A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients.
ABSTRACT Entecavir is a nucleoside analogue with potent in vitro activity against lamivudine-resistant hepatitis B virus (HBV). This randomized, dose-ranging, phase 2 study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients.
Hepatitis B e antigen (HBeAg)-positive and -negative patients (n = 182), viremic despite lamivudine treatment for > or =24 weeks or having documented lamivudine resistance substitutions, were switched directly to entecavir (1.0, 0.5, or 0.1 mg daily) or continued on lamivudine (100 mg daily) for up to 76 weeks.
At week 24, significantly more patients receiving entecavir 1.0 mg (79%) or 0.5 mg (51%) had undetectable HBV DNA levels by branched chain DNA assay compared with lamivudine (13%; P < .0001). Entecavir 1.0 mg was superior to entecavir 0.5 mg for this end point (P < .01). After 48 weeks, mean reductions in HBV DNA levels were 5.06, 4.46, and 2.85 log(10) copies/mL on entecavir 1.0, 0.5, and 0.1 mg, respectively, significantly higher than 1.37 log(10) copies/mL on lamivudine. Significantly higher proportions of patients achieved normalization of alanine aminotransferase levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%). One virologic rebound due to resistance occurred (in the 0.5-mg group).
In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir 1.0 and 0.5 mg daily was well tolerated and resulted in significant reductions in HBV DNA levels and normalization of alanine aminotransferase levels. One milligram of entecavir was more effective than 0.5 mg in this population.
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ABSTRACT: This study evaluated the population pharmacokinetics (PK) of entecavir in Japanese patients with chronic hepatitis B infection enrolled in 2 Japanese phase IIb clinical trials and compared them to non-Japanese patients enrolled in global phase II trials. The objectives were to identify significant and clinically meaningful covariate effects on entecavir population pharmacokinetic parameters and assess whether differences exist between Japanese and non-Japanese patients. A total of 843 observations were obtained from 142 patients who received once daily administration of entecavir at 0.1, 0.5, and 1.0 mg doses in the 2 Japanese studies. Consistent with findings in non-Japanese patients, creatinine clearance estimated with ideal body weight (ICrCL) was found to be statistically significant for clearance in a 2-compartment model. Also, the entecavir dose was identified as a covariate on intercompartmental clearance. Age, gender, and hepatic function were not identified as covariate for clearance. The estimated population average of oral clearance in a typical patient with a reference ICrCL value of 100 mL/min was 26.4 L/h (interindividual variability: 19.4%). This model-based analysis indicates that the PK of entecavir are similar in Japanese and non-Japanese chronic hepatitis B patients.Diagnostic microbiology and infectious disease 05/2011; 70(1):91-100. DOI:10.1016/j.diagmicrobio.2010.12.009 · 2.57 Impact Factor
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ABSTRACT: Entecavir (ETV) is a potent and selective inhibitor of hepatitis B virus replication. In HBeAg-positive and HBeAg-negative lamivudine-naïve patients with chronic hepatitis B (CHB), treatment with ETV at a dose of 0.5 mg daily is associated with a more potent viral suppression, a higher rate of biochemical remission and a greater improvement of liver histology compared to Lamivudine (LAM). After 3 years of ETV treatment, the majority of patients (94%) may achieve serum HBV DNA levels undetectable by sensitive PCR assays. ETV treatment of patients with LAM-resistant HBV mutants requires a higher daily dose of 1 mg yet, potent HBV suppression at 3 years is achieved only in 40% of them while the cumulative rate of genotypic HBV resistance increases from 6% in the first year to >30% in year 3. ETV resistance of HBV is rare in lamivudine-naïve patients with a reported rate of <1% after three years of treatment. In conclusion, ETV is a very potent anti-HBV drug with a high genetic barrier to resistance, highly effective in lamivudine-naïve CHB patients and most promising for their long-term treatment but not very suitable for CHB patients harboring LAM-resistant HBV mutants.Therapeutics and Clinical Risk Management 12/2007; 3(6):1077-86. · 1.47 Impact Factor
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ABSTRACT: Significant advances in the management of chronic hepatitis B (CHB) have been made over the past decade. During this period we have witnessed improvements in survival as well as reduction of disease progression in CHB patients due to the introduction of effective antiviral therapy. The need for effective antiviral therapy is underscored by the results of the REVEAL-HBV study in which 3653 hepatitis B virus (HBV) carriers were followed over 12 year period. This study demonstrated that a persistently elevated serum HBV DNA level was the most important risk factor for the development of hepatocellular carcinoma (HCC). The ultimate goal of antiviral therapy for CHB patients should include halting the progression to cirrhosis and its life threatening complications and in preventing/reducing the development of HCC. An earlier study of 651 CHB patients with cirrhosis or advanced fibrosis from countries in Asia also demonstrated that treatment with lamivudine (LVD) not only delayed disease progression but also reduced the development of HCC. These landmark studies reaffirm the need for active antiviral therapy for CHB. Current treatment options for patients with CHB include interferon and nucleos(t)ide analogues. As we gain experience with these agents, it has become increasingly clear that long-term therapy benefits patients with CHB.Therapeutics and Clinical Risk Management 09/2007; 3(4):605-12. · 1.47 Impact Factor