Northwestern Feinberg School of Medicine, Chicago, Illinois.
University of Pennsylvania, Philadelphia, Pennsylvania.
Clin Gastroenterol Hepatol. 2019 Feb;17(3):527-535.e6. doi: 10.1016/j.cgh.2018.07.003. Epub 2018 Sep 10.
BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents.
We analyzed data from 2369 patients infected with HCV genotypes 1-6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8-16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents.
Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI.
In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection-even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).
质子泵抑制剂（PPIs）常用于治疗与酸相关的疾病。由于药物之间的相互作用，一些用于慢性丙型肝炎病毒（HCV）感染的直接作用抗病毒方案在同时服用酸还原剂（包括 PPIs）的患者中疗效降低。我们分析了 9 项多中心、2 期和 3 期临床试验的数据，以确定包含格卡瑞韦和哌仑他韦（格卡瑞韦/哌仑他韦）的 HCV 治疗方案在同时服用酸还原剂的患者中的疗效和药代动力学。
我们分析了 2369 例感染 HCV 基因型 1-6 且有代偿性肝脏疾病的患者的数据，这些患者接受了为期 8-16 周的格卡瑞韦/哌仑他韦的全口服治疗方案。我们比较了接受至少一剂酸还原剂（PPI、H2 阻滞剂或抗酸剂）的患者之间的疗效和药代动力学。高剂量 PPI 定义为每日剂量大于 20mg 奥美拉唑等效剂量。目的是评估治疗后 12 周持续病毒学应答率（SVR12），并评估接受酸还原剂的患者的稳态格卡瑞韦和哌仑他韦暴露情况。
在 401 例（17%）报告使用酸还原剂的患者中，263 例使用了 PPIs（11%；109 例使用了高剂量 PPI，154 例使用了低剂量 PPI）。使用酸还原剂的患者 SVR12 率为 97.0%，未使用酸还原剂的患者 SVR12 率为 97.5%（P=0.6）。接受高剂量 PPI 的患者中有 96.3%达到 SVR12，接受低剂量 PPI 的患者中有 97.4%达到 SVR12，接受高剂量 PPI 的患者中没有病毒学失败（P=0.7）。格卡瑞韦，但不是哌仑他韦，生物利用度受到影响；接受高剂量 PPI 的患者格卡瑞韦的暴露量减少了 41%。
在对 9 项临床试验数据的分析中，我们观察到接受格卡瑞韦/哌仑他韦治疗 HCV 感染的患者 SVR12 率很高（约 97%），即使是同时服用 ARA 或高剂量 PPI 的患者也是如此。尽管高剂量 PPI 会降低格卡瑞韦的暴露，但仍观察到这一结果。临床试验注册号，NCT02243280（SURVEYOR-I）、NCT02243293（SURVEYOR-II）、NCT02604017（ENDURANCE-1）、NCT02640482（ENDURANCE-2）、NCT02640157（ENDURANCE-3）、NCT02636595（ENDURANCE-4）、NCT02642432（EXPEDITION-1）、NCT02651194（EXPEDITION-4）、NCT02446717（MAGELLAN-I）。
