Characterization and outcomes of difficult-to-treat patients starting modern first-line ART regimens: Data from the ICONA cohort

Objectives: Treatment failures to modern antiretroviral therapy (ART) raise concerns, as they could re- duce future options. Evaluations of occurrence of multiple failures to modern ART are missing and their significance in the long run is unclear. Methods: People with HIV (PWH) in the ICONA cohort who started a modern first-line ART were defined as ‘difficult to treat’ (DTT) if they experienced ≥1 among: i) ≥2 VF (2 viral loads, VL > 200 copies/mL or 1 VL > 10 0 0 copies/mL) with or without ART change; ii) ≥2 treatment discontinuations (TD) due to toxic- ity/intolerance/failure; iii) ≥1 VF followed by ART change plus ≥1 TD due to toxicity/intolerance/failure. A subgroup of the DTT participants were matched to PWH that, after the same time, were non-DTT. Treat- ment response, analysing VF, TD, treatment failure, AIDS/death, and SNAE (Serious non-AIDS event)/death, were compared. Survival analysis by KM curves and Cox regression models were employed. Results: Among 8061 PWH, 320 (4%) became DTT. Estimates of becoming DTT was 6.5% (95% CI: 5.8–7.4%) by 6 years. DTT PWH were significantly older, with a higher prevalence of AIDS and lower CD4 + at nadir than the non-DTT. In the prospective analysis, DTT demonstrated a higher unadjusted risk for all the outcomes. Once controlled for confounders, significant associations were confirmed for VF (aHR 2.23, 1.33–3.73), treatment failure (aHR 1.70, 1.03–2.78), and SNAE/death (aHR 2.79, 1.18–6.61). Conclusion: A total of 6.5% of PWH satisfied our definition of DTT by 6 years from ART starting. This appears to be a more fragile group who may have higher risk of failure.