Monocyte Activation and Ageing Biomarkers in the Development of Cardiovascular Ischaemic Events or Diabetes in People with HIV

HIV infection; Cardiovascular disease; DiabetesInfecció pel VIH; Malaltia cardiovascular; DiabetisInfección por VIH; Enfermedad cardiovascular; DiabetesWe investigated whether blood telomere length (TL), epigenetic age acceleration (EAA), and soluble inflammatory monocyte cytokines are associated with cardiovascular events or diabetes (DM) in people living with HIV (PLHIV). This was a case–control study nested in the Spanish HIV/AIDS Cohort (CoRIS). Cases with myocardial infarction, stroke, sudden death, or diabetes after starting antiretroviral therapy were included with the available samples and controls matched for sex, age, tobacco use, pre-ART CD4 cell count, viral load, and sample time-point. TL (T/S ratio) was analysed by quantitative PCR and EAA with DNA methylation changes by next-generation sequencing using the Weidner formula. Conditional logistic regression was used to explore the association with cardiometabolic events. In total, 180 participants (94 cases (22 myocardial infarction/sudden death, 12 strokes, and 60 DM) and 94 controls) were included. Of these, 84% were male, median (IQR) age 46 years (40–56), 53% were current smokers, and 22% had CD4 count ≤ 200 cells/mm3 and a median (IQR) log viral load of 4.52 (3.77–5.09). TL and EAA were similar in the cases and controls. There were no significant associations between TL, EAA, and monocyte cytokines with cardiometabolic events. TL and EAA were mildly negatively correlated with sCD14 (rho = −0.23; p = 0.01) and CCL2/MCP-1 (rho = −0.17; p = 0.02). We found no associations between TL, EAA, and monocyte cytokines with cardiovascular events or diabetes. Further studies are needed to elucidate the clinical value of epigenetic biomarkers and TL in PLHIV.This study was funded by an unrestricted and competitive grant from “The Fellowship Program” of Gilead Sciences (Exp. GLD16/00133). CoRIS is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional I + D + i and co-financed by Instituto de Salud Carlos III-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER). The integrated HIV BioBank is supported by the Instituto de Salud Carlos III RD12/0017/0037

Monocyte Activation and Ageing Biomarkers in the Development of Cardiovascular Ischaemic Events or Diabetes in People with HIV

We investigated whether blood telomere length (TL), epigenetic age acceleration (EAA), and soluble inflammatory monocyte cytokines are associated with cardiovascular events or diabetes (DM) in people living with HIV (PLHIV). This was a case-control study nested in the Spanish HIV/AIDS Cohort (CoRIS). Cases with myocardial infarction, stroke, sudden death, or diabetes after starting antiretroviral therapy were included with the available samples and controls matched for sex, age, tobacco use, pre-ART CD4 cell count, viral load, and sample time-point. TL (T/S ratio) was analysed by quantitative PCR and EAA with DNA methylation changes by next-generation sequencing using the Weidner formula. Conditional logistic regression was used to explore the association with cardiometabolic events. In total, 180 participants (94 cases (22 myocardial infarction/sudden death, 12 strokes, and 60 DM) and 94 controls) were included. Of these, 84% were male, median (IQR) age 46 years (40-56), 53% were current smokers, and 22% had CD4 count ≤ 200 cells/mm3 and a median (IQR) log viral load of 4.52 (3.77-5.09). TL and EAA were similar in the cases and controls. There were no significant associations between TL, EAA, and monocyte cytokines with cardiometabolic events. TL and EAA were mildly negatively correlated with sCD14 (rho = -0.23; p = 0.01) and CCL2/MCP-1 (rho = -0.17; p = 0.02). We found no associations between TL, EAA, and monocyte cytokines with cardiovascular events or diabetes. Further studies are needed to elucidate the clinical value of epigenetic biomarkers and TL in PLHIV.This study was funded by an unrestricted and competitive grant from “The Fellowship Program” of Gilead Sciences (Exp. GLD16/00133). CoRIS is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional I + D + i and co-financed by Instituto de Salud Carlos III-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER). The integrated HIV BioBank is supported by the Instituto de Salud Carlos III RD12/0017/0037.S

Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years.

BACKGROUND Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during untreated HIV infection and during suppressive ART. METHODS In this longitudinal study, conducted over 17 years in HIV outpatient clinics in Switzerland, we applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoints (T1-T4). T1 and T2 had to be 3 years or longer apart, as did T3 and T4. We assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing. FINDINGS Between March 13, 1990, and Jan 18, 2018, we recruited 81 people with HIV from the Swiss HIV Cohort Study. We excluded one participant because a sample did not meet quality checks (transmission error). 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37·5-47) years. Per year of untreated HIV infection (median observation 8·08 years, IQR 4·83-11·09), mean EAA was 0·47 years (95% CI 0·37 to 0·57) for Horvath's clock, 0·43 years (0·3 to 0·57) for Hannum's clock, 0·36 years (0·27 to 0·44) for SkinBlood clock, and 0·69 years (0·51 to 0·86) for PhenoAge. Per year of suppressive ART (median observation 9·8 years, IQR 7·2-11), mean EAA was -0·35 years (95% CI -0·44 to -0·27) for Horvath's clock, -0·39 years (-0·50 to -0·27) for Hannum's clock, -0·26 years (-0·33 to -0·18) for SkinBlood clock, and -0·49 years (-0·64 to -0·35) for PhenoAge. Our findings indicate that people with HIV epigenetically aged by a mean of 1·47 years for Horvath's clock, 1·43 years for Hannum's clock, 1·36 years for SkinBlood clock, and 1·69 years for PhenoAge per year of untreated HIV infection; and 0·65 years for Horvath's clock, 0·61 years for Hannum's clock, 0·74 years for SkinBlood clock, and 0·51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0·10 years, 0·02 to 0·19) and suppressive ART (-0·05 years, -0·12 to 0·02). We obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small. INTERPRETATION In a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection. FUNDING Swiss HIV Cohort Study, Swiss National Science Foundation, and Gilead Sciences

Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years

BACKGROUND: Accelerated epigenetic ageing can occur in untreated HIV infection and is partially reversible with effective antiretroviral therapy (ART). We aimed to make a long-term comparison of epigenetic ageing dynamics in people with HIV during untreated HIV infection and during suppressive ART. METHODS: In this longitudinal study, conducted over 17 years in HIV outpatient clinics in Switzerland, we applied 5 established epigenetic age estimators (epigenetic clocks) in peripheral blood mononuclear cells (PBMCs) in Swiss HIV Cohort Study participants before or during suppressive ART. All participants had a longitudinal set of PBMC samples available at four timepoints (T1-T4). T1 and T2 had to be 3 years or longer apart, as did T3 and T4. We assessed epigenetic age acceleration (EAA) and a novel rate of epigenetic ageing. FINDINGS: Between March 13, 1990, and Jan 18, 2018, we recruited 81 people with HIV from the Swiss HIV Cohort Study. We excluded one participant because a sample did not meet quality checks (transmission error). 52 (65%) of 80 patients were men, 76 (95%) were white, and the median patient age was 43 (IQR 37·5-47) years. Per year of untreated HIV infection (median observation 8·08 years, IQR 4·83-11·09), mean EAA was 0·47 years (95% CI 0·37 to 0·57) for Horvath's clock, 0·43 years (0·3 to 0·57) for Hannum's clock, 0·36 years (0·27 to 0·44) for SkinBlood clock, and 0·69 years (0·51 to 0·86) for PhenoAge. Per year of suppressive ART (median observation 9·8 years, IQR 7·2-11), mean EAA was -0·35 years (95% CI -0·44 to -0·27) for Horvath's clock, -0·39 years (-0·50 to -0·27) for Hannum's clock, -0·26 years (-0·33 to -0·18) for SkinBlood clock, and -0·49 years (-0·64 to -0·35) for PhenoAge. Our findings indicate that people with HIV epigenetically aged by a mean of 1·47 years for Horvath's clock, 1·43 years for Hannum's clock, 1·36 years for SkinBlood clock, and 1·69 years for PhenoAge per year of untreated HIV infection; and 0·65 years for Horvath's clock, 0·61 years for Hannum's clock, 0·74 years for SkinBlood clock, and 0·51 years for PhenoAge, per year of suppressive ART. GrimAge showed some change in the mean EAA during untreated HIV infection (0·10 years, 0·02 to 0·19) and suppressive ART (-0·05 years, -0·12 to 0·02). We obtained very similar results using the rate of epigenetic ageing. Contribution of multiple HIV-related, antiretroviral, and immunological variables, and of a DNA methylation-associated polygenic risk score to EAA was small. INTERPRETATION: In a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection

Identifying key predictors of recidivism among offenders attending a batterer intervention program: A survival analysis

Strategies to reduce intimate partner violence against women (IPVAW) can be targeted at different levels. Batterer intervention programs (BIPs) are among the main treatment approaches for IPVAW offenders. The most common outcome used in the evaluation of BIP effectiveness is recidivism. Efforts to increase BIP effectiveness in reducing recidivism should focus on key predictive variables of this outcome. The aim of this study was to identify key predictors of official recidivism from a large set of variables drawn from a sample of IPVAW offenders court-mandated to a community-based BIP (N = 393), with a follow-up period of between 0 and 69 months. To this end, a survival analysis was conducted using four sets of variables: individual-level, relational- and contextual-level, violence-related, and intervention process-related variables. To include all variables in the analysis simultaneously, a Cox regression model was estimated with the adaptive least absolute shrinkage and selection operator (ALASSO). From a pool of eighty-nine variables, six were selected as key predictors of recidivism: dropout, risk of future violence against non-partners, family violence exposure, immigrant status, accumulation of stressful life events, and trait anger. The area under the receiving operator characteristic (ROC) curve was .808, indicating good prediction of the model. The key predictors of recidivism found in this study should be considered by professionals and researchers in the BIP field to improve their evaluation and intervention strategies. Practical implications for future research are also discussed

Efecto de la infección VIH y el tratamiento antirretroviral en la metilación del ADN y la longitud telomérica: implicaciones sobre el envejecimiento biológico en las personas que viven con el VIH

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 25-05-2022El desarrollo de la terapia antirretroviral (TAR) para el tratamiento de la infección por el VIH constituye uno de los principales logros de la medicina moderna. La enfermedad ha pasado de ser potencialmente mortal a ser una patología crónica y manejable. Sin embargo, en los últimos años se ha observado que las personas que viven con el VIH presentan, a pesar del control virológico y la mejoría inmunológica, una mayor prevalencia de comorbilidades relacionadas con el envejecimiento, sugiriendo que la enfermedad crónica podría estar asociada con un proceso de envejecimiento prematuro. Para evaluar cómo la infección VIH y el TAR interfieren en el envejecimiento biológico, en este trabajo hemos estudiado dos mecanismos moleculares que contribuyen en este proceso: la metilación del ADN y la longitud de los telómeros. En comparación con controles sin infección VIH, hemos observado que las personas que viven con el VIH sin TAR presentan una modificación en los perfiles de metilación del ADN, principalmente en genes relacionados con la regulación de la respuesta inmune. Utilizando 4 relojes epigenéticos como biomarcadores, también observamos que la infección VIH no tratada produce una aceleración del envejecimiento epigenético, que ocurre de forma más acusada en los pacientes con menores niveles de linfocitos T CD4+ y mayores cargas virales. Después de dos años desde el inicio del TAR, nuestros resultados han mostrado que los cambios en el metiloma asociados con la infección VIH tienden a normalizarse, y que la aceleración del envejecimiento epigenético se revierte parcialmente. En un análisis longitudinal realizado en personas que viven con el VIH tratadas y con supresión virológica prolongada, nuestros resultados han mostrado que durante la infección crónica bien controlada no se produce una aceleración del envejecimiento epigenético. Además, nuestros datos sugieren que los relojes epigenéticos podrían ser buenos candidatos como biomarcadores para predecir la aparición de comorbilidades relacionadas con el envejecimiento en el contexto de la infección VIH. Por último, en un estudio de corte transversal hemos observado que las personas que viven con el VIH y que llevaban más de 5 años tomando un régimen de TAR basado en tenofovir, tienen una menor actividad telomerasa en linfocitos T CD4+ y T CD8+ y una menor longitud telomérica en linfocitos T CD8+ que los pacientes que nunca han sido expuestos a tenofovir. Estos resultados podrían sugerir un efecto inhibitorio in vivo de la telomerasa por parte del tenofovi

Relación Médico – Paciente en la actualidad. Reflexiones desde la Bioética

Objective: To analyze the problems that prevent the development of a good RMP at present, in addition to analyzing the impact of COVID-19 on this relationship, we want the reader to understand why a good RMP is essential and the problems that prevent this goal.  Method: Descriptive documentary type. Conclusion: We must work from the university to promote a humanized medicine, where communication and empathy are prioritized, where technology is not an enemy but an ally. If the pandemic has shown us anything, it is that society recognizes that physicians are valuable, but we must also give value to our patients.Objetivo: Analizar los problemas que impiden el desarrollo de una buena RMP en la actualidad, además analizamos el impacto del COVID – 19 en esta relación, buscamos que el lector comprenda porque es fundamental una buena RMP y los problemas que impiden esta meta.  Método: De tipo descriptiva documental. Conclusión: Se debe trabajar desde la universidad en fomentar una medicina humanizada, donde se priorice la comunicación y la empatía, donde la tecnología no sea un enemigo sino un aliado. Si algo nos demostró la pandemia es que la sociedad reconoce que los médicos son valiosos, pero también debemos dar valor a nuestros pacientes

Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO)

Background We investigated the efficacy of a switch to dolutegravir plus lamivudine in aviremic individuals without evidence of persistent lamivudine resistance-associated mutations in baseline proviral DNA population sequencing. Methods Open-label, single-arm, 48-week pilot trial. HIV-1 infected adults, naïve to integrase inhibitors, with CD4+ above 350 cell/μL and fewer than 50 HIV-1 RNA copies per mL the year prior to study entry switched to dolutegravir plus lamivudine. Participants were excluded if baseline proviral DNA population genotyping detected lamivudine resistance-associated mutations. To detect resistance minority variants, proviral DNA next-generation sequencing was retrospectively performed from baseline samples. Primary efficacy endpoint was proportion of participants with fewer than 50 HIV-1 RNA copies per mL at week 48. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. ART-PRO is registered with ClinicalTrials.gov, NCT03539224. Findings 41 participants switched to dolutegravir plus lamivudine, 21 with lamivudine resistance mutations in historical plasma genotypes. Baseline next-generation sequencing detected lamivudine resistance mutations (M184V/I and/or K65R/E/N) over a 5% threshold in 15/21 (71·4%) and 3/20 (15%) of participants with and without history of lamivudine resistance, respectively. At week 48, 92·7% of participants (38/41) had fewer than 50 HIV-1 RNA copies per mL. There were no cases of virologic failure. Three participants with historical lamivudine resistance were prematurely discontinued from the study (2 protocol violations, one adverse event). Ten participants (4 in the group with historical lamivudine resistance) had a transient viral rebound, all resuppressed on dolutegravir plus lamivudine. There were 28 drug-related adverse events, only one leading to discontinuation. Interpretation In this pilot trial, dolutegravir plus lamivudine was effective in maintaining virologic control despite past historical lamivudine resistance and presence of archived lamivudine resistance-associated mutations detected by next generation sequencing. Further studies are needed to confirm our results.Instituto de Salud Carlos III PI16/00837-PI16/006788.143 JCR (2020) Q1, 17/140 Medicine, Research & Experimental2.596 SJR (2020) Q1, 23/254 Biochemistry, Genetics and Molecular Biology (miscellaneous)No data IDR 2020UE