라미부딘 내성이 발생한 만성 B형간염에서 아데포비어에 대한 초기 치료 반응이 아데포비어 내성 발생에 미치는 영향
Effect of Initial Virologic Response to Adefovir on the Development of Resistance to Adefovir in Lamivudine-resistant Chronic Hepatitis B
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배경/목적: 라미부딘에 내성을 보인 만성 B형간염 환자들에서 아데포비어에 대한 초기 바이러스 반응(initial virologic response: IVR)의 의의를 평가하고, 아데포비어 내성률을 알아보며, 아데포비어 내성과 관련된 인자들을 분석하고자 하였다. 대상 및 방법: 라미부딘 내성으로 인해 아데포비어를 12개월 이상 투여한 81명의 HBeAg 양성 만성 B형간염 환자를 대상으로 하였다. IVR은 치료 6개월에 HBV DNA가 4 log copies/mL 미만일 때로 정의하였다. 아데포비어에 대한 내성 돌연변이는 RPMP 분석 방법을 이용하여 평가하였다. 결과: 아데포비어 투약 후 IVR은 37/81명(45.7%)에서 나타났으며 치료 전 높은 ALT (P=0.002), 치료 전 낮은 HBV DNA (P=0.015)와 관련이 있었다. 비IVR군은 IVR군에 비해 12, 18, 24개월째 HBV DNA가 유의하게 높았다(4.7 vs 2.6, 4.5 vs 2.3, 4.4 vs 2.4 log10 copies/mL; P<0.01). 추적관찰기간 동안 표현형 내성이 17명(21.0%)에서 나타났고, 유전형 돌연변이가 9명(11.1%)에서 관찰되었다. 치료 12, 24 개월째 표현형 내성의 누적발생률은 8.7%, 32.5%였으며, 유전형 내성의 누적발생률은 0%, 14.6%였다. 아데포비어 내성에 관련된 인자로는 치료 전 높은 HBV DNA (P=0.019)와 비IVR (P<0.001)이었다. 결론: 치료 24 개월째 아데포비어에 대한 표현형 내성과 유전형 내성의 누적발생률은 32.5%, 14.6%였다. 치료 전 HBV DNA가 높은 경우와 비IVR (치료 6개월째 HBV DNA가 4 log10 copies/ mL 이상)인 경우가 아데포비어 내성과 관련이 있었다. 향후 라미부딘 내성 만성 B형간염 환자에서 약제 내성을 줄이기 위한 추가 연구가 필요할 것으로 생각된다.
Abstract
Background/Aims: Adefovir dipivoxil (ADV) resistance in patients with lamivudine-resistant chronic hepatitis B is not well understood. This study examined the initial virologic response (IVR) to ADV, the rate of ADV resistance and the factors associated with ADV resistance. Methods: Eighty one lamivudine-resistant HBeAg-positive patients were enrolled in this study. IVR was defined as HBV DNA < 4 log10 copies/mL after 6 months of therapy. Results: IVR was observed in 37/81(45.7%) patients and it was associated with higher pretreatment ALT (P=0.002), and low pretreatment HBV DNA level (P=0.015). The HBV DNA levels were significantly higher in the non-IVR patients than the IVR patients at 12, 18 and 24 months (4.73 vs 2.59, 4.53 vs 2.31, 4.39 vs 2.40 log10 copies/mL, respectively; P<0.01). During the follow-up period, 17(21.0%) patients showed phenotypic resistance to ADV and 9 (11.1%) patients had ADV-resistant mutations. The cumulative probabilities of the phenotypic resistance to ADV at 12 and 24 months were 8.7% and 32.5%, respectively. The cumulative probabilities of the genotypic resistance to ADV at 12 and 24 months were 0% and 14.6%, respectively. Resistance to ADV was associated with a higher pretreatment HBV DNA (P=0.019), and non-IVR (P<0.001). Conclusions: The cumulative probabilities of the phenotypic and genotypic resistance to ADV at 24 months were 32.5% and 14.6%. The high pretreatment HBV DNA and non-IVR (HBV DNA ≥ 4 log10 copies/mL after 6 months of therapy) were associated with ADV resistance. (Korean J Hepatol 2007;13: 349-362)
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