Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Goldberg DS, Abt PL, Blumberg EA, et al. Trial of transplantation of HCV-infected kidneys into uninfected recipients. N Engl J Med 2017;376: DOI: /NEJMc

2 Title: A Trial of Transplanting HCV-infected Kidneys into Uninfected Recipients Table of Contents Study Investigators.2 Evaluation of Potential Study Candidates Table S1: Inclusion and Exclusion Criteria..5 Kidney Allograft and Donor Criteria; Hepatitis C Genotype Methods.6 Figure S1: Consort Diagram.7 Table S2: Characteristics of Enrolled Patients.8 Table S3: Recipient and Transplant Characteristics....9 Table S4: Donor Characteristics.. 10 Figure S2: Recipient Creatinine Trend 11 Table S5: Recipient Hepatic Laboratory Values. 12 Table S6: Adverse Events

3 THINKER Study Investigators David S. Goldberg, M.D., M.S.C.E. Peter L. Abt, M.D. Emily A. Blumberg, M.D. Vivianna M. Van Deerlin, M.D., Ph.D. Matthew Levine, M.D., Ph.D. K. Rajender Reddy, M.D. Roy D. Bloom, M.D. Susanna M. Nazarian, M.D., Ph.D. Deirdre Sawinski, M.D. Paige Porrett, MD, PhD Ali Naji, M.D., Ph.D. Richard Hasz, B.S., M.F.S Gift of Life Donor Program, Philadelphia, PA Lawrence Suplee, M.S. Gift of Life Donor Program, Philadelphia, PA Jennifer Trofe-Clark, PharmD Anna Sicilia, B.S. 2

4 Maureen McCauley, B.A. Midhat Farooqi, M.D., Ph.D. Children s Mercy Hospital, Kansas City, MO Caren Gentile, M.S. Jennifer Smith, B.S. Peter P. Reese, M.D., M.S.C.E. 3

5 Evaluation of Potential Study Candidates Informed Consent The processes of informed consent included three steps on different days, each led by a physician. First, one principal investigators (D.G. or P.R.) telephoned the potential participant and described HCV, its complications, the goals of the trial and invited the patient to attend an in-person educational presentation. Second, the presentation addressed risks of HCV and logistics of trial participation. The presentation described elbasvir/grazoprevir treatment and the fact that if HCV were not cured, a second antiviral regimen would be provided to the participant at no cost. However, any participant without cure after both regimens would have to seek additional treatments through insurance or private means. The presentation also described that organ donors in the trial might be classified as Public Health Service elevated risk for window infection with HIV. The third step was history, physical and signing the consent document. Participants were then rendered eligible for HCV-viremic kidney offers through an opt-in mechanism in the allocation system administered by the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS). Hepatology Evaluation During the third step of informed consent, the patient underwent evaluation by a transplant hepatologist (DG). This evaluation included transient elastography as well as review of relevant serologies and physical exam. 4

6 Table S1: Inclusion and Exclusion Criteria for the THINKER Trial* Inclusion Criteria Exclusion Criteria On chronic hemodialysis or peritoneal dialysis Hepatocellular carcinoma Listed for an isolated kidney transplant with 548 days of accrued transplant waiting time and/or 548 days of dialysis time No available living kidney donor HIV positive Patients with primary focal segmental glomerulosclerosis (FSGS), FSGS recurring after previous transplant, or disease process with increased risk of causing early graft failure Blood group A, B, or O HCV RNA positive (can be isolated HCV antibody positive provided the subject has no history of previously treated HCV) Between years of age Hepatitis B surface antigen positive Have a panel reactive antibody level 97% Any chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD) with abnormal liver enzymes Obtained agreement for participation from the patient s treating transplant nephrologist No evident contraindication to liver transplantation Persistently elevated liver transaminases Blood group AB (due to short expected waiting time on the kidney transplant waiting list) Able to travel to the University of Pennsylvania for routine post-transplant and study visits Significant hepatic fibrosis on screening elastography ( F2 fibrosis) Women agreed to use birth control in accordance with Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) Known allergy or intolerance to tacrolimus that would require post-transplant administration of cyclosporine following transplant Men and women must agree to use at least one Pregnant or nursing (lactating) women barrier method to prevent any secretion exchange No active illicit substance abuse Waitlisted for a multi-organ transplant (e.g., pancreas-kidney) Weigh at least 50kg Cardiomyopathy (e.g., left-ventricular heart failure, pulmonary hypertension) that would preclude liver transplantation Able to provide informed consent 5

7 Kidney allograft and Donor criteria Allograft criteria included deceased donor age <60 years, absence of diabetes and kidney donor profile index <85%. The kidney donor profile index ranges from 1 to 100%; lower percentages indicate better kidney quality. Donors were required to have positive qualitative HCV nucleic acid test (NAT) and genotype 1 HCV. Surrogates for the donors provided authorization for the donors and/or organs to be involved in research. Hepatitis C Genotype Methods Because HCV genotyping is not routinely available for deceased organ donors, we developed a protocol for genotype testing concurrent with organ allocation. The local organ procurement organization (Gift of Life Donor Program, Philadelphia, PA) facilitated shipping of donor blood specimens to HUP. HCV genotypes for donors and subsequently for recipients (after transplantation) were determined using the esensor HCVg Direct Test and XT-8 System (GenMark Diagnostics, Carlsbad, CA) which was fully validated as a laboratory-developed procedure and used routinely for all clinical testing in the HUP Molecular Pathology Laboratory. This assay detects HCV genotypes 1-6 and some mixed infections. Nucleic acid extraction was performed on the QIAcube (Qiagen, Valencia, CA), followed by generation of genotype amplicons, and analysis on an esensor XT-8 instrument. 6

8 Figure S1. Flow Chart of Recruitment, Enrollment and Follow-up of Study Participants* Enrollment Assessed for eligibility (n=285) Meeting blood type, age and wait-list time priority criteria Preliminarily eligible and invited to educational session (n=38) Excluded (n= 247) Not yet on Dialysis (n= 141) Previous/Multi-organ Transplant (n= 58) Contraindication for Liver Transplant (n= 16) Under weight requirement (n= 8) HIV/HCV/HBV (n= 8) Living Donor (n= 6) Became ineligible for a transplant (n= 5) Recurrence Risk (n= 2) High PRA (n= 2) Declined to participate (n=16) Allocation Attended Educational Session Activated for HCV+ kidneys on Waitlist (n=14) Declined to participate (n= 2) Screen fail (n= 4) Due to liver evaluation In process of screening and/or activation when trial ended (n= 2) Transplanted (n= 10) Awaiting Transplant (n=4) Follow-Up Lost to follow-up (n= 0) Analysis Analysed (n= 10) * Data as of November , the date of the 10 th kidney transplant. 7

9 Table S2: Kidney Transplant Candidates Baseline Data Age Gender Race Etiology of ESRD Liver stiffness, kpa Mode of dialysis BMI Waiting time at enrollment, days 65 Female White Interstitial nephritis 4.2 HD Male Black Hypertension 5.6 HD Female White Polycystic 7.1 HD Female White Diabetes 6.1 HD Male Asian IgA Nephropathy 5.1 PD Male White Diabetes 5.6 HD Male White IgA Nephropathy 4.9 HD Female White Anatomical 4 HD Male Black Secondary FSGS 6.1 HD Female White Diabetes 6.7 PD Female White Lithium Toxicity 7.8 HD Male White Polycystic 6.9 HD Male Black Diabetes 7.0 HD Male Black Diabetes 6.5 HD This table shows data of the kidney transplant candidates who consented for THINKER trial participation and were activated as eligible for Hepatitis C-viremic kidney allograft offers through the US kidney allocation system (n=14) Abbreviations: HD=hemodialysis; PD=peritoneal dialysis; BMI=body mass index; FSGS=focal segmental glomerulosclerosis Liver stiffness measured via transient elastography (Fibroscan) at the time of screening for study enrollment. 8

10 Table S3: Recipient and Transplant Characteristics* Age Gender Race Etiology of ESRD 65 Female White Interstitial Liver stiffness, kpa Mode of dialysis BMI Waiting time at enrollment, days Time from enrollment to transplant, days Match run rank 4.2 HD nephritis 50 Male Black Hypertension 5.6 HD Female White Polycystic 7.1 HD Female White Diabetes 6.1 HD Male Asian IgA 5.1 PD Nephropathy 53 Male White Diabetes 5.6 HD Male White IgA 4.9 HD Nephropathy 51 Female White Anatomical 4 HD Male Black Secondary 6.1 HD FSGS 63 Female White Diabetes 6.7 PD Abbreviations: HD=hemodialysis; PD=peritoneal dialysis; BMI=body mass index; FSGS=focal segmental glomerulosclerosis * All patients had a panel of reactive antibodies (PRA) of 0 at waitlisting. Recipient characteristics at enrollment unless otherwise indicated. Liver stiffness measured via transient elastography (Fibroscan) at the time of screening for study enrollment. Match run rank equals the patient s rank on the waitlist for the kidney that the patient received. All those patients ranked higher on the match run than the eventual kidney recipients declined the organ. 9

11 Table S4: Donor Characteristics * Race Gender OPTN/ UNOS region Age Cause of death Mechanism of death Terminal creatinine, mg/dl DCDD Cold ischemia time, hours:minutes White Male Anoxia Cardiovascular 0.5 No 22:30 48% White Female 3 28 Anoxia Drug intoxication 0.5 No 20:30 32% White Male 2 31 Anoxia Drug intoxication 1.4 No 13:14 46% KDPI White Female 2 45 CVA Intra-cranial hemorrhage 1.0 No 10:45 73% White Male Anoxia Cardiovascular 0.5 No 16:31 48% White Female 3 28 Anoxia Drug intoxication 0.5 No 27:45 32% White Male 2 29 Anoxia Drug intoxication 0.79 No 9:01 35% White Male 2 30 Anoxia Drug intoxication 1.4 Yes 16:26 58% White Male 2 25 Anoxia Drug intoxication 1.24 No 13:20 23% White Male 2 32 Anoxia Drug intoxication 0.6 Yes 13:01 37% Abbreviations: OPTN/UNOS=Organ Procurement Transplantation Network/United Network Organ Sharing; DCDD=Donation After Circulatory Determination of Death; KDPI=Kidney Donor Profile Index; CVA=Cerebrovascular accident * All donors were categorized as Public Health Service (PHS) increased risk, defined as being at increased risk for HBV, HCV, and/or HIV. All the donors had negative nucleic acid testing for hepatitis B and HIV. None of the donors had a past medical history of hypertension or diabetes mellitus. Kidney donor profile index is the calculated value of the quality of the donor kidney, scored from 1-100%, with increasing numbers associated with worse quality Note--ordering scrambled from Table S3 10

12 Figure S2: Serum Creatinine after Transplantation of Hepatitis C-viremic Deceased Donor Kidney Transplants into Hepatitis-C Virus-Negative Recipients Note: n= 10 recipients; 6-month creatinine: median: 1.09, IQR: ; 6-month egfr: median: 62.8, IQR:

13 Table S5: Transaminases and Total Bilirubin after Transplantation Week 1 Week 4 Week 8 Week 12 Week 24 ID T Bili AST ALT T Bili AST ALT T Bili AST ALT T Bili AST ALT T Bili AST ALT Data on 10 hepatitis-c virus-negative recipients who received hepatitis-c-viremic deceased donor kidney transplants* * When a participant had multiple laboratory values during the same week, the highest (most unfavorable) value was selected for the table. 12

14 Table S6: Serious Adverse Events among Recipients SAE Category Start Date Intra-operative Bleeding (nasal; related to anesthesia trauma) Post-op reintubation/failed extubation Post-op reintubation/failed extubation Procedural Complications Procedural Complications Procedural Complications Stop Date Outcome Severity/ Grade Related * Expected Action Taken 7/28/16 7/28/16 Resolved 3 Unrelated No None 7/24/16 7/24/16 Resolved 3 Unrelated No None 8/4/16 8/4/16 Resolved 3 Unrelated No None Pneumonia Respiratory, Thoracic 9/15/16 9/15/16 Resolved 3 Unrelated No None Hyperkalemia Small bowel obstruction Renal Pelvic Mass & Native Nephrectomy Hyperparathyroidism; Parathyroidectomy Focal segmental glomerulosclerosis Metabolism and Nutritional Disorder Gastrointestinal disorder Renal Disorder 10/11/1 6 Metabolism and Nutritional Disorder 9/30/16 9/30/16 Resolved 2 Unrelated No None 12/2/16 12/3/16 Resolved 2 Unrelated No None 1/19/17 Resolved 2 Unrelated No None 3/15/17 3/17/17 Resolved 3 Unrelated No None Renal disorder 4/7/17 Ongoing 3 Possible No Angiotensin receptor blocker Serious adverse events (SAEs) among hepatitis-c negative recipients who received kidney transplants from hepatitis C-viremic deceased donors (n= 10) The investigators adjudicated whether serious adverse events were related and expected based on whether they were plausibly and primarily related to and expected from HCV infection or its treatment, not whether they were related to or expected from kidney 13

15 transplantation generally. The study received oversight from the University of Pennsylvania Institutional Review Board (Penn IRB# ) and from a three-member Data Safety and Monitoring Board. 14