Impacto del tratamiento antirretroviral con y sin nucleós(t)idos sobre la densidad mineral ósea y los biomarcadores de remodelado óseo

Tesis doctoral inédita, leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 18 de mayo de 2016Introducción. Las alteraciones de la densidad mineral ósea (DMO) son frecuentes en los pacientes VIH. Evaluamos la pérdida de DMO y la evolución de los biomarcadores de metabolismo óseo asociadas al inicio del tratamiento antirretroviral comparando 2 pautas con y sin nucleósidos. Métodos. Se incluyeron pacientes infectados por VIH naïve a tratamiento antirretroviral que participaban en el subestudio óseo del ensayo clínico abierto, randomizado NEAT001/ANRS143, que evaluó eficacia y seguridad de darunavir (800 mg una vez al día) potenciado con ritonavir (100 mg una vez al día) acompañado de raltegravir (400 mg dos veces al día, pauta ahorradora de nucleósidos) o tenofovir (245 mg una vez al día) y emtricitabina (200 mg una vez al día, pauta estándar). Los criterios de inclusión fueron: carga viral VIH superior a 1000 copias/mL, recuento de células CD4 inferior a 500 cels/μL, excepto en los pacientes con infección sintomática. Los criterios de exclusión fueron: HBsAg positivo, embarazo, malignidad activa, aclaramiento de creatinina inferior a 60 mL/min, tratamiento para la osteoporosis, corticoides sistémicos o tratamiento con estrógenos. Se evaluó como objetivo primario el porcentaje medio de cambio en la DMO en columna, cadera y cuello femoral y los cambios en los biomarcadores óseos a las 48 semanas de seguimiento en las 2 pautas de tratamiento. Resultados. Se incluyeron 133 pacientes, 65 pacientes en el grupo de DRV/r + RAL y 68 pacientes en el grupo de DRV/r + TDF/FTC. A las 48 semanas de seguimiento el grupo tratado con DRV/r + TDF/FTC presento una mayor pérdida de DMO frente a la pauta libre de NRTI, diferencia media -1.49% (IC95% -2.94, - 0.04) en la columna lumbar, -2.04% (IC95% -3.53, -0.55) en el cuello femoral y - 2.57% (IC95% -3.79, -1.35) en la cadera. En cuanto a los nuevos casos de osteoporosis y de osteopenia, no se encontraron diferencias entre los 2 grupos de tratamiento, sin embargo el grupo expuesto a DRV/r + TDF/FTC presentó pérdida DMO ≥5% en 42.7% de los pacientes, frente al 13.9% del grupo tratado con DRV/r + RAL, (p=0.0002). No se encontraron diferencias entre los dos grupos en la aparición de nuevas fracturas. En cuanto a los biomarcadores óseos, se encontró un incremento significativamente mayor en el grupo tratado con DRV/r + TDF/FTC en tanto en los biomarcadores de formación como de resorción. La pérdida ósea ≥5% se asoció a niveles bajos de P1NP en la randomización (p=0.02). Discusión. Las pautas ahorradoras de NRTI, basadas en raltegravir, se asocian con una menor pérdida de DMO que las pautas convencionales, pudiendo ser consideradas en pacientes con alto riesgo de osteopenia y/o de osteoporosis.Introduction. Alterations in bone mineral density (BMD) are common in HIV patients. We evaluate BMD loss and evolution of biomarkers of bone metabolism associated with the initiation of antiretroviral therapy comparing two regimens with and without nucleosides. Methods. Antiretroviral-naïve adults with HIV were included into bone substudy of open clinical trial, randomized NEAT001 / ANRS143, which evaluated efficacy and safety of darunavir (800 mg once daily) boosted with ritonavir (100 mg once day) plus raltegravir (400 mg twice daily, NRTI-sparing regimen) or tenofovir (245 mg once daily) and emtricitabine (200 mg once daily, standard regimen). Inclusion criteria were: HIV viral load above 1000 copies/mL, CD4 count below 500 cells/uL, except in patients with symptomatic infection. Exclusion criteria were: HBsAg positive, pregnancy, active malignancy, creatinine clearance less than 60 mL / min, treatment for osteoporosis, systemic corticosteroids or oestrogen therapy. We evaluated the average percentage change in BMD at the spine, hip and femoral neck and changes in bone biomarkers at 48 weeks of follow-up in the 2 treatment guidelines as the primary objective. Results. 133 patients, 65 patients were included in the group of DRV/r + RAL and 68 patients in the DRV/r + TDF/FTC. At 48 weeks of follow-up, the group treated with DRV/r + TDF/FTC presented a higher BMD loss comparing to sparing-NRTI regimen, mean difference -1.49% (95% CI -2.94, -0.04) in lumbar spine, -2.04% (95% CI -3.53, -0.55) in femoral neck and -2.57% (95% CI -3.79, -1.35) in hip. Regarding to the new cases of osteoporosis and osteopenia, no differences between the 2 treatment groups were found, however the group treated with DRV/r + TDF/FTC presented loss DMO ≥5% in 42.7% of the patients, compared to 13.9% of the group treated with DRV/r + RAL (p = 0.0002). No differences between the two groups in the occurrence of new fractures were found. On the topic of bone biomarkers, a significantly greater increase in the group treated with DRV/ r + TDF/FTC in both formation and resorption biomarkers was found. Multivariate analyses showed relationship between bone loss greater than ≥5% and low levels of P1NP at randomization (p = 0.02). Discussion. The NRTI-sparing regimen, based on raltegravir, was associated with lower BMD loss than conventional regimen, and may be considered in patients with high risk of osteopenia or osteoporosis

Use of Monoclonal Antibodies in Immunocompromised Patients Hospitalized with Severe COVID-19: A Retrospective Multicenter Cohort

This work was supported by the Research Institute Puerta de Hierro-Segovia de Aranda (IDIPHSA), funding number 0040200108 (2.400€).Objective: We aim to describe the safety and efficacy of sotrovimab in severe cases of COVID-19 in immunocompromised hosts. Methods: We used a retrospective multicenter cohort including immunocompromised hospitalized patients with severe COVID-19 treated with sotrovimab between October 2021 and December 2021. Results: We included 32 patients. The main immunocompromising conditions were solid organ transplantation (46.9%) and hematological malignancy (37.5%). Seven patients (21.9%) had respiratory progression: 12.5% died and 9.4% required mechanical ventilation. Patients treated within the first 14 days of their symptoms had a lower progression rate: 12.0% vs. 57.1%, p = 0.029. No adverse event was attributed to sotrovimab. Conclusions: Sotrovimab was safe and may be effective in its use for immunocompromised patients with severe COVID-19. More studies are needed to confirm these preliminary data.Depto. de MedicinaFac. de MedicinaTRUEResearch Institute Puerta de Hierro-Segovia de Aranda (IDIPHSA)pu

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

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Puesta en marcha del Doble Grado Internacional en Derecho UCM - Sorbona en el marco de la alianza europea de universidades UNA EUROPA

Implementación de mejoras que potencien el Doble Grado Internacional en Derecho impartido conjuntamente entre la UCM y la Universidad de la Sorbona y que esta doble titulación internacional refuerce el papel de la UCM en la alianza europea UNA EUROP

Estrategias de prevención y tratamiento de la infección por SARS-CoV-2 (Severe Acute Respiratory Coronavirus 2) en pacientes con enfermedad renal crónica: revisión de la literatura

Resumen: La COVID-19 ha demostrado ser especialmente agresiva con los pacientes con enfermedad renal crónica (ERC). La menor tasa de respuesta inmunológica y la mayor facilidad para la progresión a formas graves de enfermedad ha propiciado este hecho, que se ha mantenido en la era posvacunal de la pandemia. Paradójicamente, la ERC ha sido excluida de la mayoría de los ensayos clínicos de las principales herramientas terapéuticas desarrolladas frente a SARS-CoV-2. Sin embargo, se ha ido reuniendo experiencia de uso de estos fármacos en distintos estadios de la ERC que avala su uso con garantías de eficacia y seguridad.El objetivo de esta revisión es reunir todas las indicaciones de tratamiento frente a la COVID-19 en los distintos estadios de la enfermedad adaptadas a la ERC en sus distintas fases, incluyendo el tratamiento sustitutivo renal. Abstract: COVID-19 has proven to be particularly aggressive in patients with chronic kidney disease (CKD). The lower immune response rate and the greater susceptibility to progress to severe forms of the disease have contributed to this phenomenon, which has persisted in the post-vaccination era of the pandemic. Paradoxically, CKD has been excluded from most clinical trials of the main therapeutic tools developed against SARS-CoV-2. However, experience in the use of these drugs has been accumulating in different stages of CKD, supporting their use with guarantees of efficacy and safety.The objective of this review is to gather all treatment indications for COVID-19 in the different phases of the disease, tailored to CKD in its various stages, including renal replacement therapy

Lack of impact of protease inhibitor resistance-associated mutations on the outcome of HIV-1-infected patients switching to darunavir-based dual therapy

[Background]: Little is known about the impact of baseline resistance-associated mutations (RAMs) on the outcomes of alternative therapeutic strategies such as dual regimens. We assessed the efficacy of boosted darunavir plus raltegravir (DRV + RAL) dual regimen as a simplification strategy in virologically suppressed patients with protease inhibitors RAMs.[Methods]: Retrospective, multicentre study on the evolution of 228 heavily pretreated patients who switched to boosted DRV + RAL according to genotypic sensitivity score (GSS). Patients were classified as full susceptible (GSS = 2; n = 177), or with reduced darunavir susceptibility (GSS < 2; n = 51).[Results]: Median (range) number of prior antiretroviral regimens was 9 (6–14), with a median (range) of 2 (1–3), 4 (3–6), and 5 (2–9) major mutations to non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. The median time of virological suppression before simplification was 49 months (IQR 39.8–63.5). Patients with reduced darunavir GSS showed a higher number of protease inhibitors-RAMs (9.3 vs 4.5, p < .01) and were suppressed for longer time (median, 61 months). At week 96, the rate of virological failure was low (two cases, 0.9%; 95% confidence interval, CI, 0.4–2.7%), and the efficacy, excluding non-virological reasons, was 96.8% (95%CI, 90.2–98.4%), without differences according to GSS or protease inhibitors-RAMs. Furthermore, significant improvements in CD4+ counts and CD4/CD8 ratio were observed (p < .01) in both groups.[Conclusions]: Treatment simplification to a dual regimen of boosted DRV + RAL after long-term virological suppression was not associated with a high risk of treatment failure, even in patients harbouring protease inhibitors-resistant HIV infection.This study was supported by the MSD Investigator-Initiated Studies Program (MISP) under grant number 57180

Tecnologías de la información e influencia en la aplicación de los principios de innovación

El objetivo del artículo es analizar la influencia de las tecnologías de la información en la aplicación de los principios de la innovación. Se aplicó una encuesta a 149 empresarios en Aguascalientes. Después de un análisis de correlación y una regresión lineal, el estudio reveló que existe una relación fuerte entre la utilización de TICS, y la disposición que tiene la empresa a innovar; por lo que al incrementar la utilización de tecnologías de información, también se incrementa la aplicación de innovación en las organizaciones

Factor structure and validity of the Parental Competence Questionnaire in the Paediatric Hospital Emergency Setting (ECP-U)

Objective: To confirm the structure and examine the psychometric properties of the Parental Competence Questionnaire in the Paediatric Hospital Emergency Setting (ECP-U). Methods: An instrumental validation study of the ECP-U questionnaire and an examination of its psychometric properties were carried out. Results: The participants were 260 mothers and fathers seeking care in the paediatric emergency department of a hospital in Valencia (Spain) with children aged 0 to 14 years old. The five-factor structure of the ECP-U was confirmed with excellent statistical fits. Second-order models and a more parsimonious four-factor structure with adequate but marginal fits are proposed. With the exception of the “parental agency” factor (in both models examined) and the “active social support” factor (in the original five-factor structure), the internal consistency of the different factors was modest (≥ 0.70). A negative correlation was found between the Parental Stress Scale and the ECP-U for most factors. Conclusions: Validity and reliability analyses indicate that the ECP-U is an instrument with modest psychometric properties. Implications for practice: The ECP-U is an instrument that can be used by future researchers to identify different levels of parental competence in paediatric hospital emergency departments. This will enable help to be given to families with parenting issues and problems. The underlying concern is to reduce the number of frequent users and “Non-Urgent Presentations” to paediatric emergency departments due to low parental competence

Development and validation of a parental competence questionnaire in the paediatric hospital emergency setting (ECP-U)

Objective: To develop and validate a parental competence questionnaire for parents of children seeking care in hospital emergency departments. Methods: An instrumental study of the development of an assessment questionnaire was carried out in three phases: 1) review of relevant measures and item generation, 2) content validity evaluation, 3) psychometric evaluation. Exploratory factor analysis was performed to examine the factorial structure. Internal consistency was evaluated using ordinal alpha. Hypothesis testing was determined between the resulting factors, the Parental Stress Scale and the State-Trait Anxiety Inventory. Results: The participants were 270 parents of children aged 0–14 years old from a referral hospital in Valencia (Spain). An 18-item questionnaire was developed, comprising five factors that explain 53.0% of the variance: 1) “emotional management and expression”, 2) “passive social support”, 3) “parental agency”, 4) “basic needs and care” and 5) “active social support”. The internal consistency for the different factors was modest (>0.70). A negative correlation between the Parental Stress Scale and the parental competence questionnaire was found for most of the factors. Conclusions: This questionnaire on parental competence in the hospital emergency department (ECP-U) is a useful and simple self-report instrument for assessing the parental competence of parents with children in the emergency department. Practical implications: The resulting questionnaire is of practical value to both healthcare professionals and researchers in this field. It can be administered quickly in clinical practice and used to identify parents' levels of parental competence and refer those with difficulties to appropriate support services