Second-generation DAAs presented several advantages: virologic response values higher than the average achieved by previous IFN-based therapies, reduced treatment duration, and the possibility of different combinations of therapies to meet patient needs. Thus, IFN-free therapies appear to be valuable alternatives for the treatment of chronic hepatitis C.

SUMMARYWhat is known and objective: Interferon-free (IFN-free) therapies for hepatitis C virus (HCV) have been developed to provide more effective, tolerable and safer therapeutic strategies. To date, no network meta-analysis (NMA) evaluating the safety profile of these regimens has been performed. This systematic review and NMA aimed to evaluate safety outcomes of IFN-free treatment options for chronic hepatitis C. Methods: A systematic review was performed according to PRISMA and Cochrane recommendations. A literature search was conducted in PubMed/Medline, Scopus, Cochrane Library, International Pharmaceutical Abstracts and Web of Science electronic databases and included only randomized clinical trials that provided safety outcomes of interest of evaluated secondgeneration direct-acting antivirals: incidence of any adverse events (AEs) and serious AE. NMA allowed estimating probability for the relative safety of the interventions. A consistency model was used to draw conclusions about relative safety of treatments, presented as odds ratio (OR) and corresponding 95% credible interval (CrI). Results: Fifty-one clinical trials were included (13 089 participants). Most participants had hepatitis C genotype 1 virus (76%) and were treated for 12 weeks. Two NMAs were built to investigate the incidence of AEs and serious AEs, comparing 13 and 10 IFN-free treatment options, respectively. For the outcome incidence of AEs, few significant differences were observed, which were explained by the presence of RBV. Elbasvir with grazoprevir and placebo were both safer than ombitasvir in combination with paritaprevir, ritonavir, daclatasvir plus RBV [ORs with 95% Crl of 4Á09 (1Á17-14Á09) and 2Á40 (1Á19-4Á77), respectively] and sofosbuvir with RBV [ORs with 95% Crl of 0Á22 (0Á07-0Á72) and 2Á69 (1Á53-4Á80), respectively]. Furthermore, elbasvir with grazoprevir was safer than sofosbuvir used with velpatasvir and RBV [OR 0Á19 (95% CrI 0Á03-0Á98)]; ombitasvir in combination with paritaprevir, ritonavir, daclatasvir was safer than the same therapy but combined with RBV [OR 2Á14 (95% CrI 1Á09-4Á44)]; and sofosbuvir used with velpatasvir was safer than sofosbuvir with RBV [OR 2Á07 (95% CrI 1Á13-3Á79)]. Elbasvir with grazoprevir (50%) followed by placebo (28%) had the highest probabilities of less AEs. No significant differences were observed for serious AE outcomes.What is new and conclusion: This meta-analysis included a large number of therapies. Small differences were observed in any AEs, but not in serious AEs. WHAT IS KNOWN AND OBJECTIVEHepatitis C is a severe disease with treatment that has high rates of adverse events (AEs). Therefore, treatment discontinuation often occurs, particularly with interferon-based regimens. 1Boceprevir and telaprevir, which are first-generation direct-acting antivirals (DAAs) that are normally used with peginterferon and ribavirin (RBV) in double or triple therapies, can lead to discontinuation because of the complexity of the therapeutic regimen, viral relapse and drug interactions.2 Furthermore, ...

Administration of LED/SOF + RBV to treatment-naïve patients with or without cirrhosis, and non-cirrhotic treatment-experienced patients, did not promote significant additional benefits. Furthermore, it is still unclear whether cirrhotic treatment-experienced patients could benefit from combined therapy.