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1.
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
2.
J Acquir Immune Defic Syndr ; 82(4): 377-385, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31567725

RESUMO

BACKGROUND: Effects of prolonged nevirapine prophylaxis exposure on growth among HIV-exposed uninfected (HEU) infants are unknown. This study examines the impact of extended nevirapine prophylaxis from 6 weeks to 6 months on the growth of HEU infants followed for 18 months and also identifies correlates of incident wasting, stunting, underweight, and low head circumference in the HPTN 046 trial. METHODS: Intention-to-treat analysis examined the effect of extended nevirapine exposure on: weight-for-age Z-score, length-for-age Z-score, weight-for-length Z-score, and head circumference-for-age Z-score. Multivariable linear mixed-effects and Cox proportional hazard models were used to compare growth outcomes between the study arms and identify correlates of incident adverse growth outcomes, respectively. RESULTS: Compared to placebo, extended prophylactic nevirapine given daily from 6 weeks to 6 months did not affect growth in HEU breastfeeding (BF) infants over time (treatment × time: P > 0.05). However, overall growth declined over time (time effect: P < 0.01) when compared with WHO general population norms. Male sex was associated with higher risk of all adverse growth outcomes (P < 0.05), whereas short BF duration was associated with wasting (P = 0.03). Maternal antiretroviral therapy exposure was protective against underweight (P = 0.02). Zimbabwe tended to have worse growth outcomes especially stunting, compared to South Africa, Uganda and Tanzania (P < 0.05). CONCLUSIONS: It is reassuring that prolonged exposure to nevirapine for prevention-of-mother-to-child HIV transmission does not restrict growth. However, targeted interventions are needed to improve growth outcomes among at-risk HEU infants (i.e., male sex, short BF duration, lack of maternal antiretroviral therapy exposure, and resident in Zimbabwe).

3.
Clin Infect Dis ; 66(11): 1668-1677, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29272387

RESUMO

Background: Human immunodeficiency virus (HIV)-infected pregnant women increasingly receive antiretroviral therapy (ART) to prevent mother-to-child transmission (PMTCT). Studies suggest HIV-exposed uninfected (HEU) children face higher mortality than HIV-unexposed children, but most evidence relates to the pre-ART era, breastfeeding of limited duration, and considerable maternal mortality. Maternal ART and prolonged breastfeeding while on ART may improve survival, although this has not been reliably quantified. Methods: Individual data on 19 219 HEU children from 21 PMTCT trials/cohorts undertaken from 1995 to 2015 in Africa and Asia were pooled to estimate the association between 24-month mortality and maternal/infant factors, using random-effects Cox proportional hazards models. Adjusted attributable fractions of risks computed using the predict function in the R package "frailtypack" were used to estimate the relative contribution of risk factors to overall mortality. Results: Cumulative incidence of death was 5.5% (95% confidence interval, 5.1-5.9) by age 24 months. Low birth weight (LBW <2500 g, adjusted hazard ratio (aHR, 2.9), no breastfeeding (aHR, 2.5), and maternal death (aHR, 11.1) were significantly associated with increased mortality. Maternal ART (aHR, 0.5) was significantly associated with lower mortality. At the population level, LBW accounted for 16.2% of 24-month mortality, never breastfeeding for 10.8%, mother not receiving ART for 45.6%, and maternal death for 4.3%; combined, these factors explained 63.6% of deaths by age 24 months. Conclusions: Survival of HEU children could be substantially improved if public health practices provided all HIV-infected mothers with ART and supported optimal infant feeding and care for LBW neonates.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Aleitamento Materno , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Adolescente , Adulto , África , Ásia , Mortalidade da Criança , Pré-Escolar , Feminino , HIV-1 , Humanos , Lactente , Masculino , Adulto Jovem
4.
J Infect Dis ; 215(3): 368-377, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27932619

RESUMO

Background: Among infants exposed to human immunodeficiency virus (HIV) type 1, mixed breastfeeding is associated with higher postnatal HIV-1 transmission than exclusive breastfeeding, but the mechanisms of this differential risk are uncertain. Methods: HIV-1-exposed Ugandan infants were prospectively assessed during the first year of life for feeding practices and T-cell maturation, intestinal homing (ß7hi), activation, and HIV-1 coreceptor (CCR5) expression in peripheral blood. Infants receiving only breast milk and those with introduction of other foods before 6 months were categorized as exclusive and nonexclusive, respectively. Results: Among CD4+ and CD8+ T cells, the expression of memory, activation, and CCR5 markers increased rapidly from birth to week 2, peaking at week 6, whereas cells expressing the intestinal homing marker increased steadily in the central memory (CM) and effector memory T cells over 48 weeks. At 24 weeks, when feeding practices had diverged, nonexclusively breastfed infants showed increased frequencies and absolute counts of ß7hi CM CD4+ and CD8+ T cells, including the HIV-1-targeted cells with CD4+ß7hi/CCR5+ coexpression, as well as increased activation. Conclusions: The T-cell phenotype associated with susceptibility to HIV-1 infection (CCR5+, gut-homing, CM CD4+ T cells) was preferentially expressed in nonexclusively breastfed infants, a group of infants at increased risk for HIV-1 acquisition.


Assuntos
Aleitamento Materno/efeitos adversos , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Adolescente , Adulto , Linfócitos T CD4-Positivos/imunologia , Movimento Celular , Suscetibilidade a Doenças , Feminino , Infecções por HIV/transmissão , Humanos , Memória Imunológica , Lactente , Recém-Nascido , Intestinos/imunologia , Ativação Linfocitária , Linfopoese , Mães , Fenótipo , Estudos Prospectivos , Receptores CCR5/biossíntese , Uganda , Adulto Jovem
5.
Pediatr Infect Dis J ; 36(1): 36-43, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27749648

RESUMO

BACKGROUND: The objective of this analysis was to assess the cost-effectiveness of TB diagnosis using microscopic observation drug susceptibility (MODS), Xpert MTB/RIF (Xpert) and empiric treatment for all patients, in addition to current clinical diagnostic practices in children less than 5 years of age in a national tuberculosis (TB) referral hospital in Uganda. METHODS: A decision analysis was conducted from the healthcare perspective, with a primary outcome of incremental cost-effectiveness expressed as cost per year of life gained (YLG). RESULTS: Cost-effectiveness of the algorithms depended strongly on 3 variables: the prevalence of TB, probability of death if TB was untreated and accuracy of existing diagnostic algorithms. Xpert and MODS had similar cost-effectiveness profiles and were preferred in settings where the prevalence of TB and probability of death from untreated TB were low. As the underlying probability of TB disease and death increased, treating all children with clinically suspected disease became more cost-effective. In settings where the probability that an untreated child will die of TB-whether a result of high prevalence of TB or high mortality from untreated TB-treating all children for TB is likely to be the most cost-effective approach until better diagnostic tests can be developed. CONCLUSIONS: The cost-effectiveness of diagnostic tools for TB in children depends on the population, natural history of untreated TB and existing diagnostic practices. In settings where the risk of TB death is high, empiric treatment of all children for TB should be considered until a more sensitive, low-cost diagnostic test is available.


Assuntos
Tuberculose/diagnóstico , Tuberculose/economia , Algoritmos , Pré-Escolar , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Humanos , Lactente , Recém-Nascido , Uganda
6.
Clin Vaccine Immunol ; 21(12): 1661-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25298109

RESUMO

To determine whether immune function is impaired among HIV-exposed but -uninfected (HEU) infants born to HIV-infected mothers and to identify potential vulnerabilities to vaccine-preventable infection, we characterized the mother-to-infant placental transfer of Haemophilus influenzae type b-specific IgG (Hib-IgG) and its levels and avidity after vaccination in Ugandan HEU infants and in HIV-unexposed U.S. infants. Hib-IgG was measured by enzyme-linked immunosorbent assay in 57 Ugandan HIV-infected mothers prenatally and in their vaccinated HEU infants and 14 HIV-unexposed U.S. infants at birth and 12, 24, and 48 weeks of age. Antibody avidity at birth and 48 weeks of age was determined with 1 M ammonium thiocyanate. A median of 43% of maternal Hib-IgG was transferred to HEU infants. Although its level was lower in HEU infants than in U.S. infants at birth (P < 0.001), Hib-IgG was present at protective levels (>1.0 µg/ml) at birth in 90% of HEU infants and all U.S. infants. HEU infants had robust Hib-IgG responses to a primary vaccination. Although Hib-IgG levels declined from 24 to 48 weeks of age in HEU infants, they were higher than those in U.S. infants (P = 0.002). Antibody avidity, comparable at birth, declined by 48 weeks of age in both populations. Early vaccination of HEU infants may limit an initial vulnerability to Hib disease resulting from impaired transplacental antibody transfer. While initial Hib vaccine responses appeared adequate, the confluence of lower antibody avidity and declining Hib-IgG levels in HEU infants by 12 months support Hib booster vaccination at 1 year. Potential immunologic impairments of HEU infants should be considered in the development of vaccine platforms for populations with high maternal HIV prevalence.


Assuntos
Anticorpos Antibacterianos/sangue , Afinidade de Anticorpos/imunologia , Cápsulas Bacterianas/imunologia , Infecções por HIV/imunologia , Vacinas Anti-Haemophilus/imunologia , Haemophilus influenzae tipo b/imunologia , Complicações Infecciosas na Gravidez/imunologia , Adulto , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Troca Materno-Fetal , Gravidez , Vacinação , Vacinas Conjugadas
8.
J Acquir Immune Defic Syndr ; 58(4): 399-407, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21826009

RESUMO

BACKGROUND: This phase III, randomized, clinical trial compared single-dose nevirapine (sdNVP) plus HIV hyperimmune globulin (HIVIGLOB) with sdNVP alone for preventing maternal-to-child transmission of HIV. Primary objectives were to determine rates of HIV infection among infants and to assess the safety of HIVIGLOB in combination with sdNVP in HIV-infected Ugandan pregnant women and their infants. METHODS: Mother-infant pairs were randomized to receive 200 mg of nevirapine to women in labor and 2 mg/kg NVP to newborns within 72 hours after birth (sdNVP arm) or to receive sdNVP plus a single intravenous 240-mL dose of HIVIGLOB given to women at 36- to 38-week gestation and a single intravenous 24-mL dose to newborns within 18 hours of birth (HIVIGLOB/sdNVP arm). Risk of HIV infection was determined using Kaplan-Meier and risk ratio estimates at birth, 2, 6, 14 weeks, 6, and 12 months of age. RESULTS: Intent-to-treat analysis included 198 HIVIGLOB/sdNVP and 294 sdNVP mother-infant pairs. At 6 months of age, the primary endpoint, there was no statistically significant difference in HIV transmission in the HIVIGLOB/sdNVP arm vs. the sdNVP arm [18.7% vs. 15.0%; risk ratio = 1.240 (95% confidence interval: 0.833 to 1.846); P = 0.290]. Similarly, the proportion of serious adverse events in the HIVIGLOB/sdNVP and sdNVP arms, respectively, for mothers (18.9% vs. 19.3%; P = 0.91) and infants (62.6% vs. 59.5%; P = 0.51) was not significantly different. CONCLUSIONS: Giving mother-infant pairs an infusion of peripartum HIV hyperimmune globulin in addition to sdNVP for preventing maternal-to-child transmission was as safe as sdNVP alone but was no more effective than sdNVP alone in preventing HIV transmission.


Assuntos
Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , Imunoglobulinas Intravenosas/administração & dosagem , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Adolescente , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Humanos , Imunoglobulinas Intravenosas/efeitos adversos , Lactente , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/estatística & dados numéricos , Nevirapina/administração & dosagem , Nevirapina/efeitos adversos , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/prevenção & controle , Uganda/epidemiologia , Adulto Jovem
9.
J Acquir Immune Defic Syndr ; 53(1): 20-7, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19779355

RESUMO

Objective: To assess serious gastroenteritis risk and mortality associated with early cessation of breastfeeding in infants enrolled in 2 prevention of maternal-to-child HIV-transmission trials in Uganda.Methods: We used hazard rates to evaluate serious gastroenteritis events by month of age and mortality among HIV-exposed uninfected infants enrolled in the HIV Network for Prevention Trials (HIVNET 012) (1997­2001) and HIV hyperimmune globulin (HIVIGLOB)/nevirapine (NVP) (2004­2007) trials. HIV-infected mothers were counseled using local infant feeding guidelines current at the time.Results: Breastfeeding cessation occurred earlier in HIVIGLOB/NVP compared with HIVNET 012 (median 4.0 versus 9.3 months,P,0.001). Rates of serious gastroenteritis were higher in HIVIGLOB/NVP (8.0/1000 child-months) than in HIVNET 012 (3.1/1000 child-months; P , 0.001). Serious gastroenteritis events also peaked earlier at 3­4 and 7­8 months (16.2/1000 and 15.0/1000 child-months,respectively) compared with HIVNET 012 at 9­10 months (20.8/1000 child-months). All cause infant mortality did not statistically differ between the HIVIGLOB/NVP and the HIVNET 012 trials [3.2/1000 versus 2.0/1000 child-months, respectively (P = 0.10)].Conclusions: Early breastfeeding cessation seen in the HIVIGLOB/NVP trial was associated with increased risk of serious gastroenteritis among HIV-exposed uninfected infants when compared with later breastfeeding cessation in the HIVNET 012 trial.Testing interventions, which could decrease HIV transmission through breastfeeding and allow safe


Assuntos
Aleitamento Materno/efeitos adversos , Gastroenterite/etiologia , Gastroenterite/mortalidade , Infecções por HIV/prevenção & controle , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal , Desmame , Adulto , Feminino , Infecções por HIV/transmissão , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/etiologia , Doenças do Recém-Nascido/mortalidade , Masculino , Relações Mãe-Filho , Gravidez , Fatores de Tempo , Uganda , Adulto Jovem
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