Introduction: Because inflammation is associated with mortality and has been linked to HIV transcription in lymphoid tissues during ART, it is necessary to address the long-term effects of switching 3-drug (3DR) to 2-drug regimens (2DR) on inflammation. Methods: This was a nested study in the Spanish AIDS Research Network. We selected HIV-infected ART-naive patients initiating 3DR who achieved viral suppression in the first 48 weeks of ART and either remained on 3DR during their follow-up or switched to 2DR (3TC+bPI; 3TC+DTG; DTG+RPV). We assessed the trajectories on inflammatory predictors of mortality during virologic suppression using multivariate piecewise mixed models. Findings: We analyzed 619 plasma samples from 148 patients (3DR, N=90; 2DR, N=58), the median follow-up was 4.6 (IQR 3.2-6.2) years. There were no significant differences in baseline characteristics between groups. After adjusting for potential confounders, patients with 3DR experienced a slow decline of IL6, high-sensitivity C-reactive protein (hs-CRP), sCD14, sCD163, and D-dimer over time. In contrast, compared to 3DR, switching to 2DR was associated with increases in IL-6 (p=0.001), CRP (p=0.003), and D-dimer (p=0.001) after year 3 from virologic suppression. 2DR was associated with a higher risk of CRP quartile increase (aOR 3.3, 95%CI 1.1-10) and D-dimer quartile increase (aOR 3.7, 95%CI 1.1-13). The adjusted biomarker trajectories did not reveal a distinct pattern according to the type of 2DR used (bPI vs DTG). Interpretation: In this observational study in virally suppressed individuals, maintaining 3DR was associated with a more favorable long-term anti-inflammatory profile than switching to 2DR. The potential clinical implications of these findings on the development of non-AIDS events deserve further investigation. Funding: This work was supported by Instituto de Salud Carlos III, co-financed by the European Development Regional Fund ‘‘A way to achieve Europe’’ (ERDF) (AC17/00019, PI18/00154, COV20/00349, ICI20/00058, the Spanish AIDS Research Network RD16/0025/0001project), and Gilead Sciences (Investigator sponsored research 17- 10192). Declaration of Interest: Outside the submitted work, S. S.-V. reports personal fees from ViiV Healthcare, Janssen Cilag, Gilead Sciences, and MSD as well as non-financial support from ViiV Healthcare and Gilead Sciences and research grants from MSD and Gilead Sciences. J.M.-S. non-financial support from ViiV Healthcare, non-financial support from Jannsen Cilag, non-financial support from Gilead Sciences, outside the submitted work. J.P. reports grants from Instituto de Salud Carlos III during the conduct of the study; grants and personal fees from Gilead Sciences, personal fees from Janssen Cilag, personal fees from ViiV Health Care, personal fees from MSD, outside the submitted work. S.M. reports grants, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Janssen, grants, personal fees and non-financial support from MSD, grants, personal fees and non-financial support from Gilead, outside the submitted work. There are no potential conflicts of interest. Ethical Approval: The Institutional Review Boards of the Carlos III Health Institute located in Madrid, Spain, the Ethics Committee at University Hospital Ramon y Cajal approved the study (ceic.hrc@salud.madrid.org, approval number 133-17).
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