The advent of direct‐acting antiviral therapy for hepatitis C virus (HCV) has generated tremendous interest in transplanting organs from HCV‐infected donors. We conducted a single‐arm trial of orthotopic heart transplantation (OHT) from HCV‐infected donors into uninfected recipients, followed by elbasvir/grazoprevir treatment after recipient HCV was first detected (NCT03146741; sponsor: Merck). We enrolled OHT candidates aged 40‐65 years; left ventricular assist device (LVAD) support and liver disease were exclusions. We accepted hearts from HCV‐genotype 1 donors. From May 16, 2017 to May 10, 2018, 20 patients consented for screening and enrolled, and 10 (median age 52.5 years; 80% male) underwent OHT. The median wait from UNOS opt‐in for HCV nucleic‐acid‐test (NAT)+ donor offers to OHT was 39 days (interquartile range [IQR] 17‐57). The median donor age was 34 years (IQR 31‐37). Initial recipient HCV RNA levels ranged from 25 IU/mL to 40 million IU/mL, but all 10 patients had rapid decline in HCV NAT after elbasvir/grazoprevir treatment. Nine recipients achieved sustained virologic response at 12 weeks (SVR‐12). The 10th recipient had a positive cross‐match, experienced antibody‐mediated rejection and multi‐organ failure, and died on day 79. No serious adverse events occurred from HCV transmission or treatment. These short‐term results suggest that HCV‐negative candidates transplanted with HCV‐infected hearts have acceptable outcomes.

Abbreviations

DAA direct‐acting antiviral DSA donor‐specific antibody DSMB data safety and monitoring board HCV ,hepatitis C virus HUP Hospital of the University of Pennsylvania LVAD Left ventricular assist device NAT nucleic acid testing NS5A nonstructural protein 5A OHT orthotopic heart transplantation OPTN Organ Procurement and Transplantation Network SVR sustained virologic response UNOS United Network for Organ Sharing

1 INTRODUCTION In 2017, more than 600 patients who were wait‐listed for orthotopic heart transplantation (OHT) in the United States died or became too sick for transplantation.1 Because of the opiate crisis, hundreds of potential organ donors each year develop HCV infection and die of a drug overdose.2 Historically, most of their organs were discarded. The introduction of direct‐acting antiviral (DAA) therapies for HCV with cure rates >95% and manageable side effects led our group and others to propose trials of transplanting HCV‐infected organs into well‐informed HCV‐negative recipients, followed by DAA treatment.3, 4 However, there are few published data on outcomes for recipients of HCV‐infected hearts,5 including treatment response, allograft survival, and adverse events, and none that involved a formal clinical trial protocol with prospective data collection. The transplantation of HCV‐infected hearts was nearly abandoned in the era of interferon‐based HCV treatment regimens because of concerns about virally mediated coronary vasculopathy and development of severe and rapidly progressive liver disease. In 2006, JAMA published a landmark study demonstrating that recipients of heart transplants from HCV‐seropositive donors had significantly worse survival, independent of the recipient's HCV status.6 However, HCV treatment options during this era had low cure rates (30%‐40% for genotype 1) and included interferon, which caused severe side effects that were exacerbated in organ transplant recipients (eg, cytopenias), and challenging drug‐drug interactions. Furthermore, interferon upregulates the immune response, which could trigger allograft rejection, a risk that may also be intensified in the setting of HCV infection.7-19 Results of this JAMA study also reinforced concerns that HCV might promote endothelial injury and vascular injury in the allograft.20 DAAs for HCV subsequently prompted reconsideration of transplanting HCV‐infected hearts.3 To date, 5 single‐center studies/series of transplanting organs from HCV nucleic acid testing positive (NAT+) donors into uninfected recipients have been published. All reported 100% cure rates defined as sustained virologic response at 12 weeks (SVR‐12), but only one involved heart transplantation.5, 21-24 Because all 5 studies included modest numbers of patients, more data on outcomes after donor‐derived, de novo HCV infection are needed to buttress informed consent for future transplant candidates considering these organs.4 The aim of this pilot trial was to determine the safety and efficacy of transplanting 10 hearts from HCV‐viremic donors into HCV‐negative patients followed by elbasvir/grazoprevir treatment upon detection of HCV viremia (NCT03146741; sponsor: Merck). As a secondary aim, we took advantage of data in the concurrent THINKER trial (NCT02743897; sponsor: Merck) and compared HCV‐treatment responses between the 5 OHT recipients in the USHER trial and 7 HCV‐negative recipients of kidneys from the same deceased donors.

2 METHODS This study was a single‐arm clinical trial (USing Hepatitis c positive hearts for negative Recipients: USHER) at the Hospital of the University of Pennsylvania (HUP) and approved by the University of Pennsylvania Institutional Review Board (Protocol #826708). An external data safety and monitoring board provided oversight including review of adverse event data. The protocol and IRB‐approved modifications are included as Appendix S1A,B. The trial started May 16, 2017. The protocol authorized 10 heart transplantations, which took place between June 18, 2017 and April 10, 2018. Follow‐up data extend through December 10, 2018. 2.1 Participant criteria We designed the criteria with the goal of enrolling patients anticipated to have prolonged wait times for an HCV‐negative transplant. We excluded patients with conditions that would substantially elevate the risks of liver disease (eg, congenital cardiac disease requiring a Fontan procedure), death, or allograft failure after transplantation. The main inclusion criteria were the following: (1) wait‐listed for heart transplantation due to either New York Heart Association Class III or IV congestive heart failure refractory to maximal medical therapy and/or conventional surgery, and/or inoperable coronary artery disease with intractable anginal symptoms, and/or malignant ventricular arrhythmias unresponsive to medical or surgical therapy; (2) blood group O, A, or B (which are associated with long expected waiting times for transplant); (3) no evident contraindication to liver transplantation other than the underlying cardiac disorder; (4) ages 40‐65 years at enrollment; (5) listed only for a heart transplant; (6) negative HIV antibody, HCV antibody, and hepatitis B surface antigen; and (7) no illicit drug use. A hepatologist (D.G.) confirmed the absence of liver disease after history, physical, and serologic evaluation. Each participant's transplant cardiologist affirmed that participation was appropriate. Unlike the THINKER trial, transient elastography was not part of screening due to the potential for falsely elevated values from right heart pressure/volume overload, rather than hepatic stiffness from fibrosis and/or ongoing inflammation. All candidates consented to abstain from sexual activity and/or use barrier protection while HCV‐infected. Appendix S2 lists the full set of inclusion and exclusion criteria. 2.2 Informed consent The processes of informed consent included 3 physician‐led steps on different days. First, one of the principal investigators (R.M., D.G., P.R.) contacted the potential participant and described HCV, its complications, the trial's goals, and invited the patient to attend an in‐person educational presentation. Second, the presentation addressed HCV risks and the trial design. The third step was history, physical, and signing the consent. The presentation and consent specified that if HCV were not cured, a second antiviral regimen would be provided to the participant at no cost. However, any participant not cured after 2 HCV treatments would have to seek additional antiviral therapy by paying for it through insurance or personal funds. Participants were then rendered eligible for offers of HCV‐NAT+ hearts via the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) allocation system. 2.3 Deceased donor criteria Donor criteria included a detectable HCV RNA and genotype 1 or 4; donor age ≤55 years; no cirrhosis; no history of coronary artery disease; no congenital heart disease except a repaired atrial septal defect provided the donor had normal right ventricular function; and no history of arrhythmia except during resuscitation from fatal event. Echocardiographic criteria included left ventricular ejection fraction ≥50%, normal right ventricular function, and no left ventricular hypertrophy or significant valvular disease or congenital heart disease. Donor right heart catheterization criteria included right atrial pressure ≤10 mm Hg, pulmonary artery wedge pressure ≤18 mm Hg, and cardiac index ≥2.1 l/min/m2. The full set of donor criteria are listed in Appendix S3. Our rationale for genotype restriction was to minimize participant risk. The regimen of elbasvir/grazoprevir is not approved by the US Food and Drug Administration (FDA) to treat genotype 2 or 3 HCV, and when we designed the trial, there were no FDA‐approved regimens for these genotypes in the setting of renal failure, which is an important consideration because acute kidney injury can complicate OHT. Surrogates for the donors provided research authorization for the donors and/or organs. 2.4 Hepatitis C virus genotyping We developed a protocol for genotype testing that would occur during the organ allocation process.25 We used the eSensor HCVg Direct Test and XT‐8 System (GenMark Diagnostics, Carlsbad, CA) to ascertain HCV genotypes for donors and organ recipients. We performed nucleic acid extraction using the QIAcube (Qiagen, Valencia, CA), followed by analysis on an eSensor XT‐8 instrument. 2.5 Organ selection and immunosuppression Following confirmation of acceptable HCV genotype, the clinical transplant teams made decisions about allograft acceptance. All USHER recipients received our center's usual regimen of oral tacrolimus, mycophenolate mofetil, and oral prednisone. All initially received basiliximab induction therapy. The center protocol involves allograft biopsy posttransplantation at 1, 3, and 4 weeks, then every other week through month 3, then monthly until 1 year, as well as when clinically indicated. OHT recipients undergo screening for anti‐HLA donor‐specific antibody (DSA) at 1 to 2 weeks after transplantation, and in the event of suspected or documented allograft rejection. 2.6 Posttransplant protocol for HCV treatment The molecular pathology laboratory at HUP determined the quantity of HCV RNA in recipient plasma with either the COBAS AmpliPrep/COBAS TaqMan HCV Test, v2.0 or the cobas HCV Test, for use on the 6800/8800 Systems (Roche Diagnostics Systems, Inc.) with an analytic sensitivity of approximately 15 IU/mL of plasma and a linear range between 15 and 100 000 000 IU/mL. We tested OHT recipients for HCV infection or transmission with RNA viral load testing on day 3 posttransplant. We started a 12‐week course of daily elbasvir/grazoprevir therapy when results were positive. We did not treat patients “on‐call” to the operating room for several reasons: (1) posttransplant treatment on day 3 increased the likelihood that patients were clinically stable at the time of treatment initiation, and less likely to have treatment interruption for transplant complications; (2) to better reflect a real‐world scenario where DAA therapy would not be available on‐call as such medications are not stocked by hospital formularies; and (3) to provide data on the HCV transmission rates via transplantation, because recipient infection might not always take place. Among recipients infected by HCV viral genotype 1a, specimens were analyzed at a reference laboratory for baseline nonstructural protein 5A (NS5A) resistance‐associated substitutions. When these substitutions were present, the protocol called for extending elbasvir/grazoprevir therapy to 16 weeks and adding oral ribavirin. We subsequently measured HCV RNA at weeks 1, 2, 4, 8, and 12 (when antiviral therapy was completed), and subsequently at weeks 4, 8, and 12 (SVR‐12, the usual definition of cure) after therapy was completed.27-32 A similar treatment protocol was followed for THINKER trial participants who received kidneys from the same donors as USHER recipients.22 2.7 Outcomes The primary outcomes were posttreatment SVR‐12 and major adverse events attributable to HCV therapy. 2.8 Single genome sequencing and analysis To investigate the cause of a case of nonresponse to antiviral therapy, we conducted single genome sequencing of plasma from a deceased donor at the time of organ procurement, the heart recipient from that donor at day 3 posttransplant, and a kidney recipient (the nonresponder) from the same donor at day 3 and day 21 posttransplant. Viral RNA was extracted and complementary DNA synthesized, as previously described.32 Single genome sequencing, a method of end‐point dilution polymerase chain reaction (PCR), which minimized in vitro error and accurately represents the diversity of complex populations with linkage of sequence length, was performed over the 3’ half genome. Amplicons were sequenced by next‐generation sequencing on the MiSeq (Illumina). Raw reads of each amplicon were aligned de novo to generate a single contig using Geneious R10. Sequences were analyzed by maximal likelihood phylogenetic trees generated using PhyML 3.0 and visualized with Highlighter plots (www.HIV.lanl.gov), which allows tracing of common ancestry between sequences based on individual nucleotide polymorphisms. All sequences were deposited in Genbank, accession numbers MK473174‐MK473312. 2.9 Statistical analysis Statistical analyses were descriptive. Continuous variables were described as means or medians, as appropriate. Categorical variables were described by their frequencies.

3 RESULTS Figure 1 shows study enrollment. Among 35 potentially eligible participants invited to an educational presentation, 10 declined and 25 attended the presentation. Twenty subsequently completed informed consent and were activated for HCV‐positive heart offers, and 10 heart transplantations from HCV‐infected donors were completed. Figure 1 Open in figure viewer PowerPoint Flow chart of recruitment, enrollment, and follow‐up of study participants in the USHER trial Table 1 displays the characteristics of the 10 OHT recipients (Table S1A,B shows the characteristics of 10 additional patients who were enrolled but not transplanted). The median recipient age was 52.5 years (interquartile range [IQR] 45‐65). All self‐identified as white, and 80% were male. Eighty percent were blood group O. The median days between initial waitlisting for heart transplant and USHER trial consent was 94.5 days (IQR 8‐211; range 3‐842 days) for the 10 transplanted recipients. The median time from activation in the OPTN/UNOS allocation system for HCV‐NAT+ hearts to transplantation for the 10 recipients was 39 days (IQR 17‐57). Table 1. Demographic and clinical characteristics of 10 recipients of hepatitis C virus infected hearts in the USHER trial Characteristic Median age at consent in y (range) 52.5 (45‐65) Male gender, n (%) 8 (80) White race, n (%) 10 (100) Etiology of heart disease, n (%) Idiopathic dilated cardiomyopathy 5 (60) Hypertrophic cardiomyopathy 3 (30) Ischemic cardiomyopathy 1(10) Familial dilated cardiomyopathy 1 (10) Median weight in kg (range) 97.5 (74.3‐125.6) Median height cm (range) 179.7 (149.9‐190.5) Median body mass index in kg/m2 (range) 32.4 (24.7‐36.0) Blood type, n (%) O 8 (80) A 2 (20) UNOS waitlist status at transplantation 1A 2 (20) 1B 5 (50) 2 3 (30) Median panel reactive antibodies at listing (range) 0 (0‐82) Median days from activation to transplantation (range) 39 (5‐132) Median days from waitlisting to study consent (range) 94.5 (3‐842) Table 2 shows deceased donor and allograft characteristics. All donors were younger than 40 years of age, 90% were male, and all had drug intoxication as the mechanism of death. All were infected with genotype 1a HCV. Five donors to USHER also provided 7 kidneys to THINKER recipients. Table S2 provides additional detail about the donors. Table 2. Deceased donor and allograft characteristics Characteristic Median age in y (range) 34 (25‐38) Male gender, n (%) 9 (90) White race, n (%) 9 (90) Median height in centimeters (range) 178 (173‐188) Type 1a HCV genotype, n (%) 10 (100) Anoxia as cause of death, n (%) 10 (100) Drug intoxication as mechanism of death, n (%) 10 (100) Heart donor/recipient sex mismatch, n (%) 1 (10) THINKER kidney donor, n (%) 5 (50) Median terminal creatinine in mg/dL (range) 1.21 (0.6‐4.4) Median kidney donor profile index (range) 54 (29‐72) Figures 2A,B display trends in transaminases at or around the date of posttransplant study visits, showing that all 10 recipients developed aminotransferase elevations. The highest aspartate aminotransferase (AST) was 202 U/L (upper limit of normal [ULN] is 40 U/L at our center) and the highest alanine transaminase (ALT) was 213 U/L (ULN is 52 U/L at our center). During the HCV treatment period from the first week to 12‐ to 14‐weeks posttransplantation, the general trend was decline of these transaminase levels. Six of the 10 recipients had transient elevations in bilirubin, of which 2 had peak levels between 4 and 5.9 mg/dL; the other 4 peaked at <2.5 mg/dL (ULN is 1.2 mg/dL). Figure 2 Open in figure viewer PowerPoint A, Aspartate aminotransferase at intervals defined by study visits after heart transplantation in the USHER trial (n = 10). B, Alanine aminotransferase at intervals defined by study visits after heart transplantation in the USHER trial (n = 10). ALT, alanine aminotransferase; AST, aspartate aminotransferase. Dotted lines indicate the upper limit of the reference range at the Hospital of the University of Pennsylvania laboratory: ALT range = 7‐52 U/L; AST range = 13‐40 U/L 3.1 Response to antiviral therapy among the 10 USHER recipients and 7 recipients of kidneys from the same HCV‐infected donors All 10 USHER recipients had detectable HCV on day 3 posttransplantation, with initial HCV viral loads varying from 25 IU/mL to 40 million IU/mL. All 10 recipients were initiated on elbasvir/grazoprevir in the hospital. Figure S1 shows donor viral load and recipient response to antiviral therapy. Nine had undetectable HCV NAT within 4 weeks of initiation of HCV therapy. The 10th OHT recipient had a day‐3 HCV viral load of 40 million IU/mL, for which reason the investigators extended elbasvir/grazoprevir therapy to 16 weeks. This recipient did not achieve an undetectable viral load until 63 days after initiation of therapy. All 9 patients who completed HCV therapy achieved SVR‐12. The one patient who did not achieve SVR became HCV‐NAT negative within 7 days of initiating therapy and remained negative for the duration of treatment but died 79 days posttransplantation from complications of antibody‐mediated rejection. We tested plasma of all 10 heart recipients for NS5A resistance–associated nucleotide substitutions. In 9 patients, no substitution was detected. In the final patient, the presence of NS5A substitutions could not be assessed due to an HCV viral load below the limit of sensitivity of the assay, an indeterminate result. The 5 panels in Figure 3 display HCV NAT levels for 5 recipients of hearts and 7 kidney transplant recipients at our center who shared the same 5 donors. Table S3 shows characteristics of these 7 kidney recipients. For recipients of organs from 4 of the 5 donors (panels 2, 3, 4, and 5), the heart recipient had undetectable HCV RNA earlier than at least 1 kidney recipient. Notably, panel 5 shows a striking case in which the USHER heart recipient had an undetectable viral load by day 10, whereas a kidney recipient from the same donor stopped responding to elbasvir/grazoprevir around day 20 and required augmented therapy with sofosbuvir, ribavirin, and elbasvir/grazoprevir for 16 additional weeks. The kidney recipient did not endorse medication nonadherence, and tacrolimus levels at clinic visits were detectable. Subsequently, this kidney recipient developed SVR‐12, as did the other 6 kidney recipients. Figure 3 Open in figure viewer PowerPoint Hepatitis C viral load detected by polymerase chain reaction among deceased organ donors (n = 5) who provided organs for heart transplant recipients (n = 5) in the USHER trial as well as kidney transplant recipients (n = 7) in the THINKER trial Because this kidney recipient was initially a nonresponder, the investigators decided to extend the therapy with elbasvir/grazoprevir for the heart recipient from the same donor to 16 weeks and to add ribavirin 400 mg twice a day. The ribavirin was not tolerated due to anemia and stopped. The heart recipient also achieved SVR‐12. To further investigate these different responses to antiviral therapy from a single donor, we sequenced the 3’ half HCV genomes from donor plasma stored at organ procurement and from the kidney and heart transplant recipients’ plasma 3 days posttransplant. The majority of the donor plasma virus contained 2 NS5A resistance–associated nucleotide substitutions, and both recipients were infected with highly similar NS5A‐resistant virus populations (Figure S2A,B). Notably, this heart recipient's NS5A resistance–associated nucleotide substitution was not detected in routine clinical screening (indeterminate result noted earlier). At 21 days posttransplant in the kidney recipient, sequencing identified a single closely related population of viruses encoding the 2 resistance mutations, but no additional resistance mutations to explain why the virus was able to replicate at high levels. 3.2 Immunologic outcomes One patient underwent OHT with a weakly positive cross‐match against the donor and initially received basiliximab induction. After subsequent review of the retrospective cross‐match, the patient received thymoglobulin on postoperative day 4 to suppress the development of B and T cell responses. Unfortunately, the recipient developed antibody‐mediated rejection with positive DSA and allograft dysfunction. The patient received aggressive immunosuppression, including rituximab and intravenous steroids. Although cardiac function returned to normal, the patient subsequently experienced multiorgan failure due to sepsis from a presumed disseminated fungal infection and died on day 79 after transplantation. Despite profound immunosuppression, the HCV viral load was undetectable and liver aminotransferases were normal. No other patients developed antibody‐mediated rejection or DSA. Two other recipients did have grade 2R acute cellular rejection on allograft biopsy, which resolved in subsequent allograft pathology to grade 1 or 0. Figure S3 shows cardiac allograft biopsy results. 3.3 Other serious adverse events Adverse events were reviewed by the DSMB; none were adjudicated as related to HCV infection or antiviral therapy. In addition to the previously noted death, 2 patients developed acute kidney injury, with 1 requiring months of dialysis before recovering sufficient kidney function to stop renal replacement therapy. Table S4 shows all serious adverse events among USHER participants.

4 DISCUSSION This pilot trial provides important evidence that HCV‐infected hearts can be transplanted into HCV‐negative recipients with acceptable clinical outcomes and high cure rates. In the presence of intense immunosuppression, all 10 USHER participants responded rapidly to antiviral therapy. Transaminase elevations were minor and transient, suggesting that hepatic inflammation due to HCV infection was not a concern. Although serious adverse events included one death and acute kidney injury requiring prolonged dialysis therapy, these adverse events appeared to be unrelated to HCV or its therapy and instead reflect the general risks of heart transplantation. We present a novel comparison of 5 USHER recipients to the 7 recipients of kidneys from the same donors. The substantial variation in the trajectories of HCV viral load after donor‐derived infection may offer a cautionary lesson for transplant centers that some recipients may need repeat or augmented HCV therapy to achieve cure. The USHER trial results should provide some reassurance that DAA treatments will enable better outcomes with transplantation of HCV‐infected hearts than were achieved in the interferon treatment era. Specifically, the 2005 retrospective analysis in JAMA by Gasink et al reported a doubling of the risk of death and implicated liver disease and coronary vasculopathy as plausible mechanisms for these outcomes with transplanting hearts from HCV‐infected donors.6 By contrast, aminotransferase elevations in USHER were common in the first weeks after transplantation but only mild or moderate in magnitude. This manuscript includes only 6‐ to 12‐month follow‐up for OHT recipients, but we identified no clinical evidence of accelerated coronary artery disease in participants. The USHER results are consistent with the case series reported by Schlendorf et al at Vanderbilt, where OHT recipients of HCV‐infected hearts were initiated on antiviral therapy in hepatology clinic once they were clinically stable and discharged from the hospital, and a case report from Baylor.33 Notably, the Vanderbilt group reported 2 cases of primary graft dysfunction as well as a late case of unexplained graft dysfunction.5 Our study is distinct from the Vanderbilt case series and the Baylor case report for several reasons: (1) USHER is the first formal clinical trial involving OHT using HCV‐NAT+ donor organs for uninfected recipients with prespecified inclusion/exclusion criteria and defined outcomes; (2) USHER was conducted concurrently with an a trial involving HCV‐NAT+ donor kidneys, which enabled a novel comparison of data on the viral kinetics of HCV transmission in heart vs kidney transplant recipients; and (3) USHER participants received DAA treatment early posttransplant, which in several cases required enteral administration of crushed without impacting HCV cure rates. Taken together, the results of USHER trial and the Vanderbilt and Baylor reports should encourage greater acceptance of HCV‐infected cardiac allografts, but also highlight the need for centers to publish the results of larger numbers of patients with longer follow‐up. This article also presents fresh data on potential challenges in treating donor‐derived HCV that should be considered by centers developing their own protocols. The concurrent conduct of clinical trials in heart and kidney transplantation using HCV‐infected organs and the measurement of quantitative viral loads in the organ donor enabled our group to present unique data on divergent outcomes for recipients of organs from the same donors. Notably, 1 heart recipient responded rapidly to antiviral therapy while a kidney recipient from the same donor failed initial antiviral therapy and subsequently the team added sofosbuvir and ribavirin to elbasvir/grazoprevir; fortunately, this recipient achieved SVR‐12 with the augmented regimen. Single genome sequencing of the donor, heart, and kidney recipients’ viruses showed that the majority of viruses that circulated in the donor and were transmitted to organ recipients contained 2 NS5A‐resistance mutations, but the kidney recipient's virus did not contain additional shared mutations that could explain the on‐treatment failure of DAA therapy (notably, we were able to achieve SVR‐12 with an augmented regimen). Therefore, we hypothesize that a higher inoculum of NS5A‐resistant virus in the kidney transplant recipient may have caused the failure of initial therapy. In addition, we call attention to another USHER participant who developed a very elevated HCV viral load of 40 000 000 IU/mL, for which reason our team empirically extended the elbasvir/grazoprevir therapy from 12 to 16 weeks. These outcomes suggest that acute infection in the setting of immunosuppression will occasionally lead to rapid viral replication and suggest the possible benefit of close monitoring of HCV RNA, characterizing NS5A resistance–associated nucleotide substitutions, and implementing early treatment. The study has limitations including small sample size and generalizability. The trial comprised only 10 transplantations at one center, although when the USHER results are considered together with other studies, it appears plausible that HCV cure rates from donor‐derived, de novo HCV infection in transplantation will approach 100%.5, 23 Second, some patients may have been motivated to enroll in USHER by the potential to reduce waiting time to transplantation.34 However, because more publications have emerged reporting high cure rates and manageable complications with HCV‐infected organs, it is likely that more centers will compete for these organs and there may be only a modest reduction in waiting time by accepting them. Third, we restricted transplantation to organs from donors with HCV genotypes 1 and 4 given our choice of antiviral therapy. The current availability of pangenotypic DAAs that have few relevant drug interactions and can be given in the presence of renal dysfunction will likely eliminate the need to perform donor HCV genotyping and restriction to certain genotypes.35 Finally, DAA therapies for HCV remain expensive and obtaining insurance approval may be difficult in some circumstances.36 If transplanting HCV‐infected hearts into uninfected recipients becomes the standard of care, centers will need to identify mechanisms to support the cost of these therapies; pretransplant approval by insurance carriers may be the best option, so treatment is not delayed. In summary, this single‐arm trial of OHT from HCV‐NAT+ deceased donors into 10 uninfected recipients showed 100% cure rates among the 9 patients completing antiviral therapy. Although one recipient died, and another required prolonged dialysis, no adverse event was adjudicated as related to HCV or its therapy. Taken together with other studies, the USHER results provide further evidence that wider use of HCV‐infected organs should be a priority. However, the findings suggest the importance of monitoring patients closely for the possibility of resistance to antiviral therapy and broadening or extending therapy when necessary.

ACKNOWLEDGMENTS We gratefully acknowledge the extensive efforts of staff from the Gift of Life Donor Program (Philadelphia, PA) and other organ procurement programs that helped coordinate information about organ donors and HCV genotype specimen collection. We acknowledge the remarkable efforts of the molecular pathology laboratory at the Hospital of the University of Pennsylvania that implemented a rapid HCV genotype method that is available 24 hours and 7 days a week. Many transplant staff members at the University of Pennsylvania also made important contributions to the care of THINKER patients. We also acknowledge our research coordinator, Caitlin Phillips, for her efforts in data cleaning and organization. We thank the USHER trial participants and recognize the generosity of the organ donors and their families. The study was sponsored by an investigator‐initiated grant from Merck to the University of Pennsylvania. Merck provided funds for study activities as well as elbasvir/grazoprevir.

DISCLOSURE The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation: P.R. receives investigator‐initiated research support from Merck and CVS, is associate editor for the American Journal of Kidney Diseases, and a consultant for COHRDATA. P.A. is a member and received travel reimbursements from American Society of Transplant Surgeons, American Society of Nephrology, and the International Hepatobiliary Pancreas Association, is an editor for Clinical Transplantation, Liver Transplantation, and American Journal of Transplantation, and a counselor for American Society of Transplant Surgeons. E.B. is a site investigator and on the advisory board for trials funded by Merck. R.B. receives research support from Veloxis, CareDx, and Shire, is a consultant for Veloxis, an advisor to CSL Behring, receives royalties from UpToDate, and is an editor for AJKD. R.R. receives research support for investigator‐initiated grants from Merck, Gilead, Abbvie, Intercept, Conatus, Mallinckrodt, and Grifols, is an advisor for Merck, Abbvie, Gilead, Shionogi, and Dova, and is on the data safety and monitoring board (DSMB) for a Novartis trial. M.L. has received research support from Pfizer. D.G. has received investigator‐initiated research support from Merck, Intercept, Zydus, and Gilead. The other authors have no conflicts of interest to disclose.

Open Research DATA AVAILABILITY STATEMENT The authors will share the protocol, consent and education documents with other investigators. Following IRB approval, the authors will share aggregate data for all participant characteristics and outcomes recorded for the trial. Because of the trial's small size, we will not share individual patient‐level data because of the risk that such disclosure might make it possible to identify patients. The data may be obtained via email requests to the corresponding author Dr. Peter Reese: peter.reese@uphs.upenn.edu.

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