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N Engl J Med. 2017 Jun 1;376(22):2134-2146. doi: 10.1056/NEJMoa1613512.

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection.

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From Hospital Saint Joseph, Marseille (M.B.), and University Hospital of Bordeaux, Pessac (V.L.) - both in France; Henry Ford Health System, Detroit (S.C.G.); Northwestern University, Chicago (S.L.F.); Ottawa Hospital Research Institute, Ottawa (C.L.C.), and St. Paul's Hospital, Vancouver, BC (A.R.) - both in Canada; Huntington Medical Research Institutes, Pasadena (M.T.), Cedars-Sinai Medical Center, Los Angeles (T.T.T.), and Gilead Sciences, Foster City (R.H.H., L.M.S., H.D.-S., E.S., J.Z., K.C.H., G.M.S., D.M.B., J.G.M.) - all in California; Digestive Disease Associates, Catonsville, MD (N.R.); Baylor College of Medicine, Houston (J.M.V.); Monash Health and Monash University, Clayton, VIC (S.P.), and Royal Prince Alfred Hospital, Sydney (S.I.S.) - both in Australia; Icahn School of Medicine at Mount Sinai (M.B.B.) and Columbia University Medical Center (E.C.V.) - both in New York; ifi-Institute for Interdisciplinary Medicine, Hamburg (P.B.), Hannover Medical School, Hannover (M.P.M.), and Johann Wolfgang Goethe University Medical Center, Frankfurt (S.Z.) - all in Germany; University of Washington (C.S.L.) and Swedish Medical Center (K.V.K.) - both in Seattle; Gastro One, Germantown, TN (Z.H.Y.); Beth Israel Deaconess Medical Center, Boston (M.P.C.); University of Miami, Miami (E.R.S.); and University of Pennsylvania, Philadelphia (K.R.R.).



Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.


We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group.


In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower.


Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 numbers, NCT02607735 and NCT02639247 .).

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