S Fourati1,2, J Guedj3,4, S Chevaliez1,2, T H T Nguyen3, F Roudot-Thoraval5, I Ruiz2,6, A Soulier1,2, G Scoazec6, A Varaut6, L Poiteau1,2, M Francois6, A Mallat6, C Hézode6, J-M Pawlotsky1,2. 1. Department of Virology, Henri Mondor Hospital, National Reference Center for Viral Hepatitis B, C and D, University of Paris-Est, Créteil, France. 2. INSERM U955, Créteil, France. 3. INSERM U1137, IAME, Paris, France. 4. Université Paris Diderot, Sorbonne Paris Cité, Paris, France. 5. Department of Public Health, Henri Mondor Hospital, University of Paris-Est, Créteil, France. 6. Department of Hepatology, Henri Mondor Hospital, University of Paris-Est, Créteil, France.
Abstract
BACKGROUND: The combination of sofosbuvir (SOF) plus an NS5A inhibitor for 12 weeks is highly efficacious in patients with chronic hepatitis C. As the costs of generic production of sofosbuvir and NS5A inhibitor are rapidly decreasing, the combination of these DAAs will be the standard treatment in most low- to middle-income countries in the future. AIM: To identify key predictors of response that can be used to tailor treatment decisions. METHODS: A cohort of 216 consecutive patients infected with HCV genotype 1 (1a: n = 57; 1b: n = 77), 2 (n = 4), 3 (n = 33) or 4 (n = 44) were treated with sofosbuvir (SOF) + daclatasvir (n = 176) or SOF + ledipasvir (n = 40) for 12 weeks. The viral kinetics was analysed using the biphasic model and the cure boundary was used to predict time to clear HCV. RESULTS: The overall SVR rate was high (94.4%; n = 204), regardless of the time to viral suppression or low-level viraemia at the end of treatment. The model-based predicted HCV RNA levels at the end of treatment could not differentiate patients who did from those who did not achieve SVR. The presence of NS5A resistance-associated substitutions [position 28 (OR = 70.3, P<.001) and/or 31 (OR = 61.6, P = .002)] at baseline was predictive of virological failure in cirrhotic patients but was not associated with on-treatment viral kinetics. CONCLUSION: This real-world study confirms the excellent results of clinical trials with therapies based on a combination of SOF plus an NS5A inhibitor. It suggests that a personalized approach including baseline NS5A inhibitor resistance testing may inform treatment decisions in cirrhotic patients.
BACKGROUND: The combination of sofosbuvir (SOF) plus an NS5A inhibitor for 12 weeks is highly efficacious in patients with chronic hepatitis C. As the costs of generic production of sofosbuvir and NS5A inhibitor are rapidly decreasing, the combination of these DAAs will be the standard treatment in most low- to middle-income countries in the future. AIM: To identify key predictors of response that can be used to tailor treatment decisions. METHODS: A cohort of 216 consecutive patients infected with HCV genotype 1 (1a: n = 57; 1b: n = 77), 2 (n = 4), 3 (n = 33) or 4 (n = 44) were treated with sofosbuvir (SOF) + daclatasvir (n = 176) or SOF + ledipasvir (n = 40) for 12 weeks. The viral kinetics was analysed using the biphasic model and the cure boundary was used to predict time to clear HCV. RESULTS: The overall SVR rate was high (94.4%; n = 204), regardless of the time to viral suppression or low-level viraemia at the end of treatment. The model-based predicted HCV RNA levels at the end of treatment could not differentiate patients who did from those who did not achieve SVR. The presence of NS5A resistance-associated substitutions [position 28 (OR = 70.3, P<.001) and/or 31 (OR = 61.6, P = .002)] at baseline was predictive of virological failure in cirrhotic patients but was not associated with on-treatment viral kinetics. CONCLUSION: This real-world study confirms the excellent results of clinical trials with therapies based on a combination of SOF plus an NS5A inhibitor. It suggests that a personalized approach including baseline NS5A inhibitor resistance testing may inform treatment decisions in cirrhotic patients.
Authors: Ernest Asante-Appiah; Rong Liu; Stephanie Curry; Patricia McMonagle; Sony Agrawal; Donna Carr; Laura Rokosz; Frederick Lahser; Karin Bystol; Robert Chase; Stuart Black; Eric Ferrari; Paul Ingravallo; Ling Tong; Wensheng Yu; Joseph Kozlowski Journal: Antimicrob Agents Chemother Date: 2018-10-24 Impact factor: 5.191