Expression of sulfamethoxazole biotransformation pathways in a macaque model of HIV infection

Potentiated sulfonamide antibiotics such as trimethoprim/sulfamethoxazole (cotrimoxazole or TMP/SMX) remain the drugs of choice for treatment and prevention of Pneumocystis jiroveci pneumonia, toxoplasma encephalitis, and Isospora infections in HIV infection (aidsinfo.nih.gov). However, HIV-infected patients show a markedly increased risk of delayed hypersensitivity (HS) reactions to TMP/SMX (20-57% incidence) when compared to the general population (3% incidence). The typical manifestation is maculopapular rash with or without fever, and TMP/SMX is the most common cause of cutaneous drug reactions in HIV-infected patients TMP/SMX can also lead to thrombocytopenia, hepatotoxicity, and bullous skin eruptions in more severely affected patients. The risk of sulfonamide HS increases with progression to AIDS, with higher risk seen at lower CD4+ counts. This risk has been attributed, at least in part, to acquired alterations in SMX drug disposition in HIV infection. We hypothesized that HIV infection leads to impaired hepatic SMX detoxification or enhanced SMX bioactivation pathways, which may contribute to the increased incidence of sulfonamide HS. We addressed this question using liver tissue from SIVmac239-infected macaques, a well accepted model of HIV infection. The aim of this study was to evaluate differences in the hepatic expression and activity of SMX biotransformation pathways from drug naïve SIV-infected macaques compared to sex- and age-matched uninfected controls. Male Rhesus macaques (Macaca mulatta) chronically infected with SIVmac239 (N=3), along with age and sex-matched uninfected controls (N=3), were obtained through the Wisconsin National Primate Research Center. Animals were studied during chronic infection, at least 10 weeks after inoculation. All macaques were screened prior to inclusion in the study with a physical exam, CBC, and serum biochemical panel. Infected animals also had a CD4+ count and viral load performed prior to sampling. All animals were fed a fixed formula global primate diet (Teklad, Harlan Laboratories, Madison WI), and no animals had a history of prior TMP/SMX exposure.