From Johann Wolfgang Goethe University, Frankfurt am Main (S.Z.), and Medizinische Hochschule Hannover, Hannover (H.W.) - both in Germany; Weill Cornell Medical College, New York (I.M.J.), and Premier Medical Group of the Hudson Valley, Poughkeepsie (P.V.) - both in New York; AbbVie, North Chicago (T.B., J.X., T.P.-M., B.D.-T., L.L., T.P., B.B.), and Center for Liver Diseases, University of Chicago Medical Center, Chicago (D.M.J.) - both in Illinois; Centro Hospitalar de Lisboa Norte and Medical School of Lisbon, Lisbon, Portugal (R.T.M.); Texas Liver Institute, University of Texas Health Science Center, San Antonio (F.P.); Hôpital Saint Joseph, Marseille, France (M.B.); Johns Hopkins University, Baltimore (M.S.S.); Liver and Intestinal Research Centre, Vancouver, BC, Canada (E.T.); St. Vincent's Hospital (Melbourne), Fitzroy, Australia (P.D.); Saint Louis University, St. Louis (A.M.D.); and Southern California Liver Centers and Southern California Research Center, Coronado (T.H.).
N Engl J Med. 2014 Apr 24;370(17):1604-14. doi: 10.1056/NEJMoa1401561. Epub 2014 Apr 10.
In this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon-ribavirin.
We enrolled patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon-ribavirin and had a relapse, a partial response, or a null response. Patients were randomly assigned in a 3:1 ratio to receive coformulated ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin (1000 or 1200 mg daily) or matching placebos during the 12-week double-blind period. The primary end point was the rate of sustained virologic response 12 weeks after the end of study treatment. The primary efficacy analysis compared this rate among patients assigned to the active regimen with a historical response rate (65%) among previously treated patients with HCV genotype 1 infection and no cirrhosis who had received retreatment with telaprevir and peginterferon-ribavirin.
A total of 394 patients received at least one study-drug dose. In the active-regimen group, 286 of 297 patients had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% confidence interval, 94.2 to 98.4). This rate was noninferior and superior to the historical control rate. Rates were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients). Pruritus occurred more frequently with the active regimen (in 13.8% of patients) than with placebo (5.2%, P=0.03). Three patients in the active-regimen group (1.0%) discontinued the study drugs owing to adverse events. Hemoglobin values of grade 2 (8.0 to <10.0 g per deciliter) and grade 3 (6.5 to <8.0 g per deciliter) occurred in 4.7% and 0.3% of patients in the active-regimen group, respectively.
Rates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response. (Funded by AbbVie; SAPPHIRE-II ClinicalTrials.gov number, NCT01715415.).
在这项 3 期试验中，我们评估了 ABV-450 联合利托那韦（ABT-450/r）、奥比他韦（又名 ABT-267）、达沙布韦（又名 ABT-333）和利巴韦林在既往接受过聚乙二醇干扰素-利巴韦林治疗的 HCV 患者中的疗效和安全性。
我们招募了患有 HCV 基因型 1 感染且无肝硬化的患者，这些患者既往接受过聚乙二醇干扰素-利巴韦林治疗，并且发生了复发、部分应答或无应答。患者以 3:1 的比例随机分配，接受 coformulated ABT-450/r-ombitasvir（ABT-450 的每日剂量为 150mg、ritonavir 的每日剂量为 100mg、ombitasvir 的每日剂量为 25mg）和 dasabuvir（每日两次 250mg）联合利巴韦林（每日 1000 或 1200mg）或匹配安慰剂治疗，为期 12 周的双盲期。主要终点是研究治疗结束后 12 周持续病毒学应答率。主要疗效分析将接受活性治疗方案的患者的这一比率与既往接受过 telaprevir 和聚乙二醇干扰素-利巴韦林治疗的 HCV 基因型 1 感染且无肝硬化的既往治疗患者的历史应答率（65%）进行比较。
共有 394 名患者至少接受了一剂研究药物。在活性治疗组中，297 名接受治疗的患者中有 286 名在治疗后第 12 周达到持续病毒学应答，总体应答率为 96.3%（95%置信区间，94.2 至 98.4）。这一比率与历史对照率相当，并且优于历史对照率。既往复发（86 名患者中有 82 名）患者的应答率为 95.3%，既往部分应答（65 名患者中有 100%）患者的应答率为 100%，既往无应答（146 名患者中有 139 名）患者的应答率为 95.2%。与安慰剂（5.2%）相比，活性治疗方案（13.8%的患者）更常出现瘙痒。由于不良反应，3 名患者（1.0%）停止使用研究药物。活性治疗组分别有 4.7%和 0.3%的患者血红蛋白值为 2 级（8.0 至 <10.0g/dL）和 3 级（6.5 至 <8.0g/dL）。
在既往接受过 HCV 基因型 1 感染治疗的患者中，包括既往无应答的患者，12 周无干扰素联合治疗方案的应答率超过 95%。（由 AbbVie 资助；SAPPHIRE-II ClinicalTrials.gov 编号，NCT01715415。）
