HLA-allelotype associations with nevirapine-induced hypersensitivity reactions and hepatotoxicity: a systematic review of the literature and meta-analysis

ObjectiveVarious 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.MethodsA 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).ResultsThirteen 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 (I-2=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 (I-2=0%). For HLA-C*04 carriage, the OR in four different ethnic populations for cADRs was 2.63 (95% CI: 1.97-3.52; I-2=0%). The OR for carriage of HLA-DRB1*01 in a multiethnic cohort was 2.94 (95% CI: 1.92-4.50; I-2=0%) for nevirapine hepatotoxicity.ConclusionHLA-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.