Friday, November 9, 2012

Triple Therapy for Hepatitis C: High Cure Rate, Greater Risks

Triple Therapy for Hepatitis C: High Cure Rate, Greater Risks

  • Categorized in: Department of Veterans Affairs (VA),
  • Hepatitis, Infectious Disease, October 2012

    Annette M. Boyle
    LOS ANGELES — The approval last year of the first new drugs for treatment of hepatitis C (HCV) in 20 years substantially increased the rate of virologic cure for patients with the most common form of the disease. At the same time, the complex regime of medications has made adherence more difficult, increased the likelihood of development of treatment-resistant strains of HCV and made the role of the pharmacist in HCV management more important than ever.

    Pamela S. Belperio, PharmD, BCPS, AAHIVE, National Public Health Clinical Pharmacist, VA Greater Los Angeles Healthcare System
    The new drugs, boceprevir and telaprevir, are the first commercially available HCV direct-acting antiviral agents. Both drugs are HCV NS3/4A protease inhibitors (PIs) that target viral replication and are Food and Drug Administration (FDA) approved for the treatment of adults with chronic HCV infection caused by genotype 1 viruses. Genotype 1 accounts for 70% to 90% of the cases of HCV in the United States.

    Genotype 1 HCV has been the least responsive to the traditional dual therapy of weekly injections of pegylated interferon and daily oral ribavinin. According to the FDA, less than 45% of HCV patients with genotype 1 achieve sustained virologic response (SVR) or cure as indicated by undetectable plasma HCV levels six months after cessation of dual therapy. More than 70% of genotypes 2 and 3 achieve SVR with the pegylated interferon/ribavinin combination.

    The new three-drug regimen adds either boceprevir or telaprevir to pegylated interferon and ribavinin. Neither of the new drugs can be used on its own to treat HCV.

    “New hopes for a cure have been made possible with the addition of these new treatments. Patients who have never received HCV treatment may have up to a 25 to 30% better chance of achieving a SVR with the new triple therapy compared to traditional treatment with pegylated interferon and ribavirin alone,” said Pamela S. Belperio PharmD, BCPS, AAHIVE, National Public Health Clinical Pharmacist, VA Greater Los Angeles Healthcare System.

    Patients who had been treated in the past but relapsed or had insufficient response may have up to a 60% chance of responding to the new treatment combination, Belperio told U.S. Medicine.

    The complex triple therapy regimen requires patients to take 12 to 18 pills a day in three doses at seven- to nine-hour intervals. In addition, the pills must be taken with specific foods and often produce troublesome adverse effects such as taste changes, tiredness, rash, anemia and low energy — all factors that Belperio notes are associated with high rates of non-adherence. Patients who do not strictly follow the treatment protocol are unlikely to achieve SVR in the current course and may also limit future treatment options.

    “BOC and TVR carry the risk of inducing HCV resistant mutations, and it is likely that cross-resistance to future generations of PIs will develop in some patients who do not achieve SVR,” noted the authors of the new VA guidelines for management and treatment of HCV, published in the American Journal of Gastroenterology this spring. “Extensive patient monitoring for virologic response and counseling on adherence will be necessary to minimize the development of resistant variants.”

    This need for close monitoring makes the role of pharmacists critical to HCV management in the VA.

    “The VA recognizes that pharmacists are ideal for managing patients on HCV treatment. Hepatitis C-related patient education, testing, adherence counseling, management of comorbidities affecting HCV treatment (such as diabetes and smoking cessation), medication dose adjustments, drug-interaction and side-effect management are all roles that VA pharmacists are performing to help manage hepatitis C infected patients in VA,” Belperio said.

    In recognition of that role, the VA conducted several intensive four-hour regional “boot-camp” trainings on HCV in 2011. As a result, the number of VA pharmacists with a scope of practice to manage HCV rose 30%.

    The triple therapy requires heightened attention to potential drug-drug interactions and awareness of existing treatments that may contraindicate use of the therapy. “Both boceprevir and telaprevir are substrates and inhibitors of the hepatic enzyme, cytochrome P450 3A, and the drug transporter, P-glycoprotein, which predisposes these agents to many drug interactions,” Belperio said. “Patients may be at risk for increased toxicity or side effects from some common medications once boceprevir or telaprevir is added, such as those used for cholesterol, heart disease or blood pressure and some steroids.”

    Pharmacists may recommend therapeutic substitutions such as replacing simvastatin with pravastatin in these instances.

    In some instances, drug interactions may reduce the effectiveness of boceprevir or telaprevir, and compromise the chance of achieving a SVR. Boceprevir or telaprevir may render medications such as birth control pills and antidepressants less effective. Because ribivirin is potentially teratogenic, pregnant patients and their partners should not use the triple therapy. Patients and their partners also should use two non-hormonal methods of contraception throughout the course of treatment and for six months afterward, because of the dangers of pregnancy, according to the guidelines. Triple therapy also is not recommended for patients with HIV.

    “These drugs also should not be used in patients on certain medications that are contraindicated because they are highly dependent on the Cytochrome 450 3A enzyme system for clearance from the body,” said Belperio. They should also not be used in any situation where the patient cannot take either pegylated interferon or ribavirin. Because boceprevir and telaprevir must be taken at the full dose to be effective, patients who are unable to tolerate the side effects or do not respond should be taken off the treatment entirely.

    By alerting patients upfront that almost everyone receiving HCV antiviral therapy will experience some adverse effects, and, by counseling patients on ways to minimize or manage those effects, pharmacists can significantly improve adherence and SVR rates. In addition, Belperio notes that engaging patients in their treatment has also been shown to be beneficial.

    The VA recently released patient-treatment booklets specific to boceprevir and teleprevir that explain the treatments themselves, how to take the medications, adverse effects, required monitoring, clinic visits and worksheets to track their progress.

    “These targeted, patient-specific materials, along with other adherence aids, such as pill boxes, mobile alarms and timers, can help remind patients to take their medications on time,” while helping patients track their viral load and course of treatment, Belperio said.

    Taking your Hepatitis C Triple Therapy

    Back to October Articles

    [1] Center for Drug Evaluation and Research. Guidance for Industry Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment. Food and Drug Administration. September 2010.
    Download PDF

    [1] Yee HS, Chang MF, Pocha C, Lim J, Ross D, Morgan TR, Monto A. Update on the Management and Treatment of Hepatitis C Virus Infection: Recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol. Published online April 24, 2012.

    An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases

     VA guidelines for management and treatment of HCV, published in the American Journal of Gastroenterology

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