만성 B형간질환 환자의 라미부딘 내성 예측인자
Predictors of Lamivudine Resistance in Patients with Chronic Hepatitis B Virus Infection
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목적: 현재까지 라미부딘 치료에 따른 내성 발생과 관련한 요소는 단편적으로 알려져 있으며 치료 결정에 기여하는 데에는 한계가 있다. 본 연구에서는 라미부딘을 투여한 만성 B형간염 혹은 간경변증 환자를 대상으로 라미부딘 내성에 관여하는 것으로 알려져 있는 요소들을 이용하여 내성 발생을 예측하는 모형을 구축하고자 하였다. 대상과 방법: B형간염바이러스로 인한 만성 간염 혹은 간경변증으로 2001년 1월부터 2003년 12월까지 3차 병원에서 라미부딘 치료를 시작한 183명을 대상으로 후향 코호트연구를 하였다. 라미부딘 치료 후 ALT 및 AST, HBeAg 및 anti-HBe, HBV DNA치는 3 내지 6개월마다 검사하였다. HBV DNA치는 Cobas Amplicor HBV Monitor test™로 측정하였다. 라미부딘 내성은 viral breakthrough로 정의하였으며 viral breakthrough는 라미부딘 치료 후 HBV DNA치가 105 copies/mL 이하로 감소하였다가 연속 2회 이상 105 copies/mL 이상으로 증가하는 경우로 하였다. 나이, 성별, 체질량지수(BMI, kg/m2), 치료 전 ALT치(IU/L), HBeAg 유무, 치료 전 HBV DNA치(copies/mL), 치료 6개월 시점의 HBV DNA치(copies/mL)가 예측인자로서 viral breakthrough에 미치는 영향을 비례위험모형을 이용하여 정량화하였다. 결과: Viral breakthrough의 누적 발생률은 12개월, 24개월 36개월에 각각 9.6%, 39.0%, 55.8%였다. 단변량 및 다변량 분석에서 치료 6개월 시점의 HBV DNA치와 치료 전 HBeAg 유무가 viral breakthrough의 유의한 예측인자였으며 치료 6개월 시점의 HBV DNA치의 상대위험률은 1.43(95% C.I. 1.09∼1.89, P=0.010)이었으며 치료 전 HBeAg은 1.77이었다(95% C.I. 1.06∼2.95, P=0.029). 결론: 치료 전 HBeAg이 양성인 경우와 치료 6개월 시점의 HBV DNA치가 내성 발생의 위험요소였으며 따라서 치료 시작 전 HBeAg 양성인 환자들에 대해서는 치료 경과에 대한 면밀한 관찰이 필요하며, 치료 6개월 시점에서 혈청 HBV DNA치가 높을 때는 치료 약제의 변경을 고려할 필요가 있다.
Abstract
Background/Aim: Drug resistance is a major concern during nucleos(t)ide analogues therapy in patients with chronic hepatitis B virus (HBV) infections. The aim of this study was to measure the risk of lamivudine resistance provided for each predictive factor in patients with chronic HBV infections. Methods: A total of 183 patients were analyzed among 315 patients with chronic HBV infections enrolled in a tertiary referral hospital between January 2001 and December 2003 on this retrospective cohort study. AST/ALT, HBeAg/anti-HBe, serum HBV DNA levels were tested for every 3 or 6 months. HBV DNA level was tested using Cobas Amplicor HBV Monitor test™. Viral breakthrough was defined as HBV DNA ≥ 5 log10 copies/mL on two consecutive visits in patients who, on treatment, achieved HBV DNA < 5 log10 copies/mL. The risk of viral breakthrough was measured using Cox proportional hazards model for variables: age, sex, BMI (kg/m2), baseline ALT, HBeAg positivity, baseline HBV DNA level, serum HBV DNA level at 6 month of lamivudine therapy. Results: The cumulative rates of viral breakthrough were 9.6%, 39.0%, 55.8% at 12, 24, 36 months, respectively. Serum HBV DNA level of 6 month of lamivudine therapy and presence of HBeAg were independent predictors for viral breakthrough. The relative risk was 1.43 (95% C.I. 1.09-1.89, P=0.010) for serum HBV DNA level at 6 months of lamivudine therapy and 1.77 (95% C.I. 1.06-2.95, P=0.029) for presence of HBeAg. Conclusions: Serum HBV DNA level at 6 months of therapy and HBeAg positivity were predictors of early lamivudine resistance in patients with chronic HBV infections. An alternate therapy should be considered when serum viral load is high at 6 months of lamivudine therapy. (Korean J Hepatol 2007;13:157- 165)
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