TY - JOUR
T1 - Twice-daily telaprevir for posttransplant genotype 1 hepatitis C virus
T2 - A prospective safety, efficacy, and pharmacokinetics study
AU - Rubin, Raymond A.
AU - Russo, Mark W.
AU - Brown, Kimberly A.
AU - Fontana, Robert J.
AU - Levitsky, Josh
AU - Vargas, Hugo
AU - Yoshida, Eric M.
AU - Brown, Robert S.
N1 - Funding Information:
From the 1Piedmont Transplant Institute, Piedmont Hospital, Atlanta, Georgia; the 2Division of Hepatology, Carolinas HealthCare System, Charlotte, North Carolina; the 3Division of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan; the 4Department of Internal Medicine, University of Michigan Health Systems, Ann Arbor, Michigan; the 5Department of Medicine and Surgery, Northwestern University, Chicago, Illinois; the 6Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, USA; the 7Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia, Canada; and the 8Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York, USA Acknowledgements: The authors thank the coordinators, patients, and site investigators involved in the study; Mohammad Bsharat, PhD (biostatistics); Varun Garg, PhD (pharmacokinetics); Kristy Grimm, PharmD (logistics); and Dr. Zachary Goodman (pathology). RA Rubin and RS Brown designed the research; MW Russo, KA Brown, RJ Fontana, J Levitsky, H Vargas, EM Yoshida, and RS Brown RS performed the clinical trial; all authors analyzed the data and contributed to writing the paper. The protocol was designed in collaboration with the principal investigators (RAR, RSB) who had unrestricted access to the data and wrote the manuscript. All coauthors reviewed and approved the final manuscript and assume responsibility for data accuracy and completeness. The work was supported by Vertex Pharmaceuticals (Boston, MA, 02110, USA). RA Rubin was employed by Vertex Pharmaceuticals during a portion of the study and has provided consulting services for Vertex. MW Russo served on Speakers Bureaus for Vertex. KA Brown, J Levitsky, and RS Brown served on Advisory Boards and Speakers Bureaus for Vertex. R Fontana, H Vargas, and E Yoshida had no conflict of interest to disclose. Telaprevir is no longer commercially available in North America, and Vertex no longer licenses telaprevir anywhere. The authors had full control over the content of the manuscript. Corresponding author: Raymond A. Rubin, Piedmont Transplant Institute, 1968 Peachtree Road, NW, 5th floor, 77 Building, Atlanta, GA 30309, USA Phone: +1 888 605 5888 E-mail: raymond.rubin@piedmont.org
Publisher Copyright:
© Başkent University 2018.
PY - 2018/4
Y1 - 2018/4
N2 - Objectives: Our objective was to determine the safety, efficacy, and pharmacokinetics of telaprevir plus pegylated interferon alfa 2a and ribavirin for chronic, posttransplant genotype 1 hepatitis C virus infection. Materials and Methods: A prospective, single-arm, multicenter, open-label, phase 2b study was conducted at 22 North American sites to assess the safety, efficacy, and pharmacokinetics of pegylated interferon alfa 2a, ribavirin, and twice daily telaprevir in liver transplant recipients with recurrent, chronic hepatitis C without cirrhosis. Baseline liver biopsies were read by a central pathologist. There were planned safety reviews after a sentinel cohort reached treatment weeks 4 and 16. Serial pharmacokinetic sampling was performed for calcineurin inhibitors, telaprevir, and ribavirin. Results: Sixty-one patients were enrolled and received ≥ 1 dose of study medication; 37 (61%) achieved sustained virologic response. Thirteen of 18 treatment-naive patients (72%), 10 of 11 patients with no or minimal fibrosis (91%), 13 of 15 patients (87%) with interleukin 28B genotype CC, and 36 of 45 patients (80%) with either undetectable or unquantifiable hepatitis C virus RNA at treatment week 4 achieved sustained virologic response. Nine patients (15%) had ≥ 1 drug-related serious adverse event and 7 (11%) discontinued all study drugs due to an adverse event. There were no deaths or acute cellular rejection episodes. During telaprevir treatment, median doses of tacrolimus and cyclosporine were 0.5 mg weekly and 25 mg daily. Target exposures were achieved for telaprevir with twice daily dosing and for ribavirin with reduced initial dosing. Conclusions: Telaprevir combination therapy for posttransplant hepatitis C virus infection yielded superior efficacy than historical controls. Adverse events were similar to, but exceeded, those in immunocompetent patients. Calcineurin inhibitor dosing levels were substantially reduced with telaprevir.
AB - Objectives: Our objective was to determine the safety, efficacy, and pharmacokinetics of telaprevir plus pegylated interferon alfa 2a and ribavirin for chronic, posttransplant genotype 1 hepatitis C virus infection. Materials and Methods: A prospective, single-arm, multicenter, open-label, phase 2b study was conducted at 22 North American sites to assess the safety, efficacy, and pharmacokinetics of pegylated interferon alfa 2a, ribavirin, and twice daily telaprevir in liver transplant recipients with recurrent, chronic hepatitis C without cirrhosis. Baseline liver biopsies were read by a central pathologist. There were planned safety reviews after a sentinel cohort reached treatment weeks 4 and 16. Serial pharmacokinetic sampling was performed for calcineurin inhibitors, telaprevir, and ribavirin. Results: Sixty-one patients were enrolled and received ≥ 1 dose of study medication; 37 (61%) achieved sustained virologic response. Thirteen of 18 treatment-naive patients (72%), 10 of 11 patients with no or minimal fibrosis (91%), 13 of 15 patients (87%) with interleukin 28B genotype CC, and 36 of 45 patients (80%) with either undetectable or unquantifiable hepatitis C virus RNA at treatment week 4 achieved sustained virologic response. Nine patients (15%) had ≥ 1 drug-related serious adverse event and 7 (11%) discontinued all study drugs due to an adverse event. There were no deaths or acute cellular rejection episodes. During telaprevir treatment, median doses of tacrolimus and cyclosporine were 0.5 mg weekly and 25 mg daily. Target exposures were achieved for telaprevir with twice daily dosing and for ribavirin with reduced initial dosing. Conclusions: Telaprevir combination therapy for posttransplant hepatitis C virus infection yielded superior efficacy than historical controls. Adverse events were similar to, but exceeded, those in immunocompetent patients. Calcineurin inhibitor dosing levels were substantially reduced with telaprevir.
KW - Hepatitis C
KW - Liver transplantation
KW - Telaprevir
UR - http://www.scopus.com/inward/record.url?scp=85045089504&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045089504&partnerID=8YFLogxK
U2 - 10.6002/ect.2016.0251
DO - 10.6002/ect.2016.0251
M3 - Article
C2 - 27855589
AN - SCOPUS:85045089504
SN - 1304-0855
VL - 16
SP - 182
EP - 190
JO - Experimental and Clinical Transplantation
JF - Experimental and Clinical Transplantation
IS - 2
ER -
