Immunogenicity of trimethoprim/sulfamethoxazole in a macaque model of HIV infection

Abstract

Background Sulfonamide hypersensitivity has a high incidence in HIV infection and correlates with low CD4+ counts, but the mechanisms are not understood. The aims of this study were to determine whether trimethoprim/sulfamethoxazole (TMP/SMX) led to SMX adduct formation, immunogenicity, or signs of drug hypersensitivity in SIV-infected rhesus macaques, and whether differences in antioxidants, pro-inflammatory mediators, or SMX disposition were predictive of drug immunogenicity. Methods Nine macaques chronically infected with SIVmac239 and 7 non-infected controls were studied. Baseline blood ascorbate, glutathione, IFN-γ, LPS, sCD14, and cytochrome b5 reductase measurements were obtained, macaques were dosed with TMP/SMX (120 mg/kg/day p.o. for 14 days), and SMX metabolites, lymph node drug adducts, drug-responsive T cells, and anti-SMX antibodies were measured. Results Four of 9 of SIV-positive (44%), and 3 of 7 SIV negative (43%) macaques had drug-responsive T cells or antibodies to SMX. Two macaques developed facial or truncal rash; these animals had the highest levels of lymph node drug adducts. Antioxidants, pro-inflammatory mediators, and SMX metabolites were not predictive of drug immunogenicity; however, the Mamu DRB1*0401/0406/0411 genotype was significantly over-represented in immune responders. Conclusions Unlike other animal models, macaques develop an immune response, and possible rash, in response to therapeutic dosages of TMP/SMX. Studying more animals with CD4+ counts < 200 cells/µl, along with moderately restricted ascorbate intake to match deficiencies seen in humans, may better model the risk of SMX hypersensitivity in HIV-infection. In addition, the role of Mamu-DRB1 genotype in modeling drug hypersensitivity in retroviral infection deserves further study.

Hepatic expression profiles in retroviral infection: relevance to drug hypersensitivity risk

“…(Wong et al. ) Based on normal hepatic SMX‐HA reduction activities found in the present study, decreased urinary SMX‐HA in retroviral infection may reflect further oxidation of SMX‐HA to SMX‐NO (which is not detected in urine due to instability) rather than altered SMX‐HA reduction by cytochrome b 5 reductase.…”

“…We expanded on the relatively small group of animals available for hepatic expression arrays with activity assays in additional liver samples, and also found no difference in N-acetylation of SMX. Further, in a recent TMP/SMX dosing study in the same population of macaques, (Wong et al 2016) we found no differences in 24-hour urinary concentrations of N-acetylated SMX in SIV-infected versus control animals (54.4% of total urinary metabolites versus 55.1%, respectively, n = 7 in each group, P = 0.45). In HIV-infected patients, some studies have found impaired N-acetylation, using caffeine or dapsone as in vivo probe drugs, in individuals with normal NAT2 genotypes.…”

“…Interferon-induced protein with tetratricopeptide repeats 2 Increased expression in dendritic cells transduced with HIV-1 Vpr (Zahoor et al 2015) Up-regulated in Sj€ ogren's syndrome; (Khuder et al 2015) expression related to disease activity in SLE (Zhao et al 2010) EIF3J 3.1 Eukaryotic translation initiation factor 3, subunit J Participates in the initiation of translation in vivo TMP/SMX dosing study in the same macaque population. (Wong et al 2016) Based on normal hepatic SMX-HA reduction activities found in the present study, decreased urinary SMX-HA in retroviral infection may reflect further oxidation of SMX-HA to SMX-NO (which is not detected in urine due to instability) rather than altered SMX-HA reduction by cytochrome b 5 reductase.…”

Antibiotic prophylaxis in immunosuppressed patients – Missed opportunities from trimethoprim-sulfamethoxazole allergy label

“…In animal and in human studies, false positive SMX antibodies have been reported in individuals receiving TMP-SMX without any apparently clinical reaction, therefore this test would not be suitable for screening. 54 , 55 …”