Since 2014, the United States Food and Drug Administration (FDA) approval of a new generation of direct-acting antiviral (DAA) oral medications has revolutionized the landscape for hepatitis C virus (HCV) treatment. Therapy with DAAs has been markedly more effective than older therapies, easier to tolerate, and highly effective, even in traditionally more difficult-to-treat patients, such as those with treatment experience, cirrhosis, or HIV coinfection. Enthusiasm for these therapies, however, has been tempered by the challenges patients and clinicians face with respect to drug access and reimbursement. Given the prohibitively high costs of the DAA medications, many insurance companies and most Medicaid programs currently approve payment only for patients with advanced liver fibrosis (Metavir F3 or F4 fibrosis) or those with other “highest priority” indications for treatment as outlined in the American Association for the Study of Liver Diseases/Infectious Diseases Society of America (AASLD/IDSA) HCV guidance section on When and Whom to Initiate HCV Therapy. For medical providers, the process of obtaining insurance approval for new HCV treatment regimens can be daunting, complicated, and time-consuming. In addition, even when drug approval occurs, it may occur only after a substantial delay, potentially resulting in loss to follow-up. The purpose of this core concept is to describe some of the economic barriers to obtaining medication, to review some cost-effectiveness data on these therapies, and to provide practical guidance on how medical providers can navigate the system to increase access to HCV treatment for their patients.
- Module 4 Overview
Evaluation and Preparation for Hepatitis C Treatment
- 0%Lesson 1
Goals for Treatment and Predicting ResponseActivities
- 1A.Core Concepts
- 1B.Goals for Treatment and Predicting Response
- 1C.ACG Treatment Resources
- Lesson 1 Quiz/CME/CNE
- 0%Lesson 2
Making a Decision on When to Initiate HCV TherapyActivities
- 2A.Core Concepts
- 2B.Making a Decision on Whether to Initiate Treatment
- 2C.Impact of Successful Treatment of Hepatitis C
- Lesson 2 Quiz/CME/CNE
- 0%Lesson 3
Cost and Access to Direct-Acting Antiviral AgentsActivities
- 0%Lesson 4
Evaluating Persons with Substance or Alcohol Use for Treatment of Hepatitis CActivities
- 4A.Core Concepts
- 4B.Addressing Substance and Alcohol Use Prior to HCV Treatment
- 4C.Harm Reduction Coalition and Hepatitis C
- Lesson 4 Quiz/CME/CNE
- 0%Lesson 5
Addressing Anticipated Adherence Problems Prior to Treatment
- Module 4 Self-Assessment
Lesson 3. Cost and Access to Direct-Acting Antiviral Agents
- Summarize the costs of direct acting antiviral agents used to treat hepatitis C.
- Describe major steps in accessing new direct-acting antiviral medications used to treat hepatitis C.
CNE/CME Continuing EducationThis lesson qualifies for 1 CME AMA PRA Category 1 Credit™ and 1 CNE contact hour. View CE Notices.
InstructionsTo complete this lesson you must work through all Lesson 3 Activities (listed below and on the left-hand navigation bar). After finishing the lesson activities, take the Lesson 3 Quiz. You can choose to obtain Continuing Medical Education (CME) or Continuing Nursing Education (CNE) credit at that point,but you must answer at least 80% of the questions correctly. After finishing the Lesson 1 Quiz, proceed to the next Lesson. After finishing all Module 4 lessons, you will be ready to take the Module 4 Self-Assessment.Table of Contents
Cost of Direct-Acting Antiviral AgentsThe “cost” of the drug typically discussed in the public arena is the wholesale acquisition cost, which is the cost of the medication set by the pharmaceutical company and this wholesale acquisition cost is generally considered a “sticker price”. The newest DAA medications are among of the most expensive oral medications in history, with daily prices ranging from $650 to $1125 (Figure 1). The wholesale acquisition costs are substantially higher than the estimated production costs for the medications (Figure 2). For example, the wholesale acquisition cost of a 12-week course of sofosbuvir is $84,000 and the estimated production cost is $68 to 136. The ultimate cost for a recommended HCV treatment course depends on the HCV genotype and the combination of medications used. For example, the cost of recommended therapy for a treatment-naive patient with genotype 1a ranges from $54,600 to $150,000 (Figure 3); these costs are further increased when patients require a longer duration of therapy, as can occur using some regimens in patients with cirrhosis or prior treatment failure. The actual price paid for the medications, however, may be significantly less than the wholesale acquisition cost, primarily as a result of contracts, rebates, and discounts. Although the wholesale acquisition cost is general public knowledge, information on the actual price paid is not available to the public and these prices may vary significantly over time. Negotiations for pricing are often conducted on behalf of insurance plans by pharmacy benefit management (PBM), a third-party generally for-profit intermediary in the pharmacy supply chain, which can greatly influence the actual drug cost and potential reimbursement rates. When insurance companies are allied with specific PBMs, the agreements may facilitate medication access by lowering drug cost but often do so in exchange for exclusivity (restrictions that dictate which medication can be prescribed) and thereby may reduce choice for the medical provider and patient. These negotiations of drug pricing between pharmaceutical companies and payers or PBMs are for all intents and purposes confidential business dealings and can obscure the price transparency that is otherwise part of a truly free market. The hope remains that more future options for therapy and market-based competition will eventually drive down the cost of these regimens.
Cost-Effectiveness of Direct-Acting Antiviral Agents
Definitions Related to Cost-Effectiveness Analysis: A cost-effectiveness analysis is a formal method to compare the costs and clinical outcomes associated with one intervention with another “standard” comparator and can be used to help set funding priorities. The unit used for this comparison is the incremental cost-effectiveness ratio (ICER), which is a statistic used to summarize the effectiveness of a health care intervention; the ICER is a ratio defined as the difference between the cost of two possible interventions divided by the difference in health effects of the two interventions (Figure 4). The most common application of ICER related to hepatitis C therapy is a cost-effectiveness analysis and the ICER is typically measured as cost per quality-adjusted life years (QALY) gained between two strategies. For example, a typical hepatitis C treatment ICER uses the costs of different therapies as the intervention comparison (cost of new therapy minus the old therapy) divided by the QALY comparison (QALY with new therapy minus QALY of old therapy) (Figure 5). The ICER is then determined as the cost in dollars per quality of life year (QALY) gained. Once the ICER is calculated, it is examined against a benchmark, generally $50,000 to $100,000 per QALY gained, which is considered in the United States to be our society’s “willingness to pay” threshold.
Issues to Consider with Cost-Effectiveness Studies: There are some caveats to consider in cost-effectiveness analyses. First, these statistical models are based on multiple assumptions regarding treatment strategies and the natural history of disease (largely based on prior literature) that should be noted carefully before interpreting results. Second, the cost-effectiveness analysis assumes the main objective is to maximize net health benefits for a target population under constrained resources, a primary goal that may not be shared by clinicians who are more focused on the welfare of the individual patients they serve. Third, these analyses comprise only one of many criteria, including political, societal, and ethical priorities, that need consideration when making decisions related to resource allocation. This last consideration is important when considering HCV therapy with DAAs. Most published cost-effectiveness analysis studies have reported that new treatments for hepatitis C appear to be cost effective compared with older comparators, but note that the benefit to society (and payers) would not occur until at least 10 years after the initial treatment. It is clear that while HCV DAAs may be cost-effective, the projected cost of widespread medication coverage of all HCV-infected patients in the US would exceed $300 billion and is neither affordable nor feasible. Further, in Chhatwhal's cost-effectiveness analysis they conclude that new drugs as currently priced will not lead to the overall reduction in the cost of HCV disease.
Cost-Effectiveness Studies with DAAs: Several cost-effectiveness studies have been published on the DAAs, with summary points listed below. Many of these studies did not include the potential treatment benefits accrued with reduction of non-liver-related morbidity and mortality, or the prevention of secondary HCV infection.
- Several cost-effectiveness analysis studies have examined ledipasvir-sofosbuvir in genotype 1 infection and most demonstrated this combination was cost-effective in selected groups compared with older standard of care (some version of interferon-based therapy), with most ICERs in the “willing to pay” range of less than $100,000 per QALY gained (Figure 6).
- In the cost-effectiveness analyses performed by Chhatwal and Najafzadeh, in addition to the cost of the drug, age and severity of fibrosis had substantial influence on the ICERs, with greater cost-savings observed in the treatment of younger patients, as well as patients with advanced fibrosis, except for treatment-experienced patients with genotype 1 and cirrhosis, since these patients with cirrhosis require a 24-week course of therapy (Figure 7).
- Studies by Linus and Najafzadeh concluded that genotype 2 or 3 is notably less cost-effective to treat than genotype 1 with sofosbuvir-based therapy in treatment-naïve non-cirrhotic patients. This is not surprising when one considers that a reasonable majority of non-cirrhotic patients with genotype 2 or 3 infection can be cured with less expensive peginterferon-based therapy.
Process to Acquire Direct-Acting Antivirals for Patients
Insurance and Medicaid Approval: Because of the very high cost of new HCV regimens, many insurance companies and Medicaid programs require a prior authorization in order for the patient to receive the medications. To date, insurance carriers do not have a uniform policy as to who qualifies for treatment using new oral DAAs. In addition, each states has its own Medicaid program related to HCV therapy, and there is no uniform national policy as to who qualifies for the treatment under Medicaid. More recently, many insurance carriers have adopted guidelines similar to those used in Medicaid guidelines. Many organizations and Medicaid programs currently approve payment only for patients with advanced liver fibrosis (Metavir F3 or F4 fibrosis) or those patients with other “highest priority” indications for treatment (Figure 8). Clinicians who care for Medicaid patients with hepatitis C should attempt to find state-specific policies on prior authorization for hepatitis C treatment by contacting their state Medicaid board. If the clinician resides in states where no official policies exist yet, we encourage access to other state guidelines to get some idea of typical requirements.
Requirements to Acquire DAAs for Patients: Insurance companies and Medicaid often have multiple requirements that must be met before DAAs are authorized. These requirements may restrict and guide who can prescribe DAAs, determine what clinical documentation and laboratory testing are necessary, and stipulate the type of methods and criteria used for fibrosis staging. After the prescription for medication has been submitted, the patient should be counseled that it may take several months to receive a decision from their insurance company. The following list outlines some of the potential requirements that providers may encounter. Keep in mind that these vary by insurance and state, so it is important to clarify what restrictions and requirements are in place for each patient:
- Provider Experience: Many insurance and state Medicaid policies stipulate that only certain medical providers that have adequate expertise in treating hepatic C can prescribe DAAs. Typically, hepatologists, gastroenterologists, and infectious diseases specialists have been granted permission to prescribe DAAs without any further requirements. General medical providers may need documentation of consultation support by experts, such as through the Extension for Community Health Outcome (ECHO) programs.
- Fibrosis Staging: In most circumstances, insurers will require proof of fibrosis staging. Degree of fibrosis can be established by (a) liver biopsy OR (b) a combination of non-invasive measures, including AST-to-platelet ratio index (APRI), FibroSURE, and transient elastography.
- Baseline Laboratory Studies: Most insurance plans will require a thorough evaluation with laboratory studies prior to receiving approval for medications to treat HCV. Typical required baseline laboratory studies are listed below. In addition, except for the HCV genotype, these laboratory studies may need to be obtained within 90 days of the date of prescription.
- HCV Genotype
- HCV RNA
- Complete blood count (CBC)
- Serum creatinine and calculated glomerular filtration rate
- Prothrombin Time (PT)/International Normalized Ratio (INR)
- Hepatic function panel: albumin, total and direct bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase
- Clinic Note Documentation: Some or all of the following patient-specific information may be required in order to qualify for treatment coverage:
- Alcohol sobriety for at least 6 months
- CAGE or AUDIT-C alcohol use survey if the patient is not 100% abstinent to alcohol
- No injection drug use for at least 6 months
- Drug or alcohol screening tests
- Pregnancy status if female of child-bearing age
- Evaluation of psychosocial readiness for treatment
- Justification of choice of regimen and duration of treatment
- Documentation of hepatitis A and B status
Medicaid Guidance: Effective November 5, 2015, the Centers for Medicare and Medicaid Services (CMS) released a guidance document (Assuring Medicaid Beneficiaries Access to Hepatitis C Drugs) for states with regard to access restrictions on DAA treatments for hepatitis C in state Medicaid programs. In this guidance, they note that although states have the discretion to establish limitations on coverage—for example, through preferred drug lists and use of prior authorization—these practices must ensure access to clinically appropriate treatment. Further, this CMS document states that limiting access to treatment to individuals with a fibrosis score of F3 or F4, requiring a period of abstinence from drug and alcohol use, or significantly limiting the types of providers able to prescribe hepatitis C drugs are examples of unreasonable restrictions on access to treatment. It remains to be seen whether this CMS guidance document will change Medicaid restrictions.
Insurance Denials: The insurance companies may block treatment with an outright denial, or they may deny a specific medication selection or duration of therapy. If the insurance company denies a medication for the patient, the medical provider should resubmit the application for the medication, with a specific appeal letter qualifying the request as a reapplication. Given the complexity of this process, assistance from a pharmacist or pharmacy technician, or someone experienced with the process, can prove crucial to ensure the a streamlined process for the patient medication approval. In general, if a patient’s medication request is rejected twice they can apply for a patient assistance program with the pharmaceutical manufacturer, if that pharmaceutical has an active patient assistance program and the patient’s financial circumstances meet the program’s requirements.
Pharmaceutical Patient Assistance Programs: If an insurance company denies a patient’s HCV medication prescription twice, providers should consider contacting the pharmaceutical company Patient Assistance Programs. Unfortunately, not all medications have pharmaceutical company Patient Assistance Programs. Of note, the Gilead Support Path Program for ledipasvir-sofosbuvir (Harvoni) and sofosbuvir (Sovaldi) now provides free medication only for eligible uninsured patients. In general, for most of the other patient assistance programs, patients are considered for Patient Assistance if their application has been rejected by their insurance company twice, the application resubmitted to their insurance company and rejected a second time (must be within 60 days), and patients have an income less than $100,000 per year. Patients should be counseled that the pharmaceutical company assistance program will likely require tax information, social security benefits, and other documents that reflect a patient’s income. The following is a list of active hepatitis C treatment pharmaceutical sponsored patient assistance programs for patients living in the United States.
Patient Advocacy Groups
Patient Advocacy Groups: Several groups have emerged that can act as advocates for patients struggling to deal with the diagnosis, symptoms and complications from Hepatitis C as well as act as advocates and resources for patients struggling through the insurance approval and drug assistance process. Such groups include:
- Patient Advocate Foundation: The Patient Advocate Foundation's Hepatitis C CareLine is a hotline (800-532-5274) for both patients and medical providers and this service non-profit organization that provides assistance, including case management services, to patients diagnosed with hepatitis C. The Hepatitis C CareLine has case managers that will assist patients in efforts to try and access new medications to treat hepatitis C.
- HCV Advocate: The HCV Advocate is a nonprofit organization founded in 1997 geared to providing education, support, and services to patients with HCV infection and coinfection with HCV and HIV, including medical providers. The website includes Educational material about HCV appropriate for patients, Information about HCV and disability services, Information about the Hepatitis C Support Project (HCSP), Updates on clinical trials for HCV treatments, and Current news updates on HCV news and HCV treatment.
- New DAAs have been highly effective in treating chronic HCV infection, but the extremely high cost of these medications has served as a major barrier to more widespread treatment access.
- The wholesale acquisition cost for each the new DAAs ranges from $750 to $1125 per day. The actual price paid for the medication may be significantly lower because of contracts, rebates, and discounts.
- Most new regimens for hepatitis C treatment have been shown to be cost-effective, but given the large numbers of persons infected wih hepatitis C in the United States, universal treatment is neither feasible nor affordable at the current prices of these medications.
- The process of acquiring prior authorization approval for DAAs for patients with hepatitis C can be confusing and time-consuming, particularly with respect to staying up to date wiht the restrictions and requirements of various insurance plans.
- Many insurance and state Medicaid programs are only approving DAAs for hepatitis C treatment for patients with F3 or F4 fibrosis.
- AASLD/IDSA. Recommendations for testing, management, and treating hepatitis C. Overview of cost, reimbursement, and cost-effectiveness considerations for hepatitis C treatment regimens.
- AASLD/IDSA. Recommendations for testing, management, and treating hepatitis C. When and in whom to initiate HCV therapy.
- Barua S, Greenwald R, Grebely J, Dore GJ, Swan T, Taylor LE. Restrictions for Medicaid Reimbursement of Sofosbuvir for the Treatment of Hepatitis C Virus Infection in the United States. Ann Intern Med. 2015;163:215-23.
- Canary LA, Klevens RM, Holmberg SD. Limited Access to New Hepatitis C Virus Treatment Under State Medicaid Programs. Ann Intern Med. 2015;163:226-8.
- Chhatwal J, Kanwal F, Roberts MS, Dunn MA. Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States. Ann Intern Med. 2015;162:397-406.
- Hill A, Khoo S, Fortunak J, Simmons B, Ford N. Minimum costs for producing hepatitis C direct-acting antivirals for use in large-scale treatment access programs in developing countries. Clin Infect Dis. 2014;58:928-36.
- Leidner AJ, Chesson HW, Xu F, Ward JW, Spradling PR, Holmberg SD. Cost-effectiveness of hepatitis C treatment for patients in early stages of liver disease. Hepatology. 2015;61:1860-9.
- Linas BP, Barter DM, Morgan JR, et al. The cost-effectiveness of sofosbuvir-based regimens for treatment of hepatitis C virus genotype 2 or 3 infection. Ann Intern Med. 2015;162:619-29.
- McEwan P, Ward T, Bennett H, et al. Estimating the clinical and economic benefit associated with incremental improvements in sustained virologic response in chronic hepatitis C. PLoS One. 2015;10:e0117334.
- Najafzadeh M, Andersson K, Shrank WH, et al. Cost-effectiveness of novel regimens for the treatment of hepatitis C virus. Ann Intern Med. 2015;162:407-19.
- Rein DB, Wittenborn JS, Smith BD, Liffmann DK, Ward JW. The cost-effectiveness, health benefits, and financial costs of new antiviral treatments for hepatitis C virus. Clin Infect Dis. 2015;61:157-68.
- Saag MS. Editorial commentary: getting smart in how we pay for HCV drugs: KAOS vs CONTROL. Clin Infect Dis. 2015 Mar 16;61:169-70.
- Sethi N, Tapper EB, Vong A, Sethi S, Rourke M, Afdhal NH. Direct costs of first-generation protease inhibitors for the treatment of genotype 1 chronic hepatitis C viral infection. J Viral Hepat. 2015.[Epub ahead of print]
- Younossi ZM, Park H, Saab S, Ahmed A, Dieterich D, Gordon SC. Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection. Aliment Pharmacol Ther. 2015;41:544-63.
FiguresFigure 2. Wholesale Acquisition Cost versus Estimated Production Cost for DAAs and 12-Week Treatment CourseSource: Hill A, Khoo S, Fortunak J, Simmons B, Ford N. Minimum costs for producing hepatitis C direct-acting antivirals for use in large-scale treatment access programs in developing countries. Clin Infect Dis. 2014;58:928-36.Figure 6. Cost Effectiveness Analysis Studies Involving Ledipasvir-Sofosbuvir1. Chhatwal J, Kanwal F, Roberts MS, Dunn MA. Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States. Ann Intern Med. 2015;162:397-406.
2. Younossi ZM, Park H, Saab S, Ahmed A, Dieterich D, Gordon SC. Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection. Aliment Pharmacol Ther. 2015;41:544-63.
3. Najafzadeh M, Andersson K, Shrank WH, et al. Cost-effectiveness of novel regimens for the treatment of hepatitis C virus. Ann Intern Med. 2015;162:407-19.Figure 7. Cost Effectiveness Analysis of Genotype 1 with Ledipasvir-SofosbuvirSource: Chhatwal J, Kanwal F, Roberts MS, Dunn MA. Cost-effectiveness and budget impact of hepatitis C virus treatment with sofosbuvir and ledipasvir in the United States. Ann Intern Med. 2015;162:397-406.Figure 8. Highest Priority for Initiating HCV Treatment Based on Highest Risk for Severe ComplicationsSource: American Association for the Study of Liver Disease, the Infectious Diseases Society of America. When and whom to initiate HCV therapy. Recommendations for testing, management, and treating hepatitis C.
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- HCV Medications
- Daclatasvir (Daklinza)
- Elbasvir-Grazoprevir (Zepatier)
- Ledipasvir-Sofosbuvir (Harvoni)
- Ombitasvir-Paritaprevir-Ritonavir (Technivie)
- Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak)
- Peginterferon alfa-2a (Pegasys)
- Peginterferon alfa-2b (PegIntron)
- Ribavirin (Copegus, Rebetol, Ribasphere)
- Simeprevir (Olysio)
- Sofosbuvir (Sovaldi)
- Sofosbuvir-Velpatasvir (Epclusa)
- Boceprevir (Victrelis)
- Telaprevir (Incivek)
- Course Modules
- Screening and Diagnosis of Hepatitis C Infection
- Evaluation, Staging, and Monitoring of Chronic Hepatitis C
- Management of Cirrhosis-Related Complications
- Evaluation and Preparation for Hepatitis C Treatment
- Treatment of Chronic Hepatitis C Infection
- Treatment of Special Populations and Special Situations
- Special Topics
- Slide LecturesCore ConceptsMaster Bibliography
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- Clinical Calculators
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