Gastroenterology

Gastroenterology

Volume 125, Issue 1, July 2003, Pages 107-116
Gastroenterology

Clinical-liver, pancreas, and biliary tract
Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1

https://doi.org/10.1016/S0016-5085(03)00700-5Get rights and content

Abstract

Background & aims:

Hepatitis B virus (HBV) genotype may influence disease progression and antiviral response. We therefore analyzed the frequency and distribution of genotypes in patients from 2 multinational phase III studies of adefovir dipivoxil. Antiviral efficacy of adefovir dipivoxil 10-mg therapy was examined with respect to HBV genotype, hepatitis B e antigen (HBeAg) serostatus, and race.

Methods:

HBV genotypes were assigned by phylogenetic analyses of DNA sequences amplified from baseline serum samples (n = 694).

Results:

Patients from Asia/Oceania were infected predominantly with genotypes B and C, whereas patients from Western European countries were infected predominantly with genotypes A and D. In Mediterranean countries, genotype D was dominant. The most common genotype in North America was C, followed by A, B, and D. Regardless of location, Asian patients were infected predominantly with genotypes B or C, whereas Caucasian patients were infected predominantly with A or D. There were significant differences in the baseline serum HBV-DNA levels of patients infected with different HBV genotypes regardless of HBeAg serostatus. Forty-eight weeks of adefovir dipivoxil 10-mg therapy resulted in potent reductions in serum HBV DNA with no significant differences based on genotype, HBeAg status, or race; similarly, there was no statistical difference in HBeAg seroconversion rates between genotypes in these patients.

Conclusions:

HBV genotypes were distributed asymmetrically with respect to race, geography, and HBeAg status. Forty-eight weeks of adefovir dipivoxil therapy resulted in significant decreases in serum HBV-DNA levels in patients regardless of HBV genotype, HBeAg status, or race.

Section snippets

Patients

Patients included in these analyses took part in 1 of 2 randomized, double-blind, placebo-controlled, phase III trials of adefovir dipivoxil. Study GS-98-437 was designed to examine the safety and efficacy of 10- and 30-mg daily doses of adefovir dipivoxil in patients with HBeAg+ chronic hepatitis B. Study GS-98-438 was conducted to determine the safety and efficacy of a 10-mg daily dose of adefovir dipivoxil in patients with HBeAg negative (HBeAg−) (presumed precore mutant) chronic hepatitis

Frequency of hepatitis B virus genotypes at baseline

A total of 700 patients from 86 sites in 15 countries enrolled in phase III clinical trials of adefovir dipivoxil. A total of 695 of these patients received at least one dose of study drug and was defined as the intent-to-treat study population. Baseline serum samples were used to amplify and sequence HBV DNA from each patient in the intent-to-treat group. HBV genotypes were determined by phylogenetic analyses of a 1032-nucleotide PCR product spanning HBsAg and the reverse-transcriptase domain

Discussion

Based on recent findings, several important questions have been raised concerning the prevalence and clinical significance of HBV genotypes.12 Among these questions are the following: what is the predominant genotype in each country? Is there a correlation between HBV genotype, HBV replication, and disease progression? Is there a correlation between HBV genotype and clinical response? By genotyping 694 chronic hepatitis B patients that participated in phase III trials of adefovir dipivoxil, we

Acknowledgements

The authors thank Mick Hitchcock and Michael Wulfsohn for critical review of this manuscript.

References (42)

  • E.J. Heathcote et al.

    Adefovir dipivoxil (ADV) for HBeAg negative chronic hepatitis B (HBV)virological & comparative viral dynamics analyses provide insight into the influence of precore mutations on the mechanisms of viral clearance

    J Hepatol

    (2001)
  • B.H. Robertson et al.

    Primate hepatitis B viruses—genetic diversity, geography and evolution

    Rev Med Virol

    (2002)
  • L.O. Magnius et al.

    Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene

    Intervirology

    (1995)
  • H. Okamoto et al.

    Typing hepatitis B virus by homology in nucleotide sequencecomparison of surface antigen subtypes

    J Gen Virol

    (1988)
  • L. Stuyver et al.

    A new genotype of hepatitis B viruscomplete genome and phylogenetic relatedness

    J Gen Virol

    (2000)
  • T.F. Baumert et al.

    Hepatitis B virus mutantsmolecular biology and clinical relevance

    Viral Hepatitis Rev

    (2000)
  • M.L. Funk et al.

    World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants

    J Viral Hepat

    (2002)
  • C. Mayerat et al.

    Does hepatitis B virus (HBV) genotype influence the clinical outcome of HBV infection?

    J Viral Hepat

    (1999)
  • J.H. Kao et al.

    Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection

    J Clin Microbiol

    (2002)
  • C.J. Chu et al.

    Clinical significance of hepatitis B virus genotypes

    Hepatology

    (2002)
  • A. Erhardt et al.

    Mutations of the core promoter and response to interferon treatment in chronic replicative hepatitis B

    Hepatology

    (2000)

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    1

    Gilead Sciences gratefully acknowledges the patients, investigators, and study site personnel who participated in clinical trials GS-98-437 and GS-98-438.

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    Copyright © 2003 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.