WTSA 2023: To Decline or Not To Decline: Consequences of Decision-Making Regarding Lung Offers from Donors with Hepatitis C

Abstract

Objective:

Lung transplants from donors with hepatitis C (HCV D+) have excellent outcomes, but these organs continue to be declined. We evaluated whether (1) being listed to consider and (2) accepting vs. declining HCV D+ offers provided a survival benefit to lung transplant candidates.

Methods:

Using the Scientific Registry of Transplant Recipients, we identified all adult (≥18 years) lung transplant candidates 2016-2021 and compared waitlist mortality between those willing vs. not willing to consider HCV D+ offers using competing risk regression. We identified all candidates offered an HCV D+ lung that was later accepted and followed them from offer decision until death or end-of-study. We estimated adjusted mortality risk of accepting vs. declining an HCV D+ lung offer using propensity-weighted Cox regression.

Results:

From 2016-2021, we identified 21,007 lung transplant candidates, 33.8% of whom were willing to consider HCV D+ offers. Candidates willing to consider HCV D+ offers had a 17% lower risk of waitlist mortality (sHR 0.83, 95%CI 0.75-0.91, p<0.001). Over the same period, 665 HCV D+ lung offers were accepted after being declined a total of 2,562 times. HCV D+ offer acceptance vs. decline was associated with a 20% lower risk of mortality (aHR 0.80, 95% CI 0.66-0.96, p=0.02).

Conclusions:

Considering HCV D+ lung offers was associated with a 17% lower risk of waitlist mortality, while accepting vs. declining an HCV D+ lung offer was associated with a 20% lower risk of mortality. Centers and candidates should consider accepting suitable HCV D+ lung offers to optimize outcomes.

INTRODUCTION

The number of lung transplant (LT) waitlist candidates continues to exceed the supply of donated lungs,¹ prompting reevaluation of organs that have previously been discarded or underutilized. In the last decade, the advent of direct-acting antiviral medications for the cure of hepatitis C (HCV) has enabled the use of organs from donors with hepatitis C (HCV D+) for lung transplant candidates, regardless of their HCV status.^{2, 3} This advance, which allows the safe use of HCV D+ lungs to expand the organ pool, coincided with an increase in the number of HCV D+ due to the ongoing opioid epidemic.⁴ Therefore, lung transplant from HCV D+ represent a key opportunity to address the supply-demand gap in lung transplantation.

Emerging data about lung transplants from HCV D+, including for recipients without HCV, in the era of direct-acting antivirals (DAAs) have shown excellent sustained virologic response and 3-year lung transplant outcomes.^{5, 6} However, while the number of recipients who receive lung transplant from HCV D+ and the number of centers performing these transplants continue to rise, HCV D+ lungs remain underutilized. Over 59% of centers still do not perform lung transplants from donors with HCV viremia to recipients without HCV (HCV D+/R−).⁶ Given the demonstrated equivalence of perioperative and 3-year transplant outcomes of lung transplant recipients of organs from donors with and without HCV,⁶ declining an offer due to donor HCV status could have severe consequences for the waitlist candidate.

Using national registry data, we sought (1) to understand whether being listed as willing to accept HCV D+ lung provided a survival benefit, (2) to understand whether – among those listed as willing to consider HCV D+ offers - accepting HCV D+ lungs provided a survival benefit compared to remaining on the waitlist, and (3) to characterize the potential consequences of declining HCV D+ offers by evaluating outcomes of waitlist candidates who were ever offered HCV D+ lungs.

METHODS

Data source

This study used data from the Scientific Registry of Transplant Recipients (SRTR). The SRTR data system includes data on all donor, wait-listed candidates, and transplant recipients in the U.S., submitted by the members of the Organ Procurement and Transplantation Network (OPTN). The Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors. This dataset has previously been described elsewhere.⁷ This study was deemed exempt from the need for institutional review board approval by the Johns Hopkins Institutional Review Board (NA_00042871, approved 09/14/2013).

Definition of donor HCV status

The United Network of Organ Sharing (UNOS) requires that all potential deceased donors receive infectious disease testing for hepatitis C virus using an antibody screening test as well as a diagnostic nucleic acid test (NAT).⁸ We classified potential lung transplant donors as HCV-positive (HCV D+) if they had a positive HCV antibody test or had a positive HCV NAT, which indicated HCV viremia. This definition was chosen to encompass all donors that would be considered HCV-positive when determining which waitlist candidates would be offered the donor lungs, as waitlist candidate willing to consider HCV-positive donor offers must sign a separate clinical consent form to have this preference indicated in their UNOS donor acceptance criteria.⁹ If these candidates are listed as willing to consider offers from donors with hepatitis C, they will be offered organs from donors that are HCV antibody-positive or HCV NAT-positive.

Study population

Using SRTR data, we first identified all adult (≥18 years old) lung-only transplant candidates on the waitlist between January 2016 and December 2021 (Figure 1A). We categorized candidates by their willingness to consider HCV D+ lung offers (willing vs. not willing).

Figure 1. Study Inclusion and Exclusion Criteria for Analyses of (A) Lung Transplant Recipients by Listing to Consider Offers from Donors with Hepatitis C and (B) Survival Benefit by Acceptance or Decline of Offers from Donors with Hepatitis C.

For Figure 1B, the number of unique candidates includes a single entry for each candidate, with the exception of the 318 candidates who declined an initial offer of lungs from a donor with hepatitis C and later accepted an offer of lungs from a different donor with hepatitis C. Those 318 candidates are represented twice in the diagram, once in the population of offer acceptors and once in the population of offer decliners.

We also identified all adult (≥18 years old) lung-only transplant candidates who were offered an HCV D+ lung allograft that was eventually used for transplantation, for any person, between January 2016 and December 2021 (Figure 1B). For each of these HCV D+ lung offers that were eventually used for transplants, we identified the candidates who declined or accepted these offers. Candidates who were offered the HCV D+ lung in error (i.e., after death or removal from waitlist) or who accepted an HCV D+ lung offer but were not transplanted were excluded. We compared demographic, clinical, and transplant characteristics between candidates who accepted versus declined the HCV D+ lungs using Chi-squared testing for categorical variables and Wilcoxon rank-sum tests for continuous variables. We used candidate characteristics at their first HCV D+ offer for these comparisons.

Waitlist survival benefit of listing as willing to consider HCV D+ offers

To evaluate the waitlist survival benefit associated with being listed as willing to consider HCV D+ lung offers, we compared the waitlist mortality of candidates who were willing vs. not willing to consider HCV D+ lung offers, using Fine and Gray’s subhazards models to account for the competing risk of transplant. We adjusted for covariates that were significant at a level of p<0.05 on univariate analysis; the final model was adjusted for candidate age, race (White, Black, other), education (completion of high school or less vs. post-high school education), diagnosis group (obstructive, pulmonary vascular, cystic fibrosis and immunodeficiency, or restrictive), blood type (O, A, B, AB), lung allocation score (LAS), and pre-transplant extracorporeal membrane oxygenation use.

Survival benefit of HCV lung offer acceptance

To evaluate the survival benefit associated with accepting an HCV D+ lung offer, we identified candidates who accepted and were transplanted with an HCV D+ lung allograft. We then compared their mortality risk to that of the waitlist candidates who had previously declined the same HCV D+ lung offer. To account for differences between offered HCV D+ lungs, we matched the candidates who accepted and declined HCV D+ offers using propensity scores. Propensity scores were calculated using candidate age, sex, race, blood type, diagnosis group, BMI, education, primary insurance type, receipt of prior lung transplant, and lung allocation score. Covariate balance was assessed and all variables had a standardized mean difference of <0.1, suggesting good balance between the two groups. We then used propensity-weighted Cox regression to evaluated mortality risk associated with accepting vs. declining the same HCV D+ lung offer.

We followed candidates from the date of lung transplant (for candidates who accepted the HCV D+ lung offer) or the date of HCV D+ offer decline (for candidates who had declined the same HCV D+ lung offer) until date of death or administrative censoring on October 31, 2022. Candidates who declined an HCV D+ offer but later accepted a different HCV D+ offer were considered to have had a time-varying exposure and contributed time-at-risk to the offer decline risk set (from initial HCV D+ decline until acceptance of a subsequent HCV D+ lung offer) as well as to the offer acceptance risk set (from HCV D+ offer acceptance until death or censoring). Candidates who declined multiple HCV D+ offers were included as independent matched controls for each HCV D+ “acceptor” who was offered the same organ. All analyses were performed using Stata 16.1/MP for Windows (College Station, Texas). Since Stata does not have a standard package for calculating confidence intervals for weighted Kaplan-Meier curves, we used the user-generated KMEST module¹⁰ to bootstrap survival probabilities for each 0.1 years. The estimated survival and 95% confidence interval generated using these methods were used to create the Kaplan Meier curves.

Subsequent outcomes following HCV lung offer decline

To evaluate the consequences of declining an HCV D+ lung offer, we followed all candidates who declined an HCV D+ lung offer that was eventually transplanted from the date of initial HCV D+ lung offer decline until eventual lung transplant from an HCV-negative donor, lung transplant from a different HCV D+, death, removal from the waitlist, or administrative censoring on October 31, 2022. We reported 3-year cumulative incidence of each potential outcome. A period of 3 years was chosen given the increase in the number of HCV D+ lung transplants since 2018.⁶

Sensitivity analyses of HCV-viremic and HCV-antibody-positive/NAT-negative donor lung offers

Since the risk of HCV transmission is substantially lower from donors who are HCV antibody-positive but HCV NAT-negative (i.e., HCV non-viremic donors) versus donors who are HCV-viremic,¹¹ decision-making might differ based on donor HCV viremia. To evaluate whether HCV-viremic offers provide survival benefit, we performed a sensitivity analysis restricted to waitlist candidates who were offered lungs from donors with HCV viremia. We also performed a sensitivity analysis restricted to waitlist candidates who were offered lungs from donors who were HCV antibody-positive but HCV NAT-negative, indicating that they had a history of hepatitis C infection but were nonviremic at the time of testing. Models were weighted and outcomes were defined using the same methods described above.

Effect measure modification by blood type and diagnosis group

Since waitlist times – and therefore potentially mortality risk – differ by blood type and disease progression, we decided a priori to conduct subgroup analyses by blood type and diagnosis group. Blood types were defined as O, A, B, or AB. Diagnosis groups were defined as obstructive, pulmonary vascular, cystic fibrosis and immunodeficiency, and restrictive, with diagnosis codes in SRTR assigned to a diagnosis group using OPTN guidelines.¹² For both blood types and diagnosis groups, we first performed an interaction term analysis, creating indicator variables for each blood type or diagnosis group and adding an interaction term for each indicator variable with offer acceptance. If the interaction term was statistically significant at a threshold of p<0.05, we performed subgroup analyses restricted to each particular group of waitlist candidates (i.e., a particular blood type or diagnosis group), then compared candidates who accepted or declined HCV-positive lung offers within this group. Models were weighted and outcomes were defined using the same methods described above.

RESULTS

Study population

From 2016-2021, we identified 21,007 lung transplant candidates. Of these, 7,106 candidates (33.8%) were listed as willing to consider HCV D+ lung offers and 13,901 (66.2%) were listed as unwilling to consider these offers. Candidates who were willing vs. not willing to consider HCV D+ offers differed significantly by age [median (Q1-Q3) 61 (53, 66) vs. 60 (52, 66), p=0.01], race, educational attainment (61.5% vs. 57.2% with greater than a high school education, p<0.001), diagnosis, LAS [median (Q1-Q3) 39 (34, 47) vs. 38 (34, 45), p<0.001), and use of pre-transplant ECMO (4.1% vs. 3.2%, p<0.001; Table 1).

Table 1. Candidate Characteristics by Listing as Willing to Consider Lung Offers from Donors with HCV.

Characteristics that significantly differed between candidates who were listed as willing vs. not willing to consider offers from donors with hepatitis C at a level of p<0.05 are indicated in bold.

Characteristic	Willing to Consider	Not Willing to Consider	P-value
N	7,106	13,901
Age (years), median (Q1-Q3)	61 (53, 66)	60 (52, 66)	0.01
Female sex	43.6%	43.5%	0.96
Race/ethnicity
White	76.2%	75.6%	0.004
Black	9.3%	10.8%
Hispanic	10.3%	9.8%
Other	4.2%	3.7%
Educational attainment
High school diploma/GED or less	38.5%	42.8%	<0.001
Post-high school education	61.5%	57.2%
Diagnosis
Obstructive	23.8%	25.1%	<0.001
Pulmonary Vascular	5.8%	6.1%
Cystic Fibrosis and	6.2%	8.2%
Immunodeficiency
Restrictive	64.2%	60.5%
Blood type
O	46.3%	47.8%	0.03
A	38.7%	36.6%
B	11.3%	11.8%
AB	3.6%	3.7%
Private primary insurance	46.1%	45.6%	0.78
Lung allocation score, median (Q1-Q3)	39 (34, 47)	38 (34, 45)	<0.001

Q1-Q3, 25^th and 75^th percentile values. GED, general educational development test.

For candidates who were listed as willing to consider HCV D+ offers, 665 HCV D+ lung offers were accepted and transplanted. Of these, 384 offers (57.7%) were from donors with HCV viremia and an additional 281 offers (42.3%) were from donors who were only HCV antibody-positive. These lungs were declined a total of 2,562 times before being accepted. Those who accepted HCV D+ offers were older (median 62 vs. 60 years old, p=0.001), less likely to be female (43.9% vs. 49.3%, p=0.01), more likely to be of White race (83.2% vs. 77.2%, p=0.006), and had a lower LAS at the time of the offer [median (Q1-Q3): 38 (34-47) vs. 41 (35-55), p<0.001]. There were no significant differences in candidate educational level (p=0.18), primary insurance (private: 40.6% vs. 44.5%, p=0.07), or blood type (p=0.22) (Table 2). The accepted organ donors had a median (Q1-Q3) age of 33 (28-39) years, 48.3% were female, 81.5% were of White race, 18.5% had a >20 pack-year smoking history, 57.7% were HCV-viremic, and 4.1% donated after circulatory death (Supplementary Table 1).

Table 2. Candidate Characteristics by Acceptance or Decline of a Lung Offer from a Donor with HCV.

Characteristics that significantly differed between candidates who accepted vs. declined offers at a level of p<0.05 are indicated in bold.

Characteristic	Accepted Offer	Declined Offer	P-value
N	665*	2,562
Age (years), median (Q1-Q3)	62 (54, 67)	60 (52, 66)	0.001
Female sex	43.9%	49.3%	0.01
Race/ethnicity
White	83.2%	77.2%	0.006
Black	8.7%	10.7%
Hispanic	6.3%	8.6%
Other	1.8%	3.5%
Educational attainment
High school diploma/GED or less	46.0%	49.5%	0.18
Post-high school education	54.0%	50.5%
Diagnosis
Obstructive	31.1%	27.5%	0.26
Pulmonary Vascular	5.0%	6.0%
Cystic Fibrosis and	5.7%	6.2%
Immunodeficiency
Restrictive	58.0%	60.2%
Other	0.2%	0.1%
Body mass index (kg/m2), median (Q1-Q3)	26 (23, 29)	26 (23, 29)	0.19
Blood type
O	45.7%	48.9%	0.22
A	42.9%	38.8%
B	8.7%	8.8%
AB	2.7%	3.6%
Private primary insurance	40.6%	44.5%	0.07
Prior lung transplant	2.4%	3.1%	0.35
Lung allocation score, median (Q1-Q3)	38 (34, 47)	41 (35, 55)	<0.001

Q1-Q3, 25^th and 75^th percentile values. GED, general educational development test.

^*318 candidates who declined a lung offer from a donor with HCV later accepted an offer from a different donor with HCV. These candidates therefore contributed person-time to both groups. There were no substantial differences in the characteristics for the two groups after exclusion of these candidates from the “declined offer” group.

Among candidates who were listed as willing to consider HCV D+ offers but declined an HCV D+ offer, the reason for decline was only available for only 667 candidates, representing 26.0% of overall declines and 80.8% of declines since the refusal code field became non-missing in December 2020. The most common reasons for refusal were donor age or quality (66.0%) and donor size/weight (16.8%).

Survival benefit of listing as willing to consider HCV D+ lung offers

Overall, candidates who were listed as willing to consider HCV D+ lung offers had a 17% lower risk of waitlist mortality [subhazard ratio (sHR) 0.83, 95% CI 0.75-0.91, p<0.001] than candidates who were not listed as willing to consider HCV D+ lung offers, accounting for the competing risk of transplant. After adjusting for candidate characteristics including age, race, education, diagnosis group, blood type, LAS, and ECMO support, candidates who were listed as willing to consider HCV D+ lung offers had a 24% lower risk of waitlist mortality [subhazard ratio (sHR) 0.76, 95% CI 0.69-0.84, p<0.001] than candidates who were not listed as willing to consider HCV D+ lung offers.

Survival benefit of HCV D+ lung offer acceptance

Survival for recipients who accepted vs. declined HCV D+ offers was 90.8% vs. 85.4% at 1 year and 74.3% vs. 70.9% at 3 years after the HCV D+ offer decision (Figure 2). After weighting candidate characteristics to minimize the difference between candidates who accepted and those who declined, accepting vs. declining an HCV D+ offer was associated with a 20% lower risk of mortality (aHR 0.80, 95% CI 0.66-0.96, p=0.02); this remained unchanged after accounting for center-level effects (aHR mortality 0.79, 95% CI 0.65-0.95, p=0.01).

Figure 2. Weighted Mortality Risk of Lung Transplant Candidates Who Accepted vs. Declined a Lung Offer from a Donor with HCV.

Plot shows propensity-weighted survival curves. Candidates are propensity-weighted on candidate age, sex, race, blood type, diagnosis group, BMI, education, primary insurance type, receipt of prior lung transplant, and lung allocation score to minimize confounding of the relationship between an HCV D+ offer acceptance/decline and mortality. After weighting, the number of candidates included as at risk at each time point for the “accepted offer” vs. “declined offer” groups was 665 vs. 619 at 0 years, 589 vs. 414 at 1 year, 239 vs. 155 at 3 years, and 31 vs. 19 at 5 years.

Consequences of declining an HCV D+ lung offer

Among those who declined an HCV D+ lung offer that was eventually accepted, 66.1% received a lung transplant from an HCV-negative donor, 12.4% received a different HCV D+ lung transplant, 5.8% were removed from the waitlist for deteriorating health, 9.0% were removed for other reasons, 5.0% had died, and 1.8% remained on the waitlist at three years after the initial HCV D+ offer decline (Figure 3).

Figure 3. Outcomes of Lung Transplant Waitlist Candidates Who Declined an Offer from a Donor with HCV.

Waitlist candidates who declined an offer from a donor with hepatitis C were followed for three years after that initial offer decline. The cumulative incidence of their outcomes out to three years are depicted.

Sensitivity analysis of acceptance vs. decline of lung offers from donors with HCV viremia and from donors positive for HCV antibodies but without HCV viremia

In a sensitivity analysis of HCV-viremic donor lung offers, those who accepted HCV-viremic offers and those who declined them were of similar age, sex, race, educational attainment, BMI, blood type, and insurance type. Those who accepted HCV-viremic offers had a lower LAS at the time of the offer [median (Q1-Q3): 37 (34-46) vs. 40 (34-54), p=0.008] (Table 3). Among those who declined lung offers from donors with HCV viremia, 57.4% received an HCV-negative lung transplant, 21.2% received a different HCV D+ lung transplant, 6.6% were removed for deteriorating health, 9.6% were removed for other reasons, 4.1% died, and 1.1% remained on the waitlist. Accepting vs. declining an offer from a donor with HCV viremia was not significantly associated with candidate mortality (aHR 0.82, 95% CI 0.62-1.08, p=0.16).

Table 3. Candidate Characteristics by Acceptance or Decline of a Lung Offer from a Donor with HCV Viremia.

Characteristics that significantly differed between candidates who accepted vs. declined offers at a level of p<0.05 are indicated in bold.

Characteristic	Accepted Offer	Declined Offer	P-value
N	384*	844
Age (years), median (Q1-Q3)	61 (53, 67)	60 (53, 66)	0.18
Female sex	42.7%	48.1%	0.08
Race/ethnicity
White	81.5%	77.8%	0.44
Black	8.9%	10.3%
Hispanic	8.1%	9.2%
Other	1.6%	2.6%
Educational attainment
Less than high school or high school	49.6%	52.1%	0.49
Post-high school education	50.4%	47.9%
Diagnosis
Obstructive	33.9%	28.7%	0.44
Pulmonary Vascular	5.5%	5.9%
Cystic Fibrosis and	4.7%	5.1%
Immunodeficiency
Restrictive	55.7%	60.2%
Other	0.3%	0.1%
Body mass index (kg/m2), median (Q1-Q3)	25 (23, 29)	27 (23, 29)	0.12
Blood type
O	46.4%	51.5%	0.28
A	40.9%	35.7%
B	9.6%	9.0%
AB	3.1%	3.8%
Private primary insurance	41.7%	42.9%	0.69
Prior lung transplant	1.3%	2.7%	0.12
Lung allocation score, median (Q1-Q3)	37 (34, 47)	40 (34, 54)	0.008

Q1-Q3, 25^th and 75^th percentile values. GED, general educational development test.

^*1 candidate who declined a lung offer from a donor with HCV viremia later accepted an offer from a different donor with HCV. This candidate therefore contributed person-time to both groups. There were no substantial differences in the characteristics for the two groups after exclusion of this candidate from the “declined offer” group.

In a sensitivity analysis of offers from donors who were positive for HCV antibodies but negative for HCV viremia (i.e. HCV-nonviremic offers), those who accepted vs. declined HCV-nonviremic offers were of older median (Q1-Q3) age [63 (54-67) vs. 60 (52-66), p=0.003] and were more likely to be of White race (85.4% vs. 76.9%, p=0.009; Supplementary Table 2). Among those who declined HCV-nonviremic lung offers, 68.3% received an HCV-negative lung transplant, 9.3% received a different HCV D+ lung transplant, 5.8% were removed for deteriorating health, 9.6% were removed for other reasons, 5.1% died, and 1.9% remained on the waitlist. Accepting vs. declining an HCV non-viremic offer was not significantly associated with candidate mortality (aHR 0.80, 95% CI 0.62-1.05, p=0.10).

Effect measure modification by candidate blood type and diagnosis group

In an interaction analysis of blood type, the association between HCV D+ offer acceptance vs. decline and mortality risk differed significantly for blood type O (p=0.01) but not for blood types A (p=0.49), B (p=0.49), or AB (p=0.15). Results of subgroup analyses by candidate blood type were consistent with these findings; candidates with blood type O who accepted an HCV D+ offer had a 30% lower risk of mortality than those who declined an HCV D+ offer (aHR 0.70, 95% CI 0.53-0.93, p=0.01). There was no significant mortality benefit for blood groups A (p=0.6), B (p=0.8), or AB (p=0.07) (Figure 4).

Figure 4. Weighted Mortality Risk of Lung Transplant Candidates Who Accepted vs. Declined a Lung Offer from a Donor with HCV, by Candidate Blood Type.

Plot shows propensity-weighted survival curves. Candidates are propensity-weighted on candidate age, sex, race, diagnosis group, BMI, education, primary insurance type, receipt of prior lung transplant, and lung allocation score to minimize confounding of the relationship between HCV D+ offer acceptance/decline and mortality. After weighting, the number of candidates included as at risk at each time point for the “accepted offer” vs. “declined offer” groups was 304 vs. 1205 for blood group O, 285 vs. 956 for blood group A, 58 vs. 217 for blood group B, and 18 vs. 88 for blood group AB.

In an analysis by diagnosis group, the baseline mortality risk was significantly higher for patients with pulmonary vascular disease (HR 1.98, 95% CI 1.23-3.19, p=0.005) and restrictive disease (HR 1.63, 95% CI 1.25-2.11, p<0.001) compared to those with obstructive disease. However, the association between HCV D+ offer acceptance and mortality risk did not differ significantly across the diagnosis groups on interaction term analysis (all p>0.05).

DISCUSSION

In this national study of outcomes for lung transplant candidates who based on their willingness to consider and then accept lung offers from donors with hepatitis C, we found that being listed as willingness to consider HCV D+ offers was associated with a 17% lower risk of mortality. Among those who were listed as willing to consider HCV D+ offers, accepting an HCV D+ offer was associated with 20% lower risk of mortality than declining that offer. For candidates who were listed as willing to consider HCV D+ offers but then declined a suitable HCV D+ offer, 14.8% were removed from the waitlist and 5.0% died without being transplanted within the next three years. Given that HCV D+ lung transplants have been shown to have equivalent outcomes to transplants from HCV-negative donors, these findings underscore the consequence of not considering HCV D+ offers at all or declining suitable HCV D+ offers.

Notably, 12.4% of the waitlist candidates who declined an HCV D+ offer eventually received a lung transplant from a different HCV D+ within three years. This was more prevalent among waitlist candidates who declined a lung offer from a donor with HCV viremia; 21.2% of those candidates eventually received an HCV D+ lung transplant within three years. These findings could indicate that there was a characteristic other than donor HCV status of the initial HCV D+ offer that led to the decline by the provider or candidate, or it could indicate greater willingness to consider and accept HCV D+ offers over time. Over the study period, published evidence to support the use of lungs from HCV D+ has grown,^{5, 13-15} with recent data showing equivalent outcomes at 3 years post-transplant for lung transplant from donors with and without HCV viremia.⁶ This evolving willingness to use HCV D+ offers over time, even among those who were willing to consider these offers early on during the study period, is in keeping with the ISHLT consensus statement prediction that our knowledge regarding the use of organs from donors with HCV in cardiothoracic transplant will evolve rapidly.¹⁶ However, while we are hopeful that our finding that many waitlist candidates eventually accepted an HCV D+ lung transplant reflects greater acceptance of the use of these organs, we need to continue to monitor uptake of this practice to optimize use of HCV D+ organs.

Lung offers from HCV D+ continue to be offered only to those whose donor acceptance criteria indicate they are specifically willing to consider HCV D+ offers. Therefore, many waitlist candidates were never offered these HCV D+ lungs. While the percentage of candidates listed as willing to consider HCV D+ lung offers has increased in recent years – as it has for other organ types¹⁷ – the number of offer declines reported in our paper underestimates the true number of “declines” because it does not include providers and candidates who decline to even consider any HCV D+ offers. Surveys of lung transplant recipients who list as willing to consider HCV D+ offers found that, pre-transplant, 75% felt completely safe or very safe to receive an HCV D+ organ, despite 33% stating that they never or rarely took risks in their everyday lives.¹⁸ A study of solid organ transplant recipients with donor-derived HCV infection found that trust in their physician’s recommendation was one of the top two reasons that patients felt confident receiving an HCV D+ organ,¹⁹ underscoring the need for transplant providers to be educated about the safety and efficacy of the use of HCV D+ organs. This is particularly important since we found that the candidates who accepted and declined these offers did not differ in terms of education or insurance, suggesting that the decision to accept or decline might instead reflect provider preference or education.

Limitations of this study stem from the use of registry data, which does not allow us to determine whether an offer was declined due to center practice, provider preference, or patient preference. In addition, we could not determine the specific reason for offer decline for the majority of candidates; offer decline could be due to the donor HCV status, another donor characteristic or organ quality concern, or other recipient reasons. However, we specifically limited our analysis to allografts that were ultimately accepted by another candidate to ensure these organs were considered generally suitable. Clarification of reasons driving decline is needed to guide strategies to improve HCV D+ offer acceptance rates. Confounding by indication is inherent in this type of analysis, but we have attempted to match patients that could have accepted the offer with similar disease severity, as captured in the registry data. Additionally, this analysis is limited to waitlist candidates that were offered HCV D+ lung offers, which requires them to be entered in UNOS as willing to consider HCV D+ offers. As the percentage and characteristics of candidates listed as willing to consider HCV D+ offers changes over time, the magnitude of the mortality effect might change. We do not have any data on hepatitis C viral transmission from donor to recipient in the registry database. The risk of viral transmission from an organ that is antibody-positive but NAT-negative is estimated to be around 0.32%,²⁰ though it might rise to 3% if the donor had needle exposure immediately prior to death.²¹ In contrast, nearly all HCV-viremic donors will transmit the virus to the recipient,²² though DAAs have a cure rate of 95-99% overall²³ and all cardiothoracic transplant patients studied have had sustained virologic response to DAA therapy.^{5, 22}

In conclusion, we found that being listed as willing to consider lung offers from donors with hepatitis C was associated with a 17% lower mortality risk, and accepting a lung offer from donor with HCV was associated with 20% lower mortality compared to declining that same offer in favor of remaining on the waitlist. While offers are declined for many reasons by patients and providers, the overall hope is that a “better” offer will become available. However, this also leaves the waitlist candidate at risk of becoming too sick to remain on the waitlist or dying. Given the demonstrated excellent outcomes of HCV D+ lung transplant recipients in the era of direct-acting antiviral medications, we hope these findings will encourage providers and candidates to accept suitable HCV D+ lung offers.

Supplementary Material

Supp.Fig1

Supplementary Figure 1. Outcomes of Lung Transplant Waitlist Candidates Who Declined an Offer from a Donor with HCV, by Blood Type. Waitlist candidates who declined an offer from a donor with hepatitis C were followed for three years (for blood types O, A, and B) or one year (for blood type AB, due to limited data) after that initial offer decline. The cumulative incidence of their outcomes are depicted.

CENTRAL PICTURE:

Mortality Risk Associated With Accepting vs. Declining a Lung Offer from a Donor with HCV

CENTRAL MESSAGE:

For lung candidates, accepting vs. declining an HCV D+ offer was associated with a 20% lower risk of mortality. 19.8% of candidates who declined an HCV D+ offer died or were delisted within 3 years.

PERSPECTIVE STATEMENT:

HCV D+ lung offers continue to be declined despite demonstrated safety and excellent outcomes. Accepting vs. declining an HCV D+ lung offer was associated with a 20% lower risk of mortality, as declining might mean waiting for an offer that never comes. Centers and candidates should carefully consider accepting suitable HCV D+ lung offers to optimize outcomes.

GLOSSARY OF ABBREVIATIONS: (in order of appearance)

HCV

hepatitis C virus

HCV D+

donors with hepatitis Cs

DAA

direct-acting antiviral

SRTR

Scientific Registry of Transplant Recipients

OPTN

Organ Procurement and Transplantation Network

HRSA

Health Resources and Services Administration

UNOS

United Network of Organ Sharing

NAT

nucleic acid test

NIA

National Institute on Aging

NIAID

National Institute of Allergy and Infectious Disease

HHRI

Hennepin Healthcare Research Institute