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Safety and efficacy of a new drug: sofosbuvir/velpatasvir/voxilaprevir (Vosevi®)

By: Shireen Farzadeh, PharmD Candidate c/o 2019

Sofosbuvir/velpatasvir/voxilaprevir (Vosevi®) is the first pangenotypic fixed-dose combination tablet that includes 400 mg of sofosbuvir, a Hepatitis C virus (HCV) nucleotide analog, 100 mg of velpatasvir, an HCV NS5A inhibitor, and 100 mg of voxilaprevir, an HCV NS3/4A protease inhibitors.1,2 In the interest of brevity, sofosbuvir/velpatasvir/voxilaprevir will be referred to by its brand name throughout the article. Vosevi® is indicated to treat adults with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection with or without cirrhosis (compensated), who were treated with an NS5A inhibitor-containing therapy, but were not cured.3 Cure meaning the HCV is not detected in the blood when its measured three months after treatment is completed.3 Unfortunately, Vosevi® is not a treatment option for patients with severe renal impairment and end stage renal disease or moderate to severe liver disease, due to the presence of sofosbuvir and voxilaprevir.2

POLARIS-1 is a phase 3 placebo-controlled trial, in which Vosevi® was administered to patients with chronic HCV genotype 1-6, who were previously treated with a regimen containing a NS5A inhibitor. Patients with genotype 1 infection who were previously treated with an NS5A-containing regimen, were randomized in a 1:1 ratio to receive either the active drug (150 patients) or a matching placebo (150 patients) once daily for 12 weeks. Patients with HCV infections of other genotypes were all enrolled into the active group (114 patients). POLARIS-1 showed sustained virologic response (SVR) of 96% with the experimental drugs, versus 0% with placebo. POLARIS-4 is a phase 3, active-comparator, open-labeled trial, in which 314 patients with HCV genotype 1-3 who were previously treated without a NS5A inhibitor were randomized in a 1:1 ratio to be administered with either the experimental drug (163 patients) or sofosbuvir/velpatasvir (151 patients) for 12 weeks. Nineteen additional patients with HCV genotype 4 were also assigned to the experimental drugs. In POLARIS-4 an SVR of 98% was observed in the experimental group compared to 90% with sofosbuvir/velpatasvir. POLARIS-1 and POLARIS-4 data concluded that 12 weeks of Vosevi® showed high efficacy and SVR in patients of all HCV genotypes and whose direct antiviral treatment (DAA)  previously failed.4

POLARIS-2 and POLARIS-3 are phase 3 open-labeled trials. In POLARIS-2, HCV patients of genotypes 1-4 and naïve to DAA with or without cirrhosis were randomized to groups given either 8 weeks of Vosevi® or 12 weeks of sofosbuvir/velpatasvir. Patients with HCV of genotypes 5-6 were assigned to the experimental group. POLARIS-2 showed SVR in 95% of patients with experimental drugs, but did not establish noninferiority. Hence, the 8-week treatment was not worse than the SVR of 98% in patients with 12 weeks of sofosbuvir/velpatasvir. In POLARIS-3, HCV patients of genotype 3 and naïve to DAA with compensated cirrhosis were randomly assigned to either 8 weeks of experimental drug or 12 weeks of sofosbuvir/velpatasvir. POLARIS-3 had an SVR of 96% in both treatments groups. POLARIS-2 and POLARIS-3 concluded that although 8 weeks of Vosevi® was not established to be noninferior to 12 weeks of sofosbuvir/velpatasvir, both treatment groups had a high SVR in HCV genotype 3 and compensated cirrhosis.5

Clinical trials have shown efficacy of Vosevi®, but as with any other medication, it is imperative that pharmacists counsel patients on side effects, monitoring parameters, and drug interactions. POLARIS-1 and POLARIS-4 demonstrated common side effects such as headache, fatigue, diarrhea, nausea, asthenia, and insomnia. Less common side effects (<5%) include, rash and depression. Patients’ lipase, creatine kinase, and bilirubin should be monitored, as Vosevi® may cause an increase their levels. Since the medication was released on the market, serious side effects observed include, hepatitis B reactivation in patients co-infected with HCV and HBV and symptomatic bradycardia when taken with amiodarone. It is imperative to counsel patients that therapeutic concentrations of Vosevi® may be affected if it is coadministered with p-glycoprotein inducers, CYP enzyme inducers, or rifampin, and that the medication may affect concentrations of P-gp, BCRP, OATP1B1, and OATP1B3 substrates. Whether or not Vosevi® poses a risk to geriatric, pediatric, or pregnant populations is unknown.1 Pharmacists should urge patients to speak to a gastroenterologist to determine if the regimen is an appropriate treatment option.3

Overall, Vosevi® is a well-tolerated medication. Advantages of the medication over some of the other HCV regimens include its once-a-day administration, 12-week duration treatment, and cost of $74,760 for a 12-week supply, which is less than that of sofosbuvir (Solvadi®) and ledipasvir/sofosbuvir (Harvoni®).1 The HCV guidance of the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America states that options are very limited for patients who have failed on NS5A inhibitors. For genotype 1, for   example, deferred treatment or increased treatment     duration of 24 weeks with weight-based ribavirin are the only options. Hence, Vosevi® is likely to provide value in treating adults with HCV genotypes 1, 2, 3, 4, 5, or 6 previously treated with an HCV regimen and failed on an NS5A inhibitor or HCV genotypes 1a or 3 previously treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor. Currently, the HCV guidance has not updated to add Vosevi® as a recommended regimen, but it will likely be indicated in the near future.6



  1. University of Washington. Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi®). Hepatitis C Online. Accessed November 17, 2017.
  2. Vosevi® (sofosbuvir/velpatasvir/voxilaprevir) [package insert]. Foster City, CA; Gilead Sciences, Inc.; Revised 07/18/2017.
  3. Gilead Sciences, Inc. EVERY ONE MATTERS. VOSEVI® (sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg) tablets. Accessed November 17, 2017.
  4. Bourlière M, Gordon SC, Flamm SL, et al. Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med. 2017;376(22):2134-2146. Doi: 10.1056/NEJMoa1613512.
  5. 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(1):113-122. doi: 10.1053/j.gastro.2017.03.047. Epub 2017 Apr 5.
  6. AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. Accessed November 17, 2017.
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