Efficacy and Safety of Modeling-Based Response Guided Therapy with Direct Acting Anti-Viral Agents for Treatment Optimization in Chronic Hepatitis C Infection- A Pilot Study

Abstract

Background: The advent of direct-acting antivirals (DAAs) has transformed the landscape of hepatitis C virus (HCV) management. However, the high cost of DAAs therapy has become a major barrier to HCV elimination. We aimed to prospectively evaluate the efficacy and safety of reducing the duration of DAAs therapy using response-guided therapy approach based on mathematical modeling of viral kinetics. Methods: Patients were treated with DAAs according to the physicians’ preference. HCV was measured at baseline and at day 2 and weeks 1, 2 and 4 after treatment initiation. The primary endpoint was the proportion of patients with sustained-virological response (SVR) at 12 and/or 24 weeks post-treatment. Findings: Twenty-nine patients (mean age 54±16, 44% females, 73% with HCV genotype 1), were enrolled and all completed therapy. Sofosbuvir/velpatasvir, elbasvir/grazoprevir, sofosbuvir/ledipasvir and glecaprevir/pibrentasvir, were administered in 38%, 27%, 21% and 14% of patients, respectively. Treatment duration was shortened in 11 of the 29 patients (38%). SVR was achieved in 28 of the 29 patients (97%). Relapse occurred post treatment in a single case of a non-cirrhotic male with genotype 3, who was treated with sofosbuvir/velpatasvir for 6 weeks. Virus sequencing did not identify baseline or treatment emergent resistance associated substitutions. Interpretation: Real-time modeling can be utilized for shortening DAAs duration in approximately 40% of patients without compromising treatment efficacy. Implementation of this model on a wider scale may lead to significant cost-saving and to improved access to anti-HCV care. Trial Registration: ClinicalTrials.gov Identifier: NCT03603327. Funding Statement: This research was supported in part by Clalit Health Services and the National Institutes of Health (NIH) and extramural NIH grants R01-AI078881 and R01GM121600. Declaration of Interests: OE has consulted for Gilead and Abbvie and received lecture fees from Gilead, Abbvie and MSD. HD has consulted for CoCrystal Inc. None of the other authors has any financial interest or conflict of interest related to this research. Ethics Approval Statement: The study was approved by the institutional review boards of Soroka and Rabin Medical Centers and was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements. All patients provided written informed consent.