Multiscale Modeling of an 8-Week Combination Regimen of Bemnifosbuvir and Ruzasvir in Patients with Chronic Hepatitis C Virus Infection.

Bemnifosbuvir (BEM) and ruzasvir (RZR) are pan-genotypic HCV polymerase (NS5B) and NS5A inhibitors, respectively. In a single-arm study (NCT05904470), 215 treatment-naïve, adherent participants with chronic HCV (with or without cirrhosis) received BEM 550 mg QD plus RZR 180 mg QD for 8 weeks. We employed a multiscale mathematical model fitted to the HCV RNA and ALT dynamics to quantify the antiviral activity and evaluate the modes of action of BEM and RZR. We found that after treatment initiation, the viral load (VL) decreased in a triphasic manner, with a very rapid first phase lasting <12 h. The population estimate of the time to reach the LLOQ (VL ≤ 15 IU/mL) was 11 days for individuals in fibrosis stages F0-F3 and 15.6 days for those in F4, while the estimate of the time to reach a hypothetical cure boundary (VL ≤6.7 × 10-4 IU/mL) was 6.5 weeks for F0-F3 and 6.9 weeks for F4, with some variability between individuals. The population estimate of the effectiveness of the 8 weeks of treatment in blocking viral replication was 98.6% for F0-F3 and 99.4% for F4, while the estimate of the effectiveness in blocking viral assembly/secretion was 99.8% for F0-F3 and 99.0% for F4. We also found a treatment-induced 70% enhancement of the rate of intracellular HCV RNA degradation. The estimated efficacy of therapy was similar across genotypes 1 to 4. Thus, our modeling supports the conclusions that BEM/RZR is pan-genotypic, has high antiviral effectiveness and leads to rapid viral clearance in both cirrhotic and non-cirrhotic patients.