New treatment combo for hep C virus infection, genotype 1

Diana SobierajIn November 2013, FDA approved simeprevir (Olysio; Janssen) for the treatment of chronic hepatitis C (CHC) infection, genotype 1, in combination with peginterferon alpha and ribavirin, in patients with compensated liver disease (including cirrhosis) who are either treatment-naive or treatment-experienced. Simeprevir is an NS3/4A protease inhibitor that directly inhibits hepatitis C virus (HCV) replication. Simeprevir is not to be used as monotherapy and has not been studied in patients who have failed a prior CHC regimen that includes simeprevir or another HCV protease inhibitor. Simeprevir is contraindicated in all conditions in which peginterferon and ribavirin are also contraindicated, since they are used in combination. This includes use in patients with decompensated cirrhosis (moderate-to-severe hepatic impairment) and, due to the risks of birth defects and fetal death associated with ribavirin, pregnant women and men whose female partners are pregnant.

Efficacy

The efficacy of simeprevir combined with peginterferon and ribavirin for treatment of CHC genotype 1 treatment-naive patients with compensated liver failure, including all stages of liver fibrosis, was established in two randomized clinical trials, QUEST-1 and QUEST-2. Collectively the trials enrolled 758 patients with genotype 1 to receive either simeprevir or placebo for 12 weeks on a background of peginterferon alpha plus ribavirin for 24 to 36 weeks. Of these patients, 88% met response-guided treatment criteria and were able to shorten their treatment duration to 24 weeks; among that 88%, 86% to 91% achieved sustained viral response at week 12 (SVR12). Patients with genotype 1a and the Q80K mutation had a lower response than did those without the mutation (58% vs. 84%). Among placebo-treated patients, only 47% to 53% of patients achieved SVR12. On-treatment failure occurred in 8% and 33% of simeprevir and placebo-treated patients, respectively. Viral relapse was also more common in the placebo group (23% vs. 11%). 

Two other studies, the PROMISE and ASPIRE trials, evaluated patients with genotype 1 who relapsed after previous interferon-based therapy. In the PROMISE trial (n=393) more patients treated with simeprevir achieved SVR12 (79%) compared with placebo (37%), on the background of peginterferon-alpha/ribavirin, for 24 to 48 weeks. Similar results were observed in the ASPIRE trial (n=132), with simeprevir 150 mg added to peginterferon-alpha/ribavirin vs. the addition of placebo. In previous relapsers, previous partial responders, and previous null responders, the achievement of SVR at 24 weeks in simeprevir vs. placebo was 77% vs. 37%, 65% vs. 9%, and 53% vs. 19%, respectively. 

Safety

The most common side effects in the QUEST trials were fatigue, itch, and headache. Rash and photosensitivity reactions occurred in 28% of patients treated with simeprevir during phase 3 trials.

Photosensitivity reactions, including those requiring hospitalization, have been observed in patients taking simeprevir along with peginterferon and ribavirin, most commonly within the first four weeks of therapy, although these reactions could occur at any time during treatment. The reaction presents as an exaggerated sunburn on the skin surfaces usually exposed to sunlight, accompanied by burning, exudation, blistering, and edema. Patients should use protective measures such as sunscreen, and protective hats and clothing, and they should limit exposure to tanning beds and sunlight. Photosensitivity to simeprevir may require drug discontinuation.

Rash, mostly reported as mild to moderate in severity, is also a common adverse effect of simeprevir taken with peginterferon and ribavirin. Patients of East Asian ancestry have demonstrated higher exposure to simeprevir, and higher exposure has been associated with increased adverse events, including rash and photosensitivity.

Simeprevir contains a sulfonamide moiety; therefore caution should be used in patients with a sulfa allergy. Simeprevir is a substrate of CYP450 3A; a weak intestinal inhibitor of CYP3A4; a weak CYP1A2 inhibitor; and an inhibitor of both p-glycoprotein and OATP1B1. Biotransformation of simeprevir is dependent upon the CYP3A system, and administration with moderate-to-strong CYP3A inhibitors can significantly increase simeprevir concentrations; therefore coadministration is not recommended. It has been established that other medications interact with simeprevir and require additional monitoring, dose adjustment, or avoidance. A comprehensive list of established drug-interactions as well as the recommended strategy for safe management is available in the simeprevir package insert.

Men and women must use two forms of contraception while being treated with a ribavirin-based regimen and for six months after therapy has ended, due to the associated risk of birth defects and fetal deaths. Women are required to have baseline and routine pregnancy testing throughout therapy and for six months thereafter.

Dosing

Simeprevir is not approved as monotherapy for CHC infection. According to the most recent national practice guidelines, simeprevir plus sofosbuvir with or without ribavirin is recommended for treatment-naive patients with genotype 1 who are ineligible for peginterferon-alpha treatment. A simeprevir-based regimen is also recommended as an alternative to the first-line sofosbuvir/peginterferon/ribavirin regimen in treatment-naive CHC patients who are eligible for interferon therapy, who have either genotype 1b or genotype 1a, and in whom the Q80K polymorphism is not detected prior to treatment. In the United States, patients with CHC genotype 1a have a high prevalence of the Q80K polymorphism, which reduces the efficacy of simeprevir; therefore testing is recommended for all patients with genotype 1a before initiation of a simeprevir-based regimen.

Simeprevir is dosed as 150 mg once daily by mouth. It should be taken with food. When used in combination with peginterferon alpha and ribavirin for genotype 1, simeprevir is dosed for the first 12 weeks of a 24- to 48-week peginterferon and ribavirin regimen. Simeprevir does not require dose adjustment in cases of mild, moderate, or severe renal impairment. However, simeprevir has not been studied in patients with a creatinine clearance below 30 mL/min, patients with end-stage renal disease, or patients requiring dialysis.

Additional resources

Recommendations for testing, managing, and treating hepatitis C infection. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America 2014. Available at

. Accessed February 14, 2014.

Diana M. Sobieraj is assistant professor of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Conn.