Efficacy and tolerability of long-term therapy using high lamivudine doses for the treatment of chronic hepatitis B.

PURPOSE

A long-term follow-up study was carried out to evaluate the tolerability and efficacy of long-term therapy (1 to 3 years) with high doses (150 or 300 mg daily) of lamivudine for chronic hepatitis B.

METHODS

Thirty-two patients were studied, including those who were seronegative for hepatitis B e antigen (HBeAg), as well as those with decompensated liver cirrhosis. Viral DNA clearance was monitored by using end-point dilution polymerase chain reaction (PCR), a highly sensitive method. Hepatitis B virus (HBV) polymerase gene mutations associated with resistance were determined by sequencing.

RESULTS

Response to lamivudine in the sixth month was observed in 19/32 (59.4%) patients. With one exception, viral DNA results observed at this time were maintained. The YMDD mutation was detected in 12 nonresponder patients (9 YVDD, 2 YIDD, and 1 mixed population Y(V/I)DD), generally associated with the L528M mutation. Re-takeover by the wild type was observed 6 to 18 months after lamivudine withdrawal. Lamivudine response rates in noncirrhotic and cirrhotic patients were 9/18 (50%) and 10/14 (71.4%), respectively. HBeAg to anti-HBe seroconversion was found after different periods in all responder patients. Hepatitis B surface antigen (HBsAg) clearance and anti-HBs seroconversion were occasionally found.

CONCLUSIONS

In nonresponder patients, resistant mutants appeared up to the second year of lamivudine therapy. In spite of the presence of resistant mutants, maintenance of therapy was usually associated with a lower viral load. In responder patients, maintenance of therapy was associated with continued absence of detectable HBV DNA in serum, as monitored by highly sensitive methods. No significant side effects caused by lamivudine were observed in our patients, even in those with liver cirrhosis.