title: HLA-allelotype associations with nevirapine-induced hypersensitivity reactions and hepatotoxicity: a systematic review of the literature and meta-analysis.
abstract: OBJECTIVE
  Various studies have investigated associations between immunogenetic (HLA-allelotypes) factors and the risk of nevirapine-induced hypersensitivity reactions. However, results from individual studies have been inconsistent. To evaluate the association between HLA alleles and nevirapine hypersensitivity, a systematic review and meta-analysis was carried out.
  
  
  METHODS
  A literature review of articles published up to December 2014 was performed. Where both allelotype and phenotype data from two or more studies could be combined, a Mantel-Haenszel random effects model was used to obtain a pooled odds ratio (OR) and 95% confidence intervals (CIs).
  
  
  RESULTS
  Thirteen case-control studies investigating nevirapine hypersensitivity and HLA-allelotypes were identified. The OR (95% CI) for HLA-B*35 and cutaneous adverse drug reactions (cADRs) was 2.45 (95% CI: 1.10-5.48), with significant heterogeneity (I²=69%). The association between HLA-B*58:01 and hepatotoxicity in black African patients showed an OR of 3.51 (95% CI: 1.72-7.19) with no between study heterogeneity (I²=0%). For HLA-C*04 carriage, the OR in four different ethnic populations for cADRs was 2.63 (95% CI: 1.97-3.52; I²=0%). The OR for carriage of HLA-DRB1*01 in a multiethnic cohort was 2.94 (95% CI: 1.92-4.50; I²=0%) for nevirapine hepatotoxicity.
  
  
  CONCLUSIONS
  HLA-C*04 carriage may be a common risk factor for cADRs to nevirapine in populations of differing ethnicity, whereas HLA-B*35 and HLA-DRB1*01 appear to be driven predominantly by an association within Thai and White populations, respectively. Heterogeneity between studies could be reduced by undertaking an individual patient data meta-analysis allowing the standardization of phenotype definitions and investigation of common haplotypes between populations.
authors.affiliation: aWolfson Centre for Personalised Medicine, Department of Molecular and Clinical Pharmacology bDepartment of Biostatistics, University of Liverpool, Liverpool, UK.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Cornejo Castro
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Carr
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Jorgensen
authors.forename: Ana
authors.initials: A
authors.lastname: Alfirevic
authors.forename: Munir
authors.initials: M
authors.lastname: Pirmohamed
mesh_terms: D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000208:ethnology / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics*; D056726:Genetic Association Studies; D015797:HLA-B35 Antigen / Q000235:genetics*; D015236:HLA-C Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D019829:Nevirapine / Q000009:adverse effects*; D016017:Odds Ratio; D011110:Polymorphism, Genetic
chemical_list: D015797:HLA-B35 Antigen; D015236:HLA-C Antigens; C039966:HLA-C*04 antigen; D059811:HLA-DRB1 Chains; C497841:HLA-DRB1*01 antigen; D019829:Nevirapine