Health & Medical stomach,intestine & Digestive disease

Clinical Course After Stopping Lamivudine in Chronic Hepatitis B

Clinical Course After Stopping Lamivudine in Chronic Hepatitis B
Background: The efficacy of lamivudine therapy in chronic hepatitis B is well established. However, drug-resistant YMDD mutants emerge with extended therapy. This may result in the resurgence of viral replication, the return of hepatitis and histological deterioration.
Aim: To study the safety of stopping lamivudine when the drug is no longer effective.
Methods: In the 5-year Asian Lamivudine Study, 34 patients from a single centre were included in this study. They had harboured YMDD mutants for at least 2 years. Lamivudine was discontinued and they were followed up at regular intervals. Clinical symptoms, liver biochemistry and viral serology were monitored.
Results: In a median follow-up of 20 months after stopping lamivudine (range, 7-39 months), 20 of the 34 patients (58.8%) had elevated alanine aminotransferase (ALT), 13 patients (38.2%) had elevated ALT one to five times the upper limit of normal and seven patients (20.6%) had an ALT flare (ALT more than five times the upper limit of normal with detectable hepatitis B virus DNA). There was no liver decompensation. ALT flare could be predicted by ALT over twice the upper limit of normal at the time of stopping lamivudine (P = 0.037).
Conclusions: It is relatively safe to stop lamivudine after YMDD mutants have emerged. ALT levels greater than or equal to twice the upper limit of normal at the time of stopping lamivudine have a higher risk for ALT flare.

Hepatitis B virus (HBV) infection is one of the most common and serious infectious diseases in the world. It is estimated that 400 million people world-wide are suffering from chronic hepatitis B infection. Chronic hepatitis B in Asia is mainly acquired at birth and during early childhood, leading to major mortality and morbidity in adult life. Approximately 25% of chronic hepatitis B patients die prematurely due to complications of liver cirrhosis or hepatocellular carcinoma. Lamivudine is the first oral therapy for the treatment of chronic hepatitis B. Although lamivudine is effective in viral suppression and has minimal safety issues, it is not able to eradicate the virus in a significant proportion of patients, and extended therapy runs the risk of the emergence of drug-resistant mutants. There is a clinical dilemma with regard to the benefit and safety of stopping lamivudine after drug-resistant mutants have emerged.

A placebo-controlled study in Asian patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (the Asian Lamivudine Study) has shown that lamivudine suppresses HBV replication, enhances HBeAg seroconversion and improves necroinflammation compared with placebo at the end of 1 year of treatment. Increased HBeAg seroconversion following extended lamivudine treatment has been reported. However, lamivudine-resistant HBV mutants at the YMDD motif of the HBV polymerase genome (YMDD mutants) emerge at a cumulative rate of 24% after 1 year and 70% after 4 years of lamivudine treatment. During long-term therapy, the clinical benefits of lamivudine are greatest in patients free of YMDD mutants. A significant proportion of patients with YMDD mutants show a return of hepatitis and histological deterioration.

Stopping lamivudine treatment before HBeAg seroconversion is often associated with a relapse of hepatitis. Even in patients who have achieved HBeAg seroconversion, 23-50% show a relapse of hepatitis on cessation of lamivudine, and some show hepatic decompensation with hepatitis flare. Apart from organ transplantation patients, few publications have addressed the issue of stopping lamivudine treatment in patients harbouring YMDD mutants. The main concern is the possible risk of hepatitis flare when the wild-type HBV re-emerges.

This study describes the clinical course of patients with YMDD mutants after stopping lamivudine therapy. Analysis was performed to identify the predictive factors of biochemical flare. This provides guidance for clinicians on the safety of stopping lamivudine therapy in patients with YMDD mutants in regions in which adefovir and entecavir are not viable therapeutic options.

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