Risk of Developing Low-Level Viral Rebound Among People With HIV Receiving 2- or 3-Drug Regimens: A Case-Control Study Nested in the ICONA Cohort

Background: The risk of developing low-level viral rebound (LLVR) after achieving human immunodeficiency virus HIV-1 (HIV) RNA suppression with 2-drug regimens (2DR) compared to 3-drug 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 ≤50 copies/mL over 6 months) after 11 November 2014 (baseline [BL]). Cases were defined as PWH experiencing a single HIV-RNA of 51-199 copies/mL after BL (index date); controls were defined as those who maintained HIV-RNA ≤50 copies/mL up to the index date and were 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 were used to evaluate the association between the current antiretroviral therapy regimen (2DR [dolutegravir/lamivudine, dolutegravir/rilpivirine, dolutegravir/doravirine, or cabotegravir/rilpivirine] vs 3DR [dolutegravir, bictegravir, rilpivirine, doravirine, boosted darunavir, or boosted atazanavir-based with a backbone of tenofovir and lamivudine or emtricitabine]) and LLVR risk. In sensitivity analyses cases were defined as PWH experiencing 2 consecutive HIV-RNA of 51-199 copies/mL. Results: Among 1033 PWH (261 cases, 772 matched controls), 21% were female, median age was 43 (interquartile range [IQR], 34-51) years, and BL CD4 count was 601 (IQR, 379-826) cells/μL; 2DR use was 25% in cases versus 29% in controls (P = .23). Two years after viral suppression, cumulative LLVR incidence was 2.7% (95% CI, 2.3%-3.1%) when considering single LLVR events and 1.8% (95% CI, 1.4%-2.1%) when limited to 2 consecutive values. After adjusting for confounding, evidence for an association with current regimen was inconclusive (adjusted odds ratio, 0.86 [95% CI, .57-1.29]). Conclusions: Despite the wide range of plausibility, we can exclude a risk of LLVR higher than 29% when using 2DR versus 3DR regimens.