Lamivudine Withdrawal Research Articles

Risk factors and prognostic analysis of acute-on-chronic liver failure of chronic hepatitis B after cessation of nucleos(t)ide analogs.

To explore the risk factors and prognostic factors related to the acute-on-chronic liver failure (ACLF) occurrence and adverse outcome after withdrawal of nucleos(t)ide analogs (NAs) in chronic hepatitis B (CHB) patients. Hospitalized CHB patients with relapse after NAs withdrawal at our medical center were retrospectively included in the present study from January 2011 to May 2018. Logistic regression, Cox regression analysis, Kaplan-Meier log-rank test, and area under the receiver operating characteristic curves (AUROC) were used. A total of 389 CHB patients (including 46 ACLF patients) were included. Their median age was 48.0 years; 315 patients were male and 74 were female. The age ≥30 years and HBVDNA ≤1000 copies at admission in logistic regression were the independent risk factors for ACLF after NAs withdrawal in CHB patients. In patients who developed ACLF, only the model of end-stage liver disease combining serum natrium concentration (MELD-Na) score and relapse after Lamivudine (LAM) cessation in the Cox multivariate regression analysis were independent predictors for 12-week mortality. The artificial liver support system (ALSS) showed no improvement in the 12-week survival of ACLF patients. We further defined 22.35 as the optimal cutoff value of MELD-Na score to predict 12-week mortality for ACLF patients, with the AUROC of 0.817, a sensitivity of 76.5%, and a specificity of 75.9%. The age ≥30 years and HBVDNA ≤1000 copies at admission strongly correlate with occurrence of ACLF, and higher MELD-Na score and relapse after LAM withdrawal are closely related with 12-week mortality among patients with ACLF after NAs withdrawal.

Hepatitis B reactivation characterized by HBsAg negativity and anti-HbsAg antibodies persistence in haematopoietic stem cell transplanted patient after lamivudine withdrawal

BackgroundHBV reactivation is associated with high mortality rates in hematopoietic stem cell transplantation (HSCT) and prophylactic lamivudine (LMV) treatment is suggested to prevent this phenomenon. However, the duration of LMV treatment in HSCT patients is not fully defined and the time of immune recovery is considered the best parameter for a drug to be safely interrupted. In patients undergoing allogeneic HSCT, the time of immune recovery is not easy to define and may take years after transplantation and prolonged LMV treatments, which can lead to drug-resistant viral strains.Case presentationAn anti-HBc-positive hematological patient who was undergoing prolonged immunosuppression and who experienced HBV reactivation 3 months after the suspension of a prolonged LMV prophylaxis is described. HBV-DNA matching an atypical serological profile characterized by HbsAg negativity and anti-HBs positivity was detected in the patient. The genotypic analysis of the HBV strain identified T127P, F170FL and S204R mutations of HbsAg, which can hinder HBsAg recognition in a diagnostic assay.ConclusionsHBV reactivation in the HSCT host can be sustained by HBsAg viral variants with characteristics of altered immunogenicity that cannot be detected by usual laboratory tests. This clinical case description suggests the importance of screening for serum HBV-DNA levels in the diagnosis of HBV reactivation and monitoring HBV-DNA after prophylaxis suspension, particularly in HSCT subjects who have undergone prolonged periods of LMV treatment.

Post-transplant withdrawal of lamivudine results in fatal hepatitis flares in kidney transplant recipients, under immune suppression, with inactive hepatitis B infection.

To evaluate the consequences of lamivudine withdrawal in kidney transplant recipients, under immunosuppression, with inactive hepatitis B virus (HBV) infection. HBV infection is more frequent in kidney transplant recipients than in the general population mainly due to the high risk of acquisition during dialysis, before kidney transplantation. The records of hepatitis B surface antigen (HBsAg)-positive, immunosuppressed kidney transplant recipients, where lamivudine was withdrawn after transplantation along with reduction in immunosuppressant dose, admitted to our hospital between 2005 and 2012, were retrospectively evaluated. Three patients aged 33, 42 and 33, experienced hepatitis flares 2-3 months after lamivudine withdrawal. Serum HBV DNA levels were 2.5×107, 3.4×104 and 4×103 IU/ml in cases 1, 2, and 3, respectively. Lamivudine was re-initiated in all cases which led to rapid viral suppression. However, liver function continued to deteriorate leading to severe jaundice, coagulopathy and encephalopathy. All patients died of acute liver failure within six months after the onset of withdrawal hepatitis. Lamivudine should be continued as long as immunosuppressive therapy lasts.

Rhabdomyolysis due to Lamivudine administration in acute viral hepatitis B infection: a case report from Malaysia.

Rhabdomyolysis is a serious but rare side effect of Lamivudine treatment. Therefore, appropriate biochemical monitoring should be undertaken when it is used in the treatment of hepatitis B. This paper presents a case of Lamivudine-associated rhabdomyolysis in a 31-year-old man with congenital heart disease and hepatitis B. Three days after starting Lamivudine, the patient developed myalgia. Significant muscle tenderness and swelling of the upper and lower limbs was discovered during a physical examination. Creatine kinase was markedly raised. Lamivudine-induced rhabdomyolysis was suspected and the drug was discontinued. Symptoms and creatine kinase activity improved within four days of Lamivudine cessation and hydration. Early identification of Lamivudine-induced rhabdomyolysis is key in preventing this potentially fatal drug reaction; withdrawal of Lamivudine may contribute to complete remission of rhabdomyolysis.

Efficacy of pegylated interferon α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy

BackgroundImproving the HBe seroconversion rate of patients without HBeAg loss after long-term lamivudine therapy has become an urgent clinical problem that we have to face. Unfortunately, there is no consensus on the mananement of these patients. The aim of this study was to evaluate the efficacy of pegylated interferon (PEG-IFN) α2a in patients without HBeAg loss after the withdrawal of long-term lamivudine therapy.MethodsFifty patients with chronic hepatitis B without the loss of HBeAg after ≥96 weeks of lamivudine treatment were enrolled to withdraw from treatment to induce a biochemical breakthrough. Patients who achieved a biochemical breakthrough within 24 weeks received 48-weeks of PEG-IFN α2a therapy, and were then assessed during a subsequent 24-week follow-up period.ResultsForty-three (86.0%) patients achieved a biochemical breakthrough within 24 weeks of lamivudine withdrawal. The rates of combined response (both undetectable HBV DNA and HBeAg loss) and HBsAg loss were alone 51.2% and 20.9%, respectively after 48 weeks of PEG-IFN α2a therapy, and 44.2% and 18.6%, respectively, at 24 weeks after treatment cessation. The end-of-treatment combined response rate was 65.4% among patients with a baseline HBsAg <20,000 IU/mL, which was significantly higher than 29.4% of patients with HBsAg ≥20,000 IU/mL (P=0.031). For patients with HBsAg levels <1,500 IU/mL at 12 and 24 weeks therapy, the end-of-treatment combined response rate was 68.2% and 69.0%, which were both significantly higher than patients with HBsAg ≥1,500 IU/mL (33.3% and 14.3%; P=0.048 and 0.001). The end-of-treatment combined response rate was significantly higher among patients with HBV DNA<105 copies/mL (76.2%) compared to patients with HBV DNA ≥105 copies/mL (27.3%) after 24 weeks of therapy (P=0.004).ConclusionRetreatment with PEG-IFN α2a was effective and safe for patients without HBeAg loss after the withdrawal of long-term lamivudine therapy. HBsAg levels at the baseline, 12 and 24 weeks of therapy, and HBV DNA levels at 24 weeks of therapy, can predict the effect of PEG-IFN α2a after 48 weeks of therapy.

The rtL229 substitutions in the reverse transcriptase region of hepatitis B virus (HBV) polymerase are potentially associated with lamivudine resistance as a compensatory mutation

BackgroundIt remains unclear whether hepatitis B virus (HBV) reverse-transcriptase (RT) rtL229 substitutions influence HBV drug resistance. ObjectiveThe study was to investigate the association of HBV rtL229 substitutions with viral resistance to lamivudine (LAM). Study designEntire HBV RT genes were amplified by nested PCR and sequenced from sera of 6000 nucleos(t)ide analog-experienced patients with chronic HBV infection. The incidence and clinic relevance of rtL229 substitutions were analyzed. Replication-competent viral amplicons which harbored HBV genomes of wild-type, rtM204I, or rtM204I in conjunction with various rtL229 substitutions (rtL229F/W/M/V) were constructed. The amplicons were transfected into HepG2 cells for phenotyping of replication capacity and susceptibility to nucleos(t)ide analogs. ResultsThe rtL229 substitutions were detected in 6.57% (394/6000) of patients. Individual substitution incidences were 2.77%, 0.97%, 0.83% and 0.55% for rtL229V, rtL229F, rtL229M and rtL229W, respectively. The incidence of rtL229 substitutions was significantly higher in LAM-experienced patients (341/4220, 8.1%) than in LAM-naïve patients (53/1780, 3.0%), and were independently associated with genotypic LAM resistance (77.9% vs. 21.2%, OR 8.806, 95%CI 6.345–12.223) and low viral replication (HBV DNA <1000IU/mL) (4.60% vs. 24.2%, OR 0.478, 95%CI 0.254–0.898). Representative cases follow-up showed that rtL229F developed subsequent to rtM204I emergence during LAM treatment and regressed with rtM204I after LAM withdrawal. Functionally, rtL229F did not confer reduced susceptibility to LAM, but could restore replication capacity of rtM204I strain. ConclusionThe rtL229 substitutions were potentially associated with LAM resistance in Chinese patients and rtL229F had characteristics of a compensatory mutation of rtM204I mutant.

Long-Term Recurrence-Free Survival After Liver Transplantation from an ABO-Incompatible Living Donor for Treatment of Hepatocellular Carcinoma Exceeding Milano Criteria in a Patient With Hepatitis B Virus Cirrhosis: A Case Report

The early results of liver transplantations (OLT) in patients with advanced hepatocellular carcinoma (HCC) were poor because of frequent tumor recurrence. However, OLT has significant, theoretical advantage that it removes both the tumor and the organ that is at a risk of malignancy. The Japanese law on organ transplantation limited the availability of cadaveric liver donors until its revision on July 17, 2011. ABO-incompatible OLT was formerly contraindicated because performed anti-A/B antibodies on recipient endothelial cells raised the risk of antibody-mediated humoral graft rejection. We have herein described four successful cases of steroid withdrawal among adult patients who underwent living donor OLT from ABO-incompatible donors. In addition, we transplanted a liver from a living donor into an ABO-incompatible recipient on August 9, 2004. The 55-year-old man with HCC due to hepatitis B virus (HBV) a cirrhosis had a Child-Pugh score of C, and Model for End-stage Liver Disease score of 22. Two tumors greater than 5 cm, exceeded the Milan criteria. His des-gamma-carboxy prothrombin level was 6 mAu/mL, and alpha-fetoprotein, 18.78 ng/mL. Antirejection therapy included multiple perioperative plasmaphereses and splenectomy; with an immunosuppressive regimen consisting of tacrolimus, methylprednisolone, and mycophenolate mofetil. The maintenance dose of immunosuppression did not differ from that of ABO-identical cases. After transplantation, we used intrahepatic arterial infusion therapy with prostaglandin E1 (PG E1). The patient had complications of portal vein thrombosis, hepatic artery thrombosis, and acute myocardial infarction, which were treated by interventional radiology in the posttransplantation period. We controlled the HBsAb titer by administering hepatitis B immunoglobulin and lamivudine (200 IU/L doses) for 1 year after OLT and 100 IU/L doses thereafter. As a result, the patient achieved long-term, disease-free graft survival without steroids. He currently has good liver function and leads a normal lifestyle. Our results suggested the feasibility of controlling antibody-mediated humoral rejection and other complications in living donor liver transplantations into ABO-incompatible adults via intrahepatic arterial PG E1 infusion splenectomy, and plasmapheresis with regular immunosuppression. Withdrawal of steroids, HBV vaccination, and lamivudine, an nucleoside analog reverse transcriptase inhibitor, have achieved long-term (7 years) survival without recurrent HBV infection or tumor.

Quantification of HBsAg and HBV-DNA during Therapy with Peginterferon alpha-2b plus Lamivudine and Peginterferon alpha-2b Alone in a German Chronic Hepatitis B Cohort

Peginterferon alpha-2b (PEG-IFNa2b) and lamivudine are efficient treatment options for chronic hepatitis B virus (HBV) infection. We assumed that a combination therapy of PEG-IFNα-2b plus lamivudine will be more effective than PEG-IFNα-2b alone concerning loss of HBV-DNA, HBeAg seroconversion, and HBsAg reduction. Patients with chronic hepatitis B were randomised to nine months treatment with PEG-IFNα-2b 1.5 µg/kg o. i. w. or PEG- IFNα-2b plus lamivudine 100 mg/d. The study was designed with 60 patients per treatment arm. The primary endpoint was defined as loss of HBV-DNA (< 400 copies/mL) 24 weeks after the end of therapy. HBV-DNA (PCR), HBsAg (Architect, Abbott), and HBeAg (Axsym, Abbott) were determined prior to and at the end of treatment as well as at follow-up. HBV-genotypes were determined by Innolipa (Innogenetics). Only 32 patients were randomised to combination therapy and 27 individuals to monotherapy due to low recruitment rates. On treatment reduction of HBV-DNA was significantly higher during combination therapy compared to PEG-IFNa-2b monotherapy (- 4.60 ± 2.71 vs. - 2.41 ± 2.17 log; p = 0.003). However, there was no difference in the number of cases achieving HBV-DNA < 400 copies/mL, ALT normalisation, or HBeAg seroconversion at follow-up. None of the parameters was significantly related to HBV-genotypes. In a post-hoc analysis serum HBsAg levels were analysed as an additional prognostic parameter for treatment response (n = 29). Combination therapy showed a stronger, but not significant HBsAg decline during (- 0.7 ± 1.17 log IU/mL vs. - 0.26 ± 0.61 log IU/mL; p = 0.35) and after therapy (- 0.68 ± 1.29 log IU/mL vs. - 0.24 ± 0.56 log IU/mL; p = 0.82). Two of three cases with a 2-log HBsAg decline to HBsAg levels < 100 IU/mL eliminated HBsAg during long-term follow-up. The study was underpowered with respect to the primary endpoint due to low recruitment rates. However, in the post-hoc analysis HBsAg decline was over two-fold stronger at the end of treatment and follow-up after combination therapy and did not rebound after lamivudine withdrawal. These results may indicate the usefulness of future combination therapies without discontinuation of nucleos(t)ide analogues.

Safety of Complete and Sustained Prophylaxis Withdrawal in Patients Liver-transplanted for Hepatitis B Virus-related Cirrhosis at Low Risk of Hepatitis B Virus Recurrence

BackgroundHBV (hepatitis B virus) reactivation after liver transplantation may be related to persistence of covalently closed circular (ccc) DNA. We investigated the safety of HBV prophylaxis withdrawal in selected HBV transplanted patients. MethodsThirty patients transplanted 64-195 months earlier (23 males, median age 56 years), HBsAg-positive, HBeAg, and HBV-DNA-negative at transplant (43% HCV/HDV coinfected), with undetectable intrahepatic total and ccc-DNA were enrolled. All patients underwent HBIg withdrawal and continued lamivudine with monthly HBsAg and HBV-DNA monitoring and sequential liver biopsies. Those with confirmed intrahepatic total and ccc-DNA undetect-ability 24 weeks after stopping HBIg also underwent lamivudine withdrawal and were followed up without prophylaxis. ResultsTwenty-five patients did not exhibit signs of HBV recurrence after prophylaxis withdrawal (median follow-up 28.7 months, range 22-42). Five patients became HBsAg-positive: one early after HBIg withdrawal, the other four after HBIg and lamivudine withdrawal. None of these patients experienced clinically relevant events. In the first patient, HBIg were reinstituted with prompt HBsAg negativization. Of the other four, one remained HBsAg-positive with detectable HBV-DNA and mild alanine transaminase elevation and was successfully treated with tenofovir. In the remaining three, HBsAg positivity was transient and followed by anti-HBs se-roconversion; thus no antiviral treatment was needed. ConclusionPatients with undetectable HBV viremia at transplant and no evidence of intrahepatic total and ccc-DNA may safely undergo cautious weaning of prophylaxis, showing the low rate of HBV recurrence after a 2-year follow-up. Undetectability of intrahepatic ccc-DNA may help to identify patients at low risk of recurrence; yet studies with longer follow-up are needed.

The therapeutic response of antiviral therapy in HBsAg-positive renal transplant recipients and a long-term follow-up

Early prediction of lamivudine (LAM) response by individualized monitoring of serum HBV DNA like roadmap concept, and investigation of the outcome after LAM discontinuation in renal transplant recipients (RTRs) with chronic hepatitis B (CHB). We conducted a study on 19 RTRs with HBV infection receiving LAM treatment for 2years from 2004 to 2007. HBV DNA level was assessed at baseline, 12, 24, 52, and 104weeks after treatment. Risk factors of tyrosine-methionine-aspartate-aspartate (YMDD) mutation on treatment and relapse rate of HBV after LAM discontinuation were analyzed. HBV DNA levels became undetectable in 32, 37, 63, and 53% of patients after 12, 24, 52, and 104weeks of LAM treatment, respectively. Overall, three (16%) and five (33%) patients were detected with YMDD mutations at week 52 and 104, respectively. In the concept of roadmap, of the seven patients with inadequate virologic response (IAVR) at week 24, five had YMDD mutations. There was no significant association of YMDD mutations with age, gender, genotype, cirrhosis, HBeAg status, baseline HBV DNA, precore/core promoter mutations, and primary response, except IAVR at week 24 (P=0.001). The relapse rate of HBV after LAM discontinuation was high (75%) during a median follow-up of 65weeks. The rate of LAM resistance in RTRs is similar to immunocompetent CHB patients in a 2-year therapy. By roadmap concept, RTRs with IAVR require a change in therapy to prevent viral resistance. Relapse after LAM withdrawal is frequent. Long-term antiviral therapy is crucial for immunosuppressed patients.

Poor durability of lamivudine effectiveness despite stringent cessation criteria: A prospective clinical study in hepatitis B e antigen‐negative chronic hepatitis B patients

Lamivudine, a nucleoside analog, is commonly used for treatment of chronic hepatitis B (CHB) but its durability of effectiveness after withdrawal is still uncertain. This study was designed to assess the durability of lamivudine treatment with stringent cessation criteria in hepatitis B e antigen (HBeAg)-negative patients and to explore potential predictive factors. Sixty one HBeAg-negative CHB patients who had received lamivudine for at least 24 months and had maintained undetectable serum hepatitis B virus (HBV) DNA plus normal alanine aminotransferase for ≥ 18 months before withdrawal were included. They were followed up monthly during the first 4 months and at 3-month or 6-month intervals thereafter. Relapse was defined as serum HBV DNA ≥ 10(4) copies/mL. Thirty one of 61 patients relapsed during follow-up, over 90% occurred within 18 months after lamivudine withdrawal. Cumulative relapse rates at months 6, 12, 24, 36, 48 and 60 were 26.2%, 43.6%, 49.7%, 52.1%, 56.1% and 56.1%, respectively. Cox regression revealed that age was the only predictive factor for relapse, with lower relapse rates found in younger patients. Hepatitis B surface antigen (HBsAg) turned negative in eight patients, and none of them relapsed during follow-up. Effectiveness of lamivudine treatment is not durable in HBeAg-negative CHB patients even when stringent cessation criteria are adopted, with the exception of patients aged ≤ 20 years. The ideal end point of lamivudine treatment is clearance of serum HBsAg.

Safety of complete and sustained prophylaxis withdrawal in patients liver-transplanted for HBV-related cirrhosis at low risk of HBV recurrence

HBV reactivation after liver transplantation may be related to persistence of covalently closed circular (ccc) DNA. We investigated the safety of HBV prophylaxis withdrawal in selected HBV transplanted patients. Thirty patients transplanted 64-195months earlier (23 males, median age 56yrs), HBsAg-positive, HBeAg, and HBV-DNA negative at transplant (43% HCV/HDV co-infected), with undetectable intrahepatic total and ccc-DNA were enrolled. All patients underwent HBIg withdrawal and continued lamivudine with monthly HBsAg and HBV-DNA monitoring and sequential liver biopsies. Those with confirmed intrahepatic total and ccc-DNA undetectability 24weeks after stopping HBIg, also underwent lamivudine withdrawal and were followed-up without prophylaxis. Twenty-five patients did not exhibit signs of HBV recurrence after prophylaxis withdrawal (median follow-up 28.7months, range 22-42). Five patients became HBsAg-positive: one early after HBIg withdrawal, the other four after HBIG and lamivudine withdrawal. None of these patients experienced clinically relevant events. In the first patient, HBIg were reinstituted with prompt HBsAg negativization. Of the other four, one remained HBsAg-positive with detectable HBV-DNA and mild ALT elevation and was successfully treated with tenofovir. In the remaining three, HBsAg positivity was transient and followed by anti-HBs seroconversion, thus no antiviral treatment was needed. Patients with undetectable HBV viremia at transplant and no evidence of intrahepatic total and cccDNA may safely undergo cautious weaning of prophylaxis, showing low rate of HBV recurrence after a 2 year follow-up. Undetectability of intrahepatic ccc-DNA may help to identify patients at low-risk of recurrence, yet studies with longer follow-up are needed.

Hepatitus B virus reactivation in HBV-DNA negative and positive patients with hematological malignancies

Reactivation of hepatitis B virus (HBV) is a frequent complication of chemotherapy (CT) in patients with HBsAg carriers. In this prospective study, we documented CT induced HBV reactivation risk in patients with hematological malignancies. HBV reactivation risk is influenced by baseline viral load. Therefore, we divided our study population into two groups according to HBV-DNA status. HBV-DNA negative patients (n=18) were treated with nucleoside analogues once HBV reactivation was observed. HBV-DNA positive patients (n=12) commenced lamivudine before the initiation of the CT. In HBV-DNA negative patients HBV reactivation was found in 10 patients (55·5%). HBV reactivation was significantly more frequent in chronic lymphocytic leukemia (CLL) patients (P=0·008) and in patients receiving rituximab containing chemotherapy regimens (P=0·06). Eight patients (80·0%) responded to antiviral treatment after HBV reactivation. Two CLL patients experienced a flare-up after the withdrawal of antiviral therapy. In HBV-DNA positive patients, HBV reactivation was observed in four patients (33·3%) during lamivudine treatment and in two patients after lamivudine withdrawal. This study demonstrated the increased risk of CT-induced HBV reactivation in CLL patients, for the first time.

Long-term efficacy of nucleoside monotherapy in preventing HBV infection in HBsAg-negative recipients of anti-HBc-positive donor livers

Transmission of hepatitis B virus (HBV) infection occurs in up to 87.5% of HBsAg-negative recipients of anti-HBc-positive donor livers in the absence of HBV prophylaxis. There is no standardized prophylactic regimen to prevent HBV infection in this setting. The aim of this study was to determine the long-term efficacy of nucleoside analogue to prevent HBV infection in this setting. A retrospective study of HBsAg-negative patients receiving liver transplantation (LT) from anti-HBc-positive donors during a 10-year period. Twenty patients were studied, mean age was 50.2±8.3years, 40% were men, and 90% were Caucasian. The median MELD score at the time of LT was 18 (12-40). None of the patients received hepatitis B immune globulin. Eighteen patients received nucleoside analogue monotherapy: 10 received lamivudine and 8 received entecavir. None of these 18 patients developed HBV infection after a median follow up of 32 (1-75) months. One patient received a second course of hepatitis B vaccine 50months after LT with anti-HBs titer above 1,000mIU/mL. Lamivudine was discontinued and the patient remained HBsAg negative 18months after withdrawal of lamivudine. Two patients who were anti-HBs positive before LT were not started on HBV prophylaxis after LT; both developed HBV infection after LT. Nucleoside monotherapy is sufficient in preventing HBV infection in HBsAg-negative recipients of anti-HBc-positive donor livers. HBV prophylaxis is necessary in anti-HBs-positive recipients of anti-HBc-positive donor livers.

Description of liver disease in a cohort of HIV/HBV coinfected patients

Background Factors associated with advanced liver disease have been incompletely explored in HIV/HBV coinfected patients. Objectives To describe liver-related morbidity, mortality, and related risk factors, in HIV/HBV coinfected patients. Study design We followed-up 107 consecutive HIV/HBV coinfected patients. Clinical, biological and virological data were collected every 3 months. Liver-related mortality and a composite score were used to define advanced liver disease. Results The patients were mainly sub-Saharan Africans (61%) or Europeans (33%). Forty-four percent of patients had liver biopsy, 78% of patients received lamivudine. Advanced liver disease (ALD) was diagnosed in 19/107 patients during follow-up (mean 4.8 years): 10 extensive fibrosis, 5 cirrhosis, 3 hepatocellular carcinoma resulting from cirrhosis, and 1 fulminant hepatitis following lamivudine withdrawal. Eleven patients died, 4 from HBV-related liver disease. In univariate analysis, male gender, mean HIV and HBV viral loads, and raised AST/ALT transaminases were associated with increased risk of ALD. The strongest associations, in a multivariate model, were mean AST transaminase and cumulated time receiving lamivudine, with a favourable effect. 39% of patients with increased mean AST presented with ALD, versus 7% when normal mean AST (Relative Risk 5.5). Conclusions During HIV/HBV coinfection, transaminase levels are strongly associated with ALD. Normal mean AST has a high negative predictive value, contrary to previously reported data in HIV/HCV patients.

Stringent cessation criterion results in better durability of lamivudine treatment: a prospective clinical study in hepatitis B e antigen-positive chronic hepatitis B patients

The cessation criteria for lamivudine treatment vary in published articles and their results are contradictory, especially factors predicting relapse. To clarify these contradictions, this long-term follow-up study of 125 Chinese hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients was designed with stringent cessation criterion. All patients received lamivudine and achieved HBeAg seroconversion (group A, n = 82) or loss (group B, n = 43) with undetectable hepatitis B virus (HBV) DNA by PCR assay during the treatment. Lamivudine was withdrawn >or=6 months after HBeAg seroconversion/loss occurred. The median treatment durations were 24 (12-54) months and 36 (18-89) months in group A and group B, respectively. Patients were followed up for median 24 (2-84) months. The cumulative relapse (defined as serum HBV DNA >or=10(4) copies/mL) rates in the two groups at months 12, 24, 36 and 48 were 23.4%vs 35.0%, 25.0%vs 37.7%, 25.0%vs 41.1% and 29.4%vs 41.1%, respectively (log-rank test, P = 0.119). For patients whose total treatment duration >or=18 months in group A, the cumulative relapse rates at months 12, 24, 36 and 48 were 18.3%, 20.1%, 20.1% and 25.1%, which was significantly lower than those with a shorter duration (log-rank test, P = 0.002). The mean age and median total duration were statistically different between relapsers and nonrelapsers in group A (33.9 +/- 13.6 vs 23.1 +/- 11.0 years, P < 0.001 and 24 vs 26 months, P = 0.003). Cox regression revealed that age was the only predictive factor for relapse (RR, 1.069; 95% CI, 1.032-1.106, P < 0.001). Patients aged <30 years relapsed less frequently in 5 years (12.3%vs 53.5%, P = 0.001). In conclusion, for patients who maintained HBeAg seroconversion for >or=6 months and total duration for >or=18 months, lamivudine withdrawal is a reasonable option. Prolonged treatment may be required for patients aged greater than 30 years to reduce relapse.

Withdrawal of lamivudine in HBeAg-positive chronic hepatitis B patients after achieving effective maintained virological suppression

Background A recommendation was made by the ACT-HBV Asia-Pacific Steering Committee regarding the withdrawal of lamivudine in chronic hepatitis B patients after achieving effective maintained virological suppression. The outcome of patients following this therapeutic guideline has not been clearly investigated. Objective In this study, we examined the outcome of patients adherent to the lamivudine withdrawal guideline. Study design Seventy-one chronic hepatitis B patients achieving seroconversion of hepatitis B e antigen (HBeAg) as well as effective maintained virological suppression during lamivudine therapy were included. Lamivudine was withdrawn provided that undetectable HBV-DNA had been documented on two separate occasions at least 6 months apart. The patients were followed for a median period of 15 months (range, 6–72 months). The effect of pre-therapeutic clinical and virological factors on time to relapse was analyzed. Results Of the 71 patients, 19 (27%) relapsed, of whom 5 showed reappearance of HBeAg and 14 had HBeAg-negative hepatitis. Cox proportional hazard model showed pre-therapeutic HBV-DNA level was the only predictor for time-to-relapse (hazard ratio = 1.023, 95% confidence interval = 1.004–1.043, P = 0.020). Categorical analysis showed that 15/34 (44.1%) and 4/37 (10.8%) patients with pretreatment HBV-DNA levels >10 8 and ≤10 8 copies/mL, respectively, relapsed during follow-ups. The accumulative relapse rates were significantly different between the two groups of patients (Kaplan–Meier method, P = 0.003). Conclusions In patients with pretreatment HBV-DNA levels ≤10 8 copies/mL, lamivudine could be withdrawn after achieving effective maintained virological suppression. Relapse of HBeAg-negative hepatitis remained a major problem.

Successful cessation of lamivudine using interferon in a patient with chronic hepatitisB who received prophylactic lamivudine treatment during chemotherapy.

Lamivudine (LMV) prophylaxis is effective in preventing hepatitisB virus (HBV) reactivation in patients with chronic hepatitisB undergoing chemotherapy. However, the optimal duration of LMV prophylaxis remains unclear. We report herein the case of a woman with localized follicular B-cell lymphoma who received chemotherapy with LMV prophylaxis. She achieved complete response to lymphoma, and LMV treatment was continued for 8months after completion of chemotherapy. HBV status was still inactive. LMV was then stopped, but reactivation of hepatitis developed 1month after cessation of LMV. LMV was restarted, resulting in successful treatment of reactivated hepatitis. Interferon (IFN) was used for 6months before withdrawal of LMV, which was successfully ceased without flare hepatitis. This report describes the utility of sequential therapy with LMV and IFN to treat flare after withdrawal of LMV in hepatitisB carriers who receive LMV prophylaxis during chemotherapy and to prevent flare after withdrawal of LMV.

Liver enzyme elevation after lamivudine withdrawal in HIV–hepatitis B virus co‐infected patients: the Swiss HIV Cohort Study

Background The principal causes of liver enzyme elevation among HIV-hepatitis B virus (HBV) co-infected patients are the hepatotoxic effects of antiretroviral therapy (ART), alcohol abuse, ART-induced immune reconstitution and the exacerbation of chronic HBV infection. Objectives To investigate the incidence and severity of liver enzyme elevation, liver failure and death following lamivudine (3TC) withdrawal in HIV-HBV co-infected patients. Methods Retrospective analysis of the Swiss HIV Cohort Study database to assess the clinical and biological consequences of the discontinuation of 3TC. Variables considered for analysis included liver enzyme, HIV virological and immunological parameters, and medication prescribed during a 6-month period following 3TC withdrawal. Results 3TC was discontinued in 255 patients on 363 occasions. On 147 occasions (109 patients), a follow-up visit within 6 months following 3TC withdrawal was recorded. Among these patients, liver enzyme elevation occurred on 42 occasions (29%), three of them (2%) with severity grade III and five of them (3.4%) with severity grade IV elevations (as defined by the AIDS Clinical Trials Group). Three patients presented with fulminant hepatitis. One death (0.7%) was recorded. Conclusions HBV reactivation leading to liver dysfunction may be an under-reported consequence of 3TC withdrawal in HIV-HBV co-infected patients. Regular monitoring of HBV markers is warranted if active therapy against HBV is discontinued.

A case of lamivudine-sensitive de novo acute hepatitis B induced by rituximab with the CHOP regimen for diffuse large B cell lymphoma

A case of de novo acute hepatitis B that showed symptoms of general malaise and anorexia during rituximab therapy with the CHOP regimen for diffuse large B cell lymphoma is reported. Lamivudine was strikingly effective, showing a rapid recovery from liver damage with jaundice. Hepatitis B virus (HBV) DNA in serum became and stayed undetectable even after the withdrawal of lamivudine, although HBsAg remained positive over 42 months from the onset. Liver biopsy showed a picture suggestive of acute viral hepatitis with multinucleated giant hepatocytes and CD38-positive plasma cell infiltration into liver parenchyma. Immunohistochemically, CD3-positive T-cells were predominant cells that infiltrated in liver parenchyma, whereas CD20-positive B cells were essentially null. Hence, it is suggested from these findings that B lymphocytes might be crucial for the continuous latency in HBV infection and may give rise to de novo acute hepatitis B if totally deleted. Moreover, the CHOP regimen might have some additive effects with the repeated on-off use of corticosteroids to the onset of the disease. In addition, significance of plasma cell infiltration in this setting is discussed.