Formulary Management of the Protease Inhibitors Boceprevir and Telaprevir for Chronic Hepatitis C Virus

BACKGROUND: Hepatitis C virus (HCV) is the most common chronic blood borne 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. OBJECTIVES: 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. CONSLUSIONS: 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.

• The current American Association for the Study of Liver Diseases (AASLD) Practice Guidelines (2011) recommend triple therapy with a protease inhibitor, peginterferon, and ribavirin as the standard treatment for hepatitis C. • Both telaprevir and boceprevir have been studied in treatmentnaïve and previous partial responders, but only telaprevir has been studied in prior null responders. • Managed care considerations of hepatitis C pertinent to decision makers include increased total drug treatment costs and potential increase in utilization, patient management and adherence, comparative safety and efficacy, and appropriate utilization management controls. • The 12-week regimen of telaprevir therapy has a wholesale acquisition cost (WAC)  What this review adds f o R M u l A R y M A n A g e M e n T H epatitis C virus (HCV) is the most common chronic bloodborne illness in the United States. Approximately 3.9 million people in the United States have chronic infection. 1 HCV is a leading cause of liver transplant and liver cancer in the United States and worldwide. 2,3 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. 4 The progressive decline may be a result of increased education and public awareness of transmissible risk factors. 4 Wong et al. (2000) estimated that direct medical expenditures for HCV would grow to $10.7 billion over the 2010-2019 period despite a stable disease rate. 5 HCV is transmitted by exposure to infected blood or blood products with injectable drug abuse being the leading cause. 6 HCV has at least 6 genotypes and 50 different subtypes (i.e., HCV subtype 1a, 1b, etc.), with genotype 1 being the most interferon (peginterferon) and ribavirin has been the standard recommended treatment for HCV prior to the release of the protease inhibitors. 6 Telaprevir and boceprevir were approved by the U.S. Food and Drug Administration (FDA) in May 2011 in combination with peginterferon alfa and ribavirin for the treatment of genotype 1 chronic hepatitis C in adult patients with compensated liver disease, including cirrhosis, who are treatment-naïve or who have been previously treated with interferon-based treatment (Table 1). 8,9 Both agents inhibit the NS3/4A serine protease essential for replication of HCV. 10,11 The introduction of the protease inhibitors, or directly acting antivirals, significantly changes the landscape of HCV management for both treatmentnaïve and treatment-experienced patients. common in the United States. 3 For every 100 people infected with HCV, 75-85 people will develop chronic infection; 60-70 will develop chronic liver disease; 5-20 will develop cirrhosis; and 1-5 will die of cirrhosis or liver cancer. 7 Acute HCV illness manifests symptomatically in 20%-30% of patients. 4 Possible symptoms include abdominal pain, fever, fatigue, loss of appetite, nausea, and vomiting. The remaining 70%-80% of patients may be asymptomatic or experience only mild symptoms. 4 The American Association for the Study of Liver Diseases (AASLD) Practice Guidelines (2011) represent the gold standard for guidance on the management of hepatitis C. 6 These guidelines were approved and are supported by the AASLD, the Infectious Diseases Society of America, and the American College of Gastroenterology. 6 The combination of pegylated The purpose of this article is to (a) provide an overview of the clinical data for telaprevir and boceprevir, including the pharmacokinetics, phase 3 pivotal trial efficacy, and safety; and (b) offer insight to managed care decision makers on management strategies for HCV based on factors that include clinical data, cost, need for adherence, and coverage determination.

■■ Search Method and Results
A MEDLINE review was performed for articles published and available through September 15, 2011, using keywords "telaprevir" and "boceprevir" with an emphasis on published randomized controlled trials ( Figure 1). The literature search was limited to articles in English, clinical trials, randomized controlled trials, and research conducted in humans; review articles and meta-analyses were excluded. Additional information was obtained from the FDA website.

Pharmacokinetics
Telaprevir. Telaprevir is bioavailable and absorbed in the small intestine. 12 For optimal exposure, telaprevir must be taken with food (not low fat). Systemic exposure (area under the curve [AUC]) is increased by 237% in conjunction with a standard fat meal (533 kilocalories and 21 grams fat) compared with the fasted state. When co-administered with peginterferon, maximum concentration at steady state (C max,ss ) and AUC are increased by 43% and 38%, respectively. Ribavirin does not affect telaprevir plasma concentrations, and maximum plasma concentrations are reached in 4 to 5 hours after a dose. 13 In vitro studies have shown telaprevir to be a substrate and inhibitor of P-glycoprotein (P-gp) and CYP3A, resulting in clinically significant drug interactions (see Table 2). 13 Telaprevir is 59% to 76% bound to plasma proteins (alpha-1-acid glycoprotein and albumin).
In the phase 2 studies PROVE 2 and PROVE 3, a population pharmacokinetic analysis was performed using pharmacokinetic data from all subjects. After oral administration, the apparent total clearance was about 31.6 liters (L) per hour and 37.5 L per hour in PROVE 2 and PROVE 3, respectively. 13 Telaprevir undergoes hepatic metabolism, and primary route of elimination is fecal. Elimination half-life is 4 to 4.7 hours.
Boceprevir. Boceprevir should be taken with food, but type of meal and timing are not crucial. Clinical trials demonstrated boceprevir AUC increased up to 65% when taken with food. 14 Boceprevir reaches maximum plasma concentration 3 hours after a dose. An in vitro study showed boceprevir to be a P-gp substrate. 14,10 Boceprevir is also a CYP3A4/5 substrate and strong inhibitor and is approximately 75% plasma protein bound (see Table 2 for clinically significant drug interactions). 14 In vitro studies showed boceprevir to be primarily metabolized through the aldoketoreductase (AKR)-mediated pathway to ketone-reduced metabolites (inactive). Mean apparent clearance of boceprevir is 157 L per hour, and its elimination halflife is approximately 3.4 hours. The primary route of elimination is fecal.

Efficacy and Safety
Telaprevir. The efficacy and safety of telaprevir was studied in three phase 3 pivotal trials: ADVANCE (Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection), 15 ILLUMINATE (Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection), 16 and REALIZE (Telaprevir for Retreatment of HCV Infection). 17 The study designs, samples, and efficacy and safety outcomes are shown in Table 3.
Limits: English, "human," "clinical trial," or "randomized controlled trial"   Head-to-head comparative clinical trials are lacking between telaprevir and boceprevir. Both agents have studies in treatment-naïve and previous partial responders, but only telaprevir has been studied in prior null responders. 17 AASLD guidelines recommend the use of telaprevir for prior null responders. 6 Although both agents were studied with peginterferon, telaprevir was used with peginterferon alfa-2a while boceprevir trials used peginterferon alfa-2b. There may be speculation that the overall efficacy of the protease inhibitors could be affected by choice of peginterferon because there are efficacy differences between peginterferon alfa-2a and alfa-2b in the hepatitis C population. Some payers may require the use of one specific peginterferon in a utilization management program, regardless of the protease inhibitor used. Current literature and FDA labeling for the protease inhibitors does not support the use of one distinct peginterferon product over the other. The rationale for peginterferon preferred product selection by a payer could be multifaceted, including product cost, manufacturer discounts, channel steerage, and clinical differences.
In cross-trial comparisons, telaprevir appears to have a Boceprevir. The efficacy and safety of boceprevir was studied in two phase 3 pivotal trials: SPRINT-2 (Boceprevir for Untreated Chronic HCV Genotype 1 Infection) and RESPOND-2 (Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection). The study designs, samples, and efficacy and safety outcomes are shown in Table 4.

■■ Managed Care Considerations
The arrival of the protease inhibitors has had a significant impact on the management of genotype 1 hepatitis C. Both agents have demonstrated significantly improved sustained virologic response (SVR) rates compared with conventional dual therapy with peginterferon and ribavirin. However, both protease inhibitors introduce issues that managed care decision makers will need to address in order to optimize cost-effective use. Decision makers need to consider increased total drug treatment costs, patient management and adherence, comparative safety and efficacy, and appropriate utilization management controls when deciding on a strategy for hepatitis C treatment.

RESPOND-2 19
Control: PR for 4 weeks (lead-in period), followed by placebo with PR for 44 weeks (total treatment duration 48 weeks) Response-guided: PR for 4 weeks (lead-in period), followed by boceprevir with PR for 32 weeks • Patients would end therapy if HCV RNA levels were undetectable (lower limit of detection 9.3 IU per mL) at week 8 and 12 (total treatment duration 36 weeks) • Patients with a detectable level at week 8 but undetectable at week 12 received PR for an additional 12 weeks (total treatment duration 48 weeks) Fixed duration: PR for 4 weeks (lead-in period), followed by boceprevir with PR for 44 weeks (total treatment duration = 48 weeks) The following doses were used: • boceprevir 800 mg orally 3 times daily with food • peginterferon alfa-2b 1.5 mcg per kg subcutaneously weekly • ribavirin weight-based dosing 600 to 1,400 mg orally daily in divided doses at morning and evening Patients were stratified by previous response to therapy (nonresponse or relapse) and HCV subtype (1a or 1b). Nonresponse was defined as a decrease in the HCV RNA level at least 2 log 10 IU per mL by week 12 but with a detectable level during therapy period. Relapse was defined as undetectable (lower limit of detection 9.3 IU per mL) HCV RNA level at the end of treatment, but detectable levels during follow-up. Patients discontinued all treatment if they had a detectable HCV RNA level at week 12.  significantly elevated risk of rash compared with boceprevir (22% vs. 2% in previously untreated patients). 10,11 Stevens-Johnson syndrome occurred in 1 patient about 11 weeks after completing telaprevir treatment. 15 Anemia appeared to occur at similar rates with telaprevir and boceprevir in cross-trial comparisons (19% vs. 20% in previously untreated patients). 10,11 Although anemia was managed differently in the clinical trials (telaprevir patients received ribavirin dose/frequency modifications, and boceprevir patients received erythropoiesis-stimulating agents [ESAs]), practitioners will likely consider the use of ESAs with either protease inhibitor depending on their own clinical experience with these agents. 15,[17][18][19] Managed care payers may include provisions in utilization management programs that manage anemia in patients receiving either of the protease inhibitors with ribavirin dose reduction (efficacy of the regimen is not compromised if the ribavirin dose is reduced; ribavirin concentrations achieved will be similar to that of full dosing in a nonanemic patient) and allow the use of ESAs at particular hemoglobin levels if ribavirin dose reduction is insufficient to manage anemia. Comparative trials and studies in different patient subgroups, including those with human immunodeficiency virus (HIV) coinfection, are needed to fully understand the differences between the protease inhibitors.

Drug Cost
Telaprevir and boceprevir will bring substantial new pharmacy costs to the management of hepatitis C.  (Table 1). Telaprevir's higher cost may be balanced by the significantly easier dosing regimen of telaprevir (12 weeks in all cases) versus the more confusing, response-guided boceprevir regimen. Additional costs will be incurred in the management of adverse effects from the oral agents. Anemia managed by ESAs would add significant cost to the regimen versus management via ribavirin dose reduction. Rates of anemia were 36% in the telaprevir-treated patients versus 17% for patients treated only with peginterferon and ribavirin. 11 Anemia occurred in 45%-50% of boceprevir-treated patients versus 20%-30% of patients treated only with peginterferon and ribavirin. 10 In the SPRINT-2 trial, anemia with boceprevir was managed via ESA 40,000 units administered weekly, with a mean duration of 94 weeks of ESA therapy in the response-guided group and 156 weeks in the fixed-duration group versus 121 weeks in the peginterferon-ribavirin group. 18 Forty-three percent of boceprevir-treated patients received ESAs compared with 24% of patients receiving only peginterferon plus ribavirin in clinical trials. 10 The WAC of a vial of 40,000 units of ESA is $679.00. 20 Depending on the duration of therapy, ESAs could add significantly to the total costs of the regimens of the protease inhibitors. Laboratory monitoring and clinic visits may also be increased as patients are monitored for response and adherence.
Prior to the approval of the protease inhibitors, McAdam-Marx et al. (2011) found that average total all-cause costs were $19,665 per patient per year (PPPY) in 2009 dollars for HCVinfected patients. 21 The cost of HCV management will more than double or triple for patients with genotype 1 infection treated with triple therapy. Additionally, WAC pricing does not account for mark-ups in pharmacy provider channels or drug manufacturer rebates. Due to the increased costs, payers should strongly consider implementation of utilization and care management programs that help ensure that the right patients receive the appropriate therapy and are adherent to therapy.

Utilization Management
A clinically focused, comprehensive utilization management program is imperative in the management of hepatitis C. The utilization management criteria should include the following factors: appropriate patient selection, concomitant therapy, safety considerations, dosing, and continuation of therapy. Appropriate patient selection may exclude groups not studied in phase 3 trials with the oral protease inhibitors, including viral genotypes other than 1 and individuals with HIV coinfection. In these groups, treatment with the standard dual therapy may be applicable. Concomitant therapy with peginterferon and ribavirin is critical to the success of protease inhibitor therapy. Utilization management programs may be used to mandate triple therapy in patients with genotype 1 infection unless they have contraindications to the protease inhibitors. A utilization management program should also ensure appropriate dosing of protease inhibitors and peginterferon as well as approval of therapy durations limited to what is necessary to complete treatment. Both telaprevir and boceprevir have numerous contraindications and serious drug interactions. Coverage criteria should consider screening for these situations prior to approving therapy. Finally, both protease inhibitors have guidelines regarding treatment futility (Figure 2). These criteria predict treatment failures based on viral loads at specific time points. Management programs may include these stopping points verbatim to ensure patients are being monitored and responding to therapy. However, if managed care decision makers decide to follow the futility rules, 2 points must be considered. First, coverage approvals should extend beyond required laboratory checks to allow for reporting of viral loads without the patient running out of medication. Second, meeting the futility rules should stop coverage of both the protease inhibitor and the peginterferon.

Treatment-naȉve* and prior-relapse patients:
Week 24 Week 48 Not detectable at week 4 and week 12continue PR through week 48 unless detectable at week 24

Prior partial-and null-responder patients:
Week 1

Treatment-naȉve patients:
Week 28 Week 48 Not detectable at week 4 and week 24continue triple therapy with boceprevir + PR through week 36

Prior-relapse and partial-responder patients:
Week 8 HCV RNA level (Undetectable: ≤ 9.3 IU per mL) Week 36 Detectable at week 8 and not detectable at week 12complete boceprevir at week 36 and continue PR through week 48 Week 48 4 weeks of PR followed by 44 weeks of triple therapy with boceprevir + PR

Patients with cirrhosis:
Week 48

FIGURE 2
Hepatitis C Treatment Algorithm: Telaprevir a and Boceprevir b

Discontinue telaprevir
Week 48 Patient adherence is crucial to the cost-effective use of the protease inhibitors in hepatitis C. Nonadherent patients are at significant risk of treatment failure and resistance development. 22 Managed care decision makers may implement a care management program in conjunction with utilization management criteria to ensure patients are monitored for appropriate use and adherence to therapy. Many specialty pharmacies have experience in care management of hepatitis C. Ideally, a care management program would include regular (weekly or monthly) calls from a pharmacist to the patient to assess current adherence to therapy. Prescription claims could also be monitored to ensure consistent filling, and a call could be placed to members suspected of having a gap in care. Payers may consider limiting distribution of hepatitis C treatments to a specialty pharmacy that offers comprehensive care management to patients. Finally, managed care decision makers should educate the specialty pharmacy and practitioners on the specifics of the utilization management criteria, which will reduce potentially duplicative efforts by the payer and the specialty pharmacy in care requirements, such as laboratory tests, or potentially inconsistent periods for approved duration of therapy. Provider education could be delivered via training modules and/or having a subject matter expert available to answer questions on the criteria.
The release of telaprevir and boceprevir marks a unique event in which 2 disease-changing therapies received FDA approval within days of each other. Such events provide payers with the opportunity to gather information and data on how new therapies are adopted, alter existing utilization of established therapies, and impact medical and pharmacy costs. Prime Therapeutics reported that the utilization of drugs for hepatitis C decreased by 22.1% in 2010 compared with 2009, contributing to a 15.2% decrease in drug cost for these drugs (-$0.03 per member per month), 9% of which was in medical benefit costs and 91% was in pharmacy benefit costs. 23 Although pharmacy costs will increase with the use of the protease inhibitors, the total cost of caring for patients with hepatitic C infection should decrease due to the increased cure rates with the protease inhibitors. The release of the protease inhibitors will cause the first surge in use of hepatitis C agents as treatment-naïve and previously treated patients attempt therapy. Payers should gather data on the changes in utilization and how the different products perform (e.g., use of prescription claims to determine utilization trend, cost per claim after applicable discounts, and medical claims information to monitor for adverse events such as anemia). This information could prove useful in determining the value that the market places on different aspects of competing drugs including dosing, safety profile, cost, and effectiveness of utilization management tools. Additionally, comprehensive data collection could further define the true cost of the 2 agents when taking into consideration discounts, channel, and adverse events.

■■ Conclusions
With FDA approval of the new protease inhibitors, 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. Despite the great advancement in hepatitis C treatment, the protease inhibitors have a significant adverse effect profile and pill burden. An appropriate utilization management strategy should be implemented to ensure patients receive optimal benefit from therapy.