Efficacy and Safety of a Two-drug direct-acting Antiviral Agent Regimen Ruzasvir 180 mg and Uprifosbuvir 450 mg for 12 Weeks in Adults With Chronic Hepatitis C Virus Genotype 1, 2, 3, 4, 5 or 6

Eric Lawitz; Edward Gane; Jordan J. Feld; Maria Buti; Graham R. Foster; Mordechai Rabinovitz; Eduard Burnevich; Helena Katchman; Krzysztof Tomasiewicz; Fred Lahser; Beth Jackson; Melissa Shaughnessy; Stephanie Klopfer; Wendy W. Yeh; Michael N. Robertson; George J. Hanna; Eliav Barr; Heather L. Platt; on behalf of the C-BREEZE-2 Study Investigators


J Viral Hepat. 2019;26(9):1127-1138. 

In This Article

Abstract and Introduction


Ruzasvir (MK-8408, an NS5A inhibitor) and uprifosbuvir (MK-3682, a nonstructural protein 5B nucleotide inhibitor) are highly potent direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection. A phase III clinical trial evaluating the two-drug combination of ruzasvir 60 mg plus uprifosbuvir 450 mg suggested suboptimal efficacy in certain HCV genotypes (C-BREEZE 1; NCT02759315). The aim of the present study was to evaluate the efficacy and safety of ruzasvir in combination with uprifosbuvir administered at a higher dose than that assessed in the earlier study (C-BREEZE 2: NCT02956629/Merck protocol PN041). Treatment-naïve or interferon (with or without ribavirin)-experienced participants with or without compensated cirrhosis were enrolled. All participants received ruzasvir 180 mg plus uprifosbuvir 450 mg once daily for 12 weeks. The primary objectives were the proportion of participants with HCV RNA <15 lU/mL at 12 weeks after the end of study therapy (SVR12), and safety and tolerability of the study drug. Overall, 282 participants were enrolled. SVR12 (n/N) was 91.3% (42/46) in participants infected with HCV genotype (GT) 1a; GT1b, 96.7% (29/30); GT2, 91.5% (43/47); GT3, 73.8% (45/61); GT4, 98.2% (55/56); GT5, 100.0% (18/18); and GT6, 90.9% (20/22). Adverse events (AEs) were reported by 61.3% of participants; drug-related AEs were reported by 33.3%. The most frequent (≥5% of participants) drug-related AEs in all participants were fatigue (7.8%) and headache (7.4%). In conclusion, the two-drug combination of ruzasvir 180 mg plus uprifosbuvir 450 mg for 12 weeks was highly effective and well tolerated in participants infected with HCV GT1, GT2, GT4, GT5 and GT6, with a lower efficacy in GT3-infected persons.


The development of direct-acting antiviral agents (DAAs) has transformed the treatment of hepatitis C virus (HCV) infection,[1] and pangenotypic regimens are now available that result in high rates of sustained virologic response (SVR) across all HCV genotypes (GT).[2] Treatment options have transitioned from genotype-specific regimens such as sofosbuvir/ledipasvir,[3] elbasvir/grazoprevir,[4] and paritaprevir/ombitasvir/ritonavir/dasabuvir[5] to pangenotypic regimens such as glecaprevir/pibrentasvir[6] and sofosbuvir/velpatasvir.[7] An additional regimen under investigation for pangenotypic activity is the combination of ruzasvir/uprifosbuvir.

Ruzasvir (MK-8408) is a potent HCV nonstructural protein 5A (NS5A) complex inhibitor.[8] In vitro, it retains activity against RASs selected by first-generation NS5A inhibitors in individuals infected with HCV GT1a.[8] Uprifosbuvir (MK-3682) is a potent HCV NS5B polymerase nucleotide inhibitor with pangenotypic activity in vitro and a high barrier to resistance. The safety and efficacy of ruzasvir, uprifosbuvir and the nonstructural protein 3/4A protease inhibitor grazoprevir was explored in the phase II C-CREST studies (ClinicalTrials.gov numbers NCT02332707 and NCT02332720).[9–11] In these studies, the three-drug regimen of ruzasvir 60 mg and uprifosbuvir 450 mg in combination with grazoprevir 100 mg, with or without ribavirin, demonstrated high efficacy and excellent tolerability in a broad population that included treatment-naïve and prior interferon-experienced, cirrhotic and noncirrhotic participants with HCV GT1-6 infection, and also participants who had experienced virologic relapse after treatment with all-oral DAA regimens.[9–11] Given the high efficacy of ruzasvir/uprifosbuvir/grazoprevir, the relative contribution of grazoprevir was evaluated in a phase II nonrandomized study by evaluating the two-drug regimen of ruzasvir 60 mg and uprifosbuvir 450 mg. Removal of grazoprevir would eliminate drug-drug interactions caused by the NS3/4A protease inhibitor drug class and would also eliminate concerns regarding hepatic transaminase elevations with the protease inhibitor, thus potentially enabling use of the two-drug regimen in a broader range of populations. In the C-BREEZE 1 study (NCT02759315), ruzasvir 60 mg and uprifosbuvir 450 mg were well tolerated but demonstrated lower efficacy for those infected with GT3 and GT6 infection compared with those with GT1, GT2 or GT4 infection.[12] It was hypothesized that a higher dose of ruzasvir might improve the efficacy of this regimen and support a pangenotypic profile. In the present study, we evaluated the efficacy, safety and tolerability of the combination of ruzasvir 180 mg and uprifosbuvir 450 mg in participants with HCV GT1-GT6 infection.