Effect of IL28B Genotype on Early Viral Kinetics During Interferon-Free Treatment of Patients With Chronic Hepatitis C
Effect of IL28B Genotype on Early Viral Kinetics During Interferon-Free Treatment of Patients With Chronic Hepatitis C
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DOI：
10.1053/j.gastro.2011.12.057
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发表时间：
2012-04-01
期刊：
影响因子：
29.4
通讯作者：
Shulman, Nancy S.
中科院分区：
文献类型：
--
作者：
Chu, Tom W.;Kulkarni, Rohit;Shulman, Nancy S.
背景与目的：尽管白细胞介素28B（干扰素，λ 3） （IL28B）基因型影响慢性丙型肝炎患者对聚乙二醇干扰素和利巴韦林的反应，但其对无干扰素联合治疗中直接作用抗病毒药物反应的影响尚不清楚。我们分析了IL28B基因型对核苷聚合酶抑制剂mericitabine （RG7128）和丙型肝炎病毒（HCV）蛋白酶抑制剂danoprevir无干扰素联合治疗时病毒动力学（VK）反应的影响。方法：我们对慢性HCV基因型1感染患者进行了一项双盲、剂量递增研究，这些患者未接受干扰素治疗或对先前的聚乙二醇干扰素和利巴韦林治疗无反应。患者依次被分配到7个队列中的1个，然后随机分配到接受长达13天的美西他滨（500或1000毫克，每天两次）加达诺韦（100或200毫克，每8小时一次，或600或900毫克，每天两次）或安慰剂治疗的组。87例患者中有83例进行了IL28B单核苷酸多态性rs12979860的基因分型。VKs仅在接受13天最佳剂量治疗的患者中进行分析，使用双相模型来描述治疗期间病毒衰变的第一和第二阶段斜率。结果：在第14天（无干扰素治疗结束），CC多态性患者血清HCV RNA水平的平均下降幅度（5.01 log(10) IU/mL）略高于无干扰素多态性患者（4.59 log(10) IU/mL）。模型显示，具有CC多态性的患者具有稍好的早期VKs，在病毒衰变的β阶段最为明显。观察到对β期的混合效应，在CC患者中，其程度降低但延长，在随访期间对聚乙二醇干扰素和利巴韦林也有更好的治疗反应。结论：IL28B基因型似乎影响接受无干扰素治疗的慢性丙型肝炎患者的早期VKs。
BACKGROUND & AIMS: Although interleukin 28B (interferon, lambda 3) (IL28B) genotype affects the response of patients with chronic hepatitis C to peginterferon and ribavirin, little is known regarding its effect on response to direct-acting antivirals in interferon-free combinations. We analyzed the effects of IL28B genotype on the viral kinetic (VK) response to an interferon-free combination of the nucleoside polymerase inhibitor mericitabine (RG7128) and the hepatitis C virus (HCV) protease inhibitor danoprevir. METHODS: We performed a double-blind, dose-escalation study of patients with chronic HCV genotype 1 infection who were interferon treatment naive or had not responded to previous therapy with peginterferon and ribavirin. Patients were sequentially assigned to 1 of 7 cohorts then randomly assigned to groups that received up to 13 days of treatment with mericitabine (500 or 1000 mg, twice daily) plus danoprevir (100 or 200 mg, every 8 hours, or 600 or 900 mg, twice daily) or placebo. Eighty-three of 87 patients were genotyped for the IL28B single-nucleotide polymorphism rs12979860. VKs were analyzed only in patients who received 13 days of treatment, at optimal doses, using a biphasic model to describe first- and second-phase slopes of viral decay during therapy. RESULTS: At day 14 (the end of interferon-free treatment), the mean reduction in the serum level of HCV RNA was slightly greater in patients with the CC polymorphism (5.01 log(10) IU/mL) than those without (4.59 log(10) IU/mL). Modeling revealed that patients with the CC polymorphism had slightly better early VKs, most apparent in the beta-phase of viral decay. A mixed effect on the beta-phase was observed, which was reduced in magnitude but prolonged in patients with CC, who also had better on-treatment response to peginterferon and ribavirin during follow up. CONCLUSIONS: IL28B genotype appears to affect early VKs in patients with chronic hepatitis C receiving interferon-free treatment.