Kirby Institute, University of New South Wales and St Vincent's Hospital, Sydney, Australia.
The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas.
Gastroenterology. 2015 Feb;148(2):355-366.e1. doi: 10.1053/j.gastro.2014.10.007. Epub 2014 Oct 13.
BACKGROUND & AIMS: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy.
Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24).
Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy.
Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.
针对慢性丙型肝炎病毒（HCV）基因型 2 或 3 感染，使用聚乙二醇干扰素和利巴韦林进行 24 周的治疗，能使 70%-80%的患者获得持续病毒学应答（SVR）。我们进行了一项随机、双盲、2b 期临床试验，旨在评估非结构蛋白 5A（NS5A）抑制剂达拉他韦是否能提高疗效并缩短疗程。
在北美、欧洲或澳大利亚的研究中心招募 HCV 基因型 2 或 3 感染患者（n=151），随机分配至接受 12 或 16 周达拉他韦（每日 60mg 一次）或 24 周安慰剂，均联合聚乙二醇干扰素 alfa-2a 和利巴韦林治疗。对未达到早期病毒学应答标准的达拉他韦组患者，治疗延长至 24 周。主要终点是治疗 24 周后获得 SVR（SVR24）。
各组 HCV 基因型患者的基线特征相似。然而，与 HCV 基因型 2 患者（71 例）相比，HCV 基因型 3 患者（80 例）更年轻（平均年龄分别为 45 岁和 53 岁），肝硬化比例更高（分别为 23%和 1%）。HCV 基因型 2 感染患者中，12 周达拉他韦组、16 周达拉他韦组和安慰剂组的 SVR24 分别为 83%、83%和 63%；HCV 基因型 3 感染患者的 SVR24 分别为 69%、67%和 59%。基因型间的差异主要归因于 HCV 基因型 3 感染患者治疗后复发的频率较高。在两种 HCV 基因型的达拉他韦治疗组中，达拉他韦组与安慰剂组的 SVR24 率差异的 80%置信区间下限均高于-20%，表明非劣效性。各组安全性发现相似，与聚乙二醇干扰素 alfa 和利巴韦林治疗的预期结果一致。
达拉他韦联合聚乙二醇干扰素 alfa-2a 和利巴韦林治疗 12 或 16 周，是 HCV 基因型 2 或 3 感染患者耐受性良好且有效的治疗方法。含达拉他韦的方案可缩短这些患者的治疗时间。临床试验注册：NCT01257204。
