RESUMO
BACKGROUND: Pregnancy represents a period of high HIV acquisition risk. Safety data for the monthly dapivirine vaginal ring (DVR) during pregnancy are limited. Here, we report data from the first 2 cohorts of pregnant participants in MTN-042/DELIVER, a phase 3b, randomized, open-label safety trial of DVR and oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). MTN-042 is being conducted in 3 cohorts beginning with later gestational ages when risks of drug exposure are less. METHODS: Eligible pregnant individuals aged 18-40 years in Malawi, South Africa, Uganda, and Zimbabwe were randomized 2:1 to monthly DVR or daily TDF/FTC. Participants in cohort 1 initiated product use between 36 weeks 0 days (36 0/7 weeks) and 37 6/7 weeks gestation; participants in cohort 2 initiated product use between 30 0/7 and 35 6/7 weeks gestation. All participants continued product use until delivery or 41 6/7 weeks gestation. Pregnancy outcomes and complications were assessed and summarized using descriptive statistics and compared with local background rates obtained through a separate chart review. RESULTS: One-hundred and fifty participants were enrolled into cohort 1 with 101 randomized to DVR and 49 to TDF/FTC. One-hundred and fifty-seven participants were enrolled into cohort 2 with 106 randomized to DVR and 51 to TDF/FTC. In both cohorts, pregnancy complications were rare and similar to local background rates. CONCLUSION: In this first study of a long-acting HIV prevention agent in pregnancy, adverse pregnancy outcomes and complications were uncommon when DVR and TDF/FTC were used in the third trimester of pregnancy, suggesting a favorable safety profile for both prevention products.
Assuntos
Infecções por HIV , Feminino , Gravidez , Humanos , Infecções por HIV/prevenção & controle , Emtricitabina , Idade Gestacional , Malaui , Tenofovir/efeitos adversosRESUMO
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: 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
BACKGROUND: The effect of pneumococcal vaccination of mothers with human immunodeficiency virus (HIV) on infant responses to childhood vaccination has not been studied. We compared the immunogenicity of 10-valent pneumococcus conjugate vaccine (PCV-10) in HIV-exposed uninfected infants born to mothers who received PCV-10, 23-valent pneumococcus polysaccharide vaccine (PPV-23), or placebo during pregnancy. METHODS: Antibody levels against 7 serotypes were measured at birth, before the first and second doses of PCV-10m and after completion of the 2-dose regimen in 347 infants, including 112 born to mothers who received PPV-23, 112 who received PCV-10, and 119 who received placebo during pregnancy. Seroprotection was defined by antibody levels ≥0.35 µg/mL. RESULTS: At birth and at 8 weeks of life, antibody levels were similar in infants born to PCV-10 or PPV-23 recipients and higher than in those born to placebo recipient. After the last dose of PCV-10, infants in the maternal PCV-10 group had significantly lower antibody levels against 5 serotypes than those in the maternal PPV-23 group and against 3 serotypes than those in the maternal placebo group, and they did not have higher antibody levels against any serotype. The seroprotection rate against 7 serotypes was 50% in infants in the maternal PCV-10 group, compared with 71% in both of the maternal PPV-23 and placebo groups (Pâ <â .001). CONCLUSIONS: Administration of PCV-10 during pregnancy was associated with decreased antibody responses to PCV-10 and seroprotection rates in infants. Considering that PCV-10 and PPV-23 had similar immunogenicity in pregnant women with HIV and that administration of PPV-23 did not affect the immunogenicity of PCV-10 in infants, PPV-23 in pregnancy may be preferred over PCV-10.
Assuntos
Infecções por HIV , Infecções Pneumocócicas , Anticorpos Antibacterianos/uso terapêutico , Feminino , HIV , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Polissacarídeos , Gravidez , Streptococcus pneumoniae , Vacinação , Vacinas ConjugadasRESUMO
BACKGROUND: Pneumococcal vaccination is recommended in people with HIV, prioritizing PCV. We compared the immunogenicity of PCV-10 and PPV-23 administered antepartum or postpartum. METHODS: This double-blind study randomized 346 pregnant women with HIV on antiretrovirals to PCV-10, PPV-23, or placebo at 14-34 weeks gestational age. Women who received placebo antepartum were randomized at 24 weeks postpartum to PCV-10 or PPV-23. Antibodies against 7 serotypes common to both vaccines and 1 serotype only in PPV-23 were measured by ELISA/chemiluminescence; B- and T-cell responses to serotype 1 by FLUOROSPOT; and plasma cytokines/chemokines by chemiluminescence. RESULTS: Antibody responses were higher after postpartum versus antepartum vaccination. PCV-10 generated lower antibody levels than PPV-23 against 4 and higher against 1 of 7 common serotypes. Additional factors associated with high postvaccination antibody concentrations were high prevaccination antibody concentrations and CD4+ cells; low CD8+ cells and plasma HIV RNA; and several plasma cytokines/chemokines. Serotype 1 B- and T-cell memory did not increase after vaccination. CONCLUSIONS: Antepartum immunization generated suboptimal antibody responses, suggesting that postpartum booster doses may be beneficial and warrant further studies. Considering that PCV-10 and PPV-23 had similar immunogenicity, but PPV-23 covered more serotypes, use of PPV-23 may be prioritized in women with HIV on antiretroviral therapy. CLINICAL TRAILS REGISTRATION: NCT02717494.
Assuntos
Infecções por HIV , Infecções Pneumocócicas , Anticorpos Antibacterianos , Citocinas , Feminino , Infecções por HIV/complicações , Humanos , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas , Polissacarídeos , Período Pós-Parto , Gravidez , Vacinação , Vacinas ConjugadasRESUMO
BACKGROUND: Pneumococcus remains an important cause of morbidity in pregnant women with HIV and their infants. We compared the safety and immunogenicity of PCV-10 and PPV-23 with placebo administered in pregnancy. METHODS: This double-blind, multicentre, randomised controlled trial was done at eight outpatient clinics in Brazil. Eligible participants were adult women with HIV who were pregnant at a gestational age between 14 weeks and less than 34 weeks and who were taking antiretroviral therapy at study entry. Participants were randomly assigned (1:1:1) to receive either PCV-10, PPV-23, or placebo. Participants and study teams were unaware of treatment allocation. Antibodies against seven vaccine serotypes in PCV-10 and PPV-23 were measured by ELISA. The primary outcomes were maternal and infant safety assessed by the frequency of adverse events of grade 3 or higher; maternal seroresponse (defined as ≥2-fold increase in antibodies from baseline to 28 days after immunisation) against five or more serotypes; and infant seroprotection (defined as anti-pneumococcus antibody concentration of ≥0·35 µg/mL) against five or more serotypes at 8 weeks of life. The study was powered to detect differences of 20% or higher in the primary immunological outcomes between treatment groups. This trial is registered with ClinicalTrials.gov, NCT02717494. FINDINGS: Between April 1, 2016, and Nov 30, 2017, we enrolled 347 pregnant women with HIV, of whom 116 were randomly assigned to the PCV-10 group, 115 to the PPV-23 group, and 116 to the placebo group. One participant in the PCV-10 group did not receive the vaccine and was excluded from subsequent analyses. The frequency of adverse events of grade 3 or higher during the first 4 weeks was similar in the vaccine and placebo groups (3% [90% CI 1-7] for the PCV-10 group, 2% [0-5] for the PPV-23 group, and 3% [1-8] for the placebo group). However, injection site and systemic grade 2 adverse reactions were reported more frequently during the first 4 weeks in the vaccine groups than in the placebo group (14% [9-20] for the PCV-10 group, 7% [4-12] for the PPV-23 group, and 3% [1-7] for the placebo group). The frequency of grade 3 or higher adverse effects was similar across maternal treatment groups (20% [14-27] for the PCV-10 group, 21% [14-28] for the PPV-23 group, and 20% [14-27] for the placebo group). Seroresponses against five or more serotypes were present in 74 (65%) of 114 women in the PCV-10 group, 72 (65%) of 110 women in the PPV-23 group, and none of the 113 women in the placebo group at 4 weeks post vaccination (p<0·0001 for PPV-23 group vs placebo and PCV-10 group vs placebo). Seroresponse differences of 20% or higher in vaccine compared with placebo recipients persisted up to 24 weeks post partum. At birth, 76 (67%) of 113 infants in the PCV-10 group, 62 (57%) of 109 infants in the PPV-23 group, and 19 (17%) of 115 infants in the placebo group had seroprotection against five or more serotypes (p<0·0001 for PPV-23 vs placebo and PCV-10 vs placebo). At 8 weeks, the outcome was met by 20 (19%) of 108 infants in the PCV-10 group, 24 (23%) of 104 infants in the PPV-23 group, and one (1%) of 109 infants in the placebo group (p<0·0001). Although a difference of 20% or higher compared with placebo was observed only in the infants who received PPV-23 at 8 weeks of life, the difference between the two vaccine groups was not appreciable. INTERPRETATION: PCV-10 and PPV-23 were equally safe and immunogenic in pregnant women with HIV and conferred similar levels of seroprotection to their infants. In areas in which childhood PCV administration decreased the circulation of PCV serotypes, PPV-23 administration to pregnant women with HIV might be more advantageous than PCV by virtue of including a broader range of serotypes. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.
Assuntos
Anticorpos Antibacterianos/imunologia , Infecções por HIV/complicações , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Adulto , Fármacos Anti-HIV/uso terapêutico , Brasil , Método Duplo-Cego , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Lactente , Recém-Nascido , Masculino , Placenta/imunologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Vacinas Pneumocócicas/efeitos adversos , Gravidez , Gestantes , Streptococcus pneumoniae/imunologia , Adulto JovemRESUMO
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. 3.3âkg); and reached lower weight (5.9 vs. 8.5âkg) and height (53.6 vs. 68.8âcm) at 6 months. With the exception of vascular cell adhesion molecule, inflammatory markers were generally higher (Pâ≤â0.005) 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 (Pâ<â0.001). In HEU, elevated levels of high-sensitivity C-reactive protein and IP-10 at birth were associated with lower weight at birth (Pâ=â0.04) and at 6 months (Pâ=â0.04). 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.
Assuntos
Infecções por HIV/imunologia , Inflamação/imunologia , Monócitos/imunologia , Mães , Estresse Oxidativo/imunologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Adulto , Biomarcadores/sangue , Brasil/epidemiologia , Feminino , Infecções por HIV/sangue , Humanos , Imunofenotipagem , Lactente , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Inflamação/sangue , Inflamação/virologia , Estudos Longitudinais , Masculino , Gravidez , Complicações Infecciosas na Gravidez/sangueRESUMO
BACKGROUND: Human papillomavirus (HPV) testing as primary cervical cancer screening has not been studied in Caribbean women. We tested vaginal self-collection versus physician cervical sampling in a population of Haitian women. METHODS: Participants were screened for high-risk HPV with self-performed vaginal and clinician-collected cervical samples using Hybrid Capture 2 assays (Qiagen, Gaithersburg, MD). Women positive by either method then underwent colposcopy with biopsy of all visible lesions. Sensitivity and positive predictive value were calculated for each sample method compared with biopsy results, with κ statistics performed for agreement. McNemar tests were performed for differences in sensitivity at ≥cervical intraepithelial neoplasia (CIN)-I and ≥CIN-II. RESULTS: Of 1845 women screened, 446 (24.3%) were HPV positive by either method, including 105 (5.7%) only by vaginal swab and 53 (2.9%) only by cervical swab. Vaginal and cervical samples were 91.4% concordant (κ = 0.73 [95% confidence interval, 0.69-0.77], P < 0.001). Overall, 133 HPV-positive women (29.9%) had CIN-I, whereas 32 (7.2%) had ≥CIN-II. The sensitivity of vaginal swabs was similar to cervical swabs for detecting ≥CIN-I (89.1% vs. 87.9%, respectively; P = 0.75) lesions and ≥CIN-II disease (87.5% vs. 96.9%, P = 0.18). Eighteen of 19 cases of CIN-III and invasive cancer were found by both methods. CONCLUSIONS: Human papillomavirus screening via self-collected vaginal swabs or physician-collected cervical swabs are feasible options in this Haitian population. The agreement between cervical and vaginal samples was high, suggesting that vaginal sample-only algorithms for screening could be effective for improving screening rates in this underscreened population.