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
glutathione 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-1 beta,
IL-6 or tumour
necrosis factor-alpha (
TNF-alpha) by PBMC. The cytotoxicities of SMX and
SMX-HA to PBMC were assessed in 45 HIV-infected patients with prior
TMP-SMX therapy, and in eight HIV- controls. Twelve HIV-infected subjects were studied prospectively before primary
Pneumocystis carinii pneumonia (PCP)
therapy or rechallenge with
TMP-SMX in previously hypersensitive subjects.
Cytokine production was measured in four hypersensitive and two non-hypersensitive HIV-infected subjects, and three HIV-uninfected controls. The cytotoxicity of
SMX-HA to PBMC was significantly greater in the 22 HIV-infected patients with prior
hypersensitivity than both the 23 HIV-infected patients without
hypersensitivity and the control group. Cytotoxicity was significantly reduced by
glutathione only in the hypersensitive group. SMX did not induce cytotoxicity 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-1 beta and
TNF-alpha, 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
hypersensitivity to
TMP-SMX in HIV-infected patients, and that in vitro cytotoxicity could be useful in the diagnosis of
hypersensitivity and predicting its likelihood.