K E Sherman1, R Ke2, S D Rouster1, E A Abdel-Hameed1, C Park1, J Palascak3, A S Perelson2. 1. Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA. 2. Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA. 3. Division of Hematology & Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Abstract
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.
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.
Authors: James J Goedert; M Elaine Eyster; Michael M Lederman; Titica Mandalaki; Philippe De Moerloose; Gilbert C White; Anne L Angiolillo; Naomi L C Luban; Kenneth E Sherman; Marilyn Manco-Johnson; Liliana Preiss; Cindy Leissinger; Craig M Kessler; Alan R Cohen; Donna DiMichele; Margaret W Hilgartner; Louis M Aledort; Barbara L Kroner; Philip S Rosenberg; Angelos Hatzakis Journal: Blood Date: 2002-09-01 Impact factor: 22.113
Authors: Hongxing Qin; Norah J Shire; Erica D Keenan; Susan D Rouster; M Elaine Eyster; James J Goedert; Margaret James Koziel; Kenneth E Sherman Journal: Blood Date: 2004-09-16 Impact factor: 22.113
Authors: Tara L Kieffer; Christoph Sarrazin; Janice S Miller; Martin W Welker; Nicole Forestier; Hendrik W Reesink; Ann D Kwong; Stefan Zeuzem Journal: Hepatology Date: 2007-09 Impact factor: 17.425