Reau Nancy, Robertson Michael N, Feng Hwa-Ping, Caro Luzelena, Yeh Wendy W, Nguyen Bach-Yen T, Wahl Janice, Barr Eliav, Hwang Peggy, Klopfer Stephanie O
Rush University Medical Center Chicago IL.
Merck & Co., Inc Kenilworth NJ.
Hepatol Commun. 2017 Aug 22;1(8):757-764. doi: 10.1002/hep4.1081. eCollection 2017 Oct.
Concomitant proton pump inhibitor (PPI) use reduces plasma concentrations of certain nonstructural protein 5A inhibitors, which are key components of modern hepatitis C infection (HCV) treatments. These reduced concentrations may decrease efficacy, leading to challenging treatment failures due to the development of resistance-associated substitutions. This post-hoc analysis assessed 12-week sustained viral response (SVR12) and pharmacokinetics of fixed-dose combination elbasvir/grazoprevir (EBR/GZR) in patients with HCV infection and self-reported PPI use. Data were derived from six phase 3 EBR/GZR trials with treatment-naive or treatment-experienced genotype 1- or 4-infected patients, with or without compensated cirrhosis. Baseline PPI use was defined as ≥7 consecutive days of use between study days -7 and 7. Bivariate analyses assessed PPI use and factors associated with SVR12 with sex, age (continuous and dichotomous), cirrhosis status, prior treatment status, baseline HCV RNA (continuous and dichotomous), HCV genotype, and baseline resistance-associated substitutions as variables in the models. Overall, 12% (162/1,322) of EBR/GZR-treated patients reported baseline PPI use. Of those, 96% achieved SVR12. In patients without PPI use, 97% achieved SVR12. PPI use was not a predictive factor in achieving SVR12 based on a univariate analysis ( 0.188). In the bivariate models, none of the interaction terms involving PPI use were statistically significant. There was no significant effect of PPI usage, regardless of adjustment for considered factors. The estimated area under the curve and maximum concentration values for EBR were comparable among patients with and without reported PPI use. : These results demonstrate that PPI use with EBR/GZR had no clinically significant effect on SVR12 rates in genotype 1/4-infected patients with or without compensated cirrhosis. (clinicaltrials.gov identifiers: NCT02092350, NCT02105467, NCT02105662, NCT02105688, NCT02105701, NCT02358044) ( 2017;1:757-764).
同时使用质子泵抑制剂（PPI）会降低某些非结构蛋白5A抑制剂的血浆浓度，这些抑制剂是现代丙型肝炎病毒（HCV）治疗的关键组成部分。这些浓度降低可能会降低疗效，由于耐药相关替代物的出现导致具有挑战性的治疗失败。这项事后分析评估了HCV感染且自我报告使用PPI的患者中固定剂量组合的艾尔巴韦/格拉瑞韦（EBR/GZR）的12周持续病毒学应答（SVR12）和药代动力学。数据来自六项3期EBR/GZR试验，受试患者为初治或经治的1型或4型感染患者，有无代偿性肝硬化。基线PPI使用定义为研究第-7天至第7天之间连续使用≥7天。双变量分析评估了PPI使用情况以及与SVR12相关的因素，将性别、年龄（连续和二分法）、肝硬化状态、既往治疗状态、基线HCV RNA（连续和二分法）、HCV基因型以及基线耐药相关替代物作为模型中的变量。总体而言，接受EBR/GZR治疗的患者中有12%（162/1322）报告基线使用PPI。其中，96%实现了SVR12。在未使用PPI的患者中，97%实现了SVR12。基于单变量分析，PPI使用不是实现SVR12的预测因素（P = 0.188）。在双变量模型中，涉及PPI使用的交互项均无统计学意义。无论对所考虑因素进行何种调整，PPI使用均无显著影响。报告使用PPI和未使用PPI的患者中，EBR的曲线下面积估计值和最大浓度值具有可比性。这些结果表明，对于有或无代偿性肝硬化的1/4型感染患者，使用EBR/GZR时PPI对SVR12率没有临床显著影响。（clinicaltrials.gov标识符：NCT02092350、NCT02105467、NCT02105662、NCT02105688、NCT02105701、NCT02358044）（《》2017；1：757 - 764） 。 （此处原文括号内期刊信息不完整）
