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1.
Artigo em Inglês | MEDLINE | ID: mdl-32015036

RESUMO

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. Target amprenavir area under the concentration time curve (AUC) was >10th percentile (27.7 µg*hr/mL) of median area under the curve for ritonavir-boosted fosamprenavir in adults receiving twice-daily fosamprenavir/ritonavir, 700mg/100 mg. Twenty-nine women were included in the analysis. Amprenavir AUC0-12 was lower [(geometric mean ratio (GMR) 0.60 (CI 0.49-0.72; p<0.001)] while its apparent oral clearance was higher [(GMR 1.68 (CI 1.38-2.03; p<0.001)] in the third trimester compared to postpartum. Similarly, ritonavir AUC0-12 was lower in the second [GMR 0.51 (CI 0.28-0.91; p=0.09)] and third trimesters [(GMR 0.72 (CI 0.55-0.95; p=0.005)] compared to postpartum, while its apparent oral clearance was higher in the second [GMR 1.98 (CI 1.10-3.56; p=0.06)] and third trimesters [(GMR 1.38 (CI 1.05-1.82; p=0.009)] compared to postpartum. Amprenavir area under the curve exceeded the target for 6/8 (75%) in the 2nd trimester; 18/28 (64%) in the 3rd trimester; and 19/22 (86.4%) postpartum, and the trough concentrations (Cmin) of amprevavir were 4-16 fold above the mean amprenavir-protein-adjusted IC50 of 0.146µg/mL. Although amprenavir plasma concentrations in women receiving ritonavir-boosted fosamprenavir were lower during pregnancy compared to postpartum, the reduced amprenavir concentrations were still above the exposures needed for viral suppression.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31923087

RESUMO

BACKGROUND: This study aims to evaluate the pharmacokinetics of an increased dose of darunavir (800 mg twice daily) with 100 mg ritonavir during pregnancy and postpartum. METHODS: Darunavir (DRV) and ritonavir (RTV; r) intensive pharmacokinetic evaluations were performed at steady state during the second and third trimesters of pregnancy (DRV/r 800/100 mg bid) and 2-3 weeks postpartum (DRV/r 600/100 mg twice daily). Plasma concentrations of darunavir and ritonavir were measured using high-performance liquid chromatography (HPLC). Target darunavir area under the concentration time curve (AUC) was >70% (43.6 mcg*hr/mL) of median AUC (62.3 mcg*hr/mL) in non-pregnant adults on twice daily darunavir-ritonavir 600/100 mg. RESULTS: Twenty-four women were included in the analysis. Darunavir AUC0-12 was lower with the increased dose during the second [(geometric mean ratio (GMR) of 0.62 (IQR 0.44-0.88; p=0.055)] and third trimesters (GMR 0.64 (IQR 0.55-0.73; p=<0.001) compared to postpartum. Darunavir apparent clearance was higher in during the second (GMR 1.77 (IQR 1.24-2.51; p=0.039) and third trimesters (GMR 2.01 (IQR 1.17-2.35; p=<0.001) compared to postpartum. Similarly, ritonavir AUC0-12 was lower during the third trimester (GMR 0.65 (IQR 0.52-0.82; p=0.007) compared to postpartum, while its apparent clearance was higher during the third trimester (GMR 1.53 (IQR 1.22-1.92; p=0.008) compared to postpartum. No major drug-related safety concerns were noted. CONCLUSION: Increasing darunavir dose to 800 mg BID failed to significantly increase darunavir exposure compared to 600 mg BID. Other strategies, such as increasing the ritonavir dose should be investigated.

3.
J Acquir Immune Defic Syndr ; 83(1): 72-80, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31651545

RESUMO

BACKGROUND: HIV-infected, postpartum women on antiretroviral therapy (ART) have high rates of viremia. We examined predictors of postpartum viremia in the PROMISE study. METHODS: Women with pre-ART CD4 T-cell counts ≥400 cells/mm who started ART during pregnancy were randomized postpartum to continue ART (CTART) or discontinue ART (DCART). Viral load and self-reported adherence were collected every 12 weeks, up to 144 weeks. Women in DCART reinitiated therapy when clinically indicated. Viremia was defined as 2 consecutive viral loads >1000 copies/mL after 24 weeks on ART. Adherence was dichotomized as missing versus not missing ART doses in the past 4 weeks. Predictors of viremia were examined using Cox proportional hazards regression with adherence as a time-varying covariate. RESULTS: Among 802 women in the CTART arm, median age at entry was 27 years and median CD4 T-cell count 696 cells/mm. Of 175 women in CTART with viremia (22%), 141 had resistance data, and 12% had resistance to their current regimen. There was an estimated 0.12 probability of viremia by week 48 and 0.25 by week 144. Predictors of viremia included missed ART doses within the past 4 weeks, younger age, shorter duration of pre-entry ART, and being from the South American/Caribbean region. Of 137 women in DCART who reinitiated therapy, probability of viremia was similar to CTART (0.24 by week 96; 0.27 by week 144). CONCLUSIONS: Rates of postpartum viremia are high and viremia is more likely in younger postpartum women who start ART later in pregnancy. Interventions should target these higher-risk women.

4.
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.
J Acquir Immune Defic Syndr ; 81(5): 521-532, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31295174

RESUMO

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

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.
J Int AIDS Soc ; 22(2): e25257, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30816632

RESUMO

INTRODUCTION: In many African settings, women concurrently face substantial risk of human immunodeficiency virus type 1 (HIV-1) infection, sexually transmitted infections (STIs) and unintended pregnancies. Few studies have evaluated STI risk among users of hormonal implants and copper intrauterine devices (IUDs) although these long-acting reversible contraceptive methods are being promoted widely because of their benefits. Within a prospective study of women at risk for HIV-1, we compared the risk of acquisition of Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis among women using different contraceptive methods. METHODS: MTN-020/ASPIRE was a randomized trial of the dapivirine vaginal ring for HIV-1 prevention among 2629 women aged 18 to 45 years from Malawi, South Africa, Uganda and Zimbabwe, of whom 2264 used copper IUDs or progestin-based injectables or implants during follow-up. Screening for the above STIs occurred semi-annually. RESULTS: Over 3440 person-years of follow-up, 408 cases of C. trachomatis (incidence 11.86/100 person-years), 196 of N. gonorrhoeae (5.70/100 person-years) and 213 cases of T. vaginalis (6.19/100 person-years) were detected. C. trachomatis and N. gonorrhoeae incidence were not significantly different across contraceptive methods. T. vaginalis incidence was significantly higher for copper IUD users compared to depot medroxyprogesterone acetate (DMPA), implant and norethisterone enanthate users. CONCLUSION: Among African women at high HIV-1 risk, STIs were common. Risk of cervical infections did not differ across contraceptive methods. Significantly higher rates of T. vaginalis were observed among progestin-based methods compared to copper IUD users. Overall, these findings call for more intensive routine screening for STIs, and they support current World Health Organization guidance that women should have a wide range of contraceptive options.

9.
AIDS ; 33(5): 845-853, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649056

RESUMO

BACKGROUND: HIV-exposed-uninfected (HEU) infants have increased infectious morbidity and mortality; little is known about their levels of inflammation and monocyte activation. METHODS: Plasma samples obtained at birth and 6 months from 86 HEU mother-infant pairs enrolled in the National Institute of Child Health and Human Development cohorts in Brazil were compared with 88 HIV-unexposed mother-infant pairs. HIV-infected mothers received antiretroviral therapy during pregnancy, their infants received zidovudine prophylaxis and were not breastfed. IL-6, soluble TNFα receptor I (sTNF-RI) and II, soluble CD14, soluble CD163, IFN-γ-induced protein 10 (IP-10), vascular cell adhesion molecule, oxidized LDL, D-dimer and high-sensitivity C-reactive protein were assayed by ELISA at birth and at 6 months. sTNF-RI and IL-6 were considered coprimary endpoints. RESULTS: Among HIV-infected mothers, 79% had HIV-RNA less than 400 copies/ml prior to delivery. Compared with HIV-unexposed, HEU infants had a lower mean gestational age (38.7 vs. 39.3 weeks) and weight (3.1 vs. 3.3 kg); and reached lower weight (5.9 vs. 8.5 kg) and height (53.6 vs. 68.8 cm) at 6 months. With the exception of vascular cell adhesion molecule, inflammatory markers were generally higher (P ≤ 0.005) in HEU at birth, but at 6 months only sTNF-RI and IL-6 remained higher. For HEU pairs, only IP-10 was associated with maternal levels at birth (P < 0.001). In HEU, elevated levels of high-sensitivity C-reactive protein and IP-10 at birth were associated with lower weight at birth (P = 0.04) and at 6 months (P = 0.04). CONCLUSION: HIV-exposed infants have heightened inflammation and monocyte activation at birth, which for some markers persisted to 6 months of life and was not related to maternal inflammatory status. Inflammation may contribute to the increased HEU infectious morbidity and poor growth.

10.
Clin Infect Dis ; 68(2): 273-279, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-29868833

RESUMO

Background: Adverse pregnancy outcomes for women who conceive on antiretroviral therapy (ART) may be increased, but data are conflicting. Methods: Human immunodeficiency virus-infected, nonbreastfeeding women with pre-ART CD4 counts ≥400 cells/µL who started ART during pregnancy were randomized after delivery to continue ART (CTART) or discontinue ART (DCART). Women randomized to DCART were recommended to restart if a subsequent pregnancy occurred or for clinical indications. Using both intent-to-treat and as-treated approaches, we performed Fisher exact tests to compare subsequent pregnancy outcomes by randomized arm. Results: Subsequent pregnancies occurred in 277 of 1652 (17%) women (CTART: 144/827; DCART: 133/825). A pregnancy outcome was recorded for 266 (96%) women with a median age of 27 years (interquartile range [IQR], 24-31 years) and median CD4+ T-cell count 638 cells/µL (IQR, 492-833 cells/µL). When spontaneous abortions and stillbirths were combined, there was a significant difference in events, with 33 of 140 (23.6%) in the CTART arm and 15 of 126 (11.9%) in the DCART arm (relative risk [RR], 2.0 [95% confidence interval {CI}, 1.1-3.5]; P = .02). In the as-treated analysis, the RR was reduced and no longer statistically significant (RR, 1.4 [95% CI, .8-2.4]). Conclusions: Women randomized to continue ART who subsequently conceived were more likely to have spontaneous abortion or stillbirth, compared with women randomized to stop ART; however, the findings did not remain significant in the as-treated analysis. More data are needed on pregnancy outcomes among women conceiving on ART, particularly with newer regimens.


Assuntos
Aborto Espontâneo/induzido quimicamente , Antirretrovirais/efeitos adversos , Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Natimorto , Adulto , Antirretrovirais/administração & dosagem , Feminino , Humanos , Gravidez , Adulto Jovem
11.
AIDS ; 32(17): 2507-2516, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30134297

RESUMO

OBJECTIVE: To evaluate elvitegravir and cobicistat pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery. DESIGN: Nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and their children in the United States. METHODS: Intensive steady-state 24-h pharmacokinetic profiles after 150 mg of elvitegravir and 150 mg of cobicistat given orally in fixed dose combination once-daily were performed during the second trimester, third trimester, and postpartum. Infant washout samples were collected after birth. Elvitegravir and cobicistat were measured in plasma by a validated liquid chromatography with tandem mass spectrometry assay with a lower quantitation limit of 10 ng/ml. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-participant comparisons. RESULTS: Thirty pregnant women taking elvitegravir and cobicistat once-daily enrolled in the study. Compared with paired postpartum data, elvitegravir AUC0-24 was 24% lower in the second trimester [n = 14, P = 0.058, geometric mean ratios (GMR) = 0.76, 90% confidence interval (CI) 0.57-1.0] and 44% lower in the third trimester (n = 24, P = 0.0001, GMR = 0.56, 90% CI 0.42-0.73), while cobicistat AUC0-24 was 44% lower in the second trimester (n = 14, P = 0.0085, GMR = 0.56, 90% CI 0.37-0.85) and 59% lower in the third trimester (n = 24, P < 0.0001, GMR = 0.41, 90% CI 0.30-0.57). Median cord blood elvitegravir concentration was 540.6 ng/ml and the median ratio of cord blood to maternal plasma elvitegravir concentrations was 0.91. CONCLUSION: Standard elvitegravir and cobicistat dosing during pregnancy results in significantly lower exposure which may increase the risk of virologic failure and mother-to-child transmission. Additional studies are needed to optimize elvitegravir and cobicistat dosing regimens in pregnant women.


Assuntos
Fármacos Anti-HIV/farmacocinética , Cobicistat/farmacocinética , Infecções por HIV/tratamento farmacológico , Período Pós-Parto , Complicações Infecciosas na Gravidez/tratamento farmacológico , Gravidez , Quinolonas/farmacocinética , Administração Oral , Adulto , Fármacos Anti-HIV/administração & dosagem , Cromatografia Líquida , Cobicistat/administração & dosagem , Feminino , Humanos , Recém-Nascido , Pessoa de Meia-Idade , Plasma/química , Estudos Prospectivos , Quinolonas/administração & dosagem , Espectrometria de Massas em Tandem , Estados Unidos , Adulto Jovem
12.
N Engl J Med ; 378(10): 911-923, 2018 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-29514030

RESUMO

BACKGROUND: Pregnant women with an elevated viral load of hepatitis B virus (HBV) have a risk of transmitting infection to their infants, despite the infants' receiving hepatitis B immune globulin. METHODS: In this multicenter, double-blind clinical trial performed in Thailand, we randomly assigned hepatitis B e antigen (HBeAg)-positive pregnant women with an alanine aminotransferase level of 60 IU or less per liter to receive tenofovir disoproxil fumarate (TDF) or placebo from 28 weeks of gestation to 2 months post partum. Infants received hepatitis B immune globulin at birth and hepatitis B vaccine at birth and at 1, 2, 4, and 6 months. The primary end point was a hepatitis B surface antigen (HBsAg)-positive status in the infant, confirmed by the HBV DNA level at 6 months of age. We calculated that a sample of 328 women would provide the trial with 90% power to detect a difference of at least 9 percentage points in the transmission rate (expected rate, 3% in the TDF group vs. 12% in the placebo group). RESULTS: From January 2013 to August 2015, we enrolled 331 women; 168 women were randomly assigned to the TDF group and 163 to the placebo group. At enrollment, the median gestational age was 28.3 weeks, and the median HBV DNA level was 8.0 log10 IU per milliliter. Among 322 deliveries (97% of the participants), there were 319 singleton births, two twin pairs, and one stillborn infant. The median time from birth to administration of hepatitis B immune globulin was 1.3 hours, and the median time from birth to administration of hepatitis B vaccine was 1.2 hours. In the primary analysis, none of the 147 infants (0%; 95% confidence interval [CI], 0 to 2) in the TDF group were infected, as compared with 3 of 147 (2%; 95% CI, 0 to 6) in the placebo group (P=0.12). The rate of adverse events did not differ significantly between groups. The incidence of a maternal alanine aminotransferase level of more than 300 IU per liter after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (P=0.29). CONCLUSIONS: In a setting in which the rate of mother-to-child HBV transmission was low with the administration of hepatitis B immune globulin and hepatitis B vaccine in infants born to HBeAg-positive mothers, the additional maternal use of TDF did not result in a significantly lower rate of transmission. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01745822 .).


Assuntos
Antivirais/uso terapêutico , Vírus da Hepatite B/isolamento & purificação , Hepatite B/transmissão , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Tenofovir/uso terapêutico , Adolescente , Adulto , Alanina Transaminase/sangue , Antivirais/efeitos adversos , DNA Viral/isolamento & purificação , Método Duplo-Cego , Feminino , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Vacinas contra Hepatite B , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Tenofovir/efeitos adversos , Carga Viral , Adulto Jovem
13.
J Acquir Immune Defic Syndr ; 78(3): 308-313, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29528944

RESUMO

BACKGROUND: Concentrations of antiretrovirals in the genital tract play a key role in preexposure prophylaxis. This study aims to describe rilpivirine (Edurant) concentrations in the genital tract in pregnant and postpartum women. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials Protocol P1026s is an ongoing, prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women that include a cohort receiving rilpivirine combination regimen. Intensive pharmacokinetics evaluations were performed at steady state during the second and third trimester, and postpartum. Plasma and directly aspirated cervicovaginal fluid (CVF) samples were collected at 4 time points around an observed dose and measured using high-performance liquid chromatography with ultraviolet detection, [plasma; lower limit of quantification (LLQ) = 10 ng/mL] or liquid chromatography-tandem mass spectrometry (CVF; LLQ = 1 ng/mL). RESULTS: A total of 24 women were included in the analysis. For all time points combined, median (interquartile range) rilpivirine concentrations were 70 ng/mL (23-121) in CVF and 92 ng/mL (49-147) in plasma. The CVF to plasma AUC(0-4) ratios were significantly higher in the second (0.90, 90% CI: 0.61 to 1.46) and third trimesters of pregnancy compared with postpartum (0.40, 90% CI: 0.19 to 0.87). Three of 189 (1.6%) plasma samples in 2 women were below the LLQ and the corresponding CVF concentrations. Seventeen additional CVF concentrations (10.6%) were below LLQ in 13 participants. No major safety concerns were noted. CONCLUSIONS: Rilpivirine concentrations were higher in the CVF during pregnancy compared with postpartum. CVF Rilpivirine is likely to achieve inhibitory concentrations effective for preventing peripartum HIV transmission.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Colo do Útero/metabolismo , Infecções por HIV/tratamento farmacológico , Período Pós-Parto , Complicações Infecciosas na Gravidez/tratamento farmacológico , Rilpivirina/uso terapêutico , Vagina/metabolismo , Adolescente , Feminino , Humanos , Gravidez , Adulto Jovem
14.
Curr Opin Obstet Gynecol ; 30(2): 116-122, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29406461

RESUMO

PURPOSE OF REVIEW: Zika virus' impact on pregnancy became widely known in 2015 with a dramatic increase in the number of babies born with microcephaly in Recife, Brazil. A mosquito-borne virus resulting in congenital anomalies is unique, and Zika's ability to cause neurological defects on a large scale was a grim reminder of the Rubella epidemic in the 1950s. Over the past 2 years, studies have provided insight on how Zika virus (ZIKV) infects cells and causes disease, but much remains unknown about the long-term risks of Zika exposure on infant growth and development. RECENT FINDINGS: The impact of ZIKV on pregnancy extends beyond microcephaly and may only first be identified in infancy. The virus has a long latency in semen and can be transmitted sexually. Transplacental passage occurs through infection of Hofbauer cells in the trophoblast. A major difficulty in management of ZIKV disease is that most infections are asymptomatic and the diagnostic methods are not ideal, making both diagnosis and ascertainment of timing of infection problematic. Several different types of vaccines are in development. Large studies are ongoing to determine the risk and total spectrum of anomalies based on the timing of infection and other environmental exposures. SUMMARY: This review will summarize the epidemic, what we have learned, what we hope to learn, and current recommendations for care and management.


Assuntos
Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/transmissão , Anormalidades Múltiplas/virologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Transmissão Vertical de Doença Infecciosa , Insetos Vetores , Masculino , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/virologia , Sêmen/virologia , Doenças Virais Sexualmente Transmissíveis , Infecção por Zika virus/diagnóstico
15.
AIDS ; 32(6): 729-737, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29369162

RESUMO

OBJECTIVE: To evaluate dolutegravir pharmacokinetics during pregnancy compared with postpartum and in infant washout samples after delivery. DESIGN: Ongoing, nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and infants. METHODS: Intensive steady-state 24 h pharmacokinetic profiles after dolutegravir 50 mg once-daily were performed during the second trimester (2T), third trimester (3T) and postpartum. Maternal delivery and postnatal infant samples were collected after birth. Dolutegravir was measured by validated LC-MS/MS; quantitation limit was 0.005 µg/ml. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-subject comparisons. RESULTS: Twenty-nine enrolled participants had a median age of 32 years (range 21-42). Pharmacokinetic data were available for 15 (2T), 28 (3T) and 23 (postpartum) women. Median dolutegravir AUC0-24,Cmax and C24 were 25-51% lower in the 2T and 3T compared with postpartum. The median cord blood/maternal plasma concentration ratio was 1.25 (n = 18). In 21 infants, median elimination half-life was 32.8 h after in utero exposure. Viral load at delivery was less than 50 copies/ml for 27/29 women (93%). Twenty-nine infants were HIV-negative. Renal abnormalities noted on ultrasound in two infants were deemed possibly related to dolutegravir. CONCLUSION: Dolutegravir exposure is lower in pregnancy compared with postpartum in the same women on once-daily dosing. Median AUC0-24 during pregnancy was similar to, whereas trough concentrations were lower than, those seen in nonpregnant adults. Trough concentrations in pregnancy were well above dolutegravir EC90 (0.064 µg/ml). Dolutegravir readily crosses the placenta. Infant elimination is prolonged, with half-life over twice that of historical adult controls.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Período Pós-Parto , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Cromatografia Líquida , Feminino , HIV/isolamento & purificação , Inibidores de Integrase de HIV/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Recém-Nascido , Masculino , Plasma/química , Gravidez , Estudos Prospectivos , Espectrometria de Massas em Tandem , Carga Viral , Adulto Jovem
16.
J Acquir Immune Defic Syndr ; 77(4): 383-392, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29239901

RESUMO

BACKGROUND: No randomized trial has directly compared the efficacy of prolonged infant antiretroviral prophylaxis versus maternal antiretroviral therapy (mART) for prevention of mother-to-child transmission throughout the breastfeeding period. SETTING: Fourteen sites in Sub-Saharan Africa and India. METHODS: A randomized, open-label strategy trial was conducted in HIV-1-infected women with CD4 counts ≥350 cells/mm (or ≥country-specific ART threshold if higher) and their breastfeeding HIV-1-uninfected newborns. Randomization at 6-14 days postpartum was to mART or infant nevirapine (iNVP) prophylaxis continued until 18 months after delivery or breastfeeding cessation, infant HIV-1 infection, or toxicity, whichever occurred first. The primary efficacy outcome was confirmed infant HIV-1 infection. Efficacy analyses included all randomized mother-infant pairs except those with infant HIV-1 infection at entry. RESULTS: Between June 2011 and October 2014, 2431 mother-infant pairs were enrolled; 97% of women were World Health Organization Clinical Stage I, median screening CD4 count 686 cells/mm. Median infant gestational age/birth weight was 39 weeks/2.9 kilograms. Seven of 1219 (0.57%) and 7 of 1211 (0.58%) analyzed infants in the mART and iNVP arms, respectively, were HIV-infected (hazard ratio 1.0, 96% repeated confidence interval 0.3-3.1); infant HIV-free survival was high (97.1%, mART and 97.7%, iNVP, at 24 months). There were no significant differences between arms in median time to breastfeeding cessation (16 months) or incidence of severe, life-threatening, or fatal adverse events for mothers or infants (14 and 42 per 100 person-years, respectively). CONCLUSIONS: Both mART and iNVP prophylaxis strategies were safe and associated with very low breastfeeding HIV-1 transmission and high infant HIV-1-free survival at 24 months.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Aleitamento Materno , Quimioprevenção/métodos , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Transmissão Vertical de Doença Infecciosa/prevenção & controle , África ao Sul do Saara , Pré-Escolar , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Índia , Lactente , Recém-Nascido , Período Pós-Parto , Resultado do Tratamento
17.
HIV Clin Trials ; 19(6): 209-224, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30890061

RESUMO

BACKGROUND: IMPAACT PROMISE 1077BF/FF was a randomized study of antiretroviral therapy (ART) strategies for pregnant and postpartum women with high CD4+ T-cell counts. We describe postpartum outcomes for women in the study who were randomized to continue or discontinue ART after delivery. METHODS: Women with pre-ART CD4+ cell counts ≥350 cells/mm3 who started ART during pregnancy were randomized postpartum to continue or discontinue treatment. Women were enrolled from India, Malawi, South Africa, Tanzania, Uganda, Zambia, and Zimbabwe. The primary outcome was a composite of progression to AIDS-defining illness or death. Log-rank tests and Cox regression models assessed treatment effects. Incidence rates were calculated per 100 person-years. A post hoc analysis evaluated WHO Stage 2/3 events. All analyses were intent-to-treat. FINDINGS: 1611 women were enrolled (June 2011-October 2014) and 95% were breastfeeding. Median age at entry was 27 years, CD4+ count 728 cells/mm3 and the majority of women were Black African (97%). After a median follow-up of 1.6 years, progression to AIDS-defining illness or death was rare and there was no significant difference between arms (HR: 0·55; 95%CI 0·14, 2·08, p = 0.37). WHO Stage 2/3 events were reduced with continued ART (HR: 0·60; 95%CI 0·39, 0·90, p = 0.01). The arms did not differ with respect to the rate of grade 2, 3, or 4 safety events (p = 0.61). INTERPRETATION: Serious clinical events were rare among predominately breastfeeding women with high CD4+ cell counts over 18 months after delivery. ART had significant benefit in reducing WHO 2/3 events in this population.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Saúde Materna , Adulto , Aleitamento Materno , Contagem de Linfócito CD4 , Progressão da Doença , Feminino , Infecções por HIV/virologia , Humanos , Período Pós-Parto , Gravidez , Resultado do Tratamento , Adulto Jovem
18.
Obstet Gynecol ; 130(3): 502-510, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28796679

RESUMO

OBJECTIVE: To evaluate whether there is increased mother-to-child transmission of human immunodeficiency virus (HIV)-1 associated with deliveries at 40 weeks of estimated gestational age (EGA) or greater in pregnant women with HIV-1 viral loads of 1,000 copies/mL or less. METHODS: We performed a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative Perinatal and Longitudinal Study in Latin American Countries and International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 cohorts. We included pregnant women with HIV-1 with recent viral loads of 1,000 copies/mL or less at the time of delivery and compared delivery outcomes at between 38 and less than 40 weeks EGA with delivery outcomes at 40 weeks EGA or greater, the exposure of interest. Our primary outcome of interest was mother-to-child transmission, and secondary outcomes included indicators of maternal and neonatal morbidity. We examined the association between EGA and mother-to-child transmission using Poisson distribution. Associations between EGA and secondary outcomes were examined through bivariate analyses using Pearson χ and Fisher exact test or the nonparametric Mann-Whitney U test. RESULTS: Among the 2,250 eligible neonates, eight neonates were infected with HIV-1 (overall transmission rate 0.4%, 95% CI 0.2-8.1%, 40 weeks EGA or greater 0.5% [3/621, 95% CI 0.2-1.4%], less than 40 weeks EGA 0.3% [5/1,629, 95% CI 0.1-0.7%]); there was no significant difference in transmission by EGA (rate ratio 1.57, 95% CI 0.24-8.09, P=.77). There was no difference in maternal viral load between the two groups nor was there a difference in timing of transmission among neonates born with HIV-1. CONCLUSION: In pregnant women with well-controlled HIV-1, the risk of mother-to-child transmission did not differ significantly by EGA at delivery, although we were not powered to demonstrate equivalence of proportions of mother-to-child transmission between EGA groups.


Assuntos
Infecções por HIV/tratamento farmacológico , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Adulto , Parto Obstétrico , Feminino , Idade Gestacional , Infecções por HIV/transmissão , Humanos , Recém-Nascido , Estudos Longitudinais , Assistência Perinatal , Gravidez , Terceiro Trimestre da Gravidez , Carga Viral
19.
Clin Infect Dis ; 65(6): 982-989, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28575201

RESUMO

Background: Pregnancy outcomes of perinatally human immunodeficiency virus-infected women (PHIV) are poorly defined. Methods: We compared preterm delivery and birth weight (BW) outcomes (low BW [LBW], <2500 g), small-for-gestational-age [SGA], and BW z scores [BWZ]) in HIV-exposed uninfected infants of PHIV vs nonperinatally HIV-infected (NPHIV) pregnant women in the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART Toxicities or International Maternal Pediatric Adolescent AIDS Clinical Trials P1025 studies. Mixed effects models and log binomial models were used to assess the association of maternal PHIV status with infant outcomes. Age-stratified analyses were performed. Results: From 1998 to 2013, 2270 HIV-infected pregnant women delivered 2692 newborns (270 born to PHIV and 2422 to NPHIV women). PHIV women were younger, (mean age 21 vs 25 years, P < .01) and more likely to have a pregnancy CD4 count <200 cells/mm3 (19% vs 11%, P = .01). No associations between maternal PHIV status and preterm delivery, SGA, or LBW were observed. After adjustment, BWZ was 0.12 lower in infants of PHIV vs NPHIV women (adjusted mean, -0.45 vs -0.33; P = .04). Among women aged 23-30 years (n = 1770), maternal PHIV was associated with LBW (aRR = 1.74; 95% confidence interval, 1.18, 2.58; P < .01). Conclusion: The overall lack of association between maternal PHIV status and preterm delivery or infant BW outcomes is reassuring. The higher rates of LBW observed in PHIV women aged 23-30 years warrants further mechanism-based investigations as this is a rapidly growing and aging population worldwide. Clinical Trials Registration: PHACS SMARTT study, NCT01310023. Clinical Trials Registration: IMPAACT 1025, NCT00028145.


Assuntos
Peso ao Nascer , Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , Transmissão Vertical de Doença Infecciosa , Complicações Infecciosas na Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Adulto , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/sangue , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Gravidez , Estudos Prospectivos , Estados Unidos/epidemiologia , Adulto Jovem
20.
PLoS One ; 12(5): e0176009, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28489856

RESUMO

BACKGROUND: Health benefits of postpartum antiretroviral therapy (ART) for human immunodeficiency virus (HIV) positive women with high CD4+ T-counts have not been assessed in randomized trials. METHODS: Asymptomatic, HIV-positive, non-breastfeeding women with pre-ART CD4+ T-cell counts ≥ 400 cells/mm3 started on ART during pregnancy were randomized up to 42 days after delivery to continue or discontinue ART. Lopinavir/ritonavir plus tenofovir/emtricitabine was the preferred ART regimen. The sample size was selected to provide 88% power to detect a 50% reduction from an annualized primary event rate of 2.07%. A post-hoc analysis evaluated HIV/AIDS-related and World Health Organization (WHO) Stage 2 and 3 events. All analyses were intent to treat. RESULTS: 1652 women from 52 sites in Argentina, Botswana, Brazil, China, Haiti, Peru, Thailand and the US were enrolled (1/2010-11/2014). Median age was 28 years and major racial categories were Black African (28%), Asian (25%) White (15%). Median entry CD4 count was 696 cells/mm3 (IQR 575-869), median ART exposure prior to delivery was 19 weeks (IQR 13-24) and 94% had entry HIV-1 RNA < 1000 copies/ml. After a median follow-up of 2.3 years, the primary composite endpoint rate was significantly lower than expected, and not significantly different between arms (continue arm 0.21 /100 person years(py); discontinue 0.31/100 py, Hazard ratio (HR) 0.68, 95% CI: 0.19, 2.40). WHO Stage 2 and 3 events were significantly reduced with continued ART (2.08/100 py vs. 4.36/100 py in the discontinue arm; HR 0.48, 95%CI: 0.33, 0.70). Toxicity rates did not differ significantly between arms. Among women randomized to continue ART, 189/827 (23%) had virologic failure; of the 155 with resistance testing, 103 (66%) failed without resistance to their current regimen, suggesting non-adherence. CONCLUSIONS: Overall, serious clinical events were rare among young HIV-positive post-partum women with high CD4 cell counts. Continued ART was safe and was associated with a halving of the rate of WHO 2/3 conditions. Virologic failure rates were high, underscoring the urgent need to improve adherence in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00955968.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Contagem de Linfócito CD4 , Infecções por HIV/tratamento farmacológico , Período Pós-Parto , Adulto , Farmacorresistência Viral , Feminino , Humanos , Carga Viral
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