2 research outputs found
Arterial effects of T cell, monocyte and cytomegalovirus (CMV) immune activation in children and adolescents with Human Immunodeficiency Virus (HIV) infection
A infecção pelo Vírus da Imunodeficiência Humana (HIV) pode predispor à presença de fatores de risco cardiovascular e promover a ativação do sistema imunológico, contribuindo para a formação de lesões ateroscleróticas. A existência de coinfecções, como pelo Citomegalovírus (CMV) e a ativação imunológica inespecífica poderiam intensificar o processo de inflamação crônica e acelerar os danos vasculares decorrentes desta. O objetivo principal deste estudo foi avaliar se a recorrência da infecção pelo CMV, a magnitude da resposta imunológica específica ao CMV ou da ativação inespecífica de células T e monócitos associava-se ao aumento da espessura das camadas média e íntima das carótidas (cIMT) em crianças e adolescentes coinfectados pelo HIV e CMV. Consistiu-se de um estudo longitudinal, em que 40 crianças e adolescentes coinfectados pelo HIV e CMV foram acompanhados por 2 anos. Periodicamente avaliou-se a presença de recorrência do CMV, com o uso de detecção de DNA do CMV no soro por meio da técnica de Reação em Cadeia da Polimerase; a ativação imunológica perante este vírus com o ensaio do Quantiferon CMVR, a dosagem de anticorpos IgM e IgG contra o CMV. Também, nós medimos a ativação imunológica inespecífica de células T usando a dosagem do receptor I de TNF solúvel (sTNFRI) e a quantificação da presença HLADR+CD38+TCD8+; e a de monócitos por meio da dosagem de CD14 solúvel (sCD14). Para caracterizar adicionalmente as crianças estudadas, outros parâmetros foram registrados periodicamente: 1-Relativos à infecção pelo HIV: parâmetros clínicos e quantificação de linfócitos CD4+/CD8+ e de RNA-HIV; 2-Parâmetros antropométricos: Peso, estatura, circunferência abdominal e Índice de Massa Corporal (IMC); 3-Parâmetros Laboratoriais: lipoproteínas, glicemia, insulinemia, hemoglobina glicosilada e cálculo do índice HOMA IR. Devido à baixa incidência de recorrência da infeção pelo CMV (0,97/100 pessoas-mês) não foi possível analisar este fator no presente estudo. De maneira geral, na entrada do estudo aespessura da íntima/média das artérias carótidas da maioria (70%) dos adolescentes situava- se acima do Percentil 75 da distribuição de referência, sendo que durante o período de 2 anos não ocorreu incremento significativo da medida desse parâmetro arterial. Não foi identificada associação entre a magnitude da ativação da imunidade específica ao CMV e a evolução da cIMT ao longo de dois anos. Apesar de ter sido detectado que pequenos incrementos nos indicadores de ativação imunológica inespecífica (TNRFI, sCD14 e/ou HLADR+CD38+) associaram-se a discretas reduções da cIMT ao final de dois anos, a ativação imunológica de células T e monócitos não se associou ao incremento da espessura da íntima/média arterial durante esse período de tempo. Embora não tenhamos confirmado a nossa hipótese, dados obtidos nesse estudo podem se tornar referencia para planejamento de estudos mais amplos e com maior período de observação.Human Immunodeficiency Virus (HIV) infection might predispose the presence of cardiovascular risk factors and promote the activation of the immune system contributing to the formation of atherosclerotic lesions. The presence of coinfections, such as by Cytomegalovirus, and the immunological unspecific activation may intensify the process of chronic inflammation and accelerate the vascular damage resulting from it. The main objective of this study was to evaluate whether the recurrence of CMV infection and the degree of the CMV-specific cellular immune response or the unspecific activation of T cells and monocytes were associated with the increase in the thickness of the carotid intima-media thickness (cIMT) in HIV/CMV-coinfected children and adolescents. A longitudinal study was carried out in which 40 HIV/CMV-coinfected children and adolescents were followed-up for 2 years. Periodically, it was determined the presence of CMV recurrence with the use of CMV-DNA detection in serum by Polymerase Chain Reaction; the specific immunological activation of this virus with the Quantiferon CMVR assay and the dosage of IgM and IgG antibodies against CMV. Also, we measured the nonspecific immunological activation of T cells using the soluble TNF receptor I (sTNFRI), and the presence of HLADR+CD38+TCD8+; and that of monocytes by soluble CD14 dosage (sCD14). To further characterize the studied children, other parameters were periodically evaluated: 1-HIV-related: clinical parameters and quantification of CD4+/CD8+ lymphocytes and HIV-RNA; 2-Anthropometric parameters: weight, height, abdominal circumference, and Body Mass Index (BMI); 3-Laboratory parameters: lipoproteins, fasting glucose, fasting insulinemia, glycosylated hemoglobin, and calculation of HOMA IR. Due to the low incidence of CMV recurrence (0.97/100 persons-month), it was not possible to analyze this factor in the present study. Overall, the cIMT of most (70%) adolescents were higher than the 75 percentile of the reference distribution at enrollment, and no significant increment occurred over a 2 year period. No association between the degree of CMV-specific immunity activation and the evolution of cIMT over 2 years was identified. Although it was found that small increments on the unspecific immunological activation markers (TNRFI,sCD14 and/or HLADR+CD38+) were associated with discrete reductions of the cIMT at the end of two years, the immunological activation did not associate with an increment of the carotid intima/media thickness over this time period. Even if we have not confirmed our hypothesis, the data obtained in this study can be used for planning bigger studies with a more prolonged observation period
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Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1–2 trial
BackgroundSafe and potent antiretroviral medications in child-friendly formulations are needed to treat young children living with HIV-1. We aimed to select dosing for a dispersible tablet formulation of dolutegravir that achieved pharmacokinetic exposures similar to those in adults, and was safe and well tolerated in young children.MethodsInternational Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) P1093 is a phase 1-2 ongoing multicentre, open-label, non-comparative study of dolutegravir. A 5 mg dispersible tablet formulation of dolutegravir was studied in children aged 4 weeks to less than 6 years old, weighing at least 3 kg, with HIV RNA of greater than 1000 copies per mL and no previous treatment with integrase strand transfer inhibitor recruited from IMPAACT clinical research sites in Africa, the Americas, and Asia. Doses were selected on the basis of intensive pharmacokinetic evaluation on days 5-10, with safety and tolerability assessed up to 48 weeks. The primary objectives of this study are to evaluate the pharmacokinetics of dolutegravir in combination with optimised background therapy and to establish the dose of dolutegravir that achieves the targeted 24-h trough concentration and 24-h area under the curve for infants, children, and adolescents with HIV-1, to establish the safety and tolerability of dolutegravir at 24 and 48 weeks, and to select a dose that achieves similar exposure to the dolutegravir 50 mg once daily dose in adults. This analysis included participants treated with the proposed dose of dolutegravir dispersible tablets in two stages for each of three age cohorts. This trial is registered at ClinicalTrials.gov (NCT01302847) and is ongoing.FindingsWe recruited 181 participants from April 20, 2011, to Feb 19, 2020; of these, 96 received dolutegravir dispersible tablets. This analysis included 73 (35, 48% female) participants who received the final proposed dose with median (range) age of 1 year (0·1 to 6·0), weight (minimum-maximum) of 8·5 kg (3·7 to 18·5), plasma HIV-1 RNA concentration of 4·2 log10 copies per mL (2·1 to 7·0), and CD4% of 24·0% (0·3 to 49·0); 64 (87·7%) were treatment-experienced. The selected dose within each age cohort (≥2 years to <6 years, ≥6 months to <2 years of age and ≥4 weeks to <6 months) achieved geometric mean trough (ng/mL) of 688, 1179, and 1446, and 24 h area-under-the-curve (h·mg/L) of 53, 74, and 65, respectively. No grade 3 or worse adverse events were attributed to dolutegravir.InterpretationIn this study, the proposed once daily dosing of dolutegravir dispersible tablets provided drug exposures similar to those for adults, and was safe and well tolerated. These data support the use of dolutegravir dispersible tablets as first-line or second-line treatment for infants and children aged less than 6 years living with HIV-1.FundingNational Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, and ViiV Healthcare-GlaxoSmithKline