HIV as a Host Susceptibility State for Severe Drug Hypersensitivity: Disentangling Biological Susceptibility from Drug Exposure in the FAERS Database

Background: HIV infection has long been associated with increased incidence of severe cutaneous adverse reactions (SCAR). It remains unknown whether this increased incidence is a direct biological result of HIV infection, differences in drug exposure, or other demographic factors. Objective: To evaluate the association between HIV and SCAR and determine whether this relationship persists after adjusting for demographic factors and structured drug exposure. Methods: We analyzed reports from the FDA Adverse Event Reporting System (FAERS) from 2013-2023. SCAR outcomes included Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruption (GBFDE). HIV status was determined using antiretroviral exposure, indication text, and machine-learning imputation. Logistic regression models were constructed sequentially: unadjusted, demographic-adjusted, and fully adjusted with drug principal components to account for polypharmacy. Drug-level disproportionality and HIV-drug interaction analyses were also performed. Results: In unadjusted models, HIV was strongly associated with SCAR (OR ~2.0-2.7). Adjustment for demographics attenuated this association, and further adjustment for drug exposure reduced the effect to near null for overall SCAR and DRESS. A modest residual association persisted for SJS/TEN (OR ~1.3). Disproportionality analyses demonstrated enrichment of specific high-risk drugs in PLWH. Interaction modeling revealed drug-specific amplification of SCAR risk in HIV, notably for carbamazepine and clarithromycin, whereas other drugs showed minimal interaction. Conclusion: The association between HIV and SCAR is largely explained by differences in drug exposure and demographic factors. Residual risk is drug-specific rather than uniform, supporting a model in which HIV modifies susceptibility to select drug triggers rather than acting as a global risk factor. Further prospective and retrospective studies are required to quantify associations.