Benefits and risks of nucleoside analog therapy for hepatitis B


  • Jules L. Dienstag

    Corresponding author
    1. Gastrointestinal Unit (Medical Services), Massachusetts General Hospital and the Department of Medicine and Office of the Dean for Medical Education, Harvard Medical School, Boston, MA
    • Gastrointestinal Unit/Jackson 7, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114
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    • fax: 617-726-3673.

  • Potential conflict of interest: From 2007-2008, Dr. Dienstag was a member of scientific advisory boards for Bristol-Myers Squibb, Gilead Sciences, Metabasis, and Nucleonics; ad hoc consultant for Abbott Molecular, Achillion Pharmaceuticals, Amgen, Avant Immunotherpeutics, Boehringer-Ingelheim, Cubist, CombinatoRx, and Pharmasset; research grant support from NIDDK and Vertex; stock options from Achillion, Metabasis, and Nucleonics; and clinical trial data monitoring/adjudication committees for Schering-Plough Research Institute, Genzyme, and Human Genome Sciences.


Five oral agents have been approved for the treatment of chronic hepatitis B, ranging in virological potency, clinical efficacy, barrier to resistance, and side-effect profile. The degree of histological, biochemical, and serological improvement with therapy generally corresponds to the degree of suppression of serum hepatitis B virus (HBV) DNA achieved with therapy. Conversely, for agents with a low barrier to resistance, the profundity of HBV DNA suppression in individual patients correlates inversely with the likelihood of resistance. The durability of hepatitis B e antigen (HBeAg) responses after a consolidation period of an additional 6–12 months of therapy is ∼80% in western populations, lower in Asian populations. Loss of hepatitis B surface antigen (HBsAg) during a year of oral-agent therapy is limited, except with the most potent agents, but extending therapy for a second year and beyond can yield frequencies of HBsAg responses close to those reported in trials of interferon-based therapy. The oral agents are approved for 1–2 years of therapy, but treatment is continued indefinitely in the majority of patients (except for the ∼20% of patients who are HBeAg-reactive who achieve a durable HBeAg response). HBeAg responses and virological/biochemical benefit continue to be maintained and to increase with continued therapy beyond the first year. Data continue to accumulate supporting the link between long-term HBV DNA suppression and reduction in hepatic fibrosis, hepatic decompensation, and liver-related mortality. All the benefits of a single year of injectable peginterferon therapy can be achieved with the newer, low-resistance oral agents continued beyond the first year, without interferon side effects. Future studies are needed to develop drug regimens that are even more effective in achieving clinical endpoints, that are not hampered by resistance, and that are more confined in treatment duration but are more durable. (HEPATOLOGY 2009;49:S112–S121.)