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Title: Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study

In order to shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor–NS5B nucleotide analogue. In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNA <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. Furthermore, the primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. Between April 5, 2015, and April 15,more » 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). There were no patients who experienced any serious adverse events. In this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings.« less
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [3] ;  [3] ;  [3] ;  [3] ;  [3] ;  [5] ;  [5] ;  [6] ;  [7] ;  [7] ;  [7] ;  [8] ;  [8] ;  [7] ;  [9] ;  [9] more »;  [9] ;  [9] ;  [10] ;  [11] ;  [9] « less
  1. Humany and Helath Medical Centre, Hong Kong (China); Second Liver Cirrhosis Diagnosis and Treatment Center, Beijing (China)
  2. Pitie-Salpetriere Hospital Univ. Hospital, Paris (France)
  3. Second Liver Cirrhosis Diagnosis and Treatment Center, Beijing (China)
  4. Inst. of Infectious Disease, Beijing (China)
  5. Southern Medical Univ., Guangzhou (China). Dept. of Infectious Disease
  6. Humany and Helath Medical Centre, Hong Kong (China); Southern Medical Univ., Guangzhou (China). Dept. of Infectious Disease
  7. Humany and Helath Medical Centre, Hong Kong (China)
  8. Hong Kong Molecular Pathology Diagnostic Centre, Hong Kong (China)
  9. Emory Univ. School of Medicine, Atlanta, GA (United States). Center for AIDS Research
  10. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics; North Carolina State Univ., Raleigh, NC (United States). Dept. of Mathematics
  11. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics
Publication Date:
Report Number(s):
LA-UR-17-20260; LA-UR-15-28932
Journal ID: ISSN 2468-1253
Grant/Contract Number:
AC52-06NA25396; 5P30-AI-50409; R01-AI028433; R01-AI078881; R01-OD011095
Type:
Accepted Manuscript
Journal Name:
The Lancet Gastroenterology & Hepatology
Additional Journal Information:
Journal Volume: 1; Journal Issue: 2; Journal ID: ISSN 2468-1253
Publisher:
Elsevier
Research Org:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science
OSTI Identifier:
1360712
Alternate Identifier(s):
OSTI ID: 1364534

Lau, George, Benhamou, Yves, Chen, Guofeng, Li, Jin, Shao, Qing, Ji, Dong, Li, Fan, Li, Bing, Liu, Jialiang, Hou, Jinlin, Sun, Jian, Wang, Cheng, Chen, Jing, Wu, Vanessa, Wong, April, Wong, Chris L. P., Tsang, Stella T. Y., Wang, Yudong, Bassit, Leda, Tao, Sijia, Jiang, Yong, Hsiao, Hui-Mien, Ke, Ruian, Perelson, Alan S., and Schinazi, Raymond F.. Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study. United States: N. p., Web. doi:10.1016/S2468-1253(16)30015-2.
Lau, George, Benhamou, Yves, Chen, Guofeng, Li, Jin, Shao, Qing, Ji, Dong, Li, Fan, Li, Bing, Liu, Jialiang, Hou, Jinlin, Sun, Jian, Wang, Cheng, Chen, Jing, Wu, Vanessa, Wong, April, Wong, Chris L. P., Tsang, Stella T. Y., Wang, Yudong, Bassit, Leda, Tao, Sijia, Jiang, Yong, Hsiao, Hui-Mien, Ke, Ruian, Perelson, Alan S., & Schinazi, Raymond F.. Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study. United States. doi:10.1016/S2468-1253(16)30015-2.
Lau, George, Benhamou, Yves, Chen, Guofeng, Li, Jin, Shao, Qing, Ji, Dong, Li, Fan, Li, Bing, Liu, Jialiang, Hou, Jinlin, Sun, Jian, Wang, Cheng, Chen, Jing, Wu, Vanessa, Wong, April, Wong, Chris L. P., Tsang, Stella T. Y., Wang, Yudong, Bassit, Leda, Tao, Sijia, Jiang, Yong, Hsiao, Hui-Mien, Ke, Ruian, Perelson, Alan S., and Schinazi, Raymond F.. 2016. "Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study". United States. doi:10.1016/S2468-1253(16)30015-2. https://www.osti.gov/servlets/purl/1360712.
@article{osti_1360712,
title = {Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study},
author = {Lau, George and Benhamou, Yves and Chen, Guofeng and Li, Jin and Shao, Qing and Ji, Dong and Li, Fan and Li, Bing and Liu, Jialiang and Hou, Jinlin and Sun, Jian and Wang, Cheng and Chen, Jing and Wu, Vanessa and Wong, April and Wong, Chris L. P. and Tsang, Stella T. Y. and Wang, Yudong and Bassit, Leda and Tao, Sijia and Jiang, Yong and Hsiao, Hui-Mien and Ke, Ruian and Perelson, Alan S. and Schinazi, Raymond F.},
abstractNote = {In order to shorten the course of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, we examined the antiviral efficacy and safety of 3 weeks of response-guided therapy with an NS3 protease inhibitor and dual NS5A inhibitor–NS5B nucleotide analogue. In this open-label, phase 2a, single centre study, Chinese patients with chronic HCV genotype 1b infection without cirrhosis were randomly allocated by a computer program to one of three treatment groups (sofosbuvir, ledipasvir, and asunaprevir; sofosbuvir, daclatasvir, and simeprevir; or sofosbuvir, daclatasvir, and asunaprevir) until six patients in each group (1:1:1) achieved an ultrarapid virological response (plasma HCV RNA <500 IU/mL by day 2, measured by COBAS TaqMan HCV test, version 2.0). Patients with an ultrarapid virological response received 3 weeks of therapy. Patients who did not achieve an ultrarapid response were switched to sofosbuvir and ledipasvir for either 8 weeks or 12 weeks. Furthermore, the primary endpoint was the proportion of patients with a sustained virological response at 12 weeks (SVR12) after treatment completion, analysed in the intention-to-treat population. All patients who achieved an ultrarapid virological response were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02470858. Between April 5, 2015, and April 15, 2015, 26 eligible patients were recruited. 12 patients were assigned to sofosbuvir, ledipasvir, and asunaprevir; six to sofosbuvir, daclatasvir, and simeprevir; and eight to sofosbuvir, daclatasvir, and asunaprevir. Six patients in each group achieved an ultrarapid virological response (18 [69%]). All patients with an ultrarapid virological response who were given 3 weeks of triple therapy achieved SVR12. The most common adverse events were fatigue (one [17%] of six patients receiving sofosbuvir, ledipasvir, and asunaprevir; one [17%] of six patients receiving sofosbuvir, daclatasvir, and simeprevir; and two [33%] of six patients receiving sofosbuvir, daclatasvir, and asunaprevir) and headache (one [17%] patient in each group). There were no patients who experienced any serious adverse events. In this proof-of-concept study, all patients with chronic HCV without cirrhosis who achieved an ultrarapid virological response on triple direct-acting antiviral regimens by day 2 and received 3 weeks of treatment were cured, with excellent tolerability. By shortening the duration of therapy from the currently recommended 12 weeks to 3 weeks, we could drastically reduce the cost of therapy and the rate of adverse events. Further large-scale studies should be done to confirm our findings.},
doi = {10.1016/S2468-1253(16)30015-2},
journal = {The Lancet Gastroenterology & Hepatology},
number = 2,
volume = 1,
place = {United States},
year = {2016},
month = {7}
}