Cross-Study Analysis of the Relative Efficacies of Oral Antiviral Therapies for Chronic Hepatitis B Infection in Nucleoside-Naive Patients

Jules L. Dienstag; Lee-Jen Wei; Dong Xu; Bruce Kreter


Clin Drug Invest. 2007;27(1):35-39. 

In This Article

Abstract and Introduction


Background and objective: Lamivudine and adefovir were approved for treatment of chronic hepatitis B virus (HBV) infection based on placebo-controlled trials, and entecavir was recently approved on the basis of its superiority over lamivudine in phase II/III trials; however, to date, these three therapies have not been compared head to head.
Methods: To evaluate the relative efficacy of these therapies, we applied a predefined protocol of established statistical techniques to compare data from phase III entecavir trials with published clinical trial results with lamivudine, adefovir and placebo in nucleoside-naive hepatitis B e antigen (HBeAg)-positive and -negative populations.
Results: A comprehensive literature search identified 612 publications/data sources, of which 28 satisfied predefined inclusion criteria. Independent reviewers extracted week 48-52 histological, virological, biochemical and serological endpoints from these sources, which were analysed with a fixed-effects model. For each of the three histological endpoints in HBeAg-positive patients (Histological Improvement, Ranked Assessment of Necroinflammation [RA-N] and Ranked Assessment of Fibrosis [RA-F]), entecavir was superior to adefovir. Entecavir was superior to lamivudine for Histological Improvement and comparable to lamivudine for RA-N and RA-F. With respect to reducing HBV DNA levels, entecavir (-6.98 log10 copies/mL) was more effective than lamivudine (-5.46 log10 copies/mL, p < 0.0001) and adefovir (-3.60 log10 copies/mL, p < 0.0001), and lamivudine was more effective than adefovir (p < 0.0001). The parallel goals of HBV DNA reduction below the limit of quantitation (LOQ) [by polymerase chain reaction] and ALT normalisation were achieved more often with entecavir (69% and 67% of patients, respectively) than with lamivudine (38% and 59%, respectively; p < 0.0001 and p < 0.05, respectively) or adefovir (21% and 48%, respectively; both p < 0.0001), and more often with lamivudine than with adefovir (p < 0.0001 and p < 0.05, respectively). HBeAg seroconversion rates were higher with entecavir (21% of patients) and lamivudine (18%) than with adefovir (12%, p < 0.01 and p < 0.05, respectively). For each of the three histological endpoints in the HBeAg-negative population, entecavir was comparable to adefovir. Entecavir was superior to lamivudine for Histological Improvement, and comparable to lamivudine for RA-N and RA-F, and all three antivirals were superior to placebo. Entecavir proved superior to lamivudine and adefovir in lowering HBV DNA levels (-5.20 vs -4.66 vs -3.91 log10 copies/mL, respectively; p < 0.0005 and p < 0.0001, respectively) and in suppressing HBV DNA below the LOQ (91% vs 73% vs 51% of patients, respectively; both p < 0.0001); in the latter respect, lamivudine was in turn superior to adefovir (p < 0.0001). Entecavir was also superior to lamivudine in normalising ALT (76% vs 69% patients, respectively; p < 0.05).
Conclusions: Over a 12-month treatment period, this analysis predicts that the antiviral efficacy of entecavir would be superior to that of lamivudine, which in turn would be superior to that of adefovir, in nucleoside-naive patients with chronic HBV infection.


Until 2005, lamivudine and adefovir were the only two oral antiviral drugs approved for treatment of chronic hepatitis B virus (HBV) infection; both were approved based on results from placebo-controlled clinical trials. Entecavir, a novel, potent and selective guanosine analogue, was approved for the oral treatment of chronic HBV infection by the US FDA in early 2005 based on results of comparative phase III trials versus lamivudine.[1,2,3]

Apart from clinical trials comparing entecavir with lamivudine,[1,2,3] adequate, well controlled, head-to-head comparisons of these three orally administered antiviral agents in nucleoside-naive adults with chronic HBV infection have not been undertaken. Therefore, the relative clinical efficacies of entecavir, adefovir and lamivudine are unknown. Furthermore, individual interstudy comparisons are difficult to interpret because virological assays based on different methodologies, sensitivities and dynamic ranges were used in the clinical trials of each of these three antiviral agents. For example, lamivudine registration trials relied on hybridisation assays (sensitivity of 105-106 copies/mL) for HBV DNA,[4,5,6] while polymerase chain reaction (PCR) assays were used in clinical trials of adefovir (sensitivity of 102-103 copies/mL)[7,8] and entecavir (sensitivity of 300 copies/mL).[2,3] Furthermore, since the development of these three antivirals occurred over a period of approximately 10 years, the patients participating in these studies may not have been drawn from comparable populations.

In an attempt to control for these temporal, methodological and study-population differences in individual clinical trials, we applied a prospectively defined analysis protocol with established statistical techniques to compare data from the phase III trials of entecavir with efficacy data from published clinical trials of lamivudine and adefovir in nucleoside-naive adults with chronic HBV infection. This approach allowed us to evaluate the relative rankings of entecavir, adefovir, lamivudine and placebo for accepted histological, biochemical, virological and serological endpoints.


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