Persistent monocyte activation and remodeling in people with HIV after 36 months of switching from a 3-drug regimen to B/F/TAF or DTG/3TC: a sub-study of the DEBATE trial
- 1Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia
- 2Virology Unit, Azienda Ospedaliero-Universitaria Policlinico
- 3Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia
Abstract
Introduction: The DEBATE study is a randomised trial comparing standard three-drug antiretroviral therapy (ART) with either a two-drug regimen (DTG/3TC) or an alternative three-drug regimen (B/F/TAF) in people with HIV who are virally suppressed. While these regimens are effective in controlling the virus, their impact on the innate immune system is less well understood. Monocytes play a pivotal role in inflammation by bridging innate and adaptive immunity and maintaining the viral reservoir. Persistent monocyte activation in individuals treated with ART, as indicated by altered subsets, proinflammatory cytokines and soluble markers, has been associated with chronic inflammation and non-AIDS comorbidities. This highlights the clinical relevance of monocyte activation even when viral suppression is achieved.
Methods: Eleven virally suppressed people with HIV (PWH) randomized to switch to dolutegravir/lamivudine (DTG/3TC, n=6) or to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF, n=5) were studied. Peripheral blood mononuclear cells (PBMC) collected at baseline and 36 months after the switch were analyzed using a 17-parameter flow cytometry panel to characterize monocyte phenotype.
Results: Monocyte remodeling in chronically infected, ART-treated PWH involved chemokine receptors such as CX3CR1, CCR5 and CXCR4, which play important roles in cell migration, inflammation and viral reservoir maintenance. Moreover, the upregulation of TAM receptors (MerTK and Tyro3) and CD38 might enhance inflammatory effects in people switching to another three-drug regimen (3DR, B/F/TAF) rather than in those switching to a two-drug regimen (2DR, DTG/3TC). Nonetheless, in DTG/3TC-treated people, inflammation and viral reservoir maintenance might be promoted by the pSTAT3 pathway.
Discussion: Persistent monocyte activation and immune senescence remain detectable in ART-experienced, virologically suppressed people with HIV after switching to either B/F/TAF or DTG/3TC, indicating that regimen optimization alone does not restore innate immune homeostasis. The enhanced expression of migratory and HIV-related receptors suggests ongoing reservoir maintenance and residual inflammation.
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BibTeX
@article{santacroce2026persistent,
title = {{Persistent monocyte activation and remodeling in people with HIV after 36 months of switching from a 3-drug regimen to B/F/TAF or DTG/3TC: a sub-study of the DEBATE trial}},
author = {Elena Santacroce and Alin Liviu Ciobanu and Lara Gibellini and Domenico Lo Tartaro and Sara De Biasi and William Gennari and Enrica Roncaglia and Barbara Beghetto and Giulia Nardini and Cinzia Puzzolante and Jovana Milic and Andrea Cossarizza and Cristina Mussini},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1957183},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1957183/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Persistent monocyte activation and remodeling in people with HIV after 36 months of switching from a 3-drug regimen to B/F/TAF or DTG/3TC: a sub-study of the DEBATE trial
AU - Elena Santacroce
AU - Alin Liviu Ciobanu
AU - Lara Gibellini
AU - Domenico Lo Tartaro
AU - Sara De Biasi
AU - William Gennari
AU - Enrica Roncaglia
AU - Barbara Beghetto
AU - Giulia Nardini
AU - Cinzia Puzzolante
AU - Jovana Milic
AU - Andrea Cossarizza
AU - Cristina Mussini
PY - 2026
DA - 2026/10/14
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1957183
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1957183/full
AB - Introduction: The DEBATE study is a randomised trial comparing standard three-drug antiretroviral therapy (ART) with either a two-drug regimen (DTG/3TC) or an alternative three-drug regimen (B/F/TAF) in people with HIV who are virally suppressed. While these regimens are effective in controlling the virus, their impact on the innate immune system is less well understood. Monocytes play a pivotal role in inflammation by bridging innate and adaptive immunity and maintaining the viral reservoir. Persistent monocyte activation in individuals treated with ART, as indicated by altered subsets, proinflammatory cytokines and soluble markers, has been associated with chronic inflammation and non-AIDS comorbidities. This highlights the clinical relevance of monocyte activation even when viral suppression is achieved. Methods: Eleven virally suppressed people with HIV (PWH) randomized to switch to dolutegravir/lamivudine (DTG/3TC, n=6) or to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF, n=5) were studied. Peripheral blood mononuclear cells (PBMC) collected at baseline and 36 months after the switch were analyzed using a 17-parameter flow cytometry panel to characterize monocyte phenotype. Results: Monocyte remodeling in chronically infected, ART-treated PWH involved chemokine receptors such as CX3CR1, CCR5 and CXCR4, which play important roles in cell migration, inflammation and viral reservoir maintenance. Moreover, the upregulation of TAM receptors (MerTK and Tyro3) and CD38 might enhance inflammatory effects in people switching to another three-drug regimen (3DR, B/F/TAF) rather than in those switching to a two-drug regimen (2DR, DTG/3TC). Nonetheless, in DTG/3TC-treated people, inflammation and viral reservoir maintenance might be promoted by the pSTAT3 pathway. Discussion: Persistent monocyte activation and immune senescence remain detectable in ART-experienced, virologically suppressed people with HIV after switching to either B/F/TAF or DTG/3TC, indicating that regimen optimization alone does not restore innate immune homeostasis. The enhanced expression of migratory and HIV-related receptors suggests ongoing reservoir maintenance and residual inflammation.
SN - 1664-3224
ER -