Class and Mechanism: Ledipasvir is a potent inhibitor of HCV NS5A, a viral phosphoprotein that plays an important role in viral replication, assembly, and secretion. Sofosbuvir is a nucleotide analog inhibitor of hepatitis C virus NS5B polymerase—the key enzyme mediating HCV RNA replication. The triphosphate form of sofosbuvir (GS-461203) mimics the natural cellular uridine nucleotide and is incorporated by the HCV RNA polymerase into the elongating RNA primer strand, resulting in chain termination.
Manufacturer for United States: The fixed-dose combination of ledipasvir and sofosbuvir (Harvoni) (Figure 1) is manufactured by Gilead Sciences.
FDA Status: On October 10, 2014, the fixed-dose combination ledipasvir-sofosbuvir (Harvoni) was approved by the FDA for the treatment of chronic hepatitis C genotype 1 infection in adults. On November 12, 2015 the FDA expanded the approval of ledipasvir-sofosbuvir to include (a) treatment of chronic hepatitis C genotypes 4, 5, and 6 and (b) patients coinfected with HIV.
Indications: The fixed dose combination ledipasvir-sofosbuvir (90 mg/400 mg) is FDA-approved for the treatment of chronic hepatitis C genotype 1 in both treatment-naive and treatment-experienced patients. The treatment duration depends on prior treatment experience and the presence or absence of cirrhosis. Treatment experience is defined as patients who have failed treatment with either peginterferon plus ribavirin or peginterferon plus ribavirin plus a HCV protease inhibitor.
Genotype 1 treatment-naïve patients with or without cirrhosis: 12 weeks
Genotype 1 treatment-experienced patients without cirrhosis: 12 weeks
Genotype 1 treatment-experienced patients with cirrhosis: 24 weeks
Treatment experience is defined as patients who have failed treatment with either peginterferon plus ribavirin or peginterferon plus ribavirin plus a HCV protease inhibitor.
Note: a treatment duration of 8 weeks can be considered in treatment-naive patients without cirrhosis who have a baseline HCV RNA level less than 6 million IU/mL.
Dosing: Ledipasvir-sofosbuvir (90 mg/400 mg) is a fixed-dose combination tablet (Figure 2). The recommended dosage is one tablet once daily, with or without food.
For patients with mild to moderate renal impairment, no dosage adjustment of ledipasvir-sofosbuvir is recommended. There are insufficient data regarding the safety and efficacy of ledipasvir-sofosbuvir in patients with severe renal impairment (eGFR less than 30 ml/min/1.73m2) or end-stage renal disease requiring dialysis. Thus, no dosage recommendation has been given for patients with severe renal impairment or end-stage renal disease requiring dialysis.
For patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C), no dosage adjustment is recommended, but the safety and efficacy of ledipasvir/sofosbuvir in patients with decompensated cirrhosis has not been established.
Clinical Use: The combination of ledipasvir-sofosbuvir has primarily been studied as an all-oral (interferon-free) combination regimen in treatment-naive and treatment-experienced patients with genotype 1 chronic HCV infection. Phase 3 studies (ION-1, ION-2, and ION-3) have consistently shown SVR12 rates greater than 90% with a 12-week course of ledipasvir-sofosbuvir in patients with genotype 1 chronic HCV. For treatment-experienced patients with cirrhosis, the SVR12 rates were significantly better with 24 weeks of therapy than with 12 weeks. A subanalysis of the ION-3 trial showed that treatment-naive patients without cirrhosis had excellent SVR12 rates with only 8 weeks of ledipasvir-sofosbuvir if their pre-treatment HCV RNA level was less than 6 million IU/mL. For the treatment of patients with genotype 1 infection, the addition of ribavirin to ledipasvir-sofosbuvir did not provide significant benefit. The approved clinical use for ledipasvir-sofosbuvir is only for genotype 1 chronic HCV-infected adults. Ledipasvir-sofosbuvir does not have a specific indication for HIV-infected persons.
Cost and Medication Access: The wholesale acquisition cost (WAC) for ledipasvir-sofosbuvir is $1125 per pill.
Cost of 8-week course of therapy = $63,000
Cost of 12-week course of therapy = $94,500
Cost of 24-week course of therapy = $189,000
Gilead Sciences has an active ledipasvir-sofosbuvir patient assistance program for eligible patients with hepatitis C who do not have insurance and do not have coverage through Medicaid or Medicare. Information regarding the Gilead Sciences ledipasvir-sofosbuvir (Harvoni) patient assistance program can be obtained at the Support Path for Solvaldiand Harvoni web site and by contacting them directly by phone at 1-855-769-7284 (hours of operation Monday through Friday between 9:00 am and 8:00 pm Eastern Time).
Adverse Effects: Available data from clinical trials has demonstrated the combination of ledipasvir-sofosbuvir has been very well tolerated. The most common reported adverse effects are fatigue and headache.
Major Drug Interactions: Ledipasvir-sofosbuvir has significant drug-drug interactions with P-gp inducers (e.g., St. John's wort and rifampin). The concomitant use of ledipasvir-sofosbuvir with P-gp inducers is not recommended. Additional drug-drug interactions may occur with ledipasvir-sofosbuvir and other medications and these are detailed in the Ledipasvir-sofosbuvir (Harvoni) Full
Resistance: In vitro, ledipasvir can select for the primary NS5A mutations Q30E and Y93H with genotype 1a and Y93H with genotype 1b; these mutations confer high-level reduced susceptibility to ledipasvir. In phase 3 trials, the most common mutations detected at failure for genotype 1a were Q30R, Y93H or N, and L31M; with genotype 1b, the most common mutation was Y93H. In vitro, the substitution S282T is associated with a 2- to 18-fold reduced susceptibility to sofosbuvir. The S282T mutation was not detected in any of the ledipasvir-sofosbuvir phase 3 trials. Ledipasvir has excellent in vitro activity against the NS5B S282T mutants. Similarly, sofosbuvir retains full activity against the NS5A ledipasvir-associated mutations.
Summary: The fixed dose combination of ledipasvir-sofosbuvir provides a very attractive and effective one pill once a day option for treatment of genotype 1 chronic hepatitis C infection. This regimen is the first FDA-approved interferon- and ribavirin-free regimen to treat hepatitis C. Three phase 3 trials (ION-1, ION-2, and ION-3) have demonstrated SVR rates consistently above 90%. The 24-week regimen for treatment-experienced cirrhotic patients is very expensive. Although ledipasvir-sofosbuvir is FDA approved only for genotype 1 HCV, it is also recommended therapy for patients with genotype 4, 5, or 6 in the American Association for the Study of Liver Diseases, Infectious Diseases Society of America, (AASLD/IDSA) guidance. In addition, although ledipasvir-sofosbuvir is not specifically FDA-approved for HIV-infected patients, it will likely generate significant interest for use in this arena based on results from the ION-4 trial.