In vitro cytotoxicity as a marker of hypersensitivity to sulphamethoxazole in patients with HIV

Abstract

SUMMARY Hypersensitivity to trimethoprim-sulphamethoxazole (TMP-SMX) in patients with HIV infection may be a result of either immune dysregulation, a direct cytotoxicity of the SMX-hydroxylamine metabolite (SMX-HA) (rather than SMX per se), or glutathione deficiency. We evaluated the in vitro cytotoxicity of SMX and SMX-HA to peripheral blood mononuclear cells (PBMC) of HIV-infected subjects to determine if the degree of in vitro cytotoxicity is associated with hypersensitivity, whether glutalhione inhibits cytotoxicity, and whether in vitro cytotoxicity is predictive for the development of hypersensitivity. Given that fever is often a prominent feature of hypersensitivity, we also assessed whether SMX or SMX-HA could induce the in vitro production of IL-lβ, IL-6 or tumour necrosis factor-alpha (TNF-α) by PBMC. Thecytotoxicitics of SMX and SMX-HA to PBMC were assessed in 45 HFV-infected patients with prior TMP-SMX therapy, and in eight HIV controls. Twelve HIV-infected subjects were studied prospectively before primary Pnvumocystis carinii pneumonia (PCP) therapy or reehallenge with TMP-SMX in previously hypersensitive subjects. Cylokine production was measured in four hypersensitive and two non-hypersensitive HlV-infccted subjects, and three HIV-uninfected controls. The cytotoxicity of SMX-HA to PBMC was significantly greater in the 22 HIV-infectcd patients with prior hypersensitiviiy than both the 23 HIV-infeeled paiients without hypersensitivity and the control group. Cytotoxicity was significantly reduced by glutalhione only in the hypersensitive group. SMX did not induce eylotoxicity in any group. In 12 subjects studied prospectively. SMX-HA cytotoxicity was also significantly greater in those with subsequent hypersensitivity. Exposure of PBMC to SMX-HA resulted in a modest increase in the production of IL-6, IL-1β and TNF-α, although no major difference was detected between subjects with or without hypersensitivity. These data suggest that SMX-HA and glutathione deficiency are involved in the pathogenesis of hypersensilivity to TMP-SMX in HIV-infected patients, and that in vit ro cytotoxicity could be useful in the diagnosis of hypersensilivity and predicting its likelihood.