(A-269) Disproportionality analysis of reports of HIV resistance to integrase strand-transfer inhibitors from the WHO global safety database

Background: Integrase strand-transfer inhibitors (INSTI) comprised drugs used in the treatment (antiretroviral therapy - ART) and prevention (pre-exposure prophylaxis - PrEP and post-exposure prophylaxis - PEP) of HIV. However, acquired, transmitted and pretreatment HIV drug resistance are growing causes of concern for INSTI.

Objectives: To assess spontaneous reports of HIV resistance to INSTI from the WHO pharmacovigilance database and investigate whether it is differentially reported for specific INSTI agents.

Methods: We performed a disproportionality analysis using VigiBase®, the WHO global database of individual case safety reports (ICSR) to identify HIV resistance to the INSTI bictegravir (BIC), cabotegravir (CAB), dolutegravir (DTG), elvitegravir (ELV) e raltegravir (RAL). ICSR were identified through the Medical Dictionary for Regulatory Activities - MedDRA preferred terms (PT) – “drug resistance”, “drug resistance mutation”, “genotype drug resistance test”, “genotype drug resistance test positive”, “multiple-drug resistance” and “pathogen resistance” between October 2007 and September 2024. Signals of disproportionate reporting of at least one resistance-related MedDRA PT comparing INSTI and pathogen resistance to INSTI compared to all other drugs in the database were expressed by the reporting odds ratios (ROR), with 95% confidence intervals (CI). Cases of HIV resistance were described according to age group, sex and region.

Results: Of 35,406,826 ICSR, 173, 5,897, 18,057, 277 and 13,590 involved exposure to BIC, CAB, DTG, ELV and RAL, respectively. Most cases of HIV resistance were reported for BIC (16.8%) and ELV (13.6%), while HIV resistance among those exposed to CAB, DGT and RAL varied from 2.4% to 3.1%. Cases of HIV resistance were predominantly observed in males and cases aged 18 to 64 years old. The majority of the cases were reported in Europe and the Americas. Disproportionate signals for pathogen resistance (the most common PT) were observed for all INSTI, with the strongest found for BIC (ROR = 670.2; CI 95% 380.5 - 1180.4) and the weakest for DTG (ROR = 105.8; CI 95% 92.3 - 121.3). Higher ROR were shown for BIC compared to CAB, DTG and RAL; ELV compared to RAL, CAB and DTG and RAL compared to DTG.

Conclusions: HIV resistance was differentially reported for all INSTI; stronger signals found for ELV and RAL compared to DTG align with DTG’s higher barrier to HIV resistance. The greater ROR observed for BIC warrant attention. These results should guide the monitoring of INSTI to avoid cross-resistance and virologic failure, preserving future ART options.