达卡他韦联合索非布韦治疗既往治疗或未经治疗的慢性 HCV 感染。

Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.

机构信息

From Johns Hopkins University (M.S.S.) and Mercy Medical Center (P.J.T.) - both in Baltimore; Bristol-Myers Squibb, Hopewell (D.F.G., T.E., D.S., C.P., D.M.G.), and Bristol-Myers Squibb, Princeton (M.W.-R., S.-P.H.) - both in New Jersey; Fundacion de Investigacion, San Juan, Puerto Rico (M.R.-T.); University of Pennsylvania, Philadelphia (K.R.R.); Southern California GI and Liver Center, Coronado (T.H.); Weill Cornell Medical College, New York (I.J.); University of Texas Health Science Center, San Antonio (E.L.); University of Michigan, Ann Arbor (A.S.L.); Orlando Immunology Center, Orlando (F.H.), Miami Research Associates, South Miami (H.S.), and University of Florida, Gainesville (D.R.N.) - all in Florida; University of Colorado Denver, Aurora (G.T.E.); Bristol-Myers Squibb, Wallingford, CT (M.G., D.H., F.M.); Skillman, NJ (R.H.); and Gilead Sciences, Foster City, CA (W.S.).

出版信息

N Engl J Med. 2014 Jan 16;370(3):211-21. doi: 10.1056/NEJMoa1306218.

DOI:10.1056/NEJMoa1306218

PMID:24428467

Abstract

BACKGROUND

All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3.

METHODS

In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy.

RESULTS

Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea.

CONCLUSIONS

Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).

摘要

背景

对于慢性丙型肝炎病毒（HCV）感染者，全口服联合治疗是理想的选择。我们评估了达拉他韦（HCV NS5A 复制复合物抑制剂）加索非布韦（核苷酸类似物 HCV NS5B 聚合酶抑制剂）在感染 HCV 基因型 1、2 或 3 的患者中的疗效。

方法

在这项开放性标签研究中，我们最初随机分配 44 例初治的 HCV 基因型 1 感染患者和 44 例 HCV 基因型 2 或 3 感染患者，分别接受达拉他韦 60mg 每日一次口服和索非布韦 400mg 每日一次口服，联合或不联合利巴韦林，治疗 24 周。该研究扩展至纳入 123 例基因型 1 感染的额外患者，他们随机接受达拉他韦加索非布韦，联合或不联合利巴韦林，治疗 12 周（82 例初治患者）或 24 周（41 例先前用特拉普韦或博赛泼维联合聚乙二醇干扰素-α-利巴韦林治疗失败的患者）。主要终点是治疗结束后 12 周时持续病毒学应答（HCV RNA 水平<25IU/ml）。

结果

共有 211 例患者接受了治疗。在基因型 1 感染的患者中，126 例初治患者中有 98%，41 例先前用 HCV 蛋白酶抑制剂治疗未获得持续病毒学应答的患者中有 98%，在治疗结束后 12 周时获得了持续病毒学应答。26 例基因型 2 感染患者和 18 例基因型 3 感染患者中，分别有 92%和 89%在 12 周时获得了持续病毒学应答。在 HCV 1a 和 1b 亚型（分别为 98%和 100%）和 CC 和非-CC IL28B 基因型（分别为 93%和 98%）的患者中，以及在接受利巴韦林和未接受利巴韦林的患者中（分别为 94%和 98%），12 周时持续病毒学应答率均较高。最常见的不良反应是疲劳、头痛和恶心。