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1.
J Infect Dis ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32006006

RESUMO

BACKGROUND: Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and vaccines are needed. Live RSV vaccine D46/NS2/N/ΔM2-2-HindIII, attenuated by deletion of the RSV RNA regulatory protein M2-2, is based on previous candidate LID/ΔM2-2, but incorporates prominent differences versus MEDI/ΔM2-2 which was more restricted in replication in Phase 1. METHODS: RSV-seronegative children ages 6-24 months received one intranasal dose [105 plaque forming units (PFU)] of D46/NS2/N/ΔM2-2-HindIII (n=21) or placebo (n=11) (NCT03102034/NCT03099291) and were monitored for vaccine shedding, reactogenicity, RSV-antibody responses and RSV-associated medically-attended acute respiratory illness (RSV-MAARI) and antibody responses during the following RSV season. RESULTS: All 21 vaccinees were infected with vaccine; 20 (95%) shed vaccine [median peak titers: 3.5 log10 PFU/mL (immunoplaque assay); 6.1 log10 copies/mL (PCR)]. Serum RSV-neutralizing antibodies and anti-RSV F IgG increased ≥4-fold in 95% and 100%, respectively. Mild upper respiratory symptoms and/or fever occurred in vaccinees (76%) and placebo recipients (18%). Over the RSV season, RSV-MAARI occurred in 2 vaccinees and 4 placebo recipients. Three vaccinees had ≥4-fold increases in serum RSV-neutralizing antibody titers after the RSV season without RSV-MAARI. CONCLUSION: D46/NS2/N/ΔM2-2-HindIII had excellent infectivity and immunogenicity, and primed for anamnestic responses, encouraging further evaluation of this attenuation strategy.

2.
Clin Infect Dis ; 2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31927562

RESUMO

BACKGROUND: Early antiretroviral treatment (ART) is recommended for HIV-infected infants. However, few antiretroviral options are available for neonates. METHODS: The Early Infant Treatment Study in Botswana tested HIV-exposed infants using DNA PCR within 96 hours of birth, and HIV-infected infants started nevirapine (NVP) 6mg/kg BID, zidovudine (ZDV), and lamivudine (3TC) at age <7 days. Nevirapine trough concentrations were tested at 1 and 2 weeks. NVP was switched to lopinavir-ritonavir (LPV-r) at week 2, 3, 4, or 5 according to delivery gestational age (≥38, 37, 36, 35 weeks). RESULTS: Forty HIV-infected infants started ART at median age 2 days (range 1-5). Nevirapine trough concentrations were highly variable and below therapeutic target (3000ng/mL) for 50% of 2-week measurements; concentrations did not correlate with viral decline at weeks 2, 4, or 12. Two deaths unrelated to ART occurred through 24 weeks. Only one unscheduled treatment modification was required. Within 4 weeks of transition to LPV-r, 9 (22.5%) had transient HIV RNA increases, likely due to poor LPV-r palatability. At 12 weeks, HIV-1 RNA was <40 copies/mL for 22 (55%) of 40 (93% <400 copies/mL); by 24 weeks, 27 (71%) of 38 were <40 copies/mL (84% <400 copies/mL). HIV-1 RNA response at 12 and 24 weeks did not differ by baseline HIV RNA, or other factors. CONCLUSIONS: NVP/ZDV/3TC started in the first week of life was safe and effective, even when trough NVP levels were below target. Transient viral increases occurred following transition to LPV-r, but by 12 and 24 weeks most children achieved and maintained viral suppression.

3.
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.

4.
Sci Transl Med ; 11(520)2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31776292

RESUMO

Neonatal HIV-1 infection is associated with rapidly progressive and frequently fatal immune deficiency if left untreated. Immediate institution of antiretroviral therapy (ART), ideally within hours after birth, may restrict irreversible damage to the developing neonatal immune system and possibly provide opportunities for facilitating drug-free viral control during subsequent treatment interruptions. However, the virological and immunological effects of ART initiation within hours after delivery have not been systematically investigated. We examined a unique cohort of neonates with HIV-1 infection from Botswana who started ART shortly after birth and were followed longitudinally for about 2 years in comparison to control infants started on treatment during the first year after birth. We demonstrate multiple clear benefits of rapid antiretroviral initiation, including an extremely small reservoir of intact proviral sequences, a reduction in abnormal T cell immune activation, a more polyfunctional HIV-1-specific T cell response, and an innate immune profile that displays distinct features of improved antiviral activity and is associated with intact proviral reservoir size. Together, these data offer rare insight into the evolutionary dynamics of viral reservoir establishment in neonates and provide strong empirical evidence supporting the immediate initiation of ART for neonates with HIV-1 infection.

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.
Lancet HIV ; 6(8): e552-e558, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31307946

RESUMO

Antiretroviral agents with long-acting properties have potential to improve treatment outcomes substantially for people living with HIV. In November 2017, the Long acting/Extended Release Antiretroviral Resource Program (LEAP) convened a workshop with the aim of shaping the research agenda and promoting early development of long-acting or extended release products for key populations: pregnant and lactating women, children aged up to 10 years, and adolescents aged 10-19 years. Goals included strategies and principles to ensure that the needs of children, adolescents, and pregnant and lactating women are considered when developing long-acting formulations. Research should focus not only on how best to transition long-acting products to these populations, but also on early engagement across sectors and among stakeholders. A parallel rather than sequential approach is needed when establishing adult, adolescent, and paediatric clinical trials and seeking regulatory approval. Pregnant and lactating women should be included in adult clinical trials. Adolescent-friendly trial design is needed to improve recruitment and retention of young people.

7.
J Acquir Immune Defic Syndr ; 81(4): 473-480, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241542

RESUMO

BACKGROUND: CYP2B6 516 genotype-directed dosing improves efavirenz (EFV) exposures in HIV-infected children younger than 36 months, but such data are lacking in those with tuberculosis (TB) coinfection. METHODS: Phase I, 24-week safety and pharmacokinetic (PK) study of EFV in HIV-infected children aged 3 to <36 months, with or without TB. CYP2B6 516 genotype classified children into extensive metabolizers (516 TT/GT) and poor metabolizers [(PMs), 516 TT]. EFV doses were 25%-33% higher in children with HIV/TB coinfection targeting EFV area under the curve (AUC) 35-180 µg × h/mL, with individual dose adjustment as necessary. Safety and virologic evaluations were performed every 4-8 weeks. RESULTS: Fourteen children from 2 African countries and India with HIV/TB enrolled, with 11 aged 3 to <24 months and 3 aged 24-36 months, 12 extensive metabolizers and 2 PMs. Median (Q1, Q3) EFV AUC was 92.87 (40.95, 160.81) µg × h/mL in 8/9 evaluable children aged 3 to <24 months and 319.05 (172.56, 360.48) µg × h/mL in children aged 24-36 months. AUC targets were met in 6/8 and 2/5 of the younger and older age groups, respectively. EFV clearance was reduced in PM's and older children. Pharmacokinetic modeling predicted adequate EFV concentrations if children younger than 24 months received TB-uninfected dosing. All 9 completing 24 weeks achieved viral suppression. Five/14 discontinued treatment early: 1 neutropenia, 3 nonadherence, and 1 with excessive EFV AUC. CONCLUSIONS: Genotype-directed dosing safely achieved therapeutic EFV concentrations and virologic suppression in HIV/TB-coinfected children younger than 24 months, but further study is needed to confirm appropriate dosing in those aged 24-36 months. This approach is most important for young children and currently a critical unmet need in TB-endemic countries.

8.
AIDS ; 33(3): 377-385, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30475262

RESUMO

: In 2015, only 53 infants born in the United States acquired HIV - the lowest recorded number of perinatal HIV infections. Recognizing this significant achievement, we must acknowledge that the United States has not yet reached the goal of eliminating perinatal HIV transmission. This analysis describes different approaches to perinatal HIV preventive services among five states and the District of Columbia as case studies. Continuous focus on improving identification, surveillance and prevention of HIV infection in pregnant women and their infants is necessary to reach the goal of eliminating perinatal HIV transmission in the United States.

9.
J Pediatr Infect Dis ; 13(3): 185-201, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30100780

RESUMO

Introduction: Western-constructed neuropsychological tests have been used in low and middle income countries to assess the impact of HIV/AIDS and other chronic illnesses. We explore using such instruments cross-culturally in a sub-Saharan Africa setting. Methods: IMPAACT P1104S was a two-year observational study carried out at six clinical sites (South Africa- 3 sites, Malawi, Uganda and Zimbabwe) to assess and compare neuropsychological outcomes in three cohorts of children 5-11 years of age: HIV-infected (HIV), HIV-exposed but uninfected (HEU) and HIV unexposed and uninfected (HU). Descriptive statistics compared socio-demographic characteristics among children at sites. Instruments included the KABC-II cognitive ability, TOVA attention/impulsivity, BOT-2 motor proficiency tests, and BRIEF executive function problems. Test characteristics were assessed using intraclass and Spearman non-parametric correlations, linear regression and principal factor analyses. Results: Of the 611 participants, 50% were male and mean age ranged from 6.6 to 8 years. In Malawi, Uganda and Zimbabwe, substantial proportions of families lived in rural settings in contrast to the South African sites. Intraclass correlation coefficients between weeks 0 and 48 were highest for the KABC scores, ranging between 0.42 to 0.71.Correlations among similar test domains were low to moderate but significant, with positive correlation between KABC Sequential and TOVA scores and negative correlation between BRIEF and KABC scores. TOVA response time scores correlated negatively with the BOT-2 Total points score. Strong and significant associations between individual measures of growth, disability and development with all test scores were observed. Performance-based measures were markedly lower for HIV compared to HEU and HU participants, even after controlling for age, sex and site. Factor analyses confirmed the underlying theoretical structure of the KABC scaled item scores. Conclusion: The KABC, TOVA, BRIEF and BOT-2 were valid and reliable tools for assessing the neuropsychological impact of HIV in four sub-Saharan African countries.

10.
J Int AIDS Soc ; 21(5): e25111, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29852062

RESUMO

INTRODUCTION: Most African countries perform infant HIV testing at 6 weeks or later. The addition of targeted testing at birth may improve retention in care, treatment outcomes and survival for HIV-infected infants. METHODS: HIV-exposed infants were screened as part of the Early Infant Treatment (EIT) study in Botswana. Screened infants were ≥35 weeks gestational age and ≥2000 g at birth. Risk factors for mother-to-child transmission (MTCT) were assessed by maternal obstetric card or verbally. Risk factors included <8 weeks ART in pregnancy, last known CD4 <250 cells/mm3 , last known HIV RNA >400 copies/mL, poor maternal ART adherence, lack of maternal zidovudine (ZDV) in labour, or lack of infant post-exposure prophylaxis. Infants underwent dried blood spot testing by Roche Cobas Ampliprep/Cobas Taqman HIV-1 qualitative PCR. RESULTS: From April 2015 to April 2016, 2303 HIV-exposed infants were tested for HIV in the EIT study. Of these, 369 (16%) were identified as high risk for HIV infection by information available at birth, and 12 (0.5% overall, 3.25% of high risk) were identified as HIV positive at birth. All 12 positive infants were identified as high risk at the time of screening, and only 2 risk factors were required to identify all positive infants: either <8 weeks of maternal ART in pregnancy (75%) or lack of maternal HIV suppression at last test (25%). CONCLUSIONS: In utero MTCT occurred only among infants identified as high risk at delivery, using information available from the mother or obstetric record. Birth testing that targets high-risk infants based on maternal ART receipt is likely to identify the majority of in utero HIV transmissions, and allows early ART initiation for these infants.


Assuntos
Infecções por HIV/diagnóstico , Infecções por HIV/transmissão , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Adulto , Botsuana , Teste em Amostras de Sangue Seco , Feminino , Humanos , Gravidez , Complicações Infecciosas na Gravidez , Risco
11.
Am J Trop Med Hyg ; 98(1): 67-70, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29165225

RESUMO

Laboratory data and prior pediatric reports indicate that HIV protease inhibitor (PI)-based antiretroviral therapy (ARV) kills gametocytes and reduces rates of gametocytemia, but not asymptomatic parasitemia, in a high malaria-transmission area. To determine whether ARV regimen impacts these rates in areas with less-intense malaria transmission, we compared asymptomatic parasitemia and gametocytemia rates in HIV-infected children by ARV regimen in Lilongwe, Malawi, an area of low-to-moderate transmission intensity. HIV PI lopinavir-ritonavir (LPV-rtv) ARV- or non-nucleoside reverse transcriptase inhibitor nevirapine ARV-treated children did not differ in the rates of polymerase chain reaction-detected asymptomatic parasitemia (relative risk [RR] 0.43 95% confidence interval [CI] [0.16, 1.18], P value 0.10) or microscopically detected gametocytemia with LPV-rtv ARV during symptomatic malaria (RR 0.48 95% CI [0.22,1.04] P value 0.06). LPV-rtv ARV was not associated with reduced rates of asymptomatic parasitemia, or gametocytemia on days of symptomatic malaria episodes, in HIV-infected children. Larger studies should evaluate whether ARV impacts transmission.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções Assintomáticas/epidemiologia , Coinfecção/epidemiologia , Infecções por HIV/parasitologia , Malária Falciparum/epidemiologia , Parasitemia/epidemiologia , África ao Sul do Saara/epidemiologia , Pré-Escolar , Coinfecção/parasitologia , Coinfecção/virologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Malária Falciparum/complicações , Masculino , Repetições de Microssatélites/genética , Plasmodium falciparum/genética , Prevalência
12.
AIDS ; 31(13): 1797-1807, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28590330

RESUMO

: On 5-6 May 2016, the division of AIDS of the National Institute of Allergy and Infectious Diseases convened a workshop on 'HIV Birth Testing and Linkage to Care for HIV Infected Infants.' The goal of the workshop was to evaluate birth testing for early infant diagnosis (EID) of HIV, delineate technological resources for advancing a point-of-care (POC) HIV test implementable at birth and chart out the implementation hurdles for initiating early antiretroviral therapy to HIV-infected infants diagnosed at birth. The workshop addressed research and regulatory needs involved in the optimization of POC EID testing and challenges associated with implementation of EID, focusing on testing at birth. Scientific gaps and areas of intervention to accelerate and scale-up EID initiatives and birth testing were identified. These include discussion of the evidence supporting an early mortality peak among HIV-infected infant and justifying a role for birth HIV testing, including POC testing; evaluation of the current POC EID technology pipeline and test performance characteristics required for effective programmatic uptake; mathematical modeling of different testing scenarios and solutions with inclusion of birth testing; the adoption of setting-specific EID testing algorithms to achieve efficient linkage to care including early antiretroviral therapy initiation; the development of appropriate quality assurance programs to ensure accuracy of test results and enable sustainability of the testing program. Addressing these gaps and answering these challenges will be important in helping improve outcomes for HIV-infected infants and accelerate achieving the Joint United Nations Program for HIV and AIDS 90-90-90 targets in children.


Assuntos
Diagnóstico Precoce , Infecções por HIV/diagnóstico , Programas de Rastreamento/métodos , Cuidado Pós-Natal/métodos , Política de Saúde , Administração de Serviços de Saúde , Humanos , Lactente , Recém-Nascido , National Institute of Allergy and Infectious Diseases (U.S.) , Testes Imediatos , Nações Unidas , Estados Unidos
13.
J Pediatric Infect Dis Soc ; 6(3): e69-e74, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28339668

RESUMO

Background: The US Advisory Committee on Immunization Practices recommends a booster dose of quadrivalent meningococcal conjugate vaccine (MCV4) after initial immunization for patients at high risk for meningococcal infection. Methods: The International Maternal Pediatric Adolescents AIDS Clinical Trials (IMPAACT) P1065 trial evaluated the use of MCV4 in human immunodeficiency virus (HIV)-infected children and youth. The final step of this trial was an open-label study of an MCV4 booster dose 3.5 years after primary MCV4 immunization. Antibody titers were evaluated at the time of the booster vaccine and 1, 4, and 24 weeks after the booster. Immunogenicity was measured by rabbit serum bactericidal antibody (rSBA) against each meningococcal serogroup. Immunologic memory was defined as either seroprotection (rSBA titer ≥1:128) or a ≥4-fold increase 1 week after the booster dose. Primary response was defined as either a ≥4-fold response or seropositivity 4 weeks after the booster in the absence of immunologic memory. Adverse events were assessed for 4 weeks after the booster dose. Results: Of 174 participants with serology results at entry and 1 and 4 weeks later, the percentage with protective antibody levels at entry varied according to serogroup, ranging from a low of 26% for serogroup C to a high of 68% for serogroup A. A memory response to at least 1 serogroup occurred in 98% of the participants: 93% each for serogroups A and Y, 88% for serogroup C, and 94% for serogroup W-135; 83% had a memory response to all 4 serogroups. Overall, rates of any memory or primary response were ≥90% for all serogroups. No serious adverse events were encountered. Conclusions: A booster dose of MCV4 elicited a memory response in 88% to 94% of previously immunized HIV-infected participants depending on serogroup, including those who lacked a protective titer level for that serogroup before booster vaccination.


Assuntos
Imunização Secundária/métodos , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/administração & dosagem , Vacinas Meningocócicas/imunologia , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/imunologia , Adolescente , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias , Contagem de Linfócito CD4 , Criança , Grupos Étnicos , Feminino , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Humanos , Memória Imunológica/imunologia , Masculino , Infecções Meningocócicas/imunologia , Vacinas Meningocócicas/efeitos adversos , Neisseria meningitidis Sorogrupo A/imunologia , Neisseria meningitidis Sorogrupo C/imunologia , Neisseria meningitidis Sorogrupo W-135/imunologia , Neisseria meningitidis Sorogrupo Y/imunologia , Coelhos , Sorogrupo , Ensaios de Anticorpos Bactericidas Séricos , Estados Unidos , Vacinação , Vacinas Conjugadas/efeitos adversos , Adulto Jovem
14.
AIDS ; 31(8): 1129-1136, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28323755

RESUMO

OBJECTIVES: To determine safety-specific, efficacy-specific and genotypic-specific dose requirements of efavirenz (EFV) in children aged 3 to less than 36 months with HIV infection. DESIGN: IMPAACT P1070 was a 24-week prospective cohort trial of EFV (as open capsules) and two nucleoside reverse transcriptase inhibitors in children with HIV infection 3 to less than 36 months without tuberculosis (Cohort 1). METHODS: CYP2B6 G516T genotype was determined, and intensive pharmacokinetics was performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35-180 µg*h/ml. Pharmacokinetic and CYP2B6 G516T genotype data were used to model EFV exposures based on Food and Drug Administration (FDA)-approved doses. RESULTS: Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow-up; 38 516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT vs. 516GG/GT (median 490 vs. 107 µg*h/ml; P = 0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, pharmacokinetic modeling predicted that 83% of participants met the AUC target (31/38 516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce subtherapeutic AUCs in almost one-third of participants with 516GG/GT and excessive AUCs in more than 50% with 516TT genotypes. CONCLUSION: CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to outperform other dosing approaches.


Assuntos
Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Citocromo P-450 CYP2B6/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos
15.
J Pediatric Infect Dis Soc ; 6(3): 294-296, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27103489
16.
PLoS One ; 11(12): e0165140, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27936233

RESUMO

BACKGROUND: HIV and malaria geographically overlap. HIV protease inhibitors kill malaria parasites in vitro and in vivo, but further evaluation in clinical studies is needed. METHODS: Thirty-one children from Malawi aged 4-62 months were followed every 3 months and at intercurrent illness visits for ≤47 months (September 2009-December 2011). We compared malaria parasite carriage by blood smear microscopy (BS) and confirmed clinical malaria incidence (CCM, or positive BS with malaria symptoms) in children initiated on HIV antiretroviral therapy (ART) with zidovudine, lamivudine, and either nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor, or lopinavir-ritonavir (LPV-rtv), a protease inhibitor. RESULTS: We found an association between increased time to recurrent positive BS, but not CCM, when anti-malarial treatment and LPV-rtv based ART were used concurrently and when accounting for a LPV-rtv and antimalarial treatment interaction (adjusted HR 0.39; 95% CI (0.17,0.89); p = 0.03). CONCLUSIONS: LPV-rtv in combination with malaria treatment was associated with lower risk of recurrent positive BS, but not CCM, in HIV-infected children. Larger, randomized studies are needed to confirm these findings which may permit ART optimization for malaria-endemic settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT00719602.


Assuntos
Antimaláricos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Malária Falciparum/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Coinfecção , Quimioterapia Combinada , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/crescimento & desenvolvimento , Humanos , Lactente , Lamivudina/uso terapêutico , Lopinavir/uso terapêutico , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Malaui , Masculino , Nevirapina/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Ritonavir/uso terapêutico , Carga Viral/efeitos dos fármacos , Zidovudina/uso terapêutico
17.
Pediatr Infect Dis J ; 35(12): 1333-1335, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27583590

RESUMO

HIV protease inhibitor use in pediatrics is challenging due to the poor palatability and/or toxicity of concomitant low-dose ritonavir. Atazanavir without ritonavir (unboosted) is not recommended for patients with prior virologic failure, a common problem for perinatally-infected adolescents. Atazanavir 400 mg once-daily provided suboptimal exposure. Higher unboosted doses or splitting the daily dose to twice-daily warrants investigation in this treatment-experienced population.


Assuntos
Sulfato de Atazanavir/farmacocinética , Infecções por HIV/tratamento farmacológico , Adolescente , Adulto , Sulfato de Atazanavir/administração & dosagem , Sulfato de Atazanavir/sangue , Sulfato de Atazanavir/uso terapêutico , Criança , Humanos , Estudos Prospectivos , Adulto Jovem
18.
J Pediatric Infect Dis Soc ; 5(2): 131-7, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27199469

RESUMO

BACKGROUND: Limited data are available for once-daily (QD) darunavir (DRV)/ritonavir (r) in the pediatric population. Coadministration of etravirine (ETR) may alter the pharmacokinetics (PK) of DRV. We evaluated the PK interactions between DRV/r (QD) and ETR QD or twice-daily (BID) in children, adolescents, and young adults. METHODS: Human immunodeficiency virus-infected subjects 9 to < 24 years old on optimized background therapy including DRV/r 800/100 mg QD alone or combined with ETR 200 mg BID or ETR 400 mg QD were enrolled. Protocol-defined target drug exposure ranges based on adult data were used to assess the adequacy of each regimen. Intensive 24-hour blood sampling was performed, and PK parameters were determined using noncompartmental analysis. RESULTS: Thirty-one subjects (14 males) completed the study; 16 received DRV/r QD alone (group 1), 6 received DRV/r plus ETR BID (group 2A), and 9 received DRV/r plus ETR QD (group 2B). The geometric mean (90% confidence interval [CI] geometric mean) for DRV area under the curve at 24 hours (AUC24) was 57.9 (49.6-67.6), 74.9 (44.4-126.5), and 66.4 (50.8-86.9) mg × h/L for patients in groups 1, 2A, and 2B, respectively. The increased DRV exposure when coadministered with ETR was not statistically significant. The geometric mean (90% CI geometric mean) of ETR AUC24 was 8.6 (4.4-16.8) and 11.9 (7.5-18.9) mg × h/L for groups 2A and 2B, respectively, with comparable C24. CONCLUSIONS: The results suggest that DRV/r QD with ETR 400 mg QD or 200 mg BID is appropriate and support further evaluation of the safety and efficacy of the once-daily regimen in older children, adolescents, and young adults.


Assuntos
Fármacos Anti-HIV/farmacocinética , Darunavir/farmacocinética , Infecções por HIV/tratamento farmacológico , Piridazinas/administração & dosagem , Ritonavir/farmacocinética , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Criança , Darunavir/administração & dosagem , Feminino , Humanos , Masculino , Ritonavir/administração & dosagem , Sulfonamidas , Adulto Jovem
19.
Pediatr Infect Dis J ; 35(9): e271-4, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27187753

RESUMO

BACKGROUND: Rilpivirine (RPV), a recently developed, once daily human immunodeficiency virus non-nucleoside reverse transcriptase inhibitor, is not currently approved for pediatric patients, but is sometimes prescribed for adolescents with multiple treatment failures, for regimen simplification or to minimize toxicity. Darunavir/ritonavir (DRV/r) administered once daily is also increasingly used in adolescents and may alter RPV pharmacokinetics (PK). We evaluated the PK interactions between RPV and DRV/r once daily in adolescents and young adults. METHODS: Human immunodeficiency virus-infected subjects 12 to <24 years old receiving a stable background therapy including RPV 25 mg once daily without or combined with DRV/r 800/100 mg once daily were enrolled. Intensive 24-hour blood sampling was performed, and PK indices were determined using noncompartmental analysis. Protocol-defined target drug exposure ranges based on adult data were used to assess the adequacy of each regimen. RESULTS: Fifteen subjects receiving RPV without and 14 subjects with DRV/r were enrolled. When dosed without DRV/r, the RPV geometric mean (90% confidence interval) for RPV AUC0-24, Cmax and C24 h were 2.38 µg h/mL (1.92-2.94), 0.14 µg/mL (0.12-0.18) and 0.07 µg/mL (0.03-0.10), respectively, similar to adult values. RPV concentrations were significantly increased with concomitant DRV/r use: RPV AUC24, Cmax and C24 h were 6.74 µg h/mL (4.89-9.28), 0.39 µg/mL (0.27-0.57) and 0.23 µg/mL (0.17-0.32), respectively, well above the target ranges based on adult data. DRV/r PK was not affected by coadministration of RPV. CONCLUSIONS: RPV PK in this adolescent population was similar to adults when dosed without DRV/r. DRV/r coadministration increased RPV exposure 2- to 3-fold, indicating that drug-related side effects should be closely monitored.


Assuntos
Fármacos Anti-HIV , Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Rilpivirina , Ritonavir/uso terapêutico , Adolescente , Adulto , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Criança , Interações de Medicamentos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Rilpivirina/sangue , Rilpivirina/farmacocinética , Rilpivirina/uso terapêutico , Adulto Jovem
20.
Clin Infect Dis ; 62(6): 761-769, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26658057

RESUMO

Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population.


Assuntos
Antituberculosos/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Tuberculose Latente/tratamento farmacológico , Período Pós-Parto , Tuberculose Resistente a Múltiplos Medicamentos/prevenção & controle , Tuberculose/tratamento farmacológico , Tuberculose/prevenção & controle , Adulto , Antituberculosos/farmacocinética , Ensaios Clínicos como Assunto/ética , Ensaios Clínicos como Assunto/legislação & jurisprudência , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Tuberculose Latente/sangue , Tuberculose Latente/microbiologia , Gravidez , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Estados Unidos
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