This trial was supported by Gilead Sciences, Inc.
All-oral combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naïve patients with genotype 1 HCV infection
Article first published online: 28 MAY 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 60, Issue 1, pages 56–64, July 2014
How to Cite
Wyles, D. L., Rodriguez-Torres, M., Lawitz, E., Shiffman, M. L., Pol, S., Herring, R. W., Massetto, B., Kanwar, B., Trenkle, J. D., Pang, P. S., Zhu, Y., Mo, H., Brainard, D. M., Subramanian, G. M., McHutchison, J. G., Habersetzer, F. and Sulkowski, M. S. (2014), All-oral combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naïve patients with genotype 1 HCV infection. Hepatology, 60: 56–64. doi: 10.1002/hep.27053
Potential conflict of interest: Dr. Herring received grants from Gilead. Dr. Pol consults for and received grants and lecture fees from Bristol-Myers Squibb, Gilead, Roche, and MSD. He consults for and received lecture fees from Boehringer Ingelheim, Tibotec, Vertex, Novartis, Abbott/AbbVie, Sanofi, and GlaxoSmithKline. Dr. Rodriguez-Torres consults for and received grants from Akros, Bristol-Myers Squibb, Genentech, Hoffman-La Roche, Inhibitex, Merck, Pharmasset, Santaris, and Vertex. She consults for Janssen. She received grants from Abbott, Anadys, Beckman, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Human Genome Sciences, Idenix, Idera, Johnson & Johnson, Mochida, Novartis, Pfizer, Scynexis, Siemens, and Zymogenetics. Dr. Pang owns stock in and is employed by Gilead. Dr. McHutchison owns stock in and is employed by Gilead. Dr. Brainard owns stock in and is employed by Gilead. Dr. Trenkle owns stock in and is employed by Gilead. Dr. Subramanian owns stock in and is employed by Gilead. Dr. Massetto owns stock in and is employed by Gilead. Dr. Mo is employed by Gilead. Dr. Shiffman advises, is on the speakers' bureau for, and received grants from Gilead, Merck, and Roche/Genentech. He advises, consults for, and is on the speakers' bureau for Janssen. He advises and received grants from Achillion, Bristol-Myers Squibb, Boehringer Ingelheim, Globeimmune, and Novartis. He advises and is on the speakers' bureau for Bayer, Salix, and Vertex. He advises and consults for Gen-Probe and GlaxoSmithKline. He received grants from AbbVie, Beckman-Colter, Idenix, Intercept, Lumena, and Mochida. Dr. Lawitz advises, is on the speakers' bureau for, and received grants from Merck and Vertex. He is on the speakers' bureau for and received grants from Gilead and GlaxoSmithKline. He advises and received grants from AbbVie, Achillion, Idenix, Janssen, Novartis, and Santaris. He advises BioCryst, Biotica, Enanta, and Theravance. He is on the speakers' bureau for Kadmon. He received grants from Boehringer Ingelheim, Bristol-Myers Squibb, Intercept, Medtronic, Presidio, and Roche. Dr. Wyles consults for and received grants from Gilead, AbbVie, and Bristol-Myers Squibb. He received grants from Vertex and Janssen. Dr. Habersetzer consults for and advises Gilead. He consults for Transgene and Boehringer Ingelheim. Dr. Zhu is employed by and owns stock in Gilead. Dr. Kanwar is employed by and owns stock in Gilead. Dr. Sulkowski consults for and received grants from Gilead, Merck, AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Vertex, and Idenix. He consults for Pfizer.
- Issue published online: 26 JUN 2014
- Article first published online: 28 MAY 2014
- Accepted manuscript online: 5 FEB 2014 10:25AM EST
- Manuscript Accepted: 31 JAN 2014
- Manuscript Received: 12 DEC 2013
This phase II trial assessed the efficacy and safety of a combination regimen of the nonstructural protein (NS)5A inhibitor ledipasvir (LDV), NS3 protease inhibitor vedroprevir (VDV), non-nucleoside NS5B inhibitor tegobuvir (TGV), and ribavirin (RBV) in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype 1 without cirrhosis. Patients were randomized 1:2 to LDV 30 mg once daily (QD; Arm 1; n = 46) or LDV 90 mg QD (Arm 2; n = 94); patients in both arms also received VDV 200 mg QD, TGV 30 mg twice-daily, and RBV 1,000-1,200 mg/day. Patients in Arm 2 with vRVR, defined as HCV RNA below the lower limit of quantification (LLOQ) from treatment weeks 2 to 10, were randomized 1:1 to stop treatment at 12 weeks or continue for 24 weeks. Sustained virologic response 12 weeks after treatment (SVR12) was higher in patients receiving 90 mg of LDV for 24 weeks (63%), compared with LDV 90 mg for 12 weeks (54%) and LDV 30 mg for 24 weeks (48%). In patients with very rapid virologic response (vRVR) in Arm 2, SVR12 was achieved by 68% and 81% of patients treated for 12 and 24 weeks, respectively. Virologic breakthrough was more common in patients with HCV genotype 1a and was associated with resistance-associated variants for all three direct-acting antiviral agents (DAAs); however, in all but 1 patient who relapsed, resistance-associated variants directed against only one or two of the DAAs were detected. The most common adverse events were fatigue, headache, nausea, rash, and diarrhea. Conclusion: In patients with HCV genotype 1, an interferon-free regimen containing LDV/VDV/TGV/RBV was well tolerated and led to SVR12 in up to 63% of patients. LDV 90 mg is currently being investigated in combination with the nucleotide polymerase inhibitor, sofosbuvir. (Hepatology 2014;60:56–64)