By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved another oral interferon-free regimen for the treatment of chronic hepatitis C (HCV) genotypes 1 and 4. This fixed combination of two direct-acting antiviral agents contains an inhibitor of HCV NS5A, elbasvir (EBR) and an inhibitor of HCV NS3/4A protease, grazoprevir (GZR). EBR/GZR was granted breakthrough therapy designation and is marketed as Zepatier.
INDICATIONS
EBR/GZR is indicated with or without ribavirin for treatment of chronic HCV genotypes 1 or 4 infections in adults.1
DOSAGE
The recommended dose is one tablet once daily with or without food.1 The duration of treatment is 12 weeks for those with genotype 1a (without NS5A polymorphism) or genotype 1b in patients who are treatment-naïve (TN) or peginterferon/ribavirin-experienced, and treatment-naïve genotype 4 infections. For genotype 1a and 1b patients who are peginterferon/RBV- and protease inhibitor-experienced (TE), treatment duration is 12 weeks with the addition of ribavirin. For genotype 1a positive for NS5A polymorphism, or peginterferon/RBV treatment-experienced genotype 4, treatment duration is 16 weeks with ribavirin. Dose is the same with or without cirrhosis or any degree of renal impairment. EBR/GZR is available as tablets, each containing elbasvir (50 mg) and grazoprevir (100 mg).
POTENTIAL ADVANTAGES
EBR/GZR provides another option for the treatment of chronic HCV genotypes 1 and 4. The drug may be used in patients with renal impairment, including those with end-stage renal disease on dialysis.1 It also may be used in cirrhotic patients at the same dose as non-cirrhotic patients.
POTENTIAL DISADVANTAGES
EBR/GZR is less effective in HCV genotype 1a with baseline NS5A polymorphisms at amino acid positions 18, 30, 31, or 93.1 The estimated prevalence is 12%.2 EBR/GZR is contraindicated in patients with moderate or severe hepatic impairment. EBR is a substrate of OATP1B1/3, and both EBR/GZR are substrates of CYP3A4. Co-administration with an OATP1B1/3 inhibitor or strong inducers of CYP3A and efavirenz are contraindicated. There is higher systemic exposure of EBR and GZR in females and Asians. These populations experienced a higher rate of late ALT elevations in clinical trials.
COMMENTS
EBR/GZR is a combination of two direct-acting antiviral agents with different mechanisms of action and non-overlapping resistance profiles.1 Its efficacy was shown in two placebo-controlled trials and four uncontrolled trials.1 These included TN and TE subjects with genotypes 1 and 4, with and without cirrhosis or co-infected with HIV-1.1 The efficacy endpoint is sustained viral response 12 weeks after cessation of treatment (SVR12). Overall, SVR12 was 95% with or without HIV-1 co-infection. SVR12 was slightly higher numerically in genotype 1b, 98% vs 92% and 96% vs 94%, respectively. The sustained viral responses for cirrhotic vs non-cirrhotics were 97% vs 94% and 100% vs 94%, respectively. In TE subjects who failed prior peginterferon with RBV, with or without cirrhosis, SVR12 was 94% as monotherapy (12 weeks) and 97% for combination with ribavirin (16 weeks). Rates were similar in both cirrhotic and non-cirrhotic subjects. The overall SVR12 was 94% for subjects with severe renal impairment. In TE subjects who failed peginterferon/RBV and protease inhibitor, overall SVR12 was 96%. In subjects with genotype 4, SVR12 ranged from 97-100%. Adverse events include fatigue, headaches, nausea, elevation of ALT, and serum bilirubin.1
CLINICAL IMPLICATIONS
EBR/GZR provides another option for the treatment of HCV genotypes 1 and 4. It provides single tablet, interferon/RBV-free regimen for treatment-naïve or peginterferon/RBV-experienced genotype 1a (without baseline NS5A polymorphism), genotype 1b and treatment-naïve genotype 4. It also offers a new treatment option for patients with chronic kidney disease and a shorter treatment duration (12-16 vs 24 weeks) for some TE patients with cirrhosis. The current American Association for the Study of Liver Diseases/Infectious Diseases Society of America guideline for interferon/RBV-free option is ledipasvir/sofosbuvir.3 EBR/GZR offers a significant cost advantage: $18,200 for a 28-day supply compared to $31,500 for ledipasvir/sofosbuvir.
REFERENCES
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Zepatier Prescribing Information. Merck & Co., Inc. January 2016.
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Asselah T, et al. Direct-acting antivirals for the treatment of hepatitis C virus infection: Optimizing current IFN-free treatment and future perspectives. Liver Int 2016;36(Suppl S1):47-57.
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The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: http://www.hcvguidelines.org. Accessed Feb. 10, 2016.
