Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Université Paris Diderot, Department of Hepatology, AP-HP Hôpital Beaujon, Clichy, France.
Swedish Medical Center, Seattle, Washington.
Clin Gastroenterol Hepatol. 2018 Mar;16(3):417-426. doi: 10.1016/j.cgh.2017.09.027. Epub 2017 Sep 22.
BACKGROUND & AIMS: Hepatitis C virus (HCV) has high genotypic diversity and global distribution. Agents that are effective against all major HCV genotypes, with shorter treatment duration, are needed to reduce disease burden. Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) have a high barrier to resistance and synergistic antiviral activity. We evaluated the safety and efficacy of 8 and 12 weeks' treatment with glecaprevir/pibrentasvir in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis in 3 separate phase 3 trials.
We performed 2 open label, single-arm studies (SURVEYOR-II, Part 4 and ENDURANCE-4) and a randomized, double-blind, placebo-controlled study (ENDURANCE-2). In the ENDURANCE-2 study, adult patients with untreated or previously treated HCV genotype 2 infection without cirrhosis were randomly assigned (2:1) to groups given once-daily oral glecaprevir/pibrentasvir (n = 202; 300 mg/120 mg) or placebo (n = 100) for 12 weeks. In the SURVEYOR-II, Part 4 and ENDURANCE-4 studies, adult patients with untreated or previously treated patients with HCV genotype 2, genotype 4, genotype 5, or genotype 6 infection, without cirrhosis, were given once-daily oral glecaprevir/pibrentasvir (n = 121 in ENDURANCE-4 and n = 145 in SURVEYOR-II) for 12 or 8 weeks, respectively. In all studies the primary endpoint was sustained virologic response at 12 weeks after treatment (SVR12) in the intention-to-treat population.
Among patients receiving glecaprevir/pibrentasvir for 8 weeks, rates of SVR12 were 98% (95% CI, 94.1-99.3) in those infected with HCV genotype 2 and 93% (95% CI, 83.6-97.3) in those infected with HCV genotypes 4, 5, or 6. Among patients receiving glecaprevir/pibrentasvir for 12 weeks, rates of SVR12 were 99.5% (95% CI, 98.5-100) in those infected with HCV genotype 2 and 99% (95% CI, 97.6-100) in those infected with HCV genotype 4, 5, or 6. No virologic failures occurred in patients with HCV genotype 4, 5, or 6 infections. The frequency and severity of adverse events in patients receiving glecaprevir/pibrentasvir were similar to those of patients who received placebo.
In 3 Phase 3 studies, 8 weeks' treatment with glecaprevir/pibrentasivr produced an SVR12 in at least 93% of patients with chronic HCV genotype 2, 4, 5, or 6 infection without cirrhosis, with virologic failure in less than 1%. The drug combination had a safety profile comparable to 12 week's treatment with glecaprevir/pibrentasvir. ClinicalTrials.gov numbers: NCT02640482 (ENDURANCE-2), NCT02636595 (ENDURANCE-4), and NCT02243293 (SURVEYOR-II).
丙型肝炎病毒（HCV）具有高度的基因型多样性和全球分布。需要具有更短治疗时间的、能够有效对抗所有主要 HCV 基因型的药物，以降低疾病负担。格拉帕韦（一种 NS3/4A 蛋白酶抑制剂）和哌仑他韦（一种 NS5A 抑制剂）具有很高的耐药屏障和协同抗病毒活性。我们在 3 项 3 期临床试验中评估了 8 周和 12 周格拉帕韦/哌仑他韦治疗无肝硬化的 HCV 基因型 2、4、5 或 6 感染患者的安全性和疗效。
我们进行了 2 项开放性标签、单臂研究（SURVEYOR-II，第 4 部分和 ENDURANCE-4）和一项随机、双盲、安慰剂对照研究（ENDURANCE-2）。在 ENDURANCE-2 研究中，未经治疗或先前未经治疗的无肝硬化 HCV 基因型 2 感染的成年患者被随机分为（2:1）每日一次口服格拉帕韦/哌仑他韦（n=202；300 mg/120 mg）或安慰剂（n=100）治疗 12 周。在 SURVEYOR-II，第 4 部分和 ENDURANCE-4 研究中，未经治疗或先前未经治疗的 HCV 基因型 2、4、5 或 6 感染、无肝硬化的成年患者分别每日口服一次格拉帕韦/哌仑他韦（ENDURANCE-4 中 n=121，SURVEYOR-II 中 n=145）治疗 12 或 8 周。在所有研究中，主要终点是治疗后 12 周持续病毒学应答（SVR12）的意向治疗人群。
在接受格拉帕韦/哌仑他韦治疗 8 周的患者中，HCV 基因型 2 感染者的 SVR12 率为 98%（95%CI，94.1-99.3），HCV 基因型 4、5 或 6 感染者的 SVR12 率为 93%（95%CI，83.6-97.3）。在接受格拉帕韦/哌仑他韦治疗 12 周的患者中，HCV 基因型 2 感染者的 SVR12 率为 99.5%（95%CI，98.5-100），HCV 基因型 4、5 或 6 感染者的 SVR12 率为 99%（95%CI，97.6-100）。HCV 基因型 4、5 或 6 感染者均无病毒学失败。接受格拉帕韦/哌仑他韦治疗的患者的不良反应频率和严重程度与接受安慰剂的患者相似。
在 3 项 3 期研究中，格拉帕韦/哌仑他韦治疗 8 周，至少 93%的无肝硬化慢性 HCV 基因型 2、4、5 或 6 感染患者达到 SVR12，病毒学失败率低于 1%。该药物组合的安全性与格拉帕韦/哌仑他韦治疗 12 周相似。临床试验编号：NCT02640482（ENDURANCE-2）、NCT02636595（ENDURANCE-4）和 NCT02243293（SURVEYOR-II）。
