Christine M. Durand, MD; Mary G. Bowring, MPH; Diane M. Brown, MSN; Michael A. Chattergoon, MD, PhD; Guido Massaccesi, BS; Nichole Bair, BSN; Russell Wesson, MBChB; Ashraf Reyad, MBBCh; Fizza F. Naqvi, MD; Darin Ostrander, PhD; Jeremy Sugarman, MD; Dorry L. Segev, MD, PhD; Mark Sulkowski, MD; Niraj M. Desai, MD
Disclaimer: The opinions expressed in this paper are the authors’ and do not necessarily represent those of Merck Sharp & Dohme.
Acknowledgment: The authors thank Alexandra Valsamakis, MD, PhD, for her assistance in HCV RNA testing and the Living Legacy Foundation of Maryland for its assistance in evaluating deceased donors.
Grant Support: In part, by a research grant from the Investigator-Initiated Studies Program of Merck Sharp & Dohme. Dr. Durand is supported by National Cancer Institute grant K23CA177321-01A1. Ms. Bowring is supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01AG042504 (to Dr. Segev). Dr. Segev is also supported by NIDDK grant K24DK101828. Dr. Sulkowski is supported National Institute of Allergy and Infectious Diseases grant K24DA034621.
Disclosures: Dr. Durand reports grants from Merck Sharp & Dohme during the conduct of the study and personal fees from Merck Sharp & Dohme, Gilead Sciences, and Bristol-Myers Squibb (BMS) and grants from GlaxoSmithKline, ViiV Healthcare, Gilead Sciences, and BMS outside the submitted work. Dr. Sugarman serves on the Merck Sharp & Dohme KGaA Bioethics Advisory Panel and Stem Cell Research Oversight Committee and is a member of Quintile's Ethics Advisory Panel. Dr. Segev reports personal fees from Sanofi and Novartis outside the submitted work. Dr. Sulkowski reports grants and personal fees from AbbVie during the conduct of the study and grants, personal fees, and research funds from Gilead; grants and personal fees from Janssen and Merck Sharp & Dohme; personal fees from Wiley and Sons and Trek; and grants from the National Institutes of Health outside the submitted work. Dr. Desai reports grants, personal fees, and nonfinancial support from Merck Sharp & Dohme during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-2871.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See the . Statistical code and data set: Available from Dr. Durand (e-mail, firstname.lastname@example.org).
Requests for Single Reprints: Christine M. Durand, MD, Department of Medicine, Johns Hopkins University School of Medicine, 725 North Wolfe Street, PCTB Suite 211, Baltimore, MD 21205; e-mail, email@example.com; or Niraj M. Desai, MD, Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 771, Baltimore, MD 21205; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Durand and Ms. Brown: Department of Medicine, Johns Hopkins University School of Medicine, 725 North Wolfe Street, PCTB Suite 211, Baltimore, MD 21205.
Ms. Bowring and Dr. Segev: Epidemiology Research Group in Organ Transplantation, Department of Surgery, Johns Hopkins University School of Medicine, 2000 East Monument Street, Baltimore, MD 21205.
Dr. Chattergoon and Mr. Massaccesi: Department of Medicine, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Room 550B, Baltimore, MD 21205.
Ms. Bair and Drs. Wesson, Reyad, and Desai: Department of Surgery, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 771, Baltimore, MD 21205.
Dr. Naqvi: Department of Nephrology, Johns Hopkins University School of Medicine, Sheikh Zayed Tower Room 7127, 1800 Orleans Street, Baltimore, MD 21287.
Dr. Ostrander: Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 459, Baltimore, MD 21205.
Dr. Sugarman: Berman Institute of Bioethics and Department of Medicine, Johns Hopkins University, 1809 Ashland Avenue, Baltimore, MD 21205.
Dr. Sulkowski: Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 450D, Baltimore, MD 21205.
Author Contributions: Conception and design: C.M. Durand, M.A. Chattergoon, G. Massaccesi, J. Sugarman, D.L. Segev, M. Sulkowski, N.M. Desai.
Analysis and interpretation of the data: C.M. Durand, M.G. Bowring, M.A. Chattergoon, G. Massaccesi, J. Sugarman, D.L. Segev, M. Sulkowski, N.M. Desai.
Drafting of the article: C. Durand, G. Massaccesi, M. Sulkowski, N.M. Desai.
Critical revision for important intellectual content: C.M. Durand, M.A. Chattergoon, F.F. Naqvi, J. Sugarman, M. Sulkowski, N.M. Desai.
Final approval of the article: C.M. Durand, M.G. Bowring, D.M. Brown, M.A. Chattergoon, G. Massaccesi, N. Bair, R. Wesson, A. Reyad, F.F. Naqvi, D. Ostrander, D.L. Segev, J. Sugarman, M. Sulkowski, N.M. Desai.
Provision of study materials or patients: D.M. Brown, A. Reyad, F.F. Naqvi, N.M. Desai.
Statistical expertise: M.G. Bowring, D.L. Segev.
Obtaining of funding: C.M. Durand, D. Ostrander, M. Sulkowski, N.M. Desai.
Administrative, technical, or logistic support: M.G. Bowring, D.M. Brown, N. Bair, F.F. Naqvi, D. Ostrander.
Collection and assembly of data: C.M. Durand, M.G. Bowring, D.M. Brown, M.A. Chattergoon, G. Massaccesi, N. Bair, R. Wesson, D. Ostrander, N.M. Desai.
Given the high mortality rate for patients with end-stage kidney disease receiving dialysis and the efficacy and safety of hepatitis C virus (HCV) treatments, discarded kidneys from HCV-infected donors may be a neglected public health resource.
To determine the tolerability and feasibility of using direct-acting antivirals (DAAs) as prophylaxis before and after kidney transplantation from HCV-infected donors to non–HCV-infected recipients (that is, HCV D+/R− transplantation).
Open-label nonrandomized trial. (ClinicalTrials.gov: NCT02781649)
10 HCV D+/R− kidney transplant candidates older than 50 years with no available living donors.
Transplantation of kidneys from deceased donors aged 13 to 50 years with positive HCV RNA and HCV antibody test results. All recipients received a dose of grazoprevir (GZR), 100 mg, and elbasvir (EBR), 50 mg, immediately before transplantation. Recipients of kidneys from donors with genotype 1 infection continued receiving GZR–EBR for 12 weeks after transplantation; those receiving organs from donors with genotype 2 or 3 infection had sofosbuvir, 400 mg, added to GZR–EBR for 12 weeks of triple therapy.
The primary safety outcome was the incidence of adverse events related to GZR–EBR treatment. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks after prophylaxis.
Among 10 HCV D+/R− transplant recipients, no treatment-related adverse events occurred, and HCV RNA was not detected in any recipient 12 weeks after treatment.
Nonrandomized study design and a small number of patients.
Pre- and posttransplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R– kidney transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection.
Merck Sharp & Dohme.
Table 1. Recipient and Donor Characteristics
Appendix Table 1. Donor Biopsy Findings
Table 2. Donor HCV Characteristics and Recipient HCV Status After Transplant
Pre- and posttransplantation HCV RNA levels in non–HCV-infected recipients of kidneys from HCV-infected donors.
Shown are plasma HCV RNA levels before transplantation (baseline); during DAA treatment on POD1; at TW1, TW2, TW4, TW8, and TW12 after transplantation; and at FW4, FW8, and FW12 after DAA treatment. Lower limit of quantification is 15 IU/mL. DAA = direct-acting antiviral; FW = follow-up week; HCV = hepatitis C virus; POD = postoperative day; TW = treatment week.
Appendix Table 2. Recipient Urinary Protein–Creatinine Ratio or Standard Dipstick Result
Posttransplantation liver function tests in non–HCV-infected recipients of kidneys from HCV-infected donors.
Shown are ALT (A) and AST (B) values measured at baseline and during posttransplantation follow-up. ALT = alanine aminotransferase; AST = aspartate aminotransferase; FW = follow-up week; HCV = hepatitis C virus; TW = treatment week.
* Missing for 1 patient.
Pre- and posttransplantation HCV-specific CD8+ T-cell responses among non–HCV-infected recipients of kidneys from HCV-infected donors.
The number of positive peptide pools identified for each recipient before transplantation and at FW8 is shown. T-cell responses were measured by interferon-γ enzyme-linked immunospot using a matrix of 6 peptide pools containing overlapping peptides of optimal cytotoxic T-lymphocyte HCV epitopes. Pools with more than 50 spot-forming cells per million peripheral blood mononuclear cells were considered positive. FW = follow-up week; HCV = hepatitis C virus.
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David A. Goodkin, Brian A. Bieber
Arbor Research Collaborative for Health, Ann Arbor, MI
April 27, 2018
Conflict of Interest:
The Dialysis Outcomes and Practice Patterns Study (DOPPS) Program is supported by Amgen, Kyowa Hakko Kirin, and Baxter Healthcare. Additional support for specific projects and countries is provided by Merck Sharp & Dohme Corp., AstraZeneca, the European Renal Association-European Dialysis and Transplant Association, Fresenius Medical Care Asia-Pacific Ltd, Fresenius Medical Care Canada Ltd, the German Society of Nephrology, Janssen, the Japanese Society for Peritoneal Dialysis, Keryx, Kidney Care UK, MEDICE Arzneimittel Pütter GmbH & Co KG, Proteon, and Vifor Fresenius Medical Care Renal Pharma. Public funding and support is provided for specific DOPPS projects, ancillary studies, or affiliated research projects by: Australia: the National Health and Medical Research Council; Canada: Cancer Care Ontario through the Ontario Renal Network; France: MEDICE Arzneimittel Pütter GmbH & Co KG; Thailand: Thailand Research Foundation, the Chulalongkorn University Matching Fund, the King Chulalongkorn Memorial Hospital Matching Fund, and the National Research Council of Thailand; the United Kingdom: the National Institute for Health Research via the Comprehensive Clinical Research Network; and the United States: the National Institutes of Health. All support is provided without restrictions on publications.
Kidney Transplantation from Hepatitis C Virus-infected Donors to Infected Versus Non-infected Recipients
To The Editor:Durand and colleagues (1) report successfully transplanting ten hepatitis C virus (HCV)-infected renal allografts into HCV-negative recipients, using direct-acting antiviral drugs to prevent infection in the recipients. We appreciate the importance of not discarding HCV+ organs in light of the long transplantation waiting list of dialysis patients (exceeding 95,000 in the US alone). However, we think it would be more appropriate to first seek HCV+ waitlisted patients, before offering HCV+ kidneys to HCV-negative patients. The direct-acting agents fail to attain sustained viral responses among up to 5% of HCV-infected individuals (2) and it seems preferable not to expose HCV-negative patients to the virus when some will fail to respond to the drugs. Durand and colleagues state that the current practice of excess discarding of HCV+ donor kidneys “may partly result from the lack of HCV-infected transplant candidates.” Recently we reviewed the database of the Dialysis Outcomes and Practices Patterns Study (DOPPS) to determine the prevalence of HCV-positivity among hemodialysis patients on transplantation waitlists across the 21 participating countries (3,4). Internationally, 5.2% were HCV+. In the US, 4.8% were HCV+ indicating that more than 4,600 US patients would be candidates to receive HCV+ organs. We propose that HCV+ organs should first be matched across the substantial population of HCV+ patients on the waitlist. They should only be offered to HCV-negative recipients if no match is found, and then only after careful explanation to the recipients of the risks that they may become infected with HCV and simultaneously undergo potent immunosuppression. References1. Durand CM, Bowring MG, Brown DM et al. Direct-acting antiviral prophylaxis in kidney transplantation from hepatitis C virus-infected donors to noninfected recipients. Ann Intern Med. 2018;168:533-40.2. Falade-Nwulia O, Suarez-Cuervo C, Nelson DR et al. Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review. Ann Intern Med. 2017;166:637-48.3. Goodkin DA, Bieber B. International prevalence of hepatitis C positivity among hemodialysis patients awaiting transplantation. Kidney Int. 2018;93:1249.4. Young EW, Goodkin DA, Mapes DL et al. The Dialysis Outcomes and Practice Patterns Study (DOPPS): an international hemodialysis study. Kidney Int. 2000;57(suppl 74):574-581.
Durand CM, Bowring MG, Brown DM, Chattergoon MA, Massaccesi G, Bair N, et al. Direct-Acting Antiviral Prophylaxis in Kidney Transplantation From Hepatitis C Virus–Infected Donors to Noninfected Recipients: An Open-Label Nonrandomized Trial. Ann Intern Med. ;168:533–540. doi: 10.7326/M17-2871
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Published: Ann Intern Med. 2018;168(8):533-540.
Published at www.annals.org on 6 March 2018
Gastroenterology/Hepatology, Infectious Disease, Viral Hepatitis.
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