Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir In Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 153; no. 1; pp. 113 - 122
• Main Authors: Jacobson, Ira M, Lawitz, Eric, Gane, Edward J, Willems, Bernard E, Ruane, Peter J, Nahass, Ronald G, Borgia, Sergio M, Shafran, Stephen D, Workowski, Kimberly A, Pearlman, Brian, Hyland, Robert H, Stamm, Luisa M, Svarovskaia, Evguenia, Dvory-Sobol, Hadas, Zhu, Yanni, Subramanian, G. Mani, Brainard, Diana M, McHutchison, John G, Bräu, Norbert, Berg, Thomas, Agarwal, Kosh, Bhandari, Bal Raj, Davis, Mitchell, Feld, Jordan J, Dore, Gregory J, Stedman, Catherine A.M, Thompson, Alexander J, Asselah, Tarik, Roberts, Stuart K, Foster, Graham R
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2017
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - therapeutic use; Carbamates - administration & dosage; Carbamates - adverse effects; Carbamates - therapeutic use; Clinical Trial; Comparison; Direct-Acting Antiviral Agent; Drug Therapy, Combination; Female; Gastroenterology and Hepatology; Hepatitis C, Chronic - drug therapy; Heterocyclic Compounds, 4 or More Rings - administration & dosage; Heterocyclic Compounds, 4 or More Rings - adverse effects; Heterocyclic Compounds, 4 or More Rings - therapeutic use; Humans; Macrocyclic Compounds - administration & dosage; Macrocyclic Compounds - adverse effects; Macrocyclic Compounds - therapeutic use; Male; Middle Aged; Shortened Duration Therapy; Sofosbuvir - administration & dosage; Sofosbuvir - adverse effects; Sofosbuvir - therapeutic use; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - therapeutic use; Sustained Virologic Response; Young Adult; clinical trial; shortened duration therapy; comparison; direct-acting antiviral agent; DAA; hepatitis C virus; HCV; sustained virologic response; SVR; Direct-Acting Antiviral Agent; Shortened Duration Therapy; Clinical Trial; Comparison; CI
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2017.03.047

Abstract Background & Aims Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) following 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). Methods In 2 phase 3, open-label trials, patients with HCV infection who had not previously been treated with a direct-acting antiviral agent were randomly assigned to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the non-inferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a non-inferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups to a performance goal of 83%. Results In POLARIS-2, 95% (95% CI, 93%–97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish non-inferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%–99%; difference in the stratum-adjusted Mantel-Haenszel proportions of 3.4%; 95% CI, –6.2% to –0.6%). The difference in the efficacy was primarily due to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%–99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportions of patients who discontinued treatment owing to adverse events were low (0–1%). Conclusions In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was non-inferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800 and POLARIS-3, NCT02639338