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

Abstract

The use of co-trimoxazole in HIV-positive patients has been associated with a high frequency (40-80%) of hypersensitivity reactions. This has been attributed to the bioactivation of the sulphonamide component, sulphamethoxazole (SMX), to its toxic hydroxylamine and nitroso metabolites. The aim of this study was to determine whether functionally significant polymorphisms in the genes coding for enzymes involved in SMX metabolism influence susceptibility to SMX hypersensitivity. HIV-positive patients with (n = 56) and without (n = 89) SMX hypersensitivity were genotyped for allelic variants in CYP2C9, GSTM1, GSTT1, GSTP1 and NAT2 using polymerase chain reaction (PCR) and/or PCR-restriction fragment length polymorphism analysis. The CYP2C9*2/*3 genotype and CYP2C9*3 allele frequencies were nine- and 2.5-fold higher in the hypersensitive group compared to non-sensitive patients, respectively, although they were not statistically significant when corrected for multiple testing. There were no differences in the frequencies of the GSTM1 and GSTT1 null genotypes, and the slow acetylator genotype, between hypersensitive and non-sensitive patients, while GSTP1 frequency was lower (although non-significant) in the hypersensitive group [21% versus 32%, odds ratio (OR) = 0.5, Pc = 0.24]. Comparison of the genotype frequencies in HIV-positive and -negative patients showed that the NAT2 slow acetylator genotype frequency in the HIV-positive patients (74%) was significantly (Pc = 0.0003, OR = 2.3) higher than in control subjects (56%). Our results show that genetic polymorphisms in drug metabolizing enzymes are unlikely to be major predisposing factors in determining individual susceptibility to co-trimoxazole hypersensitivity in HIV-positive patients.

Enzyme-Mediated Protein Haptenation of Dapsone and Sulfamethoxazole in Human Keratinocytes: II. Expression and Role of Flavin-Containing Monooxygenases and Peroxidases

“…Consistent with this conclusion, previous studies failed to demonstrate a clear association between variant CYP2C9 alleles and the incidence of sulfonamide-induced CDRs (Pirmohamed et al, 2000).…”

Enhanced antigenicity leads to altered immunogenicity in sulfamethoxazole-hypersensitive patients with cystic fibrosis

“…23,24 Furthermore, association analysis of drug metabolizing enzyme gene polymorphisms have revealed that differences in drug metabolism are unlikely to be major factors in determining individual susceptibility. 25,26 These data indicate that environmental factors, more than genetic factors, increase the risk of developing sulfamethoxazole hypersensitivity. In this respect, patients with HIV infection and cystic fibrosis develop sulfamethoxazole hypersensitivity reactions much more frequently than the general population.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Individuals infected with HIV are particularly vulnerable to these reactions, which occur in at least one-third of patients (Ͼ10-fold the number expected in the general population) (Jaffe et al, 1983;Gordin et al, 1984;Wolkenstein et al, 2000). Some (Carr et al, 1994;Kaufmann et al, 1996) but not all studies (Delomenie et al, 1994;Pirmohamed et al, 2000;Wolkenstein et al, 2000) in HIV-infected patients report slow acetylation as a risk factor for hypersensitivity reactions. There is little clinical value in knowing an individual's acetylator status before commencing treatment with sulfonamides since the frequency of hypersensitivity reactions is small relative to that of slow acetylator status.…”