TY - JOUR
T1 - Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection
T2 - A randomised, double-blind, phase 2 trial
AU - Lawitz, Eric
AU - Lalezari, Jay P.
AU - Hassanein, Tarek
AU - Kowdley, Kris V.
AU - Poordad, Fred F.
AU - Sheikh, Aasim M.
AU - Afdhal, Nezam H.
AU - Bernstein, David E.
AU - DeJesus, Edwin
AU - Freilich, Bradley
AU - Nelson, David R.
AU - Dieterich, Douglas T.
AU - Jacobson, Ira M.
AU - Jensen, Donald
AU - Abrams, Gary A.
AU - Darling, Jama M.
AU - Rodriguez-Torres, Maribel
AU - Reddy, K. Rajender
AU - Sulkowski, Mark S.
AU - Bzowej, Natalie H.
AU - Hyland, Robert H.
AU - Mo, Hongmei
AU - Lin, Ming
AU - Mader, Michael
AU - Hindes, Robert
AU - Albanis, Efsevia
AU - Symonds, William T.
AU - Berrey, Michelle M.
AU - Muir, Andrew
N1 - Funding Information:
EL has received research support and grants from Abbott, Achillion, Anadys, Biolex, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, GlobeImmune, Idenix, Idera, Inhibitex, Intercept, Janssen, Medarex, Medtronic, Merck, Novartis, Pharmasset, Roche, Schering-Plough, Santaris, Scynexis, Vertex, ViroChem, and ZymoGenetics; was on the speakers’ bureau for Gilead, Merck, and Vertex; and has served on advisory boards for Abbott, Achillion, Anadys, Biolex, Biotica, GlobeImmune, Inhibitex, Merck, Novartis, Pharmasset, Tibotec, Theravance, and Vertex. TH has received research grants from Bristol-Myers Squibb, Abbott Pharmaceuticals, Gilead Sciences, Janssen Pharmaceuticals, Ikaria Pharmaceuticals, Takeda Pharmaceuticals, Mochida Pharmaceuticals, Sundise Pharmaceuticals, Roche Pharmaceuticals, Eisai Pharmaceuticals, Vertex Pharmaceuticals; and has received honoraria as a speaker for Gilead. KVK has received research support and grants from Abbot, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Conatus, Gilead, Ikaria, Intercept, Janssen, Merck, Mochida, and Vertex; has served as a consultant to Exjade; has received honoraria (speaking and advisory board) from Merck and Novartis; and has served on advisory boards for Abbott, Gilead, and Vertex. FFP has received research grants from Achillion, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Human Genome Science, Idenix, Inhibitex, Janssen, Merck, Novartis, Pharmasset, Salix, and Vertex; has served as a consultant or adviser to Achillion, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Idenix, Inhibitex, Janssen, Kadmon, Merck, Novartis, Salix, and Vertex; and was on the speakers’ bureau for Genentech, Gilead, Kadmon, Merck, Salix, and Vertex. AMS has received research grants from Gilead and Pharmasset. NHA has received research support from Abbott, Echosens, Gilead, GlaxoSmithKline, Novartis, Pharmasset, Quest, Schering-Plough/Merck, and Vertex; has received honoraria (consultant and adviser) from Boehringer Ingelheim, Echosens, Gilead, GlaxoSmithKline, Ligand, Medgenics, Novartis, Springback, and Vertex. DEB has received honoraria for serving on speakers’ bureau from Gilead. ED has served on advisory boards and has received honoraria from Gilead. BF has received research support from Gilead. DRN has received research support and has served as a consultant and adviser to Gilead. DTD has received research support, served as a consultant, and was on the speakers’ bureau for Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Idenix, and Merck. IMJ has received research support and grants from Abbott, Achillion, Anadys, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Janssen, Novartis, Pfizer, Schering-Plough/Merck, and Vertex; was on the speakers’ bureau for Bristol-Myers Squibb, Genentech, Gilead, Schering-Plough/Merck, and Vertex; and has received consultancy fees from Abbott, Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Enanta, Genentech, Gilead, GlaxoSmithKline, Idenix, Janssen, Kadmon, Novartis, Presidio, Schering-Plough/Merck, and Vertex. DJ has received research grants from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, and Janssen; and has served on advisory boards for Abbott, Astex, Biotica, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, Inhibitex, Janssen, Merck, and Vertex. MR-T has received research support and grants from Abbott, Akros, Anadys, Beckman Coulter, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead, GlaxoSmithKline, Hoffman-La Roche, Human Genome Sciences, Idenix, Idera, Inhibitex, Johnson and Johnson, Merck, Mochida, Novartis, Pfizer, Pharmasset, Santaris, Scynexis, Siemens Healthcare Diagnostics, Vertex, and Zymogenetics; and has served as a consultant for Akros, Bristol-Myers Squibb, Genetech, Hoffman-La Roche, Inhibitex, Janssen, Merck, Pharmasset, Santaris, and Vertex. KRR has received research support and grants from Anadys, Bristol-Myers Squibb, Genentech, Gilead, Ikaria, Janssen, Merck, and Vertex; and has served on advisory boards for Bristol-Myers Squibb, Genentech, Gilead, Janssen, Merck, Novartis, and Vertex. MSS has received research grants from Abbott, BIPI, Bristol-Myers Squibb, Gilead, Janssen, Merch, Roche, and Vertex; and has served as a consultant to Abbott, BIPI, Bristol-Myers Squibb, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, and Vertex. NHB has received research support from Bristol-Myers Squibb, Genentech, Gilead, Johnson and Johnson, Merck, Pharmasset, Vertex, and Zymogene; has served as a consultant to Abbott; and was on the advisory boards and speakers’ bureau for Gilead and Vertex. RHH, HM, ML, MM, RH, EA, WTS, and MMB are employees and stockholders of Gilead Sciences. AM has received research grants from Abbott, Achillion, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Medtronic, Merck, Pfizer, Scynexis, and Vertix; and has served as a consultant to Achillion, GlaxoSmithKline, Merck, Scynexis, and Vertex. JPL, GAA, and JMD declare that they have no conflicts of interest.
Funding Information:
This study was sponsored by Gilead Sciences. DRN was supported in part by the NIH/NCATS Clinical and Translational Science Award to the University of Florida (grant number UL1 TR000064) . Editorial assistance was provided by Jane Anderson of J Anderson Solutions, LLC (Chapel Hill, NC, USA) and David McNeel (Gilead Sciences).
PY - 2013/5
Y1 - 2013/5
N2 - Background: Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection. Methods: In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1-3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18-70 years, had an HCV RNA concentration of 50 000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 μg per week) and ribavirin (1000-1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772. Findings: In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events-fatigue, headache, nausea, and chills-were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77-97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80-98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37-77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12. Interpretation: Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. Funding: Gilead Sciences.
AB - Background: Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection. Methods: In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1-3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18-70 years, had an HCV RNA concentration of 50 000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 μg per week) and ribavirin (1000-1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772. Findings: In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events-fatigue, headache, nausea, and chills-were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77-97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80-98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37-77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12. Interpretation: Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. Funding: Gilead Sciences.
UR - http://www.scopus.com/inward/record.url?scp=84876740954&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876740954&partnerID=8YFLogxK
U2 - 10.1016/S1473-3099(13)70033-1
DO - 10.1016/S1473-3099(13)70033-1
M3 - Article
C2 - 23499158
AN - SCOPUS:84876740954
VL - 13
SP - 401
EP - 408
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
SN - 1473-3099
IS - 5
ER -