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Comparative Study
. 2025 Jul 15;39(9):1106-1119.
doi: 10.1097/QAD.0000000000004198. Epub 2025 Apr 1.

Dolutegravir plus lamivudine downregulates cellular stress responses vs. three-drug HIV regimens

Victoria Rios-Vazquez  1 , Wilhelm A J W Vos  1   2 , Marc J T Blaauw  1   3 , Louise E Van Eekeren  1 , Albert L Groenendijk  4 , Adriana Navas  1 , Nadira Vadaq  1 , Leo A B Joosten  1   5 , Mihai G Netea  1   6 , Willem L Blok  2 , Janneke E Stalenhoef  2 , Lambert Van Den Heuvel  7 , Andre J A M Van Der Ven  1 , Jan Van Lunzen  1
Affiliations
Comparative Study

Dolutegravir plus lamivudine downregulates cellular stress responses vs. three-drug HIV regimens

Victoria Rios-Vazquez et al. AIDS. .

Abstract

Objective: To compare the systemic and immune effects of two-drug regimens (2DR) and three-drug regimens (3DR) in people with HIV (PWH).

Design: In a cross-sectional study, multiomics data were analyzed in dolutegravir (DTG) plus lamivudine (3TC) 2DR and 3DR comprising DTG with two nucleoside reverse transcriptase inhibitors (NRTIs).

Methods: Data from the 2000HIV cohort of virally suppressed PWH on combination antiretroviral treatment (cART) regimens were analyzed. Groups included DTG + 3TC ( n = 191), DTG + 3TC + abacavir (ABC) ( n = 188), and DTG + tenofovir disoproxil fumarate or tenofovir alafenamide (TDF/TAF) + emtricitabine (FTC) ( n = 115). Systemic functions were assessed via plasma protein profiling (Olink Explore, 2367 proteins), while peripheral blood mononuclear cells (PBMCs) were used to evaluate immune effects by analyzing Bulk RNA-Seq and ex-vivo cytokine production capacity.

Results: Plasma protein analysis revealed that 2DR associated to lower protein expression and pathways related to metabolism, stress responses, chemokine signaling, and immune responses compared to 3DR. Four proteins - CXCL8, DDC, PMM2, and EPS8L2 - were consistently downregulated in 2DR. Differential gene expression analysis identified 17 overlapping downregulated genes across all 3DR vs. 2DR comparisons, linked to chromatin structure, cellular senescence, stress response, and cytokine activity. Cytokine production was similar across 2DR and 3DR groups, except for enhanced interleukin (IL)-17 production in DTG + TDF + FTC users.

Conclusions: Reducing NRTIs in DTG-based 2DR, particularly by omitting ABC or TAF/TDF, suggests decreased activation of stress response and immune-related pathways. Importantly, the functional capacity of circulating immune cells remains largely unchanged between 2DR and 3DR.

Keywords: HIV; antiretroviral therapy; dolutegravir; multiomics; reverse transcriptase inhibitors.

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Conflict of interest statement

All authors are part of the 2000HIV collaboration, supported by ViiV Healthcare. This research was funded by ViiV Healthcare. However, ViiV Healthcare had no involvement in data quality control, statistical analyses, or the final interpretation of the results.

Figures

Fig. 1
Fig. 1
Overview of study design and multiomics analysis in the 2000HIV cohort.
Fig. 2
Fig. 2
Differential protein expression and pathway enrichment in PWH using 2DR and 3DR.
Fig. 3
Fig. 3
Overrepresentation of overlapping DEP between PWH using 2DR vs. 3DR.
Fig. 4
Fig. 4
Differential gene expression and pathway enrichment in PWH using 2DR and 3DR.
Fig. 5
Fig. 5
Overrepresentation of overlapping DEG between PWH using 2DR vs. 3DR.
See this image and copyright information in PMC

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