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Home , Elbasvir, Grazoprevir

STEPS New Drug Reviews

Elbasvir/ (Zepatier) for Virus Infection JESSICA EARLY, MD, and GEORGE MAXTED, MD, Tufts University School of Medicine, Malden, Massachusetts

STEPS new drug reviews /grazoprevir (Zepatier) is a fixed-dose combination of a (HCV) cover Safety, Tolerability, NS5A inhibitor and HCV NS3/4A protease inhibitor. It is labeled for the treatment of chronic Effectiveness, Price, and Simplicity. Each indepen- HCV genotype 1 or 4 infection in treatment-naive or treatment-experienced adults with or dent review is provided without compensated cirrhosis. It is also labeled for use in patients coinfected with human by authors who have no immunodeficiency virus 1 (HIV-1). financial association with the drug manufacturer. This series is coordinated Drug Dosage Dose form Cost* by Allen F. Shaughnessy, PharmD, MMedEd, Con- Elbasvir/grazoprevir One tablet per day for 50-mg/100-mg tablets $60,000 for a 12-week tributing Editor. (Zepatier) 12 or 16 weeks, with course and $80,000 for or without † a 16-week course A collection of STEPS pub- lished in AFP is available *—Estimated retail price of treatment based on information obtained at http://www.goodrx.com (accessed Decem- at http://www.aafp.org/ ber 23, 2016). afp/steps. †—The duration of treatment and the need for adding ribavirin depend on previous treatment and the presence of polymorphisms; product labeling should be consulted for current recommendations.

SAFETY and some protease-inhibitor HIV medica- Clinically significant reactions are rare with tions will significantly raise plasma concen- elbasvir/grazoprevir treatment. In studies of trations of grazoprevir, increasing the risk approximately 1,700 patients, 1% of patients of liver damage. Use of elbasvir/grazoprevir had an alanine aminotransferase level greater has not been studied in pregnancy, and it than five times the upper limit of normal.1 should not be used by pregnant women. It Increases in alanine aminotransferase levels is unknown whether elbasvir/grazoprevir is were usually asymptomatic and occurred at excreted in breast milk.1 or after two months of treatment. Most cases resolved during or at completion of therapy. TOLERABILITY Elbasvir/grazoprevir should not be used in Elbasvir/grazoprevir is generally well tol- patients with moderate to severe hepatic erated. The most common adverse effects impairment (Child-Pugh score of B or C). are headache (17%), fatigue (16%), and No dosage adjustments are necessary for nausea (9%).2 In clinical trials, less than patients with any level of renal impairment, 1% of patients discontinued the medication including those on hemodialysis. because of adverse effects.1-3 Elbasvir/grazoprevir is metabolized in the liver via the cytochrome P450 3A enzyme EFFECTIVENESS system and can be affected by the many Two placebo-controlled studies of 656 total medications that induce or inhibit this sys- patients showed that elbasvir/grazoprevir pro- tem. (Tegretol), duces a response rate (i.e., sustained virologic (Sustiva), phenytoin (Dilantin), rifampin, response four months after treatment) in and St. John’s wort will dramatically decrease 95% to 99% of patients.2,3 Treatment-naive plasma concentrations of both elbasvir and patients with HCV genotype 1a have a slightly grazoprevir. Cyclosporine (Sandimmune) lower response rate (92%). Response rates are

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higher in treatment-naive patients with geno- treatment should be considered if alanine type 1b (99%) or genotype 4 (100%), although aminotransferase levels are persistently above the study size was smaller in the latter group.2 10 times the upper limit of normal. Viral load Response rates are lowest (70%) in patients should be checked 12 weeks after cessation of with NS5A resistance–associated polymor- treatment to confirm response. phisms of genotype 1a, which are present in about 12% of patients in the United States. Bottom Line Patients with this characteristic should also Elbasvir/grazoprevir is a safe and effective be treated with ribavirin, which increases the treatment for HCV genotypes 1 and 4, with response rate to 100%.1 There are no effective- or without compensated cirrhosis or HIV-1 ness studies comparing elbasvir/grazoprevir coinfection. Patients with renal impairment, with other new long-term HCV medications. including those on hemodialysis, can use the medication. Treatment regimens vary based PRICE on whether the patient has had previous Elbasvir/grazoprevir costs approximately treatment and the presence of NS5A resis- $60,000 for a 12-week course and $80,000 for tance–associated polymorphisms. Physicians a 16-week course. Comparatively, a 12-week should be aware of possible drug interactions course of / (Epclusa) before adding or changing medications in a costs approximately $73,000, and an eight- patient taking elbasvir/grazoprevir. week course of /sofosbuvir (Har- Address correspondence to Jessica Early, MD, at jearly@ voni) costs approximately $65,000. challiance.org. Reprints are not available from the authors. SIMPLICITY Author disclosure: No relevant financial affiliations. Elbasvir/grazoprevir, 50 mg/100 mg, is taken orally once per day with or without food for REFERENCES 12 or 16 weeks. Patients with HCV genotype 1a should be tested for the presence of NS5A 1. DailyMed. Label:​ Zepatier—elbasvir and grazopre- vir tablet, film coated [prescribing information]. resistance–associated polymorphisms before https:​//dailymed.nlm.nih.gov/dailymed/drug​Info. initiation of treatment. Potential drug inter- cfm?setid=164dc​02a-9180-426a-b8b5-04ab​39d2​ actions with existing treatments should also bbd4. Accessed July 21, 2016. 2. Zeuzum S, Ghalib R, Reddy KR, et al. Grazoprevir- be assessed before beginning therapy. The elbasvir combination therapy for treatment-naive cir- duration of treatment and the need for add- rhotic and noncirrhotic patients with chronic hepatitis C ing ribavirin depend on previous treatment virus genotype 1, 4, or 6 infection: ​a randomized trial. and the presence of polymorphisms, and the Ann Intern Med. 2015;​163(1):​1-13. 3. Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus product labeling should be consulted for cur- elbasvir in treatment-naive and treatment-experienced rent recommendations. Serum hepatic func- patients with hepatitis C virus genotype 1 infection and tion should be tested before starting therapy stage 4-5 chronic kidney disease (the C-SU R FER study):​ a combination phase 3 study [published correction and at week 8 of a 12-week treatment or at appears in Lancet. 2015;​386(10006):​1824]. Lancet. week 12 of a 16-week treatment. Stopping 2015;386(10003):​ ​1537-1545. ■

394 American Family Physician www.aafp.org/afp Volume 95, Number 6 ◆ March 15, 2017