The use of sulfamethoxazole-trimethoprim (TMP-SMX) is associated with idiosyncratic/hypersensitivity reactions which significantly limit its use, and the frequency of these reactions is increased in HIV infected patients. Numerous studies support the hypothesis that bioactivation of sulfonamides is an initial step in the cascade of events which result in adverse drug reactions (ADR). The long-term goal of this project is to develop strategies which either prevent or minimize ADR to TMP-SMX, thereby maximizing the number of patients able to continue therapy with the most effective anti-pneumocystis agent. The objective of the present proposal is to test the hypothesis that the increased incidence of ADR in HIV infected patients is secondary to alterations in xenobiotic biotransformation.
The specific aims are to determine: 1. IF ARYLAMINE N-ACETYLATION ACTIVITY IS REDUCED IN HIV INFECTED PATIENTS. If oxidation to form a hydroxylamine is the critical step in the bioactivation pathway, the rate of acetylation (an alternative elimination route) may be a determinant in the incidence of ADR to sulfonamides. The hypothesis that HIV patients with an acute infection exhibit a reduced rate of acetylation will be tested by combined phenotype/genotype determination. SMX acetylation clearance in HIV infected patients with acute bacterial/fungal infection, those without and acute infection and normal volunteers will also be determine. 2. IF IN VITRO CYTOTOXICITY OF HYDROXYLAMINE METABOLITES IS A VALID PREDICTOR OF PREDISPOSITION TO HYPERSENSITIVITY REACTIONS IN HIV- INFECTED PATIENTS. Several studies have demonstrated that patients experiencing an ADR to TMP-SMX exhibit a greater in vitro cytotoxicity towards peripheral blood mononuclear cells (PBMC) by metabolites of SMX than patients without hypersensitivity. To test the validity of this in vitro test as a surrogate marker for hypersensitivity, the ability of the test to discriminate between patient populations with different risks for ADR will be examined. 3. IF SERUM FROM HIV-INFECTED PATIENTS EXPERIENCING HYPERSENSITIVITY REACTIONS TO TMP-SMX POSSESS ANTIBODIES DIRECTED TOWARDS NEOANTIGENS IN PBMC. The hypothesis that the association between in vitro cytotoxicity and in vivo hypersensitivity is due to the development of neoantigens which, in turn, elicit an immune response will be tested.
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