Time to HIV viral rebound and frequency of post-treatment control after analytical interruption of antiretroviral therapy: An individual data-based meta-analysis of 24 prospective studies

Background: There is a global need to explore novel interventions conferring sustained HIV control without antiretroviral therapy (ART). The only current strategy to test efficacy is through an analytical treatment interruption (ATI). Inclusion of ‘placebo’ controls in future clinical trials poses ethical, logistical, and economic challenges and might be unnecessary if sufficient up-to-date data exists from non-intervention cohorts of people with HIV (PWH) who stop ART. To understand viral rebound dynamics and rates of post-treatment HIV control in the absence of any intervention, we undertook an individual participant data meta-analysis on time to viral rebound after ATI. Methods: We included individual-level data from clinical studies with >5 separate available plasma HIV RNA viral load (pVL) measurements within the first 84 days post-ATI in PWH receiving either placebo or no intervention. Eligible prospective studies were identified through literature search on PubMed. Early-ART was defined as ART initiation within 6 months of HIV acquisition; others were classified as late-ART or unknown. Results : In total, 24 studies published between 2000-2024 with 382 individuals were included. Median participant age was 42 years, 91% male, 75% white, 45% received early-ART. Median time to pVL >50, >400, and >10,000 copies/mL was 16 days (interquartile range [IQR]:13–25), 21 (IQR:15–28), and 32 (IQR:20–35), respectively. Post-treatment control defined as pVL <50 copies/mL at day 84 occurred in 4% (n=14) of participants (6% for early-ART and 1% for late-ART). Multivariable analysis identified at late ART initiation as an independent risk factor for earlier VL rebound (hazard ratio [HR] 1.25, P =0.005). Conclusion : Sustained control of pVL <50 copies/ml after 84 days off ART is rare in PWH who stop therapy, especially in those starting ART late. When designing future interventional HIV cure/remission trials, these findings help inform study size and design, potentially removing the need for a placebo arm thereby minimizing unnecessary risks to participants and their partners, while optimising resources.