title: Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials.
abstract: Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 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).
  
  
  
  In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly 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 noninferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%.
  
  
  
  In POLARIS-2, 95% (95% confidence interval [CI], 93%-97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority 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 -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily 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 proportion of patients who discontinued treatment because of adverse events was low (range, 0%-1%).
  
  
  
  In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior 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.
authors.affiliation: Mount Sinai Beth Israel, New York, New York; Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: ira.jacobson@nyumc.org.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.affiliation: Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Bernard E
authors.initials: BE
authors.lastname: Willems
authors.affiliation: Ruane Medical and Liver Health Institute, Los Angeles, California.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ruane
authors.affiliation: ID Care, Hillsborough, New Jersey.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Nahass
authors.affiliation: William Osler Health System, Brampton Civic Hospital, Brampton, Ontario, Canada.
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Borgia
authors.affiliation: University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Shafran
authors.affiliation: Emory University, Atlanta, Georgia.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Workowski
authors.affiliation: Atlanta Medical Center, Atlanta, Georgia.
authors.forename: Brian
authors.initials: B
authors.lastname: Pearlman
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Hyland
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Stamm
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Evguenia
authors.initials: E
authors.lastname: Svarovskaia
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: G Mani
authors.initials: GM
authors.lastname: Subramanian
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Brainard
authors.affiliation: Gilead Sciences, Inc, Foster City, California.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: James J. Peters Veterans Affairs Medical Center, Bronx, New York; Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Norbert
authors.initials: N
authors.lastname: Bräu
authors.affiliation: Medical Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.affiliation: Institute of Liver Studies, Kings College Hospital, London, United Kingdom.
authors.forename: Kosh
authors.initials: K
authors.lastname: Agarwal
authors.affiliation: Gastroenterology and Nutritional Medical Services, Bastrop, Louisiana.
authors.forename: Bal Raj
authors.initials: BR
authors.lastname: Bhandari
authors.affiliation: Digestive Care, South Florida Center of Gastroenterology, Wellington, Florida.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Davis
authors.affiliation: Toronto Western Hospital Liver Centre, Toronto, Ontario, Canada.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Feld
authors.affiliation: St Vincent's Hospital Sydney, University of New South Wales Sydney, Sydney, New South Wales, Australia; Kirby Institute, University of New South Wales Sydney, Sydney, New South Wales, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dore
authors.affiliation: Christchurch Hospital, University of Otago, Christchurch, New Zealand.
authors.forename: Catherine A M
authors.initials: CAM
authors.lastname: Stedman
authors.affiliation: St. Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Thompson
authors.affiliation: Hôpital Beaujon, Université Paris Diderot, INSERM UMR 1149, Centre de Recherche sur l'Inflammation, Clichy, France.
authors.forename: Tarik
authors.initials: T
authors.lastname: Asselah
authors.affiliation: Alfred Hospital, Melbourne, Victoria, Australia.
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Roberts
authors.affiliation: Royal London Hospital, London, United Kingdom.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Foster
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D011810:Quinoxalines; D000069474:Sofosbuvir / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000072230:Sustained Virologic Response; D055815:Young Adult; D001562:Benzimidazoles; D001578:Benzopyrans
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D006576:Heterocyclic Compounds, 4 or More Rings; D047029:Lactams, Macrocyclic; D007930:Leucine; D047028:Macrocyclic Compounds; D011392:Proline; D011810:Quinoxalines; D000069474:Sofosbuvir; D013449:Sulfonamides; C000619503:voxilaprevir; C000604171:velpatasvir; D001562:Benzimidazoles; D001578:Benzopyrans
keywords: Clinical Trial; Comparison; Direct-Acting Antiviral Agent; Shortened Duration Therapy