In 1994, the Centers for Disease Control and Public Health Service (PHS) released a report entitled “Guidelines for preventing transmission of human immunodeficiency virus (HIV) through transplantation of human tissue and organs.”1 This report was motivated by a case of HIV transmission to a transplant recipient from a screened, antibody-negative donor. While the initial criteria focused on behaviors or other exposures defining a group at increased risk for recent HIV infection, these criteria were also applied to evaluate risk for other stigmatized infectious diseases, such as hepatitis B virus and hepatitis C virus (HCV). Donors meeting these criteria were labeled “PHS High Risk.” In 2013, the PHS published a modified set of criteria for increased risk donors (PHS-IR) for hepatitis B, HCV, and HIV, and these definitions were incorporated into Organ Procurement and Transplantation Network (OPTN) policy.2 Since 2007, OPTN policy 4.1.1 has required that transplant programs document informed consent from potential recipients or their legal representatives regarding acceptance of such organs.
The incremental magnitude of risk conferred by this designation was always low, and has decreased further with the advent of uniform nucleic acid testing of potential donors. A meta-analysis of published studies found pooled transmission risks ranging from 4.9/10 000 (if the risk factor is IV drug use) to 0.04/10 000 (if the risk factor is hemophilia).3 By comparison, according to the National Safety Council, the lifetime risk of dying in a motor vehicle accident is 90/10 000.4 And, for most patients with end-stage organ failure, the immediate risks of death are much higher. For this reason, the PHS-IR status of the organ does not influence the probability of survival after transplantation.5
Despite these safety data, clinical experience and several studies have shown patients and their families to be initially hesitant to accept “Increased Risk” organs, particularly if they are not adequately counseled about the magnitude of risk versus benefit.6,7 A similar concern may exist among transplant professionals.8,9 Therefore we aimed to determine the impact of the “Increased Risk” label on organ utilization.
MATERIALS AND METHODS
The OPTN database was queried to identify all standard criteria donors (SCD) in the United States between January 1, 2010, and December 31, 2013. The OPTN data system includes data on all donors, waitlisted candidates, and transplant recipients in the United States, submitted by the members of the OPTN, and has been described elsewhere. The Health Resources and Services Administration, U.S. Department of Health and Human Services provides oversight to the activities of the OPTN contractor. Institutional Review Board exemption was obtained from the US Department of Health and Human Administration. OPTN data are as of October 23, 2015, and are subject to change based on future data submission and correction.
SCD was determined using the kidney criteria (age <50 or 50-59 without hypertension, elevated creatinine, or death from cerebrovascular accident), and a donor was defined as anyone from whom at least 1 organ is procured for the purposes of transplantation. All such donors with a known PHS-IR status (“yes” or “no”) were included (11 [<1%] donors were excluded for having unknown PHS-IR status). ECD organs were excluded. These dates were selected as the 4-year period just prior to the most recent change in the PHS-IR criteria.
All analyses were performed in SAS EG v.5.1 and R v3.2.3 (packages used: lme4 and boot). Utilization rates were computed, stratifying by donor organ, donor PHS Increased Risk status, and donor age (pediatric [0-17 years] and adult [18+ years]). Utilization rates were defined as the number of organs transplanted out of the number of organs that, in a perfect world, would be available for donation from each donor (ie, 2 kidneys, 1 liver, 1 heart). Lung utilization rates were computed as “at least 1 lung transplanted.” Adjusted utilization rates for PHS Increased Risk donor organs were also computed, controlling for donor height, weight, age group (for pediatric, 0-10 years and 11-17 years; for adult, 18-34, 35-50, and >50 years), and cause of death (anoxia, head trauma, stroke, and other), via multivariable logistic regression models. Because of the correlation between PHS-IR status and HCV status, we performed an additional sensitivity analysis including HCV (positive versus negative or not reported) as a covariate. To assess the number of otherwise usable organs that were potentially not used per year because of the PHS Increased Risk status, the model was run at baseline with all covariates along with the PHS Increased Risk indicator, and again with this indicator set to 0 (assuming there are no PHS-IR donors). Comparisons were made using χ2 tests.
Additionally, utilization rates were compared by donation service area (DSA) using an “empty” hierarchical regression model, stratified by organ, donor age, and PHS Increased Risk donor status. The intraclass correlation coefficient (ICC) was computed for each stratification, which calculates the percentage of variation beyond mere chance. Confidence intervals for the ICC were estimated using a percentile bootstrap methodology.
Lastly, export rates were calculated, stratified by organ, donor age, and PHS Increased Risk status, and compared using χ2 tests. Export was defined as the number of organs transplanted outside of the recovering DSA, and the rate was out of all organs transplanted.
Overall, there were 20 885 SCD deceased donors with a known PHS Increased Risk donor status recovered during the study period; of these, there were 3000 pediatric donors and 17 885 adult donors. For pediatric donors, 201 (7%) were classified as PHS-IR, and for adult donors, 2657 (15%) were classified as PHS-IR. Unadjusted organ utilization rates are shown in Figure 1. The utilization rates for PHS-IR donors were lower across all organs compared to non–PHS-IR donors, with the exception of adult liver in which rates were identical. The lower utilization rate for PHS-IR organs was statistically significant for pediatric kidney, liver, and lung, as well as adult kidney, lung and heart. Covariate-adjusted utilization rates are shown in Figure 2. Despite adjustment for donor age, height, weight, and cause of death, all adult PHS-IR organs remained statistically significantly less likely to be used than organs not bearing that label. Adjusted utilization of pediatric PHS-IR organs remained numerically lower but the differences were not statistically significant except for livers. In sensitivity analysis, additionally controlling for HCV status affected the statistical significance of adult liver only, going from significant to not significant (data not shown). Extrapolating from the adjusted model, if the PHS-IR label did not exist there could be an additional 313 transplants performed in the United States each year; for adults, 119 kidneys, 91 hearts, 70 lungs, 19 livers, and for pediatrics, 3 kidneys, 4 hearts, 3 lungs, 4 livers.
In addition to PHS-IR organs having lower national utilization rates, they also have higher variability in utilization between DSAs, as shown in Figure 3. In other words, some DSAs use these organs at the same rate as non–PHS-IR organs, while other DSAs use them at a much lower rate. For example, the utilization rate of PHS-IR kidneys from adult donors varies by DSA from 20% to 100% as shown in Figure 4. Consistent with this finding, export rates of PHS-IR organs from one DSA to another were also higher than for non–PHS-IR organs, as shown in Figure 5.
This study aimed to test the hypothesis that the “PHS Increased Risk” label negatively affects organ utilization. We found that organs bearing this label were significantly less likely to be used (ie more likely to be discarded), despite the fact that the risk of disease transmission in a nucleic acid testing–negative donor is extremely low. Furthermore, there exists significant variation between DSAs in utilization of these organs, and higher export rates than with non–PHS-IR organs. These additional findings offer construct validity to the hypothesis and suggest that some transplant programs are more comfortable using these organs than others.
Based on these findings, we believe that poor understanding of the true risk associated with PHS-IR label results in uninfected viable organs to be discarded. Our estimates suggest that if this label did not exist, an additional 313 patients could undergo transplantation each year in the United States. This estimate is now probably even higher, because a 2015 change to the PHS-IR criteria has resulted in an increase in proportion of organs with this label from 12% to 20%.10 Furthermore, the opioid epidemic has in some areas of the country led to an increase in the numbers of PHS-IR donors.11
Although it is unlikely that the PHS designation will be eliminated, the transplant community could partially address this problem through better patient and provider education. Even some transplant professionals do not fully appreciate the low magnitude of risk with these organs, and centers with standardized processes and consent forms tend to have higher utilization rates.12 Many patients are initially reluctant to consider these organs, but most can be swayed with adequate education.13 Therefore, members of the United Network for Organ Sharing Disease Transmission Advisory Committee are working with the American Society of Transplantation, the American Society of Transplant Surgeons, and the National Association of Transplant Coordinators to provide tools that can be used by transplant programs to better educate patients and providers regarding the true risk of transmission associated with PHS-IR organs. In addition, the advent of highly effective antiviral therapy for HCV has made it possible to use more HCV-positive organs than before; the results of ongoing studies in this area are eagerly anticipated.
Two important limitations to this study must be mentioned. First, although covariate-adjustment was used to account for potential confounders, there is always the possibility of unmeasured confounders. For example, it is possible that PHS-IR donors tend to be more hemodynamically unstable or have other unfavorable characteristics not reported in the OPTN database. Second, and more important, is the possibility that some patients, despite fully comprehending the low risk of disease transmission, still choose to decline these organs. In other words, some patients may fundamentally prefer to risk dying on the waiting list rather than accepting a much lower risk of disease transmission. Thus, even in the ideal world with perfect patient and provider education, utilization rates of PHS-IR organs may never fully normalize, and export rates may remain higher.
In summary, this study found that the PHS Increased Risk label reduces organ utilization. These findings support efforts toward improved education of patients, their caregivers, and transplant professionals about the low risk of disease transmission associated with these organs.
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