Association of HBV DNA and ALT Level with YMDD motif Mutation Type in Lamivudine Resistance for Chronic Hepatitis B

Abstract

BACKGROUND: The emergence of lamivudine resistant hepatitis B virus(HBV), with point mutation in the YMDD motif of DNA polymerase gene, has been reported in chronic hepatitis B patients with lamivudine treatment. The aim of this study was to investigate the distribution patterns and clinical aspects of lamivudine resistant HBV mutant during long-term lamivudine therapy. METHOD: We retrospectively analyzed 93 consecutive patients with chronic hepatitis B or liver cirrhosis who were lamivudine resistant. Patients received 100 mg of lamivudine per day orally for at least 9 months. The duration of lamivudine therapy was from 9 to 94 months(mean 36.2 months). YMDD motif mutants and serum HBV DNA were investigated by using restriction fragment mass polymorphism(RFMP) and Digene® Hybrid capture II assay, respectively. RESULTS: The HBV DNA breakthrough was occurred at 22.8±14.9(5-79) months after starting lamivudine therapy. At the point of breakthrough, the level of ALT was 186.3±199.7(15-1469) U/L and HBV DNA was 7.65±0.09(5.23-9.09) log10 copies/mL. They were lower than the level of ALT and HBV DNA before the therapy. Among 93 patients, 42 patients(45.2%) and 27 patients(29.0%) had YIDD and YVDD mutant, respectively. 24 patients(25.8%) had YIDD/YVDD mixed mutant. There was not significant to the level of ALT, HBV DNA at the point of viral breakthrough between three groups. Additional mutation, `L-to-M' in 528th amino acid was found at 78 patients(83.9%)(64.2% with YIDD mutant and 100% with YVDD mutant). CONCLUSION: During the long-term therapy of lamivudine in patients with chronic hepatitis B or liver cirrhosis, YIDD mutant was more frequent than YVDD mutant, YIDD/YVDD mutant was found frequently. Between mutant groups, the level of ALT and HBV DNA at the point of viral breakthrough was not significant.

목적: 라미부딘은 강력한 항 HBV 작용이 있으나 HBV를 완전히 제거하지 못하며 충분한 항바이러스 효과를 얻기 위해서는 장기적인 유지 요법이 필수적이나 투여 도중 상당수에서 라미부딘 내성 돌연변이 바이러스가 발생한다. 이에 저자들은 라미부딘을 9개월 이상 투여한 환자에서 라미부딘 내성을 일으키는 YMDD motif 변이종의 발현 양상 및 혈청 ALT, HBV DNA에 미치는 영향을 조사 하였다. 방법: 라미부딘으로 치료받은 93명의 만성 B형간염 또는 간경변증 환자를 대상으로 하였다. 이들은 모두 최소 9개월 이상 투약과 12개월 이상 혈청검사 추적이 가능하였으며, 라미부딘 100mg 투약 중 viral breakthrough를 나타낸 환자들이었다. YMDD motif 변이는 Restriction Fragment Mass Polymorphism(RFMP)법으로 측정 하였으며 혈청 HBV DNA는 Digene® Hybrid capture II assay로 측정 하였다. 결과: 대상 환자들의 평균나이는 43.1세였고 남녀 비는 75:18이었다. 라미부딘의 평균 투약 기간은 36.2±17.9 개월 이었으며, 내성을 보이는 YMDD 변이형의 발생 시기는 평균 22.8±14.9 개월이었다. Viral breakthrough시 DNA 정량은 7.65±0.09(5.23-9.09) log10 copies/mL, ALT 수치는 186.3±199.7 U/L이었다. YMDD motif 변이형 발생 시 YIDD 변이형이 42/93(45.2%), YVDD 변이형이 27/93(29.0%), YIDD/YVDD 혼합 변이형이 24/93(25.8%) 였으며, 발생 시기 및 발생 시 ALT, HBV DNA 치에는 세군 간의 차이가 없었다. 이들 변이형 발생 시에 rtL528M 동반이 78/93(83.9%)에서 관찰 되었는데, YIDD 변이형에서 63.4%, YVDD 변이형에서는 전 환자에서 동반되어 발생하였다.