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Effects of integrase inhibitor-based antiretroviral therapy on brain outcomes according to time since acquisition of HIV-1 infection.

ABSTRACT: Integrase strand transfer inhibitors (INSTI) are a main component of the current antiretroviral regimens recommended for treatment of HIV infection. However, little is known about the impact of INSTI on neurocognition and neuroimaging. We developed a prospective observational trial to evaluate the effects of INSTI-based antiretroviral therapy on comprehensive brain outcomes (cognitive, functional, and imaging) according to the time since HIV-1 acquisition. We recruited men living with HIV who initiated antiretroviral therapy with INSTI < 3 months since the estimated date of HIV-1 acquisition (n = 12) and > 6 months since estimated date of HIV-1 acquisition (n = 15). We also recruited a group of matched seronegative individuals (n = 15). Assessments were performed at baseline (before initiation of therapy in HIV arms) and at weeks 4 and 48. Baseline cognitive functioning was comparable between the arms. At week 48, we did not find cognitive differences between starting therapy with INSTI earlier than 3 months or later than 6 months after acquisition of HIV-1 infection. Functional status was poorer in individuals diagnosed earlier. This effect recovered 48 weeks after initiation of therapy. Regarding brain imaging, we found that men living with HIV initiating antiretroviral therapy later experienced a greater decrease in medial orbitofrontal cortex over time, with expected negative repercussions for decision-making tasks.

SUBMITTER: Prats A

PROVIDER: S-EPMC8163778 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Monocytes are increasingly implicated in the inflammatory consequences of HIV-1 disease, yet their phenotype following antiretroviral therapy (ART) initiation is incompletely defined. Here, we define more completely monocyte phenotype both prior to ART initiation and during 48 weeks of ART. METHODS:Cryopreserved peripheral blood mononuclear cells (PBMCs) were obtained at baseline (prior to ART initiation) and at weeks 12, 24, and 48 of treatment from 29 patients participating in ACTG clinical trial A5248, an open label study of raltegravir/emtricitibine/tenofovir administration. For comparison, cryopreserved PBMCs were obtained from 15 HIV-1 uninfected donors, each of whom had at least two cardiovascular risk factors. Thawed samples were stained for monocyte subset markers (CD14 and CD16), HLA-DR, CCR2, CX3CR1, CD86, CD83, CD40, CD38, CD36, CD13, and CD163 and examined using flow cytometry. RESULTS:In untreated HIV-1 infection there were perturbations in monocyte subset phenotypes, chiefly a higher frequency and density (mean fluorescence intensity-MFI) of HLA-DR (%-p = 0.004, MFI-p = .0005) and CD86 (%-p = 0.012, MFI-p = 0.005) expression and lower frequency of CCR2 (p = 0.0002) expression on all monocytes, lower CCR2 density on inflammatory monocytes (p = 0.045) when compared to the expression and density of these markers in controls' monocytes. We also report lower expression of CX3CR1 (p = 0.014) on patrolling monocytes at baseline, compared to levels seen in controls. After ART, these perturbations tended to improve, with decreasing expression and density of HLA-DR and CD86, increasing CCR2 density on inflammatory monocytes, and increasing expression and density of CX3CR1 on patrolling monocytes. CONCLUSIONS:In HIV-1 infected patients, ART appears to attenuate the high levels of activation (HLA-DR, CD86) and to increase expression of the chemokine receptors CCR2 and CX3CR1 on monocyte populations. Circulating monocyte phenotypes are altered in untreated infection and tend to normalize with ART; the role of these cells in the inflammatory environment of HIV-1 infection warrants further study.

Project description:BackgroundIntegrase inhibitors (INI) induce a rapid decline of HIV-RNA in plasma and CD4+ T-cell recovery in blood. Both characteristics are also associated with immune reconstitution inflammatory syndrome (IRIS). Whether the use of INI-containing combination antiretroviral therapy (cART) increases the risk of IRIS is being questioned.MethodsStudy within the Dutch ATHENA HIV observational cohort. HIV-1 infected late presenters initiating cART after March 2009 were included if they had <200 CD4+ T-cells per μL and were diagnosed with an opportunistic infection. IRIS was defined either according to the criteria by French et al. (IRISFRENCH) or by a clinical IRIS diagnosis of the physician (IRISCLINICAL). The primary outcomes were the association between INI and the occurrence of IRISFRENCH and IRISFRENCH+CLINICAL in multivariable logistic regression.Findings672 patients with a median CD4+ T-cell count of 35 cells per μL were included. Treatment with INI was independently associated with IRISFRENCH as well as IRISFRENCH+CLINICAL (OR 2·43, 95%CI:1·45-4·07, and OR 2·17, 95%CI:1·45-3·25). When investigating INI separately, raltegravir (RAL) remained significantly associated with IRISFRENCH (OR 4·04 (95%CI:1·99-8·19) as well as IRISFRENCH+CLINICAL (OR 3·07, 95%CI:1·66-5·69), while dolutegravir (DTG) became associated with IRISFRENCH+CLINICAL after it replaced RAL as preferred INI in the cohort after 2015 (OR 4·08, 95%CI:0·99-16·82, p=0·052). Too few patients used elvitegravir to draw meaningful conclusions. Steroid initiation for IRIS was more likely in those who initiated INI versus in those who did not, but no increased hospital (re)admission or mortality rates were observed.InterpretationIn HIV late presenters from a resource rich setting, INI based treatment initiation increased the risk of IRIS. This was observed for RAL and DTG when being initiated as preferential INI in the presence of specific AIDS-conditions, indicative of channeling bias. Although we controlled for all relevant measured confounders, we cannot exclude that the observed association is partially explained by residual confounding. INI use was not associated with mortality nor hospitalization. Therefore, our observation is no reason to avoid INI in late presenters.FundingThe ATHENA database is maintained by Stichting HIV Monitoring and supported by a grant from the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment.

Project description:IntroductionIntegrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART) has been associated with weight gain, though there is limited information on associations between ART-related weight gain and cardiometabolic outcomes among people living with HIV-1 (PLWH). We, therefore, evaluated risks of incident cardiometabolic outcomes following INSTI versus non-INSTI-based ART initiation in the United States.MethodsWe conducted a retrospective study using IBM MarketScan Research Databases (12 August 2012-31 January 2021). Treatment-naïve PLWH initiating ART (index date) on/after 12 August 2013 (approval date of the first second-generation INSTI, dolutegravir) were included and censored at regimen switch/discontinuation, end of insurance eligibility or end of data availability. We used inverse probability of treatment weights constructed with baseline (12 months pre-index) characteristics to account for differences between INSTI- and non-INSTI-initiating cohorts. Doubly robust hazard ratios (HRs) obtained from weighted multivariable Cox regression were used to compare time to incident cardiometabolic outcomes (congestive heart failure [CHF], coronary artery disease, myocardial infarction, stroke/transient ischemic attack, hypertension, type II diabetes, lipid disorders, lipodystrophy and metabolic syndrome) by INSTI-initiation status.ResultsWeighted INSTI (mean age = 39 years, 23% female, 70% commercially insured, 30% Medicaid insured) and non-INSTI (mean age = 39 years, 24% female, 71% commercially insured, 29% Medicaid insured) cohorts included 7059 and 7017 PLWH, respectively. The most common INSTI-containing regimens were elvitegravir-based (43.4%), dolutegravir-based (33.3%) and bictegravir-based (18.4%); the most common non-INSTI-containing regimens were darunavir-based (31.5%), rilpivirine-based (30.4%) and efavirenz-based (28.3%). Mean±standard deviation follow-up periods were 1.5±1.5 and 1.1±1.2 years in INSTI- and non-INSTI-initiating cohorts, respectively. INSTI initiators were at a clinically and significantly increased risk of experiencing incident CHF (HR = 2.12, 95% confidence interval [CI] = 1.08-4.05; p = 0.036), myocardial infarction (HR = 1.79, 95% CI = 1.03-5.65; p = 0.036) and lipid disorders (HR = 1.26, 95% CI = 1.04-1.58; p = 0.020); there was no evidence of an increased risk for other individual or composite outcomes.ConclusionsOver a short average follow-up period of <2 years, INSTI use among treatment-naïve PLWH was associated with an increased risk of several cardiometabolic outcomes, such as CHF, myocardial infarction and lipid disorders, compared to non-INSTI use. Further research accounting for additional potential confounders and with longer follow-up is warranted to more accurately and precisely quantify the impact of INSTI-containing ART on long-term cardiometabolic outcomes.

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Effects of integrase inhibitor-based antiretroviral therapy on brain outcomes according to time since acquisition of HIV-1 infection.

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