• Prescrire Int. 2015 Jan 1; 24 (156): 5-10.

AbstractAbout 50% of patients with chronic hepatitis C virus (HCV) genotype 1 infection have a sustained virological response to a 48-week course of the peginterferon alfa + ribavirin combination. Adding a viral protease inhibitor to this combination for 12 to 32 weeks enhances antiviral effects but increases the risk of serious adverse effects. Between 70% and 80% of patients with HCV genotype 2 or 3 infection have a sustained virological response to a 24-week course of the peginterferon alfa + ribavirin combination. Sofosbuvir, a nucleotide inhibitor of viral (or HCV) NS5B RNA polymerase,has been authorised in the European Union for the treatment of chronic hepatitis C, in combination with other drugs. Despite the inclusion of several clinical trials, initial evaluation of sofosbuvir provides only a minimal picture of the harm-benefit balance. Sofosbuvir has not been compared directly with viral protease inhibitors in randomised clinical trials. In a trial involving 121 patients with HCV genotype 1 infection, the sustained viral response rate was 90% when sofosbuvir was added to the peginterferon alfa + ribavirin combination for 12 weeks, versus about 60% with peginterferon alfa + ribavirin alone. In a randomised, unblinded, noninferiority trial in 527 previously untreated patients with HCV genotype 2 or 3 infection, sofosbuvir + ribavirin combination therapy given for 12 weeks had virological efficacy similar to peginterferon alfa-2a + ribavirin combination therapy given for 24 weeks. However, there were signs that sofosbuvir might be less effective against HCV genotype 3. In an uncontrolled study of 114 patients with HCV genotype 1 infection who could not receive peginterferon alfa, the sofosbuvir + ribavirin combination yielded sustained virological responses in about 75% of cases. Similar results were obtained in a double-blind, placebo-controlled trial in 280 patients with HCV genotype 2 or 3 infection. Too few cases of HCV genotype 4, 5 or 6 infection were included in clinical trials to determine the value of sofosbuvir in these patients. The adverse effects of sofosbuvir are poorly documented, mainly because of the limited number of patients in clinical trials and the lack of blinding in several trials. In particular, more data are needed on possible effects on the heart, blood cells and muscle. Renal failure can lead to sofosbuvir overdose, while co-administration of P-glycoprotein inhibitors can lead to sofosbuvir under dosing. There are no data available on the use of sofosbuvir in pregnant women. Contraception is necessary when sofosbuvir is used in combination with ribavirin because the latter drug is teratogenic, potentially for several months after treatment discontinuation. When HCV liver disease warrants medical treatment, sofosbuvir seems to be at least as effective as viral protease inhibitors such as boceprevir, and also less toxic. Its use can shorten treatment duration by several months. There are many uncertainties, however, about its adverse effects and drug interactions. Adding sofosbuvir to the-peginterferon a/fa + ribavirin combination is an option for patients with genotype 1 infection,while sofosbuvir is an alternative to peginterferon a/fa for patients with genotype 2 or 3 infection. Waiting for more thorough evaluation is another reasonable option, depending on clinical status, given the slow progression of hepatitis C and the many outstanding questions concerning sofosbuvir.

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