Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2, 4, 5, or 6 Infection Without Cirrhosis
Efficacy of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2, 4, 5, or 6 Infection Without Cirrhosis
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DOI：
10.1016/j.cgh.2017.09.027
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发表时间：
2018-03-01
影响因子：
12.6
通讯作者：
Mensa, Federico J.
中科院分区：
文献类型：
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作者：
Asselah, Tarik;Kowdley, Kris V.;Mensa, Federico J.
背景与目的：丙型肝炎病毒（HCV）具有高度的基因型多样性和全球性分布。需要对所有主要HCV基因型有效且治疗持续时间较短的药物来减轻疾病负担。Glecaprevir（一种NS 3/4A蛋白酶抑制剂）和pibentasvir（一种NS 5A抑制剂）具有高耐药性屏障和协同抗病毒活性。我们在3个独立的3期临床试验中评估了8周和12周的格列卡普韦/匹布他韦治疗HCV基因型2、4、5或6型感染而无肝硬化的患者的安全性和有效性。方法：我们进行了2项开放标签、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，未接受治疗或既往接受过治疗的HCV基因型2型感染且无肝硬化的成人患者被随机分配（2：1）至每日一次口服格雷匹韦/匹布他韦（n = 202; 300 mg/120 mg）或安慰剂（n = 100）组，持续12周。在SURVEYOR-II第4部分和ENDURANCE-4研究中，未接受治疗或既往接受过治疗的HCV基因型2、基因型4、基因型5或基因型6感染的成人患者（无肝硬化）接受每日一次口服格列匹韦/匹布他韦（ENDURANCE-4中n = 121，SURVEYOR-II中n = 145），分别持续12周或8周。在所有研究中，主要终点是意向治疗人群中治疗后12周的持续病毒学应答（SVR 12）。在接受格列卡普韦/匹布他韦治疗8周的患者中，SVR 12的发生率为98%，（95% CI，94.1-99.3），感染HCV基因型2和93%（95% CI，83.6-97.3），感染HCV基因型4，5，或6。在接受12周格列卡普韦/匹布他韦治疗的患者中，感染HCV基因型2的患者的SVR 12发生率为99.5%（95% CI，98.5-100），感染HCV基因型4、5或6的患者的SVR 12发生率为99%（95% CI，97.6-100）。HCV基因型4、5或6型感染的患者中无病毒学失败。在接受glecaprevir/pibentasivir的患者中不良事件的频率和严重程度与接受安慰剂的患者相似。结论：在3项3期研究中，使用glecaprevir/pibentasivr治疗8周在至少93%的慢性HCV基因型2、4、5或6型感染而无肝硬化的患者中产生了SVR 12，病毒学失败率小于1%。该药物组合的安全性特征与12周的glecaprevir/pibentasvir治疗相当。
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.METHODS: 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.RESULTS: 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.CONCLUSION: 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.