Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Unité de Santé Publique, Paris, France.
AP-HP, Hôpital Cochin, Unité d'Hépatologie, Paris, France.
Lancet. 2019 Apr 6;393(10179):1453-1464. doi: 10.1016/S0140-6736(18)32111-1. Epub 2019 Feb 11.
Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort.
We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458.
Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27).
Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection.
INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.
虽然直接作用抗病毒药物已广泛用于治疗慢性丙型肝炎病毒（HCV）感染患者，但它们的临床疗效尚未得到很好的报道。我们在法国 ANRS CO22 Hepather 队列中比较了接受直接作用抗病毒药物治疗和未治疗的患者之间的死亡、肝细胞癌和失代偿性肝硬化的发生率。
我们在法国 32 个专家肝脏中心招募了患有慢性 HCV 感染的成年患者进行了一项前瞻性研究。我们排除了慢性乙型肝炎患者、有失代偿性肝硬化、肝细胞癌或肝移植史的患者、以及接受干扰素-利巴韦林联合或不联合第一代蛋白酶抑制剂治疗的患者。主要研究结局是全因死亡率、肝细胞癌和失代偿性肝硬化的发生率。使用时间依赖性 Cox 比例风险模型来量化直接作用抗病毒药物与这些结局之间的关联。这项研究在 ClinicalTrials.gov 注册，编号为 NCT01953458。
在 2012 年 8 月 6 日至 2015 年 12 月 31 日期间，有 10 166 名患者符合研究条件。9895（97%）名患者有可用的随访信息并纳入分析。中位随访时间为 33.4 个月（IQR 24.0-40.7）。9895 名患者中有 7344 名在随访期间开始接受直接作用抗病毒药物治疗，2551 名患者在最后一次随访时仍未接受治疗。在随访期间，有 218 名患者死亡（129 名接受治疗，89 名未接受治疗），258 名患者报告患有肝细胞癌（187 名接受治疗，71 名未接受治疗），106 名患者患有失代偿性肝硬化（74 名接受治疗，32 名未接受治疗）。接受直接作用抗病毒药物治疗与肝细胞癌（未调整的危险比[HR]2.77，95%CI 2.07-3.71）和失代偿性肝硬化（3.83，2.29-6.42）的风险增加相关。在调整了变量（年龄、性别、体重指数、地理位置、感染途径、纤维化评分、HCV 初治、HCV 基因型、酒精摄入、糖尿病、动脉高血压、生物变量和肝硬化患者的终末期肝病模型评分）后，暴露于直接作用抗病毒药物与全因死亡率（调整后的 HR 0.48，95%CI 0.33-0.70）和肝细胞癌（0.66，0.46-0.93）的风险降低相关，但与失代偿性肝硬化（1.14，0.57-2.27）无关。
接受直接作用抗病毒药物治疗与死亡率和肝细胞癌风险降低相关，应考虑在所有慢性 HCV 感染患者中使用。
法国 INSERM-ANRS（法国北部和南部艾滋病-乙型肝炎研究）、ANR（法国国家研究署）、DGS（法国卫生总局）、MSD、Janssen、Gilead、AbbVie、Bristol-Myers Squibb 和 Roche。
