Characteristics associated with receipt of treatment among patients diagnosed with chronic hepatitis C virus

Although current guidelines recommend that nearly all patients with chronic hepatitis C virus (HCV) infection receive treatment, a substantial proportion remain untreated. We conducted an administrative claims analysis to provide real‐world data on treatment patterns and characteristics of treated versus untreated patients among individuals with HCV in the United States. Adults with an HCV diagnosis from 01 July 2016 through 30 September 2020 and continuous health plan enrolment for 12 months before and ≥1 month after the diagnosis date were identified in the Optum Research Database. Descriptive and multivariable analyses were conducted to evaluate the association between patient characteristics and the rate of treatment. Of 24,374 patients identified with HCV, only 30% initiated treatment during follow‐up. Factors associated with increased rate of treatment included younger age versus age 75+ (hazard ratio [HR] 1.50–1.83 depending on age group), commercial versus Medicare insurance (HR 1.32), and diagnosis by a specialist versus a primary care physician (HR 2.56 and 2.62 for gastroenterology and infectious disease or hepatology, respectively) (p < .01 for all). Several baseline comorbidities were associated with decreased rate of treatment, including psychiatric disorders (HR 0.87), drug use disorders (HR 0.85) and cirrhosis (HR 0.42) (p < .01 for all). These findings highlight existing HCV treatment inequities, particularly among older patients and those with psychiatric disorders, substance use disorders or chronic comorbidities. Targeted efforts to increase treatment uptake in these populations could mitigate a considerable future burden of HCV‐related morbidity, mortality and healthcare costs.

treatment of all individuals with chronic HCV infection, excepting those who have a short life expectancy due to non-liver-related conditions. 4,5 Unfortunately, a substantial proportion of patients with chronic HCV remain untreated despite this guidance. Recent US studies indicate that less than 30% of patients with chronic HCV infection initiate treatment. 6,7 Given the demonstrated benefits of successful HCV treatmentincluding lower all-cause mortality and reduced rates of cirrhosis and HCC 8 -improved understanding of factors that contribute to inequities in treatment access among patients with chronic HCV has been an area of active research. African American or Hispanic race/ethnicity, [9][10][11] for example, is among those characteristics that have been associated with lower rate of receiving treatment for chronic HCV, in addition to reduced access to medical care, 10 drug/alcohol use disorders 6,[9][10][11][12] and comorbidity burden. 9 However, previous analyses of this topic were generally limited to particular geographical regions or hospital systems. The objective of the present study was to provide real-world data on rates of treatment initiation, treatment patterns and characteristics associated with receipt of treatment among patients diagnosed with HCV using an administrative claims database including over 71 million patients and spanning multiple healthcare provider networks across the United States.

| Study design and data source
This was a retrospective observational study using administrative This study was conducted in accordance with the Declaration of Helsinki. 13 Because no identifiable protected health information was accessed in the conduct of this study, institutional review board approval or waiver of approval was neither required nor sought.

| Study population
The study population included adult patients who were enrolled in commercial or Medicare Advantage with Part D insurance plans and had a diagnosis of chronic HCV (≥1 inpatient medical claim or ≥2 non-inpatient medical claims on different dates ≥30 days apart with a diagnosis code for chronic or unspecified hepatitis C in any position on the claim; see Supplemental Table for  Included patients were required to have continuous health plan enrolment during the 12 months preceding the index date (baseline period) and for ≥1 month after the index date (follow-up period, which ended on the earlier of health plan disenrolment or 31 October 2020, the end of the study period). Patients were excluded if they had any pharmacy fill for HCV therapy (boceprevir, daclatasvir, elbasvir/ grazoprevir, glecaprevir/pibrentasvir, interferon or peginterferon, sofosbuvir or sofosbuvir combination therapy, ombitasvir combination therapy, ribavirin, simeprevir or telaprevir) during the 12-month baseline period; evidence of chronic or unknown HCV diagnosis during the baseline period; any medical claim with a diagnosis code for hepatitis B virus (Supplemental Table) during the baseline or followup periods; or unknown sex, geographical region or insurance type.
Patients were assigned to study cohorts based on HCV treatment status (treated vs. untreated). Those who initiated any HCV therapy during the follow-up period were considered treated.

| Statistical analysis
Study variables were analysed descriptively and stratified by treatment status (treated vs. untreated). Variables that were assessed only among treated patients (i.e. treatment patterns) were stratified by insurance type (commercial vs. Medicare). Numbers and percentages were provided for categorical variables; means and standard deviations were provided for continuous variables. Between-cohort differences in patient characteristics were evaluated using twosample t-tests for continuous measures and chi-squared tests for categorical measures. The association between patient characteristics and the rate of treatment was analysed using a Cox proportional hazards model adjusted for demographics, insurance type, index year, baseline HCRU, comorbid conditions and index provider specialty. All analyses were conducted using SAS software version 9.4 (SAS Institute) and statistical significance was defined as p ≤ .05.  The proportion of treated patients whose index provider was a gastroenterologist was 27.5% versus only 7.7% for untreated patients (p < .001).

| Treatment patterns
Among patients who received HCV treatment during follow-up, the mean time from diagnosis to treatment initiation was 168 days (SD 215 days, median 86 days) ( Table 2). Time to treatment initiation was longer for patients with Medicare insurance (mean 179 days, SD 229 days, median 87 days) than for those with commercial insurance (mean 157 days, SD 199 days, median 85 days) (p < .001). The three most common treatment regimens were sofosbuvir and ledipasvir (37%), sofosbuvir and velpatasvir (30%) and glecaprevir and pibrentasvir (28%). All other regimens were used by <2% of study patients. Mean (SD) PDC for DAA medications among all treated patients was 0.98 (0.05) and did not differ meaningfully between patients who had commercial versus Medicare insurance.

| DISCUSS ION
Current guidelines recommend treatment for nearly all patients with chronic HCV. 4 Despite these broad and unequivocal guidelines, the majority (70%) of patients diagnosed with chronic HCV in this realworld population remain untreated-and even among patients who were treated, time from diagnosis to treatment initiation was extremely long (>5 months). Patients who were older and/or had certain comorbidities, including cirrhosis, dementia, drug use disorders and psychiatric disorders, were most likely to remain untreated. To our knowledge, this is the only nationwide US analysis to date of factors contributing to undertreatment of chronic HCV. 10 Our results align with existing evidence that a small proportion of US patients with chronic HCV receive treatment, currently estimated at less than 30%. 6,7 In comparison, more than 90% of HIVinfected adults receiving medical care in the United States have been prescribed antiretroviral therapy. 15 Our results are also congruent with previous findings that patients with chronic HCV are less likely to receive treatment if they have an overall higher burden of medical comorbidities, 9 which tend to increase with age, or psychiatric conditions, including drug/alcohol use disorders. 6,9,10,12,16 The undertreatment observed among these groups is concerning, given that The causes of low treatment rates among patients with HCV are multifactorial and include some patient-side barriers, such as missed medical appointments or patient preference. 9,11,16,25 However, treatment decisions made by clinicians also play a substantial role. In a review of medical records from 905 patients seen in HCV specialty clinics, common chart-documented reasons for clinicians deciding not to provide treatment included ongoing drug/alcohol use by the patient and psychiatric or medical comorbidities. 9 Studies incorporating medical chart review or physician interviews indicate that some clinicians assume patients with substance use issues will be noncompliant with treatment or have a high risk of reinfection, 16,26,27 while others hesitate to provide HCV treatment to patients with psychiatric comorbidities because of increased potential for drug-drug interactions. 27,28 There is also evidence that some clinicians choose not to treat patients with medical conditions they consider to be life-limiting, such as chronic kidney disease, malignancy and severe COPD. 9 These patient-and provider-side barriers are exacerbated by  33 However, the extent to which commercial health insurance providers have followed this lead is not known. It is possible that state level rules and changes impact this population, but this study was not able to assess the impact of such rules.
Importantly, real-world data have shown that the benefits of HCV treatment for patients who have a higher comorbidity burden, psychiatric disorders or substance use disorders are similar to those for the general population of patients with HCV. 19,20,23,[34][35][36][37][38][39] In addition, while adverse events due to HCV treatment among patients with psychiatric disorders were previously of great concern due to the psychiatric side effects of older interferon-based regimens, 40,41 studies of treatment with newer regimens have shown good tolerability in this patient population. 38,39 DAA treatment among patients with HCV who have psychiatric disorders has also been shown to significantly reduce the frequency of both of nonpsychiatric and psychiatric hospitalisations in the year after initiation. 42 Given that patients with psychiatric or substance use disorders in particular are known to experience substantial health disparities in the United States, [43][44][45] the presence of barriers to HCV treatment may exacerbate existing health inequities for these vulnerable populations. 32 Interventions designed to increase HCV treatment uptake are therefore a critical element of the global effort to eliminate HCV as a public health threat. 3 Approaches that incorporate electronic medical record-based alerts, which have been shown to increase rates of HCV screening and linkage to care, 46-48 could be similarly leveraged to prompt treatment initiation for patients diagnosed with HCV.
Better education of nonspecialist clinicians regarding the broad applicability of current guidelines and/or broader implementation of a simplified treatment algorithm geared toward nonspecialists 49 may also help mitigate the HCV treatment gap, 47,48,50 a suggestion supported by our finding that patients who were diagnosed by or referred to a gastroenterologist, hepatologist or infectious disease doctor were more than twice as likely to receive treatment as patients diagnosed by a primary care physician, potentially due to better knowledge of guidelines among specialists.

| Conclusions
This real-world analysis of insured US adults with chronic HCV infection showed that contrary to current guidelines, many patients remained untreated-particularly those who were older and those with psychiatric disorders, substance use disorders or chronic comorbidities. The inequities in HCV treatment highlighted by this study represent a lost opportunity to mitigate a considerable future burden of morbidity, mortality and associated healthcare costs. Improving provider education about updated guidelines, disseminating real-world efficacy/safety data for populations previously considered high risk for receiving HCV treatment, and implementing targeted efforts to increase HCV treatment uptake in undertreated populations could both reduce the burden exacted by HCV on patients and healthcare systems, and help make substantial inroads toward the ultimate goal of eradicating this disease.

ACK N O WLE D G E M ENTS
This work was funded by Gilead Sciences, Inc. Medical writing assistance was provided by Yvette Edmonds, PhD (Optum Life Sciences) and was funded by Gilead. which was contracted by Gilead to conduct the study and provide medical writing assistance.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data used to generate these results cannot be disclosed publicly.
Proprietary data obtained from the Optum Research Database may be accessed only with strict data security and privacy protocols, and oversight with a restrictive license agreement.