Emergence of Adefovir-resistant Mutants after Reversion to YMDD Wild-type in Lamivudine-resistant Patients

Abstract

The levels of hepatitis B virus (HBV) DNA have been reported to be a predominant viral risk factor associated with increased rates of cirrhosis and hepatocellular carcinoma. Lamivudine (LAM) is the first nucleoside analogue approved for the treatment of Chronic hepatitis B (CHB) with good potency, safety profile and low cost. However, it frequently results in marked drug resistance, which has been reported to occur up to 67% by 4 years of therapy. Adefovir dipivoxil (ADV) has been applied for the LAM-resistant patients, and it has shown to be effective against both wild-type and LAM-resistant forms of HBV. A pilot study in patients with LAM resistance showed no differences in HBV DNA suppression and serum alanine aminotransferase (ALT) normalization between patients treated with the combination of LAM and ADV and those receiving ADV alone. A recent study showed that switching to ADV in patients with LAM-resistant HBV was associated with higher risk of ADV-resistance compared with ADV and LAM combination therapy. This study was undertaken to evaluate the effect of reversion to YMDD wild-type on emergence of adefovir (ADV)-resistant mutation and antiviral activity of ADV in lamivudine (LAM)- resistant patients during ADV monotherapy. We determined YMDD mutations and ADV-resistant mutations before and every 3 months during ADV monotherapy in 33 LAM-resistant patients using RFMP method. Reversion to pure YMDD wild-type HBV occurred in 6% (2/33), 9% (3/33), 20% (4/20) and 35% (6/17) of patients after 12, 24, 36 and 48 weeks, respectively. Five (29%) patients were found to have pure YMDD mutants at 48 weeks of therapy. Among 33 patients, 4 (12%) patients developed ADV-resistant mutations at 48 weeks of therapy. ADV-resistant mutants emerged in all patients after reversion to YMDD wild-type HBV. The mean serum hepatitis B virus (HBV) reductions, evaluated at 24 weeks of therapy, were not different between patients with and without reversion to YMDD wild-type HBV (-3.1 log10 copies/mL vs -3.4 log10 copies/mL, p>0.05). In conclusion, ADV-resistant mutations emerged after reversion to YMDD wild-type in LAM resistant patients who received ADV monotherapy. Thus, ADV add-on therapy may be necessary to reduce the incidence of developing ADV resistance in patients with LAM resistance.