justified in such patients with hematological diseases and/or for those receiving rituximab-containing regimens,regardless of their antiHBs or serum HBV DNA status.     

Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients

Hepatitis B surface antigen (HBsAg)-positive kidney transplant recipients have increased liver-related mortality. The impact of lamivudine treatment on patient survival, the optimal time to start treatment, and the feasibility of discontinuing treatment have not been determined. This study examined these issues with a novel management protocol. Serum hepatitis B virus (HBV) DNA levels were measured serially in HBsAg-positive kidney transplant recipients, and lamivudine was administered preemptively to patients with increasing HBV DNA levels with or without elevation of aminotransferase levels. Outcomes of patients who underwent transplantation before or after institution of this preemptive management strategy (in January 1996) were compared. Eleven de novo patients (91.7%) who underwent transplantation between 1996 and 2000 and 15 existing patients (39.5%) who underwent transplantation between 1983 and 1995 received preemptive lamivudine therapy for 32.6 +/- 13.3 months. The treatment criteria were met by de novo patients at 8.4 +/- 6.2 months (range, 1-18 months) after transplantation. Suppression of HBV DNA and normalization of aminotransferase levels were achieved in all treated patients, and 21.4% had hepatitis B e antigen (HBeAg) seroconversion. The survival of preemptively managed de novo transplant patients was similar to that of HBsAg-negative controls, whereas HBsAg-positive patients who underwent transplantation before January 1996 had inferior survival (relative risk of death, 9.7 [P <.001]; relative risk of liver-related mortality, 68.0 [P <.0001]). Eleven patients (40.7%) developed lamivudine resistance. Discontinuation of lamivudine was attempted in 12 low-risk patients after stabilization and was successful in 5 (41.7%). In conclusion, preemptive lamivudine therapy based on serial HBV DNA levels and clinical monitoring improved the survival of HBsAg-positive renal allograft recipients. Treatment can be discontinued safely in selected patients after stabilization to minimize the selection of drug-resistant HBV mutants.     

Reactivation of hepatitis B e antigen-negative chronic hepatitis B in a bone marrow transplant recipient following lamivudine withdrawal.

Reactivation of hepatitis B virus (HBV) is a recognized complication of bone marrow transplantation (BMT). Lamivudine is a nucleoside analogue with potent antiviral activity that has been used in the prophylaxis of HBV reactivation in at-risk BMT recipients. Currently, no data exist regarding the safety of nucleoside analogue withdrawal in these patients. A 32-year-old BMT recipient with hepatitis B e antigen (HBeAg)-negative, chronic HBV who developed a serious flare of hepatic inflammation due to a rebound in viral replication within 12 weeks of discontinuing lamivudine therapy is described. The patient remained HBeAg-negative despite high level viremia, suggesting the emergence of a mutant viral strain. The patient's acute hepatitis resolved promptly with the reinstitution of lamivudine therapy. Further studies are necessary to define the safety and efficacy of nucleoside analogues in the prevention of HBV reactivation in at-risk BMT recipients. Clinicians should consider the risk of inducing serious flares of hepatic inflammation due to abrupt nucleoside analogue withdrawal in these patients.     

REVIEW: Hepatitis B and liver transplantation

Liver transplantation in hepatitis B virus (HBV)-infected patients is very commonly followed by recurrence of infection in the transplanted liver. Most recipients with HBV recurrence will develop chronic hepatitis that follows a more aggressive course than is seen in non-immuno-compromized subjects and this frequently results in graft failure. The presence of hepatitis B e antigen or significant levels of HBV-DNA in the serum is highly predictive of recurrence and this has led to the view that patients, whose serum is positive for these conventional markers of replication, should be excluded from transplantation. The key to improving the results of transplantation in patients with HBV infection lies in the development of effective strategies to prevent reinfection. High dose anti-HBs immunoglobulin is effective in patients who are coinfected with hepatitis D, those transplanted for fulminant hepatitis and cirrhotic patients who have very low levels of viral replication prior to transplantation. Unfortunately, immunoprophylaxis does not seem to influence the outcome in those patients with higher levels of replication. There are several new orally active nucleoside analogues that are potent inhibitors of hepatitis B replication that may be effective for both the prevention and treatment of recurrent disease. The most promising are lamivudine (2',3', dideoxy, 3', thiacytidine) and famciclovir (a guanosine analogue). Both agents have been extensively evaluated in animal models of HBV and have been shown to rapidly suppress viral replication. The initial experience with these agents in liver transplant recipients has been promising and a number of studies are currently underway to determine whether these drugs, used alone or in combination with immunoprophylaxis, are able to prevent recurrence in those patients at highest risk of post-transplant HBV recurrence.     

Retrospective evaluation of the risk of hepatitis B virus reactivation after transplantation

Abstract: Numerous case reports describe patients with previously documented immunity developing active hepatitis B virus (HBV) infection after transplantation. However, the risk of reactivation of HBV under long‐term immunosuppression in hepatitis B core antibody (HBcAb)‐positive, hepatitis B surface antigen (HBsAg)‐negative transplant recipients has not been clearly described. Herein, we present a long‐term follow‐up for 49 HBcAb‐positive, HBsAg‐negative recipients (27 liver, 18 kidney, 4 pancreas) transplanted between June 1996 and April 2001. Among these, 37 recipients (76%) were HBsAb positive at transplantation. Immunosuppression consisted of various antibody induction regimens in 20 (41%) of the recipients with either tacrolimus (33 [67%])‐ or cyclosporine (16 [33%])‐based maintenance immunosuppression. The incidence and duration of HBV prophylaxis was not significant. No patient received hepatitis B immunoglobulin (HBIG) before or after transplantation. Additionally, only two patients received lamivudine, which was started post transplant without clinical indication. The mean length of follow‐up was 3.1±1.4 years. At the last follow‐up, overall patient and graft survival were 98% and 96%, respectively. Patient survival was 96% in liver, 100% in kidney, and 100% in pancreas transplant recipients. The graft survival for each organ type was 93% in liver, 100% in kidney, and 75% in pancreas transplant recipients at the end of follow‐up. There was no incidence of HBV reactivation defined as recurrence of HBsAg and/or HBV DNA positivity. These data suggest that the risk of reactivation of HBV in HBcAb‐positive, HBsAg‐negative transplant recipients under immunosuppression is negligible, regardless of immunosuppressive regimen, lamivudine prophylaxis, or HBsAb status. These patients should have access to transplantation as they enjoy excellent patient and graft survival rates.     

Liver transplantation for hepatitis B

Up to now the outcomes of liver transplantation in patients with chronic viral hepatitis B have not been very good because the recurrence of viral hepatitis in the graft has been high and resulted in a high early graft failure of liver transplant recipients. However, the administration of a combined therapy with lamivudine and hyperimmune anti-HBs globulin has led to a marked improvement in transplantation results and an increase in the number of liver transplantations for this indication. Four men (aged 47 to 55 years) underwent liver transplantation for cirrhosis, caused by chronic viral hepatitis B, at our centre. All were HBsAg carriers. They were our first patients who received therapy with the combined immunoprophylactic regimen of lamivudine and hyperimmune anti-HBs globulin. HBV DNA negativity was achieved in all patients prior to transplantation; three of them were pretreated with lamivudine. At 4 to 17 months of follow-up, sustained suppression of HBV replication (HBV DNA negativity) was maintained in all four patients. No complications associated with this treatment were observed and no emergence of resistant mutants was detected. The combined therapy for chronic viral hepatitis B administered to liver transplant recipients at our centre showed very good outcomes. However, the development of resistant mutants during this therapy poses a problem, which may hopefully be overcome with the use of new antivirotics, such as adefovir or tenofovir.     

Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants

Lamivudine has been shown to be an effective therapy for chronic hepatitis B, but resistance to this nucleoside agent is common after prolonged use. Five patients with chronic hepatitis B virus (HBV) infection developed resistance to lamivudine after 9 to 19 months of treatment. In 4 patients this occurred after liver transplantation and the remaining individual had stable cirrhosis. In each case, resistance was confirmed to be caused by one or more mutations in the HBV-DNA polymerase gene and was associated with active underlying liver disease. The patients were treated with adefovir dipivoxil in a dose of 5 to 30 mg daily. Two to 4 log(10) reductions in HBV-DNA levels were observed in 4 cases, and the fifth patient became negative by quantitative polymerase chain reaction (PCR) after retransplantation in conjunction with hepatitis B immunoglobulin (HBIg). Virologic improvement was associated with stable or declining serum alanine transaminase levels in 4 patients. HBV-DNA suppression has been sustained during a mean treatment period of 13 months (range 11 to 15 months), including 1 patient in whom lamivudine has been discontinued. Mild changes in renal function were observed during treatment in most cases but did not require early discontinuation of the drug. This study provides evidence that adefovir dipivoxil can be an effective treatment for lamivudine-resistant HBV mutants as well as wild-type HBV.     

Hepatitis B in renal transplant recipients: An assessment of the relationship of viral replication to liver pathology

To determine the natural history of hepatitis B virus (HBV) infection in renal transplant recipients, 16 recipients who remained chronic HBsAg carriers were followed for 2–15 years by assaying hepatitis Be antigen (HBeAg) and hepatitis B viral DNA (HBV DNA). The results were compared with sequential liver biochemistry and histology. Similarly, nine HBsAg-negative renal transplant patients were studied for up to 10 years. It was found that different patterns of HBV replication were described in a majority of long-term HBsAg-positive renal transplant patients with intermittent virus replication being particularly common. A minority of patients with viral replication showed co-existing elevated transaminases. Development of liver disease was more common among HBsAg-positive patients, but when the various patterns of infection were correlated with long-term outcome, no one pattern was clearly more predictive of an adverse outcome.     

Hepatitis B and Renal Disease

Glomerulonephritis is an important extrahepatic manifestation of chronic hepatitis B virus (HBV) infection. The uncommon occurrence, variability in renal histopathology, and heterogeneity in clinical course present challenges in clinical studies and have resulted in a relative paucity of data and uncertainty with regard to the optimal management of HBV-related glomerular diseases. The advent of nucleos(t)ide analogue medications that effectively suppress HBV replication has markedly altered the clinical outcomes of kidney transplant recipients with HBV infection, but the emergence of drug resistance is an escalating problem. This article reviews the recent knowledge of the pathogenesis and treatment of HBV-related membranous nephropathy, and discusses the management of hepatitis B in kidney transplant recipients, which is continuously evolving.     

Role of lamivudine in the reactivation of hepatitis B virus infection in immunodepressed patients.

INTRODUCTION: hepatitis B virus (HBV) reactivation in immunocompromised states is a well-known event that may be a serious problem in endemic areas of infection. Presently, the investigation of hepatitis B status has been recommended prior to receiving cytotoxic treatment. Lamivudine has been used in the reactivation of HBV in immunocompromised states. We report our corresponding data for lamivudine in the treatment of HBV reactivation after intensive chemotherapy in patients with lymphoma and after kidney transplantation. CLINICAL OBSERVATION: we present two cases of HBV reactivation after chemotherapy for lymphoma and two cases after cadaveric renal transplantation treated with lamivudine (100-150 mg/day). RESULTS: we observed a prompt clinical improvement in all patients after lamivudine treatment. Furthermore, laboratory data showed a rapid biochemical and antiviral response. However, the response in lymphoma patients was quicker than in patients who had post-transplantation reactivation of HBV. Therapy was well tolerated and no relevant side effects appeared during follow-up (twenty four months). The HBV remained negative in three cases. CONCLUSION: lamivudine is effective and safe in the treatment of HBV reactivation in immunodepressed patients. Lamivudine therapy should be considered for the treatment of HBV reactivation in patients with prior hepatitis B or chronic hepatitis B with inactive viral replication.     

Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation

BACKGROUND & AIMS: Lamivudine has become a main therapeutic option for treating hepatitis B virus (HBV) infection. Although drug resistance develops, the clinical course after selection of antiviral-resistant HBV mutants seems to be benign. However, we observed a severe clinical course of hepatitis B infection in several liver transplant recipients after the emergence of lamivudine resistance. This was associated with high viral load in the blood. METHODS: In this report, we characterize the molecular mechanisms underlying drug-dependent enhanced replication of particular lamivudine-resistant HBV mutants selected in these patients, which were associated with sudden onset of liver failure. RESULTS: The clinical course was characterized by a sudden rise in serum bilirubin, prothrombin time, and transaminase. HBV sequence analysis of these patients revealed both mutations in the "a-determinant" of the envelope and the YMDD (tyrosine, methionine, aspartate, aspartate) motif (domain C) of the polymerase protein. Transfection experiments with replication competent vectors indicated that the "a-determinant" changes were not associated with resistance, whereas mutations in the YMDD motif conferred resistance to lamivudine. More importantly, combinations of mutations in the "a-determinant" and the YMDD motif in patients with a severe hepatitis were not only resistant to lamivudine treatment, but showed enhanced replication in vitro in the presence of lamivudine. This observation was confirmed in separate laboratories. CONCLUSIONS: Severe and fatal hepatitis B infection can occur during lamivudine therapy and may be associated with certain HBV mutants selected during sequential nucleoside and HBIg treatment. The lamivudine-enhanced replication shown by these mutants suggests that continuation of therapy with lamivudine could be deleterious in some patients.