IN-VITRO CYTOTOXICITY AS A MARKER OF HYPERSENSITIVITY TO SULFAMETHOXAZOLE IN PATIENTS WITH HIV

Hypersensitivity to trimethoprim-sulphamethoxazole (TMP-SMX) in patien ts with HIV infection may be a result of either immune dysregulation, a direct cytotoxicity of the SMX-hydroxylamine metabolite (SMX-HA) (ra ther than SMX per se), or glutathione deficiency. We evaluated the in vitro cytotoxicity of SMX and SMX-HA to peripheral blood mononuclear c ells (PBMC) of HIV-infected subjects to determine if the degree of in vitro cytotoxicity is associated with hypersensitivity, whether glutat hione inhibits cytotoxicity, and whether in vitro cytotoxicity is pred ictive for the development of hypersensitivity. Given that fever is of ten a prominent feature of hypersensitivity, we also assessed whether SMX or SMX-HA could induce the in vitro production of IL-1beta, IL-6 o r tumour necrosis factor-alpha (TNF-alpha) by PBMC. The cytotoxicities of SMX and SMX-HA to PBMC were assessed in 45 HIV-infected patients w ith prior TMP-SMX therapy, and in eight HIV- controls. Twelve HIV-infe cted subjects were studied prospectively before primary Pneumocystis c arinii pneumonia (PCP) therapy or rechallenge with TMP-SMX in previous ly hypersensitive subjects. Cytokine production was measured in four h ypersensitive and two non-hypersensitive HIV-infected subjects, and th ree HIV-uninfected controls. The cytotoxicity of SMX-HA to PBMC was si gnificantly greater in the 22 HIV-infected patients with prior hyperse nsitivity than both the 23 HIV-infected patients without hypersensitiv ity and the control group. Cytotoxicity was significantly reduced by g lutathione only in the hypersensitive group. SMX did not induce cytoto xicity in any group. In 12 subjects studied prospectively, SMX-HA cyto toxicity was also significantly greater in those with subsequent hyper sensitivity. Exposure of PBMC to SMX-HA resulted in a modest increase in the production of IL-6, IL-1beta and TNF-alpha, although no major d ifference was detected between subjects with or without hypersensitivi ty. These data suggest that SMX-HA and glutathione deficiency are invo lved in the pathogenesis of hypersensitivity to TMP-SMX in HIV-infecte d patients, and that in vitro cytotoxicity could be useful in the diag nosis of hypersensitivity-and predicting its likelihood.