THERAPY WITH NUCLEOSIDE ANALOGUES FOR HEPATITIS B VIRUS INFECTION

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Alpha interferon has been the mainstay of treatment for chronic hepatitis B since its introduction in the mid-1980s, but only approximately 30% to 40% of patients respond to this therapy.17 Interferon's principal mechanism of action against hepatitis B is unknown but postulated to include inhibition of hepatitis B virus (HBV) replication and enhancement of cell-mediated immune cytolysis of HBV-infected hepatocytes. Therefore, immunosuppressed patients, such as those with human immunodeficiency virus (HIV) infection and those who have undergone organ transplantation, respond poorly to interferon. Other subgroups with suboptimal responses to interferon include patients with perinatal acquisition of HBV infection, patients with normal aminotransferase levels, and patients infected with precore-mutant strains of HBV. In addition, response to interferon can be accompanied by an acute exacerbation of hepatic injury, rendering it unsafe for use in patients with decompensated liver disease. Finally, even in the well-compensated patient, interferon therapy may be accompanied by cumbersome adverse effects.

The development of nucleoside analogues has launched a revolution in the treatment of hepatitis B. Unlike interferon, lamivudine and the newer nucleoside analogues famciclovir, lobucavir, and adefovir dipivoxil block replication of HBV directly by inhibiting HBV polymerase; their activities are thought to be independent of any host immune response to the virus. These drugs are highly bioavailable by the oral route and are extremely well tolerated. Therefore, the potential exists for long-term use of these agents to suppress HBV infection. The purpose of this article is to provide a brief overview of this rapidly evolving field.

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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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  • Cited by (0)

    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.

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