Search

Background To determine by multi-omic analysis changes in metabolites, lipids, and proteins as a consequence of transient viral rebound (tVR) in children with perinatally acquired HIV-1 (PHIV). Methods Plasma samples from children with PHIV and with tVR (first episode of transient RNA-HIV viral load >20 copies/ml followed by suppression) on the time-point immediately before (pre-tVR) and after (post-tVR) the tVR were assessed. Multi-omic analyses were performed using nLC-Orbitrap, GC-qTOF-MS, and LC-qTOF-MS. Results Comparing pre- and post-tVR time-points, HIV-1 children with tVR (n = 5) showed a trend to a decrease in ratio CD4/CD8 (p = 0.08) but no significant differences were observed in plasma metabolites, lipids, or proteins. Post-tVR condition was compared with a reference group of children with PHIV with persistent viral control (n = 9), paired by sex, age, and time under antiretroviral treatment. A total of 10 proteins, 8 metabolites, and 2 lipids showed significant differences (p < 0.05): serotransferrin, clusterin, kininogen-1, succinic acid, threonine, 2-hydroxyisovaleric acid, methionine, 2-hydroxyglutaric, triacylglyceride 50:0 (TG50:0), and diacylglyceride 34:1 (DG34:1) were upregulated while alpha-2-macroglobulin, apolipoprotein A-II, carboxylic ester hydrolase, apolipoprotein D, coagulation factor IX, peptidase inhibitor 16, SAA2-SAA4 readthrough, oleic acid, palmitoleic acid, and D-sucrose downregulated on post-tVR time-point compared to the reference group. Ratio CD4/CD8 correlated with apolipoprotein A-II, DG34:1, and methionine (p = 0.004; ρ = 0.71, p = 0.016; ρ = −0.63; and p = 0.032; ρ = −0.57, respectively). Nadir CD4+ correlated inversely with kininogen-1 (p = 0.022; ρ = −0.60) and positively with D-sucrose (p = 0.001; ρ = 0.77). Conclusions tVR followed by suppression implies changes in soluble proteins, lipids, and metabolites that correlate with immunological parameters, mainly ratio CD4/CD8, that decreased after tVR. These distinct soluble biomarkers could be considered potential biomarkers of immune progression.

Background Early combined antiretroviral treatment (cART) in perinatally acquired HIV-1 children has been associated with a rapid viral suppression, small HIV-1 reservoir size and reduced mortality and morbidity. Immunometabolism has emerged as an important field in HIV-1 infection offering both relevant knowledge regarding immunopathogenesis and potential targets for therapies against HIV-1. Objectives To characterize the proteomic, lipidomic and metabolomic profile of HIV-1-infected children depending on their age at cART initiation. Patients and methods Plasma samples from perinatally HIV-1-infected children under suppressive cART who initiated an early cART (first 12 weeks after birth, EARLY, n = 10) and late cART (12–50 weeks after birth, LATE, n = 10) were analysed. Comparative plasma proteomics, lipidomics and metabolomics analyses were performed by nanoLC-Orbitrap, UHPLC-qTOF and GC-qTOF, respectively. Results Seven of the 188 proteins identified exhibited differences comparing EARLY and LATE groups of HIV-1-infected children. Despite no differences in the lipidomic (n = 115) and metabolomic (n = 81) profiles, strong correlations were found between proteins and lipid levels as well as metabolites, including glucidic components and amino acids, with clinical parameters. The ratio among different proteins showed high discriminatory power of EARLY and LATE groups. Conclusions Protein signature show a different proinflammatory state associated with a late cART introduction. Its associations with lipid levels and the relationships found between metabolites and clinical parameters may potentially trigger premature non-AIDS events in this HIV-1 population, including atherosclerotic diseases and metabolic disorders. Antiretroviral treatment should be started as soon as possible in perinatally acquired HIV-1-infected children to prevent them from future long-life complications.

Objectives To assess the clinical and immunovirological outcomes among naive patients with advanced HIV presentation starting an antiretroviral regimen in real-life settings. Methods This was a multicentre, prospective cohort study. We included all treatment-naive adults with advanced HIV disease (CD4+ T cell count Results We included 1594 patients with advanced HIV disease [median CD4+T cell count of 81 cells/mm3and 371 (23.3%) with AIDS-defining illness] and with a median follow-up of 4.44 years. The most common ART used was an integrase strand transfer inhibitor (InSTI) regimen (46.9%), followed by PI (35.7%) and NNRTI (17.4%), with adjusted mortality rates at 3 years of 3.1% (95% CI 1.8%–4.3%), 4.7% (95% CI 2.2%–7.1%) and 7.6% (95% CI 5.4%–9.7%) (P = 0.001), respectively. Factors associated with increased mortality included older age and history of injection drug use, whilst treatment with an InSTI regimen was a protective factor [HR 0.5 (95% CI 0.3–0.9)]. A sensitivity analysis with propensity score procedure confirms these results. Patients who started an InSTI achieved viral suppression and CD4+ T cell count above 350 cells/mm3significantly earlier. Conclusions In this large real-life prospective cohort study, a significant lower mortality, earlier viral suppression and earlier immune reconstitution were observed among patients with advanced HIV disease treated with InSTIs.

The cytokine signature present in COVID-19 could provide information on the pathogenic mechanisms of the disease and could identify possible prognostic biomarkers and possible therapeutic targets. In this longitudinal work, we studied the clinical and biochemical parameters and circulating cytokine levels of 146 patients at the time of admission for COVID-19 and 4–6 weeks later. The main objective of this study was to determine whether basal cytokines could be early prognostic biomarkers of COVID-19, and also to analyze the impact of comorbidities, such as obesity or metabolic syndrome (MS), in the cytokine profile. The levels of most inflammatory cytokines were elevated on admission in relation to the level that was reached 4–6 weeks later, except for IL-1β, which was lower on admission; these levels were irrespective of the presence of obesity or MS since the cytokine storm masks these inflammatory processes. Among the cytokines analyzed, those that correlated with a worse prognosis of COVID-19 were resistin, IL-6, IL-8, IL-15, MCP-1 and TNF-α. Specifically, resistin and IL-15 are the best early predictors of requiring invasive ventilation. Therefore, resistin and IL-15 should be included in the personalized treatment decision algorithm of patients with COVID-19.

Introduction Standard therapy for HIV treatment has consisted of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug regimens (2DR) has been considered for selected patients in part to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase inhibitor (INSTI)-based three-drug regimens (3DR) versus 2DR of dolutegravir (DTG) + rilpivirine (RPV) or DTG + lamivudine (3TC). Methods All patients in the Spanish VACH cohort switching to INSTI-based 3DR or a 2DR consisting of DTG + RPV or DTG + 3TC between May 2, 2016 and May 15, 2019 were included. Kaplan-Meier curves and Cox proportional hazard models were used to assess time to/risk of discontinuation due to treatment failure (TF) (defined as virologic failure [VF], immunologic failure, or disease progression) and adverse events (AEs). Three secondary analyses were performed: (1) in restricting the analysis to patients who were virologically suppressed (HIV RNA < 50 copies/mL) at switch; (2) matched analysis (2:1, matched by age, sex, number of previous VFs, and line of regimen), and (3) using VF as the primary endpoint in all patients. Results Overall, 5047 3DR and 617 2DR patients were analyzed. Baseline characteristics differed between groups; 2DR patients were older, more treatment experienced, and more likely to be virologically suppressed at switch. Time to discontinuation due to TF was significantly shorter for 2DR (P = 0.002). The hazard ratio (HR) for discontinuation due to TF on 2DR vs 3DR was 2.33 (P = 0.003). No difference was observed for time to discontinuation (P = 0.908) or risk of discontinuation due to AEs (HR = 0.80; P = 0.488). Results were qualitatively similar in virologically suppressed patients, matched analysis, and for VF. Conclusion In the real world, the risks of discontinuation due to TF and VF were more than two times higher in patients switching to DTG-based 2DR than INSTI-based 3DR, with no difference in discontinuation due to AEs. Plain Language Summary People living with HIV (PLHIV) need lifelong treatment to prevent progression to AIDS. Standard HIV treatments use three different drugs in combination, but these can potentially cause unwanted side effects. Treatments using just two drugs have been developed. These aim to reduce side effects and treat HIV effectively. This study included 5664 participants in Spain who were split into two groups: 5047 participants switched from their old treatment to a three-drug regimen (3DR), and 617 participants switched to a two-drug regimen (2DR). The researchers measured how long it took for the participants to stop taking their treatment because it was not working, or it caused too many side effects. At the end of the study, more than 70% of participants in either group were still taking the same treatment. Of the 30% of participants who stopped treatment because it stopped working, those taking a 2DR stopped sooner than those taking a 3DR. This difference started to appear at about 18 months and got bigger until the study ended, which was 3 years after starting treatment. Participants taking a 2DR were twice as likely to stop treatment because it was not working than those taking a 3DR. There was no difference between the groups for how long it took for participants to stop their treatment because of side effects. These results show that for some PLHIV, the 2DR stopped working sooner than 3DR, without the benefit of fewer side effects.

Summary Background Factors affecting outcomes of SARS-CoV-2 infection in people living with HIV are unclear. We assessed the factors associated with SARS-CoV-2 diagnosis and severe outcomes among people living with HIV. Methods We did a retrospective cohort study using data from the PISCIS cohort of people with HIV in Catalonia (Spain) between March 1 and Dec 15, 2020. We linked PISCIS data with integrated health-care, clinical, and surveillance registries through the Public Data Analysis for Health Research and Innovation Program of Catalonia (PADRIS) to obtain data on SARS-CoV-2 diagnosis, chronic comorbidities, as well as clinical and mortality outcomes. Participants were aged at least 16 years in care at 16 hospitals in Catalonia. Factors associated with SARS-CoV-2 diagnoses and severe outcomes were assessed using univariable and multivariable Cox regression models. We estimated the effect of immunosuppression on severe outcomes (hospital admission for >24 h with dyspnoea, tachypnoea, hypoxaemia, asphyxia, or hyperventilation; or death) using Kaplan-Meier survival analysis. Findings We linked 20 847 (72·8%) of 28 666 participants in the PISCIS cohort with PADRIS data; 13 142 people had HIV. 749 (5·7%) people with HIV were diagnosed with SARS-CoV-2: their median age was 43·5 years (IQR 37·0–52·7), 131 (17·5%) were female, and 618 (82·5%) were male. 103 people with HIV (13·8%) were hospitalised, seven (0·9%) admitted to intensive care, and 13 (1·7%) died. SARS-CoV-2 diagnosis was more common among migrants (adjusted hazard ratio 1·55, 95% CI 1·31–1·83), men who have sex with men (1·42, 1·09–1·86), and those with four or more chronic comorbidities (1·46, 1·09–1·97). Age at least 75 years (5·2, 1·8–15·3), non-Spanish origin (2·1, 1·3–3·4), and neuropsychiatric (1·69, 1·07–2·69), autoimmune disease (1·92, 1·14–3·23), respiratory disease (1·84, 1·09–3·09), and metabolic disease (2·59, 1·59–4·23) chronic comorbidities were associated with increased risk of severe outcomes. A Kaplan-Meier estimator showed differences in the risk of severe outcomes according to CD4 cell count in patients with detectable HIV RNA (p=0·039) but no differences were observed in patients with undetectable HIV RNA (p=0·15). Interpretation People living with HIV with detectable HIV viraemia, chronic comorbidities, and some subpopulations could be at increased risk of severe outcomes from COVID-19. These groups should be prioritised in clinical management and SARS-CoV-2 vaccination programmes. Funding Fundacio "la Caixa". Translations For the Catalan, Spanish and Russian translations of the Summary see Supplementary Materials section.

Introduction Weight gain after starting antiretroviral therapy (ART) is a major problem that can increase morbidity. Our main objective was to evaluate the effects of initial ART on weight change in a large prospective cohort of HIV‐positive individuals. Methods This was a prospective cohort study of 13,198 subjects included in the Spanish HIV Research Network (CoRIS) between January 2004 and November 2018. We included subjects who started triple ART and achieved HIV RNA suppression within 48 weeks. We fitted linear mixed models adjusted for potential confounders to compare longitudinal changes in weight. We used Cox proportional‐hazard models to compare treatment groups’ times to transition to a higher body mass index (BMI) category. Results We analysed data from a total of 1631 individuals resulting in 14,965 persons/years and 14,085 observations. Individuals retained in the final multivariable model were representative of the overall cohort. NNRTI‐based first‐line ART was associated with a lower average weight gain compared to PI‐ (+0.7 kg per year, 95% CI 0.5 to 1.0, p

Resumen Objetivo Determinar la proporcion de personas con infeccion por VIH o sida que se encontraban en seguimiento en la cohorte VACH en 2012 y que resultaron perdidas del mismo en 2013 y 2014, asi como establecer las caracteristicas sociodemograficas relacionadas con dicha perdida. Metodos Consideramos perdidos del seguimiento a los sujetos con menos de un registro de consulta por ano analizado. Construimos modelos de regresion logistica para la estimacion de las razones de ventajas (odds ratio [OR]) y sus intervalos de confianza del 95% (IC del 95%) de las variables relacionadas con la perdida de seguimiento. Resultados El porcentaje global de perdidas en seguimiento fue del 15,5% (IC del 95%: 14,9-16,1). Las variables asociadas con la perdida de seguimiento fueron no recibir tratamiento antirretroviral (TAR) (OR: 1,948; IC del 95: 1,651-2,298), ser inmigrante (OR: 1,746; IC del 95: 1,494-2,040), el consumo de farmacos por via intravenosa como mecanismo de transmision del VIH (OR: 1,498; IC del 95: 1,312-1,711), encontrarse en situacion de desempleo (OR: 1,331; IC del 95: 1,179-1,503), no tener pareja (OR: 1,948, IC del 95: 1,651-1,298), pertenecer a un estrato socioeconomico bajo (OR: 1,279; IC del 95: 1,143-1,431) y ser atendido en un hospital con menos de 1.000 pacientes en seguimiento (OR: 1,257; IC del 95%: 1,121-1,457), ademas de menor edad y menos tiempo de seguimiento en la cohorte. Conclusiones El 15,5% de los pacientes fueron perdidos del seguimiento en un periodo de 2 anos en la cohorte VACH. Ello se asocio a una serie de variables sociodemograficas y epidemiologicas, cuya identificacion puede ser util para disenar iniciativas focalizadas sobre las poblaciones mas susceptibles de abandonar los circuitos asistenciales y a orientar estrategias disenadas a la consecucion del objetivo 90-90-90.

The immunological, biochemical and molecular mechanisms associated with poor immune recovery are far from known, and metabolomic profiling offers additional value to traditional soluble markers. Here, we present novel and relevant data that could contribute to better understanding of the molecular mechanisms preceding a discordant response and HIV progression under suppressive combined antiretroviral therapy (cART). Integrated data from nuclear magnetic resonance (NMR)-based lipoprotein profiles, mass spectrometry (MS)-based metabolomics and soluble plasma biomarkers help to build prognostic and immunological progression tools that enable the differentiation of HIV-infected subjects based on their immune recovery status after 96 weeks of suppressive cART. The metabolomic signature of ART-naïve HIV subjects with a subsequent late immune recovery is the expression of pro-inflammatory molecules and glutaminolysis, which is likely related to elevate T-cell turnover in these patients. The knowledge about how these metabolic pathways are interconnected and regulated provides new targets for future therapeutic interventions not only in HIV infection but also in other metabolic disorders such as human cancers where glutaminolysis is the alternative pathway for energy production in tumor cells to meet their requirement of rapid proliferation.

Teràpia antiretroviral; Diagnòstic i gestió del VIH; Teràpia amb inhibidors de la proteasa Terapia antirretroviral; Diagnóstico y gestión del VIH; Terapia con inhibidores de la proteasa Antiretroviral therapy; HIV diagnosis and management; Protease inhibitor therapy Background Since 1996, the standard of care (SOC) therapy for HIV treatment has consisted of a backbone of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug combinations (2DC) has been considered for selected patients to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase strand transfer inhibitor (INSTI)-containing triple therapy (TT) to dolutegravir- (DTG) and/or boosted protease inhibitor (bPI)-based 2DC in a large Spanish cohort of HIV patients. Methods A retrospective analysis was performed using data from the VACH cohort, a prospective multicentre Spanish cohort of adult HIV patients. All treatment experienced patients initiating a TT of an INSTI combined with two NRTIs or a 2DC-containing DTG and/or a bPI between 01/01/2012 and 01/06/2017 were included. The unit of analysis was patient-regimens. The overall sample analysis was complemented with two sub-analyses. The first sub-analysis focused on patients treated with a backbone plus DTG compared to those treated with DTG+ one other antiretroviral. The second sub-analysis focused on patients with HIV RNA

© 2020 The Authors., [Background]: The underlying mechanisms of incomplete immune reconstitution in treated HIV-positive patients are very complex and may be multifactorial, but perturbation of chemokine secretion could play a key role in CD4+ T-cell turnover., [Methods]: We evaluated the circulating baseline and 48-week follow-up concentrations of SDF-1/CXCL12, fractalkine/CX3CL1, MCP-1/CCL2, MIP-α/CCL3, MIP-β/CCL4 and RANTES/CCL5, and we estimated their association with CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) to investigate multiple chemokine-chemokine receptor signatures associated with immune dysregulation preceding poor immune recovery., [Findings]: The circulating concentrations and gene expression patterns of SDF-1/CXCL12 (CXCL12 rs1801157) and MCP-1/CCL2 (CCR2 rs1799864_814) were associated with immune recovery status. CCR2 rs1799864_814 and CCR5 rs333_814 (Δ32) determine the baseline plasma RANTES and MIP-α concentrations, respectively, in participants with poor immune response., [Interpretation]: SDF-1/CXCL12 and MCP-1/CCL2 could be considered prognostic markers of immune failure despite suppressive antiretroviral therapy. The strong linkage disequilibrium (LD) between CCR2 rs1799864_814 and CCR5 rs1800024 indicated that the alleles of each gene are inherited together more often than would be expected by chance., This work was supported by the Fondo de Investigacion Sanitaria [PI10/02635, PI13/0796, PI14/ 0063, PI14/0700, PI16/00503, PI17/0420, PI17/0498, PI18/01216, PI19/01337 and PI20/00326]-ISCIII-FEDER (co-funded by the European Regional Development Fund/European Social Fund; “A way to make Europe”/”Investing in your future”); Programa de Suport als Grups de Recerca AGAUR (2014SGR250, 2017SGR948); Gilead Fellowship Program GLD14/293and GLD19/00,008; and The SPANISH AIDS Research Network [RD12/0017/0005, RD16/0025/0002, RD16/0025/0006, RD16/0025/0019]-ISCIII-FEDER (Spain). FV is supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII. PD is supported by grants from the Programa de Intensificación de Investigadores (INT19/00036)-ISCIII. YMP is supported by the Servicio Andaluz de Salud through Programa Nicolás Monardes (C-0013/17). JVG is supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “FI19/00330″ through the program “Contratos Predoctorales de Formación en Investigación en Salud”. EY is supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “FI20/00118″ through the program “Contratos Predoctorales de Formación en Investigación en Salud”. LR is supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CD20/00105″ through the program “Sara Borrell”. AR is supported by a grant from the Acció Instrumental d'incorporació de científics i tecnòòlegs (PERIS SLT002/16/00,101), Departament de Salut, Generalitat de Catalunya, by IISPV through the project “2019/IISPV/05″ (Boosting Young Talent), by GeSIDA through the "III Premio para Jóvenes Investigadores 2019″ and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00,146″ through the Miguel Servet Program.

Plasma glycoproteins are a composite biomarker of inflammation and can be detected by 1H-NMR. The aim of this study was to prospectively appraise the clinical value of plasma glycoproteins assessed by 1H-NMR in people living with HIV (PLWH). A total of 221 patients with HIV infection were recruited and studied at baseline and at 48 and 144 weeks. Patients were distributed into two groups according to baseline CD4+ T-cell number below or above 200 cells/&micro, L. Patients with fewer than 200 cells/&micro, L were distributed into the responders and nonresponders according to antiretroviral therapy (ART) response at 144 weeks. Glycoprotein concentrations were determined by 1H-NMR arising from the protein bond N-acetylglucosamine and N-acetylgalactosamine signals (GlycA), and N-acetylneuraminic acid signal (GlycB) associated with the sugar&ndash, protein bond concentration and aggregation state (shapes (height/width)). Basal glycoprotein concentrations were higher in patients with &lt, 200 CD4+ T-cell/&mu, L (Glyc A: 1040(917.9&ndash, 1199.1) vs. 950.4(845.5&ndash, 1050.9), p &lt, 0.001, and Glyc B: 521(440.3&ndash, 610.3) vs. 468.6(417.9&ndash, 507.0) &mu, mol/L, p &lt, 0.001) being reduced by ART. The height/width (H/W) ratio was the parameter showing a better association with this clinical status. Baseline glycoproteins predict the condition of responder/nonresponder. In this study, 1H-NMR glycoproteins provide novel insights to assess inflammation status and have prognostic value in PLWH.

Plasma glycoproteins are a composite biomarker of inflammation and can be detected by 1H-NMR. The aim of this study was to prospectively appraise the clinical value of plasma glycoproteins assessed by 1H-NMR in people living with HIV (PLWH). A total of 221 patients with HIV infection were recruited and studied at baseline and at 48 and 144 weeks. Patients were distributed into two groups according to baseline CD4+ T-cell number below or above 200 cells/µL. Patients with fewer than 200 cells/µL were distributed into the responders and nonresponders according to antiretroviral therapy (ART) response at 144 weeks. Glycoprotein concentrations were determined by 1H-NMR arising from the protein bond N-acetylglucosamine and N-acetylgalactosamine signals (GlycA); and N-acetylneuraminic acid signal (GlycB) associated with the sugar–protein bond concentration and aggregation state (shapes (height/width)). Basal glycoprotein concentrations were higher in patients with < 200 CD4+ T-cell/μL (Glyc A: 1040(917.9–1199.1) vs. 950.4(845.5–1050.9), p < 0.001, and Glyc B: 521(440.3–610.3) vs. 468.6(417.9–507.0) μ mol/L, p < 0.001) being reduced by ART. The height/width (H/W) ratio was the parameter showing a better association with this clinical status. Baseline glycoproteins predict the condition of responder/nonresponder. In this study, 1H-NMR glycoproteins provide novel insights to assess inflammation status and have prognostic value in PLWH.

Altres ajuts: GLD13/00168 Altres ajuts: GLD14/293 Altres ajuts: PERIS/SLT002-16-00101 Poor immunological recovery in treated HIV-infected patients is associated with greater morbidity and mortality. To date, predictive biomarkers of this incomplete immune reconstitution have not been established. We aimed to identify a baseline metabolomic signature associated with a poor immunological recovery after antiretroviral therapy (ART) to envisage the underlying mechanistic pathways that influence the treatment response. This was a multicentre, prospective cohort study in ART-naive and a pre-ART low nadir (

A relationship between polymorphisms in genes encoding interleukin 7 (IL-7) and its cellular receptor (IL-7R) and antiretroviral therapy (ART)-associated immune recovery in HIV subjects has been previously reported. However, details of this relationship remain unclear, and the association of these polymorphisms with circulating IL-7/IL-7R levels is scarce. Here, we explored whether IL-7/IL-7R axis was associated with quantitative CD4+ T-cell recovery in HIV-infected subjects. IL-7/IL-7R polymorphisms were assessed by genotyping, and multiple inheritance models were used to estimate both, their association with low pre-ART CD4+ T-cell counts and incomplete immune recovery status after 48 weeks of suppressive ART. Integrated data from genetic variants association and soluble plasma IL-7/IL-7R quantification suggest that IL-7/IL-7R genotype expression could alter the homeostatic balance between soluble and membrane-bound receptors. The haplotype analyses indicates that allele combinations impacts pre-ART circulating CD4+ T-cell counts, immune recovery status and the absolute increment of CD4+ T-cell counts. The knowledge about how IL-7/IL-7R axis is related to quantitative CD4+ T-cell recovery and immune recovery status after initiating ART could be useful regarding T-cell reservoirs investigations in HIV subjects., This work was supported by the Fondo de Investigacion Sanitaria [PI10/02635, PI13/0796, PI14/1693, PI16/00503, PI16/00684, PI19/01337]-ISCIII-FEDER; Programa de Suport als Grups de Recerca AGAUR (2014SGR250, 2017SGR948); Gilead Fellowship Program GLD14/293 and GLD17/00299; The SPANISH AIDS Research Network [RD12/0017/0005, RD16/0025/0002, RD16/0025/0006, RD16/0025/0019, RD16/0025/0020]-ISCIII-FEDER (Spain) and Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (Proyecto de Investigación de Excelencia; CTS2593). FV is supported by grants from the Programa de Intensificación de Investigadores (INT15/226)-ISCIII. YMP and ERM are supported by the Servicio Andaluz de Salud through Programa Nicolás Monardes (C-0013/17 and C-0032/17, respectively). E.R-M was also supported by Programa Miguel Servet ISCIII, FEDER, CPII014/00025. AR is supported by a grant from the Acció Instrumental d’incorporació de científics i tecnòlegs (PERIS SLT002/16/00101), Departament de Salut, Generalitat de Catalunya and Agencia Estatal de Investigación (Acciones de carácter internacional “Europa Investigación”; EUIN2017-89297), Ministry of Economy and Competitiveness. We are also grateful to GESIDA for ‘‘Premio para Jóvenes Investigadores 2019’’ to AR.

Background: Approximately 25% of elite controllers (ECs) lose their virological control by mechanisms that are only partially known. Recently, immunovirological and proteomic factors have been associated to the loss of spontaneous control. Our aim was to perform a metabolomic approach to identify the underlying mechanistic pathways and potential biomarkers associated with this loss of control. Methods: Plasma samples from EC who spontaneously lost virological control (Transient Controllers, TC, n=8), at two and one year before the loss of control, were compared with a control group of EC who persistently maintained virological control during the same follow-up period (Persistent Controllers, PC, n=8). The determination of metabolites and plasma lipids was performed by GC-qTOF and LC-qTOF using targeted and untargeted approaches. Metabolite levels were associated with the polyfunctionality of HIV-specific CD8+T-cell response. Findings: Our data suggest that, before the loss of control, TCs showed a specific circulating metabolomic profile characterized by aerobic glycolytic metabolism, deregulated mitochondrial function, oxidative stress and increased immunological activation. In addition, CD8+ T-cell polyfunctionality was strongly associated with metabolite levels. Finally, valine was the main differentiating factor between TCs and PCs. Interpretation: All these metabolomic differences should be considered not only as potential biomarkers but also as therapeutic targets in HIV infection. Funding: This work was supported by grants from Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Fondos FEDER; Red de Investigacion en Sida, Gilead Fellowship program, Spanish Ministry of Education and Spanish Ministry of Economy and Competitiveness. Declaration of Interest: The authors declare no competing interests. Ethical Approval: All subjects included in the study gave their informed consent, and protocols were approved by the institutional ethical committees.

Background: Integrase strand-transfer inhibitors (INSTIs) constitute at present one of the pillars of first-line ART. Objectives: To study the prevalence of and the trend in transmitted drug resistance (TDR) to INSTIs in ART-naive patients in Spain. Methods: During the period 2012-17, 1109 patients from CoRIS were analysed. The Stanford algorithm v8.7 was used to evaluate TDR and transmission of clinically relevant resistance. To describe individual mutations/polymorphisms, the most recent IAS list (for INSTIs) and the 2009 WHO list update (for the backbone NRTIs used in combination with INSTIs in first-line treatment) were used. Results: Clinically relevant resistance to the INSTI class was 0.2%: T66I, 0.1%, resistance to elvitegravir and intermediate resistance to raltegravir; and G163K, 0.1%, intermediate resistance to raltegravir and elvitegravir. No clinical resistance to dolutegravir or bictegravir was observed. The prevalence of INSTI TDR following the IAS-USA INSTI mutation list was 2.6%, with no trend towards changes in the prevalence throughout the study period. The overall prevalence of NRTI WHO mutations was 4.3%, whereas clinically relevant resistance to tenofovir, abacavir and emtricitabine/ lamivudine was 1.7%, 1.9% and 0.7%, respectively. Conclusions: Given the low prevalence of clinically relevant resistance to INSTIs and first-line NRTIs in Spain, it is very unlikely that a newly diagnosed patient will present with clinical resistance to a first-line INSTI-based regimen. These patients may not benefit from INSTI and NRTI baseline resistance testing.

HIV and antiretroviral therapy affect lipid metabolism. Lipidomics quantifies several individual species that are overlooked using conventional biochemical analyses, outperforming traditional risk equations. We aimed to compare the plasma lipidomic profile of HIV patients taking efavirenz (EFV) or rilpivirine (RPV). Patients &ge, 18 years old on EFV co-formulated with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) with HIV-RNA &lt, 50 copies/mL for &ge, 6 months were randomized to continue EFV/FTC/TDF (n = 14) or switch to RPV/FTC/TDF (n =15). Lipidomic analyses conducted by mass spectrometry (MS) were performed at baseline and after 12 and 24 weeks. OWLiver&reg, Care and OWLiver&reg, tests were performed to estimate the presence of fatty liver disease (NAFLD). No significant differences (83% male, median age 44 years, 6 years receiving EFV/FTC/TDF, CD4+ count 740 cells/mm3, TC 207 [57 HDL-C/133 LDL-C] mg/dL, TG 117 mg/dL) were observed between the groups at baseline. Significant reductions in plasma lipids and lipoproteins but increased circulating bilirubin concentrations were observed in patients who switched to RPV/FTC/TDF. Patients on RPV/FTC/TDF showed a decrease in the global amount of storage lipids (-0.137 log2 [fold-change] EFV vs. 0.059 log2 [fold-change] RPV) but an increase in lysophosphatidylcholines (LPCs) and total steroids. Compared with EFV, RPV increased metabolites with anti-inflammatory properties and reduced the repository of specific lipotoxic lipids.

Objectives Ritonavir-boosted atazanavir and darunavir are protease inhibitors that are recommended for initial treatment of HIV infection because each has shown better lipid effects and overall tolerability than ritonavir-boosted lopinavir. The extent to which lipid effects and overall tolerability differ between treatments with atazanavir and darunavir and whether atazanavir-induced hyperbilirubinaemia may result in more favourable metabolic effects are issues that remain to be resolved. Methods A 96-week randomized clinical trial was carried out. The primary endpoint was change in total cholesterol at 24 weeks. Secondary endpoints were changes in lipids other than total cholesterol, insulin sensitivity, total bilirubin, estimated glomerular filtration rate, and CD4 and CD8 cell counts, and the proportion of patients with plasma HIV RNA

Leptin, adiponectin and IL18 are adipokines related with obesity, insulin resistance and dyslipidemia in the general population. Treated HIV-1-infected patients with lipodystrophy may develop insulin resistance and proatherogenic dyslipidemia. We assessed the relationship between plasma adipokine levels, adipokine genetics, lipodystrophy and metabolic disturbances. Plasma leptin, adiponectin and IL18 levels were assessed in 446 individuals: 282 HIV-1-infected patients treated with antiretroviral drugs (132 with lipodystrophy and 150 without) and 164 uninfected controls (UC). The LEP2410A > G, LEPRQ223R, ADIPQ276G > T, ADIPOR2-Intron5A > G and IL18-607C > A polymorphisms were validated by sequencing. Leptin levels were higher in UC than in HIV-1-infected, either with or without lipodystrophy (p < 0.001 for both comparisons) and were lower in patients with lipodystrophy compared with those without lipodystrophy (p = 0.006). In patients with lipodystrophy, leptin had a positive correlation with insulin and with HOMA-IR. Adiponectin levels were non-significantly different in UC and HIV-1-infected patients. Patients with lipodystrophy had lower adiponectin levels than non-lipodystrophy subjects (p < 0.001). In patients with lipodystrophy, adiponectin was negatively correlated with insulin, HOMA-IR and triglycerides. Plasma IL18 levels were higher in HIV-1-infected patients compared with UC (p < 0.001), and no differences were found according to the presence of lipodystrophy. In patients with lipodystrophy there was a negative correlation between IL18 levels and LDLc. Genetic analyses indicated no significant associations with lipodystrophy nor with insulin resistance or with lipid abnormalities. In conclusion, HIV-1-infected patients have reduced plasma leptin levels. This reduction is magnified in patients with lipodystrophy whose adiponectin levels were lower than that of non-lipodystrophy subjects. Plasma IL18 levels are increased in infected patients irrespective of the presence of lipodystrophy. The polymorphisms assessed are not associated with lipodystrophy or metabolic disturbances in treated HIV-1-infected patients. (C) 2012 Elsevier Ltd. All rights reserved.

Background A clinical trial comparing the rate of discontinuation and tolerability of two post-exposure prophylaxis (PEP) regimens was performed. Methods A total of 255 individuals attending the emergency rooms of six hospitals for exposure to HIV and criteria to receive PEP were randomized to receive zidovudine/ lamivudine plus either lopinavir/ritonavir ( n=131) or atazanavir ( n=124; day 0). The primary end point was the rate of PEP discontinuation before day 28 of follow-up. Secondary end points were incidence of side effects, follow-up at days 90 and 180 and rate of seroconversions. Results A total of 55 patients (29 in lopinavir/ritonavir and 26 in atazanavir arms) did not attend the first scheduled appointment (day 1) and were excluded from the analysis. The rate of discontinuation before day 28 owing to any cause was similar between groups (37/102 [36%] in lopinavir/ritonavir and 35/98 [36%] in atazanavir arms, P=0.82). Adverse events were the reason for discontinuation or switching of PEP in 33 individuals (16/102 [16%] in the lopinavir/ritonavir arm and 17/98 [17%] in the atazanavir arm, P=0.84). Adverse events were reported in 92/200 (46%) of individuals on PEP who attend at least the day 1 appointment (50/102 [49%] in the lopinavir/ ritonavir arm and 42/98 [43%] in the atazanavir arm, P=0.38). There were no seroconversions. Conclusions The rate of discontinuation of PEP before day 28 was similar with zidovudine/lamivudine plus either lopinavir/ritonavir or atazanavir. The rate of discontinuation of PEP because of adverse events was low in both arms. Almost 50% of the patients of both arms suffered side effects. New strategies are needed to improve the tolerance.

Objectives Treated HIV-1-infected patients with lipodystrophy often develop insulin resistance and proatherogenic dyslipidaemia. Zinc alpha-2 glycoprotein (ZAG) is a recently characterized adipokine which has been shown to be involved in the development of obesity and metabolic syndrome in uninfected subjects. We assessed the relationship between circulating ZAG levels and metabolic derangements in HIV-1-infected patients receiving antiretroviral drugs. Methods Plasma ZAG levels were assessed in 222 individuals: 166 HIV-1-infected patients treated with antiretroviral drugs (77 with lipodystrophy and 89 without lipodystrophy) and 56 uninfected controls. Plasma ZAG levels were assessed by enzyme-linked immunosorbent assay (ELISA) and were correlated with fat distribution abnormalities and metabolic parameters. Results HIV-1-infected patients had lower plasma ZAG levels compared with uninfected controls (P

Peroxisome proliferator-activated receptor gamma (PPARγ) is involved in obesity and in some components of the metabolic syndrome in unselected population. To determine whether PPARγ genetic variants are associated with the risk of developing lipodystrophy and its associated metabolic disturbances in HIV-1-infected patients treated with HAART and to assess PPARγ mRNA expression in subcutaneous adipose tissue (SAT). The study group comprised 278 patients infected with HIV-1 and treated with antiretroviral drugs (139 with lipodystrophy and 139 without) and 105 uninfected controls (UC). The PPARγ Pro12Ala (C > G) single nucleotide polymorphism (SNP) was assessed using PCRRFLPs on white cell DNA. PPARγ mRNA expression in SAT was assessed in 38 patients (25 with lipodystrophy and 13 without) and in 21 UC by real-time PCR. Statistical analysis was based on Students T tests, 2 tests, Spearmans correlations tests and logistic regression tests. PPARγ Pro12Ala genotype distribution and allele frequencies were nonsignificantly different between both HIV-1-infected categories, lipodystrophy vs non-lipodystrophy (p = 0.9 and p = 0.87, respectively). Lipodystrophic patients harbouring the rare X/Ala genotype (Ala/Ala plus Pro/Ala) had significantly greater plasma total and LDL cholesterol levels compared with carriers of the common Pro/Pro genotype (p = 0.029 and p = 0.016, respectively) at univariate analyses. At multivariate analyses these associations were no longer significant. There was a near-significant decreased SAT PPARγ mRNA expression in patients with lipodystrophy compared to UC (p = 0.054). PPARγ Pro12Ala SNP has no effect on the risk of developing lipodystrophy in HIV-1-infected patients treated with HAART. PPARγ mRNA SAT expression appears decreased in lipodystrophy.

This article has been accepted for publication in Clinical Infectious Diseases ©2014 The Authors .Published by Oxford University Press on Clinical Infectious Disease 60.5. DOI: 10.1093/cid/ciu898, Background. It is unclear whether metabolic or body composition effects may differ between protease inhibitor-based regimens recommended for initial treatment of HIV infection. Methods. ATADAR is a phase IV, open-label, multicenter randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Pre-defined end-points were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. Results. At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95%CI -0.6 to 21.6); and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95%CI -0.5 to 17.6). Seven vs. five patients discontinued atazanavir/ritonavir or darunavir/ritonavir due to adverse effects. Total and HDL cholesterol similarly increased in both arms, but triglycerides increased more in atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95%CI 726.7 to 4997.7; P=0.0090), limb fat (estimated difference 1403.3 gr; 95%CI 388.4 to 2418.2; P=0.0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm2; 95%CI 1.9 to 55.0; P=0.0362) increased more in atazanavir/ritonavir than in darunavir/ritonavir arm. Body fat changes in atazanavir/ritonavir arm were associated with higher insulin resistance. Conclusions. We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically-relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and total and subcutaneous fat than darunavir/ritonavir and fat gains with atazanavir/ritonavir were associated with insulin resistance, This is an Investigator Sponsored Research study. It was supported in part by research grants from Bristol‐Myers Squibb and Janssen‐Cilag; Instituto de Salud Carlos III (PI12/01217) and Red Temática Cooperativa de Investigación en SIDA G03/173 (RIS‐EST11), Ministerio de Ciencia e Innovación, Spain. (Registration number: NCT01274780; registry name: ATADAR; EUDRACT; 2010‐021002‐38).

ObjectivesEx vivo analysis of mitochondrial function may reveal HIV progression and the impact of ART. We propose a mitochondrial and apoptotic in vitro model using Jurkat T cells incubated with plasma. The objectives of this study were to evaluate mitochondrial and apoptotic lesions in this model in relation to HIV progression, and to assess the effect of >1 year of standard non-thymidine-containing therapy.MethodsThis was a cross-sectional comparison among three age- and gender-matched groups (n = 19 × 3): healthy non-HIV-infected participants, HIV-infected long-term non-progressors (LTNPs) and standard antiretroviral-naive chronically infected patients [standard progressors (Sps)], longitudinally evaluated before (Sp1) and after (Sp2) >1 year of efavirenz + tenofovir + emtricitabine therapy. We analysed mitochondrial DNA content by RT–PCR, mitochondrial function by spectrophotometry, mitochondrial protein synthesis by western blot analysis, mitochondrial dynamics by western blot analysis (MFN2), apoptotic transition pore formation by western blot analysis (VDAC-1) and mitochondrial membrane potential and annexin V/propidium iodide fluorescence by flow cytometry.ResultsThere was a decreasing non-significant trend towards lower mitochondrial parameters for HIV-infected values with respect to uninfected control reference values. HIV progression (LTNP versus Sp1) was associated with decreased mitochondrial genetic, functional and translational parameters, which partially recovered after treatment intervention (Sp2). Mitochondrial fusion showed a trend to decrease non-significantly in Sp patients compared with LTNP patients, especially after therapy. All apoptotic parameters showed a trend to increase in Sp1 with respect to LTNP, followed by recovery in Sp2.ConclusionsWe proposed an in vitro model for mitochondrial and apoptotic assessment to test the effects of HIV infection and its therapy, resembling in vivo conditions. This model could be useful for clinical research purposes.

Background and Objectives: The influence of the polymorphisms of the CX3CR1 chemokine receptor gene on the natural history of HIV-1 infection is controversial. This study aimed to determine whether functionally active CX3CR1 genetic variants are associated with long-term nonprogressive infection of > 15 years in HIV-1-infected Spanish patients. Patients and Methods: Two single-nucleotide polymorphisms, V249I (G > A) and T280M (C > T), of the CX3CR1 gene were assessed in 271 Spaniards. These included 60 HIV-1-infected patients who were long-term nonprogressors (LTNPs) of > 15 years, 109 HIV-1-infected patients who were usual progressors (UPs), and 102 control subjects. The CCR5Δ32 was also assessed. Genotyping was performed using polymerase chain reaction and automatic sequencing analysis methods on white cell DNA. Genotype and allele frequencies were compared by the χ 2 test and the Fisher exact test. Results: The frequencies of the 249I variant allele were 42% for LTNPs, 24.5% for UPs, and 35% for healthy controls; the differences between LTNPs and UPs were significant (odds ratio 0.46; 95% CI: 0.27 to 0.75; P = 0.0017). For 280M the distribution was 16% for LTNPs, 14% for UPs, and 17% for healthy controls (P = NS). The haplotype 249I280T was significantly more common in LTNPs than in UPs (P = 0.0007). These results persisted after excluding from the analysis the individuals carrying the CCR5Δ32. Conclusions: CX3CR1 249I variant allele is more frequent in Spanish HIV-1-infected LTNPs of > 15 years. This effect is independent of the presence of the CCR5Δ32 allele.

IntroductionAlternation of antiretroviral drug regimens has been proposed as a novel treatment strategy for HIV infection. However, some concerns persist regarding antiviral efficacy, adherence, toxicity and resistance evolution in the long term.MethodsA total of 161 antiretroviral-naive HIV-1-infected patients were randomized to receive stavudine/ didanosine/efavirenz (group A) or zidovudine/lamivudine/ nelfinavir (group B) or to alternate between the two regimens every 3 months starting with regimen A (group C). Antiviral efficacy, adherence, safety and tolerability were analysed every 12 weeks.ResultsAfter 96 weeks, time to virological failure was significantly delayed in the alternating regimen compared with the standards of care regimens. Virological suppression was seen in 46%, 48% and 58% of patients in groups A, B and C, respectively, in the intention-to-treat analysis and in 75%, 76% and 97% in the on-treatment analysis (A vs C: P=0.014; B vs C: P=0.016; A vs B: P=0.849). At the end of the study, 94% of patients in group A and 92% in groups B and C reported an adherence greater than 95%. Alternating therapy was associated with a similar impact on CD4+ counts in comparison with the standards of care regimens, as well as a lower mitochondrial DNA/nuclear DNA (mtDNA/nDNA) ratio decrease in the mitochondrial substudy performed on 37 patients. The frequency and intensity of adverse events in the alternating group decreased during subsequent cycles.DiscussionOur results favour the hypothesis that proactive therapy switching may delay the accumulation of resistance mutations. Moreover, the alternating regimen was well tolerated and adherence remained comparably high in all treatment groups. The lower mtDNA/nDNA ratio decrease observed in this group may imply a lower impact on mitochondrial toxicity than in standard regimens.