Association of Direct-Acting Antiviral Treatment With Mortality Among Medicare Beneficiaries With Hepatitis C | Infectious Diseases | JAMA Network Open | JAMA Network
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Figure 1.  Study Sample Selection
Study Sample Selection

DAA indicates direct-acting antiviral drug; HCV, hepatitis C virus.

Figure 2.  Survival Stratified by Direct-Acting Antiviral (DAA) Treatment
Survival Stratified by Direct-Acting Antiviral (DAA) Treatment
Figure 3.  Adjusted Hazard Ratios (HRs) for Mortality Comparing Patients With and Patients Without Direct-Acting Antiviral (DAA) Treatment
Adjusted Hazard Ratios (HRs) for Mortality Comparing Patients With and Patients Without Direct-Acting Antiviral (DAA) Treatment

Non–dual eligible indicates the person is eligible for Medicare only. Dual eligible indicates the person is eligible for Medicare and Medicaid.

Table 1.  Patient Characteristics in the Propensity Score–Matched Samplea
Patient Characteristics in the Propensity Score–Matched Samplea
Table 2.  Comparison of Mortality Rates Between Patients With and Patients Without Direct-Acting Antiviral Treatment
Comparison of Mortality Rates Between Patients With and Patients Without Direct-Acting Antiviral Treatment
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Tanwar  S, Wright  M, Foster  GR,  et al.  Randomized clinical trial: a pilot study investigating the safety and effectiveness of an escalating dose of peginterferon α-2a monotherapy for 48 weeks compared with standard clinical care in patients with hepatitis C cirrhosis.   Eur J Gastroenterol Hepatol. 2012;24(5):543-550. doi:10.1097/MEG.0b013e3283513e69 PubMedGoogle ScholarCrossref
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Park  H, Wang  W, Henry  L, Nelson  DR.  Impact of all-oral direct-acting antivirals on clinical and economic outcomes in patients with chronic hepatitis C in the United States.   Hepatology. 2019;69(3):1032-1045. doi:10.1002/hep.30303 PubMedGoogle ScholarCrossref
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El-Serag  HB, Kanwal  F, Richardson  P, Kramer  J.  Risk of hepatocellular carcinoma after sustained virological response in veterans with hepatitis C virus infection.   Hepatology. 2016;64(1):130-137. doi:10.1002/hep.28535 PubMedGoogle ScholarCrossref
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Najafzadeh  M, Andersson  K, Shrank  WH,  et al.  Cost-effectiveness of novel regimens for the treatment of hepatitis C virus.   Ann Intern Med. 2015;162(6):407-419. doi:10.7326/M14-1152 PubMedGoogle ScholarCrossref
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Linas  BP, Barter  DM, Morgan  JR,  et al.  The cost-effectiveness of sofosbuvir-based regimens for treatment of hepatitis C virus genotype 2 or 3 infection.   Ann Intern Med. 2015;162(9):619-629. doi:10.7326/M14-1313 PubMedGoogle ScholarCrossref
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Younossi  ZM, Park  H, Dieterich  D, Saab  S, Ahmed  A, Gordon  SC.  Assessment of cost of innovation versus the value of health gains associated with treatment of chronic hepatitis C in the United States: the quality-adjusted cost of care.   Medicine (Baltimore). 2016;95(41):e5048. doi:10.1097/MD.0000000000005048 PubMedGoogle Scholar
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Backus  LI, Belperio  PS, Shahoumian  TA, Mole  LA.  Impact of sustained virologic response with direct-acting antiviral treatment on mortality in patients with advanced liver disease.   Hepatology. 2019;69(2):487-497. doi:10.1002/hep.29408 PubMedGoogle ScholarCrossref
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Singal  AG, Rich  NE, Mehta  N,  et al.  Direct-acting antiviral therapy for hepatitis C virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma.   Gastroenterology. 2019;157(5):1253-1263.e2. doi:10.1053/j.gastro.2019.07.040 PubMedGoogle ScholarCrossref
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Centers for Disease Control and Prevention. Surveillance for viral hepatitis—United States, 2014. Accessed February 26, 2020. https://www.cdc.gov/hepatitis/statistics/2014surveillance/commentary.htm#summary
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Armstrong  GL, Wasley  A, Simard  EP, McQuillan  GM, Kuhnert  WL, Alter  MJ.  The prevalence of hepatitis C virus infection in the United States, 1999 through 2002.   Ann Intern Med. 2006;144(10):705-714. doi:10.7326/0003-4819-144-10-200605160-00004 PubMedGoogle ScholarCrossref
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    Original Investigation
    Gastroenterology and Hepatology
    July 21, 2020

    Association of Direct-Acting Antiviral Treatment With Mortality Among Medicare Beneficiaries With Hepatitis C

    Author Affiliations
    • 1Now with The Moran Company, Arlington, Virginia
    • 2Department of Health Policy and Administration, College of Health and Human Development, The Pennsylvania State University, University Park
    • 3Division of Health Policy and Management, University of Minnesota School of Public Health, Minneapolis
    • 4Department of Medicine, College of Medicine, Pennsylvania State University Milton S. Hershey Medical Center, Hershey
    JAMA Netw Open. 2020;3(7):e2011055. doi:10.1001/jamanetworkopen.2020.11055
    Key Points español 中文 (chinese)

    Question  Is direct-acting antiviral therapy for hepatitis C virus infection associated with a reduction in mortality among Medicare beneficiaries?

    Findings  In this cohort study of 51 478 Medicare beneficiaries, direct-acting antiviral treatment was statistically significantly associated with a decrease in mortality among patients with and those without cirrhosis. The association of direct-acting antiviral treatment with mortality was similar for male and female beneficiaries, regardless of the presence of cirrhosis, and it was slightly smaller among patients without cirrhosis who have dual-eligibility status compared with patients with Medicare coverage only.

    Meaning  These findings suggest that increasing access to direct-acting antiviral drugs for all patients with hepatitis C virus infection, regardless of disease progression, could improve population health.

    Abstract

    Importance  Direct-acting antiviral (DAA) drugs are highly effective in curing hepatitis C virus (HCV) infection. Previous simulations showed extended life as a key health advantage of DAA drugs, but real-world evidence on the association between DAA treatment and reduced mortality is limited.

    Objectives  To examine the association of DAA treatment with mortality among Medicare beneficiaries with hepatitis C.

    Design, Setting, and Participants  This cohort study used Medicare claims data of beneficiaries who sought hepatitis C care for the first time between January 1, 2014, and December 31, 2016, after at least a 1-year washout period. Medicare Part D files were used in identifying DAA therapy initiation and completion. Death dates, demographic data, and indicators of health risks were obtained from the Master Beneficiary Summary Files. Beneficiaries with hepatitis C were considered as patients with DAA treatment if they initiated DAA therapy during the study period. Beneficiaries with hepatitis C who did not initiate DAA therapy during the study period were considered as patients without DAA treatment. Patients without DAA treatment were selected using 1-to-1 propensity score matching. Data were analyzed between September 1, 2019, and March 31, 2020.

    Exposures  Completion of DAA treatment.

    Main Outcomes and Measures  Time to death from the index date of seeking hepatitis C care after at least a 1-year washout period. Cox proportional hazards regression models with time-varying exposure were used to compare mortality rates between propensity score-matched cohorts of patients with DAA treatment and those without DAA treatment. Separate analyses were performed for patients with or without cirrhosis. Heterogeneity in the association between DAA treatment and mortality by sex and dual-eligibility status was examined.

    Results  A propensity score–matched sample of 51 478 Medicare beneficiaries with a mean (SD) age of 59.4 (11.1) years and 30 473 men (59.2%) was assessed. Of this total, 8240 patients (16.0%) had cirrhosis (5224 men [63.4%]; mean [SD] age, 62.3 [9.7] years) and 43 238 patients (84.0%) had no cirrhosis (25 249 men [58.4%]; mean [SD] age, 58.8 [11.3] years). The adjusted hazard ratio (HR) of dying between patients with DAA treatment and those without DAA treatment in the cirrhosis group was 0.51 (95% CI, 0.46-0.57). The association of DAA treatment with mortality did not differ by sex (women vs men: HR, 0.46 [95% CI, 0.38-0.56] vs HR, 0.53 [95% CI, 0.47-0.60]; P = .27) or dual-eligibility status (non–dual-eligible HR, 0.52 [95% CI, 0.43-0.63] vs dual-eligible HR, 0.50 [95% CI, 0.44-0.57]; P = .80) in the cirrhosis group. The adjusted HR of dying between patients with DAA treatment and those without DAA treatment among patients without cirrhosis was 0.54 (95% CI, 0.50-0.58). The association of DAA treatment with mortality did not differ by sex (women vs men: HR, 0.53 [95% CI, 0.46-0.60] vs HR, 0.55 [95% CI, 0.50-0.60]; P = .66) among patients without cirrhosis. However, the survival advantage associated with DAAs for non–dual-eligible beneficiaries was statistically significantly higher than for dual-eligible beneficiaries among patients without cirrhosis (HR, 0.47 [95% CI, 0.41-0.55] vs HR, 0.57 [95% CI, 0.52-0.62]; P = .02).

    Conclusions and Relevance  In this cohort study, DAA treatment appeared to be associated with a decrease in mortality among Medicare beneficiaries with or without cirrhosis. These findings suggest that increasing access to DAA drugs for all patients with HCV infection, regardless of disease progression, could improve population health.

    Introduction

    Hepatitis C virus (HCV) infection is the most common blood-borne illness in the US.1 About 2.4 million people in the US were estimated to have hepatitis C between 2013 and 2016.2 If chronic hepatitis C is untreated, serious health problems, such as hepatocellular cancer, cirrhosis, and liver damage, can occur.3 People with hepatitis C also experience increased mortality compared with the general population,4-6 and nearly 20 000 individuals in the US die each year from hepatitis C–related conditions.7

    The availability of second-generation direct-acting antiviral (DAA) drugs has provided an unprecedented opportunity to address HCV infection and thereby improve the health of this population.8,9 Direct-acting antiviral drugs are highly effective, with a cure rate of 90%,10-13 which is much higher than the 50% cure rate for the earlier interferon-based HCV therapy.14 In addition, DAA drugs have few adverse effects and improved tolerability, which are factors in patients completing the therapy.10-13 Literature on interferon-based therapy found that curing HCV infection was associated with improved clinical outcomes, such as a decrease in the incidence of hepatocellular cancer and a decrease in mortality rate.15-20 More individuals with HCV infection are expected to have these outcomes if treated with DAA drugs, given the higher cure and completion rates associated with DAA therapy.

    Several studies of clinical outcomes reported that patients with cirrhosis who were treated with DAA drugs were less likely to develop hepatocellular cancer than patients who received no DAA therapy.21,22 Previous simulations used extended lives as a key outcome to indicate that the benefits associated with DAA treatment can exceed the costs of these drugs.23-25 However, real-world evidence is limited on the association between DAA treatment and reduced mortality, information that is crucial to assessing the value of costly DAA drugs.

    Recently, a few studies examined the association of DAA treatment with mortality.26-28 One study involving patients with a history of hepatocellular carcinoma from 31 health systems across the US and Canada reported that DAA therapy was associated with a 71% reduction in mortality compared with patients who did not receive DAA drugs.28 However, the study sample was not representative of the population with hepatitis C because only 1% to 5% of patients with hepatitis C have hepatocellular carcinoma.2 The other 2 studies used a sample of patients with hepatitis C in the US Department of Veterans Affairs (VA) health system and reported that DAA treatment was associated with a decrease in mortality.26,27 However, 97% of the patients in these VA studies were men.26,27 In addition, these VA studies did not match patients with DAA treatment to those without treatment, despite different distributions of health risk in the treated and untreated groups.26,27

    In this cohort study, we examined the association between DAA treatment and reduced mortality among Medicare beneficiaries with hepatitis C. Assessing this association in Medicare is important for several reasons. First, Medicare covers many individuals born from 1946 through 1964 (“baby boomers”), the group with the highest prevalence of hepatitis C.29,30 As this population get older, they experience more hepatitis C–related complications, which may be factors in increased mortality. Medicare is, thus, expected to play a large role in hepatitis C care. In 2015, Medicare paid for half of the DAA pills prescribed in the US, making Medicare the largest payer of DAA drugs in that year.31,32

    Second, the Medicare population comprises 54% female beneficiaries,33 and 42% of the Medicare beneficiaries with hepatitis C in the present study were women. Hepatitis C progression differs between men and women.34 Women are more likely than men to clear the virus spontaneously after initial HCV infection and have slower rates of liver disease progression after chronic infection.34 Yet little is known about the survival advantage of DAA drugs among female patients.

    Third, Medicare also covers those younger than 65 years with a disability and with low income, demographic characteristics that are associated with a higher prevalence of hepatitis C than the general population.35 Most of these patients are dually eligible for both Medicare and Medicaid because of their low-income status, which has been associated with poor health outcomes.36 But potential differences in health outcomes of DAA drugs by dual eligibility status have not been explored in previous work.

    In this examination of the association between DAA treatment and mortality, we used a national cohort of Medicare beneficiaries with hepatitis C. We also assessed whether this association varied by patient sex and by dual eligibility status.

    Methods

    This cohort study was approved by the Pennsylvania State University Institutional Review Board, which waived informed consent because the study used retrospective administrative records exclusively and consent was not possible. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Data were analyzed between September 1, 2019, and March 31, 2020.

    Data

    We used Medicare claims data from January 1, 2013, to December 31, 2016, for inpatient, skilled nursing facility, outpatient, and physician services to identify beneficiaries with hepatitis C and those with cirrhosis. The 2013 files were used only to ensure that patients did not seek hepatitis C care during that year. We used January 1, 2014, to December 31, 2017, Medicare Part D files to identify DAA therapy initiation and completion. We required patients to be enrolled in Part D during the entire study period to identify DAA therapy initiation.

    Information on death dates was available in the Master Beneficiary Summary Files from January 1, 2014, through December 31, 2017, for all Medicare-enrolled patients. We also obtained demographic data and indicators of health risks from the Master Beneficiary Summary Files.

    Sample Selection

    The study population comprised Medicare fee-for-service beneficiaries who sought hepatitis C care for the first time between January 1, 2014, and December 31, 2016, after at least a 1-year washout period. We then considered the date of the first claim for hepatitis C after the washout period as the index date. Details of the washout period, index date, and robustness checks are included in eAppendix in the Supplement. We identified patients with hepatitis C using the standard algorithm used by the Centers for Medicare and Medicaid Services (eAppendix in the Supplement).37

    We excluded patients who died within 6 months after the index date. Direct-acting antiviral drugs were unlikely to be given to those patients because the course of treatment usually ranges from 3 to 6 months.

    Study Groups

    Medicare beneficiaries with hepatitis C were considered as patients with DAA treatment if they initiated therapy during the study period with 1 of the following drugs: elbasvir and grazoprevir; ledipasvir and sofosbuvir; ombitasvir, paritaprevir, and ritonavir plus dasabuvir; sofosbuvir; sofosbuvir and velpatasvir; sofosbuvir, velpatasvir, and voxilaprevir; or glecaprevir and pibrentasvir. Patients with DAA treatment completed therapy before December 30, 2017. Completion of DAA treatment was defined as prescriptions filled for the expected duration of the DAA drug, as identified in package inserts or by randomized clinical trials. The definition of completion is provided in eAppendix in the Supplement.

    Medicare beneficiaries with hepatitis C who did not initiate DAA therapy during the study period were considered as patients without DAA treatment. We selected the patients without DAA treatment using 1-to-1 propensity score matching (within 10% of the SD of propensity scores). Patients were matched on demographics and health risks at the index date. The definitions and data sources of all covariates used in the propensity score matching are provided in eTable 1 in the Supplement.

    We performed matching separately for patients with and patients without cirrhosis at the index date. In the group with DAA treatment, patients without cirrhosis at the index date were required to remain without cirrhosis until treatment. Figure 1 presents a diagram of the study sample selection.

    Outcome and Exposure

    We followed up all patients from the index date until they died or reached the end of study period (December 31, 2017). The outcome of analysis was time to death from the index date.

    Completion of DAA treatment was examined as a time-varying exposure measure. Patients with DAA treatment contributed to unexposed person-time until they completed treatment. After treatment completion, they contributed to exposed person-time. Patients without DAA treatment contributed to only unexposed person-time. Examining DAA treatment as a time-varying exposure addresses immortal bias, which favors the treatment group because treated individuals survive at least until exposure.38-40

    Statistical Analysis

    We conducted separate analyses for the cirrhosis and noncirrhosis cohorts. First, we described the patient characteristics at the index date in the full unmatched sample. Next, we compared the characteristics at the index date of the patients with DAA treatment vs those without DAA treatment in the propensity score–matched samples. We assessed that the characteristics were balanced after matching between the 2 groups when standardized differences were less than 10%.41

    We calculated mortality rates as deaths per 100 person-years in the groups with and without DAA treatment, and we obtained the crude mortality rate ratios. Kaplan-Meier survival curves were plotted for both groups. We estimated crude mortality rate ratios and plotted Kaplan-Meier curves separately for female, male, non–dual-eligible, and dual-eligible patients.

    Using the Cox proportional hazards regression model with time-varying exposure, we estimated adjusted hazard ratios (HRs) of death for patients with and those without treatment. We examined heterogeneity in the association between DAA treatment and mortality rates across different patient groups by estimating separate Cox regression models for the following subgroups: female, male, non–dual eligible, and dual-eligible. These separate models allowed the associations of DAA treatment and all other covariates with mortality to vary in each group. We assessed whether the survival advantage of DAA drugs was statistically significantly different between groups by including interaction terms between the DAA treatment and group indicators in a Cox regression model with all patients.42

    The P values were 2-sided, and P < .05 was considered as statistically significant for all comparisons. SAS, version 9.4 (SAS Institute Inc), and Stata, version 15 (StataCorp LLC), were used for the statistical analyses.

    Sensitivity Analysis

    We estimated the model limiting the sample to patients who were alive for at least 1 year after the index date. This sensitivity analysis aimed to consider a recommendation of giving DAA therapy to those with a life expectancy greater than 1 year.43 We used a propensity score–matched cohort for this analysis.

    Results
    Patient Characteristics

    The analysis included a propensity score–matched sample of 51 478 Medicare beneficiaries (mean [SD] age, 59.4 (11.1) years; 30 473 men (59.2%) and 21 005 women [40.8%]). Of this total, 8240 patients (16.0%) had cirrhosis (5224 men [63.4%] and 3016 women [36.6%]; mean [SD] age, 62.3 [9.7] years) and 43 238 patients (84.0%) had no cirrhosis (25 249 men [58.4%] and 17 989 women [41.6%]; mean [SD] age, 58.8 [11.3] years).

    Patient characteristics in the unmatched sample are reported in eTable 2 in the Supplement. In the unmatched sample, statistically significant differences were found between patients with DAA treatment and patients without DAA treatment. For example, in the group with cirrhosis, patients without DAA treatment were likely to be older (aged >75 years: 376 [9.1%] vs 1598 [15.4%]) and have other conditions such as anemia (1808 [43.9%] vs 6999 [67.5%]), lung disease (1166 [28.3%] vs 4413 [42.6%]), cardiac disease (3140 [76.2%] vs 9066 [87.4%]), dementia (254 [6.2%] vs 1796 [17.3%]), diabetes (1554 [37.7%] vs 5279 [50.9%]), kidney disorders (1150 [27.9%] vs 5351 [51.6%]), and drug and alcohol–related disorders (2052 [49.8%] vs 6531 [63.0%]).

    Table 1 presents the patient characteristics in the matched sample. Baseline patient characteristics after matching were balanced, with the estimates of standardized difference scores after matching being less than 10% for all characteristics. Among patients with cirrhosis, the median (interquartile range [IQR]) time from hepatitis C index date to treatment completion was 9.1 (5.8-15.5) months, with 1150 patients (27.9%) treated within 6 months. Among patients without cirrhosis, the median (IQR) time from hepatitis C index date to treatment completion was 8.6 (5.2-15.7) months, with 7161 (33.1%) treated within 6 months.

    Descriptive Data

    Among patients with cirrhosis, 480 deaths occurred during 10 531.2 person-years of follow-up among beneficiaries with DAA treatment (4.56 deaths per 100 person-years; 95% CI, 4.15-4.97). In comparison, 1310 deaths occurred during 9234.8 person-years of follow-up in beneficiaries without DAA treatment (14.19 deaths per 100 person-years; 95% CI, 13.42-14.95) (Table 2). The crude mortality rate ratio between the 2 groups was 0.32 (95% CI, 0.29-0.35). The 1-year risk of mortality for patients with DAA treatment was 2.2%, compared with 10.4% among patients without DAA treatment. The crude mortality rate ratio between groups did not differ by sex: 0.31 (95% CI, 0.25-0.37) in women vs 0.33 (95% CI, 0.28-0.37) in men. Similarly, no difference was observed by dual-eligibility status: 0.33 (95% CI, 0.27-0.40) in non–dual-eligible patients vs 0.32 (95% CI, 0.28-0.36) in dual-eligible patients.

    Among patients without cirrhosis, 912 deaths occurred during 55 792.9 person-years of follow-up among patients with DAA treatment (1.63 deaths per 100 person-years; 95% CI, 1.53-1.74). In contrast, 2955 deaths occurred during 61 587.8 person-years of follow-up among patients without DAA treatment (4.80 deaths per 100 person-years; 95% CI, 4.63-4.97) (Table 2). The crude mortality rate ratio between the 2 groups was 0.34 (95% CI, 0.32-0.37). The 1-year risk of mortality for patients with DAA treatment was 0.6%, compared with 2.9% among patients without DAA treatment. Little difference was observed in the crude mortality rate ratio by sex: 0.33 (95% CI, 0.29-0.38) in women vs 0.34 (95% CI, 0.31-0.37) in men. No difference was observed in the crude mortality rate ratio by dual-eligibility status: 0.31 (95% CI, 0.27-0.36) in non–dual-eligible patients vs 0.35 (95% CI, 0.32-0.38) in dual-eligible patients.

    Figure 2 depicts the Kaplan-Meier survival curves. Direct-acting antiviral treatment was associated with a statistically significant reduction in mortality in both patients with cirrhosis and those without cirrhosis. The Kaplan-Meier curves for each subgroup (men, women, non–dual-eligible, and dual-eligible) are provided in eFigures 1 and 2 in the Supplement. The curves show the survival advantage associated with DAA drugs in all of those groups, regardless of cirrhosis at the index date.

    Cox Proportional Hazards Regression

    Direct-acting antiviral treatment was associated with reduced mortality after controlling for patient characteristics (Figure 3). In patients with cirrhosis, the adjusted HR of dying between patients with DAA treatment and patients without DAA treatment was 0.51 (95% CI, 0.46-0.57). Being older, being male, having decompensated cirrhosis, and having other health conditions were associated with increased mortality; complete regression results are included in eTable 3 in the Supplement. Separate analyses by sex revealed the consistent survival advantages of DAAs for both women (HR, 0.46; 95% CI, 0.38-0.56) and men (HR, 0.53; 95% CI, 0.47-0.60) beneficiaries. This difference in HR by sex was not statistically significant (P = .27 for the interaction term) (eTable 4 in the Supplement). In addition, DAA treatment was associated with a slightly smaller reduction in mortality in non–dual-eligible patients (HR, 0.52; 95% CI, 0.43-0.63) compared with dual-eligible patients (HR, 0.50; 95% CI, 0.44-0.57). This difference was not statistically significant (P = .80 for the interaction term) (eTable 4 in the Supplement).

    In patients without cirrhosis, the adjusted HR of dying between patients with DAA treatment and those without DAA treatment was 0.54 (95% CI, 0.50-0.58). Being older, being male, and having other health conditions were associated with increased mortality (eTable 3 in the Supplement). Survival advantage associated with DAAs was observed in both women (HR, 0.53; 95% CI, 0.46-0.60) and men (HR, 0.55; 95% CI, 0.50-0.60). This difference in HR by sex was not statistically significant (P = .66 for the interaction term) (eTable 4 in the Supplement). However, DAA treatment was associated with a larger reduction in mortality among non–dual-eligible patients (HR, 0.47; 95% CI, 0.41-0.55) than among dual-eligible patients (HR, 0.57; 95% CI, 0.52-0.62). This difference was statistically significant (P = .02 for the interaction term) (eTable 4 in the Supplement).

    Sensitivity Analysis

    Findings from a sensitivity analysis of patients with hepatitis C who were alive for at least 1 year after the index date of seeking hepatitis C care were similar to those from the main analysis (eFigure 3 in the Supplement). The adjusted HR of dying between patients with DAA treatment and those without DAA treatment was 0.47 (95% CI, 0.42-0.53) among those with cirrhosis and 0.54 (95% CI, 0.50-0.58) among those without cirrhosis.

    Discussion

    Direct-acting antiviral treatment was associated with lower mortality among Medicare beneficiaries with cirrhosis (adjusted mortality ratio reduction of 49%) and those without cirrhosis (adjusted mortality ratio reduction of 46%). This finding is evidence that DAA treatment is associated with a large health advantage, even among patients without advanced liver disease. Because of the high costs of DAA drugs, payers have restricted coverage of this treatment to patients with advanced fibrosis.44-46 Some payers, such as the VA, have removed this restriction,26 but it still remains in other programs.44-46 Restrictive coverage of DAA drugs has been based in part on the uncertainty about the immediate advantages of treatment in patients without serious hepatitis C progression.26 However, results of the present study suggest that expanding the coverage of DAA drugs to all patients with HCV infection regardless of disease progression can avert deaths. Moreover, our findings also support the recent recommendation of HCV testing for all adults aged 18 to 79 years because diagnosis is a precursor to treatment.47

    The estimated survival advantage in patients without cirrhosis (46% reduction in the mortality ratio) was smaller than in previous work, which reported a 68% decrease in the mortality ratio.26 This difference may be attributed to several factors. First, it may partially stem from the analytic approach we used that addressed immortal bias by considering only time after treatment as exposed in the group of patients with DAA treatment. Second, we used propensity score matching to improve balance in patient risks between patients with DAA treatment and those without DAA treatment. Both of these approaches removed sources of selection bias that would favor the treatment group and thereby result in a smaller effect size than otherwise.

    The subgroup analyses indicated limited heterogeneity in the health advantage of DAA drugs across patient groups. First, the mortality ratio reduction after DAA treatment was similar between men and women. Being male was found to be associated with hepatitis C prevalence and fast disease progression.34 However, male sex did not play a role in the association between DAA treatment and mortality, regardless of the presence of cirrhosis. This finding is an important extension of previous evidence on the survival advantage associated with DAA drugs in men or in patients with a history of liver cancer.26,27

    Second, the association of DAA treatment with mortality was similar for patients with cirrhosis who had dual eligibility for both Medicare and Medicaid and those who had eligibility for Medicare only. However, among patients without cirrhosis, we found a smaller association of treatment with mortality for dual-eligible patients. Dual-eligible beneficiaries are sicker and have lower incomes than Medicare-only beneficiaries.48 They may have encountered barriers to health care access and to improved health outcomes, leading to a smaller association between DAA treatment and mortality. Identifying those barriers was beyond the scope of the present study, but it could help explore ways to increase the survival advantage of DAA treatment in dual-eligible beneficiaries.

    We believe that this study provides evidence that DAA treatment is associated with fewer deaths in Medicare beneficiaries with HCV infection. This association suggests that improving access to DAA drugs, perhaps with particular attention to patient groups with low DAA therapy uptake, could have favorable implications for the health outcomes of this patient population.

    Limitations

    This study has limitations. First, the Medicare claims data that we used did not include clinical information, such as genotype or sustained virologic response status. Some patients with DAA treatment in this study may not have cured HCV infection. However, not accounting for this factor leads to conservative estimates in our analysis. Second, selection bias may remain even after propensity score matching because of differences in unobservable characteristics. However, selection bias is unlikely to change the study conclusions given the large estimates of the health implications of DAA drugs. Third, we measured only overall mortality rates (ie, all-cause mortality). Some deaths in the study sample may not be related to hepatitis C, but condition-specific deaths are not identifiable in the Medicare claims data. Fourth, the 5 years of claims data that we used lacked information on the date of initial hepatitis C diagnosis. Fifth, the study findings may not generalize to patients covered by Medicaid only, commercial insurers, or Medicare Advantage.

    Conclusions

    Direct-acting antiviral treatment appeared to be associated with a decrease in mortality in Medicare beneficiaries with hepatitis C regardless of the presence of cirrhosis. This finding supports a survival advantage associated with DAA drugs and suggests that increased access to DAA therapy regardless of disease progression may improve population health.

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    Article Information

    Accepted for Publication: May 7, 2020.

    Published: July 21, 2020. doi:10.1001/jamanetworkopen.2020.11055

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Kalidindi Y et al. JAMA Network Open.

    Corresponding Author: Yamini Kalidindi, MHA, The Moran Company, 1000 Wilson Boulevard, Suite 2500, Arlington, VA 22209 (ypkalidindi@themorancompany.com).

    Author Contributions: Ms Kalidindi and Dr Jung had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Ms Kalidindi and Dr Jung share co–first authorship.

    Concept and design: All authors.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Kalidindi, Jung.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Kalidindi, Feldman.

    Obtained funding: Jung, Feldman.

    Administrative, technical, or material support: Riley.

    Supervision: Jung, Riley.

    Conflict of Interest Disclosures: Dr Jung reported receiving grants from the National Institute on Aging (NIA) and from the National Institute of Child Health and Human Development (NICHD) during the conduct of the study. Dr Feldman reported owning stock in Gilead Sciences. Dr Riley reported receiving grants from the National Institutes of Health during the conduct of the study.

    Funding/Support: This study was funded by grant R01 AG055636-01A1 from the NIA (PI: Dr Jung) and by grant R24 HD041025 from the NICHD.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The views expressed in this article are those of the authors and do not reflect the official policy or position of the NIA or the NICHD.

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