• Mark S Sulkowski, David F Gardiner, Maribel Rodriguez-Torres, K Rajender Reddy, Tarek Hassanein, Ira Jacobson, Eric Lawitz, Anna S Lok, Federico Hinestrosa, Paul J Thuluvath, Howard Schwartz, David R Nelson, Gregory T Everson, Timothy Eley, Megan Wind-Rotolo, Shu-Pang Huang, Min Gao, Dennis Hernandez, Fiona McPhee, Diane Sherman, Robert Hindes, William Symonds, Claudio Pasquinelli, Dennis M Grasela, and AI444040 Study Group.
• From Johns Hopkins University (M.S.S.) and Mercy Medical Center (P.J.T.) - both in Baltimore; Bristol-Myers Squibb, Hopewell (D.F.G., T.E., D.S., C.P., D.M.G.), and Bristol-Myers Squibb, Princeton (M.W.-R., S.-P.H.) - both in New Jersey; Fundacion de Investigacion, San Juan, Puerto Rico (M.R.-T.); University of Pennsylvania, Philadelphia (K.R.R.); Southern California GI and Liver Center, Coronado (T.H.); Weill Cornell Medical College, New York (I.J.); University of Texas Health Science Center, San Antonio (E.L.); University of Michigan, Ann Arbor (A.S.L.); Orlando Immunology Center, Orlando (F.H.), Miami Research Associates, South Miami (H.S.), and University of Florida, Gainesville (D.R.N.) - all in Florida; University of Colorado Denver, Aurora (G.T.E.); Bristol-Myers Squibb, Wallingford, CT (M.G., D.H., F.M.); Skillman, NJ (R.H.); and Gilead Sciences, Foster City, CA (W.S.).
• N. Engl. J. Med. 2014 Jan 16; 370 (3): 211-21.

BackgroundAll-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3.MethodsIn this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy.ResultsOverall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea.ConclusionsOnce-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).

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