RESUMEN
Reports thus far suggest a mild course for acute COVID-19 infection in children; however, its effects in vulnerable paediatric populations, including children with haemodynamically significant congenital heart disease, have rarely been reported. We therefore report on a 4-month-old Hispanic male with a moderate sized conoventricular ventricular septal defect and pulmonary overcirculation who presented with COVID-19-associated pneumonia.
Asunto(s)
COVID-19/fisiopatología , Defectos del Tabique Interventricular/fisiopatología , COVID-19/complicaciones , COVID-19/diagnóstico por imagen , COVID-19/terapia , Ecocardiografía , Defectos del Tabique Interventricular/complicaciones , Defectos del Tabique Interventricular/diagnóstico por imagen , Humanos , Lactante , Masculino , Terapia por Inhalación de Oxígeno , Radiografía Torácica , SARS-CoV-2RESUMEN
OBJECTIVE: The aim of this study was to evaluate safety and pharmacokinetics of maraviroc administered with standard antiretroviral prophylaxis to HIV-1 exposed infants and to determine the appropriate dose of maraviroc during the first 6 weeks of life. DESIGN: A phase I, multicentre, open-label study enrolling two sequential cohorts. METHODS: IMPAACT 2007 participants enrolled by day 3 of life and were stratified by exposure to maternal efavirenz. Cohort 1 participants received two single 8âmg/kg maraviroc doses 1 week apart with pharmacokinetic sampling after each dose. Cohort 2 participants received 8âmg/kg maraviroc twice daily through 6 weeks of life with pharmacokinetic sampling at weeks 1 and 4. Maraviroc exposure target was Cavg at least 75âng/ml. Laboratory and clinical evaluations assessed safety. RESULTS: Fifteen Cohort 1 and 32 Cohort 2 HIV-exposed neonates were enrolled (median gestational age 39 weeks, 51% male). All 13 evaluable Cohort 1 infants met the pharmacokinetic target. Median exposure for the 25 evaluable Cohort 2 infants met the pharmacokinetic target but variability was high, with 17-33% of infants below target at Weeks 1 and 4. Pharmacokinetic target achievement was similar between efavirenz exposure strata. No Grade 3+ toxicities, early study or treatment discontinuations due to maraviroc occurred. CONCLUSION: Median maraviroc exposure met the Cavg target in neonates receiving 8âmg/kg twice daily, although exposures were variable. Maternal efavirenz use did not impact maraviroc exposure and no discontinuations were due to maraviroc toxicity/intolerance. No infants acquired HIV-1 infection during follow-up. Maraviroc 8âmg/kg twice daily appears well tolerated during the first 6 weeks of life.
Asunto(s)
Infecciones por VIH , VIH-1 , Adulto , Antirretrovirales/uso terapéutico , Estudios de Cohortes , Ciclohexanos/efectos adversos , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Recién Nacido , Masculino , MaravirocRESUMEN
BACKGROUND: Heightened immune activation and exhaustion drive HIV disease progression and comorbidities. Vitamin D has pleiotropic immunomodulatory effects, but little is known about the effects of supplementation in HIV. Our study investigates changes in immune activation and exhaustion markers after 12 months of supplementation in virologically suppressed HIV-infected youth with vitamin D insufficiency. METHODS: This is a randomized, active-control, double-blind trial investigating with three different vitamin D3 doses (18,000 [standard/active-control dose], 60,000 [moderate dose] and 120,000 IU/month [high dose]) in 8-25-year-old HIV-infected youth on combination antiretroviral therapy with baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations ≤30 ng/ml. Only subjects (n=51) who maintained an undetectable HIV-1 RNA over the 12-month study period were included in this analysis. RESULTS: Baseline serum 25(OH)D concentrations and immune activation/exhaustion markers were not different between groups. By 12 months, 25(OH)D increased significantly within each dosing group with the greatest increase and most sustained concentrations ≥30 ng/ml in the high-dose group. Overall, all measured markers decreased with CD4 activation (CD4+CD38+HLA-DR+), CD8 activation (CD8+CD38+HLA-DR+), CD4 exhaustion (CD4+CD38+HLA-DR+PD1+) and inflammatory monocytes (CD14+CD16+) reaching statistical significance. When analysed separately, there were no significant decreases in the moderate- or standard-dose groups, but CD4 and CD8 activation and inflammatory monocytes decreased significantly in the high-dose group. CONCLUSIONS: Vitamin D supplementation decreased markers of T-cell activation/exhaustion and monocyte activation in HIV-infected youth, with subjects given the highest dose (120,000 IU/month) showing the greatest decreases. These data suggest that high-dose vitamin D supplementation may attenuate immune activation and exhaustion, and serve as adjuvant therapy to antiretroviral therapy in HIV. ClinicalTrials.gov identifier: NCT01523496.
Asunto(s)
Suplementos Dietéticos , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunomodulación/inmunología , Vitamina D/administración & dosificación , Adolescente , Adulto , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Terapia Antirretroviral Altamente Activa , Biomarcadores , Recuento de Linfocito CD4 , Niño , Femenino , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Factores de Riesgo , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del Tratamiento , Carga Viral , Adulto JovenAsunto(s)
Enfermedades Cardiovasculares/prevención & control , Arterias Carótidas/patología , Grosor Intima-Media Carotídeo , Suplementos Dietéticos , Infecciones por VIH/complicaciones , Vitamina D/administración & dosificación , Adolescente , Adulto , Antirretrovirales/administración & dosificación , Enfermedades Cardiovasculares/patología , Niño , Método Doble Ciego , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Low bone mineral density (BMD) is a significant comorbidity in HIV. However, studies evaluating vitamin D supplementation on bone health in this population are limited. This study investigates changes in bone health parameters after 12 months of supplementation in HIV-infected youth with vitamin D insufficiency. METHODS: This is a randomized, active-control, double-blind trial investigating changes in bone parameters with 3 different vitamin D3 doses [18,000 (standard/control dose), 60,000 (moderate dose), and 120,000 IU/monthly (high dose)] in HIV-infected youth 8-25 years old with baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL. BMD and bone turnover markers were measured at baseline and 12 months. RESULTS: One hundred two subjects enrolled. Over 12 months, serum 25(OH)D concentrations increased with all doses, but the high dose (ie, 120,000 IU/monthly) maintained serum 25(OH)D concentrations in an optimal range (≥30 or ≥20 ng/mL) throughout the study period for more subjects (85% and 93%, respectively) compared with either the moderate (54% and 88%, respectively) or standard dose (63% and 80%, respectively). All dosing groups showed some improvement in BMD; however, only the high-dose arm showed significant decreases in bone turnover markers for both procollagen type 1 aminoterminal propeptide (-3.7 ng/mL; P = 0.001) and Β-CrossLaps (-0.13 ng/mL; P = 0.0005). CONCLUSIONS: High-dose vitamin D supplementation (120,000 IU/mo) given over 12 months decreases bone turnover markers in HIV-infected youth with vitamin D insufficiency, which may represent an early, beneficial effect on bone health. High vitamin D doses are needed to maintain optimal serum 25(OH)D concentrations.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Suplementos Dietéticos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Vitamina D/farmacología , Adolescente , Adulto , Fármacos Anti-VIH/uso terapéutico , Biomarcadores , Niño , Método Doble Ciego , Femenino , Humanos , Masculino , Vitamina D/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: HIV-infected individuals are at increased risk of neurocognitive impairment compared to the general population. Studies suggest that, despite combination antiretroviral therapy (cART), HIV infection causes immune activation which results in neural damage; however, few data exist in HIV-infected youth. METHODS: HIV-infected youth 8-26-years-old on cART with virological suppression were prospectively enrolled along with healthy controls. Neurocognitive performance was assessed by age-appropriate Wechsler Intelligence Scales. Soluble and cellular markers of T-lymphocyte and monocyte activation were measured by ELISA and flow cytometry, respectively. RESULTS: 45 HIV-infected subjects and 21 controls were enrolled. Markers of T-cell and monocyte activation were higher in the HIV-infected subjects compared to controls, but proportions of inflammatory and patrolling monocytes were similar. Although there were no significant differences in neurocognitive scores between the HIV-infected and control groups, scores were low-average for four of five testing domains for the HIV-infected subjects and average for all five in the controls, and % of HIV-infected subjects with scores classified as 'low average' or below was higher than in the controls. Variables most associated with neurocognitive performance among HIV-infected subjects included activated CD4+ T-cells (% CD4+CD38+HLA-DR), monocyte activation (soluble CD14), HIV duration, age and sex. CONCLUSIONS: HIV-infected youth on cART with virological suppression show subtle evidence of neurocognitive impairment compared to healthy controls, and increased immune activation appears to play a role. Additional studies are needed to develop strategic interventions beyond cART to potentially improve neurocognitive performance and/or minimize further impairment in this vulnerable population. ClinicalTrials.gov Identifier: NCT01523496.
Asunto(s)
Disfunción Cognitiva/etiología , Disfunción Cognitiva/psicología , Infecciones por VIH/complicaciones , Infecciones por VIH/inmunología , Inmunidad , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/psicología , Adolescente , Adulto , Terapia Antirretroviral Altamente Activa , Biomarcadores , Recuento de Linfocito CD4 , Niño , Disfunción Cognitiva/diagnóstico , Estudios Transversales , Femenino , VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Masculino , Pruebas de Estado Mental y Demencia , Trastornos Neurocognitivos/diagnóstico , Resultado del Tratamiento , Carga Viral , Adulto JovenRESUMEN
Children and young adults infected with HIV are at elevated risk for cardiovascular disease (CVD). However, scarce data exist on the utility of non-invasive methods to diagnose subclinical CVD, such as pulse wave velocity (PWV), a non-invasive measure of arterial stiffness. The objectives of this study were to assess the relationship of carotid-femoral PWV with subclinical atherosclerosis measured by carotid intima-media thickness (IMT), compare measurements to healthy controls, and evaluate variables associated with PWV in HIV-infected youth. One hundred and one 8-25 year-old subjects on stable antiretroviral therapy with low-level viremia or an undetectable HIV-1 RNA were enrolled, along with 86 healthy controls similar in age, sex and race. There was no significant difference in PWV between groups (median (Q1, Q3): 5.7 (5.2, 6.3) vs 5.7 (4.9, 6.5) m/s; P = 0.81). Among the HIV-infected subjects, PWV was positively correlated with both internal carotid artery (R = 0.31, P = 0.02) and carotid bulb IMT (R = 0.29, P = 0.01). In multivariable regression, only current alcohol consumption and systolic blood pressure were independently associated with PWV in the HIV-infected group (where current alcohol consumption and higher systolic blood pressure were associated with higher PWV); whereas, age, body mass index, and current marijuana use were associated with PWV in healthy controls. In this study of PWV in HIV-infected youth, measures of arterial stiffness were not different between subjects and controls. However, in HIV-infected youth, there was a significant association between PWV and carotid IMT, as well as between PWV and current alcohol consumption. Thus, PWV may have potential as a useful, non-invasive method to assess CVD risk in HIV-infected youth, but further investigation is needed.
Asunto(s)
Enfermedades Cardiovasculares/fisiopatología , Infecciones por VIH/complicaciones , Rigidez Vascular , Adolescente , Adulto , Fármacos Anti-VIH/uso terapéutico , Presión Sanguínea , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etiología , Grosor Intima-Media Carotídeo , Niño , Estudios Transversales , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Masculino , Análisis de la Onda del Pulso , Adulto JovenRESUMEN
Vitamin D insufficiency is widespread in HIV-infected patients. HIV and/or antiretroviral therapy (ART), particularly efavirenz (EFV), may interfere with vitamin D metabolism. However, few data from randomized, controlled trials exist. Here, we investigate changes in vitamin D metabolites and binding protein (VDBP) after 6 months of supplementation in a randomized, active-control, double-blind trial investigating 2 different monthly cholecalciferol (vitamin D3) doses [60,000 (medium) or 120,000 (high) IU/month] vs. a control arm of 18,000 IU/month in 8-25year old HIV-infected youth on ART with HIV-1 RNA <1000 copies/mL and baseline 25-hydroxycholecalciferol (25(OH)D3) ≤30ng/mL. A matched healthy uninfected group was enrolled in a similar parallel study for comparison. Changes after 6 months were analyzed as intent-to-treat within/between groups [control group (low dose) vs. combined supplementation doses (medium+high)]. At 6 months, 55% vs. 82% of subjects in control and supplementation groups, respectively, reached 25(OH)D3 ≥30ng/mL (P=0.01) with no difference between medium and high doses (both 82% ≥30ng/mL). There were few differences for those on EFV vs. no-EFV, except serum VDBP decreased in EFV-treated subjects (both within- and between-groups P≤0.01). There were no significant differences between the HIV-infected vs. healthy uninfected groups. The major finding of the present study is that cholecalciferol supplementation (60,000 or 120,000 IU/month) effectively raises serum 25(OH)D3 in the majority of HIV-infected subjects, regardless of EFV use. Notably, response to supplementation was similar to that of uninfected subjects.
Asunto(s)
Colecalciferol/uso terapéutico , Infecciones por VIH/sangre , Proteína de Unión a Vitamina D/sangre , Proteína de Unión a Vitamina D/orina , Vitamina D/sangre , Vitamina D/orina , Adolescente , Adulto , Alquinos , Benzoxazinas/uso terapéutico , Ciclopropanos , Suplementos Dietéticos , Método Doble Ciego , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Unión Proteica , Vitamina D/análogos & derivados , Deficiencia de Vitamina D/sangre , Adulto JovenRESUMEN
BACKGROUND: Immune activation and exhaustion drive several comorbidities and disease progression in HIV-infected adults; however, they are not well studied in HIV-infected youth. Thus, this study sought to examine levels of immune activation and exhaustion in this population, investigate associated HIV- and non-HIV-related variables and compare results with a matched healthy control group. METHODS: HIV-infected youth 8-25 years of age on stable antiretroviral therapy with an HIV-1 RNA level <1000 copies/mL were enrolled, along with matched healthy controls. We measured T-cell and monocyte immune activation and exhaustion markers in cryopreserved peripheral blood mononuclear cell and plasma samples. RESULTS: A total of 136 subjects (80 HIV+: 66% male; 91% black) were enrolled. Markers of CD4+ and CD8+ T-cell activation were higher in the HIV-infected group versus controls [mean % CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ = 2.2 versus 1.5 (P=0.002) and 4.9 versus 2.2 (P<0.0001), respectively], as were exhausted CD4+ and CD8+ T-cells [mean % CD4+CD38+HLA-DR+PD-1+ and CD8+CD38+HLA-DR+PD-1+ = 1.0 versus 0.5 (P<0.0001) and 1.6 versus 0.7 (P<0.0001), respectively]. There were no differences in proportions of inflammatory or patrolling monocytes between groups (P>0.05); however, soluble CD14 was higher in HIV-infected compared with controls (1.6 versus 1.4 µg/mL; P=0.01). Current CD4 count, low-density lipoprotein cholesterol and age were the variables most associated with CD4+ and CD8+ T-cell activation. CONCLUSIONS: CD4+ and CD8+ T-cell immune activation and exhaustion are higher in HIV-infected youth compared with matched controls, while monocyte subpopulations are not altered despite a high soluble CD14 level. The clinical significance of the increased immune activation and exhaustion should be further explored.
Asunto(s)
Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , VIH-1 , Activación de Linfocitos/inmunología , Adolescente , Adulto , Recuento de Linfocito CD4 , Niño , Estudios Transversales , Femenino , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , Humanos , Masculino , Linfocitos T/inmunología , Carga Viral , Adulto JovenRESUMEN
BACKGROUND: HIV patients on highly-active antiretroviral therapy (HAART) have shown elevated incidence of dyslipidemia, lipodystrophy, and markers of cardiovascular disease. Evidence is beginning to emerge that implicates efavirenz (EFV) as a potential mediator of early on-set cardiovascular disease. METHODS: Pediatric and adult HIV-infected HAART-naïve, EFV-treated, nevirapine (NVP)-treated, and ritonavir-boosted lopinavir (LPV/r)-treated subjects were recruited from Black Lion Hospital in Addis Ababa, Ethiopia. Pulse wave velocity (PWV), carotid intima-media thickness (cIMT), carotid arterial stiffness, brachial artery flow-mediated dilation (FMD), body mass index, waist-to-hip circumference ratio, and skinfold thickness were measured. CD4+ cell count, fasting glucose, lipoprotein profiles and triglycerides were also determined. Results were segmented into pediatric (6-17 years of age), young adults (25-39 years old) and older adults (40-60 years old). RESULTS: PWV was generally elevated in EFV- and LPV/r-treated subjects compared to NVP-treated subjects across age groups. cIMT was elevated in EFV- and LPV/r-treated compared to NVP-treated older adults and in EFV-treated compared to HAART-naïve older adults. FMD was impaired in EFV- and LPV/r-treated compared to HAART-naïve younger adults, in EFV-treated compared to NVP-treated young and older adults, and in LPV/r-treated compared to NVP-treated older adults. Differences in lipoprotein profiles and skinfold thickness with HAART regimen were observed in pediatric and young adults, but less so in older adults. CONCLUSIONS: Whereas LPV/r and other protease inhibitors have long been recognized as mediators of HIV/HAART-associated atherosclerosis, this report supports the emerging evidence that EFV may also mediate cardiovascular disease in people living with HIV on HAART.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Aterosclerosis/sangre , Benzoxazinas/efectos adversos , Infecciones por VIH/sangre , Lopinavir/efectos adversos , Ritonavir/efectos adversos , Adolescente , Adulto , Alquinos , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/efectos adversos , Aterosclerosis/inducido químicamente , Benzoxazinas/uso terapéutico , Biomarcadores/sangre , Grosor Intima-Media Carotídeo , Niño , Ciclopropanos , Etiopía , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Lípidos/sangre , Lopinavir/uso terapéutico , Masculino , Persona de Mediana Edad , Análisis de la Onda del Pulso , Ritonavir/uso terapéutico , Adulto JovenRESUMEN
The perception of song is vital to the reproductive success of both male and female songbirds. Several neural structures underlying this perception have been identified by examining expression of immediate early genes (IEGs) following the presentation of conspecific or heterospecific song. In the few avian species investigated, areas outside of the circuit for song production contain neurons that are active following song presentation, specifically the caudal hyperstriatum ventrale (cHV) and caudomedial neostriatum (NCM). While studied in detail in the male zebra finch, IEG responses in these neural substrates involved in song perception have not been quantified in females. Therefore, adult female zebra finches were presented with zebra finch song, nonzebra finch song, randomly generated tones, or silence for 30 min. One hour later they were sacrificed, and their brains removed, sectioned, and immunocytochemically processed for FOS expression. Animals exposed to zebra finch song had a significantly higher density of FOS-immunoreactive cells in the NCM than those presented with other songs, tones, or silence. Neuronal activation in the cHV was equivalent in birds that heard zebra finch and non-zebra finch song, expression that was higher than that observed in the groups that heard no song. Interestingly, the hippocampus (HP) and adjacent parahippocampal area (AHP) were activated in a manner comparable to the NCM. These results suggest a general role for the cHV in song perception and a more specific role for the NCM and HP/AHP in facilitating recognition of and responsiveness to species-specific song in female zebra finches.