Sherman K E, Ke R, Rouster S D, Abdel-Hameed E A, Park C, Palascak J, Perelson A S
Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
Haemophilia. 2016 Jul;22(4):543-8. doi: 10.1111/hae.12918. Epub 2016 Mar 3.
Chronic hepatitis C virus (HCV) infection is an important source of morbidity and mortality among haemophiliacs. Limited data are available regarding treatment intervention using direct-acting antivirals (DAAs) and theoretical concerns regarding accumulation of drug-associated resistance variants (RAVs) remain. We conducted a pilot study of treatment with telaprevir/pegylated interferon-alfa/ribavirin to evaluate treatment response and the role of lead-in DAA therapy on mutational selection of resistance variants.
Ultra-deep sequence analysis was performed at baseline, 48 hours and 168 hours after treatment initiation.
No dominant RAVs were identified at baseline, but low-level RAVs were noted at baseline in all subjects. Viral dynamic models were used to assess treatment responses. The efficacy parameter (Ɛ) for lead-in ranged from 0 to 0.9745 (mean = 0.514). Subsequent addition of telaprevir resulted in a mean efficacy of more than 0.999. This was comparable to subjects who started all three medications simultaneously. A total of 80% achieved SVR. While rapid shifts in the RAV population following DAA initiation were observed, treatment failure associated with A156V was observed in only one patient. Adverse event profiles were similar to that observed in non-haemophilia cohorts. There was no evidence of factor inhibitor formation. There was no evidence that lead-in provided benefit in terms of response efficacy.
These data support DAA-based therapy in those with inherited bleeding disorders.
慢性丙型肝炎病毒（HCV）感染是血友病患者发病和死亡的重要原因。关于使用直接作用抗病毒药物（DAA）进行治疗干预的数据有限，且关于药物相关耐药变异体（RAV）积累的理论担忧仍然存在。我们开展了一项使用特拉匹韦/聚乙二醇化干扰素-α/利巴韦林进行治疗的试点研究，以评估治疗反应以及导入期DAA治疗对耐药变异体突变选择的作用。
在治疗开始时、48小时和168小时进行超深度序列分析。
基线时未发现优势RAV，但所有受试者在基线时均检测到低水平RAV。使用病毒动力学模型评估治疗反应。导入期的疗效参数（Ɛ）范围为0至0.9745（平均值 = 0.514）。随后添加特拉匹韦后的平均疗效超过0.999。这与同时开始使用所有三种药物的受试者相当。共有80%的患者实现了持续病毒学应答（SVR）。虽然在开始使用DAA后观察到RAV群体的快速变化，但仅在一名患者中观察到与A156V相关的治疗失败。不良事件谱与非血友病队列中观察到的相似。没有证据表明形成了因子抑制剂。没有证据表明导入期在反应疗效方面有获益。
这些数据支持对遗传性出血性疾病患者采用基于DAA的治疗。
