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Lamivudine therapy induces improvements in chronic hepatitis B in a high proportion of patients, but prolonged therapy is limited by the development of viral resistance. We analyzed clinical responses and virologic resistance in 27 patients treated continuously with lamivudine for 2 to 4 years. Serum transaminases, hepatitis B virus (HBV) DNA by both branched DNA (bDNA) signal amplification and quantitative polymerase chain reaction were monitored at 4- to 8-week intervals. Virologic resistance to lamivudine was confirmed by the presence of mutations in the YMDD motif of the polymerase gene by restriction fragment-length polymorphism analysis. Serum HBV-DNA levels decreased rapidly in all treated patients, falling by 4 to 5 logs within 1 year. Transaminase levels also decreased and were normal in 70% of patients at 1 year, at which point liver histology had improved in 81% of patients. Viral resistance began to emerge after 8 months of therapy, eventually developing in 14 patients, including 76% of hepatitis B e antigen (HBeAg)-positive patients but only 10% of HBeAg-negative patients. Lamivudine withdrawal led to reappearance of wild-type HBV species, but retreatment led to more rapid reappearance of the mutant virus. Clinical, serum biochemical, and histologic improvements were maintained in the 13 patients who did not develop resistance. Thus, long-term therapy with lamivudine resulted in maintained improvements in virologic, biochemical, and histologic features of disease in most patients with HBeAg-negative chronic hepatitis B and in the subgroup of HBeAg-positive patients with high serum transaminase levels. A high rate of resistance limited efficacy, particularly in patients who remained HBeAg positive on therapy.

Sustained responses to interferon-alpha occur in 10% to 25% of patients with chronic hepatitis C, but the long-term outcome is not well defined. We evaluated the long-term clinical, histological, and virological outcomes of 10 patients with chronic hepatitis C who were treated between 1984 and 1987 with interferon-alpha-2b for 52 +/- 6 weeks (total doses of 492 +/- 116 MU). Before therapy, all 10 had hepatitis C virus (HCV) RNA, elevations of serum aminotransferases, and chronic hepatitis with fibrosis on liver biopsy. Clinical follow up was 6 to 13 years, and liver biopsies were done 5 to 11 years after initiation of therapy. HCV RNA was assayed by qualitative and quantitative reverse transcriptase-polymerase chain reaction assays. Among 5 patients who had a 6-month sustained response after therapy, all remained HCV RNA negative, and at last follow-up, 4 had normal and 1 minimally elevated serum aminotransferase levels. Liver biopsy specimens were nonreactive for HCV RNA, and all the patients showed improvements in both inflammation and fibrosis and were either normal or had mild, nonspecific inflammatory changes. Among 5 patients without a sustained response, all continued to have HCV RNA in serum and persistent or intermittent aminotransferase elevations. Liver biopsy specimens showed little or no change in necrosis and inflammation; all except 1 patient had progression of fibrosis scores or cirrhosis. All 5 patients had symptoms of chronic hepatitis, 1 underwent liver transplantation, and another had progressive hepatic decompensation. In conclusion, patients with a 6-month posttreatment virological response have a favorable long-term clinical and histological outcome.

Long-term hepatitis B immune globulin (HBIG) has been shown to reduce hepatitis B virus (HBV) reinfection in patients transplanted for hepatitis B. The aim of this study was to determine the prevalence of HBV S gene mutations in liver transplant recipients who developed recurrent hepatitis B despite HBIG prophylaxis, and to determine if these mutations can revert after withdrawal of HBIG. The entire S gene sequences in pre- and posttransplant sera from 20 patients who developed recurrent hepatitis B despite HBIG prophylaxis were compared. Ten (50%) patients had 18 amino acid substitutions involving the 'a' determinant in the posttransplant samples. These mutations were absent in 93% of the pretransplantation clones analyzed. There was a significant correlation between the development of mutations in the 'a' determinant region and the duration of HBIG therapy. Most of the mutations result in changes in predicted antigenicity of the S protein. During follow-up, mutations in 14 (78%) of 18 affected codons in the 'a' determinant region reverted back to the pretransplantation sequences; only 1 codon had a de novo change after the withdrawal of HBIG. Two control patients who did not receive HBIG had no change in the 'a' determinant in their posttransplantation samples. These data support the hypothesis that mutations in the S gene were induced or selected by immune pressure exerted by HBIG. HBV S mutants may play a role in HBV reinfection in liver transplant recipients who received HBIG prophylaxis.