Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1
Phase 2b Trial of Interferon-free Therapy for Hepatitis C Virus Genotype 1
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DOI：
10.1056/nejmoa1306227
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发表时间：
2014-01-16
影响因子：
158.5
通讯作者：
Bernstein, Barry
中科院分区：
文献类型：
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作者：
Kowdley, Kris V.;Lawitz, Eric;Bernstein, Barry
背景在一项针对HCV基因型1感染患者的初步研究中，蛋白酶抑制剂ABT-450与利托那韦（ABT-450/r）、非核苷聚合酶抑制剂ABT-333和利巴韦林的无干扰素组合显示出抗丙型肝炎病毒（HCV）的疗效。另一种有效的药物，NS 5A抑制剂ABT-267的加入，可能会提高疗效，特别是在难以治疗的患者中。本研究的目的是评估直接作用的抗病毒剂和利巴韦林的多种方案在HCV基因型1型感染的患者中的应用，这些患者以前没有接受过治疗，或者以前对聚乙二醇化干扰素和利巴韦林的治疗没有反应。将571例既往未接受过治疗或对既往治疗无反应的无肝硬化患者随机分配至ABT-450/r方案，与ABT-267或ABT-333或两者组合，持续8、12或24周，并接受至少一个剂量的治疗。除1个亚组外，所有亚组均接受利巴韦林（剂量根据体重确定）。主要终点是治疗结束后24周的持续病毒学应答。主要疗效分析比较了接受三种直接作用的抗病毒药物和利巴韦林治疗8周的既往未治疗患者与接受相同治疗12周的患者之间的比率。（ABT-450/r剂量为150 mg ABT-450和100 mg利托那韦）加利巴韦林，治疗8周和12周的患者治疗后24周的持续病毒学应答率分别为88%和95（差异，-7个百分点; 95%置信区间，-19至5; P=0.24）。所有治疗亚组的持续病毒学应答率范围为83%至100%。最常见的不良事件是疲劳、头痛、恶心和失眠。八例（1%）停止治疗，由于不良事件。ConclusionsIn this phase 2b study，所有口服抗病毒药物和利巴韦林的治疗方案是有效的，在HCV基因型1感染的患者谁没有接受治疗之前，在那些谁没有对先前的治疗反应。（由AbbVie资助; ClinicalTrials.gov编号，NCT 01464827。）在这项2期研究中，无聚乙二醇干扰素方案对丙型肝炎病毒基因型1感染的患者有效。慢性丙型肝炎病毒（HCV）感染是肝硬化、肝癌和终末期肝病的主要原因。(1)目前治疗慢性HCV基因型1感染的标准是聚乙二醇干扰素（聚乙二醇干扰素）和利巴韦林，蛋白酶抑制剂（boceprevir或telaprevir）。(2)虽然加入蛋白酶抑制剂与应答率显著增加相关，但只有约三分之一对聚乙二醇干扰素和利巴韦林治疗无应答的患者在加入蛋白酶抑制剂重新治疗时出现持续病毒学应答。(3)（4）此外，这些治疗与不良反应有关。
BackgroundAn interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with HCV genotype 1 infection who had not received therapy previously or who had no response to prior therapy with pegylated interferon and ribavirin.MethodsIn this phase 2b, open-label study with 14 treatment subgroups, 571 patients without cirrhosis who had not received treatment previously or who had not had a response to prior therapy were randomly assigned to a regimen of ABT-450/r, combined with ABT-267 or ABT-333 or both, for 8, 12, or 24 weeks and received at least one dose of therapy. All the subgroups but 1 also received ribavirin (dose determined according to body weight). The primary end point was sustained virologic response at 24 weeks after the end of treatment. The primary efficacy analysis compared rates between previously untreated patients who received three direct-acting antiviral agents and ribavirin for 8 weeks and those who received the same therapy for 12 weeks.ResultsAmong previously untreated patients who received three direct-acting antiviral agents (with the ABT-450/r dose administered as 150 mg of ABT-450 and 100 mg of ritonavir) plus ribavirin, the rate of sustained virologic response at 24 weeks after treatment was 88% among those who received the therapy for 8 weeks and 95% among those who received the therapy for 12 weeks (difference, -7 percentage points; 95% confidence interval, -19 to 5; P=0.24). The rates of sustained virologic response across all treatment subgroups ranged from 83 to 100%. The most frequent adverse events were fatigue, headache, nausea, and insomnia. Eight patients (1%) discontinued treatment owing to adverse events.ConclusionsIn this phase 2b study, all-oral regimens of antiviral agents and ribavirin were effective both in patients with HCV genotype 1 infection who had not received therapy previously and in those who had not had a response to prior therapy. (Funded by AbbVie; ClinicalTrials.gov number, NCT01464827.)In this phase 2 study, peginterferon-free regimens were effective in patients with hepatitis C virus genotype 1 infection. Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, liver cancer, and end-stage liver disease.(1) The current standard of care for chronic HCV genotype 1 infection is pegylated interferon (peginterferon) and ribavirin, with a protease inhibitor (boceprevir or telaprevir).(2) Although the addition of a protease inhibitor has been associated with a significant increase in response rates, only approximately one third of patients who had not had a response to prior therapy with peginterferon and ribavirin had a sustained virologic response when re-treated with the addition of a protease inhibitor.(3),(4) Furthermore, these therapies are associated with adverse ...