Abstract
Background.
The use of hepatitis C virus–positive (HCV+) donors has expanded the donor pool for orthotopic heart transplantation (OHT). This study evaluated center-level trends and utilization of HCV+ donors for OHT.
Methods.
Data were extracted from the Scientific Registry of Transplant Recipients on adults (≥18 y) undergoing OHT between January 1, 2016 and December 31, 2019. Centers performing <10 OHTs during the study period were excluded. Donor utilization rates were evaluated at the center level. Center-level characteristics were compared between centers performing HCV+ donor hepatitis C virus–negative (HCV−) recipient OHTs and those not utilizing HCV+ donors for HCV− recipients.
Results.
A total of 10134 patients underwent OHT, including 613 (6.05%) HCV+ donors transplanted into HCV− recipients. The number of HCV+ OHTs increased from 15 of 2512 (0.60%) in 2016 to 285 of 2490 (11.45%) in 2019 (P < 0.001). In 2016, among 105 centers performing OHTs, 7 (6.67%) utilized HCV+ donors compared to 2019 during which 55 (52.89%) of 104 centers utilized HCV+ donors (P < 0.001). In total, 57 of 107 (53.27%) centers utilized HCV+ donors during the study period. Centers utilizing HCV+ donors had higher overall donor utilization rates (7376/24 378 [30.26%] versus 3463/15 335 [22.58%], P < 0.001) and were higher volume as compared to nonutilizing centers (mean annual OHT volume 30.72 ± 1.21 versus 16.2 ± 1.40, P < 0.001).
Conclusions.
Although the use of HCV+ donors for OHT is rapidly expanding in the United States, almost half of transplant centers remain nonutilizers. Broader education and implementation of HCV+ donor protocols may be important in expanding OHT to more patients with end-stage heart failure.
INTRODUCTION
In 1991, Pereira et al1 reported on the transmission of hepatitis C virus (HCV) through solid-organ transplantation and urged caution in the use of these donor organs. This, combined with early reports of decreased posttransplant survival in orthotopic heart transplantation (OHT) using hepatitis C virus–positive (HCV+) donors resulted in an abandonment of the practice.2 Considerable progress in the understanding of HCV and development of antiviral treatments has significantly altered attitudes toward these infected organs.3,4 The use of HCV+ OHT donors for hepatitis C virus–negative (HCV−) recipients has expanded the donor pool with recent studies showing comparable 1-y post-OHT outcomes between HCV+ and HCV− donors.5 Nevertheless, a shortage of donors persists thereby limiting potential treatment options for patients with end-stage heart failure. As of August 2020, >3500 individuals were listed for OHT.6 Though long-term outcomes have yet to be established, the advent of new HCV treatments has made the utilization of HCV+ donors an increasingly appealing option with studies in liver7 and kidney8 transplantations demonstrating favorable outcomes as well. Prior work has also examined utilization of HCV+ donors among different transplant centers. Bowring et al9 reported clustering of HCV+ donor kidney and liver transplants at a small proportion of transplant centers and suggested cautious but strategic expansion of protocols to increase the use of these organs. The current opioid epidemic and cohort of persons who inject drugs intravenously has contributed to an expanding pool of HCV+ donor organs. The aim of this study was to evaluate trends in center-level utilization of HCV+ OHTs in the United States.
MATERIALS AND METHODS
Study Cohort
The Scientific Registry of Transplant Recipients was utilized to obtain data on all adult patients (≥18 y) undergoing OHT in the United States between January 1, 2016 and December 31, 2019. Recipients with HCV were excluded. Patients undergoing concomitant OHT with another organ (eg, heart-liver, heart-lung, etc) were also excluded. Additionally, we excluded recipients who underwent OHT at a center that performed <10 total OHTs during the study period. Donors were designated as HCV+ based on the presence of HCV antibodies or positive nucleic acid amplification testing.
Center Level Data
We excluded all patients undergoing OHT at a center that performed <10 OHTs during the study period and these centers were similarly not included in this analysis. Centers were stratified into “utilizing” and “nonutilizing” centers based on the use of at least 1 HCV+ OHT donor during the study period. Overall donor utilization rates for OHT were also calculated at the individual center level.
Statistical Analysis
Continuous data are presented as mean ± SD for parametric data and median (interquartile range [IQR]) for nonparametric data. Categorical data are presented as number (percentage). Student’s t test and Mann-Whitney U test were utilized for pairwise comparison of parametric and nonparametric data, respectively. Pearson’s χ2 testing was utilized for comparison of categorical variables. HCV+ OHT volume by region throughout the United States was visually displayed. The Organ Procurement and Transplantation Network (OPTN) divides the states of Vermont and Virginia into 2 regions. For this display, Vermont was included with region 9 and Virginia was included with region 2. Using data from the United Network for Organ Sharing (UNOS) database, 1-y survival in patients undergoing OHT at utilizing and nonutilizing centers was obtained with Kaplan-Meier analysis. Log-rank testing was utilized to compare survival curves between the 2 groups. Statistical analyses were performed using the Stata 16 software package (StataCorp, 2017, Stata Statistical Software: Release 16, College Station, TX). This study was approved by the Institutional Review Board at the University of Pittsburgh (MOD18120143-003) and was performed in accordance with the guidelines of the Declaration of Helsinki.
RESULTS
Study Population
A total of 10 134 OHTs were performed between 2016 and 2019 with 613 (6.05%) of donors being HCV+ (Table 1). Recipients receiving HCV+ OHTs were significant older (55.20 versus 53.53 y, P = 0.002), however, there were no significant differences in sex or race. Similarly, the distribution of recipient diagnoses was similar between HCV− and HCV+ donors as was functional status. Ischemic time was significantly longer among HCV+ donors (212 versus 188 min, P < 0.001). The use of left ventricular–assist devices and inotropes was similar between both groups, however, recipients of HCV+ donor hearts were more likely to have received intra-aortic balloon pump support (15.66% versus 12.74%, P = 0.037). The number of HCV+ donor hearts increased from 15 in 2016 to 91 in 2017, 222 in 2018, and 285 in 2019.
TABLE 1.
Characteristics of patients undergoing heart transplant between January 2016 and December 2019, stratified by donor HCV status
| Recipient characteristics | HCV-negative donors (N = 9521) |
HCV-positive donors (N = 613) |
P |
|---|---|---|---|
|
| |||
| Age at transplant (y) | 53.53 ± 12.77 | 55.20 ± 11.61 | 0.002 |
| Sex | 0.884 | ||
| ○ Male | 6917 (72.65) | 447 (72.92) | |
| ○ Female | 2604 (27.35) | 166 (27.08) | |
| Race/ethnicity | 0.270 | ||
| ○ White | 6142 (64.51) | 408 (66.56) | |
| ○ African American | 2090 (21.95) | 136 (22.19) | |
| ○ Hispanic | 859 (9.02) | 41 (6.69) | |
| ○ Other | 430 (4.52) | 28 (4.57) | |
| Body mass index (kg/m2), median (IQR) | 27.52 (24.03–31.32) | 27.73 (24.63–31.88) | 0.038 |
| Diabetes | 2532 (26.59) | 170 (27.73) | 0.537 |
| Previous malignancy | 854 (9.00) | 1 (10.07) | 0.634 |
| Steroid use | 681 (7.35) | 37 (6.40) | 0.695 |
| Creatinine (mg/dL) | 1.24 (0.57) | 1.25 (0.42) | 0.580 |
| Bilirubin (mg/dL), median (IQR) | 0.70 (0.40–1.00) | 0.70 (0.50–1.00) | 0.288 |
| Diagnosis | 0.702 | ||
| ○ Nonischemic cardiomyopathy | 5307 (55.74) | 335 (54.65) | |
| ○ Ischemic cardiomyopathy | 2905 (30.51) | 196 (31.97) | |
| ○ Congenital | 295 (3.10) | 16 (2.61) | |
| ○ Restrictive | 388 (4.08) | 32 (5.22) | |
| ○ Valvular | 113 (1.19) | 5 (0.98) | |
| ○ Hypertrophic | 308 (3.23) | 16 (2.61) | |
| ○ Other/unknown | 205 (2.15) | 12 (1.96) | |
| Functional status | 0.150 | ||
| ○ Independent | 957 (10.88) | 45 (8.24) | |
| ○ Partially dependent | 4147 (47.14) | 262 (47.99) | |
| ○ Fully dependent | 3694 (41.99) | 239 (43.77) | |
| Ischemic time (min), median (IQR) | 188 (143–226) | 212 (179–243) | <0.001 |
| Intra-aortic balloon pump | 1213 (12.74) | 96 (15.66) | 0.037 |
| Left ventricular–assist device | 4245 (44.59) | 254 (41.44) | 0.128 |
| Inotropes | 3302 (34.68) | 198 (32.30) | 0.229 |
| Pulmonary capillary wedge pressure (mm Hg) | 17.06 (8.40) | 17.41 (8.11) | 0.344 |
| Pulmonary artery systolic pressure (mm Hg) | 38.61 (13.27) | 39.83 (13.28) | 0.035 |
| Transplant y | <0.001 | ||
| ○ 2016 | 2497 (26.23) | 15 (2.45) | |
| ○ 2017 | 2446 (25.69) | 91 (14.85) | |
| ○ 2018 | 2373 (24.92) | 222 (36.22) | |
| ○ 2019 | 2205 (23.16) | 285 (46.49) | |
HCV, hepatitis C virus; IQR, interquartile range.
Center Level Heart Transplant Volume
Transplant centers were stratified into utilizing centers (n = 57 centers) and nonutilizing centers (n = 50 centers) based on the use of at least 1 HCV+ donor heart during the study period (Table 2). The number of utilizing centers increased from 7 in 2016 to 55 in 2019 (Figure 1). Mean annual OHT volume over the study period was 30.72 for utilizing centers compared to 16.20 OHTs for nonutilizing centers (P < 0.001). Stratification of OHT volume per center, based on the number of HCV− and HCV+ donors, is shown (Figure 2). Overall, the donor utilization rates for OHT were 17.63% (613/3478) for HCV+ donors versus 25.05% (9593/38 299) for HCV− donors (P < 0.001). Utilizing centers displayed a greater proportion of donor heart utilization compared to nonutilizing centers (30.75% versus 23.18%, P < 0.001). Among utilizing centers, median HCV+ OHT volume was low at 0 for 2016 (IQR: 0–0) and 2017 (IQR: 0–1); the median volume was 1 (IQR: 0–6) in 2018 and 4 (IQR: 2–7) in 2019. Over the entire study period, the median number of HCV+ OHTs performed per center was 5 (IQR: 2–13). The percentage of status 1A/1B recipients (old allocation system) or status 1 recipients (new allocation system following the 2018 UNOS policy change) was lower among utilizing centers (70.07% versus 74.04%, P < 0.001). One-year survival after OHT was 91.51% and 91.46% at nonutilizing and utilizing centers, respectively (P = 0.914).
TABLE 2.
Characteristics of heart transplant centers utilizing HCV+ donors for OHT
| HCV+ donor nonutilizing centers (N = 50 centers) | HCV+ donor utilizing centers (N = 57 centers) | P | |
|---|---|---|---|
|
| |||
| Center classification by y | <0.001 | ||
| ○ 2016 | 98 | 7 | |
| ○ 2017 | 90 | 15 | |
| ○ 2018 | 72 | 35 | |
| ○ 2019 | 49 | 55 | |
| OHT volume by y, median (IQR) | |||
| ○ 2016 | 17 (9–26) | 23 (16–41) | 0.003 |
| ○ 2017 | 15 (10–21) | 25 (16–39) | <0.001 |
| ○ 2018 | 13 (9–21) | 27 (18–44) | <0.001 |
| ○ 2019 | 15 (9–21) | 26 (19–38) | <0.001 |
| Mean annual OHT volume per center | 16.20 (1.40) | 30.72 (1.21) | <0.001 |
| Total OHTs per center during the study period, median (IQR) | 57 (40–89) | 93 (65–158) | <0.001 |
| Overall donor utilization rates during the study period, OHT/all donors (%) | 3250/14 018 (23.18) | 6884/22 387 (30.75) | <0.001 |
| Donor utilization rates per center, OHT/all donors (%) | |||
| ○ 2016 | 911/3753 (24.27) | 1601/5235 (30.58) | <0.001 |
| ○ 2017 | 810/3518 (23.02) | 1727/5574 (30.98) | <0.001 |
| ○ 2018 | 779/3419 (22.78) | 1816/5831 (31.14) | <0.001 |
| ○ 2019 | 750/3328 (22.54) | 1740/5747 (30.29) | <0.001 |
| Median HCV+ OHT volume per center (IQR) | – | ||
| ○ 2016 | – | 0 (0–0) | |
| ○ 2017 | – | 0 (0–1) | |
| ○ 2018 | – | 1 (0–6) | |
| ○ 2019 | – | 4 (2–7) | |
| Median total HCV+ OHTs per center (IQR) | – | 5 (2–13) | – |
| Number of status 1A/1B (old) or 1 (new) recipients per total recipients (%) | 2407/3251 (74.04) | 4823/6883 (70.07) | <0.001 |
HCV+, hepatitis C virus–positive; IQR, interquartile range; OHT, orthotopic heart transplantation.
FIGURE 1.
Distribution of centers utilizing at least 1 HCV+ donor for OHT compared to nonutilizing centers from 2016 to 2019. HCV+, hepatitis C virus–positive; OHT, orthotopic heart transplantation.
FIGURE 2.
HCV− donor (in blue) orthotopic heart transplantation volume by center compared with the use of HCV+ donors (in red). HCV−, hepatitis C virus–negative; HCV+, hepatitis C virus–positive.
Regional Distribution of HCV+ Heart Transplants
The distribution of HCV+ OHTs based on OPTN region is shown (Table 3; Table S1, SDC, http://links.lww.com/TP/C128). In 2016, there were no HCV+ OHTs in regions 2, 7, 8, 9, and 10. By 2018, all regions had performed at least 1 HCV+ OHT. In 2019, region 1 demonstrated the highest proportion of HCV+ OHTs compared to the total OHT volume (27.21%). Regions 11 (18.60%), 2 (16.93%), 9 (16.48%), and 10 (10.29%) all demonstrated utilization of HCV+ OHTs donors numbering >10% of all OHTs performed. Regions performing the greatest number of HCV+ OHTs were all located in the eastern half of the United States (Figure 3).
TABLE 3.
Number of HCV+ donor heart transplants performed in relation to the total number of OHTs performed in each OPTN region by y
| OPTN region | 2016 |
2017 |
2018 |
2019 |
||||
|---|---|---|---|---|---|---|---|---|
| HCV+ OHTs, N (% total) | Total OHTs | HCV+ OHTs, N (% total) | Total OHTs | HCV+ OHTs, N (% total) | Total OHTs | HCV+ OHTs, N (% total) | Total OHTs | |
|
| ||||||||
| 1 | 2 (1.65) | 121 | 10 (8.00) | 125 | 38 (25.17) | 151 | 40 (27.21) | 147 |
| 2 | 0 | 278 | 16 (5.48) | 292 | 15 (6.10) | 246 | 42 (16.93) | 248 |
| 3 | 1 (0.33) | 302 | 0 | 324 | 13 (4.42) | 294 | 22 (7.67) | 287 |
| 4 | 2 (0.68) | 294 | 3 (1.16) | 258 | 7 (2.90) | 241 | 5 (2.29) | 218 |
| 5 | 1 (0.26) | 391 | 9 (2.49) | 362 | 16 (3.94) | 406 | 28 (6.93) | 404 |
| 6 | 1 (1.08) | 93 | 3 (3.19) | 94 | 8 (7.92) | 101 | 4 (5.56) | 72 |
| 7 | 0 | 216 | 0 | 203 | 5 (2.17) | 230 | 17 (7.23) | 235 |
| 8 | 0 | 161 | 0 | 169 | 1 (0.54) | 185 | 15 (8.77) | 171 |
| 9 | 0 | 141 | 16 (10.26) | 156 | 42 (20.29) | 207 | 29 (16.48) | 176 |
| 10 | 0 | 211 | 0 | 196 | 24 (12.57) | 191 | 21 (10.29) | 204 |
| 11 | 8 (2.63) | 304 | 34 (9.50) | 358 | 53 (15.45) | 343 | 61 (18.60) | 328 |
HCV+, hepatitis C virus–positive; OHT, orthotopic heart transplantation; OPTN, Organ Procurement and Transplantation Network.
FIGURE 3.
Regional distribution of the use of HCV+ donors for OHT based on OPTN regions from 2016 to 2019. For this display, Vermont was included with region 9 and Virginia was included with region 2 (both states are divided in the OPTN regionalization). HCV+, hepatitis C virus–positive; OHT, orthotopic heart transplantation; OPTN, Organ Procurement and Transplantation Network.
DISCUSSION
Favorable posttransplant outcomes with the use of HCV+ donor organs for transplantation into HCV− recipients, along with evolving therapies for HCV infection, have driven new interest in the potential for these organs to expand the donor pool. Others have demonstrated incorporation of these donors for other types of solid-organ transplants. Here, we demonstrate increasing use of HCV+ donors for OHT between 2016 and 2019 though transplant of these organs remains limited to only about half of centers in the United States. Centers utilizing these HCV+ organs displayed higher overall donor utilization rates. The number of HCV+ OHTs performed per center, however, remained low. Interestingly, the majority of these transplants were performed in the eastern half of the country. With the anticipated growth of potential donors from injection drug use, the pool of HCV+ donors is projected to rise. Thus, expansion of the use of HCV+ donors for OHT to more centers may increase the availability of organs for end stage heart failure patients.
Between 2016 and 2019, the use of HCV+ OHTs increased 19-fold and the number of centers performing these transplants increased >7-fold. Concurrently, multiple publications have demonstrated the relative safety of the use of HCV+ donors for OHT. One-year outcomes post-OHT have been demonstrated to be comparable to patients undergoing OHT from HCV− donors in a recent propensity-matched analysis.5 Short-term outcomes describing the use of direct-acting antiviral treatment in patients receiving HCV+ hearts have also been promising.10–13 Despite this, long-term outcomes have yet to be established and will benefit from ongoing study of these patients. Furthermore, though direct-acting antivirals have demonstrated reduced mortality risk and a reduction in viral load in patients with chronic HCV infection, the longitudinal clinical impact of this treatment in HCV+ OHT recipients remains unknown.14,15 There is little evidence exploring the rationale for use or lack of use of HCV+ donors but there are likely factors at many levels from the candidate, provider, institution, and region that may influence these decisions. Prospective and retrospective studies, from the United States and internationally, which clarify OHT outcomes from these donors will likely serve to destigmatize the disease and encourage both patients and providers to consider organs from HCV+ donors. Additionally, the World Health Organization aims to eradicate HCV by 2030 thus the decreased prevalence of HCV infection should also expand the donor pool.
In particular, there are known effects of HCV viremia on cardiac allograft vasculopathy in the OHT recipient. An analysis of OHTs performed between 1994 and 2003 found that recipients of HCV+ donors died more frequently from coronary vasculopathy.2 However, a recent analysis of modern OHTs using HCV+ donors demonstrated using intracoronary ultrasound that the rates of angiographic grade 1 allograft vasculopathy were 10% and 25% at 6-mo and 1-y follow-up, respectively.16 Importantly, no patients required percutaneous or surgical revascularization for cardiac allograft vasculopathy at 1 y in their analysis. Another analysis evaluating 50 OHTs performed in HCV− recipients using HCV+ donors found that donors with positive nucleic acid amplification testing had a higher frequency and severity of acute cellular rejection.17 Future studies of HCV+ donors with larger cohorts of patients and longer follow-up will hopefully evaluate the occurrence of such adverse events to better delineate the impact on longitudinal survival and quality of life of the OHT recipient.18 The context of studies aiming to evaluate deleterious effects of HCV+ donor use in OHT must always be weighed against the possibility that waitlisted candidates may not have received an acceptable donor offer if they had not elected to receive HCV+ organs.
The impact of various transplant center characteristics on outcomes has been studied extensively in OHT. In particular, increasing center OHT volume has been correlated with overall post-OHT survival, including with the use of marginal donors.19–22 We found that centers utilizing HCV+ donors displayed higher overall OHT volume per year. The difference in annual volume between utilizers and nonutilizers was 14 OHTs per year, which was higher than the median number of HCV+ donor OHTs per year which ranged from 0 to 4. This suggests that these were truly higher volume centers and that the use of HCV+ donors did not fully account for this difference in volume. The availability and allocation of donor organs is important to consider in the context of the recent UNOS organ allocation policy change which has resulted in improved waitlist outcomes but was also associated with increased use of temporary mechanical circulatory support before transplant.23 The impact of national policies on the population undergoing OHT is evident in these trends and potentially may play a role in the spread of the use of HCV+ donors to the 50 nonutilizing centers. The opioid epidemic, and associated pool of HCV+ donors from drug overdose deaths, has not spared any areas of the United States.24 Thus, the growing availability of HCV+ donor hearts nationwide underscores the importance of broadening implementation of HCV+ donor protocols and utilization.
Prior studies have focused on donor discard rates in the context of HCV status in an effort to identify organs that could potentially be utilized for transplant. Ariyamuthu et al25 found that HCV status was independently associated with organ discard for donor kidneys. This occurred despite the fact that the mean age for donors with positive nucleic acid amplification testing for HCV was significantly lower than HCV− donors.25 In our study, we found that overall donor utilization rates were significantly higher in centers utilizing HCV+ donors for OHT. Despite the temporal increase in the use of HCV+ donors, overall donor utilization rates each year remained stable at around 30% for utilizing centers during study period. It is plausible that higher volume centers, such as these HCV+ donor utilizing centers, are more willing to accept marginal donors. In 2017, the American Society of Transplantation projected that there were approximately 300–500 HCV+ individuals who represented potential donors and estimated that this number would rise.26 They also underscored the fact that there are no OPTN regulations preventing the use of HCV+ organs for HCV− patients.26 Overall, trends in HCV+ donor heart utilization appear to have increased and are approaching utilization rates for HCV− naive donors.27 Going forward, it will be critical to educate transplant programs regarding the benefits and safety of using HCV+ organs to minimize discard rates.
We also demonstrate geographical heterogeneity in HCV+ donor OHT in the United States. Parker et al28 examined regional patterns in the treatment of waitlisted OHT candidates and found an association between over-treatment, with inotropes or an intra-aortic balloon pump, and local competition with transplant centers. It remains to be seen how the 2018 UNOS policy change may impact these observed patterns. Others have described a relationship between regional competition for donor hearts and rates of death or removal from the waitlist due to deterioration.29 Additionally, prior work has uncovered significant variability in donor utilization and discard within regions.30 A combination of policy initiatives and updated evidence-based guidelines may help to reduce the heterogeneity in transplant practices across centers and maximize the use of donor hearts.31 Particularly with the use of HCV+ donors being limited to certain centers, regional competition for organs may become a key factor for patients waitlisted at utilizing as opposed to nonutilizing centers of HCV+ donors. Improved understanding of external factors influencing the heterogeneity of transplant practices across the country may reveal opportunities for improvements in both patient care and organ allocation.
This study has several limitations. We utilized a national database of transplants and thus are limited by the retrospective nature of the study design and the lack of granular data on institution-specific practices regarding the use of HCV+ donors. For example, there may be differences in protocols in utilizing centers when following and potentially treating recipients of HCV+ donor organs. We also acknowledge the lack of long-term data supporting the use of HCV+ donor OHTs which may be a driving factor behind the decision by some centers to not incorporate HCV+ donors.
In conclusion, we report the center-level utilization of HCV+ donors for OHT in the United States. Despite rapid growth in utilization, the use of HCV+ donors is isolated to only about half of transplant centers with these centers demonstrating higher overall OHT volume. These trends, combined with increasing data supporting the safety of the use of HCV+ donor hearts for HCV− recipients, supports the growth of this practice. Exploration of regional use of HCV+ donors uncovers opportunity for expansion of these programs particularly in the Western half of the United States to increase options for waitlisted candidates. Further studies will be required not only to elucidate clinical outcomes in these patients but also to minimize the heterogeneity in transplant center utilization of these organs to ensure equitable access for end stage heart failure patients awaiting OHT.
Supplementary Material
Footnotes
A.K. serves on a Medical Advisory Board for Medtronic, Inc. The other authors declare no funding and conflicts of interest.
Supplemental Visual Abstract; http://links.lww.com/TP/C138.
Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).
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