Early antiretroviral therapy and long-term cancer risk in HIV: 9-year outcomes from the START randomized trial

Background: Antiretroviral therapy (ART) reduces cancer risk in people with HIV (PWH) but the long-term impact of immediate ART initiation on infection-related and infection-unrelated cancers remains unclear. Methods: In the Strategic Timing of Antiretroviral Treatment (START) trial, 4684 ART-naïve adult PWH with CD4 + T-cell count above 500 cells/mm³ were randomized to immediate or deferred ART initiation arms (i.e., until CD4 + T-cells below 350 cells/mm³). In May 2015, unblinding revealed a 74% reduction in infection-related cancer risk in the immediate arm. Post-2016, participants in the deferred arm were recommended to start ART, and follow-up continued through 2021. This analysis evaluates cancer incidence (by infection-related and infection-unrelated diagnoses) between the treatment arms by time-period (overall, pre-2016 and post-2016). Results: Over a median follow-up of 9 years, 120 participants were diagnosed with cancer. The overall hazard ratio (HR) for cancer risk in the immediate versus deferred arms was 0.50 (95% CI: 0.34 to 0.73; p < 0.001). Pre-2016, the HR (immediate vs. deferred) was 0.33 (95% CI: 0.19 to 0.60; P < 0.001), while post-2016, it was 0.69 (95% CI: 0.42 to 1.13; P = 0.14), and P = 0.062 for the difference. For infection-related cancers in pre-2016 the HR was 0.24 (95% CI: 0.11 to 0.55; P < 0.001) and post-2016, HR was 0.53 (95% CI: 0.23 to 1.18; P = 0.12) and P = 0.18 for the difference. For infection-unrelated cancers, there was no significant difference in HR between immediate and deferred arms in either time period. Conclusion: Immediate ART initiation significantly reduces infection-related cancer risk in PWH that persists long-term. Clinical trial registration: NCT00867048.