PHARMACOLOGY UPDATE
Ledipasvir and Sofosbuvir Tablets (Harvoni ® )
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
The first fixed-dose combination drug product has been approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. The combination contains a previously approved HCV nucleotide analog NS5B polymerase inhibitor, sofosbuvir (SOF), and a NS5A inhibitor, ledipasvir (LDV). This represents the first treatment option for HCV genotype 1 that does not require ribavirin or interferon. The combination is marketed by Gilead as Harvoni.
INDICATION
LDV/SOF is indicated for the treatment of chronic HCV genotype 1 infection in adults.1
DOSAGE
The recommended dose is one tablet taken once daily without regard to meals.1 The duration of treatment is 12 weeks for treatment-naïve patients with or without cirrhosis and treatment-experienced patients without cirrhosis. In treatment-experienced patients with cirrhosis, treatment duration is 24 weeks.
Each tablet contains 400 mg of sofosbuvir and 90 mg of ledipasvir.
POTENTIAL ADVANTAGES
The fixed-combination has resulted in viral response of 94% or higher in a wide variety of hepatitis C genotype 1 patients. This combination does not require ribavirin or interferon — two drugs with significant side effects in many patients.
POTENTIAL DISADVANTAGES
LDV/SOF should not be used with P-gp inducers (e.g., rifampin, St. John’s wort).1 The most common adverse events were fatigue and headache.1
COMMENTS
LDV/SOF provides a potent fixed-combination for HCV genotype 1 virus. LDV is active against S282T mutation associated with SOF resistance in NS5B and mutations leading to LDV resistance were susceptible to SOF.1 LDV/SOF has been evaluated in three Phase 3 trials in adult subjects with chronic HCV genotype 1 with compensated liver disease.1,2,3,4 The primary efficacy endpoint was sustained viral response 12 weeks (SVR12) after the end of treatment. One study was conducted in treatment-naïve subjects without cirrhosis (n = 647), a second was conducted in treatment-naïve subjects (n = 865) with or without cirrhosis, and a third in treatment-experienced subjects with or without cirrhosis who failed prior therapy (n = 440). In the first study, subjects were randomized to LDV/SOF × 8 weeks, LDV/SOF and ribavirin × 8 weeks, or LDV/SOF × 12 weeks. SVR12 rates were 94%, 93%, and 95%, respectively. Relapse rates were numerically higher with 8 weeks of treatment compared to 12 weeks, 5%, 4%, and 1%, respectively. The second study evaluated LDV/SOF with or without ribavirin for 12 or 24 weeks in treatment-naïve subjects with or without cirrhosis (n = 865). In this study, subjects were randomized to LDV/SOF × 12 weeks, LDV/SOF plus ribavirin × 12 weeks, and the same two combinations for 24 weeks. SVR12 rates were 99%, 97%, 98%, and 99%, respectively. SVR12 was 94-100% in those with cirrhosis, 97-99% for genotype 1a, and 91-100% in black subjects. The third study included subjects who did not achieve SVR with peginterferon, ribavirin, and with or without a protease inhibitor. These subjects were randomized to the same four regimens as in study 2. SVR12 rates were 94%, 96%, 99%, and 99%, respectively. For those with cirrhosis, SVR rates were 86%, 82%, 95%, and 100%, respectively. A large percentage of subjects with generally poor treatment prognosis (e.g., non-CC-IL28B, prior nonresponder to interferon-based therapy, and previously treated with a protease inhibitor) responded in the 92-100% range.4
CLINICAL IMPLICATION
Ledipasvir and sofosbuvir provides a fixed-combination with two different mechanisms of action and has achieved very high rates of viral clearance in patients with genotype 1 without the use of ribavirin and interferon. It offers an important advancement in the treatment of this chronic disease. The wholesale cost is $31,500 for a 28-day supply or $94,500 for 12 weeks of therapy.
REFERENCES
- Harvoni Prescribing Information. Foster City, CA: Gilead Sciences; October 2014.
- Kowdley KV, et al. N Engl J Med 2014;370:1879-1888.
- Afdhal N, et al. N Engl J Med 2014;370:1889-1898.
- Afdhal N, et al. N Engl J Med 2014;370:1483-1493.
