Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial.
Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial.
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DOI：
10.1001/jama.2013.109309
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发表时间：
2013-08-28
影响因子：
120.7
通讯作者：
Kottilil, Shyamasundaran
中科院分区：
文献类型：
--
作者：
Osinusi, Anuoluwapo;Meissner, Eric G.;Lee, Yu-Jin;Bon, Dimitra;Heytens, Laura;Nelson, Amy;Sneller, Michael;Kohli, Anita;Barrett, Lisa;Proschan, Michael;Herrmann, Eva;Shivakumar, Bhavana;Gu, Wenjuan;Kwan, Richard;Teferi, Geb;Talwani, Rohit;Silk, Rachel;Kotb, Colleen;Wroblewski, Susan;Fishbein, Dawn;Dewar, Robin;Highbarger, Helene;Zhang, Xiao;Kleiner, David;Wood, Brad J.;Chavez, Jose;Symonds, William T.;Subramanian, Mani;McHutchison, John;Polis, Michael A.;Fauci, Anthony S.;Masur, Henry;Kottilil, Shyamasundaran
直接作用的抗病毒药物在无干扰素方案治疗慢性丙型肝炎感染中的作用需要在不同人群中进行评估。确定索非布韦与基于体重的或低剂量利巴韦林在传统治疗预测因素不利的人群中的疗效和安全性。2011年10月至2012年4月期间，在美国国立卫生研究院招募了60名HCV基因型-1、未经治疗的参与者，进行了单中心、随机、两部分、开放标签的2a期试验。在第一部分中，10名患有早期-中度肝纤维化的参与者接受索非布韦400 mg/d和基于体重的利巴韦林（≤ 75 kg 1000 mg/d或> 75 kg 1200 mg/d）治疗24周。在第二部分中，50名肝纤维化各阶段的参与者以1：1的比例随机接受索非布韦与基于体重的或低剂量的600 mg每日利巴韦林治疗24周。主要研究终点是治疗完成后24周检测不到HCV病毒载量的参与者比例（SVR 24）。在第1部分中，9例（90%，95% CI，55% - 100%）患者达到SVR 24。在第2部分中，7名（28%）接受基于体重的利巴韦林的参与者和10名（40%）接受低剂量利巴韦林的参与者复发，导致SVR 24率分别为68%（95%CI：46%-85%）和48%（95%CI：28%-69%）（p=0.251）。拟合的药代动力学-病毒动力学模型显示复发者中感染性病毒的丢失率较慢。在双变量分析中，男性、晚期肝纤维化和高基线HCV RNA与复发相关。该方案是安全的，耐受性良好，没有因不良事件而停药。索非布韦和基于体重的利巴韦林的组合导致在传统上被认为是难以治疗的人群中持续病毒学应答的高比率。男性性别、晚期肝纤维化和高基线HCV RNA被确定为这种无干扰素HCV治疗复发的预测因素。clinicaltrials.gov标识符：NCT 01441180。
The role of directly acting antiviral agents in an interferon-free regimen for the treatment of chronic Hepatitis C infections needs to be evaluated in different populations. To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin in a population with unfavorable traditional treatment predictors. Single center, randomized, two-part, open-label phase 2a trial of 60 HCV genotype-1, treatment naive participants were enrolled at the National Institutes of Health, between October 2011 and April 2012. In part 1, ten participants with early-moderate liver fibrosis were treated with 400mg daily of sofosbuvir and weight-based ribavirin (1000mg/daily if ≤ 75kg or 1200mg/daily if >75kg) for 24 weeks. In part 2, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive sofosbuvir with either weight-based or low-dose 600mg daily ribavirin for 24 weeks. The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (SVR24). In part 1, 9 (90%, 95% CI, 55% - 100%) achieved SVR24. In part 2, seven (28%) participants on weight-based ribavirin and ten (40%) participants on low-dose ribavirin relapsed leading to SVR24 rates of 68% (95% CI: 46%-85%) and 48%(95% CI 28%-69%) respectively (p=0.251) A fitted pharmacokinetic-viral kinetic model demonstrated a slower loss rate of infectious virus in relapsers. In bivariable analysis, male gender, advanced liver fibrosis and high baseline HCV RNA were associated with relapse. The regimen was safe and well tolerated with no discontinuations due to adverse events. A combination of sofosbuvir and weight-based ribavirin resulted in a high rate of sustained virologic response in a population traditionally considered difficult to treat. Male gender, advanced liver fibrosis and high baseline HCV RNA were identified as predictors of relapse to this interferon-free, HCV treatment. clinicaltrials.gov identifier: NCT01441180.
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