THERAPY WITH NUCLEOSIDE ANALOGUES FOR HEPATITIS B VIRUS INFECTION
Section snippets
HISTORICAL BACKGROUND
Experimental use of nucleoside analogues for the treatment of hepatitis B dates back at least two decades; however, experience with the early nucleoside analogues, such as vidarabine, in the early 1980s was disappointing. In the late 1980s, the efficacy of interferon was demonstrated, and interferon alpha-2b was approved by the US Food and Drug Administration for treatment of hepatitis B in 1992. Several nucleoside analogues, including acyclovir, didanosine, zidovudine, and ribavirin, were
MECHANISMS OF HBV REPLICATION AND THE EFFECT OF NUCLEOSIDE ANALOGUES
The HBV genome exists in infectious virions as relaxed circular, partially double-stranded DNA. When hepatocytes are infected with the virus, however, the HBV genome localizes to the nucleus and is converted to covalently closed circular DNA (cccDNA). HBV replication within the hepatocyte originates primarily from this cccDNA template.30 Within the nucleus, cccDNA is transcribed to form an RNA intermediate, which then migrates into the cytoplasm. In the cytoplasm, new relaxed circular DNA is
Lamivudine
To date, lamivudine is the only nucleoside analogue to have been subjected to long-term clinical trials in patients with chronic hepatitis B, and it is the only one to have been approved by the US Food and Drug Administration for this indication. This nucleoside analogue lowers HBV replication by three to four orders of magnitude.16 In preliminary studies, daily lamivudine doses of 100 and 300 mg resulted in suppression of HBV DNA to undetectable levels after a few weeks of therapy in 100% of
ADVERSE EFFECTS
The new generation of nucleoside analogues appears to be remarkably free of side effects, as suggested by the aforementioned clinical trials. Although the experience with FIAU remains a cautionary tale, lamivudine, famciclovir, lobucavir, and adefovir dipivoxil have been shown not to affect mitochondrial or chromosomal DNA synthesis at therapeutic dosages. Mild constitutional symptoms, such as malaise, fatigue, headache, nausea, and abdominal discomfort, have been reported by patients on these
RESISTANCE TO NUCLEOSIDE ANALOGUES
Emergence of resistance is the major drawback of nucleoside analogue monotherapy, which has been amply demonstrated by experience with HIV. Breakthrough of HBV replication in patients on prolonged lamivudine therapy has been well described. This phenomenon was first reported in patients receiving lamivudine following liver transplantation; in one study of lamivudine for recurrent HBV after transplantation, approximately 25% of patients experienced HBV DNA breakthrough after 1 year of therapy.33
SUMMARY AND RECOMMENDATIONS FOR USE
- 1
Lamivudine should be considered for use in patients with ongoing HBV replication, elevated aminotransferase activity, and histologic evidence of liver injury. Lamivudine is now considered first-line therapy, eclipsing interferon.
- 2
Lamivudine should be considered for patients who have failed to respond to interferon therapy, are unlikely to respond to interferon therapy (immunocompromised patients, perinatal infection, normal aminotransferase levels), or will not tolerate interferon
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Address reprints requests to Jules L. Dienstag, MD, Gastrointestinal Unit, Massachusetts General Hospital, Fruit Street, Boston, MA 02114
Research support was provided by Glaxo Wellcome, Gilead Sciences, the Hepatitis Research Fund of the Massachusetts General Hospital, a gift from Mrs. Mouna Al-Ayoub, Training Grant T32-DK07191 (PMR), and a Clinical Research Center grant to the Massachusetts General Hospital (M10RR01066) from the National Institutes of Health.