Sofosbuvir (Sovaldi), manufactured by Gilead Sciences, Inc, is a hepatitis C virus (HCV) nucleotide analogue NS5B polymerase inhibitor that is FDA approved for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. Clinical efficacy has been established only in patients with HCV genotype 1, 2, 3, or 4 infections, including those with hepatocellular carcinoma awaiting liver transplantation (meeting Milan criteria) and those with HCV/HIV-1 coinfection.1,2
Sofosbuvir, a direct-acting antiviral agent against HCV, is a prodrug converted to its pharmacologically active form, GS-461203, via hepatic metabolism. This active metabolite inhibits HCV NS5B RNA-dependent RNA polymerase, and since this enzyme is required for viral replication, GS-461203 essentially functions as a chain terminator. Dephosphorylation of this active metabolite results in the formation of another major, though inactive, metabolite, GS-331007. Time to peak occurs 0.5 to 2 hours after administration, and the drug is 61% to 65% protein bound. With an elimination half-life of 0.4 hours, the majority (approximately 80%) of the dose is renally excreted as the GS-331007 metabolite.1,2
Standard dosing for sofosbuvir is one 400-mg tablet taken orally once daily with or without food. However, treatment regimen and duration are dependent on the patient’s viral genotype; monotherapy is not recommended for CHC treatment. Patients with genotype 2 CHC should be treated with sofosbuvir and ribavirin for 12 weeks, while patients with genotype 3 CHC should be treated with sofosbuvir/ribavirin for 24 weeks.
Patients with genotype 1 or 4 CHC should be treated with a sofosbuvir, peginterferon alfa, and ribavirin combination for 12 weeks; however, CHC genotype 1 patients who are ineligible to receive an interferon-based regimen may receive sofosbuvir/ribavirin for 24 weeks as a therapeutic alternative. In patients with hepatocellular carcinoma awaiting liver transplantation, sofosbuvir/ribavirin treatment is recommended for up to 48 weeks or until the time of liver transplantation, whichever occurs first, to prevent post transplant HCV reinfection. No dose adjustment of sofosbuvir is needed for patients with mild, moderate, or severe hepatic impairment. Likewise, no adjustment is needed for patients with mild or moderate renal impairment, but the safety and efficacy of sofosbuvir has not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2
In response to promising phase II studies in which sofosbuvir was effectively utilized in previously untreated CHC patients with genotype 1, 2, or 3, Lawitz and colleagues conducted 2 multicenter phase III studies in previously untreated patients with HCV infection. In the single-group, openlabel study (NEUTRINO), investigators administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (with 98% having genotype 1 or 4). In the second study (FISSION), a non-inferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive either sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. For both studies, the primary end point was a sustained virologic response, defined as an HCV RNA level below the lower limit of quantification, at 12 weeks after completion of therapy.
For the NEUTRINO study, this end point was met in 295 patients (90% response rate), and for the FISSION study, a sustained response rate of 67% was reported in both the sofosbuvir/ribavirin group and the peginterferon/ ribavirin group, demonstrating noninferiority. Treatment discontinuation and incidence of adverse events were much lower among patients receiving sofosbuvircontaining regimens versus those receiving peginterferon/ribavirin.3
Although sofosbuvir itself has a Pregnancy Category B rating, combination treatment with ribavirin or peginterferon alfa/ ribavirin is contraindicated in women who are pregnant, or may become pregnant, as well as in men whose female partners are pregnant, due to risks for birth defects and fetal death associated with use of ribavirin. Sofosbuvir is a substrate of P-gp drug transporter and breast cancer resistance protein (BCRP) and thus should not be used with potent intestinal P-gp inducers, such as rifampin and St. John’s wort, or BCRP inducers, as these drugs may significantly decrease sofosbuvir plasma concentrations.1,2
AVAILABILITY AND COST
Sovaldi is available as a yellow, 400-mg, capsule-shaped tablet. Each bottle contains 28 tablets and should be stored at room temperature below 30°C (86°F). The wholesale acquisition cost of a 28-tablet bottle is $28,000.1,4
Ashley L. Pappas, PharmD, BCPS, is a drug information specialist at University of North Carolina (UNC) Hospitals and an adjunct assistant professor at the UNC Eshelman School of Pharmacy.
Sandra Hanna is a second-year pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.
Sofosbuvir [package insert]. Foster City, CA: Gilead Sciences, Inc; December 2013.
Sofosbuvir. Micromedex [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated March 13, 2014.
Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-1887.
US Food and Drug Administration approves Gilead’s Sovaldi (sofosbuvir) for the treatment of chronic hepatitis C [press release]. December 6, 2013. www.gilead.com/news/press-releases/2013/12/us-food-and-drug-administration-approves-gileads-sofosbuvir-sofosbuvir-for-the-treatment-of-chronic-hepatitis-c.