Increasing pharmacoequity for people with cirrhosis

Cirrhosis is associated with significant morbidity and mortality, including frequent hospitalizations and high health care costs. In the United States, cirrhosis affects ~2.2 million adults and is the ninth leading cause of death. Evidence-based cirrhosis care necessitates complex medication regimens to improve mortality as well as quality of life. Medications are the cornerstone of the management of many etiologies of cirrhosis and their complications such as HE, ascites, or variceal hemorrhage. On average, patients with cirrhosis take between 3 and 10 medications, requiring multidisciplinary and complex care to account for drug-drug interactions, adverse side effects, and potential toxicities.¹ Recent data have emerged revealing disparities in access to and use of appropriate pharmacotherapy for cirrhosis, highlighting the need for increased awareness, further study, and development of targeted interventions.

DEFINING PHARMACOEQUITY AND IMPLICATIONS FOR CIRRHOSIS CARE

Pharmacoequity, or “ensuring all individuals, regardless of race and ethnicity, socioeconomic status, or availability of resources, have access to the highest quality medications required to manage their health needs,” is critical to reducing health disparities.² In hepatology care, pharmacologic inequities may occur at any point across the therapeutic continuum (Figure 1) and include disparities in medication access, cost, and quality. Minority groups with liver disease have been found to be less likely to receive evidence-based treatments, preventive therapies, and novel medications. Specifically, analyses of the medical management of HCV, alcohol-associated cirrhosis, and primary biliary cholangitis (PBC) demonstrate a lack of pharmacoequity in the implementation of guideline-driven care. Challenges accessing medication targeting HE reveal inequities in preventive care for patients with decompensated cirrhosis,³ while the decreased rates of immunotherapy use for HCC among racial and ethnic minorities highlight disparate access to novel medications for patients with liver disease.⁴

FIGURE 1.

Areas of inequity in medication access along the therapeutic continuum. Abbreviations: MASH, metabolic dysfunction-associated steatohepatitis; ALD, alcohol- associated liver disease; HCC, hepatocellular carcinoma; PBC, primary biliary cholangitis.

Access to direct-acting antivirals remains low despite recommendations from the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases to treat all patients with HCV. CDC data from 2019 to 2020 revealed that most insured patients with newly diagnosed HCV did not receive timely treatment, with only 1 in 3 privately insured patients and 1 in 4 Medicaid or Medicare recipients initiating direct-acting antiviral therapy within 1 year of diagnosis.⁵ In this cohort, younger patients were less likely to receive HCV treatment among all insurance types, whereas racial minorities were less likely to receive treatment only among Medicaid recipients.⁵ States with Medicaid restrictions create further barriers to HCV treatment by requiring prior authorization, severe fibrosis, abstinence from substance use, or specialty provider prescription.^5,6 An analysis of statewide electronic health data in Indiana from 2011 to 2021 revealed that the greatest increase in treatment rates occurred after the removal of Medicaid restrictions.⁶ Aside from insurance type and payer restrictions, provider bias also contributes to pharmacologic inequity. In a 2021 single-center survey of Veterans Health Administration (VHA) providers treating HCV, <60% were willing to prescribe direct-acting antiviral treatment for homeless veterans or those with current alcohol use.⁷ For patients using substances such as cocaine or heroin, this number dropped to 32%.⁷

Similarly, disparities in the treatment of alcohol use disorder (AUD) in patients with alcohol-associated liver disease have been well described. Medications for AUD have been shown to decrease the risk of hepatic decompensation and all-cause mortality in patients with alcohol-associated cirrhosis.^8–10 Yet, in a large cohort of patients with alcohol-associated cirrhosis and prescription drug insurance coverage, <1% of patients received pharmacologic treatment.⁹ Interestingly, patients with comorbid anxiety or depression were more likely to be prescribed relapse-prevention medication. Conversely, women were less likely than men to be prescribed AUD treatment. This has been attributed to increased barriers to AUD diagnosis and management in women, including lower specificity of alcohol screening tests in women, higher perceived social stigma, and lack of AUD pharmacotherapy with demonstrated safety among pregnant or breastfeeding women.^8,9 Racial disparities in AUD treatment have also been shown, as Black persons were 1.5 times less likely to receive pharmacotherapy for AUD compared to Whites in a VHA study.¹⁰

Racial and gender disparities have also been observed in the pharmacologic management of PBC. Ursodeoxycholic acid, first-line therapy for PBC, delays the progression of liver disease and improves transplant-free survival. In an analysis of 11 health systems across the United States, 70% of patients with PBC received ursodeoxycholic acid, with men and African Americans significantly less likely to be treated.¹¹

Socioeconomic and racial inequities in access to preventive therapies for patients with cirrhosis are exemplified by challenges obtaining the medication rifaximin, utilized to prevent recurrent HE. Present in up to 40% of patients with cirrhosis, HE is an important yet modifiable driver of hospitalizations, economic losses, and quality of life for patients and caregivers. Rifaximin is cost-prohibitive for many patients, potentially costing over $2500 per month depending on insurance.¹² Yet it is well tolerated and highly effective, with a number needed to treat of 9 to prevent one hospital admission due to HE.¹² In an analysis of Medicare patients with cirrhosis, HE, and prescription coverage, minority groups including Black, Hispanic, and Asian patients were less likely to be prescribed rifaximin compared to White patients.⁵ This may be partially mediated by subspecialty referral. Specialist care is associated with rifaximin prescription, and lower gastroenterology referral rates have been documented for Black and Hispanic patients.⁵

Finally, access to novel therapies is another important component of pharmacoequity. Both HCC and metabolic dysfunction–associated steatotic liver disease (MASLD) have been shown to disproportionately affect minority groups. However, a recent study of immunotherapy use in patients with advanced HCC found that Black and Hispanic individuals were less likely to receive early access to immunotherapy compared to White individuals.⁶ Proposed contributing factors include provider bias and reduced access to clinical trials. A 2020 systematic review of MASLD clinical trials reported <12% Hispanic participation.¹³ Encouragingly, 21% of the study population is Hispanic in the recent phase III trial of Resmetirom, the first drug to receive accelerated FDA approval for MASLD.¹⁴ However, it remains to be seen if the benefit of this medication will translate to the real-world population given the reported annual wholesale price of $47,400. Socioeconomic disparities have also been described for glucagon-like peptide 1 receptor agonists, which are commonly used in patients with MASLD, as those with higher household incomes are more likely to receive treatment.¹⁵

POTENTIAL INTERVENTIONS

The identification of such disparities in the medical management of cirrhosis highlights the need for targeted interventions to achieve pharmacoequity. The National Institute on Minority Health Disparities provides a framework through which interventions to achieve pharmacoequity can be categorized at different levels of influence (Figure 2). At an individual level, improved patient education is necessary, as prior studies have shown that many patients with cirrhosis poorly understand their medication regimens.¹ As a health system, increased participant diversity in pharmacologic trials is imperative. Strategies to achieve increased minority representation include building collaborations between academic and community health centers, where minorities often seek care. Nontraditional models of care, such as e-consults, remote HE monitoring, and subspecialty support for primary care providers treating HCV (Project ECHO) should be leveraged to increase access to appropriate liver-directed care.^6,12 Furthermore, the electronic medical record can be programmed to provide prompts for consideration of prescriptions such as beta-blockers or rifaximin. On a community level, medical mistrust and stigma surrounding liver disease must be addressed as they are associated with reduced health care–seeking behavior and suboptimal treatment.⁸ As a society, health care reform through policy and legislative changes increasing access to care, such as Medicaid expansion to all states, needs to be prioritized.⁶ Cost-sharing strategies, including scaling prescription costs to disposable income, could have a significant impact as 25% of patients with liver disease have cost-related medication nonadherence.¹⁶

FIGURE 2.

Solutions to address disparities in access to pharmacotherapies in people with liver disease. Abbreviations: CLD, chronic liver disease; ECHO, extension for community healthcare outcomes; EMR, electronic medical record.

FUTURE DIRECTIONS

There are several gaps in our understanding of pharmacoequity for patients with cirrhosis, providing avenues for further research to inform future interventions (Table 1). Hepatologist prescription practices could be better understood through the reporting of individual provider- and practice-related quality metrics, including stratification of prescription rates by race and ethnicity.² The impact of an educational intervention for providers should be evaluated due to the low treatment rates of patients with cirrhosis and alcohol use.⁹ Geographic areas with limited access to pharmacies, known as pharmacy “deserts,” are associated with overall reduced access to medications,² though little is known about their impact on patients with liver disease. Given the success of remote monitoring for patients with congestive heart failure on diuretics, a similar infrastructure could be implemented in patients with decompensated cirrhosis.¹ Finally, little is known about the patient experience and patient-reported outcomes in our understanding of pharmacoequity in cirrhosis. Surveys and focus groups could ensure the patient’s voice is part of the discussion to elucidate additional barriers to high-quality prescription access, cost, and filling, in addition to adherence to recommended therapies.

TABLE 1.

Gaps in the literature on liver disease medication disparities research and future directions

Gaps in the literature

Examples of future directions

Hepatologist prescription practices Knowledge of institution or clinician behavior that may reduce or widen disparities in pharmacotherapies Population-based estimates of cirrhosis-related medication use and access Psychosocial barriers to medication access and adherence Impacts of pharmaco-inequity on cirrhosis-related outcomes Acceptability and access of digital technology among underrepresented minority groups, people with limited English proficiency, and rural populations Pharmacy deserts and impact on people with liver disease Patient-reported outcomes relating to medication use, cost, and adherence Impact of structural and social determinants of health on access to medications in liver disease

Incorporation of hepatologist prescription practices into multilevel quality improvement efforts for patients with cirrhosis Qualitative and mixed-methods studies of institutional and provider behaviors, implicit biases that may exacerbate disparities National prospective registry with data on socioeconomic status, insurance type, income, and other social determinants of health Utilization of subsequent data to advocate for health policy reform Investigation of impact of patient navigators on pharmacoequity in patients with liver disease Investigation of impact of pharmacy incentive programs on reducing pharmacy deserts Studies partnering with patients, caregivers, community leaders, and policymakers

CONCLUSIONS

In summary, there are significant disparities in access to and use of medications for patients with cirrhosis that impact health outcomes. Greater efforts are needed at the individual, health system, community, and societal levels to identify gaps along the therapeutic continuum and design evidence-based interventions that will achieve pharmacoequity among our vulnerable patients with liver disease.