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BACKGROUND: Pregnant people with COVID-19 experience higher risk for severe disease and adverse pregnancy outcomes, but no pharmacokinetic (PK) data exist to support dosing of COVID-19 therapeutics during pregnancy. We report PK and safety data for intravenous remdesivir in pregnancy. METHODS: IMPAACT 2032 was a phase IV prospective, open-label, non-randomized opportunistic study of hospitalized pregnant and non-pregnant women receiving intravenous remdesivir as part of clinical care. Intensive PK sampling was performed on infusion days 3, 4, or 5 with collection of plasma and peripheral blood mononuclear cells (PBMCs). Safety data were recorded from first infusion through 4 weeks post-last infusion and at delivery. Geometric mean ratios (GMR) (90% confidence intervals [CI]) of PK parameters between pregnant and non-pregnant women were calculated. RESULTS: Fifty-three participants initiated remdesivir (25 pregnant; median (IQR) gestational age 27.6 (24.9, 31.0) weeks). Plasma exposures of remdesivir, its two major metabolites (GS-704277 and GS-441524), and the free remdesivir fraction were similar between pregnant and non-pregnant participants. Concentrations of the active triphosphate (GS-443902) in PBMCs increased 2.04-fold (90% CI 1.35, 3.03) with each additional infusion in non-pregnant versus pregnant participants. Three adverse events in non-pregnant participants were related to treatment (one Grade 3; two Grade 2 resulting in treatment discontinuation). There were no treatment-related adverse pregnancy outcomes or congenital anomalies detected. CONCLUSIONS: Plasma remdesivir PK parameters were comparable between pregnant and non-pregnant women, and no safety concerns were identified based on our limited data. These findings suggest no dose adjustments are indicated for intravenous remdesivir during pregnancy.
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Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.
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Antituberculosos , Tuberculose , Adolescente , Feminino , Humanos , Gravidez , Antituberculosos/efeitos adversos , Antituberculosos/farmacocinética , Etambutol/efeitos adversos , Etambutol/farmacocinética , Infecções por HIV/tratamento farmacológico , Isoniazida/efeitos adversos , Isoniazida/farmacocinética , Período Pós-Parto , Estudos Prospectivos , Pirazinamida/efeitos adversos , Pirazinamida/farmacocinética , Rifampina/efeitos adversos , Rifampina/farmacocinética , Tuberculose/tratamento farmacológico , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase IV como Assunto , Estudos Observacionais como AssuntoRESUMO
BACKGROUND: To evaluate the frequency and associated characteristics of chronic comorbid conditions and obstetrical complications among pregnant women with human immunodeficiency virus (HIV) and receiving antiretroviral therapy (ART) in comparison to those without HIV. METHODS: We compared 2 independent concurrent US pregnancy cohorts: (1) with HIV (International Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1025, 2002-2013) and (2) without HIV (Consortium for Safe Labor Study, 2002-2007). Outcomes were ≥2 chronic comorbid conditions and obstetrical complications. For women with HIV, we assessed whether late prenatal care (≥14 weeks), starting ART in an earlier era (2002-2008), and a detectable viral load at delivery (≥400 copies/mL) were associated with study outcomes. RESULTS: We assessed 2868 deliveries (nâ =â 2574 women) with HIV and receiving ART and 211â 910 deliveries (nâ =â 193â 170 women) without HIV. Women with HIV were more likely to have ≥2 chronic comorbid conditions versus those without HIV (10 vs 3%; adjusted OR [AOR]: 2.96; 95% CI: 2.58-3.41). Women with HIV were slightly less likely to have obstetrical complications versus those without HIV (both 17%; AOR: .84; 95% CI: .75-.94), but secondarily, higher odds of preterm birth <37 weeks. Late entry to prenatal care and starting ART in an earlier era were associated with a lower likelihood of ≥2 chronic comorbidities and obstetrical complications; detectable viral load at delivery was associated with a higher likelihood of obstetric complications. CONCLUSIONS: Pregnant women with HIV receiving ART have more chronic comorbid conditions, but not necessarily obstetrical complications, than their peers without HIV.
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Fármacos Anti-HIV , Infecções por HIV , Complicações Infecciosas na Gravidez , Nascimento Prematuro , Fármacos Anti-HIV/efeitos adversos , Feminino , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/epidemiologia , Gestantes , Estados Unidos/epidemiologia , Carga ViralRESUMO
BACKGROUND: In a previous trial of antiretroviral therapy (ART) involving pregnant women with human immunodeficiency virus (HIV) infection, those randomly assigned to receive tenofovir, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r) had infants at greater risk for very premature birth and death within 14 days after delivery than those assigned to receive zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV-3TC-LPV/r). METHODS: Using data from two U.S.-based cohort studies, we compared the risk of adverse birth outcomes among infants with in utero exposure to ZDV-3TC-LPV/r, TDF-FTC-LPV/r, or TDF-FTC with ritonavir-boosted atazanavir (ATV/r). We evaluated the risk of preterm birth (<37 completed weeks of gestation), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and very low birth weight (<1500 g). Risk ratios with 95% confidence intervals were estimated with the use of modified Poisson models to adjust for confounding. RESULTS: There were 4646 birth outcomes. Few infants or fetuses were exposed to TDF-FTC-LPV/r (128 [2.8%]) as the initial ART regimen during gestation, in contrast with TDF-FTC-ATV/r (539 [11.6%]) and ZDV-3TC-LPV/r (954 [20.5%]). As compared with women receiving ZDV-3TC-LPV/r, women receiving TDF-FTC-LPV/r had a similar risk of preterm birth (risk ratio, 0.90; 95% confidence interval [CI], 0.60 to 1.33) and low birth weight (risk ratio, 1.13; 95% CI, 0.78 to 1.64). As compared to women receiving TDF-FTC-ATV/r, women receiving TDF-FTC-LPV/r had a similar or slightly higher risk of preterm birth (risk ratio, 1.14; 95% CI, 0.75 to 1.72) and low birth weight (risk ratio, 1.45; 95% CI, 0.96 to 2.17). There were no significant differences between regimens in the risk of very preterm birth or very low birth weight. CONCLUSIONS: The risk of adverse birth outcomes was not higher with TDF-FTC-LPV/r than with ZDV-3TC-LPV/r or TDF-FTC-ATV/r among HIV-infected women and their infants in the United States, although power was limited for some comparisons. (Funded by the National Institutes of Health and others.).
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Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Recém-Nascido de Baixo Peso , Complicações Infecciosas na Gravidez/tratamento farmacológico , Resultado da Gravidez , Nascimento Prematuro/epidemiologia , Tenofovir/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Estudos de Coortes , Transmissão de Doença Infecciosa/prevenção & controle , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Emtricitabina/efeitos adversos , Feminino , Humanos , Recém-Nascido , Lamivudina/uso terapêutico , Lopinavir/efeitos adversos , Lopinavir/uso terapêutico , Gravidez , Risco , Ritonavir/uso terapêutico , Tenofovir/efeitos adversos , Zidovudina/uso terapêuticoRESUMO
The purpose of this study was to evaluate the pharmacokinetics of ritonavir-boosted fosamprenavir during pregnancy and postpartum. Amprenavir (the active moiety of fosamprenavir) and ritonavir intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy and postpartum. Plasma concentrations of amprenavir and ritonavir were measured using high-performance liquid chromatography. The target amprenavir area under the concentration-versus-time curve (AUC) was higher than the 10th percentile (27.7 µg · h/ml) of the median area under the curve for ritonavir-boosted fosamprenavir in adults receiving twice-daily fosamprenavir-ritonavir at 700 mg/100 mg. Twenty-nine women were included in the analysis. The amprenavir AUC from time zero to 12 h (AUC0-12) was lower (geometric mean ratio [GMR], 0.60 [confidence interval {CI}, 0.49 to 0.72] [P < 0.001]) while its apparent oral clearance was higher (GMR, 1.68 [CI, 1.38 to 2.03] [P < 0.001]) in the third trimester than postpartum. Similarly, the ritonavir AUC0-12 was lower in the second (GMR, 0.51 [CI, 0.28 to 0.91] [P = 0.09]) and third (GMR, 0.72 [CI, 0.55 to 0.95] [P = 0.005]) trimesters than postpartum, while its apparent oral clearance was higher in the second (GMR, 1.98 [CI, 1.10 to 3.56] [P = 0.06]) and third (GMR, 1.38 [CI, 1.05 to 1.82] [P = 0.009]) trimesters than postpartum. The amprenavir area under the curve exceeded the target for 6/8 (75%) women in the 2nd trimester, 18/28 (64%) in the 3rd trimester, and 19/22 (86.4%) postpartum, and the trough concentrations (Cmin) of amprenavir were 4- to 16-fold above the mean amprenavir-protein-adjusted 50% inhibitory concentration (IC50) of 0.146 µg/ml. Although amprenavir plasma concentrations in women receiving ritonavir-boosted fosamprenavir were lower during pregnancy than postpartum, the reduced amprenavir concentrations were still above the exposures needed for viral suppression.
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Carbamatos/farmacocinética , Furanos/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Complicações Infecciosas na Gravidez/tratamento farmacológico , Ritonavir/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Área Sob a Curva , Carbamatos/efeitos adversos , Feminino , Furanos/efeitos adversos , Inibidores da Protease de HIV/efeitos adversos , Humanos , Idade Materna , Gravidez , Trimestres da Gravidez , RNA Viral/sangue , Ritonavir/efeitos adversos , Sulfonamidas/efeitos adversos , Carga ViralRESUMO
BACKGROUND: We describe enrollment and accrual challenges in the "Promoting Maternal and Infant Survival Everywhere" (PROMISE) trial conducted in resource-limited countries, as well as the challenges in transitioning participants from the antepartum to the postpartum components of the study. METHODS: PROMISE was a large multi-national randomized controlled trial of the safety and efficacy of interventions to reduce perinatal transmission of HIV-1 (HIV) during pregnancy and breastfeeding and of interventions to preserve maternal health after cessation of perinatal transmission risk. The PROMISE study included two protocols for HIV-infected pregnant women in resource-limited countries who intended to either breastfeed or formula-feed their infants and did not meet country criteria for antiretroviral treatment. The PROMISE breastfeeding protocol (1077BF) used a sequential randomization design with up to three randomizations (Antepartum, Postpartum, and Maternal Health). The PROMISE formula-feeding protocol (1077FF) had two randomizations (Antepartum and Maternal Health). Women presenting to the clinic during early or active labor or in the immediate postpartum period were registered as Late Presenters and screened to determine whether eligible to participate in the Postpartum randomization. RESULTS: The study was conducted at 14 sites in seven countries and opened to enrollment in April 2011. A total of 3259 pregnant women intending to breastfeed and an additional 284 pregnant women intending to formula feed were randomized in the Antepartum component. A total of 204 Late Presenters were registered during labor or after delivery. Enrollment was high among breastfeeding women (representing 96% of the target of 3400 women) but was lower than expected among women intending to formula feed (28% of 1000 expected) and late-presenting women (8% of 2500 expected). The successful overall enrollment and final primary study analyses results were attributed to substantial preparation before the study opened, collaboration among all stakeholders, close study monitoring during implementation and the flexibility to change and streamline the protocol. CONCLUSIONS: Experiences from the PROMISE study illustrate the challenges of enrolling in longer term studies in the setting of rapidly evolving prevention and treatment standards priorities. The lessons learned will help the community, site investigators, and study coordinators in the design and implementation of future clinical trials.
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Aleitamento Materno/métodos , Infecções por HIV/transmissão , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adolescente , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Criança , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Recursos em Saúde , Humanos , Lactente , Fórmulas Infantis , Recém-Nascido , Masculino , Mães , Gravidez , Complicações Infecciosas na Gravidez/virologia , Projetos de PesquisaRESUMO
BACKGROUND: Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS: We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS: The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS: Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).
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Antirretrovirais/uso terapêutico , Infecções por HIV/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Zidovudina/uso terapêutico , Adulto , Negro ou Afro-Americano , Antirretrovirais/efeitos adversos , Contagem de Linfócito CD4 , Quimioterapia Combinada , Feminino , Idade Gestacional , Infecções por HIV/etnologia , Infecções por HIV/transmissão , Humanos , Lactente , Mortalidade Infantil , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Nevirapina/administração & dosagem , Assistência Perinatal , Gravidez , Resultado da Gravidez , Tenofovir/uso terapêutico , Adulto Jovem , Zidovudina/efeitos adversosRESUMO
BACKGROUND: A high delivery maternal plasma HIV-1 RNA level (viral load [VL]) is a risk factor for mother-to-child transmission and poor maternal health. OBJECTIVE: To identify factors associated with detectable VL at delivery despite initiation of highly active antiretroviral therapy (HAART) during pregnancy. DESIGN: Multicenter observational study. (ClinicalTrial.gov: NCT00028145). SETTING: 67 U.S. AIDS clinical research sites. PATIENTS: Pregnant women with HIV who initiated HAART during pregnancy. MEASUREMENTS: Descriptive summaries and associations among sociodemographic, HIV disease, and treatment characteristics; pregnancy-related risk factors; and detectable VL (>400 copies/mL) at delivery. RESULTS: Between 2002 and 2011, 671 women met inclusion criteria and 13.1% had detectable VL at delivery. Factors associated with detectable VL included multiparity (16.4% vs. 8.0% nulliparity; P = 0.002), black ethnicity (17.6% vs. 6.6% Hispanic and 6.6% white; P < 0.001), 11th grade education or less (17.6% vs. 12.1% had a high school diploma; P = 0.013), initiation of HAART in the third trimester (23.9% vs. 12.3% and 8.6% in the second and trimesters, respectively; P = 0.003), having an HIV diagnosis before the current pregnancy (16.1% vs. 11.0% during the current pregnancy; P = 0.051), and having the first prenatal visit in the third trimester (33.3% vs. 14.3% and 10.5% in the second and third trimesters, respectively; P = 0.002). Women who had treatment interruptions or reported poor medication adherence were more likely to have detectable VL at delivery. LIMITATION: Data on many covariates were incomplete because women entered the study at varying times during pregnancy. CONCLUSION: A total of 13.1% of women who initiated HAART during pregnancy had detectable VL at delivery. The timing of HAART initiation and prenatal care, along with medication adherence during pregnancy, were associated with detectable VL at delivery. Social factors, including ethnicity and education, may help identify women who could benefit from focused efforts to promote early HAART initiation and adherence. PRIMARY FUNDING SOURCE: U.S. Department of Health and Human Services.
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Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Carga Viral , Adolescente , Adulto , Escolaridade , Feminino , Infecções por HIV/etnologia , HIV-1/genética , Humanos , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Adesão à Medicação , Paridade , Gravidez , Complicações Infecciosas na Gravidez/etnologia , Terceiro Trimestre da Gravidez , Cuidado Pré-Natal , RNA Viral/sangue , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
AIM: To describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period. METHODS: IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100 mg twice daily during pregnancy through to 6-12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks post-partum. PK targets were the estimated 10(th) percentile IDV AUC (12.9 µg ml(-1)h) in non-pregnant historical Thai adults and a trough concentration of 0.1 µg ml(-1), the suggested minimum target. RESULTS: Twenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12 h) and Cmax during the second trimester and post-partum (ante : post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12 h) and Cmax ratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml(-1) at delivery. All 26 infants were confirmed HIV negative. CONCLUSION: Indinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and â¼30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100 mg twice daily may be preferable to ensure adequate drug concentrations.
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Infecções por HIV/metabolismo , Inibidores da Protease de HIV/farmacocinética , Indinavir/farmacocinética , Complicações Infecciosas na Gravidez/metabolismo , Ritonavir/farmacocinética , Adolescente , Adulto , Terapia Antirretroviral de Alta Atividade , Relação Dose-Resposta a Droga , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/uso terapêutico , Humanos , Indinavir/administração & dosagem , Indinavir/sangue , Indinavir/uso terapêutico , Lactente , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Período Pós-Parto , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Ritonavir/administração & dosagem , Ritonavir/sangue , Ritonavir/uso terapêutico , Adulto JovemRESUMO
Confirming the diagnosis of childhood tuberculosis is a major challenge. However, research on childhood tuberculosis as it relates to better diagnostics is often neglected because of technical difficulties, such as the slow growth in culture, the difficulty of obtaining specimens, and the diverse and relatively nonspecific clinical presentation of tuberculosis in this age group. Researchers often use individually designed criteria for enrollment, diagnostic classifications, and reference standards, thereby hindering the interpretation and comparability of their findings. The development of standardized research approaches and definitions is therefore needed to strengthen the evaluation of new diagnostics for detection and confirmation of tuberculosis in children. In this article we present consensus statements on methodological issues for conducting research of Tuberculosis diagnostics among children, with a focus on intrathoracic tuberculosis. The statements are complementary to a clinical research case definition presented in an accompanying publication and suggest a phased approach to diagnostics evaluation; entry criteria for enrollment; methods for classification of disease certainty, including the rational use of culture within the case definition; age categories and comorbidities for reporting results; and the need to use standard operating procedures. Special consideration is given to the performance of microbiological culture in children and we also recommend for alternative methodological approaches to report findings in a standardized manner to overcome these limitations are made. This consensus statement is an important step toward ensuring greater rigor and comparability of pediatric tuberculosis diagnostic research, with the aim of realizing the full potential of better tests for children.
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Projetos de Pesquisa , Tuberculose Pulmonar/diagnóstico , Adolescente , Antituberculosos/uso terapêutico , Técnicas Bacteriológicas/tendências , Criança , Pré-Escolar , Humanos , Lactente , Padrões de Referência , Tuberculose Pulmonar/tratamento farmacológicoRESUMO
INTRODUCTION: Optimal adherence to antiretroviral therapy (ART) is crucial to promoting maternal-infant health. SETTING: Fourteen sites in 7 countries within sub-Saharan Africa and India. METHODS: The multicomponent, open-label strategy PROMISE trial enrolled breastfeeding mother-infant pairs not meeting in-country criteria for maternal ART (mART) initiation in the postpartum component within 5 days of delivery. Randomization was to mART versus infant NVP (iNVP) prophylaxis. Infants in the mART arm also received 6 weeks of iNVP. Self-reported adherence was assessed in a secondary analysis. Time-to-event analyses were performed to explore the association between adherence and maternal viral load (mVL) in the mART arm. RESULTS: Two thousand four hundred thirty-one mother-infant pairs were enrolled between 2011 and 2014; the baseline maternal median CD4 was 686 (IQR 553-869), and the median mVL was 322 copies/mL (IQR 40-1422). Self-reported adherence was lower in the mART arm compared with the iNVP arm (no missed doses within 4 weeks of all study visits: 66% vs 83%; within 2 weeks: 71% vs 85%; P < 0.0001). The iNVP adherence at week 6 was high in both arms: 97% in mART arm; 95% in iNVP arm. Time-to-event analyses showed that adherence to mART was associated with time to first mVL ≥400 copies/mL ( P < 0.0001). Missing 1 full day of doses over 3 days was associated with a 66% risk of mVL ≥1000 copies/mL (HR: 1.66; 95% CI: 1.37, 1.99). CONCLUSIONS: Postpartum women were less adherent to their own ART than mothers providing their infant's nevirapine prophylaxis. The self-reported missed mART doses were associated with high mVL. Strategies to optimize postpartum mART adherence are urgently needed. CLINICAL TRIAL NUMBER: ClinicalTrials.gov: NCT01061151; closed to follow-up.
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Infecções por HIV , HIV-1 , Feminino , Lactente , Humanos , Carga Viral , Autorrelato , Infecções por HIV/tratamento farmacológico , Mães , África SubsaarianaRESUMO
BACKGROUND: Intrapartum single-dose (SD) nevirapine (NVP) reduces perinatal transmission of human immunodeficiency virus (HIV) infection but selects for NVP-resistant virus, which compromises subsequent NVP-based therapy. A 1-week "tail" of lamivudine and zidovudine after SD-NVP decreases the risk of resistance. We hypothesized that increasing the duration or potency of the tail would further reduce this risk to <10%, using a sensitive assay to measure resistance. METHODS: HIV-infected pregnant Thai women with a CD4 cell count >250 cells/µL, most receiving zidovudine, were randomized at 28-38 weeks gestation to receive 1 of 3 intrapartum and postpartum regimens: (A) zidovudine plus enteric-coated didanosine plus lopinavir and ritonavir for 7 days, (B) zidovudine plus enteric-coated didanosine for 30 days, or (C) regimen 1 for 30 days. The incidence of NVP resistance mutations at day 10 or week 6 post partum in each arm was compared with that of a historical comparison group who received prenatal zidovudine and SD-NVP. NVP resistance was identified by consensus sequencing and a sensitive oligonucleotide ligation assay (OLA). RESULTS: At entry, the 169 participants had a median CD4 cell count of 456 cells/µL and an HIV load of 3.49 log(10) copies/mL. The incidence of mutations in each of the 3 P1032 arms was 0% by sequencing and 1.8%, 7.1%, and 5.3% by OLA in arms A, B, and C, respectively, compared with 13.4% by sequencing and 29.4% by OLA in the comparison group (P < .001 for each study arm vs comparison group). Grade 4 anemia developed in 1 woman. CONCLUSIONS: A 7-day tail of highly active combination therapy or 1 month of dual therapy after SD-NVP prevents most NVP resistance to minimal toxicity. CLINICAL TRIALS REGISTRATION: The IMPAACT P1032 Clinical Trial is NCT00109590, and the PHPT-2 Clinical Trial is NCT00398684.
Assuntos
Infecções por HIV/tratamento farmacológico , HIV/genética , Mutação , Nevirapina/administração & dosagem , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Esquema de Medicação , Farmacorresistência Viral/genética , Feminino , HIV/efeitos dos fármacos , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Pessoa de Meia-Idade , Gravidez , Complicações Infecciosas na Gravidez/virologia , Resultado do Tratamento , Carga Viral , Zidovudina/administração & dosagemRESUMO
OBJECTIVE: To assess in ART-naïve pregnant women randomized to efavirenz- versus raltegravir-based ART (IMPAACT P1081) whether pretreatment drug resistance (PDR) with minority frequency variants (<20% of individual's viral quasispecies) affects antiretroviral treatment (ART)-suppression at term. DESIGN: A case-control study design compared PDR minority variants in cases with virologic non-suppression (plasma HIV RNA >200 copies/mL) at delivery to randomly selected ART-suppressed controls. METHODS: HIV pol genotypes were derived from pretreatment plasma specimens by Illumina sequencing. Resistance mutations were assessed using the HIV Stanford Database, and the proportion of cases versus controls with PDR to their ART regimens was compared. RESULTS: PDR was observed in 7 participants (11.3%; 95% CI 4.7, 21.9) and did not differ between 21 cases and 41 controls (4.8% vs 14.6%, p = 0.4061). PDR detected only as minority variants was less common (3.2%; 95% CI 0.2, 11.7) and also did not differ between groups (0% vs. 4.9%; p = 0.5447). Cases' median plasma HIV RNA at delivery was 347c/mL, with most (n = 19/22) showing progressive diminution of viral load but not ≤200c/mL. Among cases with viral rebound (n = 3/22), none had PDR detected. Virologic non-suppression at term was associated with higher plasma HIV RNA at study entry (p<0.0001), a shorter duration of ART prior to delivery (p<0.0001), and randomization to efavirenz- (versus raltegravir-) based ART (p = 0.0085). CONCLUSIONS: We observed a moderate frequency of PDR that did not significantly contribute to virologic non-suppression at term. Rather, higher pretreatment plasma HIV RNA, randomization to efavirenz-based ART, and shorter duration of ART were associated with non-suppression. These findings support early prenatal care engagement of pregnant women and initiation of integrase inhibitor-based ART due to its association with more rapid suppression of plasma RNA levels. Furthermore, because minority variants appeared infrequent in ART-naïve pregnant women and inconsequential to ART-suppression, testing for minority variants may be unwarranted.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Inibidores de Integrase de HIV , HIV-1 , Alcinos , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Benzoxazinas , Estudos de Casos e Controles , Ciclopropanos , Farmacorresistência Viral/genética , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/genética , Humanos , Preparações Farmacêuticas , Gravidez , Gestantes , RNA , Raltegravir Potássico/uso terapêutico , Carga ViralRESUMO
BACKGROUND: Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081 compared antepartum changes in weight and body mass index (BMI) in pregnant women initiating raltegravir- or efavirenz-based combined antiretroviral therapy (cART) and examined associations between rates of weight gain and APOs. SETTING: NICHD P1081 enrolled antiretroviral-naive pregnant women living with HIV in the second and third trimester in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States. METHODS: Two hundred eighty-one women enrolled between 20 and 31 gestational weeks were randomized to raltegravir- or efavirenz-based cART and followed for ≥4 weeks. A low rate of weight gain was defined as <0.18 kg/wk and high as >0.59 kg/wk. We compared weight gain and BMI increase between treatment arms using Kruskal-Wallis tests. Logistic regression was used to investigate the association between weight gain and APOs. RESULTS: Raltegravir-based cART was associated with significantly higher antepartum weight gain (median 0.36 kg/wk versus 0.29 kg/wk, P = 0.01) and BMI increase (median 0.14 kg/m 2 /wk versus 0.11 kg/m 2 /wk, P = 0.01) compared with efavirenz-based treatment. Women on raltegravir had less low weight gain (18% versus 36%) and more high weight gain (21% versus 12%) ( P = 0.001). Women with low weight gain were more likely than those with normal weight gain to have small for gestational age infants or a composite of APOs. CONCLUSIONS: A raltegravir-based antiretroviral regimen was associated with significantly higher antepartum rate of weight gain and BMI increase compared with efavirenz-based treatment in antiretroviral-naive pregnant women.
Assuntos
Infecções por HIV , National Institute of Child Health and Human Development (U.S.) , Feminino , Gravidez , Humanos , Estados Unidos , Raltegravir Potássico/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase , Aumento de PesoRESUMO
BACKGROUND: Studies suggest that manualized, measurement-guided, depression treatment is more efficacious than usual care but impact can wane. Our study among youth with HIV (YWH), aged 12-24 years at US clinical research sites in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, found a significant reduction in depressive symptoms among YWH who received a manualized, measurement-guided treatment. This paper reports outcomes up to 24 weeks after the intervention. METHODS: Eligibility included diagnosis of ongoing nonpsychotic depression. Using restricted randomization, sites were assigned to either combination cognitive behavioral therapy and medication management algorithm tailored for YWH or to enhanced standard of care, which provided psychotherapy and medication management. Site-level mean Quick Inventory for Depression Symptomatology Self-Report (QIDS-SR) scores and proportion of youth with treatment response (>50% decrease from baseline) and remission (QIDS-SR ≤ 5) were compared across arms using t tests. RESULTS: Thirteen sites enrolled 156 YWH, with baseline demographic factors, depression severity, and HIV disease status comparable across arms. At week 36, the site-level mean proportions of youth with a treatment response and remission were greater at combination cognitive behavioral therapy and medication management algorithm sites (52.0% vs. 18.8%, P = 0.02; 37.9% vs. 19.4%, P = 0.05), and the mean QIDS-SR was lower (7.45 vs. 9.75, P = 0.05). At week 48, the site-level mean proportion with a treatment response remained significantly greater (58.7% vs. 33.4%, P = 0.047). CONCLUSIONS: The impact of manualized, measurement-guided cognitive behavioral therapy and medication management algorithm tailored for YWH that was efficacious at week 24 continued to be evident at weeks 36 and 48.
Assuntos
Terapia Cognitivo-Comportamental , Transtorno Depressivo Maior , Infecções por HIV , Adolescente , Algoritmos , Criança , Depressão/complicações , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Infecções por HIV/complicações , Infecções por HIV/psicologia , Humanos , Conduta do Tratamento Medicamentoso , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: This study evaluated atazanavir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples. SETTING: A nonrandomized, open-label, parallel-group, multicenter prospective study of atazanavir and cobicistat pharmacokinetics in pregnant women with HIV and their children. METHODS: Intensive steady-state 24-hour pharmacokinetic profiles were performed after administration of 300 mg of atazanavir and 150 mg of cobicistat orally in fixed-dose combination once daily during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Atazanavir and cobicistat were measured in plasma by validated high-performance liquid chromatography-ultraviolet and liquid chromatography-tandem mass spectrometry assays, respectively. A 2-tailed Wilcoxon signed-rank test (α = 0.10) was used for paired within-participant comparisons. RESULTS: A total of 11 pregnant women enrolled in the study. Compared with paired postpartum data, atazanavir AUC0-24 was 26% lower in the second trimester [n = 5, P = 0.1875, geometric mean of ratio (GMR) = 0.739, 90% CI: 0.527 to 1.035] and 54% lower in the third trimester (n = 6, GMR = 0.459, P = 0.1563, 90% CI: 0.190 to 1.109), whereas cobicistat AUC0-24 was 35% lower in the second trimester (n = 5, P = 0.0625, GMR = 0.650, 90% CI: 0.493 to 0.858) and 52% lower in the third trimester (n = 7, P = 0.0156, GMR = 0.480, 90% CI: 0.299 to 0.772). The median (interquartile range) 24-hour atazanavir trough concentration was 0.21 µg/mL (0.16-0.28) in the second trimester, 0.21 µg/mL (0.11-0.56) in the third trimester, and 0.61 µg/mL (0.42-1.03) in postpartum. Placental transfer of atazanavir and cobicistat was limited. CONCLUSIONS: Standard atazanavir/cobicistat dosing during pregnancy results in lower exposure which may increase the risk of virologic failure and perinatal transmission.
Assuntos
Sulfato de Atazanavir/farmacocinética , Infecções por HIV , Inibidores da Protease de HIV , Complicações Infecciosas na Gravidez , Fármacos Anti-HIV , Sulfato de Atazanavir/uso terapêutico , Criança , Cobicistat , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Transmissão Vertical de Doenças Infecciosas , Placenta , Período Pós-Parto , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Estudos ProspectivosRESUMO
BACKGROUND: Tenofovir alafenamide (TAF) is a key component of HIV treatment, but pharmacokinetic data supporting the use of TAF during pregnancy are limited. In this study, we report pharmacokinetic, safety, and birth outcomes for TAF 25 mg with a boosted protease inhibitor in pregnant women living with HIV. METHODS: IMPAACT P1026s was a multicenter, nonrandomized, open-label, phase IV prospective study. Pregnant women living with HIV receiving TAF 25 mg with a boosted protease inhibitor were eligible. Intensive pharmacokinetic assessments were performed during the second and third trimesters and 6-12 weeks postpartum. Maternal and cord blood samples were collected at delivery. Infant washout samples were collected through 5-9 days postbirth. Comparisons of paired pharmacokinetic data between pregnancy and postpartum were made using geometric mean ratios (GMR) [90% confidence intervals (CIs)] and Wilcoxon signed-rank tests with P < 0.10 considered significant. RESULTS: Twenty-nine women were enrolled from the United States (median age 31 years and weight 84.5 kg during the third trimester; 48% Black, 45% Hispanic/Latina). TAF AUCtau did not significantly differ in the second [GMR 0.62 (90% CI: 0.29 to 1.34); P = 0.46] or third trimester [GMR 0.94 (90% CI: 0.63 to 1.39); P = 0.50] vs. postpartum and were comparable with historical data in nonpregnant adults. TAF was only quantifiable in 2/25 maternal delivery samples and below the limit of quantification in all cord blood and infant washout samples, likely because of the short half-life of TAF. CONCLUSION: TAF AUCtau did not significantly differ between pregnancy and postpartum. These findings provide reassurance as TAF use during pregnancy continues to expand.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Complicações Infecciosas na Gravidez , Adenina/uso terapêutico , Adulto , Alanina , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Antivirais/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Período Pós-Parto , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Estudos Prospectivos , Inibidores de Proteases/uso terapêutico , Tenofovir/análogos & derivadosRESUMO
Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (C(24)) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (C(max)) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (P = 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV , Desoxicitidina/análogos & derivados , Infecções por HIV/tratamento farmacológico , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Organofosfonatos , Complicações Infecciosas na Gravidez/tratamento farmacológico , Inibidores da Transcriptase Reversa , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Emtricitabina , Feminino , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Lactente , Organofosfonatos/administração & dosagem , Organofosfonatos/efeitos adversos , Organofosfonatos/farmacocinética , Gravidez , Complicações Infecciosas na Gravidez/virologia , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Conflicting results have been reported among studies of protease inhibitor (PI) use during pregnancy and preterm birth. Uncontrolled confounding by indication may explain some of the differences among studies. METHODS: In total, 777 human immunodeficiency virus (HIV)-infected pregnant women in a prospective cohort who were not receiving antiretroviral (ARV) treatment at conception were studied. Births <37 weeks gestation were reviewed, and deliveries due to spontaneous labor and/or rupture of membranes were identified. Risk of preterm birth and low birth weight (<2500 g) were evaluated by using multivariable logistic regression. RESULTS: Of the study population, 558 (72%) received combination ARV with PI during pregnancy, and a total of 130 preterm births were observed. In adjusted analyses, combination ARV with PI was not significantly associated with spontaneous preterm birth, compared to ARV without PI (odds ratio [OR], 1.22; 95% confidence interval [CI], 0.70-2.12). Sensitivity analyses that included women who received ARV prior to pregnancy also did not identify a significant association (OR, 1.34; 95% CI, 0.84-2.16). Low birth weight results were similar. CONCLUSIONS: No evidence of an association between use of combination ARV with PI during pregnancy and preterm birth was found. Our study supports current guidelines that promote consideration of combination ARV for all HIV-infected pregnant women.