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Sofosbuvir for the Treatment of Genotype 1 Hepatitis C in Subjects Aged 65 Years Or Older

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Sofosbuvir for the Treatment of Genotype 1 Hepatitis C in Subjects Aged 65 Years Or Older AMERICAN ASSOCIATION FOR THE STUDY OFLIVERD I S E ASES HEPATOLOGY, VOL. 63, NO. 4, 2016 Safety and Efficacy of Ledipasvir/ Sofosbuvir for the Treatment of Genotype 1 Hepatitis C in Subjects Aged 65 Years or Older Sammy Saab,1 Sarah H. Park,1 Masashi Mizokami,2 Masao Omata,3 Alessandra Mangia,4 Ed Eggleton,5 Yanni Zhu,5 Steven J. Knox,5 Phil Pang,5 Mani Subramanian,5 Kris Kowdley,6 and Nezam H. Afdhal7 Elderly subjects have been historically underrepresented in clinical trials involving antiviral hepatitis C therapies. The aim of this analysis was to retrospectively evaluate the safety and efficacy of ledipasvir/sofosbuvir (LDV/SOF) by age groups of <65 years versus 65 years among subjects enrolled in phase 3 trials. Four open-label phase 3 clinical trials evaluated the safety and efficacy of LDV/SOF with or without ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C virus. Sustained virological response at 12 weeks, treatment-emergent adverse events (AEs), and graded laboratory abnor- malities were analyzed according to age group. Of the 2293 subjects enrolled in four phase 3 trials, 264 (12%) were 65 years of age, of whom 24 were aged 75 years. Sustained virological response at 12 weeks was achieved by 97% (1965/ 2029) of subjects aged <65 years and 98% (258/264) of subjects aged 65 years. The most common AEs in both LDV/ SOF groups that occurred in 10% of subjects were headache and fatigue. The rate of study discontinuation due to AEs was similar in the two age cohorts. The use of RBV in 1042 (45%) subjects increased the number of AEs, treatment- related AEs, and AEs leading to study drug modification/interruption, particularly among elderly subjects. Conclusions: LDV/SOF with or without RBV was highly effective for treatment of genotype 1 chronic hepatitis C virusin subjects aged 65 and older. Addition of RBV did not increase sustained virological response at 12 weeks rates but led to higher rates of AEs, especially in elderly subjects. (HEPATOLOGY 2016;63:1112-1119) hronic hepatitis C viral (HCV) infection is an million people.(2) Globally, HCV accounts for 27% of important cause of morbidity and mortality in liver cirrhosis and 25% of hepatocellular carcinoma infected individuals worldwide.(1) The World cases.(3) Although the rate of HCV is decreasing over- C (4,5) Health Organization estimates that the worldwide all due to attrition from mortality, the rate of prevalence of HCV infection is 2.2%, representing 123 HCV-related cirrhosis is anticipated to increase by Abbreviations: AE, adverse event; CI, confidence interval; eGFR, estimated glomerular filtration rate; HCV, hepatitis C virus; LDV/SOF, ledipas- vir/sofosbuvir; RAV, resistance-associated variant; RBV, ribavirin; SVR12, sustained virological response at 12 weeks Received November 5, 2015; accepted December 21, 2015. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.28425/suppinfo. Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.28425 Potential conflict of interest: Dr. Omata advises and received grants from Gilead. Dr. Mizokami advises and received grants from Gilead. Dr. Saab consults, advises, is on the speakers’ bureau, and owns stock in Gilead, AbbVie, and Bristol-Myers Squibb. He consults and advises Merck. Dr. Kowdley consults, advises, and received grants from AbbVie and Gilead. He advises and received grants from Evidera and Trio. He advises Achillion, Bristol-Myers Squibb, Enanta, Merck, and Novartis. He received grants from Immuron, Intercept, NGM, and Tobira. Dr. Mangia consults and is on the speakers’ bureau for Gilead, Bristol-Myers Squibb, and MSD. Dr. Afdhal consults, advises, and received grants from Gilead and AbbVie. He consults, advises, is employed by, and owns stock in Springbank. He consults and advises Merck, Echosens, GlaxoSmithKline, Ligand, Janssen, Achillion, Sandhill, Roivant, Co-Crystal, and Shionogi. He received grants from Bristol-Myers Squibb. Dr. Subramanian is employed by and owns stock in Gilead. Mr. Eggleton is employed by and owns stock in Gilead. Mr. Knox is employed by and owns stock in Gilead. Dr. Zhu is employed by and owns stock in Gilead. Dr. Pang owns stock in Gilead. 1112 HEPATOLOGY, Vol. 63, No. 4, 2016 SAAB ET AL. nearly two-fold between 2000 and 2030, from 472,000 coinfection, and immunosuppressed liver transplant to more than 879,000 based on estimates from US recipients who historically have lower sustained viro- population data.(6) At present, the estimated preva- logical response than the general population.(29-32) lence of HCV in the United States and Western Given the aging population of patients with HCV Europe is 0.2%-0.5% and that in Japan is 1%-3%.(7,8) and the increased efficacy of LDV/SOF over prior The elderly population is disproportionately affected antiviral therapeutic regimens, we compared the effi- by HCV. Approximately 70% of all patients with hep- cacy, safety, and tolerability of this combination atitis C in the United States and western Europe were between subjects below and above 65 years of age. born between the years 1945 and 1965.(9) In the United States, it is estimated that between 20% and 25% of patients with HCV have cirrhosis. Patients Patients and Methods with HCV-associated liver disease make up approxi- mately 40% of liver transplantation candidates, with a PATIENTS median age of 51 years at the time of registration.(10,11) Efficacy and safety data were pooled from four In Europe and Japan, HCV is identified as one of the randomized, open-label phase 3 clinical trials (ION-1, most common causes of chronic liver disease, and its ION-2, ION-3, and GS-US-337-0113) evaluating prevalence in the population aged 61-70 years has been (12-15) LDV/SOF (90 mg/400 mg) in genotype 1 HCV- up to 12%. Antiviral therapy with interferon- based therapy has been demonstrated to improve infected subjects in the United States, Europe, and patient survival and reduce the likelihood of liver- Japan. Eligible subjects were at least 18 years old with (16-18) chronic genotype 1 HCV infection and a baseline related complications. Historically, age has been 4 a major limitation of antiviral treatment with HCV RNA 10 IU/mL at screening. Both interferon-based therapy because of its poor tolerabil- treatment-naive and treatment-experienced subjects ity, adverse effects (AEs), and poorer response in older with or without cirrhosis were enrolled and included in patients.(19-25) There is a lack of efficacy and safety this pooled analysis. Details concerning the eligibility information on HCV therapy in older patients, pri- criteria for these studies are included in the supporting marily due to underreporting and the exclusion of appendix of the respective studies. Subjects were classi- elderly subjects from clinical trials.(26,27) fied as having cirrhosis if liver biopsy showed cirrhosis The combination of ledipasvir, an NS5A inhibitor, (METAVIR score 4 or Ishak score 5), if FibroScan and sofosbuvir, a nucleotide polymerase inhibitor, has indicated cirrhosis (value >12.5 kPa), or if laboratory been approved by the US Food and Drug Administra- biomarkers indicated cirrhosis (FibroTest score >0.75 tion, the European Medicines Agency, and in Japan as and aspartate aminotransferase to platelet ratio index a fixed-dose combination tablet for the treatment of >2). Deep sequencing of the NS5A and NS5B regions HCV genotype 1.(28) Ledipasvir/sofosbuvir (LDV/ was conducted at baseline and at the time of failure for SOF) has been found to be effective against a variety all subjects who had virological failure. of HCV clinical scenarios including special popula- The ION-1 study (United States and European tions such as those with compensated and decompen- Union) enrolled 865 treatment-naive subjects, and sated cirrhosis, HCV/human immunodeficiency virus 16% of subjects had cirrhosis at the time of the ARTICLE INFORMATION: From the 1University of California Los Angeles, Los Angeles, CA; 2National Center for Global Health and Medicine, Tokyo, Japan; 3Yamanashi Prefectural Hospital Organization, Yamanashi, Japan; 4Liver Unit, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy; 5Gilead Sciences, Foster City, CA; 6Swedish Medical Center, Seattle, WA; 7Beth Israel Deaconess Medical Center, Boston, MA. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Sammy Saab, M.D., M.P.H., A.G.A.F., F.A.A.S.L.D., F.A.C.G. E-mail: [email protected] Pfleger Liver Institute, UCLA Medical Center Tel: 11-310 206 6705 200 Medical Plaza, Suite 214, Los Angeles, CA 90095. Fax: 11-310-206-4197. 1113 aged treatment. A subgroup analysisout was done for ribavirin, subjects receiving 8, 12, or 24 weeks of had cirrhosis at the time440 of treatment-experienced the study. subjects, 20% of whom 1114 BASELINE CHARACTERISTICS Results STATISTICAL ANALYSIS study. SAAB ET AL. jects age (RBV; two divided doses) foronce 8, 12, daily or 24 weeks. with(90 mg/400 or mg) fixed-dose without combination tablet orally, weight-based ribavirin subject population bycacy age analysis, at pooled data baselineenrolled were ( and analyzed treated for the subjects. total In this combined effi- sis. experienced subjects, andenrolled 22% of them 341 had cirrho- treatment-naive and treatment- four studies, of whom 2029 (88%) were subjects without cirrhosis. study (United States) enrolled 647 treatment-naive was made if the hemoglobinuse/support-documentation was ities, Version 17.0 ( using the Medicalduration Dictionary (8, for 12, Regulatory and Activ- 24 weeks). All AEs were coded SOF risk difference of experiencing anused AE to between calculate LDV/ the two-sidedeach 95% age CI of group, theabnormalities overall the were Mantel-Haenszelcent method summarized was of descriptively.group. subjects In For the safety experiencing analysis,after the treatment number AEs completion and (SVR12) the or rate per- lated for for each laboratory the age sustainedbased virological on response the 12the weeks Clopper-Pearson two-sided method were 95%quantification calcu- of exact 25 IU/mL.
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