title: Safety of interferon-free therapies for chronic hepatitis C: a network meta-analysis.
abstract: 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 second-generation 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 4·09 (1·17-14·09) and 2·40 (1·19-4·77), respectively] and sofosbuvir with RBV [ORs with 95% Crl of 0·22 (0·07-0·72) and 2·69 (1·53-4·80), respectively]. Furthermore, elbasvir with grazoprevir was safer than sofosbuvir used with velpatasvir and RBV [OR 0·19 (95% CrI 0·03-0·98)]; ombitasvir in combination with paritaprevir, ritonavir, daclatasvir was safer than the same therapy but combined with RBV [OR 2·14 (95% CrI 1·09-4·44)]; and sofosbuvir used with velpatasvir was safer than sofosbuvir with RBV [OR 2·07 (95% CrI 1·13-3·79)]. Elbasvir with grazoprevir (50%) followed by placebo (28%) had the highest probabilities of less AEs. No significant differences were observed for serious AE outcomes.
  
  
  CONCLUSIONS
  This meta-analysis included a large number of therapies. Small differences were observed in any AEs, but not in serious AEs.
authors.affiliation: Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil.
authors.forename: V L
authors.initials: VL
authors.lastname: Ferreira
authors.affiliation: Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil.
authors.forename: N A
authors.initials: NA
authors.lastname: Assis Jarek
authors.affiliation: Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil.
authors.forename: F S
authors.initials: FS
authors.lastname: Tonin
authors.affiliation: Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil.
authors.forename: H H L
authors.initials: HH
authors.lastname: Borba
authors.affiliation: Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil.
authors.forename: A
authors.initials: A
authors.lastname: Wiens
authors.affiliation: Department of Pharmacy, Pharmaceutical Sciences Postgraduate Program, Universidade Federal do Paraná, Curitiba, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Pontarolo
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D016174:Hepacivirus / Q000187:drug effects; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic
chemical_list: D000998:Antiviral Agents; D007372:Interferons
keywords: hepatitis C; interferon-free; meta-analysis; network; safety