By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved a fixed-combination tablet for the treatment of chronic hepatitis C (HCV) infection in patients who have been treated unsuccessfully with selected direct-acting antiviral (DAA) agents. The combination is comprised of voxilaprevir, a new NS3/4A protease inhibitor, and two currently marketed agents: sofosbuvir (nucleotide NS5B polymerase inhibitor) and velpatasvir (NS5A protein inhibitor) (SOF/VEL/VOX). It is the second fixed combination that targets three nonstructural proteins after dasabuvir, ombitasvir, and paritaprevir (Viekira). It received a breakthrough therapy designation, a priority review, and is marketed as Vosevi.
SOF/VEL/VOX is indicated for the treatment of adult patients with chronic HCV infection without cirrhosis or with compensated cirrhosis who are infected with genotype 1, 2, 3, 4, 5, or 6, and have been treated previously with an HCV regimen containing an NS5A inhibitor.1 Additionally, it is indicated for genotype 1a or 3 infections that have been treated previously with a regimen containing sofosbuvir without an NS5A inhibitor.
The recommended dose is one tablet taken once daily with food for 12 weeks. Each tablet contains 400 mg of sofosbuvir, 100 mg of velpatasvir, and 100 mg of voxilaprevir.
SOF/VEL/VOX is a new option for patients who were not treated successfully (mainly relapsed) with specific DAA-containing HCV regimens.
SOF/VEL/VOX is not indicated for decompensated cirrhosis. There is a higher frequency of nausea and diarrhea associated with the NS3/4A component (voxilaprevir) compared to SOF/VEL.2,3
Sofosbuvir, velpatasvir, and voxilaprevir are substrates and/or inhibitors of various drug transporters and CYP enzymes, leading to numerous established and potentially significant drug-drug interactions.
The three nonstructural proteins targeted by SOF/VEL/VOX are essential for the replication of HCV. Efficacy was evaluated in two Phase III studies in DAA-experienced subjects without cirrhosis or with compensated cirrhosis.1,3 These subjects mainly relapsed (82-94%) from previous regimens.
In study 1 (POLARIS-1), subjects with genotype 1-6 (mainly 1, 3, and 4) were exposed previously to NS5A inhibitors (mainly ledipasvir and daclatasvir), with 61% exposed to both NS5A and NS5B inhibitors. Forty-six percent of subjects exhibited compensated cirrhosis. Subjects with genotype 1 at screening were randomized to SOF/VEL/VOX (n = 150) or matching placebo (n = 152) and treated for 12 weeks. Other genotypes were assigned to SOF/VEL/VOX (n = 113). All were treated for 12 weeks.
In study 2 (POLARIS-4), subjects with genotype 1-4 were exposed previously to DAA (mainly sofosbuvir) but not NS5A inhibitors.1,3 Subjects were randomized to SOF/VEL/VOX (n = 139) or SOF/VEL (n = 125) for 12 weeks. The primary efficacy endpoint was sustained virologic response (serum HCV RNA < 15 IU/mL) 12 weeks after cessation of treatment (SVR12). The rate of SVR12 was 96% for SOF/VEL/VOX compared to 0% for placebo. SVR12 ranged from 91% for genotype 4 to 100% for genotype 1b, 2, 5, and 6. SVR12 was 99% in subjects without cirrhosis and 93% in those with cirrhosis.
For POLARIS-4 (including genotypes 1, 2, and 3), SVR12 was 97% for SOF/VEL/VOX compared to 88% for SOF/VEL. The difference was because of lower SVR12 with genotype 1a (98% vs. 89%), genotype 3 (96% vs. 85%), and patients with cirrhosis (94% vs. 86%). For genotype 1b, 2, 4, 5, or 6, the addition of voxilaprevir did not appear to offer additional benefit over SOF/VEL in those treated previously with sofosbuvir without an NS5A inhibitor.1
SOF/VEL/VOX for eight weeks was compared to SOF/VEL for 12 weeks in DAA treatment-naïve subjects in two studies.2 In POLARIS-2 (subjects with genotype 1, 2, and 4 with or without compensated cirrhosis and genotype 3 without cirrhosis), SVR12 was achieved in 95% with SOF/VEL/VOX
(n = 501) compared to 98% for SOF/VEL (n = 440; noninferiority not established). The discrepancy was mainly because of genotype 1a with Q80K polymorphism.
In POLARIS-3, the eight-week regimen of SOF/VEL/VOX (n = 110) was comparable to SOF/VEL (n = 109) for 12 weeks in subjects with genotype 3 and compensated cirrhosis (SVR12 of 96% in both arms). The shorter regimen has not been FDA approved. SOF/VEL/VOX appears to be well tolerated, as the percentage of subjects who discontinued treatment was ≤ 1%.2,3
The HCV guidance of the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America indicated that there are very limited options for patients who have failed on NS5A inhibitors.4 For example, for genotype 1, options include deferred treatment, a tailored retreatment regimen based on testing for resistant-associated substitutions, or an increased treatment duration of 24 weeks with weight-based ribavirin. The approval of SOF/VEL/VOX provides another option for these patients. The cost for SOF/VEL/VOX is $74,760 for a 12-week supply.
- Vosevi Prescribing Information. Gilead Sciences, Inc. July 2017.
- Jacobson IM, Lawitz E, Gane EJ, et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology 2017;153:113-122.
- Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 2017;376:2134-2146.
- American Association for the Study of Liver Diseases, Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Treatment-experienced Genotype 1. Available at: . Accessed Aug. 21, 2017.