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The recent introduction of direct-acting antiviral agents to the armamentarium for treating patients chronically infected with hepatitis C virus (HCV) genotype 1 has improved the efficacy of antiviral treatment,1-3 but it also presents new challenges. As advanced and complex therapies evolve, ancillary staff will have to overcome a steep learning curve to ensure that patients are appropriately managed and successfully complete their treatment.

The selection of candidates for treatment is critical. The documentation of a patient's previous experience with interferon-based therapy, including dose reductions, side effects, and responses (null response, partial response, or relapse), is important in planning the treatment and estimating the chance of a response. Potential drug-drug interactions must be addressed; this may require changing or discontinuing some medications. These issues are described in other articles of this issue of Clinical Liver Disease.

This article presents practical guidelines for implementing antiviral treatment and monitoring patients throughout the course of the treatment. Triple-drug therapy is expensive and labor-intensive for both the provider and the patient. Considerable time and effort can be saved by the development of standardized protocols and flow sheets, familiarity with the drug approval process, patient education, and patient support services. Although these issues may seem mundane and require a considerable investment of time, they ultimately provide the most efficient way of administering therapy and optimizing outcomes.

Prescribing Information

  1. Top of page
  2. Abstract
  3. Prescribing Information
  4. Getting Started
  5. Empowering the Patient to Ensure Successful Therapy
  6. References

Selection of a Pharmacy

Most prescriptions for HCV therapy now require the use of specialty pharmacies. Although the patient's insurance may require a specific pharmacy, knowing what services are provided by the specialty pharmacies in your area can save you considerable work. For example, some handle the prior authorization process, whereas others defer this time-consuming process to the provider. Others offer patient education services and 24-7 phone support. All should notify you about drug shipments, potential disruptions in shipment schedules, and patient calls. The initial drug shipment should not occur before the patient has been instructed in dose timing, side-effect management, and so forth (discussed later). Finally, ensure that the pharmacy is able to refill the prescription for the entire treatment course; beware of the one-time fill situation in which the insurance company requires a different pharmacy to provide the refills. This can disrupt the continuity of care if there is a delay in transferring the prescription or reauthorization is required.

Prior Authorization

Patients must have adequate funding to afford the medications and the required monitoring during treatment. Commercial and government health insurance generally covers at least part of this cost, although coverage and copays vary widely. The process of prior authorization differs among carriers and can be straightforward or painfully complex. At a minimum, it requires demographic information, recent laboratory results (including the viral load and genotype), clinical notes, and documentation that the patient does not have an absolute contraindication to therapy.

Co-Pays, Patient Assistance Programs (PAPs), and Independent Nonprofit Organizations (INOs)

Specialty pharmacies that assist with prior authorization generally communicate information about copays to patients before they dispense medications; otherwise, this falls to the provider. Copays may differ for each of the drugs and may vary from nothing to more than half of the cost. For patients unable to afford the copays, assistance is available, but it may not be sufficient to cover the difference. Unfortunately, those with Medicare, Medicaid, and other forms of government insurance (e.g., residents of Massachusetts) are excluded from these programs. These programs are listed in Table 1. Patients with commercial insurance who have large out-of-pocket expenses may be referred to a third-party copay assistance program. These INOs sometimes offer grants to patients, and these grants vary in amount and duration. Manufacturers and PAPs can refer patients to INOs but cannot influence or control INOs or guarantee copay assistance. It is important to understand the difference between the programs and the assistance that they offer. INOs are reviewed in Table 2.

Table 1. Industry-Sponsored PAPs
CompanyMedicationsProgram NameContactRequirements/Comments
  1. Patients are required to disclose their annual income (typically Internal Revenue Service form 1040) and the number of household members; each program has specific financial coverage and requires certification that patients are treatment-appropriate candidates. Patients also must be US residents without Medicare, Medicaid, or other federal government insurance coverage (e.g., Tricare or Champus). Patients residing in Massachusetts are excluded from participation.

GenentechPegasysPegasys Access Solutions4888-941-3331 http://www.genentechaccesssolutions.comThe company refers patients to INOs for copay assistance programs and assists with the application process.
CopegusGenentech Access to Care Foundation1 DNA Way, Mail Stop 858a, South San Francisco, CA 94080-4990 888-941-3331 888-941-3334 (fax)The company provides free medicine for up to 1 year to uninsured patients, patients denied by health care plans, and patients not covered by Medicare or Medicaid. The adjusted gross income must be <$100,000. Patients must meet medical criteria. The company does not cover the costs of monitoring or office visits.
KadmonRibasphere RibapakAspire51640 Century Center Parkway, Department 053, Memphis, TN 38134 888-668-3393 800-724-8036 (fax)Patients have no insurance and meet undisclosed program guidelines.
MerckPeg-Intron Rebetol VictrelisACT Program6833-363-6379 http://www.merck.com/merckhelps/act-program/home.htmlThe company provides free reimbursement support services related to insurance issues and refers patients to the PAP for free medication if they are eligible.
Peg-Intron VictrelisMerck Cares7http://www.merck-cares.com http://www.victrelis.comA copay assistance card covers up to $200 per fill for 12 fills. The encompassing site includes access to education, resources, and support for patients.
VertexIncivekGuidance and Patient Support8855-837-8394 http://www.incivek.com/vertex-guidance-patient-supportThere is no income requirement. The company covers 20% (up to $10,000) of any type of out-of-pocket expense
Table 2. INOs That May Provide Grants for Drug Support
INOContactComments
  1. INOs operate independently. Qualifications and awards are specific to INOs and are not influenced or controlled by manufacturers of specific HCV medications.

Patient Access Network Foundation9P.O. Box 221858, Charlotte, NC 28222-1858 866-316-7263 http://www.panfoundation.orgThere is an online application. Insurance is required. Income must be below the federal poverty level. Patients must reside and receive treatment in the United States.
Patient Advocate Foundation: Co-Pay Relief Program10421 Butler Farm Road, Hampton, VA 23666 866-512-3861 http://www.patientadvocate.orgThere is an online application. Direct financial support is provided to insured patients, including Medicare Part D beneficiaries who qualify. Patients are helped on a first-come, first-serve basis.
Chronic Disease Fund116900 North Dallas Parkway, Suite 200, Plano, TX 75024 877-968-7233 http://www.cdfund.orgThis program is for privately insured patients and Medicare Part D patients unable to afford medication. There are three programs (public, private foundation, and PAP). An online application is available. Only Pegasys and Peg-Intron are covered.

Getting Started

  1. Top of page
  2. Abstract
  3. Prescribing Information
  4. Getting Started
  5. Empowering the Patient to Ensure Successful Therapy
  6. References

Patient Education

Patient education is essential to the success of therapy. Structured one-on-one or group sessions work best and should be conducted immediately before therapy is begun. The key points of this discussion are listed in Table 3. Because this education is extensive, it should be considered a billable event, and a bill for appropriate reimbursement should be submitted to the insurance company (Current Procedural Terminology code 99215). Patients must be instructed not to start oral therapy before pegylated interferon is initiated because of the risk of drug resistance.

Table 3. Pretreatment Patient Education
Talking PointSpecificsKey Points
DiseaseSimple explanation of HCVThe virus is like other viruses but lives in and can damage the liver.
The virus level does not influence disease severity.
The virus level is important only for the treatment response.
The virus can be eradicated; this is the goal of treatment.
Liver diseaseThe course is usually slow (over decades), but it is different in everyone.
Inflammation leads to scar tissue.
Scarring may lead to cirrhosis.
Cirrhosis can lead to complications.
The goal is to avoid cirrhosis.
Treatment backgroundPegylated interferonThe drug stimulates the body's defense system against viruses.
Review potential side effects.
RibavirinUnknown mechanism.
Review potential side effects.
Direct-acting antivirals for genotype 1They interfere with the virus machinery.
Review potential side effects.
They do not work without the other drugs!
Goal of treatmentDefinition of endpointsPermanent eradication of the virus (viral cure).
This does not negate the need for subsequent follow-up of liver disease.
Drug-drug interactionsPatient's medicationsAbsolutely contraindicated drugs.
Relatively contraindicated drugs
Need for dose adjustments or changes in medications.
Notify the provider of any new medications before starting them.
ContraceptionPotential teratogenicityPotential for reduced effect of oral contraception.
Alternatives: spermicide/condoms, intrauterine device, and diaphragm.
Adherence to therapyAdherence is critical.Take medications on time (every 8 hours and not just 3 times daily).
Do not change doses or hold doses without instructions.
Do not interrupt any medication (P/R/DDA).
Treatment initiationOrder of dosesPegylated interferon is always first.
Start ribavirin and telaprevir after the interferon dose.
Pegylated interferon/ribavirin lead-in with boceprevir.
Therapy monitoringWeekly and monthly labsIt is important to identify drug toxicity and treatment responses.
Missing a week 4 viral load prohibits truncation of therapy.
Side-effect managementAnemiaRibavirin dose reduction, erythropoiesis stimulating agents, and blood transfusions
RashTopical antihistamines or topical steroids. Dermatology consult.
Stop for severe rash (vesicle or bullae), drug reaction with eosinophilia and systemic symptoms, or Stevens-Johnson syndrome.
Consider a dermatology consult if the rash is severe.
Anorectal eventsOver-the-counter hemorrhoidal preparations.
3% topical lidocaine.
There may be improvement with an increased amount of fat in the diet.
Provider's ability to manage these eventsWho to call on weekends and evenings.

Drug-Drug Interactions

Drug-drug interaction can influence the safety, tolerance, and effectiveness of therapy. This is discussed in detail in another article in this journal. The patient's medication list should be reviewed at each visit, and the patient should be instructed to check with you before any new medications, including over-the-counter and herbal preparations, are started.

On-Treatment Monitoring

Laboratory testing must follow a predefined schedule in order to appropriately modify the treatment duration, address adverse events, and discontinue treatment when it becomes futile. Viral load evaluation time points are critical in determining eligibility for truncating therapy, and the results are sometimes required by the patient's insurer to continue therapy.

Because therapy is guided by viral levels, your laboratory should use a sensitive test (lower limit of detection = 10-15 IU/mL) and should provide results within a week. Thus, you may need to do some investigation to find out which assays are available from each laboratory and what their turn-around times will be. Although most tests (not all) currently available through reference laboratories are sensitive to this level, they are not all able to quantitate viral levels to this lower limit of detection. This is fine as long as one recognizes that “below the limit of quantification” does not mean that the virus is undetectable. The same assay should be used on each occasion, and this typically requires requesting the test by its specific laboratory code rather than simply requesting “HCV RNA, quantitative.” Assays and their accession numbers with the common reference labs are shown in Table 4.

Table 4. Quantitative HCV RNA Assays and Accession Numbers at the More Common Reference Laboratories
CompanyContactCodeDescriptionQuantificationLower Limit of DetectionTurn-Around TimeComments
  1. Bolded entries are ideal or preferred tests. Some laboratories or specific tests may be unavailable in certain regions. Be aware that methodologies may change without notice. Check your local laboratories for testing availability and testing specifics.

  2. Abbreviation: PCR, polymerase chain reaction.

Clinical Pathology Laboratories12800-633-47574563HCV RNA, PCR, qualitative/quantitative<43-69,000,000 IU/mL10-25 IU/mLUp to 3 days, Monday-FridayMethodology not stated
4571HCV RNA, PCR, quantitative< 43-69,000,000 IU/mL 24-48 hours, Monday-Friday 
LabCorp13http://www.labcorp.com550146HCV, qualitative, RNA PCR with reflex to quantitative43-69,000,000 IU/mL10-25 IU/mLUp to 5 daysPCR amplification and DNA probe with real-time PCR, quantitative
550080HCV, quantitative, real-time PCR25-69,000,000 IU/mL7.1 IU/mLUp to 6 days (typically <3 days)TaqMan real-time PCR
550070HCV, quantitative, real-time PCR (graphical)25-69,000,000 IU/mL7.1 IU/mLUp to 6 daysSame as 550080 but with graphics
140639HCV, quantitative, PCR (NGI Quantasure)2-2,000,000 IU/mL2 IU/mLUp to 16 daysPCR amplification
Quest14800-824-615210636HCV RNA, quantitative, branched DNA, TMA5-7,700,000 IU/mL5 IU/mL5 daysBranched DNA or TMA
34024HCV RNA, qualitative, PCRNot available50 IU/mL PCR for genotype 1a or 1b, false positive with heparin
10073HCV RNA, quantitative, TMA5-7500 IU/mL5 IU/mL7 daysNot an appropriate test for a baseline or for establishing early virological response
35645HCV RNA, quantitative, real-time PCR43-69,000,000 IU/mL10-25 IU/mLUp to 3 days, Tuesday-SaturdayReal-time PCR with COBAS AmpliPrep/COBAS TaqMan
10565HCV RNA (Heptimax)5-69,000,000 IU/mL5 IU/mLUp to 14 daysToo slow turn-around

Because the monitoring points, stopping rules, and treatment durations are complicated and differ with the drug being used and the patient's previous response, we find it helpful to use flow sheets that identify these critical time points and remind us about what action is indicated. These have proven to be invaluable for monitoring viral responses, cytopenia, and dose modifications.

Side-Effect Management

Side effects are discussed in detail in another article in this journal. The patient should recognize and report side effects as soon as possible so that early intervention can minimize their severity. Although most side effects develop gradually, anemia can sometimes develop rapidly and can be a challenge to manage. We find it helpful to measure the hemoglobin level more frequently, perhaps even weekly, if the patient is elderly or has renal dysfunction, preexisting anemia, or a history of anemia with a previous course of therapy. Ribavirin dose reduction is the first step and can often circumvent the need for growth factors, transfusions, or dose interruptions. Erythropoietin should be considered if the hemoglobin level falls quickly (erythropoietin is not Food and Drug Administration–approved for this indication).

Empowering the Patient to Ensure Successful Therapy

  1. Top of page
  2. Abstract
  3. Prescribing Information
  4. Getting Started
  5. Empowering the Patient to Ensure Successful Therapy
  6. References

Finally, we find that enlisting the patient in the care team helps the patient to take a more active role in maintaining adherence to dosing and the monitoring schedule. This should start during pretreatment education and should be reinforced by including the patient in reviews of laboratory results (particularly viral levels) and by emphasizing the key points of the educational outline during clinic visits during treatment.

References

  1. Top of page
  2. Abstract
  3. Prescribing Information
  4. Getting Started
  5. Empowering the Patient to Ensure Successful Therapy
  6. References