Viral dynamic modelling of Hepatitis C and resistance-associated variants in haemophiliacs

• Published in: Haemophilia : the official journal of the World Federation of Hemophilia Vol. 22; no. 4; pp. 543 - 548
• Main Authors: Sherman, K. E., Ke, R., Rouster, S. D., Abdel-Hameed, E. A., Park, C., Palascak, J., Perelson, A. S.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2016; Wiley
• Subjects: Antiviral Agents - therapeutic use; BASIC BIOLOGICAL SCIENCES; direct-acting antivirals; Drug Resistance, Viral; Genotype; haemophilia; HCV; Hemophilia A - complications; Hepacivirus - genetics; Hepatitis C - complications; Hepatitis C - drug therapy; Hepatitis C virus; Humans; Models, Biological; Oligopeptides - therapeutic use; Real-Time Polymerase Chain Reaction; resistance-associated variants; RNA, Viral - analysis; RNA, Viral - metabolism; Sequence Analysis, DNA; Treatment Failure; treatment response; viral dynamic models; Viral Load; viral dynamic models; haemophilia; resistance-associated variants; HCV; treatment response; direct-acting antivirals
• ISSN: 1351-8216; 1365-2516; 1365-2516
• DOI: 10.1111/hae.12918

Aim 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. Methods Ultra‐deep sequence analysis was performed at baseline, 48 hours and 168 hours after treatment initiation. Results 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. Conclusion These data support DAA‐based therapy in those with inherited bleeding disorders.