ABT-450/r-ombitasvir 和 dasabuvir 联合利巴韦林治疗肝硬化合并丙型肝炎。
ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.
机构信息
From the Texas Liver Institute-University of Texas Health Science Center, San Antonio (F.P.); Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, University Paris-Est, INSERM Unité 955, Créteil, France (C.H.); AbbVie, North Chicago, IL (R.T., S.S.L., B.D.S.-T., C.A.C., A.L.C., T.P., B.B.); Digestive Disease Institute, Virginia Mason Medical Center, Seattle (K.V.K.); Johann Wolfgang Goethe University, Frankfurt (S.Z.), Medizinische Hochschule Hannover, Hannover (H.W.), and Universitätsklinikum Leipzig, Leipzig (T.B.) - all in Germany; Institute of Liver Studies, King's College Hospital, London (K.A.); Liver Institute of Virginia, Newport News (M.L.S.); University of British Columbia, Vancouver, Canada (E.M.Y.); and Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona (X.F.).
出版信息
N Engl J Med. 2014 May 22;370(21):1973-82. doi: 10.1056/NEJMoa1402869. Epub 2014 Apr 11.
BACKGROUND
Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside polymerase inhibitor dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis.
METHODS
We randomly assigned 380 patients with Child-Pugh class A cirrhosis to receive either 12 or 24 weeks of treatment with ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. The rate of sustained virologic response in each group was compared with the estimated rate with a telaprevir-based regimen (47%; 95% confidence interval [CI], 41 to 54). A noninferiority margin of 10.5 percentage points established 43% as the noninferiority threshold; the superiority threshold was 54%.
RESULTS
A total of 191 of 208 patients who received 12 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 91.8% (97.5% CI, 87.6 to 96.1). A total of 165 of 172 patients who received 24 weeks of treatment had a sustained virologic response at post-treatment week 12, for a rate of 95.9% (97.5% CI, 92.6 to 99.3). These rates were superior to the historical control rate. The three most common adverse events were fatigue (in 32.7% of patients in the 12-week group and 46.5% of patients in the 24-week group), headache (in 27.9% and 30.8%, respectively), and nausea (in 17.8% and 20.3%, respectively). The hemoglobin level was less than 10 g per deciliter in 7.2% and 11.0% of patients in the respective groups. Overall, 2.1% of patients discontinued treatment owing to adverse events.
CONCLUSIONS
In this phase 3 trial of an oral, interferon-free regimen evaluated exclusively in patients with HCV genotype 1 infection and cirrhosis, multitargeted therapy with the use of three new antiviral agents and ribavirin resulted in high rates of sustained virologic response. Drug discontinuations due to adverse events were infrequent. (Funded by AbbVie; TURQUOISE-II ClinicalTrials.gov number, NCT01704755.).
背景
含干扰素的方案治疗丙型肝炎病毒（HCV）感染与增加毒性作用在患者也有肝硬化。我们评估了蛋白酶抑制剂 ABT-450 与利托那韦（ABT-450/r），NS5A 抑制剂 ombitasvir（ABT-267），非核苷聚合酶抑制剂 dasabuvir（ABT-333）和利巴韦林的无干扰素联合治疗在一个开放性标签的 3 期试验包括以前未经治疗和以前治疗过的丙型肝炎基因型 1 感染和代偿性肝硬化的成年人。
方法
我们随机分配 380 例丙型肝炎基因型 A 肝硬化患者接受 12 或 24 周的治疗 ABt-450/r-ombitasvir（每天一次剂量的 150 毫克 ABT-450，100 毫克利托那韦，和 25 毫克 ombitasvir），dasabuvir（250 毫克，每日两次）和利巴韦林，根据体重给药。主要疗效终点是治疗结束后 12 周持续病毒学应答。每个组的持续病毒学应答率与估计的 telaprevir 为基础的方案进行比较（47%；95%置信区间[CI]，41-54）。10.5 个百分点的非劣效性边界确定 43%为非劣效性阈值；优势阈值为 54%。
结果
共有 191 例接受 12 周治疗的 208 例患者在治疗后第 12 周有持续病毒学应答，应答率为 91.8%（97.5%CI，87.6-96.1）。共有 165 例接受 24 周治疗的 172 例患者在治疗后第 12 周有持续病毒学应答，应答率为 95.9%（97.5%CI，92.6-99.3）。这些利率优于历史对照率。最常见的三种不良事件是疲劳（12 周组患者 32.7%，24 周组患者 46.5%），头痛（27.9%和 30.8%，分别）和恶心（17.8%和 20.3%，分别）。血红蛋白水平低于每 10 克每分升 12 周和 24 周组各 7.2%和 11.0%的患者。总的来说，有 2.1%的患者因不良事件而停止治疗。
结论
在这个专门在丙型肝炎基因型 1 感染和肝硬化患者中评估的无干扰素的 3 期试验中，使用三种新的抗病毒药物和利巴韦林的多目标治疗导致高持续病毒学应答率。由于不良事件而停药的情况很少见。（由 AbbVie 资助； TURQUOISE-II ClinicalTrials.gov 编号，NCT01704755）。
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