HCV kinetic and modeling analyses project shorter durations to cure under combined therapy with daclatasvir and asunaprevir in chronic HCV-infected patients

• Published in: PloS one Vol. 12; no. 12; p. e0187409
• Main Authors: Canini, Laetitia, Imamura, Michio, Kawakami, Yoshiiku, Uprichard, Susan L., Cotler, Scott J., Dahari, Harel, Chayama, Kazuaki
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 07.12.2017; Public Library of Science (PLoS)
• Subjects: Antiviral Agents - administration & dosage; Antiviral Agents - therapeutic use; Biology and life sciences; Complications and side effects; Daclatasvir; Dosage and administration; Drug therapy; Hepacivirus - physiology; Hepatitis C; Hepatitis C, Chronic - drug therapy; Humans; Imidazoles - administration & dosage; Imidazoles - therapeutic use; Isoquinolines - administration & dosage; Isoquinolines - therapeutic use; Kinetics; Life Sciences; Medicine and health sciences; Research and Analysis Methods; Sulfonamides - administration & dosage; Sulfonamides - therapeutic use; United States; United Kingdom
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0187409

High cure rates are achieved in HCV genotype-1b patients treated with daclatasvir and asunaprevir, DCV/ASV. Here we analyzed early HCV kinetics in genotype-1b infected Japanese subjects treated with DCV/ASV and retrospectively projected, using mathematical modeling, whether shorter treatment durations might be effective. HCV RNA levels were measured frequently during DCV/ASV therapy in 95 consecutively treated patients at a single center in Japan. Mathematical modeling was used to predict the time to cure, i.e, <1 virus copy in the extracellular body fluid. Patients with HCV<15 IU/ml at week 1 (n = 27) were excluded from modeling analysis due to insufficient HCV RNA data points. Eighty nine of the 95 included patients (94%) achieved cure, 3 (3%) relapsed due to treatment-emergent resistance, and 3 (3%) completed therapy but were lost during follow up. Model fits from 68 patients with sufficient data points indicate that after a short pharmacological delay (15.4 min [relative standard error, rse = 26%]), DCV/ASV effectiveness in blocking HCV production was 0.999 [rse~0%], HCV half-life in blood was t1/2 = 1.7 hr [rse = 21%], and HCV-infected cell loss rate was 0.391/d [rse = 5%]. Modeling predicted that 100% and 98.5% of patients who had HCV<15 IU/ml at days 14 and 28 might have been cured with 6 and 8 weeks of therapy, respectively. There was a trend (p = 0.058) between younger age and shorter time to cure. Modeling early HCV kinetics under DCV/ASV predicts that most patients would achieve cure with short treatment durations, suggesting that 24 weeks of DCV/ASV treatment can be significantly shortened.