A, Transmission of HCV infection based on donor HCV profile. B, Treatment status among 67 HT recipients with dd (donor-derived)-HCV. Ab indicates antibody; DAA, direct-acting antiviral; NAT, nucleic acid test; SVR12, sustained virologic response at 12 weeks following treatment completion.
aSeptember 2016 through May 15, 2019.
Thirty-day (A) and 1-year (B) survival rates for patients who developed donor-derived (dd) hepatitis C virus (HCV) (orange lines) and those who did not (blue lines). Thirty-day (C) and 1-year (D) survival rates for recipients of HCV-positive (orange lines) and HCV-negative (blue lines) donor hearts performed during the same period.
eFigure 1. Clinical protocol for heart transplantation using HCV-positive donors
eFigure 2. Heart Allocation Waitlist Statuses, as defined by the Organ Procurement and Transplantation Network
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Schlendorf KH, Zalawadiya S, Shah AS, et al. Expanding Heart Transplant in the Era of Direct-Acting Antiviral Therapy for Hepatitis C. JAMA Cardiol. 2020;5(2):167–174. doi:10.1001/jamacardio.2019.4748
Will inclusion of hepatitis C–positive donors increase the donor pool, reduce wait-list duration, and enable a cure of donor-derived hepatitis C with acceptable 1-year morbidity and mortality?
In this case series of 80 patients who underwent heart transplant using hearts from hepatitis C–positive donors, the median wait-list time was 4 days (interquartile range, 1-18), donor-derived hepatitis C infection was easily curable with direct-acting antivirals despite immunosuppression, and 1-year survival, which exceeded 90%, was not significantly different when compared with survival among patients who were transplanted with hearts from hepatitis C–negative donors during the same period.
Using hepatitis C–positive donors may afford a strategy to substantially expand the donor pool for patients awaiting heart transplant, increasing transplant volumes, and reducing morbidity and mortality on the wait-list.
For patients awaiting heart transplant, hepatitis C–positive donors offer an opportunity to expand the donor pool, shorten wait times, and decrease wait-list mortality. While early reported outcomes among few heart transplant recipients have been promising, knowledge of 1-year outcomes in larger cohorts of patients is critical to shared decision-making with patients about this option.
To better define the association of hepatitis C–positive donors with heart transplant volumes, wait-list duration, the transmission and cure of donor-derived hepatitis C, and morbidity and mortality at 1 year.
Design, Setting, and Participants
This was a prospective, single-center observational study of 80 adult (age 18 years or older) patients who underwent heart transplant using hearts from hepatitis C–positive donors between September 2016 and April 2019 at a large academic medical center. Among donors, who were considered hepatitis C–positive if results from hepatitis C antibody and/or nucleic acid testing were positive, 70 had viremia and 10 were seropositive but did not have viremia. Follow-up was available through May 15, 2019. Comparisons were drawn with patients who underwent transplant with hearts from hepatitis C–negative donors during the same period.
In addition to standard posttransplant management, transplant recipients who developed donor-derived hepatitis C infection were treated with direct-acting antivirals.
Main Outcomes and Measures
The main outcomes included wait-list duration and 1-year survival in all patients, and for those who developed donor-derived hepatitis C, the response to direct-acting antiviral treatment.
Of 80 patients, 57 (71.3%) were men, 55 (68.7%) were white, and 17 (26.3%) were black; the median age at transplant was 54.5 years (interquartile range, 46-62 years). Following consent to accept hearts from hepatitis C-exposed donors, the median days to heart transplant was 4 (interquartile range, 1-18). No recipients of donors with negative nucleic acid testing results (10 [12.5%]) developed donor-derived hepatitis C. Of 70 patients who were recipients of donors with positive nucleic acid testing results, 67 (95.7%) developed donor-derived hepatitis C over a median follow-up of 301 days (interquartile range, 142-617). Treatment with direct-acting antivirals was well tolerated and yielded sustained virologic responses in all treated patients. Within the cohort with infection, 1-year patient survival was 90.4%, which was not significantly different compared with the cohort without infection or with patients who received transplants from hepatitis C–negative donors during the same period.
Conclusions and Relevance
In the era of direct-acting antivirals, hepatitis C–positive donors are a viable option to expand the donor pool, potentially reducing wait-list duration and mortality. In heart transplant recipients with donor-derived hepatitis C, infection is well-tolerated and curable, and 1-year survival is equivalent to that in recipients of hepatitis C–negative donors.
For patients awaiting heart transplant (HT), the shortage of donor hearts contributes to prolonged wait times, increased reliance on mechanical circulatory support (MCS), and higher mortality rates. During the most recent era, median wait times ranged from 70 to 535 days depending on blood type, and in 2018, more than 950 patients died while waiting for a transplant or were removed from the wait-list because of progressive illness.1
Previous experience using hepatitis C virus (HCV)–positive donors was a high rate of HCV infection and unacceptably poor outcomes in recipients.2,3 However, since the introduction of direct-acting antivirals (DAAs) that have a high cure rate of HCV,4,5 there is renewed interest in using organs from HCV-positive donors as a strategy to expand the donor pool. This is particularly crucial given the increase in drug overdose as a cause of donor death and rising rates of HCV infection in users of intravenous drugs.6,7
In the fall of 2016, our center (Vanderbilt University Medical Center) developed a clinical protocol for HT from HCV-positive donors and published our preliminary experience in 13 patients.8 While early reported outcomes from our center and others have been encouraging,8-10 information about outcomes at 1 year post-HT and beyond is critical to shared decision-making with patients about this new option. In this article, we report our experience among 80 HT recipients of HCV-positive donors, 44 (55%) of whom have at least 1 year of follow-up post-HT.
As part of the clinical protocol (eFigure 1 in the Supplement), 80 patients underwent HT from HCV-positive donors between September 2016 and April 2019; follow-up was available through May 15, 2019. We defined an HCV-positive donor as one for whom the results of either HCV antibody or HCV nucleic acid testing (NAT) were positive. All patients received education about HCV and HCV-positive donors, including the possibility of these donors expanding the donor pool, the high likelihood of disease transmission from HCV NAT–positive donors, and the lack of long-term data in using these donors for HT in the era of DAAs. Patients gave written informed consent to be recipients of HCV-positive donors before organs were offered for transplant. Data collection and analysis were performed with institutional review board approval from Vanderbilt University Medical Center.
Beginning in September 2016, select wait-listed patients deemed to be at high risk for wait-list mortality were given the opportunity to consent to HCV-positive donors. In September 2018, based on our promising early outcomes, we extended this opportunity to all waitlisted patients, only 10 of whom declined consideration of these donors. Following consent, a candidate’s United Network for Organ Sharing (UNOS) listing registration was modified accordingly.
Patients who were recipients of transplants from HCV-positive donors were treated per our center's standard immunosuppression protocol, with an initial regimen of mycophenolate mofetil (1 g every 12 hours), tacrolimus (titrated to a trough level of 8-12 ng/mL), and a steroid taper. The use of induction was at the discretion of the transplant cardiologist and generally reserved for patients who met our center’s induction criteria. Immunosuppression was not modified in any patient because of donor HCV status or HCV treatment regimen. Patients underwent surveillance endomyocardial biopsies per our standard protocol, as well as coronary angiography at 1 year post-HT for surveillance of coronary allograft vasculopathy (CAV).
Following transplant, all patients were referred to the transplant hepatology service. Choice and duration of DAAs was at the discretion of the hepatology service and driven by factors that included HCV genotype, potential drug-drug interactions, and insurance formularies. No dose adjustments were made for renal function. The HCV genotype was checked once on detection of recipient viremia and viral loads were checked weekly on Fridays in the inpatient setting and monthly in the outpatient setting until 4-week and 12-week sustained viral response was achieved and documented.
Data collection and analysis were performed after obtaining informed patient consent and approval from the institutional review board. Data collection on recipients continues and consists of (1) details of HCV testing results and treatment and (2) details of recipients’ posttransplant courses, including immunosuppression regimen and occurrence of graft dysfunction, rejection, liver dysfunction, graft vasculopathy, and death. Data on patients who received transplants from HCV-negative donors during the same period were retrospectively collected and included recipient and donor demographics and the occurrence of graft dysfunction, rejection, graft vasculopathy, and death.
Descriptive analyses were performed for various patient characteristics. Summary statistics for continuous variables were reported as mean (SD) or median (interquartile range [IQR]: 25%-75%); categorical variables were reported as proportions. The statistical analysis was performed using Stata, version 13 (StataCorp) and statistical significance was set at P < .05. The data presented reflect follow-up through May 15, 2019.
Between September 2016 and April 2019, a total of 239 patients ages 18 years and older underwent HT at our institution, including 80 (33.5%) from HCV-positive donors. For all but 2 patients (2.5%), recipients of HCV-positive donors were HCV naive at the time of HT. Two patients had a history of HCV that was treated with DAAs and cured before they were listed for transplant. Donor and recipient characteristics and initial induction and immunosuppressive regimens are presented in Table 1. In 6 patients (7.5%), cyclosporine was used in place of tacrolimus because of adverse effects experienced early post-HT that were attributable to tacrolimus. In 4 highly sensitized patients (5.0%), thymoglobulin induction (1.0 mg/kg for 1-3 doses) was used.
Among all 80 recipients of HCV-positive donor hearts, the median active wait-list time from the time patients consented to accept HCV-positive donor hearts was 4 days (interquartile range [IQR], 1-18). Among the subset of patients (66 [82.5%]) who had accrued active wait-list time before being given the opportunity to consent to receive an HCV-positive donor heart, the median active wait-list time was 28 days (IQR, 6-168) preconsent vs 4 days (IQR, 1-15) postconsent.
Transmission rates of HCV based on donor HCV profile are depicted in Figure 1A. For all but 3 patients (4.3%), the 70 recipients of hearts from NAT-positive donors developed donor-derived (dd) HCV (transmission rate, 95.7%). Conversely, none of the 10 recipients of hearts from NAT-negative donors developed infection (transmission rate, 0%). For 2 patients for whom the donor tested seronegative but NAT-positive, 1 recipient developed dd-HCV and the other did not.
Among the cohort of patients with dd-HCV, the details of HCV testing as well as treatment characteristics and outcomes are presented in Table 2 and Figure 1B. Hepatitis C genotype 1a was most common, followed by genotypes 3, 1b, and 2. The median time from HT to detection of viremia was 5 days (IQR, 2-11). As of May 15, 2019, 55 of 67 patients with dd-HCV (82%) initiated and/or completed HCV treatment. With 3 exceptions (5.5%), those with dd-HCV received DAAs once deemed to be clinically stable in the outpatient setting at a median of 55 days (IQR, 39-74) post-HT. For 3 patients with complicated postoperative courses requiring prolonged inpatient stays, DAAs were initiated inpatient at a median of 93 days (IQR, 43-248) post-HT. For most patients, treatment duration was 12 weeks. For 2 patients (3.6%) who had persistent low-level viremia 4 weeks after starting treatment, treatment duration was extended to 24 weeks at the discretion of the hepatology service. There have been no treatment failures and only 1 case of premature treatment discontinuation because of a patient’s death. For the 37 patients (67.3%) who have been followed up for at least 12 weeks after DAA therapy completion, the rate of sustained virologic response at 12 weeks (SVR12) is 100%.
Among the subset of patients with dd-HCV, for whom the median follow-up time was 273 days (IQR, 136-617), 30-day and 1-year patient survival rates were 92.5% and 90.4%, respectively (Figure 2A and B). Six patients died: 5 of primary graft failure at a median of 10 days (IQR, 6-13) post-HT and before the initiation of HCV therapy, and 1 of pulmonary embolism at 112 days post-HT during HCV therapy. Severe primary graft dysfunction (PGD), defined as dependence on left or biventricular mechanical support (excluding an intra-aortic balloon pump) within 24 hours of HT, occurred in 11 patients, ultimately resulting in death in 5 patients, 1 of whom underwent an urgent retransplant before his death.
Among the subset of patients with dd-HCV, 10 (14.9%) had acute cellular rejection episodes for which treatment was required. One patient (1.5%) had a single antibody-mediated rejection episode requiring treatment.
As of May 15, 2019, 29 of 67 patients with dd-HCV (43.3%) have undergone coronary angiography at 1 year post-HT for CAV surveillance. Of those, 9 (31.0%) demonstrated signs of CAV, including 7 (24.1%) with International Society for Heart and Lung Transplantation CAV grade 1, 1 (3.4%) with CAV grade 2, and 1 (3.4%) with CAV grade 3. No patients with dd-HCV have died or required retransplant because of CAV.
Among all recipients of hearts from HCV-positive donors, the median hospital length of stay (LOS) after HT was 15 days (IQR, 12-23) and was not significantly different between those patients who developed dd-HCV (median LOS, 15 days; IQR, 12-23) and those who did not (median LOS, 17 days; IQR, 14-19; P = .79 for the difference). Among the subset of patients with dd-HCV, there were no readmissions attributable to HCV infection or its treatment.
Three patients with confirmed dd-HCV (4.5%) developed acute pancreatitis at a mean (SD) of 48 (37) days post-HT before initiation of HCV treatment. For 2 of these patients, the pancreatitis resolved with bowel rest and intravenous hydration. For 1 patient, the pancreatitis resolved only following initiation of HCV treatment. With the exception of 7 patients who manifested severe PGD complicated by multiorgan dysfunction early post-HT and 1 patient with acute pancreatitis that resolved with bowel rest, no patients exhibited signs of significant liver injury, defined as a transaminase level or total bilirubin level 3 or more times the upper limit of normal. In all surviving patients, transaminase and bilirubin levels returned to normal following treatment of underlying causes. No significant drug-drug interactions occurred. A comparison of donor characteristics and HT outcomes in the 67 patients with dd-HCV (83.8%) and the 13 patients without dd-HCV (16.3%) is presented in Table 3.
The key characteristics and outcomes of the 80 recipients of transplants from HCV-positive donors included in this cohort compared with the 159 transplants from HCV-negative donors that occurred during the same period are presented in Table 3. In both groups, donors were frequently recovered from UNOS regions 11, 10, 3, and 4. However, compared with HCV-negative donors, HCV-positive donors were also frequently recovered from UNOS region 2. Recipients of transplants from HCV-positive donors exhibited significantly higher rates of severe PGD than recipients of transplants from HCV-negative donors (13.7% vs 3.1%; P = .002). Conversely, there were no significant differences between groups in hospital LOS post-HT, rejection requiring treatment, incidence of CAV at 1 year post-HT, or survival at 30 days and 1 year (Figure 2C and D).
It is difficult to draw meaningful conclusions from a comparison of wait times between recipients of transplants from HCV-positive vs HCV-negative donors because many patients in the latter group gave consent to undergo transplants from HCV-positive donors but were ultimately transplanted with organs from donors who were HCV-negative. However, of the 10 patients on the wait-list who declined to consent to receive hearts from HCV-positive donors, 8 patients remain wait-listed, 1 patient underwent left ventricular assist device as a bridge to HT, and 1 patient was removed from the wait-list for having become too ill.
We report what is, to our knowledge, the largest single-center experience to date demonstrating that HT with organs from HCV-positive donors is a feasible strategy to substantially expand the donor pool and reduce wait times. Among HT recipients who developed dd-HCV, (1) 30-day and 1-year patient survival rates exceeded 92% and 90%, respectively, and (2) DAAs were well tolerated and yielded SVR12 rates of 100% despite immunosuppression.
The percentage of deceased donors who have positive test results for HCV has increased substantially over the past 2 decades because of increased drug overdose deaths resulting from the growing opioid epidemic.7 Historically, HT from these donors portended a poor outcome.2,3 However, the introduction of DAAs has revolutionized HCV treatment and renewed interest in HCV-positive donors. At a time when utilization rates of hearts from these donors are on the rise, increased knowledge about post-HT outcomes is imperative.
Among the most striking consequences since the institution of our HCV protocol is the association it has had with HT volume and patient wait times. Between 2016 and 2018, HT from HCV-positive donors accounted for 37% of our center’s adult HT volume, contributing to a 2-fold increase in volume from 2013 to 2015 when 130 HT were performed to 2016 to 2018 when 260 HT were performed. Compared with national reported median wait times between 70 and 535 days,1 the median wait time for patients in this cohort following consent to accept hearts from HCV donors was 4 days, a duration that for many patients obviated extended periods of short-term MCS and/or transition onto more durable MCS as a bridge to HT.
A key finding of this study is that among patients with dd-HCV, rates of 30-day and 1-year survival post-HT were comparable with those of patients who underwent transplant during the same period from HCV-negative donors, as well as to reported survival rates among recipients of non–HCV donor hearts worldwide.11 However, these comparisons start at the time of HT rather than HT listing. The risk of dying on the wait-list is high—at least 10%12—and increases as wait times increase. Nearly 5% of wait-listed candidates are removed from the list pre-HT because of clinical deterioration.13 Among patients who remain wait-listed, comorbidities, including progressive renal dysfunction and stroke, accumulate as wait times increase. This is especially true for patients bridged to HT with durable MCS, for whom the decision to pursue MCS may be affected by long wait times and among whom rates of HT are significantly lower compared with those for wait-listed patients treated medically.14 In our dd-HCV cohort, 1-year survival rates exceeded those reported among patients undergoing MCS even with the newest-generation devices.15 For all of these reasons, there is likely to be a substantial benefit of shorter wait times with the inclusion of HCV-positive donors that is not detectable without use of mortality figures that start at the time of HT listing.
Historically, transplant of hearts from HCV-positive donors was associated with higher rates of allograft rejection and graft vasculopathy in HT recipients.3,16 In our experience, rates of treated rejection among transplants from HCV-positive donors were similar to those of HCV-negative transplants performed at our center and also similar to rates reported in the literature among all HT recipients.7 Conversely, the rates of any CAV at 1 year were higher in patients undergoing a transplant from an HCV-positive donor, although this difference was not statistically significant. Inferences about vasculopathy are limited by small numbers and the absence of baseline coronary angiograms in most recipients, as well as by the insensitivity of angiography for detecting early CAV. Even so, multiple studies performed in the pre-DAA era have shown an association between HCV, endothelial dysfunction, and atherosclerosis,17-20 and it is conceivable that even transient periods of HCV viremia in the donor and recipient may contribute to an inflammatory state that provokes accelerated intimal thickening in the coronary tree. Beginning in 2018, we modified our CAV surveillance protocol in patients with dd-HCV to include intravascular ultrasonography studies at baseline (4-6 weeks post-HT) and 1 year post-HT. We are currently in the process of analyzing our intravascular ultrasonography data and expect to report our preliminary findings next year.
While an association between HCV and PGD seems unlikely given the absence of detectable viremia so early after transplant, the differences in rates of severe PGD highlighted in Table 3 are noteworthy. In all groups, these rates were less than or similar to the severe PGD rates of 8% to 18% reported in the literature among all HT recipients.21 Moreover, given data suggesting that preoperative MCS may be a risk factor for PGD,22 the increased rate of PGD among transplants from HCV-positive donors may be explained in part by our decision to offer hearts from HCV-positive donors to only patients with severe illness on our wait-list before September 2018, as many of these patients were receiving MCS at the time of HT. Importantly, in a larger scale retrospective analysis of UNOS data, recipients of HCV-positive donor hearts had an equivalent risk of PGD compared with recipients of HCV-negative donor hearts, suggesting that our center’s results may not be reflected at other centers.23 Even so, the possibility of an association between HCV and PGD warrants further investigation.
This study is limited by the potential flaws inherent to all observational studies that are performed at a single center. Geographic differences in organ donation and deaths of drug overdose exist.7,24 Because our center is surrounded by donation service areas located near the epicenter of the opioid crisis, our experience with increasing HT volumes and achieving short wait times using HCV-positive donors may not be easily generalizable to other centers across the country, particularly those located in regions where there is less incidence of death due to drug overdose and presumably fewer donors with HCV infection.
To our knowledge, our experience using HCV-positive donors for HT is the world’s largest in the era of DAAs and reflects a close coordination among multidisciplinary teams (including transplant cardiologists, surgeons, hepatologists, pharmacists, infectious disease specialists, and nurse coordinators). At a time when the discrepancy between organ supply and organ demand continues to increase, our findings suggest that use of these donors is an effective way to increase the donor pool, thereby increasing transplant volumes and reducing the morbidity and mortality of patients awaiting HT. Further work is needed to illuminate longer-term outcomes, specifically CAV, to guide the optimal timing and duration of HCV treatment and better inform wait-listed patients and their clinicians as they consider this option.
Accepted for Publication: October 7, 2019.
Corresponding Author: Kelly H. Schlendorf, MD, Department of Heart Failure and Transplant Cardiology, Vanderbilt University Medical Center, 1215 21st Ave S, Room 5209, Nashville, TN 37232 (email@example.com).
Published Online: December 18, 2019. doi:10.1001/jamacardio.2019.4748
Author Contributions: Drs Schlendorf and Zalawadiya had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Schlendorf, Zalawadiya, Lindenfeld.
Acquisition, analysis, or interpretation of data: Schlendorf, Zalawadiya, Shah, Perri, Wigger, Brinkley, Danter, Menachem, Punnoose, Balsara, Sacks, Ooi, Awad, Sandhaus, Schwartz, O'Dell, Scholl, Lindenfeld.
Drafting of the manuscript: Schlendorf, Zalawadiya, Lindenfeld.
Critical revision of the manuscript for important intellectual content: Schlendorf, Zalawadiya, Shah, Perri, Wigger, Brinkley, Menachem, Punnoose, Balsara, Sacks, Ooi, Awad, Sandhaus, Schwartz, O'Dell, Carver, Edmonds, Lindenfeld.
Statistical analysis: Schlendorf, Zalawadiya.
Administrative, technical, or material support: Schlendorf, Shah, Perri, Schwartz, O'Dell, Carver, Edmonds, Lindenfeld.
Supervision: Schlendorf, Lindenfeld.
Other - data : Sandhaus.
Other - Data collection: Scholl.
Conflict of Interest Disclosures: Dr Menachem reported personal fees from Abbott Vascular outside the submitted work. No other disclosures were reported.
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