Cost-Effectiveness and Budget Impact of Hepatitis C Virus Treatment With Sofosbuvir and Ledipasvir in the United States

Editors' Notes Context Newly approved drug regimens for hepatitis C virus (HCV) treatment seem more efficacious and safer than older regimens but are expensive. Contribution In a cost-effectiveness analysis, combination therapy with sofosbuvir and ledipasvir reduced HCV-related complications and was cost-effective for most patients. However, its use would cost an additional $65 billion over the next 5 years while offsetting only $16 billion of the overall cost of HCV care. Caution Not all data came from large randomized trials. Implication If prices remain at current levels, government and private providers will need additional financial resources or will need to prioritize patients for HCV treatment. More than 3 million persons are chronically infected with hepatitis C virus (HCV) in the United States, and most of them are undiagnosed (1, 2). Infection with HCV is the leading cause of hepatocellular carcinoma (HCC) and is the most common indication for liver transplantation (3). In 2011, the economic burden associated with chronic HCV infection in the United States was $6.5 billion (4). The recent approval of 3 new drugssofosbuvir, a first-in-class, once-daily HCV RNA polymerase inhibitor; simeprevir, a once-daily protease inhibitor; and sofosbuvir plus ledipasvir, the first oral combination therapyby the U.S. Food and Drug Administration (FDA) marked the beginning of a new era for HCV treatment (57). Until then, the old standard of care (oSOC) was based on peginterferon and ribavirin with or without boceprevir and telaprevir. With the advent of the new drugs, HCV treatment can for the first time be provided without interferon-based therapy, which is associated with considerable toxicity (8). As a result, many patients who were unable to tolerate previous therapies are now eligible for HCV treatment. These agents are superior, with sustained virologic response (SVR) rates greater than 95% in most patients and shorter duration of treatment and fewer adverse effects than the oSOC (9, 10). To guide clinicians, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America jointly published a practice guideline with new recommendations for HCV treatment as a Web document with plans for ongoing updates (11). These recommendations include FDA-approved as well as off-label drug combinations of sofosbuvir and ledipasvir. Enthusiasm for the new drugs has been dampened by their cost: Sofosbuvir is currently priced at $1000 per day and sofosbuvirledipasvir at $1125 per day. The total cost of treatment can be as high as $150000 per patient. The high price of sofosbuvir has drawn criticism from patient advocates (12), U.S. lawmakers (13), the World Health Organization (14), and private payers (15), especially given that its manufacturing cost is $200 for 12-week treatment (16). Challenged with the budget needed to treat all patients with HCV, at least 35 U.S. states have restricted these treatments to Medicaid patients with advanced-stage disease (17). Similarly, private payers require prior authorization. With more than a million patients needing HCV treatment in the next 3 to 5 years in the United States, the high price of these drugs will substantially affect the budget of private payers and government (18). Treatment cost may, therefore, become the primary barrier to HCV eradication (19, 20). The manufacturer contends that sofosbuvir-based treatment provides good value (21). However, it remains unclear whether and in which patients the improved benefits of new therapies justify the increased cost compared with the oSOC. In addition, the total spending on new drugs required to treat a large number of patients with HCV is not known. Therefore, the objective of our study was to evaluate the cost-effectiveness and budget impact of sofosbuvirledipasvir from a third-party payer's perspective. Methods We developed a Markov-based, individual-level, state-transition model, MATCH (Markov-based Analyses of Treatments for Chronic Hepatitis C), that simulated the clinical course of patients with HCV who received antiviral treatment. We used a weekly cycle length to advance time in the model. The structure of the model was based on our previously published and validated Markov cohort model (22, 23). Base-Case Population Our base-case population comprised HCV-infected patients in the United States. We defined a total of 120 patient profiles based on patients' treatment history (naive or experienced), interferon tolerance (yes or no [for treatment-naive patients only]), HCV genotype (1, 2, 3, or 4), sex (male or female), and METAVIR fibrosis score (F0 [no fibrosis], F1 [portal fibrosis without septa], F2 [portal fibrosis with few septa], F3 [numerous septa without fibrosis], or F4 [cirrhosis]) (24). We also assigned baseline ages according to fibrosis score by using a validated simulation model of the HCV disease burden in the United States (Table 1 of the Supplement) (25). Supplement. Supplementary Material Treatment For each of the 120 patient profiles, we simulated 2 scenarios: treatment using the oSOC and treatment with sofosbuvirledipasvir (Table 1) (11). We used efficacy data from the following recent clinical trials of sofosbuvir and ledipasvir in treatment-naive, treatment-experienced, and interferon-intolerant patients: ION-1 (26), ION-2 (10), ION-3 (27), NEUTRINO (9), FISSION (9), VALENCE (28), POSITRON (29), FUSION (29), and the Egyptian Ancestry study (30). We defined treatment ineligibility due to interferon intolerance as presence of 1 or more of the following conditions: bipolar disorder, anemia (hemoglobin level <100 g/L), pregnancy, or neutropenia (neutrophil count <0.750109 cells/L) (31). For efficacy data from comparator groups, we used either the aforementioned clinical trials (when the study included the oSOC) or published studies of protease inhibitors and peginterferonribavirin (3240). The duration of treatment in our model varied between 8 and 48 weeks depending on treatment group, HCV genotype, and treatment history. We also included the possibility of early treatment discontinuation because of adverse events or clinical futility rules (for the oSOC only). Table 1. Treatment-Related Variables for Cost-Effectiveness Analysis of Sofosbuvir-Based Therapies and the oSOC Natural History of HCV Infection Patients who did not achieve SVR transitioned into the natural-history phase of the model, which was defined by using Markov health states. Patients could start in one of the Markov states defined on the basis of the degree of liver fibrosis (F0 to F4) (Appendix Figure 1) and could develop decompensated cirrhosis, HCC, or both; receive a liver transplant; or die of a liver-related cause. Those who achieved SVR were assumed to transition into normal health status only if they did not have cirrhosis (stage F4). In patients with cirrhosis, we assumed that disease progressed even after achievement of SVR, although at a slower rate (41). Appendix Figure 1. State-transition diagram of HCV treatment model for a cost-effectiveness analysis of sofosbuvirledipasvir. At a given time, a patient occupies one of the health states represented by the circles or ovals. Arrows between states represent possible transitions based on annual probabilities. As time progresses, patients can transition to another state and acquire cost and health utilities associated with that state. The model stops when all patients transition to the death state. A patient could transition to a death state from any of the other states because of background mortality (these transitions are not shown for clarity). DC = decompensated cirrhosis; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; LRD = liver-related death; LT = liver transplantation; SVR = sustained virologic response. * The DC and LT states were further divided into first-year and subsequent-year states to account for different mortality rates and costs; however, they are collapsed into 1 state for presentation purposes only. Data Sources for Transition Probabilities We used a published meta-regression analysis to estimate fibrosis progression from stage F0 to F4 (Table 2 of the Supplement) (42), which was dependent on the patient's baseline fibrosis score, HCV genotype, duration of HCV infection, sex, and age at HCV acquisition (42). We estimated disease progression in cirrhosis and decompensated cirrhosis from published observational studies (Table 3 of the Supplement) (43, 44). Patients developing decompensated cirrhosis or HCC were eligible to receive a liver transplant (22, 45, 46) and had higher mortality (47). All patients were at higher risk for nonliver-related death than the general population; therefore, we adjusted their all-cause mortality with sex-specific hazard ratios (2.58 for men and 1.97 for women) (4850). Medical Costs The model was developed from a third-party payer perspective. All costs were converted to a 2014 baseline by using the Consumer Price Index (51). The weekly costs of sofosbuvir and ledipasvir were $7000 and $875, respectively (52). The weekly costs of peginterferon, ribavirin, boceprevir, and telaprevir were $587, $309, $1100, and $4100, respectively (52). Because most payers receive discounts, we applied the average discount of 11% to all drugs (Supplement). We used our previously published study to estimate health statespecific annual costs (22, 53). Quality-of-Life Weights We assigned lower quality-of-life (QOL) weights to patients receiving treatment with interferon-based therapies than those receiving all-oral therapies (Table 3 of the Supplement). Patients who developed anemia had a further decrement in QOL for the duration of anemia (54). We assigned health statespecific QOL weights from a previously published study that used the EuroQol-5D instrument (55, 56) and adjusted these weights to the U.S. population norm (Table 4 of the Supplement) (57). We assumed the QOL of patients who achieved SVR to be equ