HLA alleles and hypersensitivity to carbamazepine: an updated systematic review with meta-analysis.

A considerable heterogeneity exists in the literature on the role of different HLA alleles in carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) of varying severity among diverse ethnic groups. The aim of the present study was to understand and summarize this heterogeneity and evaluate the contribution of common HLA alleles to susceptibility to cADRs in patients treated with CBZ through a meta-analysis. A literature search of Embase, Medline, Web of Knowledge, and Cochrane database of systematic reviews was performed up to 28 September 2013. A total of 20 reports were identified as eligible studies, which included 720 CBZ-intolerant [Stevens-Johnson syndrome and toxic epidermal necrolysis (bullous lesions): n=277; hypersensitivity syndrome/maculopapular exanthema (nonbullous lesions): n=359; others: n=84], 1512 CBZ-tolerant, and 1113 normal controls. We observed HLA-A*3101 and HLA-B*1502 as risk markers and HLA-B*4001 as a protective marker for susceptibility to cADRs when comparing intolerant with tolerant patients. Stratification by clinical outcome showed HLA-B*1502 and HLA-B*1511 as risk and HLA-A*2402 as protective markers for bullous lesions in the Asians [HLA-B*1502: odds ratio (OR)=80.70; 95% confidence interval (CI)=45.62-142.77; P=1.8×10(-51); I(2)=33%, HLA-B*1511: OR=17.43; 95% CI=3.12-97.40; P=1.1×10(-3); I(2)=0%, HLA-A*2402: OR=0.27; 95% CI=0.11-0.64; P=2.7×10(-3); I(2)=0%]. Furthermore, HLA-A*3101 was observed to be a universal risk marker, irrespective of cADR type [OR (bullous lesions)=5.65; 95% CI =2.70-11.78; P=4.03×10(-6); I(2)=49%, OR (nonbullous lesions)=8.58; 95% CI=5.55-13.28; P=4.46×10(-22); I(2)=0%]. Sensitivity analysis showed HLA-B*4001 as a protective marker in Chinese population for showing bullous lesions (OR=0.14; 95% CI=0.06-0.32; P=3.2×10(-6); I(2)=0%). In summary, our meta-analysis showed the presence of HLA alleles contributing toward risk of as well as protection against various CBZ-induced cADRs.