The prognosis of decompensated cirrhosis resulting from chronic hepatitis B is poor, and the benefits of treatment with interferon are outweighed by serious side effects and by the risk of fatal exacerbation of disease activity. Lamivudine rapidly reduces hepatitis B virus (HBV)-DNA in serum to undetectable levels. We have treated 35 patients with chronic hepatitis B and decompensated cirrhosis with lamivudine 100 mg or 150 mg orally once daily. Pretreatment, all were positive for HBV-DNA in serum. Ten had Child-Pugh class B and 25 had Child-Pugh class C liver disease. Seven patients underwent liver transplantation within 6 months of treatment initiation, 5 patients died within 6 months, and 23 patients were treated for at least 6 months (mean ‫؍‬ 19 months). In a majority of these 23 cases, there was a slow but marked improvement in liver function, which was most apparent after 9 months of treatment, with a decrease in serum bilirubin from 67 ؎ 13 to 30 ؎ 4 mol/L (P F .05, baseline vs. 9 months), an increase in serum albumin from 27 ؎ 1 to 34 ؎ 1g/L (P F .05), and a decrease in Child-Pugh score from 10.3 ؎ 0.4 to 7.5 ؎ 0.5 (P F .05). Three patients developed resistance to lamivudine because of a mutation in the YMDD motif, but liver function did not deteriorate. We conclude that inhibition of viral replication with lamivudine results in a significant improvement of liver function in patients with decompensated HBV cirrhosis, but the long-term benefits remain uncertain. (HEPATOLOGY 2000;31:207-210.)

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Mutations within the hepatitis B virus (HBV) polymerase gene conferring drug-resistance are selected during prolonged lamivudine (3TC) or adefovir dipivoxil (ADV) treatment. Because there is no other approved drug against HBV, treatments with 3TC or ADV are used either sequentially or in addition, depending on treatment response or failure. Considering the use of de novo or add-on 3TC؉ADV bitherapy, we investigated the possibility of the emergence of an HBV strain harboring polymerase mutations conferring resistance to both 3TC (rtL180M؉M204V) and ADV (rtN236T). We constructed the L180M؉M204V؉N236T mutant and determined its replication capacity and its susceptibility to different nucleos(t)ide analogs in transiently transfected hepatoma cell lines. The triple mutant replicates its genome in vitro, but less efficiently than either the wild-type (wt) HBV or L180M؉M204V and N236T mutants. Phenotypic assays indicated that the L180M؉M204V؉N236T mutant is resistant to pyrimidine analogs (3TC, -FTC, ␤-L-FD4C, L-FMAU). Compared with wt HBV, this mutant displays a 6-fold decreased susceptibility to ADV and entecavir and a 4-fold decreased susceptibility to tenofovir. Interferon alfa inhibited equally the replication of wt and L180M؉M204V؉N236T HBV. In conclusion, the combination of rtL180M؉M204V and rtN236T mutations impairs HBV replication and confers resistance to both 3TC and ADV in vitro. These results suggest that the emergence of the triple mutant may be delayed and associated with viral resistance in patients treated with 3TC؉ADV. T he main goals of the treatment of chronic hepatitis B virus (HBV) infection are the sustained suppression of HBV replication and a remission of liver disease. An immunomodulator, interferon alfa (IFN-␣), and two synthetic nucleos(t)ide analogs, lamivudine (3TC) and adefovir dipivoxil (ADV), are currently approved for the treatment of chronic hepatitis B. With respect to IFN-␣, the overall response rate to this drug is less than 40%, and IFN-␣ therapy is associated with a number of adverse effects. 1 3TC, a nucleoside analog of L-deoxycitydine, and ADV, a phosphonate nucleotide analog of adenosine monophosphate, target the HBV reverse transcriptase (RT) activity, thus inhibiting viral replication. They are both powerful antivirals, and monotherapy with 3TC or ADV results in significant improvement in virological, biochemical, and histological status in most of the patients. [2][3][4][5] However, long-term 3TC or ADV monotherapy leads to the emergence of drug-resistant HBV strains. 3TC-resistance increases at a rate of approximately 20% of patients per year, to reach approximately 70% of treated patients after 4 years. 6,7 Mutations conferring resistance to 3TC have been mapped in the conserved YMDD motif within the C domain of the viral RT (M204I/V). [8][9][10] They are frequently associated with compensatory mutations in the conserved B domain (V173L, L180M) that restore

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