Mark S Sulkowski1, Juhi S Moon1, Kenneth E Sherman2, Giuseppe Morelli3, Jama M Darling4, Andrew J Muir5, Mandana Khalili6, Dawn A Fishbein7, Federico Hinestrosa8, Mitchell L Shiffman9, Adrian Di Bisceglie10, K Rajender Reddy11, Brian Pearlman12, Anna S Lok13, Michael W Fried4, Paul W Stewart14, Joy Peter3, Summer Wadsworth15, Scott Kixmiller16, Anquenette Sloan17, Monika Vainorius4, Patrick M Horne3, Larry Michael14, Meichen Dong14, Donna M Evon4, Jodi B Segal18, David R Nelson3. 1. Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD. 2. Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH. 3. Department of Gastroenterology, Hepatology & Nutrition, University of Florida, Gainesville, FL. 4. Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC. 5. Division of Gastroenterology, Duke University, Durham, NC. 6. Department of Medicine, University of California San Francisco, Zuckerberg San Francisco General, Hospital and Trauma Center, San Francisco, CA. 7. Infectious Disease, Medstar Health Research Institute, Washington, DC. 8. Infectious Disease, Orlando Immunology Center, Orlando, FL. 9. Department of Gastroenterology, Liver Institute of Virginia, Richmond, VA. 10. Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO. 11. Department of Medicine, University of Pennsylvania, Philadelphia, PA. 12. Department of Internal Medicine, Wellstar Health System, Atlanta, GA. 13. Department of Internal Medicine, University of Michigan, Ann Arbor, MI. 14. Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC. 15. PRIORITIZE Patient Engagement Group consultant, Garner, NC. 16. PRIORITIZE Patient Engagement Group consultant, Greensboro, NC. 17. PRIORITIZE Patient Engagement Group consultant, Pittsboro, NC. 18. Division of Internal Medicne, Johns Hopkins University School of Medicine, Baltimore, MD.
Abstract
BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.
BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.
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