By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente, and Assistant 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 the first drug for the treatment of hepatitis C (HCV) genotype 3 infection that does not require the co-administration of interferon or ribavirin. Daclatasvir is a nonstructural 5A (NS5A) protein inhibitor that is marketed by Bristol-Myers Squibb as Daklinza.
Daclatasvir is indicated for use in combination with sofosbuvir for the treatment of chronic HCV genotype 3 infection.1
The recommended dose is 60 mg once daily in combination with sofosbuvir (400 mg) with or without food.1 The duration of treatment is 12 weeks. Daclatasvir is available as 30 mg and 60 mg tablets.
Daclatasvir plus sofosbuvir is the first interferon and ribavirin-free regimen for the treatment of HCV genotype 3.
Daclatasvir is a substrate of CYP3A isoenzymes, and the plasma levels/therapeutic effect may be affected by strong CYP3A inhibitors, as well as moderate and strong inducers.1 Strong inducers are contraindicated. Serious symptomatic bradycardia has been reported with the concomitant administration of sofosbuvir and amiodarone.1
The safety and efficacy of daclatasvir were evaluated in one Phase 3, open-label, 12-week clinical trial involving 152 subjects with compensated liver disease.1,2 The majority of these were treatment-naïve (n = 101) and the remainder were treatment-experienced (n = 51). Most treatment-experienced subjects failed with prior peginterferon/ribavirin regimens and a few were treated with sofosbuvir and ribavirin. Those with previous exposure to NS5A inhibitors were excluded. Subjects were mainly males (59%), white (90%), and many (76%) had a viral load ≥ 800,000 IU/mL. One-quarter of subjects had cirrhosis. Subjects received daclatasvir/sofosbuvir (60 mg/400 mg) for 12 weeks. Sustained viral response was defined as HCV RNA below 25 IU/mL (SVR12). Overall, treatment response was 89% (96% of those without cirrhosis and 63% in those with cirrhosis). Response in treatment-naïve subjects was numerically slightly higher, 90% vs 86%. Of the subjects without SVR12, 94% were the result of post-treatment relapse.”3 Sixty-nine percent of these subject had cirrhosis at baseline. Other potential factors contributing to relapse were very high baseline viral load and NS5A-Y93H RAV mutation. Most frequently reported adverse events were headache (14%), fatigue (14%), and nausea (12%).
Genotype 3 is a less common HCV genotype in the United States but is the most difficult genotype to treat with available direct acting agents.3 Current treatment is sofosbuvir with weight-based ribavirin plus weekly peginterferon for 12 weeks. For patients in whom interferon is not an option, previously available treatment was sofosbuvir and weight-based ribavirin for 24 weeks. Daclatasvir, when used in combination with sofosbuvir, provides an effective treatment for HCV genotype 3 infections, particularly in noncirrhotic patients. The drug is significantly less effective in patients with cirrhosis. An open-label, randomized study of daclatasvir, sofosbuvir, and ribavirin for 12 vs 16 weeks in treatment-naïve and treatment-experienced patients with genotype 3 subjects with compensated advanced fibrosis/cirrhosis (F3/F4) is scheduled for completion in December 2015.4 The cost for the combination is $49,000 for 4 weeks.
- Daklinza Prescribing Information. Bristol-Myers Squibb. July 2015.
- Nelson DR, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015;61:1127-1135.
- AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology 2015;62:932-954.
- Safety and efficacy study of daclatasvir 60mg, sofosbuvir 400mg, and ribavirin (dosed based upon weight) in subjects with chronic genotype 3 hepatitis C infection with or without prior treatment experience and compensated advanced cirrhosis for 12 or 16 weeks. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02319031?term=daclatasvir&rank=30. Accessed Oct. 23, 2015.