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1.
Clin Infect Dis ; 71(7): e105-e114, 2020 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-31848582

RESUMEN

BACKGROUND: Children living with human immunodeficiency virus (HIV) are at neuropsychological risk for cognitive and motor dysfunction. However, few prospective, multi-site studies have evaluated neuropsychological outcomes longitudinally among perinatally infected African children who received early antiretroviral treatment (ART). METHODS: We enrolled 611 children aged 5 to 11 years at 6 sites (South Africa [3], Zimbabwe, Malawi, Uganda). Of these, there were 246 children living with HIV (HIV+) who were initiated on ART before 3 years of age in a prior clinical trial comparing nevirapine to lopinavir/ritonavir (International Maternal Pediatric Adolescent Acquired Immunodeficiency Syndrome Clinical Trials [IMPAACT] P1060); 183 age-matched, exposed but uninfected (HEU) children; and 182 unexposed and uninfected (HUU) children. They were compared across 3 assessment time points (Weeks 0, 48, and 96) on cognitive ability (Kaufman Assessment Battery for Children, second edition [KABC-II]), attention/impulsivity (Tests of Variables of Attention [TOVA]), motor proficiency (Bruininks-Oseretsky Test, second edition [BOT-2]), and on the Behavior Rating Inventory of Executive Function (BRIEF). The cohorts were compared using linear mixed models, adjusting for site, child's age and sex, and selected personal/family control variables. RESULTS: The HIV+ cohort performed significantly worse than the HEU and HUU cohorts for all KABC-II, TOVA, and BOT-2 performance outcomes across all 3 time points (P values < .001). The HUU and HEU cohorts were comparable. For the KABC-II planning/reasoning subtests, the HIV+ children showed less improvement over time than the HUU and HEU groups. The groups did not differ significantly on the BRIEF. CONCLUSIONS: Despite initiation of ART in early childhood and good viral suppression at the time of enrollment, the HIV+ group had poorer neuropsychological performance over time, with the gap progressively worsening in planning/reasoning. This can be debilitating for self-management in adolescence.


Asunto(s)
Infecciones por VIH , Adolescente , Niño , Preescolar , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Lactante , Malaui/epidemiología , Estudios Prospectivos , Instituciones Académicas , Sudáfrica/epidemiología , Uganda/epidemiología , Zimbabwe/epidemiología
2.
J Antimicrob Chemother ; 70(2): 543-9, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25281400

RESUMEN

OBJECTIVES: Co-treatment of HIV and TB in young children is complicated by limited treatment options and complex drug-drug interactions. Rifabutin is an alternative to rifampicin for adults receiving a ritonavir-boosted PI. We aimed to evaluate the short-term safety and pharmacokinetics of rifabutin when given with lopinavir/ritonavir in children. PATIENTS AND METHODS: We conducted an open-label study of rifabutin dosed at 5 mg/kg three times a week in HIV-infected children≤5 years of age receiving lopinavir/ritonavir. Intensive steady-state pharmacokinetic sampling was conducted after six doses. The Division of AIDS 2004, clarification 2009, table for grading severity of adverse events was used to classify drug toxicities. The study was registered with ClinicalTrials.gov, number NCT01259219. RESULTS: Six children completed the study prior to closure by institutional review boards. The median (range) AUC0-48 of rifabutin was 6.91 (3.52-8.67) µg ·â€Šh/mL, the median (range) Cmax of rifabutin was 0.39 (0.19-0.46) µg/mL, the median (range) AUC0-48 of 25-O-desacetyl rifabutin was 5.73 (2.85-9.13) µg ·â€Šh/mL and the median (range) Cmax of 25-O-desacetyl rifabutin was 0.17 (0.08-0.32) µg/mL. The neutrophil count declined in all children; two children experienced grade 4 neutropenia, which resolved rapidly without complications. There was strong correlation between AUC0-48 measures and neutrophil counts. CONCLUSIONS: Rifabutin dosed at 5 mg/kg three times per week resulted in lower AUC0-48, AUC0-24 and Cmax values for rifabutin and 25-O-desacetyl rifabutin compared with adults receiving 150 mg of rifabutin daily, the current recommended dose. We observed high rates of severe transient neutropenia, possibly due to immaturity of CYP3A4 in young children. It remains unclear whether a safe and effective rifabutin dose exists for treatment of TB in children receiving lopinavir/ritonavir.


Asunto(s)
Antituberculosos/efectos adversos , Antituberculosos/farmacocinética , Coinfección/tratamiento farmacológico , Rifabutina/efectos adversos , Rifabutina/farmacocinética , Tuberculosis/tratamiento farmacológico , Terapia Antirretroviral Altamente Activa , Antituberculosos/administración & dosificación , Área Bajo la Curva , Preescolar , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1 , Humanos , Lactante , Lopinavir/uso terapéutico , Masculino , Rifabutina/administración & dosificación , Ritonavir/uso terapéutico , Resultado del Tratamiento , Tuberculosis/diagnóstico
3.
Int J Infect Dis ; 125: 241-249, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36347458

RESUMEN

OBJECTIVES: After South Africa's second wave of COVID-19, this study estimated the SARS-CoV-2 seroprevalence among pregnant women in inner-city Johannesburg, South Africa. METHODS: In this cross-sectional survey, 500 pregnant women who were non-COVID-19-vaccinated (aged ≥12 years) were enrolled, and demographic and clinical data were collected. Serum samples were tested using the Wantai SARS-CoV-2 spike antibody enzyme-linked immunosorbent assay and Roche Elecsys® anti-SARS-CoV-2 nucleocapsid antibody assays. Seropositivity was defined as SARS-CoV-2 antibodies on either (primary) or both (secondary) assays. Univariate Poisson regression assessed risk factors associated with seropositivity. RESULTS: The median age was 27.4 years, and HIV prevalence was 26.7%. SARS-CoV-2 seroprevalence was 64.0% (95% confidence interval [CI]: 59.6-68.2%) on the primary and 54% (95% CI: 49.5-58.4%) on the secondary measure. Most (96.6%) women who were SARS-CoV-2-seropositive reported no symptoms. On the Roche assay, we detected lower seroprevalence among women living with HIV than women without HIV (48.9% vs 61.7%, P-value = 0.018), and especially low levels among women living with HIV with a clusters of differentiation 4 <350 cells/ml compared with women without immune suppression (22.2% vs 56.4%, prevalence rate ratio = 0.4; 95% CI: 0.2-0.9; P-value = 0.046). CONCLUSION: Pregnant women attending routine antenatal care had a high SARS-CoV-2 seroprevalence after the second wave in South Africa, and most had asymptomatic infections. Seroprevalence surveys in pregnant women present a feasible method of monitoring the course of the pandemic over time.


Asunto(s)
COVID-19 , Infecciones por VIH , Embarazo , Femenino , Humanos , Adulto , Masculino , Prevalencia , Mujeres Embarazadas , Estudios Seroepidemiológicos , Sudáfrica/epidemiología , Estudios Transversales , SARS-CoV-2 , COVID-19/epidemiología , Anticuerpos Antivirales , Infecciones por VIH/epidemiología
4.
AIDS ; 32(2): 189-204, 2018 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-29112069

RESUMEN

OBJECTIVE AND DESIGN: Children with HIV infection (HIV+) are at neuropsychological risk, but few studies have evaluated this at multiple sites in low-income and middle-income countries. We compared neuropsychological outcomes at enrollment (>5 years age) among HIV+, HIV perinatally exposed uninfected (HEU), and HIV unexposed uninfected (HUU) children from four sub-Saharan countries. METHODS: IMPAACT P1060 compared nevirapine versus lopinavir/ritonavir-based antiretroviral treatment (ART) in HIV-infected children 6-35 months of age. The present study (P1104s) enrolled P1060 children at 5-11 years of age and evaluated their neuropsychological performance over 2 years using the Kaufman Assessment Battery for Children, 2nd edition (KABC-II), Tests of Variables of Attention (TOVA), Bruininks-Oseretsky Test, 2nd edition (BOT-2), and parent-reported Behavior Rating Inventory of Executive Function (BRIEF). Cohorts were compared using generalized estimating equations least-squares means adjusted for site, child age and sex, and personal and social characteristics for child and caregiver. RESULTS: Six hundred and eleven (246 HIV+, 183 HEU, 182 HUU) of the 615 enrolled at six sites [South Africa (three), Zimbabwe, Malawi, Uganda] were available for analysis. Mean age was 7.2 years, 48% male, 69% in school. Unadjusted and adjusted comparisons were consistent. HIV+ children performed significantly worse than HEU and HUU cohorts on all KABC-II cognitive performance domains and on BOT-2 total motor proficiency (P < 0.001), but not on the BRIEF Global Executive Indices. HUU and HEU cohorts were comparable on cognitive outcomes. HIV+ children initiated on ART before 1 year of age had significantly better BRIEF evaluations (lower scores - fewer behavior problems), compared with those started after (P = 0.03). CONCLUSION: Significant cognitive deficits were documented among HIV+ children at school age, even when started on ART at an early age. Earlier HIV treatment, neuropsychological monitoring, and rehabilitative interventions are all needed. Subsequent testing for 2 more years will help further evaluate how HIV infection and exposure affect the developmental trajectory.


Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Trastornos Neurocognitivos/epidemiología , África , Niño , Preescolar , Ensayos Clínicos como Asunto , Estudios de Cohortes , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas
5.
AIDS ; 27(12): 1933-40, 2013 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-24180002

RESUMEN

OBJECTIVES: An efavirenz-based antiretroviral therapy (ART) regimen is preferred for children more than 3 years of age with tuberculosis. However, rifampin, a key component of antituberculosis therapy, induces CYP2B6. An increased dose of efavirenz is recommended in adults weighing more than 50 kg who require rifampin, but there is scant information in children being treated for tuberculosis. DESIGN: Plasma efavirenz concentrations were compared in 40 children during concomitant treatment for tuberculosis and HIV-1, after stopping rifampicin, and in a control group of children without tuberculosis. Associations with antituberculosis treatment, metabolizer genotype (based on CYP2B6 516G→T, 983T→C, and 15582C→T), weight, and time after dose were evaluated. RESULTS: Compared to children with extensive metabolizer genotypes, efavirenz concentrations were increased 1.42-fold (95% confidence interval, CI 0.94­2.15) and 2.85-fold (95% CI 1.80­4.52) in children with intermediate and slow metabolizer genotypes, respectively. Concomitant antituberculosis treatment increased efavirenz concentrations 1.49-fold (95% CI 1.10­2.01) in children with slow metabolizer genotypes, but did not affect efavirenz concentrations in extensive or intermediate metabolizer genotypes. After adjustment for dose/kg, each kilogram of weight was associated with a 2.8% (95% CI 0.9­4.7) decrease in efavirenz concentrations. Despite higher milligram per kilogram doses, a higher proportion of children in the lowest weight band (10­13.9 kg) had efavirenz concentrations less than 1.0 mg/l than larger children. CONCLUSION: Antituberculosis treatment was not associated with reduced efavirenz concentrations in children, which does not support increased efavirenz doses. Children with slow metabolizer genotype have increased efavirenz concentrations during antituberculosis treatment, likely due to isoniazid inhibiting enzymes involved in accessory metabolic pathways for efavirenz.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Antituberculosos/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , Benzoxazinas/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Rifampin/uso terapéutico , Tuberculosis/tratamiento farmacológico , Alquinos , Fármacos Anti-VIH/administración & dosificación , Benzoxazinas/administración & dosificación , Niño , Preescolar , Ciclopropanos , Citocromo P-450 CYP2B6 , Interacciones Farmacológicas , Femenino , Genotipo , Infecciones por VIH/complicaciones , Humanos , Masculino , Plasma/química , Tuberculosis/complicaciones
6.
AIDS Res Hum Retroviruses ; 26(6): 613-9, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20507205

RESUMEN

The aim of this study was to quantify the plasma efavirenz concentrations over 6 months in black HIV-1-infected South African children (3-14 years), from resource-limited households, attending an outpatient clinic. The children were antiretroviral treatment (ART) naive and received efavirenz in combination with two nucleoside reverse transcriptase inhibitors according to South African national guidelines. Two blood samples were taken between 12 and 20 h after the last efavirenz dose at 1 (n = 58), 3 (n = 54), and 6 (n = 54) months post-ART initiation. A total of 328 efavirenz mid-dose plasma samples from 58 patients was determined with a validated liquid chromatography tandem mass spectrometry method. Viral suppression (<25 copies/ml) was achieved in 95% of the children after 6 months on ART. The median (range) plasma concentration at time points 1 and 2 were 2.06 (0.10-11.14) and 1.80 (0.14-10.70) microg/ml with respective mean (+/-SD) blood sampling times of 15.24 (2.03) and 16.91 (2.03) h post-evening dose. Efavirenz plasma samples within the therapeutic range of 1-4 microg/ml accounted for 58%; 17% were <1 microg/ml and 25% were >4 microg/ml over the 6 months. Efavirenz levels persistently >4 microg/ml were recorded for 13 (23%) children and 3 (5%) children had persistent efavirenz levels <1 microg/ml. Possible reasons for efavirenz plasma levels outside the accepted therapeutic range include genetic variation in drug metabolism, incorrect dosing, drug-drug interactions, and nonadherence. However, these need to be further explored and the importance of sequential plasma levels has been highlighted in this study.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Benzoxazinas/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Plasma/química , Adolescente , Alquinos , Atención Ambulatoria , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Benzoxazinas/uso terapéutico , Niño , Preescolar , Cromatografía Liquida , Ciclopropanos , Femenino , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Humanos , Masculino , Sudáfrica , Espectrometría de Masas en Tándem , Factores de Tiempo
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