The value and limitations of long-term nucleoside antiviral therapy in chronic hepatitis B

Abstract

Clinical trials of lamivudine, the first oral nucleoside analogue approved for the treatment of chronic hepatitis B, began in the early 1990s, and a substantial cohort of patients has emerged in whom treatment was continued for half a decade or longer. Patients in the early clinical experience with lamivudine, many of whom had already failed to respond to interferon, had no other options for treatment, and the early experience with lamivudine did not disappoint. Treatment with this new agent was very well tolerated, indistinguishable in side effects from treatment with placebo, and a year of treatment was associated with histologic, virologic, serologic, and biochemical improvement [1–6]. Moreover, unlike interferon, lamivudine was found to be effective in patients with high-level HBV DNA, in patients with decompensated cirrhosis, and in patients who had undergone liver transplantation for end-stage liver disease associated with chronic hepatitis B [7–15]. Recently, lamivudine treatment was shown to slow clinical progression, even suggested to prevent the emergence of hepatocellular carcinoma, in patients with advanced fibrosis (60% of whom were cirrhotic) [16]. In short, during its ‘reign’ as the only oral antiviral approved for treatment of chronic hepatitis B, lamivudine improved the clinical and virological status of patients with chronic hepatitis B and saved many lives. When antiviral therapy with interferon and lamivudine was being developed, the initial therapeutic focus fell upon patients with highly replicative, wild-type, HBeAg-reactive chronic hepatitis B. In this population treated with lamivudine, histologic necroinflammatory activity improved in more than half, progression of fibrosis was