Donor Characteristics and Regional Differences in the Utilization of HCV-Positive Donors in Liver Transplantation

Key Points Question What are the clinical characteristics of donors who are positive for hepatitis C virus (HCV), and how are these donors utilized across the United States? Findings This cross-sectional study found that HCV-positive donors were healthier and donated superior liver allografts compared with HCV-negative donors. There were substantial variations in the utilization of HCV-positive donors across the United States that were not entirely explained by the geography of the opioid epidemic. Meaning These findings suggest that policies to drive the increased utilization of HCV-positive donors should be encouraged and implemented.


Introduction
Despite an increase in the number of liver transplants (LTs) performed in the United States, the rate at which patients are placed on the waitlist continues to surpass the increased number of transplants, creating a significant mismatch between organ supply and demand. 1 The use of hepatitis C virus (HCV)-positive organs has been widely adopted as one of the solutions to the major organ shortage by increasing the donor pool. 2 Although HCV infection is estimated to affect 1% to 2% of the general US population, this risk is higher (3%-18%) among organ donors with increased risk as defined by the Public Health Service. 3 In light of the ongoing opioid epidemic and the associated rise in drug overdose deaths, the number of Public Health Service "increased risk" HCV-positive organs available has been increasing rapidly. 4,5 Even before the use of direct-acting antiviral (DAA) therapy for hepatitis C, large comparative outcome studies of patients with HCV cirrhosis showed comparable outcomes when receiving liver allografts from HCV-positive vs HCV-negative donors. 6,7 With the widespread use of DAAs, there has been a rapid rise in the utilization of HCV-positive liver allografts. 8 Based on Organ Procurement and Transplantation Network (OPTN) data, between 2016 and 2018, 7.4% of all deceased LT donors were HCV positive, representing a rise of 45% compared with the previous 3-year period (2013-2015). 9 One of the reasons for this rise is the increasing utilization of HCV-positive donors for HCV-negative recipients, with studies reporting favorable results, including improved survival for recipients with a Model for End-Stage Liver Disease (MELD) score of 20 or greater due to less waitlist mortality. [10][11][12] However, there have been limited studies on the characteristics of HCV-positive donors and allografts.
Despite advances in treatment, a large number of HCV-positive liver allografts, in the several hundreds per year, are still not being utilized. 13 As such, there is reason to believe that individual centers and regions are utilizing more of the available HCV-positive organs than others. For instance, Verna et al 14 recently reported that half of solid organ (kidney, liver, heart, and lung) transplants from HCV-positive donors to HCV-negative recipients occurred at 8 centers.
In this study, we aimed to characterize HCV-positive compared with HCV-negative donors of transplanted liver allografts using the Scientific Registry of Transplant Recipients (SRTR) database. In addition, we aimed to identify city and regional differences in the utilization of HCV-positive liver allografts in the United States with a focus solely on the utilization of donors. In doing so, we intended to identify the challenges contributing to the underutilization of HCV-positive liver allografts. We believe these data are essential to drive the increased use of HCV-positive donors moving forward.

Study Design and Patient Population
We studied all deceased LT donors that underwent hepatitis C antibody (HCV Ab) testing and HCV nucleic acid amplification testing (HCV NAT) from June 1, 2015, to December 1, 2018. The start date of our study corresponds to 3 months after HCV NAT test results began to be collected for all patients in the SRTR data set, allowing for comparison between HCV Ab-positive and HCV NAT-positive donors. Donors were excluded if they had unknown or undetermined HCV Ab or HCV NAT results, were utilized in living donor living transplant (LDLT), or had a pediatric recipient (<18 years old).
Our primary comparison was between donors who were HCV Ab positive and those who were HCV Ab negative. Although there was a recent consensus in defining HCV-positive donors as those who are NAT positive, 13 we chose a serologic definition as there is typically a delay in testing time for HCV-negative organs were evaluated. The eMethods in the Supplement include details on data collection.

Data Source
This study used data from the SRTR. The SRTR data system includes data on all donor, waitlisted candidates, and transplant recipients in the United States, submitted by the members of the OPTN.
The Health Resources and Services Administration of the US Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors.
The data reported here have been supplied by the Minneapolis Medical Research Foundation as the contractor for the SRTR. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the SRTR or the US government. As the SRTR is a publicly available deidentified patient-level data set, institutional review board approval was not required according to the policies of SRTR or Mount Sinai.

Statistical Analysis
Categorical variables are reported by percentages, and continuous variables are reported as medians with interquartile ranges (IQR). Differences between categorical variables were analyzed with the χ 2 test. Differences between quantitative variables were analyzed with a Kruskal-Wallis test. Statistical analyses were performed using the STATA software package (version 15.1; StataCorp). The threshold for statistical significance was P < .05 using 2-tailed tests.     Table 1). HCV Ab-positive donors were also more likely to have a history of heavy alcohol and tobacco use, cocaine use, and other drug abuse. The primary mechanism of death in HCV Ab-positive donors was drug overdose in 51.7% compared with 11.1% of the deaths (P < .001) in HCV Ab-negative donors.

Donor Allograft Characteristics: HCV Ab-Positive vs HCV Ab-Negative Donors
A total of 67.7% of HCV Ab-positive donors underwent liver biopsy compared with 36.2% of HCV Ab-negative donors (P < .001) (

Comparison of HCV NAT-Positive and HCV Ab-Positive Donors
Among HCV Ab-positive donors, 1216 (64.4%) were HCV NAT positive (eTable 1 in the Supplement). were similar to differences between HCV Ab-positive vs HCV Ab-negative donors and liver allografts (eTable 2 in the Supplement), and HCV Ab-positive/NAT-positive (HCV exposed + viremic) vs HCV Ab-positive/NAT-negative (HCV exposed + nonviremic) donor comparisons are shown in Table 2.

Geographic Distribution of HCV-Positive Donors Across OPTN Regions
The distribution of the number of HCV Ab-positive donors utilized in adult deceased donor LT across the 11 OPTN regions is shown in Figure 2A

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Donor Characteristics and Regional Differences in HCV-Positive Liver Transplantation region. In regions that utilized lower rates of HCV-positive allografts for their region, the organs usually were being utilized in nearby regions. A similar regional distribution was seen with the number of HCV NAT-positive donors utilized in LT (eFigure 2 and eTable 4 in the Supplement).

The Volume of HCV-Positive Donors Across Organ Procurement Organization Centers
The distribution of the total number of HCV Ab-positive donors utilized in LT across the top 25 organ procurement organization (OPO) centers is shown in Figure 2B.

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Donor Characteristics and Regional Differences in HCV-Positive Liver Transplantation

Deaths From Drug Overdose Across OPTN Regions
The distribution of drug overdose and deaths in HCV Ab-positive and HCV Ab-negative is shown in eTable 9 in the Supplement. For all donors, in regions 1, 2, 9, and 10, drug overdose was the cause of death for more than 20% of all donors: region 1 at 25.7%, followed by region 2 at 24.7%, region 9 at 22.2%, and region 10 at 20.9%. On the contrary, drug overdose was the least common cause of donor death in region 4 at 4.8%. Meanwhile, in regions 1, 2, 7, 9, and 10, drug overdose was the cause of death in more than 60% of all HCV Ab-positive donors (eTable 9 in the Supplement). Similar findings were seen for NAT-positive vs NAT-negative donors.

Discussion
In this study of the SRTR database, we performed an in-depth analysis of the clinical and liver allograft characteristics and regional differences in the use of HCV Ab-positive and HCV NAT-positive donors compared with HCV-negative donors. Our data suggest that regardless of how HCV is classified (HCV Ab-positive or HCV NAT-positive), allografts from HCV-positive donors made for higher quality grafts compared with those from HCV-negative donors. HCV-positive donors were more likely to be White, which is consistent with racial/ethnic demographic characteristics of the opioid epidemic. 20 HCV-positive donors also tended to be younger, have fewer comorbidities such as obesity, diabetes, and hypertension, less steatosis in their liver, and lower liver donor risk index.
These liver allograft qualities have been associated with lower rates of biliary complications and improved rejection rates, graft survival, and overall survival. [16][17][18] Despite this, recent studies have shown that the discard rate of HCV-positive organs remains nearly double the rate of HCV-negative organs. 19 Donor characteristics such as age and presence of comorbidities are even more pronounced in HCV Ab-positive/NAT-positive donors compared with HCV Ab-positive/NATnegative donors. This distinct cohort of younger HCV-positive donors are likely more optimal donors with less allograft fibrosis. 13 We found that significant geographical variations exist in the utilization of HCV-positive donors. The geographical distribution of the opioid epidemic does not, however, fully explain all of the utilization trends that we found in this study. For example, regions 4, 6, 7, and 8 include areas of the country that have been hit heavily by the opioid epidemic but performed the fewest transplants with HCV-positive donors. 5 Explanations for this discrepancy are unclear but may include differences in rates of donor registration among potential donors and variations in the practices of transplant centers. 23 A higher relative rate of non-opioid related deaths due to trauma compared with opioid overdose may occur in some regions due to variations in public safety laws, reducing the relative number of donors who die with HCV infection. 24 That said, a higher rate of opioid-related death did not guarantee higher utilization, as we found that region 7 had among the highest rates of donor deaths from drug overdose (5th of 11) but only 4.7% of the total number of LT performed in this region was with HCV-positive donors. Region 7 also has among the highest median MELD at the time of LT, suggesting that organ demand is not the reason for the low utilization of HCV-positive donors. 25 Finally, when we investigated the destination of the HCV-positive donor allografts in regions 4, 6, 7, and 8, we found that more than 30% of the HCV-positive donor allografts in these regions were being used in nearby regions, suggesting that some of these organs were being passed up locally.
Lack of utilization of HCV-positive organs in certain high MELD regions may also be explained by higher barriers to HCV treatment in different areas of the country, which can be related to state Medicaid policies and the socioeconomic level of the region. 26 While there are currently fewer barriers to treatment compared with the early DAA era, in some states, insurers-especially Medicaid programs-have strict requirements for approval of DAA therapy, including the need for specialist prescribers, required periods of abstinence from drugs and alcohol, and a restriction of treatment to patients with higher stages of fibrosis. 27 The more stringent the Medicaid criteria for HCV treatment, the less likely it is for HCV treatment to be initiated. 28 The converse is true in states like

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Donor Characteristics and Regional Differences in HCV-Positive Liver Transplantation Massachusetts and New Hampshire (both located in region 1), where there is a lower requirement to HCV treatment and initiation of treatment is easier. 13 The socioeconomic status of the region also matters as areas with patients of lower socioeconomic status are more likely to have Medicaid insurance coverage, which has a much higher treatment denial rate compared to commercial insurance. 29 Removing financial/insurance-related barriers is key in promoting the use of HCV-positive donors as it establishes a stable setup for post-LT HCV treatment, which provides assurance to transplant centers and patients that the posttransplant course will not be complicated by effects of untreated posttransplant HCV. 28 A final explanation for the regional variation in HCV-positive donor utilization may be variations in patient perception of transplantation with organs from an HCV-positive donor. A patient survey conducted by Couri et al 30 in patients undergoing kidney transplant found that 90% were aware of HCV, but only 60% knew that it was curable, and only 46% were willing to receive an HCV-positive organ. As such, certain centers may be better at providing patients with education about the benefits of accepting HCV-positive donors. As physicians, we must be diligent in guiding our patients by highlighting the risks and benefits that come with accepting an HCV-positive donor and providing adequate informed consent. 21 One of the potential avenues to accomplish this task is by using social media as a way to disseminate knowledge about the use of HCV-positive donors to physicians and patients across the country, remove the social stigma around the use of HCV-positive grafts, and improve perception. 31,32

Strengths and Limitations
The strengths of this study are that we were able to depict the regional utilization of HCV-positive donors in liver transplantation on a fairly granular level using a large national database. As such, we could highlight and document areas that may be underusing HCV-positive grafts, which we hope may enable future advancements to bridge the gap. This study has several limitations. We did not report outcome data of HCV-positive grafts as such studies would need to also focus on recipient characteristics, and our study was primarily descriptive aimed at highlighting donor characteristics and utilization. Additionally, although we can speculate on the reasons behind the differences in regional utilization through correlation within our data (ie, incidences of drug overdose), we suspect that there are multiple confounders that are unaccounted for in the SRTR database. These may include differing institutional, physician, and patient's psychosocial and efficacy perceptions regarding HCV-positive grafts among different regions.

Conclusions
In summary, as a result of the opioid epidemic and a related increase in the number of drug overdose deaths, the utilization of HCV-positive donors is a useful approach to expand the donor pool. In this study, we found that HCV-positive donors tend to be healthier and donate superior liver allografts compared with HCV-negative donors. This association was even more pronounced in HCV viremic donors. Despite this finding, there exist substantial variations in the utilization of these donors across the country that are not entirely explained by the geography of the opioid epidemic. Lowering the barriers to HCV treatment by improving insurance coverage, eliminating outdated requirements that delay timely initiation of treatment, and improving public perception of the use of these organs through education and media may be the ideal way to improve the utilization of these organs. eFigure 1. Distribution of the ultimate destination (recipient OPTN region) of HCV Ab (+) donor grafts from each donor OPTN region eFigure 2. The volume of HCV NAT (+) donors utilized in each OPTN region eMethods. Data Collection eReferences.