Is hydroxylamine-induced cytotoxicity a valid marker for hypersensitivity reactions to sulfamethoxazole in human immunodeficiency virus-infected individuals?

Hypersensitivity (HS) reactions to sulfonamides and sulfones continue to li mit their use in human immunodeficiency virus (HIV)-infected individuals. I n vitro cytotoxicity of hydroxylamine metabolites toward peripheral blood m ononuclear cells (PBMCs) has been proposed as a marker for these HS reactio ns. To test the validity of this in vitro system, we determined the selecti ve susceptibility of PBMCs from HIV-infected patients to the cytotoxic effe cts of hydroxylamine metabolites of sulfamethoxazole (SMX) and dapsone (DDS ). Concentration-cytotoxic response data were collected using PBMCs from 12 sulfa-HS (10 SMX-HS and 2 SMX/DDS-HS) and 10 sulfa-tolerant HIV-infected i ndividuals. Although sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone h ydroxylamine (DDS-NOH) both caused concentration-dependent increases in cel l death, DDS-NOH was significantly more potent in each subject (P < .0001). A comparison of a variety of mean data for sulfa-HS and -tolerant patient populations failed to demonstrate the increased susceptibility of PBMCs fro m HS patients, noted by others, to either SMX-NOH or DDS-NOH. Moreover, any trend toward an increased susceptibility of PBMCs from HS patients was eli minated when adjusted for control cell death. PBMCs from sulfa-HS patients showed significantly greater susceptibility to the stress of short term in vitro incubation (P < .02). Mean (S.D.) vehicle control cell death values w ere 24.1% (7.6%) for HS patients and 17.1% (4.4%) for tolerant patients. No significant correlation was observed between hydroxylamine-induced or cont rol cell death and any of the recorded clinical parameters. Although severa l potential reasons are proposed to explain the disparity with past investi gations, the data suggest that in vitro cytotoxicity is not a valid marker for HS reactions in HIV-infected individuals using currently accepted exper imental procedures.