RESUMEN
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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Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Lamivudine , Oxazinas , Piperazinas , Piridonas , Humanos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Lamivudine/uso terapéutico , Lamivudine/administración & dosificación , Masculino , Oxazinas/uso terapéutico , Femenino , Adulto , Persona de Mediana Edad , Metabolómica , Lipidómica , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Plasma/química , Proteómica , Terapia Antirretroviral Altamente Activa , Sustitución de Medicamentos , Triglicéridos/sangre , Alanina/sangre , MultiómicaRESUMEN
Nuclear magnetic resonance (NMR)-based advanced lipoprotein tests have demonstrated that LDL and HDL particle numbers (LDL-P and HDL-P) are more powerful cardiovascular (CV) risk biomarkers than conventional cholesterol markers. Of interest, in people living with HIV (PLHIV), predictors of preclinical atherosclerosis and vascular dysfunction may be associated with impaired immune function. We previously stated that immunological non-responders (INR) were at higher CV risk than immunological responders (IR) before starting antiretroviral therapy (ART). Using Liposcale® tests, we characterized the lipoprotein profile from the same cohort of PLHIV at month 12 and month 36 after starting ART, intending to explore what happened with these indicators of CV risk during viral suppression. ART initiation dissipates the differences in lipoprotein-based CV risk markers between INR and IR, and only an increase in the number of HDL-P was found in INR + IR when compared to controls (p = 0.047). Interestingly, CD4+ T-cell counts negatively correlated with medium HDL-P concentrations at month 12 in all individuals (ρ = -0.335, p = 0.003). Longitudinal analyses showed an important increase in LDL-P and HDL-P at month 36 when compared to baseline values in both IR and INR. A proper balance between a proatherogenic and atherogenic environment may be related to the reconstitution of CD4+ T-cell count in PLHIV.
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Fármacos Anti-VIH , Aterosclerosis , Infecciones por VIH , Fármacos Anti-VIH/uso terapéutico , Aterosclerosis/etiología , Biomarcadores , Colesterol/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Humanos , Lipoproteínas/sangreRESUMEN
Long-term elite controllers (LTECs) are a fascinating small subset of HIV individuals with viral and immunological HIV control in the long term that have been designated as models of an HIV functional cure. However, data on the LTEC phenotype are still scarce, and hence, the metabolomics and lipidomics signatures in the LTEC-extreme phenotype, LTECs with more than 10 years of viral and immunological HIV control, could be pivotal to finding the keys for functional HIV remission. Metabolomics and lipidomics analyses were performed using high-resolution mass spectrometry (ultra-high-performance liquid chromatography-electrospray ionization-quadrupole time of flight [UHPLC-(ESI) qTOF] in plasma samples of 13 patients defined as LTEC-extreme, a group of 20 LTECs that lost viral and/or immunological control during the follow-up study (LTEC-losing) and 9 EC patients with short-term viral and immunological control (less than 5 years; no-LTEC patients). Long-term viral and immunological HIV-1 control was found to be strongly associated with elevated tricarboxylic acid (TCA) cycle function. Interestingly, of the nine metabolites identified in the TCA cycle, α-ketoglutaric acid (p = 0.004), a metabolite implicated in the activation of the mTOR complex, a modulator of HIV latency and regulator of several biological processes, was found to be a key metabolite in the persistent control. On the other hand, a lipidomics panel combining 45 lipid species showed an optimal percentage of separation and an ability to differentiate LTEC-extreme from LTEC-losing, revealing that an elevated lipidomics plasma profile could be a predictive factor for the reignition of viral replication in LTEC individuals.
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Infecciones por VIH , VIH-1 , Estudios de Seguimiento , Humanos , Ácidos Cetoglutáricos , LípidosRESUMEN
A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4+ T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4+ T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4+ T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders (p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits (p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels (p < 0.01), and low circulating RBP4 concentrations were related to a low CD4+ T-cell gain (p = 0.018 and p = 0.039 at 48 and 144 weeks, respectively). Multiple regression adjusted for clinical variables and adipokine concentrations confirmed both low APLNR and RBP4 as independent predictors for CD4+ T cells at 144 weeks (p < 0.001). In conclusion, low APLNR and RBP4 concentrations were associated with poor immune recovery in treated PLHIV and could be considered predictive biomarkers of a discordant immunological response.
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Adipoquinas/metabolismo , Receptores de Apelina/metabolismo , Biomarcadores/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Infecciones por VIH/metabolismo , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Adipoquinas/inmunología , Adulto , Terapia Antirretroviral Altamente Activa/métodos , Receptores de Apelina/inmunología , Recuento de Linfocito CD4/métodos , Linfocitos T CD4-Positivos/inmunología , Femenino , Infecciones por VIH/inmunología , VIH-1/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Plasmáticas de Unión al Retinol/inmunología , Carga Viral/fisiologíaRESUMEN
PURPOSE: The objectives of the study were to establish a procedure for in vivo film-based dosimetry for intraoperative radiotherapy (IORT), evaluate the typical doses delivered to organs at risk, and verify the dose prescription. MATERIALS AND METHODS: In vivo dose measurements were studied using XR-RV3 radiochromic films in 30 patients with breast cancer undergoing IORT using the Axxent® device (Xoft Inc.). The stability of the radiochromic films in the energy ranges used was verified by taking measurements at different depths. The stability of the scanner response was tested, and 5 different calibration curves were constructed for different beam qualities. Six pieces of film were placed in each of the 30 patients. All the pieces were correctly sterilized and checked to ensure that the process did not affect the outcome. All calibration and dose measurements were analyzed using the Radiochromic.com software application. RESULTS: The doses were measured for 30 patients. The doses in contact with the applicator (prescription zone) were 19.8 ± 0.9 Gy. In the skin areas, the doses were as follows: 1-2 cm from the applicator, 1.86 ± 0.77 Gy; 2-5 cm, 0.73 ± 0.14 Gy; and greater than 5 cm, 0.28 ± 0.17 Gy. The dose delivered to the pectoral muscle (tungsten shielding disc) was 0.51 ± 0.27 Gy. CONCLUSIONS: The study demonstrated the viability of XR-RV3 films for in vivo dose measurement in the dose and energy ranges applied in a complex procedure, such as breast IORT. The doses in organs at risk were far below the tolerances for cases such as those studied.
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Dosimetría por Película , Dosimetría in Vivo , Mama , Calibración , Humanos , Programas InformáticosRESUMEN
BACKGROUND AND PURPOSE: The relative benefit of adjuvant radiotherapy (RT) alone in older women with low-risk early breast cancer (EBC) remains unclear. It is hypothesized that adjuvant RT-alone can improve outcomes of older patients with low-risk EBC, similar to endocrine therapy (ET) alone or combination of RT + ET. METHODS: In this population based study, we identified all women aged ≥70 with T1-2, N0, ER+ve, Her-2/neu-ve EBC treated with breast conserving surgery (BCS), followed by adjuvant treatments (RT-alone, ET-alone, or RT + ET combination) from 2005 to 2015. Primary outcome measures were recurrence-free survival (RFS), overall survival (OS), and breast cancer specific survival (BCSS). Treatment details were collected and Charlson Comorbidity Index (CCI) was calculated. RESULTS: A total of 1166 patients were identified. Median follow-up was 76.5 months. Adjuvant treatments: BCS only 130 (11%), RT 378 (32.5%), ET 161 (14%), and RT + ET 497 (42.5%). Less than 60% of women completed 5-years of ET. Compared to BCS alone, RT resulted in significant improvement in RFS (HR = 0.174; p < 0.001), similar to ET (HR = 0.414; p = 0.007) and RT + ET (HR = 0.236; p < 0.001). Determinants of OS were age, tumor grade, comorbidities, and adjuvant therapy. Increased comorbidity scores (0 vs. 1; 0 vs. ≥2) were associated with reduced OS (HR = 1.40; p = 0.013 and HR = 1.98; p < 0.001), without impact on RFS or BCSS. CONCLUSIONS: Adjuvant RT-alone is a reasonable alternative to ET or RT + ET for older women with biologically favorable EBC. No difference in RFS or BCSS was noted between RT, ET, and RT + ET. Comorbidity was independently associated with reduced overall survival.
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Neoplasias de la Mama , Mastectomía Segmentaria , Anciano , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/cirugía , Terapia Combinada , Femenino , Humanos , Radioterapia AdyuvanteRESUMEN
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-ß/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. FUNDING: This work was supported by Fondo de Investigacion Sanitaria and SPANISH AIDS Research Network (ISCIII-FEDER); AGAUR and Gilead Fellowship. FV and YMP are supported by grants from the Programa de Intensificación (ISCIII) and Servicio Andaluz de Salud, respectively. JVG,EY and LR are supported by the Instituto de Salud Carlos III (ISCIII). AR is supported by Departament de Salut, Generalitat de Catalunya and by the Instituto de Salud Carlos III (ISCIII).
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Quimiocina CCL2/sangre , Quimiocina CCL2/genética , Quimiocina CXCL12/sangre , Quimiocina CXCL12/genética , Variación Genética , Receptores CCR5/genética , Adulto , Alelos , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Genotipo , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Humanos , Inmunidad , Inmunomodulación/genética , Masculino , Persona de Mediana Edad , Pronóstico , Factores de RiesgoRESUMEN
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.
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Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/inmunología , Interleucina-7/genética , Receptores de Interleucina-7/genética , Adulto , Recuento de Linfocito CD4 , Estudios de Cohortes , Femenino , Infecciones por VIH/tratamiento farmacológico , Homeostasis , Humanos , Interleucina-7/sangre , Masculino , Persona de Mediana Edad , Receptores de Interleucina-7/sangreRESUMEN
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, nâ¯=â¯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, nâ¯=â¯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. FUND: This work was supported by grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondos FEDER; Red de Investigación en Sida, Gilead Fellowship program, Spanish Ministry of Education and Spanish Ministry of Economy and Competitiveness.
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Metabolismo Energético , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , VIH-1/inmunología , Interacciones Huésped-Patógeno/inmunología , Biomarcadores , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ciclo del Ácido Cítrico , Citocinas/metabolismo , Infecciones por VIH/virología , Humanos , Metabolismo de los Lípidos , Lípidos/sangre , Activación de Linfocitos/inmunología , Metabolómica/métodos , Carga Viral , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
BACKGROUND: Elite controllers (ECs) spontaneously control plasma human immunodeficiency virus type 1 (HIV-1) RNA without antiretroviral therapy. However, 25% lose virological control over time. The aim of this work was to study the proteomic profile that preceded this loss of virological control to identify potential biomarkers. METHODS: Plasma samples from ECs who spontaneously lost virological control (transient controllers [TCs]), at 2 years and 1 year before the loss of control, were compared with a control group of ECs who persistently maintained virological control during the same follow-up period (persistent controllers [PCs]). Comparative plasma shotgun proteomics was performed with tandem mass tag (TMT) isobaric tag labeling and nanoflow liquid chromatography coupled to Orbitrap mass spectrometry. RESULTS: Eighteen proteins exhibited differences comparing PC and preloss TC timepoints. These proteins were involved in proinflammatory mechanisms, and some of them play a role in HIV-1 replication and pathogenesis and interact with structural viral proteins. Coagulation factor XI, α-1-antichymotrypsin, ficolin-2, 14-3-3 protein, and galectin-3-binding protein were considered potential biomarkers. CONCLUSIONS: The proteomic signature associated with the spontaneous loss of virological control was characterized by higher levels of inflammation, transendothelial migration, and coagulation. Galectin-3 binding protein could be considered as potential biomarker for the prediction of virological progression and as therapeutic target in ECs.
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Infecciones por VIH/inmunología , Proteoma/análisis , Adulto , Biomarcadores/sangre , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Carga Viral , Replicación ViralRESUMEN
BACKGROUND AND AIMS: Dyslipidemia in HIV-infected patients is unique and pathophysiologically associated with host factors, HIV itself and the use of antiretroviral therapy (ART). The use of nuclear magnetic resonance spectroscopy (NMR) provides additional data to conventional lipid measurements concerning the number of lipoprotein subclasses and particle sizes. METHODS: To investigate the ability of lipoprotein profile, we used a circulating metabolomic approach in a cohort of 103 ART-naive HIV-infected patients, who were initiating non-nucleoside analogue transcriptase inhibitor (NNRTI)-based ART, and we subsequently followed up these patients for 36 months. Univariate and multivariate analyses were performed to evaluate the predictive power of NMR spectroscopy. RESULTS: VLDL-metabolism (including VLDL lipid concentrations, sizes, and particle numbers), total triglycerides and lactate levels resulted in good classifiers of dyslipidemia (AUC 0.903). Total particles/HDL-P ratio was significantly higher in ART-associated dyslipidemia compared to ART-normolipidemia (pâ¯=â¯0.001). Large VLDL-Ps were positively associated with both LDL-triglycerides (ρ 0.682, pâ¯<â¯0.001) and lactate concentrations (ρ 0.416, pâ¯<â¯0.001), the last one a marker of mitochondrial low oxidative capacity. CONCLUSIONS: Our data suggest that circulating metabolites have better predictive values for HIV/ART-related dyslipidemia onset than do the biochemical markers associated with conventional lipid measurements. NMR identifies changes in VLDL-P, lactate and LDL-TG as potential clinical markers of baseline HIV-dyslipidemia predisposition. Differences in circulating metabolomics, especially differences in particle size, are indicators of important derangements of mitochondrial function that are linked to ART-related dyslipidemia.
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Antirretrovirales/efectos adversos , Colesterol/sangre , Dislipidemias/sangre , Dislipidemias/inducido químicamente , Infecciones por VIH/tratamiento farmacológico , Metaboloma , Triglicéridos/sangre , Adulto , Antirretrovirales/uso terapéutico , Dislipidemias/metabolismo , Femenino , Humanos , Masculino , Metabolómica , Persona de Mediana Edad , Valor Predictivo de las PruebasRESUMEN
OBJECTIVES: 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. DESIGN: This was a multicentre, prospective cohort study in ART-naive and a pre-ART low nadir (<200 cells/µl) HIV-infected patients (nâ=â64). METHODS: We obtained clinical data and metabolomic profiles for each individual, in which low molecular weight metabolites, lipids and lipoproteins (including particle concentrations and sizes) were measured by NMR spectroscopy. Immunological recovery was defined as reaching CD4 T-cell count at least 250 cells/µl after 36 months of virologically successful ART. We used univariate comparisons, Random Forest test and receiver-operating characteristic curves to identify and evaluate the predictive factors of immunological recovery after treatment. RESULTS: HIV-infected patients with a baseline metabolic pattern characterized by high levels of large high density lipoprotein (HDL) particles, HDL cholesterol and larger sizes of low density lipoprotein particles had a better immunological recovery after treatment. Conversely, patients with high ratios of non-HDL lipoprotein particles did not experience this full recovery. Medium very-low-density lipoprotein particles and glucose increased the classification power of the multivariate model despite not showing any significant differences between the two groups. CONCLUSION: In HIV-infected patients, a baseline healthier metabolomic profile is related to a better response to ART where the lipoprotein profile, mainly large HDL particles, may play a key role.
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Antirretrovirales/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Metaboloma , Adulto , Recuento de Linfocito CD4 , Femenino , Estudios de Seguimiento , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: Obesity and HIV-1/HAART-associated lipodystrophy syndrome (HALS) share clinical, pathological and mechanistic features. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that plays an important role in obesity and related diseases. We sought to explore the relationship between HALS and circulating levels of soluble (s) TWEAK and its scavenger receptor sCD163. METHODS: This was a cross-sectional multicenter study of 120 HIV-1-infected patients treated with a stable HAART regimen; 56 with overt HALS and 64 without HALS. Epidemiological and clinical variables were determined. Serum levels of sTWEAK and sCD163 levels were measured by ELISA. Results were analyzed with Student's t-test, Mann-Whitney U and χ2 test. Pearson and Spearman correlation were used to estimate the strength of association between variables. RESULTS: Circulating sTWEAK was significantly decreased in HALS patients compared with non-HALS patients (2.81±0.2 vs. 2.94±0.28 pg/mL, p = 0.018). No changes were observed in sCD163 levels in the studied cohorts. On multivariate analysis, a lower log sTWEAK concentration was independently associated with the presence of HALS (OR 0.027, 95% CI 0.001-0.521, p = 0.027). CONCLUSIONS: HALS is associated with decreased sTWEAK levels.
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Fármacos Anti-VIH/uso terapéutico , Síndrome de Lipodistrofia Asociada a VIH/sangre , Síndrome de Lipodistrofia Asociada a VIH/tratamiento farmacológico , Factores de Necrosis Tumoral/sangre , Adulto , Antígenos CD/sangre , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/sangre , Antígenos de Diferenciación Mielomonocítica/genética , Terapia Antirretroviral Altamente Activa , Estudios Transversales , Citocina TWEAK , Femenino , Expresión Génica , VIH-1/fisiología , Síndrome de Lipodistrofia Asociada a VIH/diagnóstico , Síndrome de Lipodistrofia Asociada a VIH/genética , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Receptores de Superficie Celular/sangre , Receptores de Superficie Celular/genética , Factores de Necrosis Tumoral/genéticaRESUMEN
OBJECTIVES: A relationship between obesity and intestinal bacterial translocation has been reported. Very little information is available with respect to the involvement of the bacterial translocation mechanistic pathway in HIV-1/highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). We determined whether lipopolysaccharide (LPS)-binding protein (LBP), cluster of differentiation 14 (CD14), myeloid differentiation protein 2 (MD2) and toll-like receptor 4 (TLR4) single-nucleotide polymorphisms and LPS, LBP and soluble CD14 (sCD14) plasma levels are involved in HALS. PATIENTS AND METHODS: This cross-sectional multicentre study involved 558 treated HIV-1-infected patients, 240 with overt HALS and 318 without HALS. Anthropometric, clinical, immunovirological and metabolic variables were determined. Polymorphisms were assessed by genotyping. Plasma levels were determined by ELISA in 163 patients (81 with HALS and 82 without HALS) whose stored plasma samples were available. Student's t-test, one-way ANOVA, two-way repeated measures ANOVA, the χ(2) test and Pearson and Spearman correlation analyses were carried out for statistical analysis. RESULTS: LBP rs2232582 TâC polymorphism was significantly associated with HALS (Pâ=â0.01 and Pâ=â0.048 for genotype and allele analyses, respectively). Plasma levels of LPS (Pâ=â0.009) and LBP (Pâ<â0.001) were significantly higher and sCD14 significantly lower (Pâ<â0.001) in patients with HALS compared with subjects without HALS. LPS levels were independently predicted by triglycerides (Pâ<â0.001) and hepatitis C virus (Pâ=â0.038), LBP levels by HALS (Pâ<â0.001) and sCD14 levels by age (Pâ=â0.008), current HIV-1 viral load (Pâ=â0.001) and protease inhibitor use (Pâ=â0.018). CONCLUSIONS: HALS is associated with LBP polymorphism and with higher bacterial translocation.
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Proteínas de Fase Aguda/metabolismo , Proteínas Portadoras/metabolismo , Síndrome de Lipodistrofia Asociada a VIH/etiología , Síndrome de Lipodistrofia Asociada a VIH/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Lipopolisacáridos/inmunología , Antígeno 96 de los Linfocitos/metabolismo , Glicoproteínas de Membrana/metabolismo , Transducción de Señal , Receptor Toll-Like 4/metabolismo , Proteínas de Fase Aguda/genética , Adulto , Terapia Antirretroviral Altamente Activa/efectos adversos , Recuento de Linfocito CD4 , Proteínas Portadoras/sangre , Proteínas Portadoras/genética , Estudios de Casos y Controles , Estudios Transversales , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1 , Síndrome de Lipodistrofia Asociada a VIH/diagnóstico , Humanos , Inflamación , Receptores de Lipopolisacáridos/sangre , Receptores de Lipopolisacáridos/genética , Lipopolisacáridos/sangre , Antígeno 96 de los Linfocitos/genética , Masculino , Glicoproteínas de Membrana/sangre , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Factores de Riesgo , Receptor Toll-Like 4/genética , Carga ViralRESUMEN
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 < 0.001). No differences were found in ZAG plasma levels according to the presence of lipodystrophy, components of the metabolic syndrome or type of antiretroviral treatment regimen. Circulating ZAG levels were strongly determined by high-density lipoprotein cholesterol (HDLc) in men (B = 0.644; P < 0.001) and showed a positive correlation with total cholesterol (r = 0.312; P < 0.001) and HDLc (r = 0.216; P = 0.005). CONCLUSIONS: HIV-1-infected patients have lower plasma ZAG levels than uninfected controls. In infected patients, plasma ZAG levels are in close relationship with total cholesterol and HDLc.
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Proteínas Portadoras/sangre , Dislipidemias/metabolismo , Glicoproteínas/sangre , Infecciones por VIH/metabolismo , VIH-1 , Adipoquinas , Adiposidad/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Antirretrovirales/uso terapéutico , Biomarcadores/sangre , Colesterol/sangre , Dislipidemias/complicaciones , Ensayo de Inmunoadsorción Enzimática , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Síndrome de Lipodistrofia Asociada a VIH/sangre , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Little information is available with respect to the involvement of resistin in lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with combination antiretroviral therapy (cART). We determined whether the resistin (rest) -420C>G single-nucleotide polymorphism and plasma resistin are associated with the development of lipodystrophy and metabolic disturbances in HIV-1-infected patients treated with cART. METHODS: The study group comprised 299 HIV-1-infected patients treated with a stable cART for at least 1 year (143 with lipodystrophy and 156 without) and 175 uninfected controls. Anthropometric, clinical, and metabolic variables were determined. Homeostasis model assessment for insulin resistance was used to evaluate insulin resistance. Plasma resistin levels were determined by enzyme-linked immunosorbent assay. The rest -420C>G was assessed using restriction fragment length polymorphism. Student t test, 1-way and 2-way analysis of variance, χ2 test, and Pearson and Spearman correlations were performed for statistical analysis. RESULTS: Genotypes containing the rest -420G variant allele were significantly more common in HIV-1-infected patients without lipodystrophy compared with those with lipodystrophy (P = 0.037). Infected patients had significantly greater plasma resistin levels than uninfected controls (P < 0.001). Among infected patients, plasma resistin levels were significantly lower in patients with lipodystrophy with respect to those without (P = 0.034). In infected patients, plasma resistin levels had a significant positive correlation with insulin and homeostasis model assessment for insulin resistance: P < 0.001 and P = 0.002 in the lipodystrophy subset and P = 0.002 and P = 0.03 in the nonlipodystrophy subset, respectively. CONCLUSIONS: In our cohort of white Spaniards, the rest -420C>G single-nucleotide polymorphism may be associated with cART-related lipodystrophy. Plasma resistin correlates with insulin resistance in infected patients with and without lipodystrophy.
Asunto(s)
Infecciones por VIH/metabolismo , VIH-1 , Resistencia a la Insulina/fisiología , Lipodistrofia/virología , Resistina/sangre , Adulto , Antropometría , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Recuento de Linfocito CD4 , Estudios de Casos y Controles , Estudios Transversales , Quimioterapia Combinada , Femenino , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Resistencia a la Insulina/genética , Resistencia a la Insulina/inmunología , Lipodistrofia/genética , Lipodistrofia/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Resistina/genética , Estadísticas no ParamétricasRESUMEN
Doripenem is a carbapenem with activity against Gram-positive and Gram-negative pathogens. This study evaluated the in vitro activity of doripenem against a collection of 87 Acinetobacter baumannii clinical isolates, showing that the activity of doripenem was superior to imipenem and meropenem for strains carrying the bla(OXA-58) gene. A. baumannii clinical isolates expressing the bla(OXA-24) gene were resistant to doripenem, imipenem and meropenem. However, in clinical isolates expressing the bla(OXA-58) gene, the percentage of isolates with a doripenem minimum inhibitory concentration >8microg/mL was much lower than that of imipenem and meropenem. This study shows that the activity of doripenem was superior to imipenem and meropenem for strains carrying the bla(OXA-58) gene.
Asunto(s)
Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Carbapenémicos/farmacología , Acinetobacter baumannii/aislamiento & purificación , Doripenem , Humanos , Imipenem/farmacología , Meropenem , Pruebas de Sensibilidad Microbiana , Tienamicinas/farmacología , beta-Lactamasas/genéticaRESUMEN
Nadifloxacin has good activity against Propionibacterium acnes as well as against both meticillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) and Staphylococcus epidermidis. The aim of this study was to evaluate the activity of this fluoroquinolone against the abovementioned microorganisms, comparing isolates collected in 2007 in Germany, a country where nadifloxacin has been used for the last 2 years, with isolates collected from 2006-2007 in Spain where nadifloxacin has not been used. A collection of P. acnes from Hungary (strains collected during 2005-2006) and a collection of P. acnes from different countries in Europe (collected during 2002) were also included. The activity of nadifloxacin was compared with ciprofloxacin, erythromycin and clindamycin. Susceptibility testing of P. acnes was performed by agar dilution, whereas the susceptibility of the different staphylococci was determined by microdilution. Although the isolates were collected from three different countries (Spain, Hungary and Germany) where the use of quinolones can produce a different effect, no significant differences in the percentages of resistance to nadifloxacin were observed in P. acnes, MSSA, MRSA and S. epidermidis. Therefore, topical antibiotics such as nadifloxacin do not have an additional effect on resistance. Moreover, nadifloxacin presented much better activity than the comparator drugs used in this study against the studied microorganisms.
Asunto(s)
Antibacterianos/farmacología , Fluoroquinolonas/farmacología , Propionibacterium acnes/efectos de los fármacos , Quinolizinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Staphylococcus epidermidis/efectos de los fármacos , Alemania , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
Based on imipenem resistance in an Acinetobacter genospecies 3 clinical isolate, we were able to identify, for the first time in this genomic species, a plasmid-encoded bla(OXA-58) gene that was 100% homologous to the same gene in Acinetobacter baumannii.