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
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
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DOI：
10.1007/s12072-020-10019-z
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发表时间：
2020-03-03
影响因子：
6.6
通讯作者：
Maeda, Shin
中科院分区：
文献类型：
--
作者：
Nozaki, Akito;Atsukawa, Masanori;Maeda, Shin
直接作用抗病毒药物（DAA）已显著提高慢性丙型肝炎（CHC）患者抗病毒治疗的有效性。在日本的一项III期试验中，使用NS 3/4A蛋白酶抑制剂glecaprevir和NS 5A抑制剂pibretasvir（G/P）治疗导致少数患者出现难治性因素。我们的目的是评估G/P的有效性和安全性，特别是在这些难治性因素的患者中，以及这些因素对治疗的影响。方法采用前瞻性、多中心、33家医疗机构参与的研究方法，对1439例患者应用G/P治疗的疗效、安全性及常见不良反应（AE）进行分析。结果1410例符合方案分析的患者中，总的SVR 12阳性率为99.1%（1397/1410），其中基因型1型占99.4%（707/711），基因型2型占99.4%（670/674），基因型3型占80.0%（16/20）。HCV基因型3（基因型1 vs. 3，p = 2.68 x 10（-5）;基因型2 vs. 3，p = 3.28 x 10（-5））除外的DAA初治患者（p = 0.008）具有显著更高的SVR 12率。在CKD 1-3期（99.1% [1209/1220]）和慢性肾脏病（CKD）4-5期（98.9% [188/190]）患者之间，或在肾病患者（99.0% [398/402]）和非肾病患者（99.1% [999/1008]）之间未观察到显著差异。多因素Logistic回归分析显示，基因型3 [OR 33.404，95%CI（7.512-148.550），p值（p = 4.06 x 10（-5））]和既往无IFN DAA经验[OR 3.977，95% CI（1.153-13.725），p值（p = 0.029）]均为非SVR 12的显著独立预测因子。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期患者的AE发生率（41.6% [79/190]）显著高于CKD 1-3期患者（26.1% [319/1220]）（p = 2.00 x 10（-5））。阿尔茨海默病患者（38.6% [155/402]）的AE也显著高于非阿尔茨海默病患者（24.1% [243/1008]）（p = 2.91 x 10（-18））。结论G/P方案治疗慢性丙型肝炎，即使合并慢性肾脏病、晚期肝纤维化等难治性因素，仍是一种安全、有效的治疗方案。然而，既往有无IFN DAA治疗经验的患者和基因型3、CKD 4期或5期以及晚期肝纤维化患者应更密切地观察。
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-naive patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 x 10(-5); genotype 2 vs. 3, p = 3.28 x 10(-5)) 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 x 10(-5))] 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 x 10(-5)). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 x 10(-18)) 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.