Comparison of Liver Transplant Wait-List Outcomes Among Patients With Hepatocellular Carcinoma With Public vs Private Medical Insurance

This cohort study compares wait-list outcomes by insurance type for patients with hepatocellular carcinoma awaiting liver transplant.


Introduction
Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths. 1 The incidence of HCC continues to increase in the United States, although a recent analysis showed that the rate of increase slowed between 2006 and 2011, likely owing to improved HCC primary prevention strategies, improvements in the treatment of viral hepatitis, and increased use of curative modalities. 2 The only curative therapies for HCC are surgical, including tumor resection, liver transplant (LT), or local ablation. 3,4 Despite these improvements in HCC incidence, there are well-documented socioeconomic and racial disparities in accessing care for patients with HCC. Black patients have incidence rates 2-fold that of white patients, 5 and in a 2018 Surveillance, Epidemiology and End Results database study, 6 the overall 5-year survival rate for patients with HCC was lower among black patients than any other racial group. Black patients were also the least likely to undergo curative therapy for HCC compared with white and Hispanic patients. 7 Another study found that black patients were significantly less likely to undergo an LT despite similar severity of liver disease, tumor characteristics, and insurance status. 8 Insurance type has also been shown to affect access to care for patients with HCC. Among US adults with HCC, patients who were uninsured or had Medicaid had more advanced tumor stage at diagnosis, lower rates of tumor-directed treatment, and lower overall survival. [9][10][11][12] As more patients are using public insurance to cover the cost of LT since the Patient Protection and Affordable Care Act Medicaid expansion policy came into effect in 2014, 13,14 these disparities are becoming increasingly concerning.
For patients with HCC with tumor burdens within the Milan criteria listed for LT, there are several challenges to ultimately receiving an LT, especially in regions with longer wait times, 15 which can be further affected by socioeconomic status and insurance type. Transplant centers are often located in urban areas, and patients from rural areas may have to travel long distances frequently to attend appointments, undergo imaging and laboratory tests, or receive multiple bridging therapies.
Furthermore, lower education levels and language barriers can make navigating the intricacies of an LT waiting list more challenging.
Although many studies have examined the associations of socioeconomic factors and insurance with the likelihood of receiving an LT, [9][10][11][12] to our knowledge, there have been no studies specifically examining the association of insurance status and other socioeconomic variables with dropout from an LT waiting list among patients with HCC already wait-listed for LT. Given the many challenges that remain despite being successfully wait-listed for LT, we hypothesized that patients with public insurance in need of an LT would have worse wait-list outcomes than patients with private insurance, including Kaiser Permanente, awaiting LT and that patients with Kaiser Permanente insurance may have superior outcomes, given Kaiser Permanente's unique integrated health care model known for its emphasis on preventive care, timely appointments for patients, and excellent care coordination. 16 As our LT center receives referrals from various forms of public and private insurance, including

Study Design and Patient Population
This retrospective cohort study included patients aged 18 years or older initially enrolled in a waiting list for LT at University of California, San Francisco with initial HCC Model for End-Stage Liver Disease (MELD) exceptions granted from January 1, 2010, to December 31, 2016. Patients who required tumor downstaging to be eligible according to Milan criteria for wait-listing were excluded. Collected variables included demographic characteristics (age, sex, self-reported race/ethnicity, insurance type, education level, US citizenship status, country of origin) at the time the patient was added to the LT waiting list (baseline), days between each MELD exception upgrade, size and number of tumors at the time of priority listing, number and type of local-regional therapies received, baseline α-fetoprotein (AFP) level, MELD score at baseline, cause of liver disease, and, if applicable, either reason for waiting list dropout or posttransplant histopathologic data.
This study was approved by the University of California, San Francisco Committee for Human Research. The study received expedited approval with minimal study risk assignment. The informed consent requirement was waived because this study used retrospective data without any intervention or deviation from standard of care. This report follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Outcome
The primary outcome for this study was dropout from the LT waiting list owing to liver-related death or HCC tumor progression. The secondary outcome was receipt of a deceased donor LT. Patients who underwent LT at another hospital or from a live donor (LD) were censored at the time of removal from the University of California, San Francisco waiting list, since insurance type may affect a patient's ability to pursue these options.

Statistical Analysis
Clinical characteristics of the groups stratified by insurance type were compared with Pearson χ 2 and Kruskal-Wallis tests. The cumulative incidence and 95% CIs for dropout and LT were calculated while accounting for competing risks and stratified by insurance type. For the primary outcome of dropout, LT was considered a competing event. For the secondary outcome of LT, dropouts owing to liverrelated death or HCC tumor progression were considered competing events.
Univariate and multivariable subdistribution hazard ratios (HRs) and 95% CIs for risk factors associated with waiting list dropout were estimated via Fine and Gray competing-risk regression. Risk factors associated with dropout with a univariate P value less than .10 were evaluated in the multivariable analysis. The final multivariable model was selected by backward elimination, and variables with 2-tailed P values of .05 or more were removed. Statistical analyses were performed with SAS statistical software version 9.4 (SAS Institute) and Stata/IC version 14.2 (StataCorp).

Patient Characteristics
Baseline patient characteristics for the 705 patients included in the study are summarized in Table 1 (Figure 1A). Median (IQR) time to dropout was 7.8 (3.9-14.5) months overall and did not differ by insurance type (Table 2).

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An additional 72 of 705 patients (10.2%) in the full cohort dropped out from the LT waiting list for reasons other than tumor progression or liver-related death. Thirty patients (4.3%) dropped out owing to another medical comorbidity or non-liver-related death, and 29 patients (4.1%) dropped out because they had inadequate social support, had substance use disorder, were nonadherent, or were lost to follow-up. Nineteen patients (2.7%) transitioned to a different insurance type after being added to the LT waiting list with HCC MELD exception but before their wait-list outcome. Thirteen patients (1.8%) declined LT (Figure 2    Although there has been much speculation, the reasons for discrepancy in care between patients with private and public insurance remain unclear, to our knowledge. Explanations previously put forth include that patients with public insurance present with more advanced disease than those with private insurance 24 and that Medicaid patients generally have less access to subspecialty care. 25 Yet, one 2015 study 26 showed that mortality and survival were worse for patients with public insurance than for those with private insurance even when presenting with early-stage HCC. In our study, all patients had similar tumor-related characteristics and had accessed subspecialty care, as demonstrated by listing on the LT waiting list; therefore, there must be other factors to explain our findings aside from tumor stage and ability to access subspecialty care.
Patients with Medicaid are more likely to be poor and unemployed and to have less education and more comorbidities than patients with private insurance, 27 all of which may contribute to worse wait-list outcomes. Lack of stable housing and adequate social support could negatively affect a patient's ability to attend health care appointments and increase the likelihood of being lost to follow-up. Lower health care literacy, which could result in a lack of understanding of disease severity and the importance of attending appointments, is also significantly associated with lower education levels and with language barriers. 28 These factors may have contributed to our finding that patients with public insurance had significantly longer periods between MELD exception upgrades. In our study, 19% of patients who dropped out of the waiting list from the public insurance group did so because of inadequate social support, nonadherence, or being lost to follow-up, compared with  29 With this change, the incentive for patients with private insurance to travel to other regions may disappear, which could help reduce some of these disparities, since patients with public insurance typically do not have this option.

Strengths and Limitations
Our study has several strengths. Most notably, this is the first study evaluating outcomes for patients with HCC on the LT waiting list by insurance type, to our knowledge. We had a large patient cohort of more 700 patients and representation of 3 different insurance types at our transplant center.
Given the long wait-list time in our region, we are in a prime position to study risk factors associated with waiting list dropout.
Our study also had limitations. Limitations to our study included its retrospective design and the fact that it was a single-center study. Our patient population in Northern California was relatively diverse; therefore, there may be issues with extrapolating our results to other centers with more homogeneous patient populations. Additionally, less than 3% of patients in our cohort transitioned to a different insurance type, so we were unable to include an analysis of insurance transition in our study. Furthermore, the specific reasons for longer MELD exception periods for patients with public insurance, which may have contributed to increased dropout rate in this patient cohort, remain unclear, and we were not able to investigate this variable given the retrospective nature of this study.

Conclusions
In conclusion, in this large, diverse cohort of patients with HCC on a waiting list for LT, patients with public medical insurance had worse wait-list outcomes despite similar tumor-and liver diseaserelated characteristics compared with patients with Kaiser Permanente medical insurance or other private medical insurance. These findings appear to be associated with delays in completing pre-LT evaluations and obtaining timely MELD exception upgrades. Public insurance should be recognized as a risk factor associated with waiting list dropout, and necessary steps should be implemented to mitigate the increased risk of dropout among these patients. These findings have increasingly meaningful implications as more patients are using public insurance to pay for LT. 13,14 Improved health care coordination and delivery could potentially help to reduce these disparities.