Association analysis of drug metabolizing enzyme gene polymorphisms in HIV-positive patients with co-trimoxazole hypersensitivity

The use of co-trimoxazole in HIV-positive patients has been associated with a high frequency (40-80%) of hypersensitivity reactions. This has been att ributed to the bioactivation of the sulphonamide component, sulphamethoxazo le (SMX), to its toxic hydroxylamine and nitroso metabolites, The aim of th is study was to determine whether functionally significant polymorphisms in the genes coding for enzymes involved in SMX metabolism influence suscepti bility to SMX hypersensitivity. HIV-positive patients with (n = 56) and wit hout (n = 89) SMX hypersensitivity were genotyped for allelic variants in C YP2C9, GSTM1, GSTT1, GSTP1 and NAT2 using polymerase chain reaction (PCR) a nd/or PCR-restriction fragment length polymorphism analysis. The CYP2C9*2/* 3 genotype and CYP2C9*3 allele frequencies were nine- and 2.5-fold higher i n the hypersensitive group compared to non-sensitive patients, respectively , although they were not statistically significant when corrected for multi ple testing. There were no differences in the frequencies of the GSTM1 and GSTT1 null genotypes, and the slow acetylator genotype, between hypersensit ive and non-sensitive patients, while GSTP1 frequency was lower (although n on-significant) in the hypersensitive group [21% versus 32%, odds ratio (OR )= 0.5, P-C = 0.24]. Comparison of the genotype frequencies in HIV-positive and -negative patients showed that the NAT2 slow acetylator genotype frequ ency in the HIV-positive patients (74%) was significantly (P-C = 0.0003, OR = 2.3) higher than in control subjects (56%). Our results show that geneti c polymorphisms in drug metabolizing enzymes are unlikely to be major predi sposing factors in determining individual susceptibility to co-trimoxazole hypersensitivity in HIV-positive patients. Pharmacogenetics 10:705-713 (C) 2000 Lippincott Williams & Wilkins.