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1.
Artigo em Inglês | MEDLINE | ID: mdl-31913997

RESUMO

BACKGROUND: Younger age at antiretroviral therapy (ART) initiation has been associated with smaller HIV reservoirs. We investigated whether younger age of ART initiation is associated with testing negative and weaker signal on a standard HIV diagnostic test in treated children. METHODS: At exit from a longitudinal study at two sites in Johannesburg, South Africa, 316 school-aged, HIV-infected children on continuous ART started at a median of 6.3 months of age, were tested with standard total nucleic acid (TNA) PCR used for infant diagnosis. All negative results were repeated. Simultaneous viral load (VL) and CD4+ T-cell counts/percentages, along with data collected over the prior four years, were used in multivariable regression to predict negative PCR results and higher cycle threshold (Ct) values (weaker signal) RESULTS:: Seven children (2.2%, 95% CI: 0.6-3.8) in the full cohort had negative PCR results; all seven were in a subset of 102 (6.9%, 95% CI: 2.0-11.8) who had initiated ART 0-4 months of age and had VL<50 copies/mL at the time of PCR testing. Only one repeat tested as negative. Younger age at ART initiation, VL<50 copies/mL at time of test, sustained VL<400 copies/mL, lower CD4+ T-cell counts and ever treated with efavirenz were significant predictors of weaker signal on the diagnostic test. CONCLUSIONS: In a small proportion of children who start ART in the first months of life and remain on continuous therapy, standard diagnostic HIV PCR tests may result as negative. Repeat testing may resolve uncertainty of diagnosis.

2.
PLoS One ; 15(1): e0228003, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31999753

RESUMO

BACKGROUND: Given well documented challenges faced by pregnant women living with HIV taking lifetime ART, it is critical to understand the impact of short-term ART exposure followed by treatment interruption on maternal health outcomes. METHODS: HIV+ breastfeeding (BF) and Formula Feeding (FF) women with CD4 counts > 350 cells/mm3, enrolled in the 1077BF/1077FF PROMISE trial were followed to assess the effect of ART during pregnancy and breastfeeding respectively. The first analysis compared ART use limited to the antepartum period (AP-only) relative to women randomized to Zidovudine. The second analysis included women with no pregnancy combination ART exposure; and compared women randomized to either ART or no ART during postpartum (PP-only). Both analyses included follow-up time beyond breastfeeding period. The primary outcome was progression to AIDS and/or death. Secondary outcomes included adverse events and HIV-related events. RESULTS: 3490 and 1137 HIV+ women were enrolled from 14 sites in Africa and India from April 2011 through September 2014 in cohort AP-only and PP-only, respectively. Most were Black African (96%); median age was 27 years; 97% were WHO Clinical Stage I; and most had a screening CD4 count ≥500 cells/mm3 (78%). The rate of progression to AIDS and/or death was similar and low across all comparison arms (AP comparison, HR = 1.14, 95%CI (0.44, 2.96), p-value = 0.79). In the PP-only cohort, the rate of WHO stage 2-3 events was lower for women randomized to ART(HR = 0.65, 95% CI 0.42, 1.01, p-value = 0.05). CONCLUSION: The incidence of AIDS and/or death was low in pregnant/postpartum HIV+ women with highCD4 cell counts for all comparison arms. This provides some reassurance that there were limited consequences for short term ART interruption in this group of asymptomatic HIV+ women during up to 4 years of follow up; and underscores that even short term ART exposure postpartum may reduce the risk of WHO grade 2-3 disease progression.

3.
AIDS Res Hum Retroviruses ; 36(1): 27-38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31179720

RESUMO

Mitochondrial impairment is reported in HIV-infected children receiving antiretroviral therapy (ART), as well as those naive to ART. Whether mitochondrial function recovers with early initiation of ART and sustained viral suppression on long-term ART is unclear. In this study, we evaluate mitochondrial markers in well-suppressed perinatally HIV-infected children initiated on ART early in life. We selected a cross-sectional sample of 120 HIV-infected children with viral load <400 copies/mL and 60 age-matched uninfected children (22 HIV-exposed uninfected) enrolled in a cohort study in Johannesburg, South Africa. Complex IV (CIV) and citrate synthase (CS) activity were measured by spectrophotometry. Mitochondrial DNA (mtDNA) content relative to nuclear DNA (nDNA) was measured by quantitative real-time polymerase chain reaction and expressed as copies/nDNA. Mitochondrial markers were impaired in HIV-infected children, including lower mean CIV activities [1.76 vs. 1.40 optical densities (OD)/min], higher risk of a CIV/CS ratio ≤0.22 (third quartile; odds ratio = 3.03, 95% confidence interval: 1.38-6.66), and lower mtDNA content. Children with shorter versus longer ART duration (<6.3 vs. ≥6.3 years) had lower means of CIV activity (1.22-1.58 OD/min) and mtDNA content (386-907 copies/nDNA). There were no differences in mitochondrial markers between children who started ART earlier (<6 months) or later (6-24 months). CIV activity was impaired in children with lower height-for-age Z-scores (HAZs). Despite early treatment and prolonged viral suppression, HIV-infected children had detectable mitochondrial impairment, particularly among those with stunted growth. Further study is required to determine if continued treatment will lead to full recovery of mitochondrial function in HIV-infected children.

4.
Clin Infect Dis ; 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31848582

RESUMO

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.

5.
N Engl J Med ; 381(14): 1333-1346, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31577875

RESUMO

BACKGROUND: The safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown. METHODS: In this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years. RESULTS: A total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], -4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, -0.39; 95% CI, -1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 person-years in the deferred group (rate difference, 0.01; 95% CI, -0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9). CONCLUSIONS: The risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, NCT01494038.).


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Antituberculosos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Isoniazida/uso terapêutico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Resultado da Gravidez , Tuberculose/prevenção & controle , Adolescente , Adulto , Antituberculosos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Isoniazida/efeitos adversos , Testes de Função Hepática , Período Pós-Parto , Gravidez , Nascimento Prematuro/epidemiologia , Estudos Prospectivos , Adulto Jovem
6.
Sci Rep ; 9(1): 10495, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324826

RESUMO

Perinatally-acquired HIV has persistent effects on long-term health outcomes, even after early treatment. We hypothesize that epigenetic indicators, such as DNA methylation, may elucidate cellular processes that explain these effects. Here, we compared DNA methylation profiles in whole blood from 120 HIV-infected children on antiretroviral therapy (ART) and 60 frequency age-matched HIV-uninfected children aged 4-9 years in Johannesburg, South Africa. Using an individual CpG site approach, we found 1,309 differentially-methylated (DM) CpG sites between groups, including 1,271 CpG sites that were hyper-methylated in the HIV-infected group and 38 CpG sites that were hypo-methylated in the HIV-infected group. Six hyper-methylated CpG sites were in EBF4, which codes for a transcription factor involved in B-cell maturation. The top hypomethylated site was in the promoter region of NLRC5, encoding a transcription factor that regulates major histocompatibility complex (MHC) class I molecule expression. Using a differentially-methylated region (DMR) approach, we found 315 DMRs between groups, including 28 regions encompassing 686 CpG sites on chromosome 6. A large number of the genes identified in both the CpG site and DMR approaches were located in the MHC region on chromosome 6, which plays an important role in the adaptive immune system. This study provides the first evidence that changes in the epigenome are detectable in children with perinatally-acquired HIV infection on suppressive ART started at an early age.

7.
J Acquir Immune Defic Syndr ; 81(5): 521-532, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31295174

RESUMO

BACKGROUND: In the multicountry PROMISE 1077BF/1077FF trial, the risk of low birth weight (LBW; <2500 g) and preterm delivery (PTD; <37 weeks) was significantly higher among women initiating a protease inhibitor-based antiretroviral treatment (ART) regimen than those receiving ZDV alone. Among those assigned to a protease inhibitor regimen, tenofovir/emtricitabine was associated with the more severe outcomes of very LBW (<1500 g) and very PTD (<34 weeks) compared with zidovudine/lamivudine. METHODS: We used multivariate logistic regression to further explore these treatment findings, taking into account demographic baseline clinical and postentry obstetrical factors. We evaluated individual adverse outcomes and composites that included stillbirth and early loss/spontaneous abortion. RESULTS: Among 3333 women delivering at least 1 live infant, median maternal age at enrollment was 26 years; 661 (20%) were primiparous, and 110 (3.3%) reported at least 1 previous PTD. Seventeen percent of newborns were LBW, 1% were very LBW, 17% had PTD, and 3% had very PTD. Treatment allocation remained strongly associated with multiple adverse outcomes after controlling for other risk factors with both ART regimens exhibiting increased risk relative to ZDV alone. Other risk factors remaining significant in at least one of the multivariate models included the following: country, gestational age at entry, maternal age, maternal body mass index, previous PTD, history of alcohol use, baseline HIV viral titer, multiple gestation, and several obstetric risk factors. CONCLUSIONS: ART effects on adverse pregnancy outcomes reported in the randomized PROMISE trial remained strongly significant even after controlling for demographic, baseline clinical, and obstetrical risk factors, which were also associated with these outcomes.

8.
PLoS One ; 14(7): e0211155, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31260455

RESUMO

BACKGROUND: The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected infants and young children is relatively understudied in regions endemic for HIV and TB. We aimed to describe incidence, clinical features and risk factors of pediatric IRIS in Sub-Saharan Africa and India. METHODS AND FINDINGS: We conducted an observational multi-centred prospective clinical study from December 2010 to September 2013 in children <72 months of age recruited from public antiretroviral programs. The main diagnostic criterion for IRIS was a new or worsening inflammatory event after initiating antiretroviral therapy (ART). Among 198 participants, median age 1.15 (0.48; 2.21) years, 38 children (18.8%) developed 45 episodes of IRIS. Five participants (13.2%) had two IRIS events and one (2.6%) had 3 events. Main causes of IRIS were BCG (n = 21; 46.7%), tuberculosis (n = 10; 22.2%) and dermatological, (n = 8, 17.8%). Four TB IRIS cases had severe morbidity including 1 fatality. Cytomegalovirus colitis and cryptococcal meningitis IRIS were also severe. BCG IRIS resolved without pharmacological intervention. On multivariate logistic regression, the most important baseline associations with IRIS were high HIV viral load (likelihood ratio [LR] 10.629; p = 0.0011), recruitment at 1 site (Stellenbosch University) (LR 4.01; p = 0.0452) and CD4 depletion (LR 3.4; p = 0.0654). Significantly more non-IRIS infectious and inflammatory events between days 4 and 17 of ART initiation were noted in cases versus controls (35% versus 15.2%: p = 0.0007). CONCLUSIONS: IRIS occurs commonly in HIV-infected children initiating ART and occasionally has severe morbidity. The incidence may be underestimated. Predictive, diagnostic and prognostic biomarkers are needed.

9.
AIDS Care ; : 1-7, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288549

RESUMO

Little is known about how growing up with HIV impacts educational outcomes in sub-Saharan African children. We evaluated if South African children living with HIV (CLWH) were in the appropriate school grade-for-age compared to uninfected control children. We observed higher rates of not being in the correct grade-for-age in CLWH compared with controls (OR 3.32, 95% CI: 2.07-5.34), adjusted for study site, sex, whether the child's biological father was alive, and caregiver education. Initiation of ART before 6 months of age reduced but did not eliminate this association. Whether these associations are due to biological factors or other social and environmental determinants, and how best to support CLWH to achieve educational goals, warrants further investigation.

10.
Nat Commun ; 10(1): 412, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30679439

RESUMO

Understanding HIV remission in rare individuals who initiated antiretroviral therapy (ART) soon after infection and then discontinued, may inform HIV cure interventions. Here we describe features of virus and host of a perinatally HIV-1 infected child with long-term sustained virological control. The child received early limited ART in the Children with HIV Early antiRetroviral therapy (CHER) trial. At age 9.5 years, diagnostic tests for HIV are negative and the child has characteristics similar to uninfected children that include a high CD4:CD8 ratio, low T cell activation and low CCR5 expression. Virus persistence (HIV-1 DNA and plasma RNA) is confirmed with sensitive methods, but replication-competent virus is not detected. The child has weak HIV-specific antibody and T cell responses. Furthermore, we determine his HLA and KIR genotypes. This case aids in understanding post-treatment control and may help design of future intervention strategies.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Suspensão de Tratamento , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Criança , Citocinas/análise , DNA Viral , Feminino , Genótipo , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , HIV-1/genética , HIV-1/patogenicidade , Humanos , Imunidade Celular , Imunofenotipagem , Recém-Nascido , Fosfoproteínas/genética , Gravidez , RNA Viral , Receptores CCR5/metabolismo , Receptores KIR/genética , Receptores KIR3DL1/genética , Carga Viral , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética
11.
Expert Rev Vaccines ; 18(1): 95-104, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30417710

RESUMO

OBJECTIVES: We evaluated memory responses and antibody persistence to diphtheria-toxoid, tetanus-toxoid, whole-cell-pertussis (DTwP), and Hepatitis-B vaccines in HIV-unexposed, HIV-exposed-uninfected and HIV-infected children previously randomized to initiate time-limited ART at 6-10 weeks (ART-Immed) or when clinically/immunologically indicated (ART-Def). METHODS: All children received DTwP booster at 15-18 months. Antibodies were measured for pertussis-toxoid, filamentous haemagglutinin (FHA), diphtheria-toxoid, tetanus-toxoid, and hepatitis-B prior to booster, 1-2 weeks post-booster and at 24 months of age. RESULTS: Pre-booster antibody GMC were lower in HIV-infected groups than HIV-unexposed children for all epitopes. Post-booster and at 24 months of age, the ART-Def group had lower GMCs and antibody proportion ≥0.1 IU/ml for tetanus-toxoid and diphtheria-toxoid compared to HIV-unexposed children. At 24 months of age, the ART-Immed group had higher GMCs, and more likely to maintain antibody titres ≥1.0 IU/ml to tetanus-toxoid and diphtheria-toxoid compared to HIV-unexposed children. Compared to HIV-unexposed children, at 15 and 24 months of age, persistence of antibody to HBsAg of ≥10 mIU/ml was similar in the ART-Immed group but lower among the ART-Def group. Antibody kinetics indicated more robust memory responses in HIV-exposed-uninfected than HIV-unexposed children to diphtheria-toxoid and wP. CONCLUSION: HIV-infected children not on ART at primary vaccination had poorer memory responses, whereas HIV-exposed-uninfected children mounted robust memory responses.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Vacina contra Difteria, Tétano e Coqueluche/imunologia , Infecções por HIV/epidemiologia , Vacinas contra Hepatite B/imunologia , Anticorpos/imunologia , Pré-Escolar , Vacina contra Difteria, Tétano e Coqueluche/administração & dosagem , Feminino , Infecções por HIV/tratamento farmacológico , Vacinas contra Hepatite B/administração & dosagem , Humanos , Imunização Secundária/métodos , Memória Imunológica , Lactente , Masculino , Fatores de Tempo
12.
Clin Infect Dis ; 69(4): 687-696, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30418528

RESUMO

BACKGROUND: Human immunodeficiency virus (HIV)-infected and HIV-exposed-uninfected (HEU) children may be at increased risk of measles infection due to waning of immunity following vaccination. We evaluated persistence of antibodies to measles vaccination at 4.5 years of age in HIV-unexposed, HEU, and HIV-infected children with CD4+ ≥25% previously randomized to immediate antiretroviral therapy (ART) interrupted at 12 months (HIV/Immed-ART-12), 24 months (HIV/Immed-ART-24), or when clinically/immunologically indicated (HIV/Def-ART). The HIV/Def-ART group initiated ART by median 5.8 (interquartile range, 4.4-10.3) months of age. METHODS: In this study, HIV-unexposed (n = 95), HEU (n = 84), HIV/Immed-ART-12 (n = 70), HIV/Immed-ART-24 (n = 70), and HIV/Def-ART (n = 62) children were scheduled to receive measles vaccination at age 9 and 15-18 months. Antimeasles serum immunoglobulin G titers were quantified using enzyme-linked immunosorbent assay at 4.5 years. RESULTS: Compared with HIV-unexposed children (2860 mIU/mL), measles antibody geometric mean titers (GMTs) were significantly lower in both HIV/Immed-ART-12 (571; P < .001) and HIV/Immed-ART-24 (1136; P < .001) but similar in the HIV/Def-ART (2777) and HEU (3242) groups. Furthermore, compared with HIV-unexposed, antibody titers ≥330 mIU/mL (ie, presumed serocorrelate for protection; 99%) were also significantly lower in HIV/Immed-ART-12 (70%; P < .001) and HIV/Immed-ART-24 (83%; P < .001) but similar in the HIV/Def-ART (90%) and HEU (98%) groups. CONCLUSIONS: HIV-infected children in whom ART was interrupted at either 12 or 24 months had lower GMTs and lower proportions with seroprotective titers than HIV-unexposed children, indicating a potential downside of ART treatment interruption. CLINICAL TRIALS REGISTRATION: NCT00099658 and NCT00102960.

13.
AIDS Res Hum Retroviruses ; 35(1): 33-39, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30298747

RESUMO

In this study, we aimed to quantify KREC (kappa-deleting recombination excision circle) levels and naive B cell output in healthy HIV-uninfected children, compared with HIV-infected South African children, before and after starting ART (antiretroviral therapy). Samples were acquired from a Child Wellness Clinic (n = 288 HIV-uninfected South African children, 2 weeks-12 years) and the Children with HIV Early Antiretroviral Therapy (CHER) trial (n = 153 HIV-infected South African children, 7 weeks-8 years). Naive B cell output was estimated using a mathematical model combining KREC levels to reflect B cell emigration into the circulation, flow cytometry measures of naive unswitched B cells to quantify total body naive B cells, and their rates of proliferation using the intracellular marker Ki67. Naive B cell output increases from birth to 1 year, followed by a decline and plateau into late childhood. HIV-infected children on or off ART had higher naive B cell outputs than their uninfected counterparts (p = .01 and p = .04). This is the first study to present reference ranges for measurements of KRECs and naive B cell output in healthy and HIV-infected children. Comparison between HIV-uninfected healthy children and HIV-infected children suggests that HIV may increase naive B cell output. Further work is required to fully understand the mechanisms involved and clinical value of measuring naive B cell output in children.


Assuntos
Antirretrovirais/uso terapêutico , Linfócitos B/imunologia , Proliferação de Células , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Imunidade Celular , Linfócitos B/química , Criança , Pré-Escolar , Estudos de Coortes , DNA/análise , Feminino , Citometria de Fluxo , Humanos , Lactente , Recém-Nascido , Antígeno Ki-67/análise , Masculino , Modelos Teóricos , África do Sul
14.
J Acquir Immune Defic Syndr ; 78 Suppl 1: S40-S48, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29994919

RESUMO

For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children's treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross-over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in "basket" trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV-infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis.


Assuntos
Antirretrovirais/uso terapêutico , Ensaios Clínicos como Assunto , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Adulto , Antirretrovirais/farmacocinética , Teorema de Bayes , Criança , Composição de Medicamentos , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Infecções por HIV/virologia , Humanos , Pediatria
15.
AIDS Behav ; 22(12): 3892-3896, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29909588

RESUMO

A growing population of youth who acquired HIV from their mothers are surviving into adulthood. This group is unique in that they experience both internalized stigma (due to their HIV status) and associative stigma (due to their mothers' HIV status). Results of a cross-sectional survey of 250 perinatally HIV-infected South African youth suggests that internalized stigma is associated with greater risk of depression, and associative stigma is associated with greater risk of depression and substance use problems. Interventions currently focus on internalized stigma; this study highlights the importance of also addressing associative stigma to improve outcomes among perinatally HIV-infected youth.


Assuntos
Grupo com Ancestrais do Continente Africano/psicologia , Consumo de Bebidas Alcoólicas/psicologia , Intoxicação Alcoólica/psicologia , Depressão/psicologia , Infecções por HIV/psicologia , Transmissão Vertical de Doença Infecciosa , Estigma Social , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Consumo de Bebidas Alcoólicas/epidemiologia , Intoxicação Alcoólica/epidemiologia , Criança , Estudos Transversais , Feminino , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Humanos , Recém-Nascido , Masculino , África do Sul/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto Jovem
16.
J Int AIDS Soc ; 21(5): e25106, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29722482

RESUMO

INTRODUCTION: Early antiretroviral therapy (ART) has improved neurodevelopmental outcomes of HIV-infected (HIV-positive) children; however, little is known about the longer term outcomes in infants commencing early ART or whether temporary ART interruption might have long-term consequences. In the children with HIV early antiretroviral treatment (CHER) trial, HIV-infected infants ≤12 weeks of age with CD4 ≥25% were randomized to deferred ART (ART-Def); immediate time-limited ART for 40 weeks (ART-40W) or 96 weeks (ART-96W). ART was restarted in the time-limited arms for immunologic/clinical progression. Our objective was to compare the neurodevelopmental profiles in all three arms of Cape Town CHER participants. METHODS: A prospective, longitudinal observational study was used. The Griffiths mental development scales (GMDS), which includes six subscales and a global score, were performed at 11, 20, 30, 42 and 60 months, and the Beery-Buktenica developmental tests for visual motor integration at 60 months. HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled for comparison. Mixed model repeated measures were used to compare groups over time, using quotients derived from standardized British norms. RESULTS: In this study, 28 ART-Def, 35 ART-40W, 33 ART-96W CHER children, and 34 HEU and 39 HU controls were enrolled. GMDS scores over five years were similar between the five groups in all subscales except locomotor and general Griffiths (interaction p < 0.001 and p = 0.02 respectively), driven by early lower scores in the ART-Def arm. At 60 months, scores for all groups were similar in each GMDS scale. However, Beery visual perception scores were significantly lower in HIV-infected children (mean standard scores: 75.8 ART-Def, 79.8 ART-40W, 75.9 ART-96W) versus 84.4 in HEU and 90.5 in HU (p < 0.01)). CONCLUSIONS: Early locomotor delay in the ART-Def arm resolved by five years. Neurodevelopmental outcomes at five years in HIV-infected children on early time-limited ART were similar to uninfected controls, apart from visual perception where HIV-infected children scored lower. Poorer visual perception performance warrants further investigation.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Desenvolvimento Infantil/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Transmissão Vertical de Doença Infecciosa , Complicações Infecciosas na Gravidez/tratamento farmacológico , Feminino , Infecções por HIV/transmissão , Humanos , Lactente , Recém-Nascido , Masculino , Atividade Motora/efeitos dos fármacos , Gravidez , Estudos Prospectivos
17.
J Acquir Immune Defic Syndr ; 78(5): 549-556, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29771780

RESUMO

BACKGROUND: Data on accelerated aging in HIV-infected children are limited. In this study, we assess 2 biomarkers of aging-telomere length and DNA methylation (DNAm) age-in a cohort of early-treated HIV-infected children and compare these aging biomarkers with HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children. SETTING: Cross-sectional study of 120 HIV-infected, 33 HEU, and 25 HUU children enrolled in a cohort study in Johannesburg, South Africa. The mean age of children was 6.4 years at the time of measurement. HIV-infected children initiated ritonavir-boosted lopinavir-based antiretroviral therapy before 2 years of age and had been on continuous antiretroviral therapy until biomarker measurement. METHODS: Telomere length was determined using multiplex quantitative polymerase chain reaction. DNAm was measured using the Illumina 450K array and DNAm age was calculated as the acceleration residual from regressing DNAm age on chronological age. RESULTS: Telomere length (ln[Kb/genome]) was shorter in HIV-infected children compared with HUU children (4.14 ± 0.85 vs. 4.53 ± 0.79, P = 0.038) and in HEU children compared with HUU children (4.05 ± 0.74 vs. 4.53 ± 0.79, P = 0.023). Age acceleration residual based on DNAm levels was not different between HIV-infected (-0.003 ± 2.95), HEU (0.038 ± 2.39), and HUU (0.18 ± 2.49) children in unadjusted analysis and after adjustment for cell type proportions. CONCLUSIONS: Unlike reports of accelerated DNAm age in HIV-infected adults, there was no evidence of accelerated biological aging by DNAm levels in this cohort of early-treated HIV-infected children. By contrast, absolute telomere length was shorter in HIV-infected and HEU children compared with HUU children, but did not differ between HIV-infected and HEU children.


Assuntos
Envelhecimento/fisiologia , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Lopinavir/uso terapêutico , Ritonavir/uso terapêutico , Envelhecimento/genética , Biomarcadores/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Metilação de DNA , Ensaio de Imunoadsorção Enzimática , Feminino , Infecções por HIV/fisiopatologia , Inibidores da Protease de HIV/administração & dosagem , Humanos , Lopinavir/administração & dosagem , Masculino , Reação em Cadeia da Polimerase Multiplex , Ritonavir/administração & dosagem , África do Sul , Telômero
18.
Child Abuse Negl ; 79: 98-106, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29428881

RESUMO

Repeated exposure to childhood adversity (abuse, neglect and other traumas experienced before age 18) can have lifelong impacts on health. For HIV-infected adolescents and youth, such impacts may include onward transmission of HIV. To evaluate this possibility, the current study measured the burden of childhood adversity and its influence on risky health behaviors among perinatally-infected adolescents and youth. We surveyed 250 perinatally-infected adolescents and youth (13-24 years) receiving care in Soweto, South Africa. Both male and female participants reported on childhood adversity (using the ACE-IQ), sexual behavior, and psychosocial state. Viral load was also abstracted from their charts. We used logistic regressions to test the association between cumulative adversity and behavioral outcomes. Half the sample reported eight or more adversities. Overall, 72% experienced emotional abuse, 59% experienced physical abuse, 34% experienced sexual abuse, 82% witnessed domestic violence, and 91% saw someone being attacked in their community. A clear gradient emerged between cumulative adversities and behavioral risk. Having experienced one additional childhood adversity raised the odds of risky sexual behavior by almost 30% (OR 1.27, 95% CI 1.09-1.48). Viral suppression was poor overall (31% had viral loads >400 copies/ml), but was not related to adversity. Adversity showed a robust relationship to depression and substance abuse. Childhood adversity is common, influences the current health of HIV-positive adolescents and youth, and puts their sexual partners at risk for HIV infection. Greater primary prevention of childhood adversity and increased access to support services (e.g., mental health) could reduce risk taking among HIV-positive adolescents and youth.


Assuntos
Experiências Adversas da Infância , Infecções por HIV/transmissão , Sexo sem Proteção/psicologia , Adolescente , Comportamento do Adolescente/psicologia , Adulto , Criança , Maus-Tratos Infantis/psicologia , Estudos de Coortes , Violência Doméstica/psicologia , Exposição à Violência/psicologia , Feminino , Infecções por HIV/psicologia , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/estatística & dados numéricos , Masculino , Saúde Mental , Gravidez , Reprodutibilidade dos Testes , Assunção de Riscos , Parceiros Sexuais , África do Sul , Transtornos Relacionados ao Uso de Substâncias/psicologia , Inquéritos e Questionários , Carga Viral , Adulto Jovem
19.
AIDS ; 32(2): 189-204, 2018 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-29112069

RESUMO

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.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Transtornos Neurocognitivos/epidemiologia , África , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Estudos de Coortes , Feminino , Humanos , Masculino , Testes Neuropsicológicos
20.
J Acquir Immune Defic Syndr ; 77(1): 64-71, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040165

RESUMO

BACKGROUND: As perinatal HIV-infected youth become sexually active, the potential for onward transmission becomes an increasing concern. In other populations, intimate partner violence (IPV) is a risk factor for HIV acquisition. We build on this critical work by studying the role of IPV in facilitating onward transmission among HIV-infected youth-an important step toward effective intervention. SETTING: Soweto, South Africa. METHODS: Self-report surveys were completed by 129 perinatal HIV-infected female youth (aged 13-24 years). We calculated the IPV prevalence and used logistic models to capture the association between IPV and health outcomes known to facilitate onward HIV transmission (eg, risky sex, poor medication adherence, depression, and substance abuse). RESULTS: A fifth of perinatal HIV-infected participants reported physical and/or sexual IPV in the past year; one-third reported lifetime IPV. Childhood adversity was common and positively associated with IPV. Past-year physical and/or sexual IPV was positively correlated with high-risk sex [odds ratio (OR) = 8.96; 95% confidence interval (CI): 2.78 to 28.90], pregnancy (OR = 6.56; 95% CI: 1.91 to 22.54), poor medication adherence to antiretroviral therapy (OR = 5.37; 95% CI: 1.37 to 21.08), depression (OR = 4.25; 95% CI: 1.64 to 11.00), and substance abuse (OR = 4.11; 95% CI: 1.42 to 11.86). Neither past-year nor lifetime IPV was associated with viral load or HIV status disclosure to a partner. CONCLUSIONS: We find that IPV may increase risk for onward HIV transmission in perinatal HIV-infected youth by both increasing engagement in risky sexual behaviors and lowering medication adherence. HIV clinics should consider integrating primary IPV prevention interventions, instituting routine IPV screening, and collocating services for victims of violence.


Assuntos
Infecções por HIV/prevenção & controle , Violência por Parceiro Íntimo/estatística & dados numéricos , Adesão à Medicação , Saúde Mental , Sexo sem Proteção , Adolescente , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , Humanos , Violência por Parceiro Íntimo/psicologia , Gravidez , Prevalência , Fatores de Risco , Assunção de Riscos , Autorrelato , Parceiros Sexuais , África do Sul/epidemiologia , Transtornos Relacionados ao Uso de Substâncias , Adulto Jovem
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