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

Background Treatment failures to modern ART raise concerns, as they could reduce future options. Evaluations of occurrence of multiple failures to modern ART are missing and their significance in the long run is unclear. Material and Methods People with HIV (PWH) in the ICONA cohort who started a modern first-line ART were defined as "difficult to treat" (DTT) if experienced ≥1 among: i) ≥2 VF (2 viral loads, VL>200 copies/mL or 1 VL>1000 copies/mL) with or without ART change; ii) ≥2 treatment discontinuations (TD) due to toxicity/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. Treatment response, analyzing 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 8,061 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), SNAE/death (aHR 2.79, 1.18-6.61). Conclusions A total of 6.5% of PWH satisfied our definition of DTT by 6 years from ART starting. This appears a more fragile group who may have higher risk of failure.