HIV resistance to integrase strand-transfer inhibitors: disproportionality analysis of individual case safety reports from the WHO global safety database (VigiBase).

OBJECTIVE to investigate whether drug resistance is differentially reported for integrase strand-transfer inhibitors (INSTIs) in a global pharmacovigilance database.

METHODS A disproportionality analysis was conducted to assess resistance to the five available INSTIs using VigiBase, the WHO global database of individual case safety reports (ICSRs). ICSRs were identified through Medical Dictionary for Regulatory Activities - MedDRA preferred terms (PTs) drug resistance, drug resistance mutation, genotype drug resistance test/test positive, multiple-drug resistance and pathogen resistance between October 2007 and September 2024. Descriptive analyses were employed to characterize individual cases according to sociodemographic and reporting-related variables. Disproportionality signals for at least one resistance-related MedDRA PTs compared with all other drugs in the database were expressed as reporting odds ratios (ROR) and information component (IC), with 95% confidence intervals (CI).

RESULTS 35,406,826 deduplicated ICSRs were identified; 22,825 comprised reports of drug resistance and 1,084 involved exposure to INSTIs. Cases of HIV resistance were predominantly males. Most reports were regarded as serious and originated from Europe and the Americas. Disproportionality signals for drug resistance were observed for all first-generation (ROR= 52.5; CI 95% = 47.6-57.9; IC = 5.56; 95% CI = 5.4-5.7 - raltegravir) and second-generation INSTIs (ROR = 55.9; CI 95% = 50.8-61.5; IC = 5.65; 95% CI = 5.5-5.8 - dolutegravir).

CONCLUSIONS HIV drug resistance to all INSTIs as well significant disproportionate safety signals were identified. These findings should be interpreted with caution given the inherent limitations of spontaneous reporting. Resistance monitoring in clinical settings is relevant.