Increasing trend of transmitted integrase inhibitor resistance in a cohort of antiretroviral therapy-naive people living with HIV.
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ABSTRACT:
SUBMITTER: Muccini C
PROVIDER: S-EPMC10243965 | biostudies-literature | 2023 May
REPOSITORIES: biostudies-literature
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Increasing trend of transmitted integrase inhibitor resistance in a cohort of antiretroviral therapy-naive people living with HIV.
Muccini Camilla C Galli Laura L Sampaolo Michela M Gianotti Nicola N Castagna Antonella A Canetti Diana D
The Journal of antimicrobial chemotherapy 20230501 5
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Project description:Cardiovascular disease is an important cause of morbidity and mortality in people living with HIV (PLWH), who commonly experience lipid disturbances. The aim of this study was to determine whether the plasma lipidomic profile differs between PLWH receiving a darunavir-based ART and those receiving integrase inhibitor-based ART. This was a cross-sectional study of unselected patients for whom metabolomic analysis was performed using ultra-high-performance liquid chromatography coupled to mass spectrometry. Data for the two subgroups were compared by calculating the log2 of the fold change for each metabolite and then grouping these into the main lipid families. Sixty-two PLWH aged 49.3 ± 8.6 years (82% men) were included: 12 patients (19.4%) had hypertension, 8 (12.9%) had type 2 diabetes, 25 (41.0%) had dyslipidaemia and 9 (14.5%) were taking statins, without significant differences in all these variables between the two groups. Twenty-five (40.3%) received darunavir-based ART and 37 (59.7%) integrase inhibitor-based ART. Although the differences were not statistically significant, patients treated with darunavir-based ART had higher concentrations of total cholesterol (211 mg/dL vs 194 mg/dL), LDL-cholesterol (132 mg/dL vs 117 mg/dL) and triglycerides (155 mg/dL vs 122 mg/dL), and lower HDL-cholesterol concentration (50 mg/dL vs 52 mg/dL). The main lipid families and metabolites differed slightly between groups (log2-fold change; P-value): ceramides (-0.07; 0.49), phosphatidylinositols (-0.05; 0.63), diacylglycerols (0.10; 0.64), phosphatidylethanolamines (0.03; 0.78), triacylglycerols (0.27; 0.18) and lysophosphatidylethanolamines (0.03; 0.83). In the integrase inhibitor-based group, the use of tenofovir alafenamide fumarate significantly increases the majority of lipid fractions, when compared with tenofovir disoproxil fumarate. The lipidomic profile did not differ between PLWH treated with darunavir-based or integrase inhibitor-based ART. This was especially true for ceramides, which are involved in cardiovascular disease. Further studies are needed to study the impact of ART in lipidomic profile.
| S-EPMC6868233 | biostudies-literature
Project description:ObjectiveAntiretroviral therapy (ART) extends the life of people with HIV (PWH), but these individuals are at increased risk for obesity, dyslipidemia, diabetes, and cardiovascular disease. These comorbidities may be a consequence of HIV-related chronic inflammation and/or adverse effects of ART on tissue regulatory adipose tissue macrophages (ATMs). We sought to determine the effects of HIV/ART on metabolically beneficial ATM populations and functions.DesignWe examined subcutaneous ATMs from PWH on integrase inhibitor-containing ART ( n = 5) and uninfected persons ( n = 9). We complemented these studies with ex vivo and in vitro analyses of peripheral blood mononuclear cell (PBMC) and murine macrophage lipid metabolism and fatty acid oxidation gene expression.MethodsATM populations were examined by flow cytometry. Macrophage lipid metabolism and fatty acid oxidation gene expression were examined by Seahorse assay and quantitative PCR.ResultsAdipose tissue from PWH had reduced populations of metabolically activated CD9 + ATMs compared to that of uninfected controls ( P < 0.001). PBMCs of PWH had lower fatty acid metabolism compared to those of uninfected controls ( P < 0.01). Analysis of murine macrophages revealed that dolutegravir reduced lipid metabolism ( P < 0.001) and increased expression of the fatty acid beta-oxidation enzyme enoyl-CoA hydratase, short chain 1 ( P < 0.05).ConclusionsWe report the loss of metabolically beneficial ATM populations in PWH on ART, altered fatty acid metabolism of blood immune cells, and evidence that dolutegravir alters macrophage fatty acid metabolism. Future studies should examine direct or indirect effects and mechanisms of dolutegravir, and other integrase inhibitors and ART classes, on fatty acid beta-oxidation.
| S-EPMC9391287 | biostudies-literature
Project description:The NOD-like receptor protein family pyrin domain containing 3 (NLRP3) inflammasome, activated in the setting of HIV, contributes to pro-atherogenic inflammation. Among antriretroviral therapy-naïve people with HIV (vs controls), levels of caspase-1-a key component of the NLRP3 inflammasome-were significantly increased. Six months of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate significantly decreased caspase-1 levels in association with CD4+/CD8+ ratio recovery.Trial registration. ClinicalTrials.gov NCT01766726.
| S-EPMC7588107 | biostudies-literature
Project description:Antiretroviral therapy for HIV-2 infection is hampered by intrinsic resistance to many of the drugs used to treat HIV-1. Limited studies suggest that the integrase inhibitors (INIs) raltegravir and elvitegravir have potent activity against HIV-2 in culture and in infected patients. There is a paucity of data on genotypic variation in HIV-2 integrase that might confer intrinsic or transmitted INI resistance.We PCR amplified and analyzed 122 HIV-2 integrase consensus sequences from 39 HIV-2-infected, INI-naive adults in Senegal, West Africa. We assessed genetic variation and canonical mutations known to confer INI-resistance in HIV-1.No amino acid-altering mutations were detected at sites known to be pivotal for INI resistance in HIV-1 (integrase positions 143, 148 and 155). Polymorphisms at several other HIV-1 INI resistance-associated sites were detected at positions 72, 95, 125, 154, 165, 201, 203, and 263 of the HIV-2 integrase protein.Emerging genotypic and phenotypic data suggest that HIV-2 is susceptible to the new class of HIV integrase inhibitors. We hypothesize that intrinsic HIV-2 integrase variation at "secondary" HIV-1 INI-resistance sites may affect the genetic barrier to HIV-2 INI resistance. Further studies will be needed to assess INI efficacy as part of combination antiretroviral therapy in HIV-2-infected patients.
| S-EPMC3134476 | biostudies-literature
Project description:BackgroundNucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens may potentially minimize antiretroviral (ART) toxicities, but demonstrate mixed efficacy and toxicity results. The impact of an integrase strand transfer inhibitor (INSTI) and protease inhibitor (PI) regimen on HIV viral dynamics and T cell kinetics remains underdescribed.ObjectiveTo compare the effect of raltegravir + ritonavir boosted lopinavir (RAL + LPV/r) to efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) on HIV kinetics and T cell dynamics.MethodsFifty participants naïve to ART underwent HIV viral kinetic sampling evaluated using biexponential mixed effects modeling. A subset of 28 subjects (with complete viral suppression) underwent flow cytometry and evaluation of soluble markers of inflammation at weeks 0, 4, and 48 of ART.ResultsRAL + LPV/r compared to EFV/TDF/FTC resulted in a prolonged first phase viral decay rate (18 vs. 13 days p < 0.01). From weeks 0 to 4, RAL + LPV/r was associated with a trend toward greater decreases in activated CD4+ T cells (-3.81 vs. -1.18 p = 0.09) and less decreases in activated effector memory CD4+ T cells (-0.63 vs. -2.69 p-0.07). These trends did not persist to week 48. No differences were noted at any time point for soluble markers of immune activation.ConclusionsThe prolonged first phase viral decay observed with RAL + LPV/r in persons starting ART did not result in differences in viral suppression at week 48. We also observed trends in declines in certain cellular markers of immune activation but it remains unclear if this could translate to long-term immunologic benefits in persons on an INSTI + PI.
| S-EPMC5613656 | biostudies-literature
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.
| S-EPMC10258864 | biostudies-literature
Project description:BackgroundHuman Immunodeficiency Virus (HIV) has claimed the lives of millions of people during the past decades. While several antiretroviral drugs like Integrase Strand Transfer Inhibitors (INSTIs) have been introduced to control HIV, Transmitted Drug Resistance (TDR) in HIV genome caused failure in treatment. This study aimed to investigate TDR and natural occurring mutations (NOPs) in HIV integrase gene in Iranian HIV patients.MethodsIn this cross-sectional study, blood samples of 30 HIV-positive patients who had never taken integrase inhibitors were considered for CD4 T cell count, RT real-time PCR, and, Nested PCR. The sequencing results were analyzed by CLC sequence viewer software and Stanford University HIV Drug Resistance Database.ResultsIn all samples, nine NOPs with a high prevalence were found; however, we did not find any drug resistance mutations, except for a mutation in one sample, which showed a low resistance level. Subtype A1 was dominant in all samples.ConclusionBased on the findings and compared to our previous study, all patients were sustainable to main integrase inhibitors, including bictegravir, raltegravir, bictegravir, elvitegravir and dolutegravir. It seems the resistant mutation pattern attributed to integrase inhibitors was not diffent among studied patients; hence, the prescription of such inhibitors helps physicians to control HIV infection in Iranian HIV-infected patients.
| S-EPMC10395453 | biostudies-literature
Project description:BackgroundHIV integrase inhibitor use is limited by low genetic barrier to resistance and possible cross-resistance among representatives of this class of antiretrovirals. The aim of this study was to analyse integrase sequence variability among antiretroviral treatment naive and experienced patients with no prior integrase inhibitor (InI) exposure and investigate development of the InI drug resistance mutations following the virologic failure of the raltegravir containing regimen.MethodsSequencing of HIV-1 integrase region from plasma samples of 80 integrase treatment naive patients and serial samples from 12 patients with observed virologic failure on raltegravir containing treatment whenever plasma vireamia exceeded >50 copies/ml was performed. Drug resistance mutations were called with Stanford DB database and grouped into major and minor variants. For subtyping bootstrapped phylogenetic analysis was used; Bayesian Monte Carlo Marcov Chain (MCMC) model was implemented to infer on the phylogenetic relationships between the serial sequences from patients failing on raltegravir.ResultsMajority of the integrase region sequences were classified as subtype B; the remaining ones being subtype D, C, G, as well as CRF01_AE , CRF02_AG and CRF13_cpx recombinants. No major integrase drug resistance mutations have been observed in InI-treatment naive patients. In 30 (38.5%) cases polymorphic variation with predominance of the E157Q mutation was observed. This mutation was more common among subtype B (26 cases, 54.2%) than non-B sequences (5 cases, 16.7%), p=0.00099, OR: 5.91 (95% CI:1.77-22.63)]. Other variants included L68V, L74IL, T97A, E138D, V151I, R263K. Among 12 (26.1%) raltegravir treated patients treatment failure was observed; major InI drug resistance mutations (G140S, Q148H and N155H, V151I, E92EQ, V151I, G163R) were noted in four of these cases (8.3% of the total InI-treated patients). Time to the development of drug resistance ranged from 2.6 to 16.3 months with mean increase of HIV viral load of 4.34 (95% CI:1.86-6.84) log HIV-RNA copies/ml at the time of emergence of the major mutations. Baseline polymorphisms, including E157Q were not associated with the virologic failure on raltegravir.ConclusionsIn InI treatment naive patients polymorphic integrase sequence variation was common, with no major resistance mutants. In the treatment failing patients selection of drug resistance occurred rapidly and followed the typical drug resistance pathways. Preexisting integrase polymorphisms were not associated with the treatment failure.
| S-EPMC3547692 | biostudies-literature
Project description:BackgroundThe use of integrase inhibitor-based antiretroviral therapy could be associated with worse weight and metabolic outcomes in patients with HIV infection.MethodsPubMed, EMBASE, and Scopus were searched from inception to March 2022. We selected randomized controlled trials (RCTs) comparing integrase inhibitors with other antiretroviral classes (efavirenz-based or protease inhibitor-based therapies) in naïve HIV patients. Random effects meta-analysis was used to assess the effects of integrase inhibitors vs. controls on weight and lipid outcomes. Effects were described as mean differences (MD) and their 95% confidence intervals (CI). Certain pieces of evidence (CoE) were evaluated using the GRADE methodology.ResultsSix RCTs (n = 3521) were included, with patients followed up between 48 and 96 weeks. The use of integrase inhibitors in comparison with other antiretroviral classes was associated with an increase in weight (MD 2.15 kg, 95%CI 1.40 to 2.90, I2 = 0%, moderate CoE), and decreases in total cholesterol (MD -13.44 mg/dL, 95%CI -23.49 to -3.39, I2 = 96%, low CoE), LDL cholesterol (MD -1.37 mg/dL, 95%CI -19.24 to -3.50, I2 = 83%, low CoE), HDL cholesterol (MD -5.03 mg/dL, 95%CI -10.61 to 0.54, I2 = 95%, low CoE), and triglycerides (MD -20.70 mg/dL, 95%CI -37.25 to -4.15, I2 = 92%, low CoE). There was a high risk of bias in two RCTs and some concerns about bias in two RCTs.ConclusionsIn HIV patients, the use of integrase inhibitor-based therapy in comparison with protease inhibitor- or NNRTI-based therapy was associated with a small increase in weight and small decreases in lipid serum levels.
| S-EPMC10253862 | biostudies-literature
Project description:Abstract Background Patients with human immunodeficiency virus (HIV) are at a significantly higher risk of cardiovascular disease (CVD) compared to HIV‐negative people. Left heart dysfunction is the most common cardiac complication in people living with HIV/acquired immune deficiency syndrome (PLWHA), and diastolic dysfunction is an important predictor of cardiovascular events. The aims of this study were (1) to detect changes in left cardiac structure and function in antiretroviral therapy (ART)‐naive PLWHA using echocardiography; and (2) to investigate the risk factors for the development of left ventricular diastolic dysfunction (LVDD) in ART‐naive PLWHA. Methods We retrospectively included 105 ART‐naïve PLWHA and included 90 healthy subjects as controls to compare the differences in left heart structure and function between the two groups. Univariate and multifactorial logistic regression were employed to explore the risk factors of the development of LVDD in ART‐naive PLWHA. Results The left ventricular end‐diastolic internal diameter (LVEDD), left ventricular mass index (LVMI), and left atrial volume index (LAVI) were significantly greater in PLWHA than in controls (p < .05). The E/A ratio, lateral e′ velocity, and mitral deceleration time were significantly lower in PLWHA than in controls (p < .05). Average E/e′ ratio was significantly higher in PLWHA than in controls (p < .05). Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were not significantly different between PLWHA and controls (p > .05). Multifactorial logistic regression analysis showed that age, body mass index (BMI), and CD4+ count <200 cells/μL were independent risk factors for LVDD in ART‐naive PLWHA (OR = 1.781, 1.228, 3.683, p < .05). Conclusions Left ventricular systolic function did not differ between PLWHA and controls, and left ventricular diastolic function was lower in PLWHA than in controls. Age, BMI, and CD4+ count were independent factors affecting LVDD in ART‐naive PLWHA. Left ventricular systolic function did not differ between patients living with HIV/AIDS (PLWHA) and controls, and left ventricular diastolic function was lower in PLWHA than in controls. Age, body mass index, and CD4+ count were independent factors affecting left ventricular diastolic dysfunction in antiretroviral therapy‐naive PLWHA.
| S-EPMC10091372 | biostudies-literature