Fatal hepatic decompensation in a patient with hepatitis B cirrhosis following famciclovir withdrawal.

Hepatitis B virus (HBV) infection is a major cause of chronic liver disease worldwide. Famciclovir is a nucleoside analogue with potent antiviral activity that appears promising in the management of patients with HBV infection. No data exist regarding the safety of nucleoside analogue withdrawal in patients treated for HBV cirrhosis. The authors describe a 41-year-old man with compensated HBV cirrhosis who developed fatal hepatic decompensation due to a rebound in viral replication within six weeks of discontinuing famciclovir therapy. Although several mutations in the HBV DNA polymerase gene have been documented, none has been associated with famciclovir resistance or adverse clinical outcomes. Clinicians should consider the risk of inducing serious flares in hepatic inflammation as a result of abrupt nucleoside analogue withdrawal. Until further data are available regarding the safety of withdrawal of these agents, indefinite treatment may be required in patients with established cirrhosis.     

Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy

Acute exacerbations of chronic hepatitis B virus (HBV) infection occur after withdrawal of lamivudine therapy in approximately 16% of patients and are considered of little clinical significance. We observed "lamivudine withdrawal hepatitis" accompanied by jaundice and incipient liver failure, but also followed by complete recovery and viral clearance. To investigate the incidence, severity, timing, and virologic characteristics of "lamivudine withdrawal hepatitis" we monitored 41 patients for at least 6 months after discontinuation of nucleoside analogue therapy. The incidence of hepatitis flares was estimated to be 7 of 41 (17%); in 2 of 41 cases (5%), hepatitis flares were associated with jaundice and incipient liver failure. A noticeable feature of the "lamivudine withdrawal hepatitis" flares were the high HBV-DNA levels at the time of the alanine transaminase (ALT) peak. All were wild-type HBV, even the one that emerged from a lamivudine-resistant strain during therapy. To minimize the risk of liver failure and to enhance the elimination of HBV following flares, lamivudine therapy was reinstituted in an icteric patient. Clinical and biochemical remission ensued, followed by loss of HBV DNA and hepatitis B e antigen (HBeAg) seroconversion. Such a virologic response did not occur in 5 other patients with a nonicteric "lamivudine withdrawal hepatitis," who were not retreated with lamivudine. Hepatitis after withdrawal of lamivudine resembles acute hepatitis B with a predominance of anicteric flares within a time frame of 6 months. Active management of hepatitis flares following withdrawal of nucleoside analogue therapy should be investigated further.     

Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B

BACKGROUND: Nucleoside analogues such as lamivudine for chronic hepatitis B have an excellent safety profile while patients are on therapy but reactivation flares occur in 19-50% of patients after stopping therapy, some of whom develop liver decompensation. AIMS: To describe and report three cases who developed fatal hepatitis B reactivation after stopping nucleoside analogue therapy. SUBJECTS AND RESULTS: Three patients are described who developed hepatitis B reactivation and liver decompensation after stopping therapy. One of the three patients was participating in a famciclovir trial and the other two were receiving lamivudine therapy for active hepatitis B infection. All three patients had documented hepatitis B flares, and all had hepatitis B virus DNA detected at that time. All patients developed decompensated liver disease despite one patient having had a prior liver biopsy showing absence of cirrhosis. Reintroduction of lamivudine therapy failed to halt progression of liver decompensation even after hepatitis B virus DNA had been demonstrated to be absent. Sequencing for lamivudine resistant mutants in two cases where serum was available failed to show evidence of mutations associated with lamivudine resistance. CONCLUSION: Hepatitis B virus reactivation, leading to decompensation and death, are possible complications of treatment withdrawal and patients should be monitored closely if therapy is ceased.     

Evolution of hepatitis B management in kidney transplantation

Chronic hepatitis B virus(HBV)infection adversely influences the clinical outcomes of renal transplant recipients owing to increased hepatic complications.Management of HBV infection in kidney transplant recipients presents a challenge to clinicians,especially in endemic regions.Interferon precipitates renal allograft dysfunction.Treatment with lamivudine,the first oral nucleoside analogue available,resulted in effective viral suppression,reduced liver-related complications,and improved patient survival so that medium-term data showed comparable patient survival rates between hepatitis B surface antigen-positive and HBsAg-negative kidney transplant recipients in the era of effective antiviral therapies.Entecavir has replaced lamivudine as first-line therapy for treatment-na?ve subjects in view of the propensity for drug resistance with the latter.Management of HBV infection in kidney transplant patients needs to take into consideration the nephrotoxicity of nucleoside/tide analogues such as adefovir and tenofovir.Prevention of HBV-related complications in kidney transplant recipients starts much earlier prior to transplantation,with vaccination of patients with chronic kidney disease and donor-recipient matching with regard to HBV status.In addition to anti-viral treatment,patients with chronic HBV infection must have regular surveillance for liver cancer and assessment for the development of cirrhosis.     

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.     

Lamivudine treatment of decompensated hepatitis B virus-related cirrhosis

BACKGROUND: Patients with decompensated hepatitis B vires (HBV)-related cirrhosis tend to have low or undetectable HBV replication. However, some patients continue to have high levels of HBV replication and effective suppression of HBV replication with antiviral agents may potentially decrease hepatic necroinflammation and improve or stabilize liver function. This review was to under stand the efficacy and safety of lamivudine in the treatment of decompensated HBV cirrhosis. DATA SOURCES: An English-language literature search (MEDLINE January 1988-July 2005) was performed, and a total of 52 articles/abstracts relevant to the issue were selected. After review of the selected papers, the meaningful results and conclusions were extracted using scientific crite ria. The papers reviewed pertained mainly to the efficacy and safety profiles of lamivudine treatment for decompensated HBV cirrhosis. RESULTS: The ultimate treatment of decompensated HBV cirrhosis is liver transplantation, but lamivudine treatment may lead to rapid suppression of viral replication and improvement of biochemical and clinical parameters, reduced morbidity and hospitalization for complications of liver disease, increased pre-transplant survival as well as reduced need for transplantation. However, viral resistance can develop after prolonged treatment with lamivudine, and breakthrough hepatitis may be fatal in few patients. Adefovir is effective for lamivudine-resistant HBV mutants. CONCLUSIONS: Antiviral therapy with lamivudine for decompensated HBV cirrhosis can be effective. However, some patients may experience a hepatitis flare with the emergence of YMDD mutants resulting in progressive worsening of liver disease, and should be referred for "rescue" therapy with other nucleoside/nucleotide analogues such as adefovir dipivoxil.     

Preemptive therapy for hepatitis B patients undergoing chemotherapy

Abstract   In areas where hepatitis B virus (HBV) is endemic, the increased use of cytotoxic or immunosuppressive therapy has resulted in an increased incidence of liver-related morbidity and mortality due to HBV reactivation in patients infected with the virus. As the hepatitis is preceded by HBV virological reactivation, administration of effective antiviral therapy to HBV (anti-HBV) such as lamivudine preemptively before or at the initiation of cytotoxic therapy and to cover the entire period of immunsuppression, has greatly reduced the risk of liver-related morbidity and mortality due to HBV reactivation. However, such an early 'preemptive' approach runs the risk of over-treating patients who might not be suffering from HBV reactivation with nucleoside analog. In addition, the duration of therapy with nucleoside analog, such as lamivudine, would be longer with this approach. Taken together, such an indiscriminant preemptive approach could result in an increased risk of developing HBV viral resistance. Indeed, severe liver damage due to the development of mutations in the polymerase gene related to lamivudine, namely at M204V and at L180M, has been reported in hepatitis B surface antigen (HBsAg) positive recipients of allogeneic bone marrow transplantation and who were treated with preemptive lamivudine. In order to further optimize the management of postchemotherapy HBV reactivation, more studies aiming to identify risk factors for HBV reactivation after chemotherapy should be undertaken.     

Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis

BACKGROUND: There is little information about the effect of infliximab on the clinical course of liver disease in Crohn's disease patients with concomitant hepatitis B virus (HBV) infection. Theoretically, immunosuppression induced by infliximab will facilitate viral replication which could be followed by a flare or exacerbation of disease when therapy is discontinued. There are no specific recommendations on surveillance and treatment of HBV before infliximab infusion. Two cases of severe hepatic failure related to infliximab infusions have been described in patients with rheumatic diseases. PATIENTS AND METHODS: Hepatitis markers (C and B) and liver function tests were prospectively determined to 80 Crohn's disease patients requiring infliximab infusion in three hospitals in Spain. RESULTS: Three Crohn's disease patients with chronic HBV infection were identified. Two of the three patients with chronic HBV infection suffered severe reactivation of chronic hepatitis B after withdrawal of infliximab therapy and one died. A third patient, who was treated with lamivudine at the time of infliximab therapy, had no clinical or biochemical worsening of liver disease during or after therapy. From the remaining 80 patients, six received the hepatitis B vaccine. Three patients had antibodies to both hepatitis B surface antigen (anti-HBs) and hepatitis B core protein (anti-HBc) with normal aminotransferase levels, and one patient had positive anti-hepatitis C virus (HCV) antibodies, negative HCV RNA, and normal aminotransferase levels. Except for the patients with chronic HBV infection, no significant changes in hepatic function were detected. CONCLUSIONS: Patients with Crohn's disease who are candidates for infliximab therapy should be tested for hepatitis B serological markers before treatment and considered for prophylaxis of reactivation using antiviral therapy if positive.     

Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies

The prevalence of hepatitis B virus (HBV) infection in patients with haematological malignancies is increased compared with the general population worldwide. HBV reactivation is common following chemotherapy and is associated with a high mortality despite prompt anti‐viral treatment. HBV reactivation may necessitate interruption of chemotherapy with adverse prognostic consequences for the haematological disease. Chemotherapy‐induced immune suppression may lead to increased HBV replication. Immune reconstitution within the weeks and months following recovery from chemotherapy may be associated with a flare of hepatitis B manifested by hepatocellular injury. Risk factors associated with HBV reactivation include detectable hepatitis B surface antigen (HBsAg), HBV DNA, Hepatitis B e (HBeAg) antigen, antibodies to hepatitis B core antigen (anti‐HBc), treatment with corticosteroids, young age and male gender. Lamivudine is effective during HBV reactivation due to immune suppression. Clinical trials have demonstrated that pre‐emptive antiviral treatment with lamivudine is superior to deferred treatment. Current recommendations emphasise screening for HBV infection in all haematology patients, particularly prior to chemotherapy. Patients who are HBsAg positive or HBV DNA positive should receive pre‐emptive treatment with lamivudine before chemotherapy. The duration of lamivudine treatment may be prolonged commensurate with the degree of immunosuppression. HBV naïve patients should be immunised against hepatitis B, as should haematopoietic stem cell donors. In summary, overt and occult HBV pose a serious, but preventable, threat. Pre‐treatment screening of patients at risk should be practiced diligently by all clinicians that treat patients with malignancies.     

Hepatitis B infection in China

Chronic HBV infection is a serious health threat in the Asian-Pacific region. The introduction of lamivudine has greatly improved the hope of these patients and is undoubtly a milestone in the management of chronic HBV infection. The combination of lamivudine with another nucleotide or nucleoside analogue or immunomodulatory agent to improve its therapeutic efficacy further must be investigated. Also, the use of lamivudine to prevent HBV reactivation on withdrawal of immunosuppressive therapy should be explored.     

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.     

A possible role for lamivudine as prophylaxis against hepatitis B reactivation in carriers of hepatitis B who undergo chemotherapy and autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma

Hepatitis B virus (HBV) reactivation, a well-known complication in immunosuppressed patients, can give rise to acute hepatitis and even fatal fulminant hepatitis. Three Japanese males with non-Hodgkin's lymphoma (NHL) who were carriers of HBV received high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT). To prevent HBV reactivation, all received oral lamivudine (150 mg/day), a nucleoside analogue, at the start of chemotherapy. All were treated at full-dose intensity, including corticosteroids, without modification of treatment regimens. All three patients completed the total course of chemotherapy and PBSCT, with no signs of HBV reactivation. Peripheral blood stem cell (PBSC) harvests and hematological recoveries after transplantation were not affected by lamivudine, which was continued for at least 16 weeks after transplantation. HBV-DNA and DNA polymerase levels remained negative/normal after discontinuation of lamivudine. Lamivudine effectively inhibits HBV replication and has few serious adverse effects, particularly those related to hematopoiesis. Thus, prophylactic use of lamivudine from initiation of chemotherapy deserves consideration in the treatment of HBV carriers who require immunosuppressive chemotherapy, and may prevent HBV reactivation.     

Treatment of HBe antigen-positive chronic hepatitis B

Spontaneous loss of hepatitis B e antigen (HBeAg) followed by seroconversion to anti-HBe usually coincides with normalization of serum alanine aminotransferase (ALT) levels, reduction in HBV DNA in serum (< 1 x 10(6) copies/mL), and a marked reduction in hepatic inflammation. Licensed antiviral therapies are the interferon (IFN) alphas and the nucleoside analogue lamivudine. Both drugs enhance the rate at which HBeAg seroconversion takes place and thus reduce progression of disease. These therapeutic agents are ineffective if given when there is no ongoing hepatitis (i.e., normal ALT), and their efficacy is greatest in individuals with the most active disease. The effectiveness of these two classes of drugs is similar, and it is possible that the two therapies combined are more effective than monotherapy with either drug. A high side-effect profile and the high risk of further morbidity when given to patients with decompensated disease limit the use of IFN-alpha. When prescribing lamivudine, drug resistance that increases with duration of therapy and the potential risk of a severe flare of hepatitis with sudden cessation of therapy, probably greatest in patients with cirrhosis, are realistic concerns. Both patient and physician need to recognize the need for close monitoring both during and after cessation of any antiviral therapy for hepatitis B.     

Management of hepatitis B in liver transplant patients

Recent therapeutic advances have allowed for routine transplantation of patients with hepatitis B. The first major breakthrough was the use of hepatitis B immune globulin, which reduced posttransplantation hepatitis B recurrence rates to approximately 20%. More recently, the nucleoside analogues lamivudine and adefovir have shown efficacy in the treatment of hepatitis B both before and after liver transplantation. Management strategies are evolving that include initiation of a nucleoside analogue pretransplantation in patients with active viral replication. Combination therapy with hepatitis B immune globulin and a nucleoside analogue is being used posttransplantation. In addition, there is interest in the use of therapeutic vaccination posttransplantation. In this report, we review strategies for managing HBV in the setting of liver transplantation and detail data regarding patient outcomes.     

Treatment of chronic hepatitis B

In the last years, marked progress has been made in the treatment of chronic hepatitis B. The efficacy of lamivudine, the first nucleoside analogue available, is limited by the high incidence of resistance. Adefovir, which was recently approved has a comparable efficacy with a very low frequency of resistance. However, adefovir needs to be indefinitely administered as withdrawal of therapy is generally associated with reactivation and sustained response is uncommon. Recent large randomized controlled trials showed that PEG IFNs induce relatively high sustained response rates both in HBeAg positive and HBeAg negative chronic hepatitis B. So far, the combination of PEG IFN with lamivudine, used simultaneously, is disappointing in terms of short-term efficacy. However, long-term efficacy needs to be assessed and different schedules of combination (for example sequential) need to be evaluated. A number of nucleoside analogues, with favourable toxicity profiles and a promise of increased effectiveness against HBV, are at various stages of clinical development. Results of phase III trials of entecavir and emtricitabine confirmed their efficacy. However, while entecavir is associated with a low incidences of resistance, emtricitabine is associated with a relatively high incidence of resistance which limits its use as a monotherapy. The efficacy and safety of new and more potent drugs like telbivudine and clevudine need to be confirmed. The future of chronic hepatitis B therapy seems to be in the combination of different drugs. Ideally, the optimal drugs to combine would meet the following criteria: they should have different sites of action on HBV DNA replication, a potent antiviral effect, an excellent safety profile and they should induce a sustained response with a limited duration of therapy. Indeed, the concept of combination therapy has been recently developed in order to increase efficacy and to decrease the occurrence of viral resistance. However, so far few combinations have been evaluated. No combination therapy demonstrated a benefit as compared with monotherapy. More potent drugs and new combinations together with the understanding of the mechanisms of resistance to therapy are important challenges to improve the efficacy of treatment and decrease in the future the global burden related to chronic hepatitis B.     

Management of viral hepatitis in hematologic malignancies

Viral hepatitis is the third major cause of liver dysfunction in allogeneic transplant recipients and has become a significant concern in patients with hematological malignancies receiving chemotherapy. Thus, identification of patients at risk for viral hepatitis is very important when evaluating and treating hematological malignancies. Serologic screening for all patients should include anti-HCV, hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) testing. Current therapies for hepatitis B (HBV) virus infection are aimed at viral suppression, while treatment for hepatitis C (HCV) virus can eradicate infection in many treated patients. To prevent HBV viral reactivation, prophylaxis with nucleoside analogues should be initiated for all HBsAg-positive patients. HCV infection appears to have little impact on short-term survival after bone marrow transplantation (BMT), but eventually can impact long-term survival due to progression of liver disease. In this review we will highlight the mechanisms of virus reactivation, clinical manifestations, and management strategies to minimize acute and chronic morbidity in this population.     

Lamivudine treatment for reverse seroconversion of hepatitis B 4 years after allogeneic bone marrow transplantation

Reverse seroconversion of hepatitis B virus (HBV) after allogeneic BMT is rare. We present a case of HBV reactivation late after allogeneic BMT which responded well to lamivudine therapy. A 35-year-old woman with CML received an allogeneic BMT. Before BMT, the patient had immunity to HBV, with serum antibodies against hepatitis B surface antigen (HBsAb), and the donor was completely negative for HBV. Four years after BMT, acute hepatitis occurred with a detectable level of HBV-DNA. Lamivudine rapidly reduced transaminase and bilirubin levels, and serum HBV-DNA decreased to negative. Retrospective analysis revealed that there had been a gradual decrease in serum HBsAb titers after BMT. Administration of lamivudine immediately after HBV replication may be more effective than vaccination of hepatitis B surface antigen-negative donors before BMT.     

Lamivudine treatment for acute severe hepatitis B: report of a case and review of the literature

The oral nucleoside analogue lamivudine has been effectively used in the treatment of chronic hepatitis B. However, there is limited data concerning the efficacy and safety of lamivudine in patients with severe acute or fulminant hepatitis B. We report the use of lamivudine in a young woman with acute HBV infection and fulminant hepatic failure. Following lamivudine treatment, we noticed a prompt clinical, biochemical, serological and virological response as it was seen in the vast majority of, previously reported, cases. Lamivudine treatment was continued until HBsAg was cleared. Our case, as well as previously reported ones, suggests that lamivudine may have a beneficial effect in selected patients with acute severe or fulminant HBV infection.