拉米夫丁对于小三阳,HBV-DNA阳性患者长期用药的研究

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Long Term Epivir-HBV (Lamivudine) in Patients with Anti-HBe/HBV-DNA Positive Liver Disease

The optimal length of lamivudine (LAM) therapy for anti-HBe/HBV-DNA positive chronic liver disease is unknown.

Frequent relapses are observed when stopping LAM after 1 year, but resistant YMDD mutations emerge at yearly rate of 15-20% on long-term therapy. The clinical impact of YMDD mutants in determining disease outcome is unclear.

The aim of the current study was to establish a nationwide database of patients on long-term LAM, in order to analyze its efficacy, the rate of YMDD mutations and the incidence of disease events after emergence of YMDD mutants.

The investigators included subjects with histological or clinical diagnoses of anti-HBe/HBV-DNA positive liver disease on continuous LAM. ALT and HBV-DNA response (< 105 genomes/ml by non-PCR assay) and breakthrough, hepatitic flares (ALT > 10 x UNL), development of HCC and liver decompensation, OLT and death were recorded.

YMDD mutants were detected by direct sequencing during HBV-DNA breakthroughs. Results: Of 443 patients (mean age 48 years, range 20-76, 84% males) 247 (55.8%) had chronic hepatitis, 150 (33.8%) Child A and 46 (10.4%) Child B-C cirrhosis.
Mean duration on LAM therapy was 24 months (range 1-64). Virological response occurred in 421 (95%) subjects. The rate of response was 88.1% at 1 year and 66.2 %, 51.5%, 42.5% at 2, 3 and 4 years.

A virological breakthrough due to YMDD mutants was seen in 139 cases (31.4%). In 34/139 patients (24.5%) the emergence of mutants caused an hepatitic flare. After ALT flare no liver failure was observed in 15 patients with chronic hepatitis, but 6 of 19 patients with cirrhosis developed liver decompensation and 3 patients died.

Development of ascites or worsening of Child-Pugh score were observed in 14/61 (22.9%) of cirrhotic who developed mutants and only in 4/135 (2.9%) without mutants (p = 0.001).

On therapy 15/139 (10.7%) subjects with and 14/304 (4.6%) without YMDD mutants developed HCC (p NS). Seven subjects (4 with HCC) with and 5 (4 with HCC) without YMDD mutants died. Five subjects without YMDD mutants had undergone OLT.

Conclusions: After 4 years on LAM, HBV-DNA is still negative and YMDD mutants are assent in 42.5% of patients with anti-HBe/HBV-DNA positive chronic hepatitis or cirrhosis. Subjects with cirrhosis who develop YMDD mutants may have a significant deterioration of disease and after an hepatitic flare may die. HCC develops on long-term LAM regardless of virological response.

01/20/03

Reference
Vito Di Marco and others. LONG TERM LAMIVUDINE IN PATIENTS WITH ANTI-HBe/HBV-DNA POSITIVE LIVER DISEASE. Abstract 835. 53rd AASLD. November 1-5, 2002. Boston, MA. Hepatology 2002: Vol 36 No 4, Pt 2 of 2.