索磷布韦、维帕他韦和沃西拉韦治疗既往 HCV 感染。

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection.

机构信息

From Hospital Saint Joseph, Marseille (M.B.), and University Hospital of Bordeaux, Pessac (V.L.) - both in France; Henry Ford Health System, Detroit (S.C.G.); Northwestern University, Chicago (S.L.F.); Ottawa Hospital Research Institute, Ottawa (C.L.C.), and St. Paul's Hospital, Vancouver, BC (A.R.) - both in Canada; Huntington Medical Research Institutes, Pasadena (M.T.), Cedars-Sinai Medical Center, Los Angeles (T.T.T.), and Gilead Sciences, Foster City (R.H.H., L.M.S., H.D.-S., E.S., J.Z., K.C.H., G.M.S., D.M.B., J.G.M.) - all in California; Digestive Disease Associates, Catonsville, MD (N.R.); Baylor College of Medicine, Houston (J.M.V.); Monash Health and Monash University, Clayton, VIC (S.P.), and Royal Prince Alfred Hospital, Sydney (S.I.S.) - both in Australia; Icahn School of Medicine at Mount Sinai (M.B.B.) and Columbia University Medical Center (E.C.V.) - both in New York; ifi-Institute for Interdisciplinary Medicine, Hamburg (P.B.), Hannover Medical School, Hannover (M.P.M.), and Johann Wolfgang Goethe University Medical Center, Frankfurt (S.Z.) - all in Germany; University of Washington (C.S.L.) and Swedish Medical Center (K.V.K.) - both in Seattle; Gastro One, Germantown, TN (Z.H.Y.); Beth Israel Deaconess Medical Center, Boston (M.P.C.); University of Miami, Miami (E.R.S.); and University of Pennsylvania, Philadelphia (K.R.R.).

出版信息

N Engl J Med. 2017 Jun 1;376(22):2134-2146. doi: 10.1056/NEJMoa1613512.

DOI:10.1056/NEJMoa1613512

PMID:28564569

Abstract

BACKGROUND

Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.

METHODS

We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group.

RESULTS

In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower.

CONCLUSIONS

Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .).

摘要

背景

接受含直接作用抗病毒药物（DAA）方案治疗后未能持续病毒学应答的慢性丙型肝炎病毒（HCV）感染者，其再治疗选择有限。

方法

我们开展了两项 3 期临床试验，纳入了先前接受过 DAA 方案治疗的患者。在 POLARIS-1 中，先前接受过含 NS5A 抑制剂方案治疗的 HCV 基因 1 型感染患者以 1:1 的比例随机分组，分别接受核苷酸聚合酶抑制剂索磷布韦、NS5A 抑制剂维帕他韦和蛋白酶抑制剂伏西瑞韦（150 例患者）或匹配安慰剂（150 例患者）治疗，每日 1 次，持续 12 周。其他 HCV 基因型（114 例患者）感染者被纳入索磷布韦-维帕他韦-伏西瑞韦组。在 POLARIS-4 中，先前接受过 DAA 方案但未接受 NS5A 抑制剂治疗的 HCV 基因 1、2 或 3 型感染患者以 1:1 的比例随机分组，分别接受索磷布韦-维帕他韦-伏西瑞韦（163 例患者）或索磷布韦-维帕他韦（151 例患者）治疗，持续 12 周。另外 19 例 HCV 基因 4 型感染者被纳入索磷布韦-维帕他韦-伏西瑞韦组。

结果

在 3 个接受活性药物治疗的组中，46%的患者有代偿性肝硬化。在 POLARIS-1 中，与安慰剂组的 0%相比，索磷布韦-维帕他韦-伏西瑞韦的持续病毒学应答率为 96%。在 POLARIS-4 中，索磷布韦-维帕他韦-伏西瑞韦和索磷布韦-维帕他韦的应答率分别为 98%和 90%。最常见的不良事件是头痛、疲劳、腹泻和恶心。在两项试验的所有接受活性药物治疗的组中，因不良事件而停药的患者比例为 1%或更低。