Risk of developing low-level viral rebound (LLVR) among people with HIV (PWH) receiving two or three drug regimens: a case control study nested in the ICONA cohort

Background The risk of developing low-level viral rebound (LLVR) after achieving HIV-RNA suppression with two-drug regimens (2DR) compared to triple regimens (3DR) remains uncertain. Methods We conducted a matched 1:3 case-control study nested within the ICONA cohort including persons with HIV (PWH) who achieved virological suppression (≥2 consecutive HIV-RNA≤50copies/ml over 6 months) after November 11, 2014 (baseline, BL). Cases were defined as PWH experiencing a single HIV-RNA of 51-199 copies/ml after BL (index date); controls as those who maintained HIV-RNA ≤50 copies/mL up to the index date and matched for history of care gaps and number of drugs failed. The cumulative incidence of LLVR after virological suppression was estimated using Kaplan-Meier methods and conditional logistic regression models evaluated the association between the currently ART regimen [2DR (dolutegravir/lamivudine, dolutegravir/rilpivirine, dolutegravir/doravirine or cabotegravir/riplivirine) vs. 3DR (doloutegravir, bictegravir, rilpivirine, doravirine, darunavir/b, atazanavir/b-based with a backbone of tenofovir and lamivudine or emtricitabine)] and LLVR risk. Sensitivity analyses restricted cases to those with two consecutive LLVR event. Results Among 1,033 PWH [261 cases, 772 matched controls; 21% female, median age 43 years (Interquartile range, IQR, 34-51), BL CD4 count 601/mm3 (IQR 379-826)], 2DR use was 25% in cases versus 29% in controls (p=0.23). Two years after viral suppression, cumulative LLVR incidence was 2.7% (95% CI 2.3-3.1) when considering all single LLVR events and 1.8% (1.4-2.1) when limited to two consecutive values. After adjusting for confounding, evidence was inconclusive [aOR 0.86, 95% CI 0.57-1.29].)]. Conclusion Despite the wide range of plausibility, we can exclude a risk of LLVR higher than 29% when using 2DR vs. 3DR regimens.