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Impact of All-Oral Direct-Acting Antivirals on Clinical and Economic Outcomes in Patients With Chronic Hepatitis C in the United States
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Hepatology Feb 19 2019 - Haesuk Park ,1 Wei Wang,1 Linda Henry,1 and David R. Nelson 2
From the 1 Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, FL; 2 Department of Medicine, University of Florida, Gainesville, FL.
Abstract
Approved treatment for hepatitis C virus (HCV) with all-oral direct-acting antivirals (DAA) therapy is now entering into its fourth year; however, little has been reported on the real-world clinical (decompensated cirrhosis [DCC] and hepatocellular carcinoma [HCC]) and economic outcomes.
A retrospective cohort analysis of the Truven Health MarketScan Database (2012-2016) was conducted. In a cohort of 26,105 patients with newly diagnosed HCV, 30% received all-oral DAA therapy (DAA group) and 70% were not treated (untreated group).
Multivariate Cox proportional hazards models were used to compare the risk of developing HCC and DCC, stratified by cirrhosis status.
Among patients with cirrhosis (n = 2157), DAA therapy was associated with a 72% and a 62% lower incidence of HCC (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.15-0.52) and DCC (HR, 0.38; 95% CI, 0.26-0.56).
Similarly, DAA therapy was associated with a 57% and a 58% lower incidence of HCC (HR, 0.43; 95% CI, 0.26-0.71) and DCC (HR, 0.42; 95% CI, 0.30-0.58) in patients with noncirrhotic HCV (n = 23,948).
A propensity score-matched cohort of 8064 HCV-infected patients who had at least a 12-month follow-up after HCV treatment was included for economic analysis.
For patients with cirrhosis in the DAA group, the mean adjusted liver-related costs ($1749 vs. $4575; P < 0.001) and all-cause medical costs ($19,300 vs. $33,039; P < 0.001) were significantly lower compared with those in the untreated group.
After adjustment for demographic characteristics, comorbidities, and pretreatment medical costs, patients with cirrhosis in the DAA group had significantly lower liver-related and all-cause health care costs compared with those in the untreated group (Fig. 2). Patients with cirrhosis in the DAA group were estimated to have mean liver-related costs of $1749, which was 62% lower than that for the untreated group ($4575; P < 0.001). All-cause medical costs were estimated at $19,300 in the treated group, which was 42% lower compared with patients in the untreated group ($33,039; P < 0.001). In contrast, patients without cirrhosis who received all-oral DAA treatment were estimated to have slightly higher liver-related costs ($726) compared with those of untreated patients ($441). All-cause medical costs were also slightly higher in the DAA-treated group ($14,071) compared with the untreated group ($13,828). However, these differences were not statistically significant.
It is important to note that in our economic analysis, we estimated that the costs for at least an 8-week DAA treatment course ranged between approximately $100,467 and $123,086. However, the actual cost paid for the DAA therapy may be significantly less than our estimation considering the high rebates and discounts negotiated between pharmaceutical companies and payers.34 [Jules: therefore overall medical costs would be lower for patients without cirrhosis]
The mean adjusted costs were not statistically different between the two groups among patients without cirrhosis.
Conclusion: In the short term, all-oral DAA treatment for HCV infection was associated with a decreased risk of developing HCC and DCC, resulting in decreased health care costs, especially in patients with cirrhosis. A longitudinal study is necessary to confirm our findings.
In conclusion, DAA therapy was found to be associated with significant reductions in the incidence of HCC and DCC among patients with and without cirrhosis. In addition, the use of DAA treatments was found to be economically sound for both liver-related and all-cause health care resource use. Yet, despite these positive findings, and the availability of these highly effective all-oral DAA therapies, the majority of patients with HCV within our study were not treated. Future studies must continue to investigate ways to improve access to treatment for all patients with HCV.
A disturbing study finding was that the majority of patients with HCV (70%) within our study were not treated. During the study period, 45% of patients with cirrhosis and 72% of patients without cirrhosis did not receive any HCV treatment. It is noteworthy that DCC and HCC incidence rates were significantly higher in patients with cirrhosis receiving DAA therapy compared with patients without cirrhosis who did not receive any treatment, suggesting that delaying this curative treatment until patients develop cirrhosis can substantially increase the risk of liver complications. the high percentage of patients not receiving treatment suggests that patients are still encountering barriers to treatment even within a group with access to health insurance. In our study, we determined that being female, having alcohol/drug use disorder, HBV, COPD, CKD, CVD, depression, cancer history, and ALD as well as being pregnant were predictors for no treatment. Therefore, identifying and then overcoming the barriers to treatment remains a significant issue in eradicating HCV and its clinical burden.
Patients in the untreated group had similar comorbidities (e.g., hypertension, diabetes) compared with patients receiving the all-oral DAA therapy, but they were more likely to have alcohol use disorder (9.1% vs. 6.5%; P < 0.001), drug use disorder (25.2% vs. 16.5%; P < 0.001), depression (21.8% vs. 15.0%; P < 0.001), and schizophrenia/bipolar disorder (4.5% vs. 2.5%; P < 0.001) and be pregnant (2.1% vs. 0.4%; P < 0.001).
Factors Associated with not Receiving DAA Therapy
As shown in Supporting Table S3, we identified factors associated with a significantly lower probability of initiating DAAs including the following: female (odds ratio [OR], 0.91; 95% CI, 0.85-0.95), alcohol use disorder (OR, 0.82; 95% CI, 0.72-0.93), drug use disorder (OR, 0.72; 95% CI, 0.67-0.78), HBV (OR, 0.58; 95% CI, 0.49-0.70), ALD (OR, 0.50; 95% CI, 0.38-0.66), COPD (OR, 0.83; 95% CI, 0.76-0.90), dyslipidemia (OR, 0.82; 95% CI, 0.77-0.88), CVD (OR, 0.86; 95% CI, 0.78-0.96), CKD (OR, 0.70; 95% CI, 0.62-0.90), depression (OR, 0.79; 95% CI, 0.73-0.85), cancer history (OR, 0.85; 95% CI, 0.76-0.96), being pregnant (OR, 0.33; 95% CI, 0.24-0.47), and use of statins (OR, 0.74; 95% CI, 0.68-0.81).
Effect of All-Oral DAA Regimen on Incident Liver Decompensation
Among patients with cirrhosis (n = 2157), there were 131 (6.1%) DCC events. The majority of DCC events (66%) occurred in patients in the untreated group, providing a DCC incidence rate of 108.7 per 1000 person-years compared with that of 32.0 per 1000 person-years among patients in the DAA-treated group (Table 4). After adjusting for covariates, we found patients with cirrhosis in the DAA-treated group had a 62% decreased risk of developing DCC compared with those in the untreated group (HR, 0.38; 95% CI, 0.26-0.56). Among patients without cirrhosis (n = 23,948), 312 DCC events (1.3%) occurred. In patients without cirrhosis, the crude DCC incidence rate was 16.2 per 1000 person-years in the untreated group and 8.0 per 1000 person-years for the DAA-treated group (Table 4).
DAA Treatment Costs
The mean all-oral DAA treatment costs for patients with HCV with cirrhosis were $123,086, which was $22,619 higher than the mean for patients with HCV without cirrhosis ($100,467) because of a longer duration of therapy (98 vs. 85 days) (Supporting Table S6).
Adjusted Medical Costs
After adjustment for demographic characteristics, comorbidities, and pretreatment medical costs, patients with cirrhosis in the DAA group had significantly lower liver-related and all-cause health care costs compared with those in the untreated group (Fig. 2). Patients with cirrhosis in the DAA group were estimated to have mean liver-related costs of $1749, which was 62% lower than that for the untreated group ($4575; P < 0.001). All-cause medical costs were estimated at $19,300 in the treated group, which was 42% lower compared with patients in the untreated group ($33,039; P < 0.001). In contrast, patients without cirrhosis who received all-oral DAA treatment were estimated to have slightly higher liver-related costs ($726) compared with those of untreated patients ($441). All-cause medical costs were also slightly higher in the DAA-treated group ($14,071) compared with the untreated group ($13,828). However, these differences were not statistically significant.
FIG. 2. Adjusted liver-related and all-cause costs per person per year by treatment status in propensity score-matched cohorts. (A) Medical costs in patients with cirrhosis. (B) Medical costs in patients without cirrhosis. Abbreviation: DAA, direct-acting antivirals.
Impact of All-Oral Direct-Acting Antivirals on Clinical and Economic Outcomes in Patients With Chronic Hepatitis C in the United States
Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States and a substantial cause of morbidity and mortality.1, 2 Many patients with chronic hepatitis C progress to advanced liver disease such as decompensated cirrhosis (DCC) and hepatocellular carcinoma (HCC).3, 4 Furthermore, HCV is currently the leading indication for liver transplantation in the United States, suggesting that the burden of fatal liver disease is increasing in the estimated 2.7 million adults chronically infected with HCV in the United States.5
Several studies reported that patients with HCV who received treatment and/or achieved a sustained virologic response (SVR, the surrogate for cure) experienced significantly reduced cumulative rates of HCC, liver transplantation, and liver-related death in the United States.6-8 Furthermore, an economic study reported that HCV therapy with peg-interferon (PEG-IFN) and ribavirin (RBV) was associated with lower follow-up health care costs.9
However, PEG-IFN therapy was plagued with significant side effects, leading to premature treatment stoppage decreasing the number of HCV-infected patients who achieved SVR rate. Fortunately, in recent years, HCV treatment has taken a major step forward with the introduction of highly efficacious direct-acting antiviral (DAA) therapy, which has demonstrated therapeutic efficacy, limited adverse effects, and a shorter treatment period compared with interferon-based regimens.10 Despite guideline recommendations, access to HCV treatment has been frequently restricted because of the high DAA drug costs and prior authorization policies in which only the sicker get treated, slowing the expected rise in treatment rates.11, 12 This delay in potentially curative treatment until development of advanced liver disease may have costly consequences.9, 13, 14
Several economic modeling studies using data from the DAA clinical trials and the literature have forecasted an economic benefit with the DAA use due to lower disease complications. However, none of these studies used real-world clinical and economic outcomes data.15-18 Therefore, the aims of this study were to determine the clinical outcomes (incidents of HCC and DCC) as well as the economic impact of all-oral DAA treatment in chronically HCV-infected patients in the United States using real-world data obtained from a large national insurance database.
Data Source
We conducted a retrospective cohort study using the Truven Health Analytic MarketScan Commercial and Medicare Supplemental databases (January 2012 to December 2016). This nationwide administrative claims database contains deidentified person-level information of diagnoses, procedures, and prescriptions for over 80 million individuals in the commercial data set and 6 million individuals in the Medicare Supplement database, which captures health care use and enrollment records across all settings including physician outpatient office visits, hospital stays, and pharmacy claims. The study population consisted of employees, dependents, and retirees with employer-sponsored or Medicare Supplemental insurance plans. Institutional review board approval was obtained from the University of Florida.
Study Population
We used 2013-2016 Truven Health Analytic MarketScan Commercial and Medicare supplemental files to establish the new chronic HCV cohort, and the 2012 data were used to ensure at least 1 year of claims prior to HCV diagnosis. The new patients with chronic HCV, defined as those who did not have an HCV diagnosis in the previous 12 months, were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes [070.44, 070.54, 070.70, 070.71, V02.62] and ICD-10-CM [B18.2, B19.20, B19.21, Z22.52]. A patient was determined to be infected with chronic HCV if they had one inpatient chronic HCV diagnosis or two outpatient diagnoses of HCV on separate days within 1 year.
Results
Patient Characteristics
We identified 26,105 patients with newly diagnosed HCV who met our inclusion/exclusion criteria between January 2013 and December 2016 (Fig. 1). Of 26,105 HCV-infected patients, 18,177 patients (70%) did not receive any HCV treatment whereas 7,928 patients (30%) received the all-oral DAA treatments. Table 1 summarizes the baseline demographic characteristics between the DAA-treated and untreated groups. Patients who received the all-oral DAA regimens were older (mean age 54.4 vs. 52.7; P < 0.001) and had significantly more cirrhosis (15.2% vs. 5.2%; P < 0.001) and NAFLD (12.9% vs. 6.7%; P < 0.01). Patients in the untreated group had similar comorbidities (e.g., hypertension, diabetes) compared with patients receiving the all-oral DAA therapy, but they were more likely to have alcohol use disorder (9.1% vs. 6.5%; P < 0.001), drug use disorder (25.2% vs. 16.5%; P < 0.001), depression (21.8% vs. 15.0%; P < 0.001), and schizophrenia/bipolar disorder (4.5% vs. 2.5%; P < 0.001) and be pregnant (2.1% vs. 0.4%; P < 0.001). The mean follow-up time was 14.7 months and 11 months for the DAA-treated and untreated groups, respectively.
Factors Associated with not Receiving DAA Therapy
As shown in Supporting Table S3, we identified factors associated with a significantly lower probability of initiating DAAs including the following: female (odds ratio [OR], 0.91; 95% CI, 0.85-0.95), alcohol use disorder (OR, 0.82; 95% CI, 0.72-0.93), drug use disorder (OR, 0.72; 95% CI, 0.67-0.78), HBV (OR, 0.58; 95% CI, 0.49-0.70), ALD (OR, 0.50; 95% CI, 0.38-0.66), COPD (OR, 0.83; 95% CI, 0.76-0.90), dyslipidemia (OR, 0.82; 95% CI, 0.77-0.88), CVD (OR, 0.86; 95% CI, 0.78-0.96), CKD (OR, 0.70; 95% CI, 0.62-0.90), depression (OR, 0.79; 95% CI, 0.73-0.85), cancer history (OR, 0.85; 95% CI, 0.76-0.96), being pregnant (OR, 0.33; 95% CI, 0.24-0.47), and use of statins (OR, 0.74; 95% CI, 0.68-0.81).
Effect of All-Oral DAA Regimen on Incident HCC
Table 2 displays the risk of developing HCC among the patients with HCV, stratified by cirrhosis status and receipt of HCV treatment. Among patients with cirrhosis (n = 2157), there were 57 (2.6%) HCC events. The majority of HCC events (70%) occurred in patients who received no treatment, providing an HCC incidence rate of 48.9 per 1000 person-years compared with the HCC incidence rate in the DAA group (11.7 per 1000 person-years). After adjusting for covariates, patients with cirrhosis in the DAA-treated group had a 72% decreased risk of developing HCC compared with those who received no treatment (hazard ratio [HR], 0.28; 95% CI, 0.15-0.52). There were 114 HCC events observed among patients without cirrhosis (n = 23,948). In patients without cirrhosis with HCV, the crude incidence rate of HCC was 5.8 per 1000 person-years in the untreated group and 3.1 per 1000 person-years in patients in the DAA-treated group. After adjusting for covariates, we found patients without cirrhosis in the DAA-treated group had a 57% decreased risk of developing HCC compared with those who received no treatment (HR, 0.43; 95% CI, 0.26-0.72).
In the sensitivity analyses for patients who did not have cancer at baseline (HR, 0.28; 95% CI, 0.14-0.54 in patients with cirrhosis; HR, 0.37; 95% CI, 0.21-0.65 in patients without cirrhosis) and patients with HCC diagnosis ≥3 months after baseline (HR, 0.29; 95% CI, 0.16-0.55 in patients with cirrhosis; HR, 0.47; 95% CI, 0.27-0.80 in patients without cirrhosis), study results remained consistent with base case analysis (Table 3). In a subgroup analysis in which we assessed HCC incidence among the minimum effectively treated patients who received either the all-oral DAA regimen of sofosbuvir/ledipasvir for at least 8 weeks or a 12-week treatment of the other all-oral DAA therapy, study results remained consistent (HR, 0.31; 95% CI, 0.16-0.59 in patients with cirrhosis; HR, 0.43; 95% CI, 0.26-0.74 in patients without cirrhosis) (Supporting Table S4). Factors associated with an increased risk of developing HCC included being older age (HR, 1.05; 95% CI, 1.04-1.07), male (HR, 2.62; 95% CI,1.76-3.89), having cirrhosis (HR, 4.52; 95% CI, 3.17-6.43), diabetes (HR, 1.58; 95% CI, 1.12-2.23), and cancer history at baseline (HR, 4.83; 95% CI, 2.41-9.70), whereas DAA treatment significantly decreased the risk of HCC (HR, 0.38; 95% CI, 0.26-0.57) (Supporting Table S5).
Effect of All-Oral DAA Regimen on Incident Liver Decompensation
Among patients with cirrhosis (n = 2157), there were 131 (6.1%) DCC events. The majority of DCC events (66%) occurred in patients in the untreated group, providing a DCC incidence rate of 108.7 per 1000 person-years compared with that of 32.0 per 1000 person-years among patients in the DAA-treated group (Table 4). After adjusting for covariates, we found patients with cirrhosis in the DAA-treated group had a 62% decreased risk of developing DCC compared with those in the untreated group (HR, 0.38; 95% CI, 0.26-0.56). Among patients without cirrhosis (n = 23,948), 312 DCC events (1.3%) occurred. In patients without cirrhosis, the crude DCC incidence rate was 16.2 per 1000 person-years in the untreated group and 8.0 per 1000 person-years for the DAA-treated group (Table 4). After adjusting for covariates, patients without cirrhosis in the DAA group had a 58% decreased risk of developing DCC compared with those in the untreated group (HR, 0.42; 95% CI, 0.30-0.58). In a sensitivity analysis in which we assessed DCC incidence without censoring patients at their date of HCC, study results were similar (HR, 0.35; 95% CI, 0.24-0.51 in patients with cirrhosis; HR, 0.42; 95% CI, 0.30-0.57 in patients without cirrhosis). We also performed a subgroup analysis in which we assessed DCC incidence in patients who received DAA therapy of at least 8 weeks of sofosbuvir/ledipasvir or 12 weeks of the other DAA regimens and found no significant change in the results (HR, 0.38; 95% CI, 0.25-0.57 in patients with cirrhosis; HR, 0.39; 95% CI, 0.27-0.56 in patients without cirrhosis) (Supporting Table S4).
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