影響慢性C型肝炎患者治療誘發貧血與病毒學反應之因素

Abstract

研究背景 慢性C型肝炎是全球及台灣重要的健康及公共衛生問題。長效型干擾素合併雷巴威林為亞洲慢性C型肝炎現行標準治療，亞洲族群患者約有六成以上可達持續病毒學反應。雷巴威林誘發溶血性貧血為慢性C型肝炎治療常見之副作用；貧血副作用降低患者生活品質，以致須減藥或提前終止治療。降低雷巴林劑量對治療成效有負面影響。近期臨床研究卻顯示接受C型肝炎治療發生貧血之患者，治療反應率較高。C型肝炎治療誘發貧血對療效之影響仍待研究。 研究目的 本研究旨在探討病毒基因型第一型C型肝炎患者接受長效型干擾素合併雷巴威林治療後發生貧血與治療反應之關聯性，預計能找出預測治療誘發貧血之危險因子、預測C型肝炎治療成效之病患特質、以及分析貧血與療效之關聯性。 研究方法 本研究為回溯性研究。針對初次接受長效型干擾素合併雷巴林治療之基因型第一型慢性C型肝炎患者進行收案。收案患者至少接受4週以上療程。紀錄患者治療前臨床特性、療程中血紅素動態、雷巴威林開立劑量、及病毒學反應。採集收案患者週邊血液進行IL28B基因及ITPA基因單核苷酸多型性鑑定，鑑定之位點分別為rs8099917及rs1127354。以統計軟體分析與治療成效及治療誘發貧血有關之預測因子。 研究結果 共計313位患者加入本研究。有3位患者於預定療程結束前失去聯繫；其餘310位患者皆已結束治療；有295已完成停藥後24週之追蹤。整體快速病毒學反應為63%，持續病毒學反應為72%，復發率為23%。共100位(32%)患者於療程第4週血紅素下降幅度大於3 g/dL；共38位(12%)患者於療程第4週血紅素低於10 g/dL。 預測快速病毒學反應之因子包括男性性別(勝算比OR 2.11; P =0.006)、血小板數目大於180 ×103/μL (OR 1.96; P =0.021)、治療前病毒量低於800,000 IU/mL(OR 4.35; P <0.001)、rs8099917基因型TT(OR 4.31; P <0.001)、以及rs1127354基因型CC(OR 2.23; P =0.005)；預測持續病毒學反應之因子包括男性性別及達成RVR。療程第4週血紅素下降幅度大於3 g/dL之預測因子為年齡大於55歲(OR 2.70; P =0.001)、血紅素基準值高於16 g/dL(OR 4.07; P <0.001)、以及rs1127354 基因型CC(OR 15.85; P <0.001)。療程第4週發生血紅素低於10 g/dL之預測因子包括年齡大於55歲(OR 2.55; P =0.042)、血紅素基準值低於14 g/dL(OR 5.88; P <0.001)、腎絲球過濾率小於60 ml/min/1.73m2(OR 2.71; P =0.037)、以及rs1127354 基因型CC(OR 28.10; P =0.002)。療程第4週血紅素下降幅度越大，達成快速病毒學反應之比率越高。 結論 慢性C型肝炎患者療程誘發貧血之預測因子為ITPA基因多形性、血紅素基準值、年齡、以及腎功能。ITPA基因多形性為快速病毒學反應之獨立預測因子。C型肝炎治療誘發貧血程度與治療療效具相關性。

Background Chronic hepatitis C (CHC) is a major cause of chronic liver disease both domestically and on a global scale. Pegylated interferon (Peg-IFN) in combination with ribavirin constitutes the current standard of care for CHC in most Asian countries. More than 60% of Asian CHC patients achieved sustained virologic response with combination therapy. Ribavirin-related hemolytic anemia is a common side effect of combination therapy and often leads to dose reduction or treatment discontinuation. Ribavirin dose reduction may compromise treatment responses. Noteworthy that recent studies revealed CHC patients with treatment-induced anemia achieved better virologic responses than those without. The association of treatment-induced anemia with virologic responses needs further investigation. Aim of the study The aim of this study was to evaluate the association between treatment-induced anemia and treatment outcomes in CHC patients. Factors predictive of virologic responses and treatment-induced anemia respectively will be analyzed as well. Methods We retrospectively enrolled naive HCV genotype 1 CHC patients who received Peg-IFN and ribavirin therapy. The treatment duration of enrolled patients was at least 4 weeks. The baseline demographics and patient characteristics were recorded, as well as on-treatment hemoglobin changes and ribavirin dosage. The virologic responses were evaluated. Genetic polymorphisms in the IL28B gene (rs8099917) and ITPA gene (rs1127354) were determined. Statistical analyses were performed to analyze factors predictive of treatment-induced anemia and treatment outcomes. Results A total of 313 patients were enrolled. All patients finished treatment except three who lost to follow-up before treatment completed. On-treatment virologic responses were determined for all patients in an intent-to-treat fashion. Sustained virologic response (SVR) was determined for 295 patients who finished posttreatment follow-up. The overall rapid virologic response (RVR) and SVR rates were 63% and 72%, respectively; the relapse rate was 23%. One hundred patients (32%) had hemoglobin decline >3 g/dL from baseline at week 4 of treatment. Thirty-eight patients (12%) had hemoglobin level <10 g/dL at week 4. The factors predictive of RVR included male gender (OR 2.11; P =0.006), baseline platelet count >180 ×103/μL (OR 1.96; P =0.021), baseline viral load <800,000 IU/mL (OR 4.35; P <0.001), rs8099917 genotype TT (OR 4.31; P <0.001), and rs1127354 genotype CC (OR 2.23; P =0.005). The predicting factors of SVR were male gender and achievement of RVR. Patient categories at risk of hemoglobin decline >3 g/dL at week 4 were age >55 years (OR 2.70; P =0.001), baseline hemoglobin >16 g/dL (OR 4.07; P <0.001), and rs1127354 genotype CC (OR 15.85; P <0.001). Age >55 years (OR 2.55; P =0.042), baseline hemoglobin <14 g/dL (OR 5.88; P <0.001), estimated glomerular filtration rate <60 ml/min/1.73m2 (OR 2.71; P =0.037), and rs1127354 genotype CC (OR 28.10; P =0.002) were predicting factors of hemoglobin level <10 g/dL at week 4. The magnitude of hemoglobin decline at week 4 was correlated with RVR rate. Conclusion For chronic hepatitis C patients receiving PegIFN plus ribavirin therapy, factors predictive of treatment-induced anemia are ITPA genetic polymorphism, baseline hemoglobin level, age, and renal function. ITPA genetic polymorphism is an independent factor of RVR. Treatment-induced anemia is also associated with treatment responses.