Abacavir hypersensitivity is associated with HLA B*5701, and pre-prescription pharmacogenetic testing for this appears to be a cost-effective use of healthcare resources.

Sulfamethoxazole (SMX) is associated with hypersensitivity reactions. Identification of drug-specific lymphocytes from hypersensitive patients suggests involvement of the immune system. Lymphocytes from humans recognize SMX and nitroso-SMX (SMX-NO), whereas cells from sensitized rats recognize only SMX-NO. In this investigation, we study the nature of SMXspecific T cells in four species. Male rats, mice, and rabbits were immunized with SMX (50 mg kg Ϫ1 ) or SMX-NO (1 mg kg Ϫ1 ). Lymphocytes and/or splenocytes were isolated and incubated with SMX, SMX-hydroxylamine or SMX-NO and proliferation were measured. Lymphocytes were also isolated from SMX-hypersensitive patients (n ϭ 3) and drug-specific proliferation was measured. In addition, rabbits were bled fortnightly for 4 months to determine whether SMX-NO-specific T cells cross-react with SMX. To confirm that SMX-NO responses were due to covalent binding and not cross-reactivity, cells were pulsed with SMX-NO and/or coincubated with glutathione. Splenocytes from mice, rats, and rabbits proliferated when stimulated with SMX-NO, but not SMX. A 2-h pulse with SMX-NO was sufficient for proliferation, whereas cells coincubated with SMX-NO and glutathione did not proliferate. Rabbit lymphocytes proliferated in the presence of SMX-NO and SMX-hydroxylamine, but not SMX. SMX-hydroxylamine was converted to SMX-NO in culture. The SMX-NO-specific response of rabbit lymphocytes was maintained for at least 4 months and the cells did not cross-react with SMX. Human lymphocytes from hypersensitive patients proliferated in the presence of SMX and both metabolites. These results highlight important differences in T-cell recognition of drug (metabolite) antigens in animals that have been sensitized against a drug metabolite and patients with hypersensitivity to the drug.

The data suggest that the -238 (but not the -308) promoter region TNF-alpha gene polymorphism is a determinant in the development of HIV-related lipodystrophy. However, the results need to be confirmed in larger numbers of patients as well as in an ethnically diverse population.

The aim of these studies was to determine whether HIV-infected patients have a plasma thiol deficiency and whether this is associated with decreased detoxification of the toxic metabolites of sulfamethoxazole. Reduced, oxidized, protein-bound, and total thiol levels were measured in 33 HIV-positive patients and 33 control subjects by an HPLC method utilizing the fluorescent probe bromobimane. The reduction of sulfamethoxazole hydroxylamine and nitrososulfamethoxazole by plasma and the plasma redox balance in the presence of nitrososulphamethoxazole were also determined by HPLC. Reduced plasma cysteine was significantly (p<0.0001) lower in HIV-positive patients (13.0+/-3.0 microM) when compared with control subjects (16.9+/-3.0 microM). Although there was no difference in oxidized, protein-bound, and total cysteine, the thiol/disulfide ratios were lower in HIV-positive patients. Reduced homocysteine was elevated in patients. Plasma from HIV-positive patients was less able to detoxify nitrososulfamethoxazole than control plasma. These findings show that the disturbance in redox balance in HIV-positive patients may alter metabolic detoxification capacity, and thereby predispose to sulfamethoxazole hypersensitivity.

Aims To test the role of acetylator status, and to investigate the reported discrepancy between acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole (SMX) hypersensitivity. Methods Forty HIV-positive patients (32 of whom were SMX-hypersensitive), and 26 healthy volunteers, were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, and phenotyped using dapsone (50 mg) as a probe, for acetylator status. Sequencing of the NAT2 exon was performed where discrepancy between phenotyping and genotyping was detected. Our results were also pooled with published studies addressing slow acetylator status in HIV-positive SMX-hypersensitive patients. Results Slow acetylator genotype and phenotype frequencies did not differ between HIV-positive SMX-hypersensitive and nonhypersensitive patients, and healthy controls, which was further confirmed in a meta-analysis of published studies (pooled odds ratio 2.25, 95% confidence interval 0. 45, 11.17). Discordance between phenotype and genotype was resolved in four of the subjects by sequencing of the whole NAT2 exon, which revealed rare mutations, leaving three (9%) HIV-positive SMX-hypersensitive patients and one (4%) healthy volunteer who continued to demonstrate the discordance. Conclusions Slow acetylator phenotype or genotype is unlikely to predispose to SMX hypersensitivity in HIV-positive patients, although a minor role cannot be excluded. Phenotype-genotype discrepancies are partly due to nondetection of all rare alleles by PCR methodology, and can be circumvented by sequencing of the gene in patients showing a discrepancy.