Innate and adaptive abnormalities in youth with vertically acquired HIV through a multicentre cohort in Spain.

INTRODUCTION: Immune abnormalities have been described among youth with vertically acquired HIV (YWVH) despite antiretroviral treatment (ART). The CD4/CD8 ratio could be a useful prognostic marker. We assess immune activation and senescence in a cohort of YWVH in comparison to youth without vertically acquired HIV. METHODS: YWVH under suppressive ART were included and compared to a group of HIV-negative donors (HD) matched by age and sex, from September 2019 to September 2020. Subset distribution and expression of activation, maturation, senescence and exhaustion markers on T and NK cells were studied on peripheral blood mononuclear cells by multiparametric flow cytometry. RESULTS: Thirty-two YWVH (median age: 24.4 years (interquartile range: 22.5 to 28.3 years)) were included. Among YWVH, CD4- and CD8-T cells showed high levels of activation (HLA-DR/CD38), IL-7 receptor expression (CD127) and exhaustion (TIM-3). Regarding NK cells, YWVH showed increased levels of activation and exhaustion markers compared to HD. Strong inverted correlations were observed between T-cell activation (HLA-DR/CD38), senescence (CD57) and exhaustion (TIGIT, PD-1) levels with the CD4/CD8 ratio among YWVH. HLA-DR, CD69, NKG2D and NKG2A expression levels on NK cells also correlated with the CD4/CD8 ratio. Age at ART initiation was directly associated with higher frequency of CD16high NK-cell subsets, exhaustion T-cell levels (CD57, TIM3) and NK cells activation levels. CONCLUSIONS: Immunological changes associated with vertically acquired HIV, characterized by increased activation and exhaustion levels in innate and adaptive immune components, are only partially restored by ART. The CD4/CD8 ratio can be a useful marker of disease progression for routine clinical practice.

Neurocognitive and quality of life study in perinatally HIV-infected young people and their peers. NeuroCoRISpeS study / Estudio neurocognitivo y de calidad de vida en jóvenes infectados por el VIH y sus pares. NeuroCoRISpeS

BACKGROUND: Assessing the role of HIV and non-HIV related factors is essential for a better understanding of the neurocognitive outcomes in perinatally HIV-infected (PHIV+) young people. The aim of our study was to assess cognition and quality of life (QoL) of a PHIV+ cohort of young people and to compare it with a control group. METHODS: Thirty PHIV+ and 30 HIV(-) healthy young adults matched by age, sex and socioeconomic status completed a protocol that included neurocognitive tests, a psychosocial semi-structured interview and a QoL questionnaire (PedsQL). Neurocognitive domain-specific and domain-general (NPZ-5) Z-scores were calculated. CDC AIDS-defining category C or not C (PHIV+/C, PHIV+/noC) was considered to evaluate differences within the PHIV+ group. Univariate and multivariate analysis were performed. RESULTS: Sixty patients were included; 67% were female; median age (IQR) 19 years (18-21). Regarding PHIV+ young people, 27% showed CDC C category (none encephalopathy), 93% were on ART and 77% had undetectable viral load. No differences regarding occupation were found, although the HIV(−) group repeated less grades (p = 0.028) and had a higher education level (p = 0.021). No differences were found between PHIV+/noC and HIV(−) participants. However, the PHIV+/C group showed poorer performance than PHIV+/noC (NPZ-5, p = 0.037) and HIV(-) subjects (crystallised intelligence, p = 0.025; intelligence quotient, p = 0.016). Higher nadir CD4+ T-cell count was related to better Z-score in memory (p = 0.007) and NPZ-5 (p = 0.025). Earlier and longer exposure to ART resulted in better performance in memory (p = 0.004) and executive functions (p = 0.015), respectively. CONCLUSIONS: No significant differences were found in the neurocognitive profile nor QoL between PHIV+/noC and HIV(-) adolescents; however, PHIV+/C participants obtained lower scores. The use of longer and earlier ART seems to have a beneficial effect

ANTECEDENTES: Para estudiar el perfil neurocognitivo de jóvenes infectados perinatalmente por VIH (PVIH+) es importante valorar tanto los factores asociados al virus como los no relacionados. El objetivo de nuestro estudio fue evaluar la cognición y la calidad de vida de una cohorte de jóvenes PVIH+ y compararlas con las de un grupo control. MÉTODOS: Treinta jóvenes PVIH+ y 30 sujetos sanos VIH− pareados por edad, sexo y nivel socioeconómico completaron un protocolo que incluía pruebas neurocognitivas, entrevista psicosocial semiestructurada y cuestionario de calidad de vida PedsQL. Se calculó el Z-score global (NPZ-5) y específico para cada dominio neurocognitivo. Adicionalmente, se consideró la categoría SIDA (PVIH+/C, PVIH+/noC). Se realizó análisis univariante y multivariante. RESULTADOS: De los 60 pacientes incluidos, el 67% eran mujeres; edad media (IQR) 19años (18-21). Respecto al grupo PVIH+, el 27% tenían categoría CDCC (ninguna encefalopatía), el 93% tomaban antirretrovirales y el 77% tenían carga viral indetectable. No hubo diferencias en cuanto a ocupación, aunque el grupo VIH− repitió menos cursos académicos (p = 0,028) y tuvo mayor nivel educativo (p = 0,021). No hubo diferencias entre los grupos PVIH+/noC y VIH−. El grupo PVIH+/C tuvo un rendimiento inferior al de PVIH+/noC (NPZ-5, p = 0,037) y VIH− (inteligencia cristalizada, p = 0,025; cociente de inteligencia, p = 0,016). Mayor nadir de célulasT CD4+ se relacionó con mejor Z-score en Memoria (p = 0,007) y NPZ-5 (p = 0,025). La exposición temprana y prolongada a la terapia antirretroviral favoreció un mejor rendimiento en Memoria (p = 0,004) y en Funciones Ejecutivas (p = 0,015), respectivamente. CONCLUSIONES: No hubo diferencias significativas en el perfil neurocognitivo ni en calidad de vida entre los adolescentes PVIH+/noC y VIH−; sin embargo, los participantes PVIH+/C obtuvieron puntuaciones más bajas. La exposición temprana y prolongada a la terapia antirretroviral parece tener un efecto beneficioso

Clinical practice update of antifungal prophylaxis in immunocompromised children / Revisión de estrategias de profilaxis antifúngica en niños inmunodeprimidos

Due to the rise in the number and types of immunosuppressed patients, invasive fungal infections (IFI) are an increasing and major cause of morbidity and mortality in immunocompromised adults and children. There is a broad group of pediatric patients at risk for IFI in whom primary and/or secondary antifungal prophylaxis (AFP) should be considered despite scant evidence. Pediatric groups at risk for IFI includes extremely premature infants in some settings, while in high-risk children with cancer receiving chemotherapy or undergoing haematopoietic stem cell transplantation (HCT), AFP against yeast and moulds is usually recommended. For solid organ transplanted, children, prophylaxis depends on the type of transplant and associated risk factors. In children with primary or acquired immunodeficiency such as HIV or long-term immunosuppressive treatment, AFP depends on the type of immunodeficiency and the degree of immunosuppression. Chronic granulomatous disease is associated with a particular high-risk of IFI and anti-mould prophylaxis is always indicated. In contrast, AFP is not generally recommended in children with long stay in intensive care units. The choice of AFP is limited by the approval of antifungal agents in different age groups and by their pharmacokinetics characteristics. This document aims to review current available information on AFP in children and to provide a comprehensive proposal for each type of patient

Las infecciones fúngicas invasoras (IFI) constituyen un problema creciente en adultos y niños inmunodeprimidos, acompañándose de una elevada morbimortalidad. El número de niños inmunodeprimidos va en aumento. Los grupos de riesgo de IFI en pediatría incluyen a los grandes prematuros, que se benefician de profilaxis con fluconazol, pacientes hemato-oncológicos sometidos a quimioterapia o trasplante de precursores hematopoyéticos con neutropenias prolongadas, en quienes la profilaxis frente a hongos filamentosos suele recomendarse en situaciones de alto riesgo. En niños sometidos a trasplante de órgano sólido, la profilaxis depende del tipo de trasplante y factores de riesgo asociados. En pacientes con inmunodeficiencias primarias o adquiridas como la infección VIH o tratamiento inmunosupresor prolongado, la profilaxis antifúngica dependerá del tipo de inmunodeficiencia primaria y del grado de inmunosupresión. La enfermedad granulomatosa crónica tiene riesgo particularmente elevado de IFI y requiere siempre profilaxis frente a hongos filamentosos. En cambio, en niños con ingresos prolongados en cuidados intensivos la profilaxis frente a IFI habitualmente no está indicada. El tipo de profilaxis está limitado por la diferente aprobación de antifúngicos a distintas edades. Este documento pretende revisar la información actual disponible respecto a profilaxis antifúngica en niños, con propuesta para la estrategia más apropiada en cada tipo de paciente

Nuevos diagnósticos de infección VIH en niños / New diagnosis of HIV infection in children

Introducción En la cohorte de niños infectados de la Comunidad de Madrid ha aumentado el número de niños de procedencia extranjera en los últimos años. Los objetivos fueron evaluar las características epidemiológicas y clínicas en los nuevos diagnósticos y describir los diferentes subtipos del VIH-1.Pacientes y métodos Se analizaron los nuevos diagnósticos desde el año 1997, dividiéndolos en 3 periodos: P1 (1997-2000), P2 (2001-2004), P3 (2005-2009). Se analizó la procedencia según regiones geográficas y país de procedencia, las diferencias clínicas e inmunovirológicas así como respuesta al tratamiento. Se evaluó el subtipo genético del VIH-1 mediante análisis filogenético de los genes de proteasa y de la retrotranscriptasa. Resultados Se identificaron 141 nuevos diagnósticos de infección VIH, siendo el porcentaje de procedencia extranjera en P1 (22,5%), P2 (50%) y P3 (68%). La procedencia ha cambiado de Latinoamérica en P1 a África subsahariana en P3. No hubo diferencias de la media de edad al diagnóstico entre autóctonos y extranjeros, el estadio clínico CDC A/B/C, carga viral, porcentaje de CD4 al diagnóstico y actuales. Había una tendencia de mejor respuesta virológica en extranjeros tras el primer ciclo de TARGA (terapia antirretroviral de gran actividad) independiente del tratamiento recibido. Se obtuvieron 66 subtipos, el 24% eran subtipos no-B (56% formas recombinantes). Todos los subtipos de los autóctonos (43) y latinoamericanos (5) eran subtipos B, sin embargo, todos los niños procedentes de África Subsahariana (14) eran subtipos no-B. Conclusión No se encontraron diferencias entre niños infectados por VIH extranjeros o autóctonos, salvo los diferentes subtipos de VIH-1 (AU)

Introduction The number of children of immigrant origin in the last few years has increased the cohort of HIV-infected children in the Community of Madrid. The objectives of the study were to evaluate the epidemiological and clinical characteristics of the new diagnosed children and describe the different subtypes of HIV-1.Patients and methods The new diagnosed children were analysed from the year 1997, divided into 3 periods: P1 (1997-2000), P2 (2001-2004), P3 (2005-2009). The regions and countries of origin, the clinical, immune and viral characteristics, as well as the response to treatment were analysed. The subtypes of HIV-1 were evaluated by phylogenetic analysis of protease genes and reverse transcriptase. Results We identified 141 new diagnoses of HIV infection, the percentage of immigrant origin in P1 was (22.5%), P2 (50%) and P3 (68%). The origin had changed from Latin America in P1 to sub-Saharan Africa in P3. There were no differences between Spanish and immigrant children in the age at diagnosis, the CDC clinical stage A/B/C, viral load, percentage of CD4 at diagnosis and actual. Better viral response was more likely in immigrants after the first regimen of HAART (Highly active antiretroviral treatment) independently of the treatment received. A total of 66 subtypes were obtained, 24% were subtypes non-B (56% recombinants forms). All subtypes of Spanish children (43) and Latin American (5) were subtypes B, and all the children from sub-Saharan Africa (14) were subtypes non-B. Conclusion There were no differences between immigrants and Spanish children infected by HIV, except the different subtypes of HIV-1 (AU)

[New diagnosis of HIV infection in children]. / Nuevos diagnósticos de infección VIH en niños.

INTRODUCTION: The number of children of immigrant origin in the last few years has increased the cohort of HIV-infected children in the Community of Madrid. The objectives of the study were to evaluate the epidemiological and clinical characteristics of the new diagnosed children and describe the different subtypes of HIV-1. PATIENTS AND METHODS: The new diagnosed children were analysed from the year 1997, divided into 3 periods: P1 (1997-2000), P2 (2001-2004), P3 (2005-2009). The regions and countries of origin, the clinical, immune and viral characteristics, as well as the response to treatment were analysed. The subtypes of HIV-1 were evaluated by phylogenetic analysis of protease genes and reverse transcriptase. RESULTS: We identified 141 new diagnoses of HIV infection, the percentage of immigrant origin in P1 was (22.5%), P2 (50%) and P3 (68%). The origin had changed from Latin America in P1 to sub-Saharan Africa in P3. There were no differences between Spanish and immigrant children in the age at diagnosis, the CDC clinical stage A/B/C, viral load, percentage of CD4 at diagnosis and actual. Better viral response was more likely in immigrants after the first regimen of HAART (Highly active antiretroviral treatment) independently of the treatment received. A total of 66 subtypes were obtained, 24% were subtypes non-B (56% recombinants forms). All subtypes of Spanish children (43) and Latin American (5) were subtypes B, and all the children from sub-Saharan Africa (14) were subtypes non-B. CONCLUSION: There were no differences between immigrants and Spanish children infected by HIV, except the different subtypes of HIV-1.

Niveles plasmáticos de antirretrovirales en niños con infección por el virus de la inmunodeficiencia humana. Influencia del género y de la edad / Plasma antiretroviral levels in children with human immunodeficiency virus infection. Influence of sex and age

Introducción Los estudios farmacológicos realizados demuestran una relación entre la concentración plasmática de antirretrovirales (ARV) y su toxicidad y actividad antiviral. Sin embargo, en niños con infección por el virus de la inmunodeficiencia humana (VIH), los datos farmacocinéticos y farmacodinámicos son heterogéneos y limitados. Pretendemos analizar los niveles de fármacos ARV en la práctica clínica, en niños infectados por VIH y su influencia en la efectividad terapéutica. Métodos Estudio observacional, prospectivo y multicéntrico, que incluye niños con infeccion por VIH, controlados en 5 hospitales terciarios entre marzo de 2006 y junio de 2008. Se determinó la concentración plasmática de ARV en el momento predosis y se analizó la relación con diferentes variables clínicas y analíticas. Resultados Se incluyó un total de 129 pacientes. El 41,3% presentaba niveles plasmáticos fuera del rango establecido. No se hallaron diferencias analíticas en función del género. Los menores de un año presentaban concentraciones infraterapéuticas y carga viral elevada, de modo más frecuente que el resto de los niños. Conclusión Las concentraciones plasmáticas de ARV son infraterapéuticas con mayor frecuencia en los menores de un año. Este hallazgo se relaciona con mayor fallo viral y supone un reto importante en esta población, que requiere un tratamiento a muy largo plazo (AU)

Introduction Pharmacologic studies have shown a relationship between plasma antiretroviral levels and toxicity/viral activity. Nevertheless, pharmacokinetic and pharmacodynamic data are inconsistent and limited in HIV-infected children. An analysis was performed of plasma antiretroviral concentrations in clinical practice and their influence on therapy efficacy in HIV-infected children. Methods Observational, prospective, multicenter study, including HIV-infected children followed up at 5 reference hospitals between March 2006 and June 2008. Pre-dose plasma antiretroviral levels were determined and the relationships with various clinical and analytical variables were investigated. Results A total of 129 patients were included, and 41.3% had antiretroviral plasma levels outside the established range. No differences were found between sexes. Children younger than 1 year had a higher rate of suboptimal levels and higher viral load than the remaining children. Conclusion Antiretroviral plasma concentrations are more frequently suboptimal in children younger than 1 year. This finding is related with greater viral failure and implies a considerable challenge in this population, which requires very long-term treatment (AU)

Extensive implementation of highly active antiretroviral therapy shows great effect on survival and surrogate markers in vertically HIV-infected children.

We performed a retrospective observational study of 253 children vertically infected with human immunodeficiency virus (1994-2001) to assess the effectiveness of antiretroviral therapies (ARTs) on survival and surrogate markers at the population level. Children were divided into 3 groups according to the ART protocols used during the follow-up period: calendar period (CP) 1 (1994-1996) received combined therapy with 2 nucleoside reverse transcriptase inhibitors (NRTIs); CP2 (1997-1998) received implementation of highly active ART (HAART) with 3 drugs (NRTIs, protease inhibitors, and non-NRTIs); and CP3 (1999-2001) received extensive HAART. The children in the CP3 group had statistically significant longer survival periods, lower virus load (VL), highest undetectable VL proportion, and highest CD4+ T cell counts. HAART is effective at the population level at decreasing VL, increasing CD4+ T cells, and increasing the survival in a higher percentage of HIV-infected children.

Viral load and CD4+ T lymphocyte response to highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children: an observational study.

An observational study was performed involving 95 children with vertically transmitted human immunodeficiency virus type 1 infection to assess the sustainability of undetectable viral loads (VLs) and increased CD4+ T lymphocyte percentages after 48 months of highly active antiretroviral therapy (HAART). The median time to achieve a 10% increase in the CD4+ T lymphocyte percentage was 11.01 months. The median time to achieve an undetectable VL was 6.4 months. At the end of the study, 64.2% of the children had achieved an undetectable VL. Of the patients with an initial VL of >3.6 log10 copies/mL, 74.7% had a decrease in the VL of 1 log10 copies/mL. By contrast, of the patients who presented with an initial VL of >4.6 log10 copies/mL, 37.9% had a decrease of >2 log10 copies/mL. Higher VL at baseline, antiretroviral therapy regimens received before HAART, and multiple drug switches while receiving antiretroviral therapy were all inversely associated with an undetectable VL. A CD4+ T lymphocyte percentage of >25% was directly associated with undetectable VL during the follow-up period. In conclusion, first-line HAART induces beneficial virological and immunological outcome responses in children.