Centre de Recherche sur l'Inflammation, Inserm UMR 1149, Université Paris Diderot, AP-HP Hôpital Beaujon, Clichy, France.
Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France.
Lancet Gastroenterol Hepatol. 2016 Sep;1(1):25-35. doi: 10.1016/S2468-1253(16)30001-2. Epub 2016 Jun 16.
Hepatitis C virus (HCV) genotype 4 infection is most commonly reported in sub-Saharan Africa and the Middle East; however, prevalence is increasing worldwide through immigration. HCV genotype 4 accounts for 20% of all infections, but clinical trial data for treatment remain limited. We assessed the combination of two direct-acting antivirals, ombitasvir (NS5A inhibitor) and paritaprevir (NS3/4A protease inhibitor; co-dosed with ritonavir) plus ribavirin in patients with HCV genotype 4 infection and compensated cirrhosis.
In this multicentre, randomised, open-label phase 3 trial (AGATE-I), treatment-naive and interferon or pegylated interferon and ribavirin treatment-experienced patients with HCV genotype 4 infection and compensated cirrhosis were recruited from academic, public, and private hospitals in Austria, Belgium, Canada, France, Germany, Greece, Italy, and the USA. Key eligibility criteria were age 18 years or older, with chronic HCV infection assessed by the presence of anti-HCV antibodies or HCV RNA. Patients were randomly assigned (1:1) to receive 25 mg ombitasvir, 150 mg paritaprevir, and 100 mg ritonavir once daily, with weight-based ribavirin dosed twice daily for either 12 weeks or 16 weeks. Randomisation was stratified by HCV treatment history (treatment-experienced vs treatment-naive patients) and further stratified by type of non-response to previous HCV treatment (null responders, partial responders, or relapsers) for treatment-experienced patients. Treatments were assigned by an interactive response technology system with computer-generated randomisation lists prepared by personnel from the study's funding sponsor who were not involved with the conduct of the study or with data analysis. The primary outcome was the proportion of patients with a sustained virological response (HCV RNA <25 IU/mL) at post-treatment week 12 (SVR12) in the intention-to-treat population, with the lower 97·5% CI compared with a clinically relevant threshold (67%; based on SVR reported for pegylated interferon and ribavirin) to achieve superiority. The safety population included all patients who received at least one dose of study drug, and safety analyses were done by the treatment duration received (12 weeks or 16 weeks). Data presented are from the planned primary interim analysis of part one of the study when all patients enrolled in part one had reached post-treatment week 12 or prematurely discontinued from the study. This trial is registered with ClinicalTrials.gov, number NCT02265237, and part two of the trial is ongoing but closed to new participants.
Between Nov 18, 2014, and May 19, 2015, we enrolled 120 eligible patients, with 59 patients assigned to receive 12 weeks of treatment and 61 patients assigned to receive 16 weeks of treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin. One patient in the 12-week group experienced virological breakthrough and one discontinued prematurely after the first day of treatment. One patient missed the post-treatment week 12 visit in the 16-week group. SVR12 was achieved in 57 (97%; 97·5% CI 86·7-99·2) of 59 patients in the 12-week group and 60 (98%; 89·6-99·8) of 61 in the 16-week group. Adverse events in more than 10% of all patients were asthenia (11 [18%] of 60 in the 12-week group; 19 [32%] of 60 in the 16-week group), fatigue (ten [17%] in the 12-week group; 20 [33%] in the 16-week group), headache (14 [23%] in the 12-week group; 14 [23%] in the 16-week group), anaemia (nine [15%] in the 12-week group; 12 [20%] in the 16-week group), pruritus (five [8%] in the 12-week group; 14 [23%] in the 16-week group), nausea (six [10%] in the 12-week group; eight [13%] in the 16-week group), and dizziness (four [7%] in the 12-week group; nine [15%] in the 16-week group).
With SVR12 achieved in a high proportion of patients, no post-treatment relapses, and a similar adverse event profile for the 12-week and 16-week treatment groups, extending treatment with ombitasvir, paritaprevir, and ritonavir plus ribavirin beyond 12 weeks seems to have no additional benefit for patients with HCV genotype 4 infection and compensated cirrhosis and might not be necessary for this patient group.
AbbVie.
丙型肝炎病毒（HCV）基因型 4 感染在撒哈拉以南非洲和中东地区最为常见；然而，随着移民的增加，全球 HCV 基因型 4 的感染率正在上升。HCV 基因型 4 占所有感染的 20%，但针对其治疗的临床试验数据仍然有限。我们评估了两种直接作用抗病毒药物，ombitasvir（NS5A 抑制剂）和 paritaprevir（NS3/4A 蛋白酶抑制剂；与利托那韦联合使用）加利巴韦林在 HCV 基因型 4 感染和代偿性肝硬化患者中的联合应用。
在这项多中心、随机、开放标签的 3 期试验（AGATE-I）中，从奥地利、比利时、加拿大、法国、德国、希腊、意大利和美国的学术、公立和私立医院招募了 HCV 基因型 4 感染和代偿性肝硬化的初治和干扰素或聚乙二醇干扰素加利巴韦林治疗的经治患者。主要入选标准为年龄 18 岁或以上，通过抗 HCV 抗体或 HCV RNA 存在评估为慢性 HCV 感染。患者被随机分配（1:1）接受每日一次 25mg ombitasvir、150mg paritaprevir 和 100mg 利托那韦，体重为基础的利巴韦林每日两次，治疗 12 周或 16 周。随机分组按 HCV 治疗史（经治与初治患者）分层，进一步按既往 HCV 治疗的无应答类型（无应答者、部分应答者或复发者）分层，用于经治患者。治疗方案由具有交互反应技术系统的计算机生成的随机分组表分配，这些分组表由研究资助者的工作人员准备，他们与研究的进行或数据分析无关。主要终点是在治疗后第 12 周（SVR12）时持续病毒学应答（HCV RNA <25IU/mL）的患者比例，其下 97.5%CI 与临床相关阈值（67%；基于聚乙二醇干扰素加利巴韦林的 SVR 报告）相比，以达到优势。安全性人群包括至少接受一剂研究药物的所有患者，安全性分析基于接受的治疗持续时间（12 周或 16 周）。报告的数据来自该研究第一部分的计划主要中期分析，当第一部分中所有入组的患者均达到治疗后第 12 周或提前退出研究时。该试验在 ClinicalTrials.gov 注册，编号为 NCT02265237，第二部分试验正在进行但已关闭新患者入组。
2014 年 11 月 18 日至 2015 年 5 月 19 日，我们招募了 120 名符合条件的患者，其中 59 名患者被分配接受 12 周的治疗，61 名患者被分配接受 16 周的 ombitasvir、paritaprevir 和利托那韦加利巴韦林治疗。1 名 12 周组患者发生病毒学突破，1 名患者在治疗的第一天后提前退出。1 名 16 周组患者在治疗后第 12 周错过随访。在 12 周组中，59 例患者中有 57 例（97%；97.5%CI 86.7-99.2）达到 SVR12，在 16 周组中，61 例患者中有 60 例（98%；89.6-99.8）达到 SVR12。所有患者中超过 10%的不良事件为乏力（12 周组 11 例[18%]；16 周组 19 例[32%]）、疲劳（12 周组 10 例[17%]；16 周组 20 例[33%]）、头痛（12 周组 14 例[23%]；16 周组 14 例[23%]）、贫血（12 周组 9 例[15%]；16 周组 12 例[20%]）、瘙痒（12 周组 5 例[8%]；16 周组 14 例[23%]）、恶心（12 周组 6 例[10%]；16 周组 8 例[13%]）和头晕（12 周组 4 例[7%]；16 周组 9 例[15%]）。
在高比例的患者中实现 SVR12，没有治疗后复发，12 周和 16 周治疗组的不良事件谱相似，因此延长 ombitasvir、paritaprevir 和利托那韦加利巴韦林的治疗时间超过 12 周似乎对 HCV 基因型 4 感染和代偿性肝硬化患者没有额外的益处，并且对于这一患者群体可能不是必需的。
艾伯维。
