Treatment Selection Choices Should Not Be Based on Benefits or Costs Alone: A Head-to-Head Randomized Controlled Trial of Antiviral Drugs for Hepatitis C.

BACKGROUND: Clinicians often face dilemmas with decisions related to formulary choices when two similar drugs are simultaneously available in the market. We studied the comparative safety, effectiveness, and treatment costs of the two first generation direct-acting antiviral agents (DAA), boceprevir and telaprevir as uncertainty existed regarding the drug of choice between these two seemingly equally Hepatitis-C treatment options. METHODS: We randomly assigned 50 patients in an open-label, pragmatic randomized controlled trial (RCT) at a VA Medical Center to either boceprevir or telaprevir in combination with peginterferon and ribavirin, stratified by the presence of cirrhosis and prior treatment experience. Tolerability was assessed at each visit and reasons for discontinuation of treatment and severity of adverse events due to PI treatment were adjudicated using a blinded adjudication committee. The primary outcome was difference in tolerability between boceprevir vs. telaprevir. Secondary outcomes included viral response rates and cost-per cure achieved. RESULTS: Higher rates of treatment discontinuations and/or severe DAA associated adverse events were seen in 10/25 (40%) patients randomized to telaprevir compared to 2/25 (8%) patients randomized to boceprevir (RR: 5; 95% CI: 1.2, 20; p<0.01). Cure rates did not appear to be significantly different between groups (telaprevir vs. boceprevir: RR 1.23; 95% CI: 0.76, 1.99; p = 0.39). On an intention-to-treat basis, total cost per cure was $44,329 for boceprevir vs. $57,115 for telaprevir. The significant side effect profile of telaprevir combined with the availability of highly efficacious second generation DAAs led to the early discontinuation of the trial. CONCLUSION: Telaprevir is associated with a significantly higher rate of severe adverse events leading to treatment discontinuations, hospitalizations or severe anemia and a substantially higher cost per SVR when compared to boceprevir. Real-time, point of care, pragmatic randomized controlled trials are necessary for guidance beyond just acquisition costs and to make evidence-based formulary selections when multiple effective treatments are available. (Clinicaltrials.gov registration: NCT02113631).

[Cost-effectiveness and safety of telaprevir and boceprevir for chronic hepatitis C in real-world clinical practice]. / Coste-efectividad y seguridad de telaprevir y boceprevir para el tratamiento de la hepatitis C crónica en la práctica clínica.

INTRODUCTION: Triple therapy with telaprevir or boceprevir has proven to be effective in the treatment of chronic hepatitis C with response rates of up to 88%. However, the treatment may be associated with important adverse effects and a high economic impact. OBJECTIVE: To assess the cost-effectiveness and safety of triple therapy with telaprevir or boceprevir for the treatment of chronic hepatitis C. METHODS: Retrospective observational study. We included all patients who had started treatment with protease inhibitors before July 31(st), 2013. We evaluated sustained virological response, the cost per patient achieving sustained virological response, and the cost of the supportive treatment for adverse events associated with triple therapy. RESULTS: Fifty-nine patients were included; 35 had been treated with telaprevir (59.3%) and 24 with boceprevir (40.7%). Sustained virological response was achieved by 38 (64.4%) patients: 24 (68.6%) patients in the telaprevir treatment arm and 14 (58.3%) patients in the boceprevir treatment arm. The cost per patient with sustained virological response was 43,555 € (95% CI 35,389-51,722 €). There were no statistically significant differences between the overall costs of therapy with telaprevir, 43,494 € (95% CI 34,795 €-55,092 €) versus boceprevir, 42,005 € (95% CI 32,122-64,243€). The mean cost of supportive care per patient was 1,500 €, while the maximum cost was 11,374 €. Due to adverse events, 8 (13.6%) patients required hospital admission, 22 (37.3%) patients attended the accident and emergency department, and 26 (44.1%) patients needed additional medical consultations. CONCLUSIONS: The treatment of triple therapy with telaprevir or boceprevir resulted in high cost per patient with sustained virological response. Due to adverse events, a high number of patients required supportive care, whose costs should be added to those of triple therapy.

Costs and Resource Utilization Associated With Anemia and Rash in Chronic Hepatitis C Patients Treated With Direct-Acting Antiviral Agents in the United States.

PURPOSE: The addition of 2 direct-acting antiviral (DAA) agents, telaprevir and boceprevir, to peginterferon and ribavirin therapy significantly improves sustained virologic response rates in patients treated for chronic hepatitis C virus (CHC) but is associated with a higher risk of adverse events (AEs), including anemia and rash. Using a large administrative claims database, this study compared the health care resource utilization and costs among CHC patients who developed anemia and/or rash while receiving DAA-based therapies (telaprevir and boceprevir) versus those who did not develop anemia or rash. Adjusted costs were compared by using regression analysis. METHODS: Adult patients with ≥1 CHC diagnosis and a prescription for boceprevir or telaprevir were selected from a US-based claims database. The date of the first DAA fill after May 13, 2011, was defined as the index date. Patients were required to have continuous eligibility and no claims for hepatitis B treatment during the 6 months before (baseline) and 12 months after (study period) the index date. Patients were categorized into 4 cohorts based on the development of anemia only, rash only, both anemia and rash (anemia/rash), or neither anemia nor rash (NAR) while receiving DAA-based therapies. Baseline characteristics and study period health care utilization and costs were compared by using univariate statistics between cohorts that developed anemia only, rash only, or anemia/rash and the cohort that did not develop anemia or rash. Adjusted costs were compared by using multivariable regressions. FINDINGS: A total of 2862 patients were identified and categorized into 4 cohorts: 1204 anemia only, 131 rash only, 188 anemia/rash, and 1339 NAR patients. During the study period, patients developing anemia and/or rash incurred significantly more outpatient, dermatologist, and total medical visits compared with the NAR cohort. The anemia-only and anemia/rash cohorts also had significantly more inpatient, emergency department, and hematologist visits, as well as significantly higher adjusted total medical costs ($18,285 and $21,435 vs $11,253), total drug costs ($76,723 and $79,689 vs $63,001), and non-CHC drug costs ($10,391 and $10,475 vs $2437). The rash-only cohort had comparable adjusted total medical and drug costs. IMPLICATIONS: CHC patients who developed anemia while receiving DAA-based therapies incurred significantly higher resource utilization and costs compared with those who did not. The study highlights the need for new CHC treatment regimens that are associated with fewer and less severe AEs, particularly anemia.

Cost utility of telaprevir-PR (peginterferon-ribavirin) versus boceprevir-PR and versus PR alone in chronic hepatitis C in The Netherlands.

BACKGROUND: The hepatitis C virus may lead to cirrhosis, liver cancer, liver transplant, and increased mortality. With standard treatment peginterferon-alpha and ribavirin (PR), sustained viral response (SVR) was less than 50 %. SVR rates improve greatly when PR is combined with telaprevir or boceprevir. OBJECTIVES: The aim of this study was to assess the cost utility of telaprevir-peginterferon-ribavirin (TPR) versus PR and boceprevir-peginterferon-ribavirin (BPR) in treatment-naïve (TN) and treatment-experienced (TE) adults with chronic hepatitis C in the Netherlands. METHODS: A Markov model with a lifelong time horizon and annual cycles was developed. Clinical data stemmed from phase III trials (TPR vs PR, BPR vs PR). A mixed treatment comparison (MTC) was developed to compare TPR and BPR indirectly. Unit costs and utilities based on EQ-5D were established in a Dutch cross-sectional study. Cost per quality-adjusted life-years (QALYs) was calculated according to the societal perspective. RESULTS: Treating TN patients with TPR generates 1.12 additional QALYs with €333 additional cost compared with PR, resulting in an incremental cost-utility ratio of €299/QALY. In TE patients, TPR dominates PR with cost savings (-€7,819) and 1.63 additional QALYs. TPR dominates BPR yielding additional QALYs (0.26 in TN; 0.71 in TE) and cost savings (-€7,296, -€18,144, respectively). CONCLUSIONS: TPR seems a cost-effective alternative to PR in TN patients and dominant in TE patients. TPR was a dominant, more effective and less costly alternative to BPR in both patient types. The cost effectiveness of both TPR and BPR is well below generally accepted willingness-to-pay thresholds and may be considered cost effective.

A population approach to disease management: hepatitis C direct-acting antiviral use in a large health care system.

BACKGROUND: The introduction of the first direct-acting antiviral agents (DAAs) for the treatment of hepatitis C virus (HCV), telaprevir and boceprevir, marked a unique event in which 2 disease-changing therapies received FDA approval at the same time. Comparative safety and effectiveness data in real-world populations upon which to make formulary decisions did not exist. OBJECTIVE: To describe the implementation, measurement, and outcomes of an enduring population-based approach of surveillance of medication management for HCV. METHODS: The foundation of the population approach to HCV medication management used by the Department of Veterans Affairs (VA) relied upon a basic framework of (a) providing data for effective regional and local management, (b) education and training, (c) real-time oversight and feedback from a higher organization level, and (d) prompt outcome sharing. These population-based processes spanned across the continuum of the direct-acting antiviral oversight process. We used the VA's HCV Clinical Case Registry-which includes pharmacy, laboratory, and diagnosis information for all HCV-infected veterans from all VA facilities-to assess DAA treatment eligibility, DAA uptake and timing, appropriate use of DAAs including HCV RNA monitoring and medication possession ratios (MPR), nonconcordance with guidance for adjunct erythropoiesis-stimulating agent (ESA) and granulocyte colony-stimulating factor (GCSF) use, hematologic adverse effects, discontinuation rates, and early and sustained virologic responses. Training impact was assessed via survey and change in pharmacist scope of practice. RESULTS: One year after FDA approval, DAAs had been prescribed at 120 of 130 VA facilities. Over 680 VA providers participated in live educational training programs including 380 pharmacists, and pharmacists with a scope of practice for HCV increased from 59 to 110 pharmacists (86%). HCV RNA futility testing improved such that only 1%-3% of veterans did not have appropriate testing compared with 15%-17% 6 months earlier. By facility, the median proportion of veterans with MPR ≥ 0.95 remained 80% for those prescribed boceprevir; for telaprevir, the median proportion was 75% and improved to 80% 6 months later. Nonconcordance with VA medication guidance was as follows: receipt of an ESA without dose reducing ribavirin, 30% boceprevir, 45% telaprevir; ESA initiated with a hemoglobin greater than 10 g/dL, 42% boceprevir, 25% telaprevir; receipt of GCSF with absolute neutrophil count above the criteria threshold, 84%. CONCLUSIONS: This clinically focused, comprehensive, population-based medication management approach affected real-time change in health services, practice, and outcomes evidenced by widespread and rapid DAA uptake, improved HCV RNA monitoring, attention to adherence, and more appropriate management of DAA-related anemia. Timely outcome sharing provided decision makers and clinicians evidence to support current HCV practices.

The cost-effectiveness of boceprevir for hepatitis C.

Hepatitis C virus (HCV) infection is costly to treat and, has high morbidity and mortality. The addition of new protease inhibitors (i.e., boceprevir, telaprevir), to the standard dual therapy with pegylated interferon-α and ribavirin, for the treatment of HCV infection has demonstrated superior efficacy with shorter treatment duration, but at higher drug acquisition costs and incidence of adverse events. Robust economic data are required to inform healthcare decision for the optimal use of these expensive antiviral agents. Accordingly, this review will explore the clinical and economic aspects of boceprevir-based treatment strategies. Important considerations, challenges and gaps for future pharmacoeconomic research in this setting are highlighted.

Boceprevir and treatment of chronic hepatitis C.

The addition of boceprevir to peginterferon and ribavirin has improved sustained response rates markedly. Boceprevir is effective in treatment naïve, relapsers, partial responders, and null responders. Those with advanced fibrosis require 44 weeks of boceprevir therapy after a 4-week peg/ribavirin lead-in. The main side effect with boceprevir is anemia and ribavirin dose reduction is an effective strategy. This review examines the current treatment paradigm of boceprevir-based treatment of chronic hepatitis C, examining treatment paradigms, predictors of response, futility rules, as well as preliminary results from studies examining boceprevir efficacy in additional populations. Further follow-up in these cohorts will be required.

Triple therapy with first generation HCV protease inhibitors: lead-in or no lead-in phase?

The standard therapeutic approach currently recommended for patients infected with genotype 1 hepatitis C virus (HCV) is the triple therapy combining pegylated interferon (PEG-IFN), ribavirin (RBV)and NS3/NS4 protease inhibitors, boceprevir or telaprevir [1]. Protease inhibitors (PIs) are direct acting antiviral drugs (DAA) which, when added to PEG-IFN and RBV, are able to achieve a significant gain in terms of sustained virological response (SVR), both in naïve and treatment-experienced patients [2­5]. The use of these new molecules, despite its in contestable benefits, reveals on the other hand new challenges: the emergence of variants with reduced sensitivity to PIs, the development of new or higher rate of side effects, drug to drug interactions, and significant increase in the overall cost of antiviral therapy. Among the two DAAs commonly used in combination with PEG-IFN and RBV (PEG-IFN/RBV) for the treatment of genotype 1 HCV patients, boceprevir has been licensed with a lead-in phase, while telaprevir has been licensed without. EMA approved regimens of both drugs are reported in Figs. 1 and 2. The lead-in phase represents an initial period of 4 weeks of dual therapy with PEG-IFN/RBV, in standard doses, followed by triple therapy. The concept of lead-in phase was initiated by the Schering­Plough company in order to improve efficacy of boceprevir-based triple therapy. Indeed, by lowering HCV RNA level, a short course of PEG-IFN/RBV may theoretically reduce the risk of viral breakthrough or resistance. However, there is still much controversy regarding the utility of the lead-in phase, some authors advocating its role in improving, and/or predicting triple therapy effectiveness, while others view it as a useless complication of the therapeutic regimen, its chief disadvantage being the inconvenience to the patient.

Economic evaluation of direct-acting antiviral therapy in chronic hepatitis C.

In 2011, the protease inhibitors boceprevir and telaprevir were approved in the United States and European Union for the treatment of hepatitis C infection. While remarkably effective, the newly approved therapies are also accompanied by additional side effects and considerable costs. Understanding the balance between costs and effectiveness is critical to making decisions about the optimal use of these new agents, especially for health care systems constrained by rising costs. Our goal for this review is to facilitate an understanding of the importance of cost-effectiveness analyses in guiding policy decisions about the use of newly approved drugs as well as future therapies for hepatitis C.

Formulary management of the protease inhibitors boceprevir and telaprevir for chronic hepatitis C virus.

BACKGROUND: Hepatitis C virus (HCV) is the most common chronic bloodborne illness in the United States. The incidence of acute hepatitis C in the United States peaked near 50,000 cases in the late 1980s but has stabilized since 2003 to less than 5,000 cases annually. The combination of pegylated interferon (peginterferon) and ribavirin has been the standard recommended treatment for HCV. Protease inhibitors telaprevir and boceprevir were approved by the FDA in May 2011 for the treatment of hepatitis C genotype 1 in combination with peginterferon and ribavirin. OBJECTIVE: To review the phase 3 trials for telaprevir and boceprevir and provide managed care considerations. METHODS: A MEDLINE review was performed for articles published and available through September 15, 2011, using keywords "boceprevir" or "telaprevir" with an emphasis on phase 3 trials. The literature search was limited to articles in English, clinical trials, randomized controlled trials, and research conducted in humans. Additional information was obtained from the FDA website. RESULTS: Three phase 3 trials are available for telaprevir, which provided data that were the basis for FDA approval. Boceprevir demonstrated efficacy and safety in 2 pivotal phase 3 trials. Both agents demonstrated statistically significantly higher rates of virologic response compared with the standard of care involving peginterferons and ribavirin. Telaprevir and boceprevir also demonstrated efficacy in the treatment of patients who had previously failed dual therapy for hepatitis C. Safety concerns for both agents include anemia, drug interactions, skin rashes, and gastrointestinal adverse events. CONCLUSIONS: Decision makers have many factors to consider in developing a strategy around hepatitis C. Increased drug costs, patient management, adherence, comparative safety and efficacy, and appropriate utilization management controls are important issues. Payers may consider developing clinical programs to encourage adherence and appropriate use and leverage an appropriate channel to ensure cost-effective therapy.