ing Phase I and Phase II clinical trials. Other forms of experimental treatment that are being examined in in vitro and Currently, interferon alfa is the only approved treatment animal models include antisense oligonucleotides and supfor chronic hepatitis B virus (HBV) infection. A 3-to 6pressive HBV mutants. month course of interferon alfa in doses of 5 MU daily or 10
Currently, the nucleoside analogs, lamivudine and fam-MU thrice weekly results in suppression of HBV replication ciclovir, are the most promising new treatment for chronic (loss of serum HBV DNA by hybridization assays and hepati-HBV infection. Lamivudine (3TC) is the (0) enantiomer of tis B e antigen [HBeAg]) and improvement in liver disease 2,3-dideoxy-3-thiacytidine. It is a potent and selective inin 30% to 40% of patients within 12 months of the onset of hibitor of HIV replication and has been approved for the treatment. 1,2 Recent studies found that most (ΓΊ80%) retreatment of HIV infection in combination with zidovudine. sponders maintained their response during long-term follow-Its activity against HBV replication was first noted in clinical up. In addition, sustained responders were more likely to trials of patients coinfected with HBV and HIV. 10 Subsequent have virus clearance (loss of serum HBV DNA by polymerase in vitro and animal studies found that lamivudine was effecchain reaction assay and hepatitis B surface antigen [HBsAg]) tive in inhibiting HBV replication in transfected human hepaand improved clinical outcome. [3][4][5][6] Interferon therapy is less tocytes (2.2.15 cells) and in HBV-infected chimpanzees. [11][12][13] effective in immunosuppressed patients and in Asians who Clinical trials showed that short (4-to 12-week) courses have normal serum transaminase (alanine transaminase of lamivudine were well tolerated and produced rapid and [ALT]) levels. 7 The low efficacy of interferon in the latter profound decrease in serum HBV-DNA levels in patients with group of patients is presumably related to immune tolerance chronic hepatitis B. 14,15 However, the effect was not sussecondary to perinatal infection. Although interferon therapy tained, and very few (0%-12%) patients lost HBeAg. The has been shown to benefit some patients with clinical cirrhoease of administration (oral) and the absence of serious sidesis, life-threatening side-effects such as sepsis and hepatic effects (in particular, the lack of myelotoxicity and absent or failure have been reported among patients with decompenmild ALT flares) led to clinical trials of lamivudine in patients sated cirrhosis, even with low-dose interferon. 8,9 Thus, more with decompensated cirrhosis or recurrent hepatitis B posteffective and safer treatment for chronic HBV infection is liver transplantation, conditions in which interferon is inefurgently needed.
fective and contraindicated. Preliminary reports found that The availability of in vitro and animal models of hepadnavilamivudine is well tolerated and effective in inhibiting HBV ral infection and replication and the recognition that HBV replication and improving liver disease in these patients. [16][17][18][19] replicates through reverse transcription of an RNA intermedi-In addition, lamivudine monotherapy beginning at least 4 ate enabled testing of many new antiviral compounds that weeks before transplantation and continuing posttranshave been shown to be effective in human immunodeficiency plantation appears to reduce the rate of HBV reinfection in virus (HIV) and herpesvirus infections. Some of these antivipatients transplanted for HBV-related cirrhosis. 20 Nevertheral agents (lamivudine, famciclovir, lobucavir, and adefovir less, long-term treatment is needed for sustained effect. In a dipivoxil) are being evaluated in clinical trials. Several recent report of 24 patients with chronic hepatitis B who HBV-specific immunomodulatory therapies have also been received lamivudine for a median of 52 weeks (range, 4-60 developed including DNA vaccination, immunization with weeks), 39% lost HBeAg and 9% lost HBsAg. 21 Unfortunately, vaccines containing pre-S and S antigens, autologous lym-2 (8%) patients developed drug-resistant mutants with redephocyte transfer, and inoculation with synthetic peptide vactection of HBV DNA in serum and elevation in ALT levels. cines that contain the cytotoxic T lymphocyte epitope of Similar mutants have been reported in other patients on longterm lamivudine therapy, [16][17][18] especially among liver transplant recipients in whom emergence or selection of mutants Abbreviations: HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis may have been facilitated by enhanced levels of HBV replica-B surface antigen; ALT, alanine transaminase; HIV, human immunodeficiency virus; tion caused by concurrent immunosuppressive therapy. In DHBV, duck hepatitis B virus; CCC, covalently closed circular; TP, triphosphate. each case, the mutation involved substitution of methionine From the Division of Gastroenterology, University of Michigan and VA Medical by valine or isoleucine in the highly conserved YMDD locus