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. 2022 Mar 14:13:848630.
doi: 10.3389/fimmu.2022.848630. eCollection 2022.

Long-Term Changes of Inflammatory Biomarkers in Individuals on Suppressive Three-Drug or Two-Drug Antiretroviral Regimens

Sergio Serrano-Villar  1   2 , María Rosa López-Huertas  3 , Daniel Jiménez  1   2 , Carlos Galera  4 , Javier Martínez-Sanz  1   2 , Elena Moreno  1   2 , Alfonso Muriel  5   6 , Félix Gutiérrez  2   7 , Carmen Busca  2   8 , Joaquín Portilla  9 , Otilia Bisbal  10 , José Antonio Iribarren  11 , Francisco Tejerina  12 , Ignacio de Los Santos  13 , Santiago Moreno  1   2
Affiliations

Long-Term Changes of Inflammatory Biomarkers in Individuals on Suppressive Three-Drug or Two-Drug Antiretroviral Regimens

Sergio Serrano-Villar et al. Front Immunol. .

Abstract

Background: 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: Nested study in the Spanish AIDS Research Network. We selected PWH ART-naive initiating 3DR who achieved viral suppression in the first 48 weeks and either remained on 3DR or switched to 2DR (3TC+bPI; 3TC+DTG; DTG+RPV). We assessed the trajectories on inflammatory markers during ART using multivariate piecewise mixed models.

Results: 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, 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), hs-CRP (p=0.003), and D-dimer (p=0.001) after year 3 from virologic suppression. 2DR was associated with a higher risk of hs-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).

Conclusions: In this study in virally suppressed individuals, maintaining 3DR was associated with a more favorable long-term inflammatory profile than switching to 2DR. The potential clinical implications of these findings on the development of non-AIDS events deserve further investigation.

Keywords: HIV; antiretroviral therapy; c reactive protein; d-dimer; inflammation.

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Conflict of interest statement

Outside the submitted work, SS-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. JM-S, non-financial support from ViiV Healthcare, non-financial support from Jannsen Cilag, non-financial support from Gilead Sciences, outside the submitted work. JP 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. SM 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. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer PH declared a past collaboration with one of the authors SS-V to the handling editor.

Figures

Figure 1
Figure 1
Details the distribution of ART combinations in the study population.
Figure 2
Figure 2
(A–F) Effects of switch to 2-drug regimens (2DR) on inflammatory biomarkers compared to remaining on 3-drug regimens (3DR). Panels represent the values predicted in piecewise linear mixed models at intervals between years 0-1, 1-2, 2-3, 3-4 and 4-8, adjusted for age, sex, country of origin, mode of transmission, educational level, maximum HIV RNA, previous AIDS, nadir CD4, and pre-ART biomarker value. Lines represent predicted mean values and dots the individual observations. The P values shown in represent the between-group comparison of biomarker trajectories from year 3 to 8. The tables piecewise comparisons for the periods 0-3 and 3-8, are provided in Table 2. 3DR, 3-drug regimens; 2DR, 2-drug regimens.
Figure 3
Figure 3
Effects of switch to 2-drug regimens (2DR), segregated by the type of 2DR regimen, on inflammatory biomarkers compared to remaining on 3-drug regimens (3DR). Panels represent the values predicted in piecewise linear mixed models at intervals between years 0-1, 1-2, 2-3, 3-4 and 4-8, adjusted for age, sex, country of origin, mode of transmission, educational level, maximum HIV RNA, previous AIDS, nadir CD4, and pre-ART biomarker value. Lines represent predicted mean values and dots the individual observations. Abbreviatures, 3DR, 3-drug regimens; 2DR-PI, protease inhibitor 2-drug regimens; 2DR-DTG, dolutegravir-based 2-drug regimens.
Figure 4
Figure 4
Adjusted odds ratio for biomarker quartile increase during follow-up by associated with switch to 2-drug regimens (2DR) compared to remaining on 3-drug regimens (3DR). Models were adjusted for age, sex, mode of transmission, education level, calendar year, baseline HIV RNA, diagnosis of AIDS during follow-up, nadir CD4, inflammatory biomarker concentration at HIV RNA suppression.
Figure 5
Figure 5
Pairwise correlations between inflammatory biomarkers. The panel represent pairwise correlations using Spearman’s Rho coefficients between each pair of inflammatory biomarkers.
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