Received Lamivudine Monotherapy Research Articles

High Seroprevalence of HBV and HCV Infection in HIV-Infected Adults in Kigali, Rwanda

BackgroundData on prevalence and incidence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in Rwanda are scarce.MethodsHBV status was assessed at baseline and Month 12, and anti-HCV antibodies at baseline, in a prospective cohort study of HIV-infected patients in Kigali, Rwanda: 104 men and 114 women initiating antiretroviral therapy (ART) at baseline, and 200 women not yet eligible for ART.ResultsBaseline prevalence of active HBV infection (HBsAg positive), past or occult HBV infection (anti-HBc positive and HBsAg negative) and anti-HCV was 5.2%, 42.9%, and 5.7%, respectively. The active HBV incidence rate was 4.2/1,000 person years (PY). In a multivariable logistic regression model using baseline data, participants with WHO stage 3 or 4 HIV disease were 4.19 times (95% CI 1.21–14.47) more likely to have active HBV infection, and older patients were more likely to have evidence of past exposure to HBV (aRR 1.03 per year; 95%CI 1.01–1.06). Older age was also positively associated with having anti-HCV antibodies (aOR 1.09; 95%CI 1.04–1.14) while having a higher baseline HIV viral load was negatively associated with HCV (aOR 0.60; 95% CI 0.40–0.98). The median CD4 increase during the first 12 months of ART was lower for those with active HBV infection or anti-HCV at baseline. Almost all participants (88%) with active HBV infection who were on ART were receiving lamivudine monotherapy for HBV.ConclusionHBV and HCV are common in HIV-infected patients in Rwanda. Regular HBsAg screening is needed to ensure that HIV-HBV co-infected patients receive an HBV-active ART regimen, and the prevalence of occult HBV infection should be determined. Improved access to HBV vaccination is recommended. Active HCV prevalence and incidence should be investigated further to determine whether HCV RNA PCR testing should be introduced in Rwanda.

Clinical Outcomes of Kidney Transplantation Recipients with Chronic Hepatitis B Infection - Single Center Experience in Hong Kong

Introduction: There is a high prevalence of chronic hepatitis B infection in South-Asia. Patients with pre-existing hepatitis B virus (HBV) infection receiving kidney transplant had been associated with inferior outcome. We aimed to evaluate the clinical outcomes of kidney transplantation recipients with HBV infection being followed up in a single center. Method: All kidney transplantation recipients being followed up in our center from 1 January 1990 to 31 December 2011 were included. Data on pre- transplantation hepatitis status and the use of anti-viral agents were collected. Graft survival and patient survival of HBV +ve and HBV -ve kidney transplantation recipients were evaluated. Results: There were 374 patients with 384 episodes of kidney transplantation during the study period, of whom 35 patients (9.35%) were HBV +ve. There was no differences in age on transplantation, time from commencement of dialysis to transplantation, proportion of living related kidney transplantation and pre transplantation diabetes between HBV +ve and HBV -ve recipients. All except one patient with HBV +ve received antiviral agent prophylactically after transplantation, majority (91%) of them received lamivudine monotherapy while 2 of them were on entecavir. One patient had flare up of hepatitis B infection and adefovir was added; two patients developed lamivudine resistance strain and required switching to entecavir or adding adefovir. Only one patient developed hepatic failure and died during follow-up period. 1-year and 5-year patient survival were 91.14% versus 95.32% and 87.65% versus 88.83% in HBV +ve and HBV -ve recipients respectively, p=0.94. 1-year and 5-year graft survival (death censored) were 97.14% versus 96.70% and 97.14% versus 92.6% respectively, p=0.76. Conclusion: With the use of antiviral agents in recent era, there was no increased risk of death or graft failure in kidney transplantation recipients with pre-existing chronic hepatitis B infection.

Combination therapy of thymosin alpha-1 and lamivudine for HBeAg positive chronic hepatitis B: A prospective randomized, comparative pilot study

Monotherapy of lamivudine, interferon-alpha (IFN-alpha), and thymosin alpha-1 (Talpha1) is unlikely to be sufficient for the eradication of a chronic hepatitis B virus (HBV) infection. The aim of our study is to elucidate whether the combination of Talpha1 and lamivudine is superior to lamivudine monotherapy in hepatitis B e antigen (HBeAg) positive naïve patients with chronic hepatitis B. Sixty-seven patients were assigned to two different groups in a randomized manner. The combination group (n = 34) received Talpha1 (1.6 mg subcutaneously, twice a week) and lamivudine (100 mg orally, daily) for 24 weeks, followed by continuous lamivudine therapy. The monotherapy group (n = 33) received lamivudine monotherapy continuously. The incidence of HBeAg seroconversion at 24 weeks was 26.5% (9/34) in the combination group and 6.1% (2/33) in the monotherapy group (P = 0.024). However, there was no statistically significant difference between 26.5% (9/34) in the combination group and 12.1% (4/33) in the monotherapy group at 52 weeks (P = 0.138). The emergence of viral breakthrough gradually increased to 35.3% (12/34) in the combination group, and to 21.2% (7/33) in the monotherapy group at 52 weeks (P = 0.201). The combination treatment of Talpha1 and lamivudine did not have an obvious benefit of virological and biochemical response as compared to the lamivudine monotherapy during the combination period. In addition, after the cessation of Talpha1 treatment, the combination therapy did not prevent the occurrence of viral and biochemical breakthroughs.

Lamivudine/pegylated interferon alfa‐2b sequential combination therapy compared with lamivudine monotherapy in HBeAg‐negative chronic hepatitis B

Monotherapy has been proven insufficient in achieving sustained control of chronic hepatitis B. We aimed to assess the efficacy of combined sequential administration of lamivudine and pegylated interferon alfa-2b in patients with hepatitis Be antigen (HBeAg)-negative chronic hepatitis B. Eighteen patients were given sequential combination treatment starting with 3 months of lamivudine monotherapy followed by 9 months of pegylated interferon alfa-2b (after a 3-month period of concomitant administration of the two drugs) and 24 patients received lamivudine monotherapy. At the end of treatment, 88.9% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy had hepatitis B virus (HBV) DNA levels below 400 copies/mL (P = not significant). At the end of treatment, 72.2% of the patients who received sequential combination treatment and 70.8% of those who received lamivudine monotherapy achieved alanine aminotransferase normalization (P = not significant). After 12 months of follow up, 33.3% of the patients who received sequential combination treatment and 16.7% of those who received lamivudine monotherapy had HBV-DNA levels below 400 copies/mL (P = 0.4). After 12 months of follow up, 72.2% of the patients who received sequential combination treatment and 25.0% of those who received lamivudine monotherapy had normal alanine aminotransferase levels (P < 0.01). Twenty-five percent of the patients in the lamivudine monotherapy group had virological breakthrough compared to none in the sequential combination treatment group (P = 0.06). Sequential combination treatment is able to improve sustained biochemical response rates and prevent the emergence of lamivudine-resistant mutants in patients with HBeAg-negative chronic hepatitis B.

Efficacy of lamivudine therapy in elderly patients with chronic hepatitis B infection

The aim of this study was to evaluate the efficacy of lamivudine therapy in elderly patients with chronic HBV infection. Patients aged >or=60 years (n = 40) received lamivudine monotherapy between February 1995 and September 2005 at Toranomon Hospital. We compared the efficacy of lamivudine therapy in these patients and in 639 patients aged <60 years, including 80 patients aged <60 years matched for sex, hepatitis B e antigen (HBeAg) status, and hepatitis B virus (HBV) DNA level. The rates of normalization of alanine aminotransferase (ALT) level in 40 patients aged >or=60 years and 639 patients aged <60 years were 85% versus 76%, and 86% versus 73% at 1 and 3 years, respectively. The respective rates of loss of HBV-DNA were 74% versus 74%, and 76% versus 68% at 1 and 3 years. The respective cumulative emergence rates of the YMDD mutant were 16% and 17% at 1 year, and 46% and 49% at 3 years. In 80 patients <60 years old matched for sex, HBeAg status, and HBV-DNA level, the rates of normalization of the ALT level and loss of HBV-DNA were similar to those in the 639 patients aged <60 years. The emergence rate of YMDD mutants in patients aged >or=60 years were similar to those in matched patients aged <60 years. Multivariate analyses identified low serum bilirubin (<1 mg/dl) as an independent factor associated with the emergence of the YMDD motif mutation in patients aged >or=60 years. Our results suggest that treatment with lamivudine is both well tolerated and efficacious in elderly patients with chronic HBV infection.

Lamivudine Plus Low-Dose Hepatitis B Immunoglobulin to Prevent Recurrent Hepatitis B Following Liver Transplantation

High-dose intravenous hepatitis B immunoglobulin (HBIG) may prevent recurrent hepatitis B virus (HBV) infection, but the cost has limited its widespread use in countries with endemic HBV infection. We report on long-term safety and efficacy of an alternative strategy of very low doses (400-800 IU/month) of intramuscular (IM) HBIG plus lamivudine. Australian and New Zealand patients who received low-dose HBIG plus lamivudine following liver transplantation for HBV-related end-stage liver disease were studied. Prior to transplantation, patients with detectable serum HBV DNA received lamivudine 100 mg daily. Posttransplantation, all patients received lamivudine 100 mg daily plus IM HBIG 400 or 800 IU daily for 1 week then monthly thereafter. Serum HBV DNA levels were measured prior to lamivudine, at transplantation, and at 12 months posttransplantation. Serum titers of antibody to HBV surface antigen were measured at 1, 3, and 12 months posttransplantation. Between February 1996 and October 2004, 147 patients received low-dose HBIG plus lamivudine. Thirty-one percent were hepatitis B e antigen positive, and 85% were HBV DNA+ prior to transplantation. The median duration of pretransplantation lamivudine was 92 days (range, 1-1775). Median follow-up posttransplantation was 1860 days. Kaplan-Meier patient survival was 92% at 1 year and 88% at 5 years. The actuarial risk of HBV recurrence was 1% at 1 year and 4% at 5 years. Baseline HBV DNA titer was associated with HBV recurrence. Low-dose IM HBIG plus lamivudine provides safe and effective long-term prophylaxis against recurrent HBV at <10% the cost of the high-dose regimen.

A systematic review and economic evaluation of adefovir dipivoxil and pegylated interferon‐alpha‐2a for the treatment of chronic hepatitis B

Standard treatments for chronic hepatitis B (CHB) include interferon-alpha (IFN-alpha) and lamivudine (LAM), but these are associated with adverse effects and viral resistance, respectively. The aim of this systematic review and economic evaluation was to assess the clinical effectiveness and cost-effectiveness of two alternative drugs for the treatment of adults with CHB: adefovir dipivoxil (ADV) and pegylated IFN-alpha-2a. We searched electronic databases, including Cochrane Systematic Reviews and Medline, for literature that met criteria defined in a research protocol. Retrieved articles were independently assessed for inclusion by two reviewers. We developed a Markov state transition model to estimate the cost-effectiveness (cost-utility) of pegylated IFN-alpha-2a and of ADV compared with nonpegylated IFN-alpha-2a, LAM and best supportive care. Seven randomized controlled trials and two systematic reviews met the inclusion criteria for our review of clinical effectiveness. ADV was significantly more effective than placebo or ongoing LAM in reducing levels of hepatitis B virus (HBV) DNA. Rates of hepatitis B e antigen (HBeAg) seroconversion were higher among patients receiving ADV than either placebo or ongoing LAM. Patients treated with pegylated IFN-alpha-2a, either as monotherapy or in combination with LAM, showed significantly reduced HBV DNA levels compared with patients treated with LAM monotherapy. HBeAg seroconversion rates at follow-up were significantly higher for pegylated IFN-alpha-2a patients than for those receiving LAM monotherapy. Results of our cost-effectiveness analysis demonstrate that incremental costs per quality adjusted life year (QALY) for a range of comparisons were between 5,994 and 16,569 British Pound, and within the range considered by NHS decision-makers to represent good value for money.

Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation

Objective: To update and extend a 2006 report on the clinical effectiveness and cost-effectiveness of adefovir dipivoxil (ADV) and pegylated interferon alpha (PEG-?) for the treatment of chronic hepatitis B (CHB). Data sources: Thirteen bibliographic databases were searched including MEDLINE, EMBASE and the Cochrane Library. Searches were run from the beginning of 2005 to September 2007. Review methods: For the clinical effectiveness review, randomised controlled trials (RCTs) comparing ADV, PEG-?-2a and PEG-?-2b with currently licensed treatments for CHB, including non-pegylated interferon alpha (IFN-?) and lamivudine (LAM), were included. Outcomes included biochemical, histological and virological response to treatment, drug resistance and adverse effects. A systematic review of economic evaluations of antiviral treatments for CHB was conducted. The economic Markov model used in the 2006 report was updated in terms of utility values, discount rates and costs. Results: Of the 82 papers retrieved for detailed screening, eight RCTs were included. Three evaluated ADV, four evaluated PEG-?-2b and one (from the original literature search) compared PEG-?-2b plus LAM with PEG-?-2b monotherapy. No RCTs of PEG-?-2a were identified. One ADV trial showed a statistically significant difference between ADV and placebo in terms of ALT response and HBV DNA levels, favouring ADV. Following withdrawal of ADV, levels were similar to those in placebo patients. In the ADV versus ADV plus LAM trial, there was a statistically significant difference in favour of the combination treatment. In the PEG-? trials, there were statistically significant differences favouring PEG-?-2b plus LAM compared with either one of the drugs given as monotherapy. For the comparison between PEG-?-2b and IFN-? and the comparison between different staggered regimens of the commencement of PEG-?-2b and LAM, there were no statistically significant differences between groups. Four full economic evaluations were identified, in addition to one identified in the original report. Two assessed PEG-?-2a; the remainder assessed ADV. PEG-?-2a was associated with increased treatment costs and gains in quality-adjusted life expectancy. In a UK study, the incremental cost-effectiveness ratio (ICER) for PEG-?-2a was £10,444 per QALY gained compared with LAM. Evaluations of ADV found that LAM monotherapy was dominated; the ICER for ADV monotherapy compared with 'doing nothing' was $19,731. The results of the updated analysis were generally robust to changes in deterministic sensitivity analysis. In a probabilistic sensitivity analysis, the same sequence of treatments was identified as optimal. In a probabilistic sensitivity analysis, PEG-?-2b had a probability of being cost-effective of 79% at a willingness-to-pay threshold of £20,000 per QALY, and 86% at a willingness-to-pay threshold of £30,000 per QALY. Conclusions: Both ADV and PEG-? are beneficial for patients with CHB in terms of suppressing viral load, reducing liver damage-associated biochemical activity, inducing HBeAg seroconversion, and reducing liver fibrosis and necroinflammation. The effects of long-term treatment with ADV are generally durable, with relatively low rates of resistance. In most cases, cost-effectiveness estimates were within acceptable ranges. Further research should assess the clinical effectiveness and cost-effectiveness of newer antiviral agents in relation to existing drugs, including the role of initiating treatment with combination therapy.

Response to Lamivudine-Resistant Hepatitis B Virus Infection Postliver Transplantation from a Hepatitis B Core Antibody Donor

To the Editor: We would like to respectfully respond to the comments of Dr. Hans Tillmann. We appreciate his interest in our case report and review. We would like to clarify that we do not believe that the liver initially harbored a lamivudine-resistant mutant, but that the mutation occurred during prolonged lamivudine exposure leading to de novo breakthrough hepatitis B virus infection. There is no reason to suspect the donor already had a lamivudine-resistant mutation, otherwise the recipient should have developed acute hepatitis B at a much earlier period due to the lack of protection by lamivudine and loss of anti-HBs after 6 months. Hepatitis B virus infection from a source other than the graft would also be very unlikely. Retrospective analysis of our cohort of 402 recipients (including the reported case), receiving 467 liver transplants between March 1998 and December 2001, revealed three cases of de novo Hepatitis B (0.6%) after a median follow up of 4.5 years (1Bonatti H Machicao V Dickson RC Mendez J Results of liver transplantation in HBV core antibody positive individuals and recipients of allografts from HBV core antibody positive individuals..Eur Surg. 2005; 37: 15Google Scholar). One case was acquired during unprotected intercourse. The second was an anti-HBc and anti-HBs negative recipient who developed acute hepatitis B 4 months after liver transplantation. Hepatitis B donor status was unknown at the time of transplantation and therefore no lamivudine prophylaxis was administered. The donor was subsequently found to be anti-HBc positive after retrospective analysis of stored serum. The third was the patient presented in the case report who developed HBV more than 3 years posttransplant while receiving continuous lamivudine prophylaxis. He was a heterosexual, elderly male without other viral exposures (HIV and HCV negative) or other viral risk factors pre- or posttransplantation. This data strongly support that the HBV infection was acquired from the graft. The development of lamivudine-resistant mutation after prolonged lamivudine therapy is not surprising. HBV DNA has been shown to persist after liver transplantation despite successful antiviral prophylaxis. Terrault et al. demonstrated HBV DNA in 8/9 patients a mean of 27 (range 13–33) months after liver transplantation for HBV despite successful HBIg prophylaxis (2Terrault NA Zhou S Combs C et al.Prophylaxis in liver transplant recipients using a fixed dosing schedule of hepatitis B immunoglobulin..Hepatology. 1996; 24: 1327-1333Crossref PubMed Google Scholar). In addition, the frequency of lamivudine resistance is known to increase with time in patients receiving lamivudine monotherapy for chronic Hepatitis B. Lai et al. described rates of 53% and 70% after 3 and 5 years of therapy (3Lai CL Dienstag J Schiff E et al.Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B..Clin Infect Dis. 2003; 36: 687-696Crossref PubMed Scopus (558) Google Scholar). The other patient in our series who developed de novo HBV from an anti-HBC graft also developed a lamiuvidine-resistant mutation after 1 year on lamivudine treatment. We agree with Dr. Tilman that the proof of our hypothesis might be possible if specimens from the liver and later on consecutive serum samples would be available for retesting. Unfortunately, we cannot provide these data. Four lessons should be learned form this case. First, donors must be tested for anti-HBc antibodies and these organs ideally should be allocated to Hepatitis B-exposed individuals. Second, serum and tissue from donors and recipients should be stored for retrospective studies. Third, a significant follow-up period is required to make any definitive statements about recurrent or de novo hepatitis B after liver transplant. Fourth, the risk for development of resistant mutations posttransplant must not be neglected.

Prevention of hepatitis B recurrence after liver transplantation using lamivudine or lamivudine combined with hepatitis B Immunoglobulin prophylaxis

The aim of our study was to determine the outcomes of liver transplant recipients receiving either lamivudine (LAM) monotherapy or LAM combined with low-dose intramuscular (IM) hepatitis B Immunoglobulin (HBIG) therapy. We performed a retrospective review of the medical records of patients that had had liver transplantation in a single center for HBV-related liver diseases from December 1999 to June 2004. A total of 165 patients received LAM monotherapy (51 patients) or combined prophylaxis (114 patients) post-liver transplantation (LT) with a mean follow-up of 20.13 months. Hepatitis B relapsed in 21 patients of the hepatitis B surface antigen (HBsAg) carriers who received LAM monotherapy, with a 1- and 2-yr actuarial risk of 27.4% and 39.7%. Recurrence occurred in 16 patients of 114 patients receiving the combined prophylaxis, with a 1- and 2-yr recurrence rate of 13.5% and 15.2% (P = 0.024). A total of 25 cases (67.6%) with YMDD mutants were detected in all the 37 patients, 14 cases (66.7%) in the monotherapy group and 11 cases (68.8%) in the combination group. In conclusion, LAM and low-dose intramuscular HBIG treatment demonstrates a better result than LAM monotherapy, as prophylaxis against post-LT reinfection of the graft, but the safety and efficacy as a substitution for high-dose intravenous HBIG with LAM needs to be investigated further.

Nonresponse to 18-month Lamivudine Monotherapy in Chronic Hepatitis B Patients with Dual Genotype B and C Infection and Acute Exacerbation

Molecular epidemiologic studies have indicated the possible existence of mixed infection of different hepatitis B virus (HBV) genotypes in chronic hepatitis B (CH-B) carriers, but the effect of dual HBV genotype B and C infection on the efficacy of lamivudine therapy remains unclear. We report four CH-B patients with dual HBV genotype B and C infection and acute exacerbation who received lamivudine monotherapy for about 18 months. None of them had achieved a sustained response at the end of the 18-month trial of treatment.

Peginterferon Alfa-2a, Lamivudine, and the Combination for HBeAg-Positive Chronic Hepatitis B

Current treatments for chronic hepatitis B are suboptimal. In the search for improved therapies, we compared the efficacy and safety of pegylated interferon alfa plus lamivudine, pegylated interferon alfa without lamivudine, and lamivudine alone for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A total of 814 patients with HBeAg-positive chronic hepatitis B received either peginterferon alfa-2a (180 microg once weekly) plus oral placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), or lamivudine alone. The majority of patients in the study were Asian (87 percent). Most patients were infected with hepatitis B virus (HBV) genotype B or C. Patients were treated for 48 weeks and followed for an additional 24 weeks. After 24 weeks of follow-up, significantly more patients who received peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine than those who received lamivudine monotherapy had HBeAg seroconversion (32 percent vs. 19 percent [P<0.001] and 27 percent vs. 19 percent [P=0.02], respectively) or HBV DNA levels below 100,000 copies per milliliter (32 percent vs. 22 percent [P=0.01] and 34 percent vs. 22 percent [P=0.003], respectively). Sixteen patients receiving peginterferon alfa-2a (alone or in combination) had hepatitis B surface antigen (HBsAg) seroconversion, as compared with 0 in the group receiving lamivudine alone (P=0.001). The most common adverse events were those known to occur with therapies based on interferon alfa. Serious adverse events occurred in 4 percent, 6 percent, and 2 percent of patients receiving peginterferon alfa-2a monotherapy, combination therapy, and lamivudine monotherapy, respectively. Two patients receiving lamivudine monotherapy had irreversible liver failure after the cessation of treatment--one underwent liver transplantation, and the other died. In patients with HBeAg-positive chronic hepatitis B, peginterferon alfa-2a offers superior efficacy over lamivudine, on the basis of HBeAg seroconversion, HBV DNA suppression, and HBsAg seroconversion.

Intrahepatic Hepatitis B Virus Covalently Closed Circular DNA Can Be a Predictor of Sustained Response to Therapy

This study aimed to determine whether intrahepatic hepatitis B virus (HBV) covalently closed circular (ccc) DNA and total HBV DNA levels at the end of therapy would predict sustained response to therapy. Hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients receiving either lamivudine monotherapy or combination of peginterferon and lamivudine had liver biopsy at the end of 1 year therapy and were followed for 52 more weeks after cessation of therapy. Serum HBV DNA, intrahepatic HBV ccc DNA, and total HBV DNA levels were determined. Forty-seven patients, including 34 males and 13 females, were studied. Twenty-seven patients received combination therapy, and 20 patients received lamivudine monotherapy. Twenty-nine patients had end-of-treatment virologic response, and 15 patients had sustained response 52 weeks after therapy. At the end of treatment, log serum HBV DNA levels correlated well with log intrahepatic HBV cccDNA and log intrahepatic total HBV DNA levels. Log intrahepatic cccDNA and log intrahepatic total DNA levels were significantly lower among patients with sustained virologic response. The adjusted odds ratio for log cccDNA was 5.3 (95% CI: 1.5-18.2, P = .009) and, for log intrahepatic HBV DNA, was 4.4 (95% CI: 1.3-14.7, P = .015) to predict sustained virologic response. Using log cccDNA at -0.80 copies/genome equivalent as cutoff, the sensitivity, specificity, and positive and negative predictive values and accuracy of predicting sustained virologic response were 73%, 78%, 56%, 86%, and 77% respectively. Intrahepatic HBV cccDNA and intrahepatic total HBV DNA levels at the end of therapy are superior to serum HBV DNA as surrogates of sustained virologic response.

Outcomes in liver transplant recipients with hepatitis B virus: Resistance and recurrence patterns from a large transplant center over the last decade

Hepatitis B virus (HBV) recurrence following liver transplantation (LTx) has been controllable primarily with the use of hepatitis B immune globulin (HBIg) and lamivudine (LAM). However, HBV resistance to LAM and/or HBIg has become an increasing problem prompting the use of newer antiviral agents. The purpose of our study was to investigate the association between therapy, HBV breakthrough, and allograft / patient survival in HBV-positive liver transplant recipients. We performed a retrospective review of the medical records of patients that were transplanted for HBV from June 1994 to May 2003. A total of 92 patients, positive for either hepatitis B surface antigen (HBsAg) or HBV deoxyribonucleic acid (DNA) pretransplant, received LAM monotherapy or HBIg (6 months) plus LAM therapy post-liver transplant. HBV breakthrough post-LTx was noted in 14 patients. All patients had detectable HBV DNA prior to liver transplantation; none of the patients that were HBV DNA negative prior to transplant had detectable HBV DNA posttransplant. Of these 14, 9 patients (64%) were switched from LAM to adefovir dipivoxil (ADF) and 5 patients (36%) to tenofovir disoproxil fumarate (TNV). In conclusion, pre-LTx HBV viremia should be considered in planning post-LTx prophylaxis. Trials to evaluate oral antiviral agents in combination with or without HBIg therapy are needed.

In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B

Both the hepatitis B virus (HBV) and the immune response of the hosts to HBV play important roles in the pathogenesis of chronic hepatitis B (CHB). Lamivudine is a potent antiviral agent with minimal immune modulator capacity. Moreover, lamivudine causes severe side effects like breakthrough of HBV DNA and breakthrough hepatitis in patients with CHB. On the other hand, vaccine therapy, a recently-developed immune therapy, exhibits potent immune modulatory potentials and almost no side effects, but possesses little antiviral capacity in patients with CHB. The aim of this clinical trial is to evaluate the efficacy of a combination therapy of lamivudine and vaccine in patients with CHB. Seventy-two patients with CHB (hepatitis B e antigen (HBeAg)-positive, 40; antibody to HBeAg (anti-HBe)-positive, 32). All patients received lamivudine at a dose of 100 mg daily for 12 months. Fifteen patients (HBeAg+, 9; anti-HBe+, 6) receiving oral lamivudine were also given a vaccine containing 20 microg of hepatitis B surface antigen, intradermally, once every 2 weeks for 12 times (combination therapy). Twelve months after the start of therapy, serum HBV DNA became negative in 9 of 9 (100%) HBeAg+ CHB patients receiving combination therapy and in 15 of 31 (48%) HBeAg+ CHB patients receiving lamivudine monotherapy (P < 0.05). The rate of seroconversion from HBeAg to anti-HBe was also significantly higher in patients receiving combination therapy (56% versus lamivudine monotherapy, 16%, P < 0.05). Of the 57 patients receiving lamivudine monotherapy, breakthrough of HBV DNA was found in 10 and breakthrough hepatitis was found in 4; however, these were not seen in any patient receiving combination therapy. Combination therapy represents a better therapeutic regimen with few complications in patients with CHB.

Outcome of lamivudine resistant hepatitis B virus mutant post-liver transplantation on lamivudine monoprophylaxis.

We aimed to investigate the clinical outcome of patients who develop lamivudine resistant hepatitis B virus mutants (YMDD mutants) after liver transplantation. Patients who received liver transplantation for hepatitis B-related liver diseases from 1999 to 2002 were studied. All patients received lamivudine monotherapy before and after liver transplantation. HBsAg and HBV DNA were regularly monitored, and YMDD mutation was detected by direct sequencing. Twenty patients were followed up for median 94 wk (range: 15-177 wk) post-liver transplantation. Six patients developed YMDD mutants, and the cumulative probability of developing YMDD mutations post-liver transplantation was 21% in 1 yr and 34% in 2 yr. One patient developed YMDD mutants before liver transplantation and died of hepatitis reactivation and liver failure 15 wk post-transplantation. The other five patients developed YMDD mutants 32-72 wk after liver transplantation. Two of them developed severe hepatitis which responded promptly to adefovir dipivoxil. The remaining three patients with YMDD mutants had minimal to mild hepatitis. The cumulative survival for patients with YMDD mutants was 83% and 28% at 1 and 2 yr, respectively. Only one patient who did not develop YMDD mutants died at week 119 due to chronic rejection. The post-transplant survival for patients with YMDD mutants was significantly poorer than those without YMDD mutants (log rank test p = 0.083). The emergence of YMDD mutants after liver transplantation on lamivudine monoprophylaxis had wide range of clinical presentations and was associated with increased mortality.

Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B

Background & Aims: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV). Methods: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level ≥1.2 times the upper limit of normal, and serum HBV DNA level ≥6 log10 copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16. Results: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG16 was −0.07 in the lamivudine group compared with −2.45 and −2.46 log10 copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001). Median change from baseline in serum HBV DNA level at week 48 was 0.0, −3.59, and −4.04 log10 copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively. ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine. Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative. Conclusions: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.

Combined Interferon and Lamivudine Therapy: Is This The Treatment of Choice for Patients With Chronic Hepatitis B Virus Infection?

Background, aim and methods-Alpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside analogue which potently inhibits hepatitis B virus (HBV) DNA replication. To investigate the possibility of an additive effect of interferonlamivudine combination therapy compared with interferon or lamivudine monotherapy, we conducted a randomised controlled trial in 230 predominantly Caucasian patients with hepatitis B e antigen (HBeAg) and HBV DNA positive chronic hepatitis B. Previously untreated patients were randomised to receive: combination therapy of lamivudine 100 mg daily with alpha interferon 10 million units three times weekly for 16 weeks after pretreatment with lamivudine for eight weeks (n = 75); alpha interferon 10 million units three times weekly for 16 weeks (n = 69); or lamivudine 100 mg daily for 52 weeks (n = 82). The primary efficacy end point was the HBeAg seroconversion rate at week 52 (loss of HBeAg, development of antibodies to HBeAg and undetectable HBV DNA). Results-The HBeAg seroconversion rate at week 52 was 29% for the combination therapy, 19% for interferon monotherapy, and 18% for lamivudine monotherapy (p = 0.12 and p = 0.10, respectively, for comparison of the combination therapy with interferon or lamivudine monotherapy). The HBeAg seroconversion rates at week 52 for the combination therapy and lamivudine monotherapy were significantly different in the per protocol analysis (36% (20/56) v 19% (13/70), respectively, p = 0.02). The effect of combining lamivudine and interferon appeared to be most useful in patients with moderately elevated alanine aminotransferase levels at baseline. Adverse events with the combination therapy were similar to interferon monotherapy; patients receiving lamivudine monotherapy had significantly fewer adverse events. Conclusions-HBeAg seroconversion rates at one year were similar for lamivudine monotherapy (52 weeks) and standard alpha interferon therapy (16 weeks). The combination of lamivudine and interferon appeared to increase the HBeAg seroconversion rate, particularly in patients with moderately elevated baseline aminotransferase levels. The potential benefit of combining lamivudine and interferon should be investigated further in studies with different regimens of combination therapy.

Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial

BACKGROUND, AIM, AND METHODSAlpha interferon is the generally approved therapy for HBe antigen positive patients with chronic hepatitis B, but its efficacy is limited. Lamivudine is a new oral nucleoside...

Lamivudine resistance inimmunocompetent chronic hepatitis B

Background: Lamivudine is a non-toxic, potent inhibitor of hepatitis B virus replication. Recently, hepatitis B virus resistance to lamivudine has been described in patients using immunosuppressive drugs after liver transplantation. Methods: From our cohort of 81 consecutive patients treated with lamivudine, we selected all immunocompetent patients who received lamivudine monotherapy for a period over 26 weeks ( n=14). Results: Lamivudine resistance with the characteristic mutation in the YMDD motif was observed in four patients (actuarial cumulative incidence: 39%). Two patterns of viral resistance were observed; incomplete response ( n=2) and viral breakthrough ( n=2). Conclusions: The observed high frequency of lamivudine resistance may have implications for the concept of long-term virus-suppressive therapy of chronic hepatitis B by lamivudine monotherapy.