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INTRODUCTION: The DOLAM trial revealed that switching from triple antiretroviral therapy (three-drug regimen; 3DR) to dolutegravir plus lamivudine (two-drug regimen; 2DR) was virologically non-inferior to continuing 3DR after 48â weeks of follow-up. Weight increased with 2DR relative to 3DR but it did not impact on metabolic parameters. METHODS: Multiomics plasma profile was performed to gain further insight into whether this therapy switch might affect specific biological pathways. DOLAM (EudraCT 201500027435) is a Phase 4, randomized, open-label, non-inferiority trial in which virologically suppressed persons with HIV treated with 3DR were assigned (1:1) to switch to 2DR or to continue 3DR for 48â weeks. Untargeted proteomics, metabolomics and lipidomics analyses were performed at baseline and at 48â weeks. Univariate and multivariate analyses were performed to identify changes in key molecules between both therapy arms. RESULTS: Switching from 3DR to 2DR showed a multiomic impact on circulating plasma concentration of N-acetylmuramoyl-L-alanine amidase (Q96PD5), insulin-like growth factor-binding protein 3 (A6XND0), alanine and triglyceride (TG) (48:0). Correlation analyses identified an association among the up-regulation of these four molecules in persons treated with 2DR. CONCLUSIONS: Untargeted multiomics profiling studies identified molecular changes potentially associated with inflammation immune pathways, and with lipid and glucose metabolism. Although these changes could be associated with potential metabolic or cardiovascular consequences, their clinical significance remains uncertain. Further work is needed to confirm these findings and to assess their long-term clinical consequences.
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Infecções por HIV , Compostos Heterocíclicos com 3 Anéis , Lamivudina , Oxazinas , Piperazinas , Piridonas , Humanos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Infecções por HIV/tratamento farmacológico , Lamivudina/uso terapêutico , Lamivudina/administração & dosagem , Masculino , Oxazinas/uso terapêutico , Feminino , Adulto , Pessoa de Meia-Idade , Metabolômica , Lipidômica , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Plasma/química , Proteômica , Terapia Antirretroviral de Alta Atividade , Substituição de Medicamentos , Triglicerídeos/sangue , Alanina/sangue , MultiômicaRESUMO
BACKGROUND: In the NEAT022 trial, switching from boosted PIs (PI/r) to dolutegravir in people with HIV (PWH) with high cardiovascular risk decreased plasma lipids, soluble CD14 and adiponectin, and showed consistent favourable, although non-significant, effects on carotid intima-media thickness (CIMT) progression at 48 weeks. We hereby communicate planned final 96 week results on biomarker changes and CIMT progression. METHODS: PWH on a PI/r-based triple therapy regimen were randomly assigned (1:1) to switch the PI/r component to dolutegravir either immediately (DTG-I group) or after 48 weeks (DTG-D group) and were followed up to 96 weeks. We assessed changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury and glomerular and tubular kidney injury, and right and left CIMT progression at 48 and 96 weeks. RESULTS: Of 415 PWH randomized, 287 (69%) and 143 (34%) contributed to the biomarker and CIMT substudies respectively. There were significant 96 week changes in biomarkers associated with inflammation, immune activation, oxidation, insulin resistance and myocardial injury. Most changes were favourable, except for adiponectin reduction, which may suggest higher insulin resistance. We were unable to detect significant changes in the progression of CIMT between arms or within arms at 96 weeks. DISCUSSION: After 96 weeks, switching from PI/r to dolutegravir in PWH with high cardiovascular risk led to significant changes in several biomarkers associated with cardiovascular disease. Although most changes were favourable, adiponectin reduction was not. There were non-significant changes in CIMT progression.
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Fármacos Anti-HIV , Doenças Cardiovasculares , Infecções por HIV , Inibidores da Protease de HIV , Resistência à Insulina , Humanos , Inibidores da Protease de HIV/uso terapêutico , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Adiponectina/uso terapêutico , Espessura Intima-Media Carotídea , Biomarcadores , Inflamação , Fármacos Anti-HIV/uso terapêuticoRESUMO
BACKGROUND: Integrase inhibitors have been recently linked to a higher risk for hypertension. In NEAT022 randomized trial, virologically suppressed persons with human immunodeficiency virus (HIV, PWH) with high cardiovascular risk switched from protease inhibitors to dolutegravir either immediately (DTG-I) or after 48 weeks (DTG-D). METHODS: Primary endpoint was incident hypertension at 48 weeks. Secondary endpoints were changes in systolic (SBP) and diastolic (DBP) blood pressure; adverse events and discontinuations associated with high blood pressure; and factors associated with incident hypertension. RESULTS: At baseline, 191 (46.4%) participants had hypertension and 24 persons without hypertension were receiving antihypertensive medications for other reasons. In the 197 PWH (n = 98, DTG-I arm; n = 99, DTG-D arm) without hypertension or antihypertensive agents at baseline, incidence rates per 100 person-years were 40.3 and 36.3 (DTG-I) and 34.7 and 52.0 (DTG-D) at 48 (P = .5755) and 96 (P = .2347) weeks. SBP or DBP changes did not differed between arms. DBP (mean, 95% confidence interval) significantly increased in both DTG-I (+2.78 mmHg [1.07-4.50], P = .0016) and DTG-D (+2.29 mmHg [0.35-4.23], P = .0211) arms in the first 48 weeks of exposure to dolutegravir. Four (3 under dolutegravir, 1 under protease inhibitors) participants discontinued study drugs due to adverse events associated with high blood pressure. Classical factors, but not treatment arm, were independently associated with incident hypertension. CONCLUSIONS: PWH at high risk for cardiovascular disease showed high rates of hypertension at baseline and after 96 weeks. Switching to dolutegravir did not negatively impact on the incidence of hypertension or blood pressure changes relative to continuing protease inhibitors.
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Most of the studies using the colorectal tissue explants challenge model have been conducted after one single dose and before reaching a steady state. We consider that longer exposure as in 28-day postexposure prophylaxis (PEP) course and in an at-risk setting, such as after a sexual risk exposure to HIV could give us valuable information about these drugs. In a substudy we assessed pharmacokinetics, changes on immune system and ex-vivo rectal mucosal susceptibility to HIV-1 infection after taking maraviroc (MVC), raltegravir (RAL), and ritonavir-boosted lopinavir (LPV/r) PEP-based regimens in 30 men who have sex with men. Participants received 28 days of twice-daily MVC (n = 11), RAL (n = 10) or LPV/r (n = 9) all with tenofovir/emtricitabine (TDF/FTC) backbone. Blood, rectal fluid, and rectal tissue samples were collected at days 7, 28, and 90 after starting PEP. The samples obtained at day 90 were considered baseline. All studied antiretrovirals were quantifiable at 7 and 28 days in all tissues. Activation markers were increased in CD4 mucosal mononuclear cells (MMCs) after 28 days of MVC: CD38 + 68.5 versus 85.1, p = .008 and CD38+DR +16.1 versus 26.7, p = .008. Exposure to MVC at both endpoints (7 and 28 days) was associated with significant suppression of HIV-1BAL (p = .005 and p = .028), but we did not observe this effect with RAL or LPV/r. Merging together changes in MMC in all arms, we found a positive correlation in the CD8 T cell lineage between the infectivity at day 7 and activation (CD38+ r = 0.43, p = .025, DR + r = 0.547, p = .003 and 38+DR+ r = 0.526, p = .05), senescence (CD57+CD28- r = 0.479, p = .012), naive cells (RA+CCR7+ r = 0.484, p = .01), and CCR5 expression (r = 0.593, p = .001). We conclude that MVC in combination with TDF/FTC was associated with viral suppression in rectal explants and that overall ex-vivo HIV infectivity correlated with activation and senescence in CD8 MMCs.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Minorias Sexuais e de Gênero , Masculino , Humanos , Maraviroc , Raltegravir Potássico/uso terapêutico , Lopinavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Fármacos Anti-HIV/uso terapêutico , Homossexualidade Masculina , Emtricitabina/uso terapêutico , Ritonavir/uso terapêutico , Profilaxia Pós-ExposiçãoRESUMO
BACKGROUND: In the NEAT022 trial, virologically suppressed persons with human immunodeficiency virus (HIV) at high cardiovascular risk switching from protease inhibitors to dolutegravir either immediately (DTG-I) or after 48 weeks (DTG-D) showed noninferior virological suppression and significant lipid and cardiovascular disease risk reductions on switching to dolutegravir relative to continuing protease inhibitors. METHODS: In post hoc analysis, major endpoints were 48-week and 96-week weight and body mass index (BMI) changes. Factors associated with weight/BMI changes within the first 48 weeks of DTG exposure, proportion of participants by category of percentage weight change, proportions of BMI categories over time, and impact on metabolic outcomes were also assessed. RESULTS: Between May 2014 and November 2015, 204 (DTG-I) and 208 (DTG-D) participants were included. Weight significantly increased (mean, +0.810 kg DTG-I arm, and +0.979 kg DTG-D arm) in the first 48 weeks postswitch, but remained stable from 48 to 96 weeks in DTG-I arm. Switching from darunavir, White race, total to high-density lipoprotein cholesterol ratio <3.7, and normal/underweight BMI were independently associated with higher weight/BMI gains. The proportion of participants with ≥5% weight change increased similarly in both arms over time. The proportions of BMI categories, use of lipid-lowering drugs, diabetes and/or use of antidiabetic agents, and hypertension and/or use of antihypertensive agents did not change within or between arms at 48 and 96 weeks. CONCLUSIONS: Switching from protease inhibitors to dolutegravir in persons with HIV with high cardiovascular risk led to modest weight gain limited to the first 48 weeks, which involved preferentially normal-weight or underweight persons and was not associated with negative metabolic outcomes. CLINICAL TRIALS REGISTRATION: NCT02098837 and EudraCT 2013-003704-39.
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Fármacos Anti-HIV , Doenças Cardiovasculares , Infecções por HIV , HIV-1 , Humanos , Inibidores de Proteases/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Magreza/tratamento farmacológico , Resultado do Tratamento , Fatores de Risco , Fármacos Anti-HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Fatores de Risco de Doenças Cardíacas , LipídeosRESUMO
We described a novel HIV autologous isolation method based in coculturing macrophages and CD4+T-cell-enriched fractions from peripheral blood collected from antiretroviral-treated (ART) HIV patients. This method allows the isolation of high viral titers of autologous viruses, over 1010HIV RNA copies/ml, and reduces the time required to produce necessary amounts for virus for use as antigens presented by monocyte-derived myeloid cells in HIV therapeutic vaccine approaches. By applying these high titer and autologous virus produced in the patient-derived cells, we intended to elicit a boost of the immunological system response in HIV therapeutic vaccines in clinical trials.
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BACKGROUND: The aim of this study was to investigate whether switching from a ritonavir-boosted PI-based regimen to a dolutegravir-based regimen improved the atherogenic properties of LDL particles in patients with HIV. METHODS: This was a substudy of the NEAT022 study (ClinicalTrials.gov NCT02098837). Adults with HIV with a Framingham score >10% or aged >50â years and being treated with a stable boosted PI-based regimen were randomized to either switch to dolutegravir or continue with boosted PI. At baseline and Week 48, we assessed atherogenic LDL properties: LDL particle size and phenotype (A, intermediate, B), oxidized LDL (ox-LDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity. RESULTS: Eighty-six participants (dolutegravir 44; PI 42) were included. Participants had a median (IQR) age of 54 (51-57) years and 79.1% were male. In the dolutegravir arm, after 48â weeks, we observed: (1) an increase in LDL size [median 1.65â Å (IQR -0.60 to 4.20); Pâ=â0.007], correlated with the decrease in triglyceride concentration [Spearman correlationâ=â-0.352 (Pâ=â0.001)], with a corresponding decrease of subjects with atherogenic LDL phenotype B (36.4% to 20.5%; Pâ=â0.039); (2) a decrease in Lp-PLA2 activity [median 1.39â µmol/min/mL (IQR -2.3 to 0.54); Pâ=â0.002]; and (3) a decrease in ox-LDL [median 14â U/L (IQR -102 to 13); Pâ=â0.006]. In the PI arm, none of these favourable lipid modifications was observed. CONCLUSIONS: Forty-eight weeks after switching from a PI-based to a dolutegravir-based regimen, patients with Framingham score >10% or aged >50â years showed improvement of several atherogenic lipid features, including LDL particle phenotype, ox-LDL and Lp-PLA2.
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Fármacos Anti-HIV , Aterosclerose , Infecções por HIV , Lipoproteínas LDL , 1-Alquil-2-acetilglicerofosfocolina Esterase/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Inibidores de Proteases/uso terapêutico , PiridonasRESUMO
Introduction: Functional cure has been proposed as an alternative to lifelong antiretroviral therapy and therapeutic vaccines represent one of the most promising approaches. Materials and Methods: We conducted a double-blind randomized placebo-controlled clinical trial to evaluate the safety, immunogenicity, and effect on viral dynamics of a therapeutic vaccine produced with monocyte-derived dendritic cells (MD-DC) loaded with a high dose of heat-inactivated autologous (HIA) HIV-1 in combination with pegylated interferon alpha 2a (IFNα-2a) in people with chronic HIV-1. Results: Twenty-nine male individuals on successful ART and with CD4+ ≥450 cells/mm3 were randomized 1:1:1:1 to receive three ultrasound-guided inguinal intranodal immunizations, one every 2 weeks: (1) vaccine ~107 MD-DC pulsed with HIA-HIV-1 (1010 HIV RNA copies) (n = 8); (2) vaccine plus three doses of 180 mcg IFNα-2a at weeks 4-6 (n = 6); (3) placebo = saline (n = 7); and (4) placebo plus three doses of 180 mcg IFNα-2a (n = 8). Thereafter, treatment was interrupted (ATI). Vaccines, IFNα-2a, and the administration procedures were safe and well tolerated. All patients' viral load rebounded during the 12-week ATI period. According to groups, changes in viral set-point between pre-ART and during ATI were not significant. When comparing all groups, there was a tendency in changes in viral set-point between the vaccine group vs. vaccine + IFNα-2a group (>0.5log10p = 0.05). HIV-1-specific T-cell responses (IFN-Æ´ Elispot) were higher at baseline in placebo than in the vaccine group (2,259 ± 535 vs. 900 ± 200 SFC/106 PBMC, p = 0.028). A significant difference in the change of specific T-cell responses was only observed at week 4 between vaccine and placebo groups (694 ± 327 vs. 1,718 ± 282 SFC/106 PBMC, p = 0.04). No effect on T-cell responses or changes in viral reservoir were observed after INFα-2a administration. Discussion: Results from this study show that intranodally administered DC therapeutic vaccine in combination with IFNα-2a was safe and well-tolerated but had a minimal impact on viral dynamics in HIV-1 chronic infected participants. Clinical Trial Registration: (www.ClinicalTrials.gov), identifier NCT02767193.
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Vacinas contra a AIDS/imunologia , Antirretrovirais/imunologia , Células Dendríticas/imunologia , Infecções por HIV/terapia , Interferon-alfa/imunologia , Vacinas contra a AIDS/administração & dosagem , Adulto , Antirretrovirais/administração & dosagem , Contagem de Linfócito CD4 , Terapia Combinada , Método Duplo-Cego , Vias de Administração de Medicamentos , Infecções por HIV/imunologia , Humanos , Interferon-alfa/administração & dosagem , Linfonodos/imunologia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Polietilenoglicóis/administração & dosagem , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Linfócitos T/imunologia , Fatores de Tempo , Suspensão de TratamentoRESUMO
A growing number of studies indicate that mRNAs and long ncRNAs can affect protein populations by assembling dynamic ribonucleoprotein (RNP) granules. These phase-separated molecular 'sponges', stabilized by quinary (transient and weak) interactions, control proteins involved in numerous biological functions. Retroviruses such as HIV-1 form by self-assembly when their genomic RNA (gRNA) traps Gag and GagPol polyprotein precursors. Infectivity requires extracellular budding of the particle followed by maturation, an ordered processing of â¼2400 Gag and â¼120 GagPol by the viral protease (PR). This leads to a condensed gRNA-NCp7 nucleocapsid and a CAp24-self-assembled capsid surrounding the RNP. The choreography by which all of these components dynamically interact during virus maturation is one of the missing milestones to fully depict the HIV life cycle. Here, we describe how HIV-1 has evolved a dynamic RNP granule with successive weak-strong-moderate quinary NC-gRNA networks during the sequential processing of the GagNC domain. We also reveal two palindromic RNA-binding triads on NC, KxxFxxQ and QxxFxxK, that provide quinary NC-gRNA interactions. Consequently, the nucleocapsid complex appears properly aggregated for capsid reassembly and reverse transcription, mandatory processes for viral infectivity. We show that PR is sequestered within this RNP and drives its maturation/condensation within minutes, this process being most effective at the end of budding. We anticipate such findings will stimulate further investigations of quinary interactions and emergent mechanisms in crowded environments throughout the wide and growing array of RNP granules.
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Infecções por HIV/virologia , HIV-1 , Proteínas do Nucleocapsídeo/imunologia , Proteases Virais/imunologia , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Montagem de VírusRESUMO
BACKGROUND: Simplified antiretroviral therapy (ART) regimens are desirable for people with HIV. We investigated the efficacy and safety of switching from triple ART to dual dolutegravir plus lamivudine therapy. METHODS: DOLAM is a phase 4, randomised, open-label, non-inferiority trial, done at six HIV clinics in Catalonia, Spain. Adults with HIV-1 receiving a triple ART regimen, aged 18 years or older, with virological suppression, a CD4 nadir of at least 200 cells per µL, who were HBsAg-negative, and without previous viral failure or resistance mutations to study drugs were eligible. Participants underwent computer-generated randomisation, stratified by the class of the third drug, and were assigned (1:1) to switch to oral dolutegravir 50 mg and lamivudine 300 mg once daily or to continue triple ART for 48 weeks. The primary endpoint was the proportion of people with an HIV RNA value of at least 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm, 8% non-inferiority margin). Both the primary and safety outcomes were evaluated in the intention-to-treat exposed population. The study is completed and was registered with EudraCT 201500027435. FINDINGS: Between July 7, 2015, and Oct 31, 2018, 265 participants were randomly assigned to switch to dolutegravir plus lamivudine (n=131) or to maintain triple ART (n=134) and all received at least one dose. Nine (7%) participants in the dual therapy group and ten (7%) in the triple therapy group were excluded before 48 weeks, mostly due to treatment discontinuations or virological failure. Participants were predominantly male (116 [87%] of 134 in the triple ART group and 111 [85%] of 131 in the dolutegravir plus lamivudine group). The difference in the proportion of participants with HIV RNA values of at least 50 copies per mL at 48 weeks between the dual therapy group (three [2%] of 131) and triple therapy group (two [1%] of 134) was 0·8 percentage points (95% CI -3·3 to 5·2), showing non-inferiority of dolutegravir plus lamivudine dual therapy compared with triple ART. 73 (56%) of 131 participants allocated to dual therapy had 150 adverse effects, compared with 78 (58%) of 134 participants allocated to triple therapy who also had 150 adverse events (p=0·68). Drug discontinuation due to adverse effects occurred in four people in the triple therapy group and three people in the dual therapy group. INTERPRETATION: Our findings show the efficacy and safety of dolutegravir plus lamivudine as a simplified therapy switch option for selected people with HIV with virological suppression on triple ART. FUNDING: Instituto de Salud Carlos III, Red de Investigación en Sida, and ViiV Healthcare.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Lamivudina/administração & dosagem , Oxazinas/administração & dosagem , Piperazinas/administração & dosagem , Piridonas/administração & dosagem , Adulto , Fármacos Anti-HIV/efeitos adversos , HDL-Colesterol/sangue , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Lamivudina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Piridonas/efeitos adversosRESUMO
BACKGROUND: Switching from boosted PIs to dolutegravir in people living with HIV (PLWH) with high cardiovascular risk improved plasma lipids at 48 weeks in the NEAT022 trial. Whether this strategy may have an impact on cardiovascular biomarkers is unknown. METHODS: We assessed 48 week changes in biomarkers associated with inflammation, endothelial dysfunction, monocyte immune activation, oxidation, insulin resistance, hypercoagulability, heart failure, myocardial injury, and glomerular and tubular kidney injury. RESULTS: Of 415 PLWH randomized in the NEAT022 study, 313 (75.4%) remained on allocated therapy and had paired samples available. Soluble CD14 (-11%, P < 0.001) and adiponectin (-11%, P < 0.001) significantly declined and high-sensitive C-reactive protein (-13%, P = 0.069) and oxidized LDL (-13%, P = 0.084) tended to decrease with dolutegravir. Switching to dolutegravir remained significantly associated with soluble CD14 and adiponectin reductions after adjustment for baseline variables. There were inverse correlations between soluble CD14 and CD4 count changes (P = 0.05), and between adiponectin and BMI changes (P < 0.001). CONCLUSIONS: Switching from boosted PIs to dolutegravir in PLWH with high cardiovascular risk led to soluble CD14 and adiponectin reductions at 48 weeks. While decreasing soluble CD14 may entail favourable health effects in PLWH, adiponectin reduction may reflect less insulin sensitivity associated with weight gain.
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Doenças Cardiovasculares , Infecções por HIV , Adiponectina , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Fatores de Risco de Doenças Cardíacas , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Receptores de Lipopolissacarídeos , Oxazinas , Piperazinas , Piridonas , Fatores de Risco , Ritonavir/administração & dosagemRESUMO
BACKGROUND: Switching from boosted PIs to dolutegravir in virologically suppressed HIV-infected patients with high cardiovascular risk significantly decreased total cholesterol and other proatherogenic lipid fractions at 48 weeks. The impact of this strategy on subclinical cardiovascular disease is unknown. METHODS: NEAT022 is a European, multicentre, open-label, randomized, non-inferiority trial. HIV-infected adults aged >50 years or with a Framingham score >10% were eligible if plasma HIV RNA was <50 copies/mL for >24 weeks on a boosted PI-based regimen. Patients were randomized 1:1 to switch from boosted PIs to dolutegravir or to continue on boosted PIs. Common carotid arteries intima-media thickness (CIMT) and pulse wave velocity (PWV) were measured following a standardized protocol in a subgroup of NEAT022 study participants at baseline and at Week 48. RESULTS: One hundred and fifty-six patients participated in the ultrasonography and arterial stiffness substudies, respectively. In each substudy, population characteristics did not differ between arms and matched those of the main study. At 48 weeks, patients who switched to dolutegravir had lower mean progression of both right (+4 versus +14.6 µm) and left (-6.1 versus +1.6 µm) CIMT and also a smaller increase in mean PWV (+0.18 versus +0.39 m/s) than patients continuing on boosted PIs, although differences were not statistically significant. CIMT trends were consistent across Framingham score, age and country. Inconsistent effects were seen in arterial stiffness. CONCLUSIONS: Relative to continuing on boosted PIs, switching to dolutegravir in virologically suppressed patients with high cardiovascular risk showed consistent favourable although non-significant trends on CIMT progression at 48 weeks.
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Fármacos Anti-HIV , Doenças Cardiovasculares , Infecções por HIV , Adulto , Fármacos Anti-HIV/efeitos adversos , Espessura Intima-Media Carotídea , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Fatores de Risco de Doenças Cardíacas , Compostos Heterocíclicos com 3 Anéis , Humanos , Oxazinas , Piperazinas , Análise de Onda de Pulso , Piridonas , Fatores de Risco , Carga ViralRESUMO
BACKGROUND: Antiretroviral treatment (ART) reduces HIV infectiousness but the effect of early ART on sexual behaviour is unclear. METHODS: We assessed, within the START randomized trial that enrolled HIV-positive adults with CD4 cell count greater than 500âcells/µl, the effect of early (immediate) versus deferred ART on: condomless sex with HIV-serodifferent partners (CLS-D); all condomless sex (CLS); HIV transmission-risk sex (CLS-D-HIV risk, defined as CLS-D and: not on ART or started ART <6 months ago or viral load greater than 200 copies/ml or no viral load in past 6 months), during 2-year follow-up. Month-12 CLS-D (2010-2014) was the primary outcome. RESULTS: Among 2562 MSM, there was no difference between immediate and deferred arms in CLS-D at month 12 [12.6 versus 13.1%; difference (95% CI): -0.4% (-3.1 to 2.2%), Pâ=â0.75] or month 24, or in CLS. Among 2010 heterosexual men and women, CLS-D at month 12 tended to be higher in the immediate versus deferred arm [10.8 versus 8.3%; difference:2.5% (-0.1 to 5.2%), Pâ=â0.062]; the difference was greater at month 24 [9.3 versus 5.6%; difference: 3.7% (1.0 to 6.4%), Pâ=â0.007], at which time CLS was higher in the immediate arm (20.7 versus 15.7%, Pâ=â0.013). CLS-D-HIV risk at month 12 was substantially lower in the immediate versus deferred arm for MSM [0.2 versus 11%; difference: -10.7% (-12.5 to -8.9%), Pâ<â0.001] and heterosexuals [0.6% versus 7.7%; difference: -7.0% (-8.8 to -5.3%), Pâ<â0.001], because of viral suppression on ART. CONCLUSION: A strategy of early ART had no effect on condomless sex with HIV-serodifferent partners among MSM, but resulted in modestly higher prevalence among heterosexuals. However, among MSM and heterosexuals, early ART resulted in a substantial reduction in HIV-transmission-risk sex, to a very low absolute level.
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Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Comportamento Sexual/estatística & dados numéricos , Adulto , Contagem de Linfócito CD4 , Preservativos/estatística & dados numéricos , Feminino , Infecções por HIV/psicologia , Heterossexualidade/psicologia , Heterossexualidade/estatística & dados numéricos , Homossexualidade Masculina/psicologia , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Assunção de Riscos , Fatores Sexuais , Comportamento Sexual/psicologia , Minorias Sexuais e de Gênero/estatística & dados numéricos , Estados Unidos , Sexo sem Proteção/psicologia , Sexo sem Proteção/estatística & dados numéricosRESUMO
BACKGROUND: Pretreatment and acquired drug resistance mutations (DRMs) can limit antiretroviral therapy effectiveness. METHODS: We review prevalence of DRMs with resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), focusing on lamivudine and rilpivirine, from 127 articles with >100,000 individuals with HIV-1 infection. RESULTS: Estimated global prevalence of pretreatment resistance to any NRTI was 4% and to any NNRTI was 6%. Most prevalent DRMs resistant to lamivudine or rilpivirine were at positions E138 (4%), V179 (1%) and M184 (1%). Estimated acquired DRM prevalence was 58% for any NRTIs and 67% for any NNRTIs, most frequently at positions M184 (58%) and Y181 (21%). CONCLUSIONS: This review suggests low risk of lamivudine- or rilpivirine-resistant mutations in treatment-naive, HIV-1-infected individuals.
Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral , Genoma Viral , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Mutação , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Saúde Global , Infecções por HIV/tratamento farmacológico , Humanos , Lamivudina/farmacologia , Lamivudina/uso terapêutico , Prevalência , Rilpivirina/farmacologia , Rilpivirina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: It is cost-effective to perform an HIV test in people with specific indicator conditions (IC) with an undiagnosed HIV prevalence of at least 0.1%. Our aim was to determine the HIV prevalence for 14 different conditions across 20 European countries. METHODS: Individuals aged 18-65 years presenting for care with one of 14 ICs between January 2012 and June 2014 were included and routinely offered an HIV test. Logistic regression assessed factors associated with testing HIV positive. Patients presenting with infectious mononucleosis-like syndrome (IMS) were recruited up until September 2015. RESULTS: Of 10,877 patients presenting with an IC and included in the analysis, 303 tested positive (2.8%; 95% CI 2.5-3.1%). People presenting with an IC in Southern and Eastern Europe were more likely to test HIV positive as were people presenting with IMS, lymphadenopathy and leukocytopenia/ thrombocytopenia. One third of people diagnosed with HIV after presenting with IMS reported a negative HIV test in the preceding 12 months. Of patients newly diagnosed with HIV where data was available, 92.6% were promptly linked to care; of these 10.4% were reported lost to follow up or dead 12 months after diagnosis. CONCLUSION: The study showed that 10 conditions had HIV prevalences > 0.1%. These 10 ICs should be adopted into HIV testing and IC specialty guidelines. As IMS presentation can mimic acute HIV sero-conversion and has the highest positivity rate, this IC in particular affords opportunities for earlier diagnosis and public health benefit.
Assuntos
Diagnóstico Precoce , Infecções por HIV/diagnóstico , HIV/isolamento & purificação , Programas de Rastreamento , Testes Sorológicos/métodos , Adolescente , Adulto , Idoso , Europa Oriental/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Prevalência , Adulto JovemRESUMO
BACKGROUND: Severe cases of primary HIV infection have been described in patients presenting with neurological involvement, AIDS defining events or other life-threatening events. These severe forms have not been fully studied. OBJECTIVES: To determine the prevalence and characteristics of severe PHI in a hospital-based cohort of primary HIV infection, and the response to the early initiation of antiretroviral therapy (ART) at 12 months. METHODS: Every patient with PHI attending Hospital Clínic of Barcelona (1997-2015) was evaluated. Severe PHI was defined using clinical, analytical and immunological criteria. Chi-squared test was used for categorical variables and Student's t-test for quantitative variables. RESULTS: 33% of 224 PHI patients (95% CI: 26.84%-39.16%) had a severe PHI. These patients had more symptoms, abnormal analytical parameters and hospital admissions. The severe PHI group had a significantly higher viral load although no differences were observed at 12 months in terms of viral suppression or CD4 count recovery. None died during PHI. CONCLUSIONS: Up to one third of patients in our cohort presented with a severe PHI, which was associated with higher hospitalization rates and higher plasma HIV RNA viral load. However, severe forms were not associated to a worse clinical, immunological or virological outcome at 12 months.
Assuntos
Infecções por HIV/tratamento farmacológico , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/isolamento & purificação , HIV-1/fisiologia , Hospitais/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Espanha/epidemiologia , Carga ViralRESUMO
BACKGROUND: The safety and efficacy of doravirine were compared with that of efavirenz as initial treatment of adults living with HIV-1 infection (NCT01632345). METHODS: A Phase IIb double-blind trial with participants stratified by screening HIV-1 RNA (≤ or >100,000 copies/ml) and randomized 1:1:1:1:1 to receive once-daily doravirine (25, 50, 100 or 200 mg) or efavirenz 600 mg (Part I) for up to 96 weeks, with open-label tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF/FTC). After dose selection at week 24, doravirine 100 mg was provided to participants receiving the other doses of doravirine and additional participants were randomized 1:1 to receive once-daily doravirine 100 mg or efavirenz 600 mg for 96 weeks with TDF/FTC (Part II). Primary outcomes were the proportion of participants with HIV-1 RNA <40 copies/ml at week 24, and central nervous system (CNS) adverse events (AEs) by weeks 8 and 24 (Parts I+II combined). RESULTS: 210 and 132 participants were randomized in Parts I and II, respectively, and 216 (108 on doravirine 100 mg, 108 on efavirenz) were evaluable for Parts I+II combined. At week 24, the proportion of participants with HIV-1 RNA <40 copies/ml was 72.9% for doravirine 100 mg and 73.1% for efavirenz (difference -0.5 [95% CI -12.3, 11.2]). In addition, CNS AEs were reported by 26.9% and 47.2% of doravirine and efavirenz recipients, respectively (difference -20.4 [95% CI -32.6, -7.5]; P=0.002). CONCLUSIONS: Doravirine 100 mg with TDF/FTC demonstrated similar antiretroviral activity and superior CNS safety compared with efavirenz 600 mg with TDF/FTC.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Piridonas/administração & dosagem , Triazóis/administração & dosagem , Adulto , Idoso , Alcinos , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade , Benzoxazinas/efeitos adversos , Ciclopropanos , Feminino , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Piridonas/efeitos adversos , Resultado do Tratamento , Triazóis/efeitos adversos , Carga Viral , Adulto JovemRESUMO
VAC-3S is a therapeutic vaccine comprising a highly conserved HIV-gp41 motif coupled with the CRM197 carrier protein. High levels of anti-3S antibodies (Abs) have been associated with improved protection of CD4+ T-cell survival. A previous phase 1 study demonstrated the safety of VAC-3S. This multicentre, randomised, double-blind, placebo-controlled phase 2 clinical trial enroled between January 2014 and March 2015 HIV-1-infected patients under ART with plasma HIV RNA levels below 50 copies/mL and CD4 counts between 200 and 500 cells/µL. Participants were immunised with 16, 32, or 64 µg of VAC-3S, and compared to placebo. The primary outcome was immunogenicity assessed by changes from baseline of anti-3S Abs levels at week 12. Secondary outcomes included adverse events and the course of plasma HIV RNA level, CD4 count, CD4/CD8 ratio, inflammation and immune checkpoints from week 0 to week 48. Vaccination was well tolerated with no serious adverse events and induced a significant increase in anti-3S Ab response in vaccinated patients (p < 0.0001), compared to placebo. In high responders, the robust increased of CD4 count was associated with a significant and sustained reduction of PD-1 expression on CD4+ T cells through week 48 (variance p = 0.0017). PD-1 expression was correlated with level of anti-3S Abs (p = 0.0092, r = -0.68) and expression of NKp44L (p < 0.0001; r = 0.54) in CD4+ T cells. Our findings regarding the increase of non-exhausted CD4+ T cells have potentially important application in personalised HIV vaccination for HIV-infected patients with high level of PD-1 to improve their T-cell immune function.
RESUMO
CONTEXT: Classical antiretroviral agents may acutely impact on metabolic, mitochondrial, renal and hepatic function in HIV-infected and uninfected persons. Fusion and integrase inhibitors are supposed to be safer, but have been scarcely investigated. To avoid any interference with HIV or other antiretrovirals, we assessed markers of these toxicities in healthy adult volunteers treated with Enfuvirtide (T20) or Raltegravir (RAL). METHODS: Twenty-six healthy participants were randomized to T20/90mg vs. placebo (n = 12) or RAL/400mg vs. placebo (n = 14) every 12h in two 7-day periods separated by a 4-week washout period. Major end-points were changes in lipid profile (total cholesterol, high-density-lipoprotein (HDL)-cholesterol, low-density-lipoprotein (LDL)-cholesterol, triglycerides), insulin resistance (glucose) and mitochondrial toxicity (mitochondrial DNA content-mtDNA-in peripheral blood mononuclear cells). Renal and hepatic toxicity (creatinine, alanine transaminase (AST), alanine aminotransferase (ALT), bilirubin and total plasma proteins) and overall safety were also analysed. Effect of period, treatment, and basal measures were evaluated for each end-point. RESULTS: Neither T20-administration nor RAL-administration yielded to any statistic significant change in the markers of metabolic, mitochondrial, renal or hepatic toxicity assessed. No symptoms indicative of drug toxicity were neither found in any subject. CONCLUSIONS: In absence of HIV infection, or concomitant treatment, short-term exposure to T20 or RAL in healthy adult volunteers did not lead to any indicative changes in toxicity markers thus presuming the safe profile of both drugs.
Assuntos
Enfuvirtida/farmacologia , Raltegravir Potássico/farmacologia , Adulto , Alanina Transaminase/análise , Alanina Transaminase/sangue , Antirretrovirais/uso terapêutico , Creatina/análise , Creatina/sangue , Enfuvirtida/metabolismo , Enfuvirtida/toxicidade , Infecções por HIV/tratamento farmacológico , Voluntários Saudáveis , Humanos , Resistência à Insulina , Rim/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipídeos/análise , Fígado/efeitos dos fármacos , Masculino , Metabolismo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Raltegravir Potássico/metabolismo , Raltegravir Potássico/toxicidadeRESUMO
Background: Both immediate and deferred switching from a ritonavir-boosted protease inhibitor (PI/r)-based regimen to a dolutegravir (DTG)-based regimen may improve lipid profile. Methods: European Network for AIDS Treatment 022 Study (NEAT022) is a European, open-label, randomized trial. Human immunodeficiency virus (HIV)-infected adults aged ≥50 years or with a Framingham score ≥10% were eligible if HIV RNA was <50 copies/mL. Patients were randomized to switch from PI/r to DTG immediately (DTG-I) or to deferred switch at week 48 (DTG-D). Week 96 endpoints were proportion of patients with HIV RNA <50 copies/mL, percentage change of lipid fractions, and adverse events (AEs). Results: Four hundred fifteen patients were randomized: 205 to DTG-I and 210 DTG-D. The primary objective of noninferiority at week 48 was met. At week 96, treatment success rate was 92.2% in the DTG-I arm and 87% in the DTG-D arm (difference, 5.2% [95% confidence interval, -.6% to 11%]). There were 5 virological failures in the DTG-I arm and 5 (1 while on PI/r and 4 after switching to DTG) in the DTG-D arm without selection of resistance mutations. There was no significant difference in terms of grade 3 or 4 AEs or treatment-modifying AEs. Total cholesterol and other lipid fractions (except high-density lipoprotein) significantly (P < .001) improved both after immediate and deferred switching to DTG overall and regardless of baseline PI/r strata. Conclusions: Both immediate and deferred switching from a PI/r to a DTG regimen in virologically suppressed HIV-infected patients ≥50 years old or with a Framingham score ≥10% was highly efficacious and well tolerated, and improved the lipid profile. Clinical Trials Registration: NCT02098837 and EudraCT: 2013-003704-39.