Timing and regimen of antiretroviral therapy and all-cause mortality in people with HIV: A time-to-event mediation analysis via opportunistic infection.

OBJECTIVES

To compare associations of antiretroviral therapy (ART) strategies with all-cause mortality and assess whether first opportunistic infection (OI) occurrence and time partly explain survival differences.

METHODS

We analyzed 38,692 people with HIV in Henan Province (2015-2024). ART initiation timing and regimen were assessed, with early initiation defined as CD4+ T cell counts ≥500 cells/μL. Cox regression estimated associations with all-cause mortality and first OI. Multistate models characterized transitions to first OI and death, and time-to-event mediation analyses quantified the contribution of OI occurrence and time.

RESULTS

During a median follow-up of 5.07 years, 2868 deaths occurred. Compared with late ART initiation, early initiation was associated with lower all-cause mortality (HR: 0.46; 95% CI: 0.41-0.52), and a lower transition hazard from OI to death (HR: 0.47; 95% CI: 0.27-0.81). Compared with PI-based regimens, INSTI- and NNRTI-based regimens showed lower observed all-cause mortality risks, with HRs (95% CI) of 0.51 (0.35-0.73) and 0.60 (0.50-0.72), respectively. At 5 years, early ART initiation and INSTI-based therapy were associated with absolute reductions in cumulative mortality risk of 8.51% and 4.76%, respectively, with residual disparity close to the total effect and a small shifting distribution effect (< 0.30%) attributable to first OI occurrence and time.

CONCLUSIONS

Earlier ART initiation, especially at CD4+T cell counts ≥500 cells/μL, was associated with better survival. INSTI- and NNRTI-based regimens showed more favorable observed mortality outcomes than PI-based regimens. OI occurrence and time explained only a limited proportion of survival differences.