在真实世界中，glecaprevir/pibrentasvir 治疗慢性丙型肝炎伴难治性因素患者的有效性和安全性：一项前瞻性多中心研究的综合分析。
The effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients with refractory factors in the real world: a comprehensive analysis of a prospective multicenter study.
机构信息
Gastroenterological Center, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan.
出版信息
Hepatol Int. 2020 Mar;14(2):225-238. doi: 10.1007/s12072-020-10019-z. Epub 2020 Mar 3.
BACKGROUND
Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment.
METHODS
In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed.
RESULTS
Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10; genotype 2 vs. 3, p = 3.28 × 10) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1-3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4-5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512-148.550), p value (p = 4.06 × 10)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153-13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4-5 (41.6% [79/190]) than CKD stage 1-3 (26.1% [319/1220]) patients (p = 2.00 × 10). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10) patients.
CONCLUSIONS
G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.
背景
直接作用抗病毒药物（DAAs）显著提高了慢性丙型肝炎（CHC）患者抗病毒治疗的效果。在日本的一项 III 期临床试验中，使用 NS3/4A 蛋白酶抑制剂 glecaprevir 和 NS5A 抑制剂 pibrentasvir（G/P）治疗导致少数患者出现难治因素。我们旨在评估 G/P 的有效性和安全性，特别是在这些难治因素的患者中，以及这些因素对治疗的影响。
方法
在一项涉及 33 家医疗机构的前瞻性、多中心研究中，1439 名患者接受了 G/P 治疗，分析了其疗效、安全性和最常见的不良事件（AE）。
结果
在方案分析中，总体 SVR12 率为 99.1%（1397/1410），基因型持续病毒学应答 SVR12 率为：基因型 1，99.4%（707/711）；基因型 2，99.4%（670/674）；基因型 3，80.0%（16/20）。DAA 初治患者（p=0.008），除 3 型（基因型 1 与 3 型，p=2.68×10；基因型 2 与 3 型，p=3.28×10）外，其他 HCV 基因型患者的 SVR12 率明显更高。CKD 1-3 期（99.1%[1209/1220]）和 CKD 4-5 期（98.9%[188/190]）患者之间，或肝硬化（99.0%[398/402]）和非肝硬化（99.1%[999/1008]）患者之间，差异均无统计学意义。多因素逻辑回归分析显示，基因型 3[OR 33.404，95%CI（7.512-148.550），p 值（p=4.06×10）]和无干扰素 DAA 治疗史[OR 3.977，95%CI（1.153-13.725），p 值（p=0.029）]是影响非 SVR12 的独立预测因素。28.2%的患者报告了 AE，1.6%的患者因药物相关 AE 而停止治疗。CKD 4-5 期（41.6%[79/190]）患者的 AE 发生率明显高于 CKD 1-3 期（26.1%[319/1220]）患者（p=2.00×10）。肝硬化（38.6%[155/402]）患者的 AE 发生率明显高于非肝硬化（24.1%[243/1008]）患者（p=2.91×10）。
结论
即使存在 CKD 和晚期肝纤维化等难治因素，G/P 方案治疗 CHC 患者也非常有效和安全。然而，有 IFN 无 DAA 治疗史和基因型 3、CKD 4 或 5 期和晚期肝纤维化的患者应更密切观察。
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