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Sofosbuvir for Hepatitis C Genotype 2 Or 3 in Patients Without Treatment Options Ira M

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Sofosbuvir for Hepatitis C Genotype 2 Or 3 in Patients Without Treatment Options Ira M T h e new england journal o f medicine original article Sofosbuvir for Hepatitis C Genotype 2 or 3 in Patients without Treatment Options Ira M. Jacobson, M.D., Stuart C. Gordon, M.D., Kris V. Kowdley, M.D., Eric M. Yoshida, M.D., Maribel Rodriguez-Torres, M.D., Mark S. Sulkowski, M.D., Mitchell L. Shiffman, M.D., Eric Lawitz, M.D., Gregory Everson, M.D., Michael Bennett, M.D., Eugene Schiff, M.D., M. Tarek Al-Assi, M.D., G. Mani Subramanian, M.D., Ph.D., Di An, Ph.D., Ming Lin, Ph.D., John McNally, Ph.D., Diana Brainard, M.D., William T. Symonds, Pharm.D., John G. McHutchison, M.D., Keyur Patel, M.D., Jordan Feld, M.D., M.P.H., Stephen Pianko, M.D., Ph.D., and David R. Nelson, M.D. ABSTRACT BACKGROUND Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom From Weill Cornell Medical College, New treatment with peginterferon is not an option, or who have not had a response to York (I.M.J.); Henry Ford Health Systems, Detroit (S.C.G.); Digestive Disease Insti- prior interferon treatment, currently have no approved treatment options. In phase 2 tute, Virginia Mason Medical Center, Seat- trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have tle (K.V.K.); University of British Columbia, Vancouver (E.M.Y.), and University of shown efficacy in patients with HCV genotype 2 or 3 infection. Toronto, Toronto (J.F.) — both in Canada; METHODS Fundacion de Investigacion, San Juan, We conducted two randomized, phase 3 studies involving patients with chronic Puerto Rico (M.R.-T.); Johns Hopkins Uni- versity School of Medicine, Baltimore HCV genotype 2 or 3 infection. In one trial, patients for whom treatment with peg­ (M.S.S.); Liver Institute of Virginia, Bon interferon was not an option received oral sofosbuvir and ribavirin (207 patients) or Secours Health System, Newport News matching placebo (71) for 12 weeks. In a second trial, patients who had not had a (M.L.S.); Texas Liver Institute, University of Texas Health Science Center, San An- response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks tonio (E.L.), and Texas Digestive Disease (103 patients) or 16 weeks (98). The primary end point was a sustained virologic Consultants, Arlington (M.T.A.-A.); Uni- versity of Colorado Denver, Aurora (G.E.); response at 12 weeks after therapy. Medical Associates Research Group, San RESULTS Diego (M.B.), and Gilead Sciences, Fos- Among patients for whom treatment with peginterferon was not an option, the rate ter City (G.M.S., D.A., M.L., J.M., D.B., W.T.S., J.G.M.) — both in California; Cen- of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) ter for Liver Diseases, School of Medi- with sofosbuvir and ribavirin, as compared with 0% with placebo (P<0.001). Among cine, University of Miami, Miami (E.S.), previously treated patients, the rate of response was 50% with 12 weeks of treat­ and University of Florida, Gainesville (D.R.N.); Duke University, Durham, NC ment, as compared with 73% with 16 weeks of treatment (difference, −23 percent­ (K.P.); and Monash Medical Centre and age points; 95% CI, −35 to −11; P<0.001). In both studies, response rates were Monash University, Melbourne, VIC, Aus- tralia (S.P.). Address reprint requests to lower among patients with genotype 3 infection than among those with genotype Dr. Jacobson at Weill Cornell Medical Col- 2 infection and, among patients with genotype 3 infection, lower among those with lege and the Center for the Study of Hepati- cirrhosis than among those without cirrhosis. The most common adverse events tis C, 1305 York Ave., New York, NY 10021, or at [email protected]; or to were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation Dr. Nelson at the University of Florida, of sofosbuvir was low (1 to 2%). 1600 SW Archer Rd., P.O. Box 100214, CONCLUSIONS Gainesville, FL 32610, or at david.nelson@ medicine.ufl.edu. In patients with HCV genotype 2 or 3 infection for whom treatment with peginter­ Drs. Jacobson and Nelson contributed feron and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbu­ equally to this article. vir and ribavirin was effective. Efficacy was increased among patients with HCV This article was published on April 23, genotype 2 infection and those without cirrhosis. In previously treated patients with 2013, at NEJM.org. genotype 3 infection, 16 weeks of therapy was significantly more effective than N Engl J Med 2013. 12 weeks. (Funded by Gilead Sciences; POSITRON and FUSION ClinicalTrials.gov DOI: 10.1056/NEJMoa1214854 numbers, NCT01542788 and NCT01604850, respectively.) Copyright © 2013 Massachusetts Medical Society. n engl j med nejm.org 1 The New England Journal of Medicine Downloaded from nejm.org by JULES LEVIN on April 24, 2013. For personal use only. No other uses without permission. Copyright © 2013 Massachusetts Medical Society. All rights reserved. T h e new england journal o f medicine hen studied in clinical trials, METHODS the current standard­of­care therapy for Wpatients with hepatitis C virus (HCV) STUDY DESIGNS AND PATIENTS genotype 2 or 3 infection — pegylated interferon We conducted two multicenter, randomized trials in combination with ribavirin for 24 weeks — to assess the efficacy and safety of sofosbuvir resulted in a sustained virologic response in 70 to administered with ribavirin in patients chroni­ 85% of patients who had not received prior cally infected with HCV genotype 2 or 3. In both treatment and in 55 to 60% of those who had studies, patients received sofosbuvir (Gilead Sci­ received treatment.1-4 However, a substantial pro­ ences) and ribavirin (Ribasphere, Kadmon) or portion of patients with HCV infection remain matching placebo. Sofosbuvir was administered untreated owing to absolute or relative contra­ orally at a dose of 400 mg once daily. Ribavirin indications to interferon therapy, such as hepatic was administered orally twice daily, with doses decompensation, autoimmune disease, and psy­ determined according to body weight (1000 mg chiatric illness.5 In addition, interferon causes a daily in patients with a body weight of <75 kg, range of constitutional symptoms or hematologic and 1200 mg daily in patients with a body weight abnormalities that may require discontinuation of ≥75 kg). of therapy in a considerable number of patients.6 The POSITRON trial was a blinded, placebo­ Some patients decide against interferon therapy controlled study that compared 12 weeks of treat­ for a variety of reasons, including aversion to in­ ment with sofosbuvir and ribavirin with match­ jections and anxiety about the adverse events as­ ing placebo in patients who had previously sociated with treatment. Moreover, the 15 to 30% discontinued interferon therapy owing to unac­ of patients with HCV genotype 2 or 3 infection ceptable adverse events, who had a concurrent who do not have a response to interferon therapy medical condition precluding therapy with an have no alternate therapeutic options. These interferon­containing regimen, or who had de­ populations — which by one estimate constitute cided against treatment with an interferon­con­ the majority of patients infected with HCV 5 — taining regimen (see the Supplementary Appen­ are in need of effective treatments. dix, available with the full text of this article at Sofosbuvir is an oral nucleotide analogue in­ NEJM.org, for further details). Prior treatment hibitor of the HCV­specific NS5B polymerase with failure with an interferon­based regimen was in vitro activity against all HCV genotypes.7 In a not a reason for exclusion. Approximately 20% phase 2 study of treatment for 12 weeks with of patients enrolled could have evidence of com­ sofosbuvir and ribavirin in patients with HCV pensated cirrhosis at screening. genotype 2 or 3 infection, 10 of 10 previously Patients were enrolled at 63 sites in the United untreated patients (100%) and 17 of 25 previously States, Canada, Australia, and New Zealand from treated patients (68%) had a sustained virologic March 2012 through May 2012. Randomization response.8,9 This oral regimen had an acceptable was performed centrally in a 3:1 ratio with safety profile, with no premature discontinua­ stratification according to the presence or ab­ tions of sofosbuvir therapy owing to adverse sence of cirrhosis. events.9 The FUSION study was a blinded, active­con­ In this article, we present the results of two trol study involving patients who had not had a phase 3 trials of treatment with sofosbuvir and response to prior treatment with an interferon­ ribavirin in patients with HCV genotype 2 or 3 containing regimen. Approximately 30% of the infection for whom treatment with peginterfer­ patients enrolled could have evidence of com­ on was not an option and in those who did not pensated cirrhosis at screening. have a response to prior interferon treatment. The Patients were enrolled at 67 sites in the United primary objective of both studies was to evaluate States, Canada, and New Zealand from May the efficacy of sofosbuvir and ribavirin, as mea­ 2012 through July 2012. Patients were randomly sured by the proportion of patients with a sus­ assigned in a 1:1 ratio to one of two treatment tained virologic response at 12 weeks after the groups: 12 weeks of sofosbuvir and ribavirin, end of treatment, and to evaluate the safety of followed by 4 weeks of matching placebo, or this regimen. 16 weeks of sofosbuvir and ribavirin. Random­ 2 n engl j med nejm.org The New England Journal of Medicine Downloaded from nejm.org by JULES LEVIN on April 24, 2013. For personal use only.
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