Author(s): Kowdley KV, Lawitz E, Crespo I, Hassanein T, Davis MN, et al.
Background: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV.
Methods: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs ≥800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978.
Results: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event.
Interpretation: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis.
Funding: Gilead Sciences.
Referred From: https://www.ncbi.nlm.nih.gov/pubmed/23499440
Author(s): Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, et al.
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Author(s): Pawlotsky JM, Chevaliez S, McHutchison JG
Author(s): Thompson A, Patel K, Tillman H, McHutchison JG
Author(s): Messina JP, Humphreys I, Flaxman A, Brown A, Cooke GS, et al.
Author(s): Al Traif I, Al Balwi MA, Abdulkarim I, Handoo FA, Alqhamdi HS, et al.
Author(s): Ray SC, Arthur RR, Carella A, Bukh J, Thomas DL
Author(s): Benhamou Y, Moussalli J, Ratziu V, Lebray P, De Backer K, et al.
Author(s): Omland LH, Osler M, Jepsen P, Krarup H, Weis N, et al.
Author(s): Reddy KR, Wright TL, Pockros PJ, Shiffman M, Everson G, et al.
Author(s): Hasan F, Asker H, Al-Khaldi J, Siddique I, Al-Ajmi M, et al.
Author(s): Alfaleh FZ, Hadad Q, Khuroo MS, Aljumah A, Algamedi A, et al.
Author(s): Derbala M, Amer A, Bener A, Lopez AC, Omar M, et al.
Author(s): El Makhzangy H, Esmat G, Said M, Elraziky M, Shouman S, et al.
Author(s): Kamal SM, Ahmed A, Mahmoud S, Nabegh L, El Gohary I, et al.
Author(s): Abdo AA, Al-Ahdal MN, Khalid SS, Helmy A, Sanai FM, et al.
Author(s): Kamal SM, E Kamary SS, Shardell MD, Hashem M, Ahmed IN, et al.
Author(s): MartÃn-Carbonero L, Puoti M, GarcÃa-Samaniego J, De Luca A, Losada E, et al.
Author(s): Issa H
Author(s): Lawitz E, Mangia A Wyles D, Rodriguez-Torres M, Hassanein T, et al.
Author(s): Wehmeyer MH, Jordan S, LÃ¼th S, Hartl J, Stoehr A, et al.
Author(s): Steinebrunner N, Sprinzl MF, Zimmermann T, WÃ¶rns MA, Zimmerer T, et al.
Author(s): Moreno C, Hezode C, Marcellin P, Bourgeois S, Francque S, et al.
Author(s): HÃ©zode C, Hirschfield GM, Ghesquiere W, Sievert W, Rodriguez-Torres M, et al.
Author(s): HÃ©zode C, Alric L, Brown A, Hassanein T, Rizzetto M, et al.
Author(s): Jensen D, Sherman KE, HÃ©zode C, Pol S, Zeuzem S, et al.
Author(s): Zoulim F, Liang TJ, Gerbes AL Aghemo A4, Deuffic-Burban S5, et al.
Author(s): Petersen T, Townsend K, Gordon LA, Sidharthan S, et al.
Author(s): Molina JM, Orkin C, Iser DM, Zamora FX, Nelson M, et al.
Author(s): Ruane PJ, Ain D, Stryker R, Meshrekey R, Soliman M, et al.
Author(s): Doss W, Shiha G, Hassany M, Soliman R, Fouad R, et al.
Author(s): Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, et al.
Author(s): Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, et al.
Author(s): Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, et al.
Author(s): Kohli A, Kapoor R2, Sims Z3, Nelson A4, Sidharthan S3, et al.
Author(s): Charlton M, Everson GT, Flamm SL, Kumar P, Landis C, et al.
Author(s): HÃ©zode C, Asselah T, Reddy KR, Hassanein T, Berenguer M, et al.
Author(s): Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ari ZB, et al.