Switching to dual antiretroviral regimens is associated with improvement or no changes in activation and inflammation markers in virologically suppressed HIV‐1‐infected patients: the TRILOBITHE pilot study

Vallejo, Alejandro; Molano, MdC; Monsalvo‐Hernando, M; Hernández-Walias, Francisco J.; Fontecha‐Ortega, M; Casado, José L.

doi:10.1111/hiv.12749

Cited by 7 publications

(6 citation statements)

References 20 publications

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“…In conclusion, the present study shows for the first time that early-onset HF seen in HIV-1-infected Hu-mice is arising in part from accumulation of the cytotoxic glycolysis metabolite MG. We also showed that this elevation in MG is arising in part from a decrease in its degradation and precipitating dysregulation of coronary microvascular ECs, microvascular leakage, and fibrosis ( Figure 10 ). We posit that an elevation in MG could also be an underlying cause increase in systemic and cardiac inflammation seen during HIV-1 infection by activating NF-κB and NRLP3 ( 4 , 5 , 19 – 21 ). These data also suggest that therapeutic strategies to lower MG levels may be useful in reducing inflammation and HF during HIV-1 infection.…”

Section: Discussionmentioning

confidence: 99%

“…Available data suggest that the pathophysiology of early-onset HF in PLWH is multifactorial, arising from persistent systemic immune activation, elevation in inflammation and oxidative stress, off-target effects of antiretroviral drugs, alcohol, aging, illicit drug use and the composition of the gut microbiome (5,(14)(15)(16)(17)(18)(19)(20)(21)(22). However, specific molecular pathways by which these cues negatively impact cardiac function are not well-defined.…”

Section: Introductionmentioning

confidence: 99%

“…Whether EcoHIV mice, another model in which gp120 from HIV-1 is replaced with murine leukemia virus gp80 for cell entry, also develops HF remains unclear (32). Others have suggested that off-target effects of antiretroviral drugs, alcohol and illicit drug use, and accelerated aging could exacerbate traditional risk factors of cardiovascular diseases and HF potentiating dyslipidemia, hyperglycemia, and endothelial dysfunction (5,(14)(15)(16)(17)(18)(19)(20)(21)33). However, the effects of antiretroviral drugs, alcohol, and illicit drugs, and aging on cardiac function in the setting of HIV-1 infection are limited, making delineation of mechanisms that trigger HF development in HIV-1 setting challenging.…”

Section: Introductionmentioning

confidence: 99%

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A Link Between Methylglyoxal and Heart Failure During HIV-1 Infection

Dash

Alomar

Cox

et al. 2021

Front. Cardiovasc. Med.

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Early-onset heart failure (HF) continues to be a major cause of morbidity and mortality in people living with human immunodeficiency virus type one (HIV-1) infection (PLWH), yet the molecular causes for this remain poorly understood. Herein NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ humanized mice (Hu-mice), plasma from PLWH, and autopsied cardiac tissues from deceased HIV seropositive individuals were used to assess if there is a link between the glycolysis byproduct methylglyoxal (MG) and HF in the setting of HIV-1 infection. At five weeks post HIV infection, Hu-mice developed grade III-IV diastolic dysfunction (DD) with an associated two-fold increase in plasma MG. At sixteen-seventeen weeks post infection, cardiac ejection fraction and fractional shortening also declined by 26 and 35%, and plasma MG increased to four-fold higher than uninfected controls. Histopathological and biochemical analyses of cardiac tissues from Hu-mice 17 weeks post-infection affirmed MG increase with a concomitant decrease in expression of the MG-degrading enzyme glyoxalase-1 (Glo1). The endothelial cell marker CD31 was found to be lower, and coronary microvascular leakage and myocardial fibrosis were prominent. Increasing expression of Glo1 in Hu-mice five weeks post-infection using a single dose of an engineered AAV2/9 (1.7 × 1012 virion particles/kg), attenuated the increases in plasma and cardiac MG levels. Increasing Glo1 also blunted microvascular leakage, fibrosis, and HF seen at sixteen weeks post-infection, without changes in plasma viral loads. In plasma from virally suppressed PLWH, MG was also 3.7-fold higher. In autopsied cardiac tissues from seropositive, HIV individuals with low viral log, MG was 4.2-fold higher and Glo1 was 50% lower compared to uninfected controls. These data show for the first time a causal link between accumulation of MG and HF in the setting of HIV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Link Between Methylglyoxal and Heart Failure During HIV-1 Infection

Dash

Alomar

Cox

et al. 2021

Front. Cardiovasc. Med.

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“…A switch to dual therapy (n = 70 boosted atazanavir plus lamivudine) did not result in a significant changes in the markers mentioned above and did not differ from the markers in patients continuing triple therapy (n = 69). In addition, Vallejo et al published a cross-sectional pilot study evaluating a broad spectrum of inflammation and immune activation biomarkers (interferon-gamma-induced protein 10, hs-CRP, sCD14, D-dimer, interferon-γ, TNF-α and IL-4) in patients on dual therapy vs. those continuing triple therapy (93). The dual therapy group consisted of 13 patients that were evaluated at 24 weeks after switch and 36 patients at 48 weeks, the control group included 26 patients.…”

Section: Immune Activation In Dual Therapymentioning

confidence: 99%

Dual Antiretroviral Therapy—All Quiet Beneath the Surface?

2021

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Infection with the human immunodeficiency virus (HIV) is characterized by progressive depletion of CD4+ lymphocytes cells as a result of chronic immune activation. Next to the decreases in the number of CD4+ cells which leads to opportunistic infections, HIV-related immune activation is associated with several prevalent comorbidities in the HIV-positive population such as cardiovascular and bone disease. Traditionally, combination antiretroviral therapy (cART) consists of three drugs with activity against HIV and is highly effective in diminishing the degree of immune activation. Over the years, questions were raised whether virological suppression could also be achieved with fewer antiretroviral drugs, i.e., dual- or even monotherapy. This is an intriguing question considering the fact that antiretroviral drugs should be used lifelong and their use could also induce cardiovascular and bone disease. Therefore, the equilibrium between drug-induced toxicity and immune activation related comorbidity is delicate. Recently, two large clinical trials evaluating two-drug cART showed non-inferiority with respect to virological outcomes when compared to triple-drug regimens. This led to adoption of dual antiretroviral therapy in current HIV treatment guidelines. However, it is largely unknown whether dual therapy is also able to suppress immune activation to the same degree as triple therapy. This poses a risk for an imbalance in the delicate equilibrium. This mini review gives an overview of the current available evidence concerning immune activation in the setting of cART with less than three antiretroviral drugs.

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“…The advantage of eliminating an antiretroviral and its direct side effects is appealing in populations who have experienced many different antiretrovirals and potential toxicities from them, or in older populations. Other studies focused on questions raised when decreasing the number of antiretrovirals in a regimen: impact on the level of 'residual' inflammation, immune activation, and HIV reservoir or shedding in different anatomical compartments [80][81][82][83][84]. Most of the dual therapies, and particularly those of interest for LMICs, are based on DTG.…”

Section: Drug-sparing Regimens In Second Linementioning

confidence: 99%