Randomized trial of lamivudine versus entecavir in entecavir-treated patients with undetectable hepatitis B virus DNA: Outcome at 2 Years

Abstract

We aimed to determine the 2-year outcomes of entecavir followed by lamivudine in patients with undetectable viral load (<12 IU/mL) and normal alanine aminotransferase (ALT) after initial entecavir treatment for at least 6 months. Patients were randomly assigned 1:1 to continue with entecavir or switch to lamivudine. Liver biochemistry and hepatitis B virus (HBV) DNA were determined at weeks 0, 4, 12, 24, 48, 72, and 96. Mutational analysis using line-probe assay were performed at weeks 0, 24, 48, and 96 and at the time of HBV DNA relapse. There was no elevation of ALT observed in any patients up to 96 weeks. At 96 weeks of follow-up, 19/25 (76%) patients in the lamivudine arm had persistently undetectable HBV DNA, compared with 25/25 (100%) patients in the entecavir arm. Six patients in the lamivudine arm had HBV DNA >20 IU/mL, occurring at a range of 12 to 96 weeks. Of these, four patients had HBV DNA of less than 100 IU/mL during rebound (three had undetectable HBV DNA after switching back to entecavir), and the remaining two patients had HBV DNA levels of 7,973 and 699 IU/mL. Three patients (12%) had evidence of drug-resistant mutations, of which two patients had rtM204I mutation and one patient had rtM204V mutation. One of these three patients had previous lamivudine exposure before entecavir treatment and one patient had questionable drug compliance. Conclusion: Sequential therapy using entecavir followed by lamivudine resulted in virological rebound in 24% of patients after 96 weeks. Prior optimal viral suppression with entecavir did not confer any significant advantage in patients who switched to lamivudine. (HEPATOLOGY 2011;53:1148-1153 C hronic hepatitis B (CHB) affects 400 million people worldwide, constituting an important health burden in areas where hepatitis B virus (HBV) infection is endemic. Up to 40% of CHB patients may develop cirrhosis and its complications, including hepatocellular carcinoma (HCC).1 Lamivudine (LAM) was the first oral nucleoside analog available for the treatment of CHB, and is effective in retarding disease progression, including liver decompensation and HCC in both patients with cirrhosis and without cirrhosis. 2,3 Unfortunately, long-term LAM therapy is associated with high rates of drug-resistance, with 76% after 8 years of treatment. 3Previous studies have identified early viral suppression to be a predictor of long-term outcomes including the development of drug resistance. In a study of 159 hepatitis B e-antigen (HBeAg)-positive CHB patients treated with LAM, viral suppression at 24 weeks was predictive of long-term resistance risks with a median follow-up of 29 months. 4 In those patients who achieved undetectable HBV DNA by real-time polymerase chain reaction (PCR) assay at week 24, the long-term resistance risk was only 8% compared to 64% for those with HBV DNA of >4 log copies/mL. Similar findings have also been shown in other antiviral agents including adefovir (ADV) and telbivudine. 5,6

Telbivudine versus entecavir in patients with undetectable hepatitis B virus DNA: a randomized trial

“…This rate of virologic breakthrough (23.4%) during the 48-week telbivudine therapy in this study was comparable to that in a previous trial, which showed a 28.8% virologic breakthrough during a 2-year telbivudine treatment regimen in patients who were HBeAg-positive [19]. This observed rate is also similar to the rate of virologic rebound (24%) observed during lamivudine treatment in patients who had achieved undetectable serum HBV DNA following the preceding entecavir treatment [27]. …”

Adherence, persistence, healthcare utilization, and cost benefits of guideline-recommended hepatitis B pharmacotherapy

“…Previously published research has focused on the comparative clinical effectiveness [18][19][20][21][22][23] and/or costeffectiveness 24-28 of oral antiviral agents in the treatment of CHB.…”

Entecavir to Telbivudine Switch Therapy in Entecavir-Treated Patients with Undetectable Hepatitis B Viral DNA

“…Fung, et al5 started treating patients with HBV DNA loss with ETV and then switched to lamivudine and continued the treatment for 2 years. The study was based on an earlier study that reported a low incidence of resistance in the first 2 years of lamivudine treatment in patients with serum HBV DNA that was undetectable with PCR (<300 copies/mL) at week 24 of lamivudine treatment 7.…”

“…Viral reemergence was observed in 6 of 25 patients (24%), and resistance was found in 3. Therefore, Fung, et al5 expressed negative views toward lamivudine-switching therapy in patients with a favorable response to ETV therapy. However, they also reported that, after rebound, 3 patients were again treated with ETV to induce HBV DNA loss.…”

“…Fung, et al5 investigated the virological outcomes of patients with HBV DNA negativity induced by ETV who switched to lamivudine: the study examined if HBV DNA loss was maintained during a 2-year treatment period, and they showed that switching therapy from ETV to lamivudine resulted in virological rebound in 24% of patients. Thus, lamivudine switch showed a high possibility of antiviral resistance even when HBV DNA loss was achieved.…”