Sharon M. Wang, PharmD, MS

Since the discovery of the hepatitis C virus (HCV) in 1989, the chronically infected population has experienced dynamic change. The prevalence of chronic HCV infection in the United States has decreased over the past decades, with the most recent estimate at approximately 2.7 million people (or 1%) of those 6 years and older.

 The decline corresponds with the increase in HCV-associated deaths and decreased transmission rather than from an increase in treatment success.

Increasing access to more effective and affordable treatments is a major public health concern.

Chronic HCV infection remains largely undertreated, with only 13% to 18% of infected individuals having received treatment.

 The largest barrier to treatment is that many infections remain undiagnosed, with fewer than half of all HCV-infected individuals being aware of their infection.

 Other barriers to treatment include contraindications or perceived contraindications by prescribers, lack of access to prescribers with HCV expertise, and patient barriers (eg, the asymptomatic nature of the infection, fear of medication side effects, and concerns regarding treatment duration, cost, and effectiveness)

 Patients and prescribers have postponed treatment in hopes of more effective and more tolerable treatments on the horizon.

After developing chronic HCV infection, 60% to 70% will progress to chronic liver disease; 5% to 20% will develop cirrhosis; and 1% to 5% will die from cirrhosis or liver cancer.

 However, these sequelae take decades to develop, and for most patients, there is no urgency for treatment. Treatment is recommended for individuals with existing liver disease or fi brosis, but may be delayed for those with less severe disease.

As the majority of patients are believed to have acquired their infection between the 1960s and the 1980s, the proportion of newly diagnosed patients with mature infection requiring immediate treatment is steadily on the rise.

 Chronic infection is more often found among individuals over age 50 years. Approximately 81% of individuals with HCV infection were born between 1945 and 1965.

 In 2012, the Centers for Disease Control and Prevention issued guidance that all persons born in this time frame should be screened for HCV at least once, regardless of risk factors.

 With increased screening, more individuals are likely to be diagnosed and receive treatment in coming years.

The goal of therapy is to eradicate HCV infection, and with it to prevent liver cirrhosis, liver failure, hepatocellular carcinoma (HCC), and death.

 The eradication of HCV is determined by a highly sensitive assay in which circulating HCV RNA is undetectable at 12 or 24 weeks after completion of treatment—known as sustained virologic response (SVR). SVR at 24 weeks has been shown to provide a durable response and is associated with improvement in liver fibrosis, reduced risk of liver-related morbidity and mortality (including liver failure, liver transplantation, and HCC), and reduced risk of all-cause mortality, even in advanced cases.

 In 2013, undetectable serum HCV RNA at 12 weeks after the end of treatment was found to be concordant with testing after 24 weeks, and has become the new standard of care and end point used in clinical trials.

Genotype 1 is the most common HCV genotype in the United States, comprising approximately 70% of all cases. It is also the most difficult to treat, requiring prolonged therapy. Beginning in 2001, pegylated interferon plus ribavirin was the standard-of-care treatment for all genotypes. A 48-week regimen with pegylated interferon and ribavirin for genotypes 1, 4, 5, and 6 typically resulted in SVR rates of 40% to 50% (

). In clinical trials, treatment-naïve patients with HCV genotypes 2 and 3 treated with pegylated interferon plus ribavirin for 24 weeks often obtained SVR rates of 70% to 80%.

The SVR rates achieved in clinical trials may not always be realized due to suboptimal patient adherence in the general population.

 Severe side effects often negatively impact patient adherence to therapy.

Pegylated interferon products have a black box warning of fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. The side effects of pegylated interferon that often cause the most frequent complaints from patients are the flu-like symptoms, which must be tolerated for up to 48 weeks. Ribavirin also has serious side effects, including anemia, which can worsen heart disease, and teratogenicity.

In 2011, 2 direct-acting antiviral (DAA) non-structural (NS) 3/4A protease inhibitors, boceprevir and telaprevir, were approved to treat genotype-1 HCV. SVR was achieved for an additional 25% to 31% of treatment-naïve patients treated with boceprevir or telaprevir plus pegylated interferon and ribavirin compared with standard dual therapy.

 Boceprevir and telaprevir require complex treatment response—guided regimens, carry signifi - cant pill burdens, and have greater incidence of severe side effects such as cytopenias and skin reactions.

 Boceprevir and telaprevir are both substrates and inhibitors of P-glycoprotein and cytochrome P450 3A4, which can cause significant drug interactions. In one cohort study, potential drug interactions that required dose adjustments or medication changes were found in half the population initiating boceprevir or telaprevir.

In late 2013, 2 additional oral DAAs were approved. Simeprevir, a third NS3/4A protease inhibitor, was approved for use in conjunction with pegylated interferon and ribavirin to treat HCV genotype 1. Advantages of simeprevir over first-generation NS3/4A protease inhibitors include once-daily dosing, slightly improved SVR rates, and an improved side effect profile. Overall, 80% of patients achieved SVR; however, among patients with genotype 1a, 58% of patients achieved SVR with the NS3 Q80K polymorphism compared with 84% of patients without the polymorphism.

 It is recommended, but not required, that patients be screened for the NS3 Q80K polymorphism prior to initiating regimens including simeprevir.

The most recent DAA addition is sofosbuvir, the first NS5B polymerase inhibitor approved to treat chronic HCV and the first approved medication for use in an all-oral HCV treatment regimen. Sofosbuvir provides the additional advantages of once-daily dosing, improved SVR rates, efficacy for all genotypes, no cytochrome P450 3A4 drug interactions, and shorter therapy duration (12 weeks total) for certain patients. Among genotype-1 treatmentnaïve patients, SVR was achieved for 89% with sofosbuvir, pegylated interferon and ribavirin for 12 weeks.

 Limited results are available for sofosbuvir use in patients with genotype 1 who had failed prior therapy with pegylated interferon, and ribavirin; however, the US Food and Drug Administration (FDA) allowed approval of sofosbuvir in this population based on extrapolated results from other difficult-to-treat patient populations. The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) have released treatment guidelines that recommend sofosbuvir regimens, including the unapproved sofosbuvir and simeprevir combination regimen, as standard-of-care treatments (

Chronic HCV infection has been costly to treat, with average wholesale prices (AWPs) of pegylated interferon products ranging from $20,309 to $44,424 per treatment as of February 2014. The treatment of genotype-1 HCV significantly increased with the addition of NS3/4A protease inhibitors. Current AWPs for NS3/4A protease inhibitors range from $43,808 to $79,632 per treatment. Sofosbuvir has been launched with AWP of $1200 per day. Based on AWP pricing, 12 to 24 weeks of sofosbuvir costs $100,800 to $201,600. The high cost of treatment has raised concerns among patient advocacy groups and payers.

 As the treatment costs vary widely across the new standardof- care regimens, this analysis quantifies the proportion of patients initiating sofosbuvir and simeprevir, including interferon-free regimens. An understanding of prescribing patterns with these new drugs will help payers manage appropriate utilization and project drug spend.

A retrospective, cross-sectional analysis was performed using de-identified data from a sample of participating clients in the research database of MedImpact Healthcare Systems, Inc, a national pharmacy benefi ts manager (PBM). Patients initiating sofosbuvir or simeprevir from November 22, 2013 (the FDA approval date for simeprevir; the FDA approval date for sofosbuvir was December 6, 2013), through February 28, 2014, were identified. The first fill date for sofosbuvir was considered the index date. If no fill for sofosbuvir was identified, the first fill date of simeprevir was defi ned as the index date. Each identifi ed patient’s HCV treatment regimen was determined by looking for fill dates of other HCVindicated medications during the concomitant therapy period, which extended from 30 days prior to the index date through 30 days after the index date. The number of patients taking each of the following FDA-approved or ASLD/IDSA-recommended regimens was identifi ed: (1) sofosbuvir, pegylated interferon and ribavirin; (2) sofosbuvir and ribavirin (no interferon products, no protease inhibitors); (3) simeprevir, pegylated interferon, and ribavirin; (4) simeprevir and sofosbuvir with ribavirin (no interferon products); (5) simeprevir and sofosbuvir (no interferon or ribavirin products). Treatment costs were quantified using February 2014 AWP for branded products and maximum acquisition cost (MAC) for generic products (ie, ribavirin products).

In the first few months of market availability of simeprevir and sofosbuvir, nearly 8 times as many patients have initiated sofosbuvir (n = 435) as initiated simeprevir (n = 57) (

). These groups are not mutually exclusive. In fact, 95% of simeprevir initiators are taking unapproved, ASLD/IDSA-recommended, interferon-free, sofosbuvir-based regimens. Only 5% of simeprevir initiators began the FDA-approved regimen with pegylated interferon and ribavirin.

Of sofosbuvir initiators, only 41% are taking concomitant pegylated interferon and ribavirin and more than half (57%) are taking interferon-free regimens indicated for genotypes 2 and 3 and interferon-ineligible genotype 1. Two percent of sofosbuvir users did not have claims for recommended concomitant therapy during the 30 days prior to and 30 days after sofosbuvir initiation.

The AWP cost per treatment for 48 weeks of pegylated interferon and ribavirin (standard of care for genotype-1 patients from 2001-2011) is $42,411 to $46,218 (Figure 4). The HCV protease inhibitor—based regimens (boceprevir, telaprevir, or simeprevir with pegylated interferon and ribavirin) are signifi cantly more expensive at AWP costs of $70,768 to $126,432. The AWP cost of a sofosbuvir- based regimen for genotype-1 treatment-naïve or relapser, interferon-eligible patients is between $122,006 and $123,909. The cost of interferon-free sofosbuvir regimens, recommended for interferon-ineligible genotype-1 patients, ranges from $180,432 (sofosbuvir, simeprevir for 12 weeks) to $202,497 (sofosbuvir, ribavirin for 24 weeks). The latter AWP treatment cost is 66% more expensive than the 12-week interferon-based sofosbuvir regimen and approximately twice as much as the protease inhibitor based–regimens that were standard of care between 2011 and 2013.

Our pharmacy claims—based analysis found that 41.1% (n = 180) of patients initiating sofosbuvir or simeprevir were taking concomitant pegylated interferon and ribavirin. A greater proportion of patients (57.1%, n = 250) initiated an interferon-free sofosbuvir regimen. Most health plans covered by our PBM elected to use prior authorization guidelines to determine appropriate use for medication coverage that is consistent with approved indications and evidence-based standard of care. As the proportion of genotype 1 among the chronic HCV population in the United States is at least 70%, it is expected that a similar proportion of sofosbuvir initiators would be on the FDA-approved regimen for genotype 1 (sofosbuvir, pegylated interferon and ribavirin). It may be that a greater proportion of genotype 2 or 3 patients have initiated therapy in this early time period or that a large proportion of genotype 1 patients initiating therapy have been deemed interferon-ineligible. The cost implications of the latter scenario are significant, as treating genotype 1 patients with an interferon-free regimen costs between $58,426 and $80,491 more per patient, and with decreased efficacy. An SVR of 72% was realized in a total of 211 treatment-naïve genotype 1 patients using sofosbuvir and ribavirin in various clinical trials.

 The AASLD/IDSA guidelines recommend that the all-oral combination of sofosbuvir with ribavirin for 24 weeks should be considered only for genotype-1 patients who require immediate treatment, because regimens with improved safety and efficacy will likely be available by 2015.

The higher costs of more efficacious treatment may be justified as the costs of treatment failure are significant. One analysis found a 10-fold difference in the costs between managing patients who achieved SVR versus those who did not achieve SVR over a 5-year period, with a retreatment rate of 19% among SVR nonachievers.

The outstanding question is whether these new standard-of-care therapies are cost-effective. A Markov model analysis, published months before sofosbuvir was approved, determined that $112,653 was the maximum drug cost for an all-oral regimen achieving 90% SVR to remain cost-effective using a $100,000 per quality adjusted life-year willingness-to-pay threshold.

 For most patients, the current all-oral sofosbuvir-based regimens do not meet the 90% SVR standard of efficacy and are much more expensive.

The standard of care for the treatment of chronic HCV infection continues to evolve. Several novel drugs are being studied in which preliminary data demonstrate close to 100% SVR (Figure 1).

 The future standard of care will be oral regimens that are more effective and presumably more tolerable. Present interferon-free regimens have less evidence of efficacy and a substantial cost (between $180,881 and $202,497 per treatment) for the majority of patients who will receive these treatments. It is yet unknown if the current trend of increasing costs for chronic HCV treatment will continue, or at what point it will no longer be sustainable.

Articles

This article is an early utilization review of newer, more effective, and more costly regimens for the treatment of hepatitis C.