Objectives:
People with HIV and extensive antiretroviral exposure may have limited/exhausted treatment options (LExTO) due to resistance, comorbidities, or antiretroviral-related toxicity. Predictors of LExTO were investigated in the RESPOND cohort.

Methods:
Participants on ART for at least 5 years were defined as having LExTO when switched to at least two anchor agents and one third antiretroviral (any class), a two-drug regimen of two anchor agents (excluding rilpivirine with dolutegravir/cabotegravir), or at least three nucleoside reverse transcriptase inhibitors. Baseline was the latest of January 1, 2012, cohort enrolment or 5 years after starting antiretrovirals. Poisson regression modeled LExTO rates and clinical events (all-cause mortality, non-AIDS malignancy, cardiovascular disease [CVD], and chronic kidney disease [CKD]).

Results:
Of 23 827 participants, 2164 progressed to LExTO (9.1%) during 130 061 person-years follow-up (PYFU); incidence 1.66/100 PYFU (95% CI 1.59–1.73). Predictors of LExTO were HIV duration more than 15 years (vs. 7.5–15; adjusted incidence rate ratio [aIRR] 1.32; 95% CI 1.19–1.46), development of CKD (1.84; 1.59–2.13), CVD (1.64; 1.38–1.94), AIDS (1.18; 1.07–1.30), and current CD4+ cell count of 350 cells/μl or less (vs. 351–500 cells/μl, 1.51; 1.32–1.74). Those followed between 2018 and 2021 had lower rates of LExTO (vs. 2015–2017; 0.52; 0.47–0.59), as did those with baseline viral load of 200 cp/ml or less (0.46; 0.40–0.53) and individuals under 40. Development of LExTO was not significantly associated with clinical events after adjustment for age and current CD4, except CKD (1.74; 1.48–2.05).

Conclusion:
Despite an aging and increasingly comorbid population, we found declining LExTO rates by 2018–2021, reflecting recent developments in contemporary ART options and clinical management. Reassuringly, LExTO was not associated with a significantly increased incidence of serious clinical events apart from CKD.