Publications by authors named "Marisa M Mussi-Pinhata"

46 Publications

Safety, immunogenicity, and transplacental antibody transport of conjugated and polysaccharide pneumococcal vaccines administered to pregnant women with HIV: a multicentre randomised controlled trial.

Lancet HIV 2021 07 27;8(7):e408-e419. Epub 2021 Apr 27.

Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.

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.
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http://dx.doi.org/10.1016/S2352-3018(20)30339-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249331PMC
July 2021

Low technology, mild controlled hypothermia for necrotizing enterocolitis treatment: an initiative to improve healthcare to preterm neonates.

Eur J Pediatr 2021 Oct 24;180(10):3161-3170. Epub 2021 Apr 24.

Department of Surgery. Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.

Necrotizing enterocolitis (NEC) treatment remains unchanged for years. Data suggest that mild controlled hypothermia could potentially improve NEC outcomes. Our units presented unfavourable outcomes on NEC. The aim was to assess our experience with low technology, mild controlled hypothermia on NEC outcomes, and improve preterm infants' healthcare. This was a single-center quality improvement study with retrospective cohort design at the neonatal intensive care unit in the university hospital. Forty-three preterm infants with NEC (Modified Bell's Stage II/III) were included: 19 in the control group (2015-2018) and 24 in the hypothermia group (2018-2020). The control group received standard treatment (fasting, abdominal decompression, and broad-spectrum antibiotics). The hypothermia group underwent cooling to 35.5 °C for 48 h after NEC diagnosis, along with conventional treatment. The primary outcomes are intestinal perforation, need for surgery, duration of parenteral nutrition, death, and extensive resection of the small intestine. There was no statistical difference in the NEC score. The hypothermia group required less surgery (aRR 0.40; 95% CI 0.19-0.85), presented less bowel perforation (aRR 0.39; 95% CI 0.18; 0.83), had a shorter duration of parenteral nutrition (aHR 5.28; 95% CI 1.88-14.89), did not need extensive intestinal resection, (0 vs 15.7%), and did not experience any deaths (0 vs 31.6%).Conclusions: In our experience, low technology, mild controlled hypothermia was feasible, not related to adverse effects, and effective treatment for NEC Modified Bell's Stage II/III. It avoided surgery, bowel perforation, and extensive intestinal resection; reduced mortality; and shortened parenteral nutrition duration. What is Known: • New approaches have been proposed to avoid enterocolitis incidence; however, the treatment of enterocolitis stage 2 has been the same for decades, and unfavourable outcomes remain despite conventional management. • Studies suggest that hypothermia can be an alternative to enterocolitis treatment. What is New: • Mild controlled hypothermia can be an additional practice to treat enterocolitis stage 2, is feasible, and is not related to adverse effects to preterm infants. • It can decrease surgery needs, duration of parenteral nutrition, and death and avoids extensive intestinal resection in preterm infants.
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http://dx.doi.org/10.1007/s00431-021-04014-1DOI Listing
October 2021

Comprehensive evaluation of risk factors for neonatal hearing loss in a large Brazilian cohort.

J Perinatol 2021 02 3;41(2):315-323. Epub 2020 Sep 3.

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.

Objectives: To determine the incidence and risk factors of hearing loss (HL) in Brazilian neonates.

Study Design: 11,900 neonates were screened for hearing and congenital CMV (cCMV). Low and high-risk babies who did not pass their hearing screening and infants with cCMV were scheduled for a diagnostic audiologic evaluation.

Results: The incidence of HL was 2 per 1000 live-born infants (95% CI: 1-3). HL was higher in high-risk neonates than in low risk babies (18.6 vs. 0.3/1000 live births, respectively). Among infants exposed to isolated risk factors, association of HL with craniofacial abnormalities/syndromes (RR = 24.47; 95% CI: 5.9-100.9) and cCMV (RR = 9.54; 95% CI: 3.3-27.7) were observed. HL was 20 to 100-fold more likely in neonates exposed to ototoxic drugs in combination with cCMV or craniofacial/congenital anomalies.

Conclusions: Strategies for the prevention of cCMV and exposure to ototoxic drugs may decrease the incidence of HL in this population.
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http://dx.doi.org/10.1038/s41372-020-00807-8DOI Listing
February 2021

International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol.

BMC Pregnancy Childbirth 2019 Aug 7;19(1):282. Epub 2019 Aug 7.

Maternal-Infant Studies Center (CEMI), San Juan, Puerto Rico.

Background: Until recently, Zika virus (ZIKV) infections were considered mild and self-limiting. Since 2015, they have been associated with an increase in microcephaly and other birth defects in newborns. While this association has been observed in case reports and epidemiological studies, the nature and extent of the relationship between ZIKV and adverse pregnancy and pediatric health outcomes is not well understood. With the unique opportunity to prospectively explore the full spectrum of issues related to ZIKV exposure during pregnancy, we undertook a multi-country, prospective cohort study to evaluate the association between ZIKV and pregnancy, neonatal, and infant outcomes.

Methods: At research sites in ZIKV endemic regions of Brazil (4 sites), Colombia, Guatemala, Nicaragua, Puerto Rico (2 sites), and Peru, up to 10,000 pregnant women will be recruited and consented in the first and early second trimesters of pregnancy and then followed through delivery up to 6 weeks post-partum; their infants will be followed until at least 1 year of age. Pregnant women with symptomatic ZIKV infection confirmed by presence of ZIKV RNA and/or IgM for ZIKV will also be enrolled, regardless of gestational age. Participants will be tested monthly for ZIKV infection; additional demographic, physical, laboratory and environmental data will be collected to assess the potential interaction of these variables with ZIKV infection. Delivery outcomes and detailed infant assessments, including physical and neurological outcomes, will be obtained.

Discussion: With the emergence of ZIKV in the Americas and its association with adverse pregnancy outcomes in this region, a much better understanding of the spectrum of clinical outcomes associated with exposure to ZIKV during pregnancy is needed. This cohort study will provide information about maternal, fetal, and infant outcomes related to ZIKV infection, including congenital ZIKV syndrome, and manifestations that are not detectable at birth but may appear during the first year of life. In addition, the flexibility of the study design has provided an opportunity to modify study parameters in real time to provide rigorous research data to answer the most critical questions about the impact of congenital ZIKV exposure.

Trial Registration: NCT02856984 . Registered August 5, 2016. Retrospectively registered.
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http://dx.doi.org/10.1186/s12884-019-2430-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686399PMC
August 2019

Contribution of Congenital Cytomegalovirus Infection to Permanent Hearing Loss in a Highly Seropositive Population: The Brazilian Cytomegalovirus Hearing and Maternal Secondary Infection Study.

Clin Infect Dis 2020 03;70(7):1379-1384

Department of Pediatrics, Otorhinolaryngology, and Head and Neck Surgery, Ribeirão Preto Medical School, University of São Paulo, Brazil.

Background: The exact contribution of congenital cytomegalovirus infection (cCMVI) to permanent hearing loss (HL) in highly seropositive populations is unknown. We determined the contribution of cCMVI to HL and estimated the effectiveness of newborn hearing screening (HS) in identifying neonates with CMV-related HL.

Methods: A total of 11 900 neonates born from a population with ≥97% maternal seroprevalence were screened for cCMVI and HL. cCMVI was confirmed by detection of CMV-DNA in saliva and urine at age <3 weeks.

Results: Overall, 68 (0.6%; 95% confidence interval [CI], 0.4-0.7) neonates were identified with cCMVI. Of the 91 (0.8%) newborns who failed the HS, 24 (26.4%) were confirmed with HL, including 7 (29.2%; 95% CI, 17.2-59.3) with cCMVI. Another newborn with cCMVI passed the HS but was confirmed with HL at age 21 days. Of the 62 neonates with cCMVI who underwent a complete hearing evaluation, 8 (12.9%; 95% CI, 6.7-23.4) had HL and most (7/8; 87.5%; 95% CI, 46.6-99.7) were identified by HS. The rate of CMV-related HL was 8 per 11 887 neonates (0.7 per 1000 live births). The prevalence ratio of HL among neonates with cCMVI compared to CMV-uninfected neonates was 89.5 (95% CI, 39.7-202.0). No late-onset cCMVI-related HL was detected during a median follow-up of 36 months.

Conclusions: cCMVI is an important cause of HL in childhood in all settings. Integrating targeted cCMVI screening among neonates who fail a HS could be a reasonable, cost-effective strategy to identify newborns with early-onset cCMVI-related HL.
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http://dx.doi.org/10.1093/cid/ciz413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931844PMC
March 2020

HCMV trimer- and pentamer-specific antibodies synergize for virus neutralization but do not correlate with congenital transmission.

Proc Natl Acad Sci U S A 2019 02 7;116(9):3728-3733. Epub 2019 Feb 7.

Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239;

Human cytomegalovirus (HCMV) causes substantial disease in transplant patients and harms the development of the nervous system in babies infected in utero. Thus, there is a major focus on developing safe and effective HCMV vaccines. Evidence has been presented that a major target of neutralizing antibodies (NAbs) is the HCMV pentamer glycoprotein gH/gL/UL128-131. In some studies, most of the NAbs in animal or human sera were found to recognize the pentamer, which mediates HCMV entry into endothelial and epithelial cells. It was also reported that pentamer-specific antibodies correlate with protection against transmission from mothers to babies. One problem with the studies on pentamer-specific NAbs to date has been that the studies did not compare the pentamer to the other major form of gH/gL, the gH/gL/gO trimer, which is essential for entry into all cell types. Here, we demonstrate that both trimer and pentamer NAbs are frequently found in human transplant patients' and pregnant mothers' sera. Depletion of human sera with trimer caused reductions in NAbs similar to that observed following depletion with the pentamer. The trimer- and pentamer-specific antibodies acted in a synergistic fashion to neutralize HCMV and also to prevent virus cell-to-cell spread. Importantly, there was no correlation between the titers of trimer- and pentamer-specific NAbs and transmission of HCMV from mothers to babies. Therefore, both the trimer and pentamer are important targets of NAbs. Nevertheless, these antibodies do not protect against transmission of HCMV from mothers to babies.
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http://dx.doi.org/10.1073/pnas.1814835116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397592PMC
February 2019

HIV-exposed-uninfected infants have increased inflammation and monocyte activation.

AIDS 2019 04;33(5):845-853

University Hospitals Cleveland Medical Center.

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.
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http://dx.doi.org/10.1097/QAD.0000000000002128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494115PMC
April 2019

Congenital Cytomegalovirus and HIV Perinatal Transmission.

Pediatr Infect Dis J 2018 10;37(10):1016-1021

From the David Geffen UCLA School of Medicine, Los Angeles, CA.

Background: Congenital cytomegalovirus (CMV) infection (cCMV) is an important cause of hearing loss and cognitive impairment. Prior studies suggest that HIV-exposed children are at higher risk of acquiring cCMV. We assessed the presence, magnitude and risk factors associated with cCMV among infants born to HIV-infected women, who were not receiving antiretrovirals during pregnancy.

Methods: cCMV and urinary CMV load were determined in a cohort of infants born to HIV-infected women not receiving antiretrovirals during pregnancy. Neonatal urines obtained at birth were tested for CMV DNA by qualitative and reflex quantitative real-time polymerase chain reaction.

Results: Urine specimens were available for 992 (58.9%) of 1684 infants; 64 (6.5%) were CMV-positive. Mean CMV load (VL) was 470,276 copies/ml (range: < 200-2,000,000 copies/ml). Among 89 HIV-infected infants, 16 (18%) had cCMV versus 42 (4.9%) of 858 HIV-exposed, uninfected infants (P < 0.0001). cCMV was present in 23.2% of infants with in utero and 9.1% infants with intrapartum HIV infection (P < 0.0001). Rates of cCMV among HIV-infected infants were 4-fold greater (adjusted OR, 4.4; 95% CI: 2.3-8.2) and 6-fold greater among HIV in utero-infected infants (adjusted OR, 6; 95% CI: 3-12.1) compared with HIV-exposed, uninfected infants. cCMV was not associated with mode of delivery, gestational age, Apgar scores, 6-month infant mortality, maternal age, race/ethnicity, HIV viral load or CD4 count. Primary cCMV risk factors included infant HIV-infection, particularly in utero infection.

Conclusion: High rates of cCMV with high urinary CMV VL were observed in HIV-exposed infants. In utero HIV infection appears to be a major risk factor for cCMV in infants whose mothers have not received combination antiretroviral therapy in pregnancy.
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http://dx.doi.org/10.1097/INF.0000000000001975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129438PMC
October 2018

Seroconversion for Cytomegalovirus Infection During Pregnancy and Fetal Infection in a Highly Seropositive Population: "The BraCHS Study".

J Infect Dis 2018 09;218(8):1200-1204

Department of Pediatrics, The University of Alabama at Birmingham.

We determined the risk of seroconversion in seronegative pregnant women living in a high seroprevalence population. Cytomegalovirus (CMV)-immunoglobulin G reactivity was determined at the 1st trimester in all women and sequentially for seronegative women. A total of 1915 of 1952 (98.1%; 95% confidence interval [CI], 97.4%-98.7%) women were seropositive, and 36 (1.8%; 95% CI, 1.3%-2.6%) were seronegative. Five of the 36-seronegative women seroconverted for a cumulative rate of 13.9% (95% CI, 4.8%-30.6%). Congenital CMV infection was diagnosed in 1 of 36 infants (2.8%; 95% CI, 0.5%-63.9%) born to seronegative women compared with 8 of 1685 (0.5%; 95% CI, 0.2%-1.0%) infants born to seropositive mothers. Even with a high risk of primary infection in seronegative women, most CMV-infected infants were born to women with pre-existing seroimmunity.
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http://dx.doi.org/10.1093/infdis/jiy321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129109PMC
September 2018

Infectious Morbidity, Mortality and Nutrition in HIV-exposed, Uninfected, Formula-fed Infants: Results From the HPTN 040/PACTG 1043 Trial.

Pediatr Infect Dis J 2018 12;37(12):1271-1278

From the David Geffen UCLA School of Medicine, Los Angeles, California.

Background: HIV-exposed uninfected (HEU) infants are a growing population with potentially poor health outcomes. We evaluated morbidity and mortality in HEU formula-fed infants enrolled in the NICHD HPTN 040/PACTG 1043 trial.

Methods: Infectious morbidity, mortality and undernutrition were evaluated within a cohort of 1000 HEU infants enrolled between April 2004 and April 2010 in Brazil (n = 766) and South Africa (n = 234) as part of the NICHD/HPTN 040 trial of 3 different antiretroviral regimens to decrease intrapartum HIV vertical transmission.

Results: Twenty-three percent of infants had at least 1 infectious serious adverse effect. Infants born to mothers with <12 years of education [adjusted odds ratio (AOR), 2.6; 95% confidence interval [CI], 1.2-5.9), with maternal viral load of >1,000,000 copies/mL at delivery (AOR, 9.9; 95% CI, 1.6-63.1) were more likely to have infectious serious adverse effects. At 6 months, the infant mortality rate per 1000 live births overall was 22 ± 2.6, 9.1 ± 1.8 in Brazil and 64.1 ± 3 in South Africa. Undernutrition and stunting peaked at 1 month of age with 18% having a weight-for-age Z score ≤-2, and 22% with height for Z score ≤-2. The likelihood of infant mortality was greater among infants born in South Africa compared with Brazil (AOR, 6.2; 95% CI, 2.5-15.8), high maternal viral load (AOR, 1.7; 95% CI, 1.01-2.9) and birth weight-for-age Z score ≤-2 (AOR, 5.2; 95% CI, 1.8-14.8).

Conclusions: There were high rates of undernutrition, stunting and infectious serious adverse effect in this study's formula-fed HEU population. Suppressing maternal HIV viral load during the peripartum period may be a modifiable risk factor to decrease infant mortality.
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http://dx.doi.org/10.1097/INF.0000000000002082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226320PMC
December 2018

Factors Associated with Lower Respiratory Tract Infections in HIV-Exposed Uninfected Infants.

AIDS Res Hum Retroviruses 2018 06 23;34(6):527-535. Epub 2018 Apr 23.

5 Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, Maryland.

To identify factors that predispose human immunodeficiency virus (HIV)-exposed uninfected infants (HEUs) to higher incidence of severe infections, hospitalization, and death in the first 6-24 months of life compared with HEUs with and without lower respiratory tract infection (LRTI) in the first 6 months of life. Nested case-control study of 107 LRTI+ infants enrolled in the International Site Development Initiative (NISDI) Perinatal and Longitudinal Study in Latin American Countries (LILAC) studies with and 140 LRTI- in the first 6 months, matched by date and place of birth. Infants and mothers had plasma antibodies measured against respiratory syncytial virus (RSV), parainfluenza (PIV) 1, 2, 3, influenza, and pneumococcus 1, 5, 6B, and 14. Compared with LRTI-, mothers of LRTI+ HEUs had lower years of education, lower CD4 cells, and higher HIV plasma viral load at delivery, but similar use of antiretrovirals and cotrimoxazole and other sociodemographic characteristics. LRTI+ and LRTI- HEUs had similar demographic and hematological characteristics and antibody concentrations against respiratory pathogens at birth. At 6 months, the rates of seroconversions to respiratory pathogens and antibody responses to tetanus vaccine were also similar. However, antibody concentrations to RSV were significantly higher in LRTI+ compared with LRTI- HEUs and marginally higher to PIV1. Maternal factors associated with advanced HIV disease, but unrelated to the use of antiretrovirals, cotrimoxazole, or the level of maternal antibodies against respiratory pathogens, contribute to the increased risk of LRTI in HEUs. In HEUs, antiretroviral and cotrimoxazole use, exposure to respiratory pathogens and humoral immune responses were not associated with the incidence of LRTI.
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http://dx.doi.org/10.1089/AID.2017.0245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994671PMC
June 2018

Cytomegalovirus Shedding in Seropositive Pregnant Women From a High-Seroprevalence Population: The Brazilian Cytomegalovirus Hearing and Maternal Secondary Infection Study.

Clin Infect Dis 2018 08;67(5):743-750

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Brazil.

Background: Most congenital cytomegalovirus (CMV) infections in highly seropositive populations occur in infants born to women with preexisting CMV seroimmunity. Although essential for developing prevention strategies, CMV shedding patterns in pregnant women with nonprimary infections have not been characterized. We investigated correlates of CMV shedding in a cohort of seropositive pregnant women.

Methods: In a prospective study, saliva, urine, vaginal swabs, and blood were collected from 120 CMV-seropositive women in the first, second, and third trimesters and 1 month postpartum. Specimens were tested for CMV DNA by polymerase chain reaction. We analyzed the contribution of the specific maternal characteristics to viral shedding.

Results: CMV shedding was detected at least once in 42 (35%) women. Mothers living with or providing daily care to young children (3-6 years) were twice as likely to shed CMV at least once compared to women with less exposure to young children (58% vs 26%; adjusted relative risk [aRR], 2.21; 95% confidence interval [CI], 1.37-3.56). Living in crowded households (≥2 people per room) was associated with viral shedding (64% vs 31%; aRR, 1.99; 95% CI, 1.26-3.13). Sexual activity as indicated by the number of sexual partners per year or condom use was not found to be a correlate of viral shedding.

Conclusions: CMV shedding is relatively frequent in seropositive pregnant women. The association between virus shedding and caring for young children as well as crowded living conditions may provide opportunities for increased exposures that could lead to CMV reinfections in seropositive women.
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http://dx.doi.org/10.1093/cid/ciy166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094000PMC
August 2018

Combined evaluation of sexually transmitted infections in HIV-infected pregnant women and infant HIV transmission.

PLoS One 2018 5;13(1):e0189851. Epub 2018 Jan 5.

David Geffen UCLA School of Medicine, Los Angeles, CA, United States of America.

Background: Sexually transmitted infections (STIs) including Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Treponema pallidum (TP), and cytomegalovirus (CMV) may lead to adverse pregnancy and infant outcomes. The role of combined maternal STIs in HIV mother-to-child transmission (MTCT) was evaluated in mother-infant pairs from NICHD HPTN 040.

Methodology: Urine samples from HIV-infected pregnant women during labor were tested by polymerase chain reaction (PCR) for CT, NG, and CMV. Infant HIV infection was determined by serial HIV DNA PCR testing. Maternal syphilis was tested by VDRL and confirmatory treponemal antibodies.

Results: A total of 899 mother-infant pairs were evaluated. Over 30% had at least one of the following infections (TP, CT, NG, and/or CMV) detected at the time of delivery. High rates of TP (8.7%), CT (17.8%), NG (4%), and CMV (6.3%) were observed. HIV MTCT was 9.1% (n = 82 infants). HIV MTCT was 12.5%, 10.3%, 11.1%, and 26.3% among infants born to women with CT, TP, NG or CMV respectively. Forty-two percent of HIV-infected infants were born to women with at least one of these 4 infections. Women with these infections were nearly twice as likely to have an HIV-infected infant (aOR 1.9, 95% CI 1.1-3.0), particularly those with 2 STIs (aOR 3.4, 95% CI 1.5-7.7). Individually, maternal CMV (aOR 4.4 1.5-13.0) and infant congenital CMV (OR 4.1, 95% CI 2.2-7.8) but not other STIs (TP, CT, or NG) were associated with an increased risk of HIV MTCT.

Conclusion: HIV-infected pregnant women identified during labor are at high risk for STIs. Co-infection with STIs including CMV nearly doubles HIV MTCT risk. CMV infection appears to confer the largest risk of HIV MTCT.

Trial Registration: NCT00099359.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189851PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755782PMC
January 2018

Immunity After Childhood Vaccinations in Perinatally HIV-exposed Children With and Without HIV Infection in Latin America.

Pediatr Infect Dis J 2018 04;37(4):304-309

Background: Perinatally HIV-infected (PHIV) children are at risk for under-vaccination and poor vaccine response at 4 years of age. Childhood vaccine coverage and immune response were compared between PHIV and HIV-exposed uninfected (HEU) children in Latin America and the Caribbean.

Methods: PHIV and HEU children were enrolled prospectively at 15 sites from 2002 to 2009. Full vaccination by age 4 years was defined as: 3 hepatitis B virus vaccine doses; 4 tetanus toxoid-containing vaccine doses; 3 doses of Haemophilus influenzae type b vaccine by age 12 months or ≥1 dose given after age 12 months; one measles-containing vaccine dose; one rubella-containing vaccine dose. Immunity was defined by serum antibody titer. Fisher exact test (for categorical measures) and t test (for continuous measures) were used for comparisons.

Results: Among 519 children seen at age 4 years, 191 had serum specimens available (137 PHIV, 54 HEU). Among those with specimens available, 29.3% initiated combination antiretroviral therapy (cART) <12 months of age, 30.9% initiated at ≥12 months of age, and 39.8% had not received cART by the time they were seen at 4 years of age. At 4 years of age, 59.9% were on PI-containing cART (cART/PI), and 20.4% were on no ART. PHIV children were less likely than HEU children to be fully vaccinated for tetanus (55.5% vs. 77.8%, P = 0.005) and measles and rubella (both 70.1% vs. 94.4%, P < 0.001). Among those fully vaccinated, immunity was significantly lower among PHIV than HEU for all vaccines examined: 20.9% versus 37.8% for hepatitis B virus (P = 0.04), 72.0% versus 90.5% for tetanus (P = 0.02), 51.4% versus 68.8% for H. influenzae type b (P = 0.05), 80.2% versus 100% for measles (P < 0.001) and 72.9% versus 98.0% for rubella (P < 0.001) vaccine, respectively.

Conclusions: Compared with HEU, PHIV children were significantly less likely to be immune to vaccine-preventable diseases when fully vaccinated. Strategies to increase immunity against vaccine-preventable diseases among PHIV require further study.
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http://dx.doi.org/10.1097/INF.0000000000001831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849487PMC
April 2018

Altered Natural Killer Cell Function in HIV-Exposed Uninfected Infants.

Front Immunol 2017 24;8:470. Epub 2017 Apr 24.

Department of Pediatric Infectious Diseases, University of Colorado School of Medicine, Aurora, CO, USA.

Objectives: HIV-exposed uninfected (HEU) infants have higher rates of severe and fatal infections compared with HIV-unexposed (HUU) infants, likely due to immune perturbations. We hypothesized that alterations in natural killer (NK) cell activity might occur in HEU infants and predispose them to severe infections.

Design: Case-control study using cryopreserved peripheral blood mononuclear cells (PBMCs) at birth and 6 months from HEU infants enrolled from 2002 to 2009 and HUU infants enrolled from 2011 to 2013.

Methods: NK cell phenotype and function were assessed by flow cytometry after 20-h incubation with and without K562 cells.

Results: The proportion of NK cells among PBMCs was lower at birth in 12 HEU vs. 22 HUU (1.68 vs. 10.30%,  < 0.0001) and at 6 months in 52 HEU vs. 72 HUU (3.09 vs. 4.65%,  = 0.0005). At birth, HEU NK cells demonstrated increased killing of K562 target cells ( < 0.0001) and increased expression of CD107a (21.65 vs. 12.70%,  = 0.047), but these differences resolved by 6 months. Stimulated HEU NK cells produced less interferon (IFN)γ at birth (0.77 vs. 2.64%,  = 0.008) and at 6 months (4.12 vs. 8.39%,  = 0.001), and showed reduced perforin staining at 6 months (66.95 vs. 77.30%,  = 0.0008). Analysis of cell culture supernatants indicated that lower NK cell activity in HEU was associated with reduced interleukin (IL)-12, IL-15, and IL-18. Addition of recombinant human IL-12 to stimulated HEU PBMCs restored IFNγ production to that seen in stimulated HUU cultures.

Conclusion: NK cell proportion, phenotype, and function are altered in HEU infants. NK cell cytotoxicity and degranulation are increased in HEU at birth, but HEU NK cells have reduced IFNγ and perforin production, suggesting an adequate initial response, but decreased functional reserve. NK cell function improved with addition of exogenous IL-12, implicating impaired production of IL-12 by accessory cells. Alterations in NK cell and accessory cell function may contribute to the increased susceptibility to infection in HEU infants.
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http://dx.doi.org/10.3389/fimmu.2017.00470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403425PMC
April 2017

Congenital Zika Virus Infection Induces Severe Spinal Cord Injury.

Clin Infect Dis 2017 08;65(4):687-690

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.

We report 2 fatal cases of congenital Zika virus (ZIKV) infection. Brain anomalies, including atrophy of the cerebral cortex and brainstem, and cerebellar aplasia were observed. The spinal cord showed architectural distortion, severe neuronal loss, and microcalcifications. The ZIKV proteins and flavivirus-like particles were detected in cytoplasm of spinal neurons, and spinal cord samples were positive for ZIKV RNA.
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http://dx.doi.org/10.1093/cid/cix374DOI Listing
August 2017

Cytomegalovirus Urinary Shedding in HIV-infected Pregnant Women and Congenital Cytomegalovirus Infection.

Clin Infect Dis 2017 Aug;65(3):405-413

David Geffen University of California, Los Angeles School of Medicine, Los Angeles, California.

Background: Cytomegalovirus (CMV) urinary shedding in pregnant women infected with human immunodeficiency virus (HIV) was evaluated to determine whether it poses an increased risk for congenital CMV infection (cCMV).

Methods: A subset of mother-infant pairs enrolled in the perinatal NICHD HPTN 040 study (distinguished by no antiretroviral use before labor) was evaluated. Maternal and infant urines were tested by qualitative real-time polymerase chain reaction (RT-PCR) for CMV DNA with quantitative RT-PCR performed on positive specimens.

Results: Urine specimens were available for 260 women with 85.4% from the Americas and 14.6% from South Africa. Twenty-four women (9.2%) had detectable CMV viruria by qualitative PCR. Maternal CMV viruria was not associated with mean CD4 cell counts or HIV viral load but was associated with younger maternal age (P = .02). Overall, 10 of 260 infants (3.8%) had cCMV. Women with detectable peripartum CMV viruria were more likely to have infants with cCMV than those without: 20.8% (5/24) versus 2.1% (5/236), (P = .0001). Women with CMV viruria had significantly higher rates of HIV perinatal transmission (29.2% vs. 8.1%, P = .002). They were 5 times (adjusted odds ratio [aOR] = 5.6, 95% confidence interval [CI] 1.9-16.8) and nearly 30 times (aOR, 29.7; 95% CI, 5.4-164.2) more likely to transmit HIV and CMV to their infants, respectively. Maternal gonorrhea (aOR, 19.5; 95% CI, 2.5-151.3) and higher maternal HIV log10 viral load (OR, 2.8; 95% CI, 1.3-6.3) were also significant risk factors for cCMV.

Conclusion: In this cohort of HIV-infected pregnant women not on antiretrovirals, urinary CMV shedding was a significant risk factor for CMV and HIV transmission to infants.

Clinical Trials Registration Number: NCT00099359.
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http://dx.doi.org/10.1093/cid/cix222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850431PMC
August 2017

Excess respiratory viral infections and low antibody responses among HIV-exposed, uninfected infants.

AIDS 2017 03;31(5):669-679

aAnschutz Medical Center, University of Colorado Denver, Aurora, Colorado, USA bDepartment of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo, Sao Paulo, Brazil cWestat, Rockville, Maryland, USA dDepartamento de Medicina da Universidade Federal de Sao Carlos, Sao Carlos, Sao Paulo eEscola de Medicina da Universidade de Minas Gerais, Belo Horizonte, Minas Gerais fHFSE - Hospital Federal dos Servidores do Estado, Rio de Janeiro gEscola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, Brazil hEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland iUniversity of California, San Francisco, California, USA.

Objective: HIV-exposed uninfected (HEUs) infants have frequent severe infection, hospitalization, and death. We performed a serologic investigation to determine the role of common childhood respiratory pathogens in the excess incidence of infections in HEUs.

Design: Prospective cohort study of mother-infant pairs.

Methods: Among 247 HEUs and 88 HIV-unexposed uninfected (HUU) infant-mother pairs, we measured maternal antibodies to respiratory syncytial virus (RSV) and pneumococcus (PNC 1, 5, 6B, 14); infant antibodies to RSV, influenza A (flu), parainfluenza viruses (1, 2, 3), and PNC 1, 5, 6B, and 14 were measured at 0 and 6 months, and antitetanus antibodies at 6 months.

Results: HIV-infected mothers had higher RSV and lower PNC antibody concentrations at delivery than uninfected mothers. Transplacental transfer of maternal antibodies, particularly for RSV, was lower in HEUs compared with HUUs. At birth, HEUs had higher concentrations of anti-RSV antibodies than HUUs, but lower antibodies to the other respiratory agents. At 6 months, HEUs had significantly higher proportions of seroconversions and higher antibody concentrations against parainfluenza viruses 1, 2, and 3. There were no significant differences in seroconversions to flu and RSV, but antibody concentrations to RSV were six-fold lower in HEUs versus HUUs at 6 months. Antibody responses to at least two doses of tetanus vaccine were also six-fold lower in HEUs compared with HUUs.

Conclusion: Six-month-old HEUs had a higher incidence of respiratory viral infections than HUUs. In addition to the low passive protection from maternal antibodies, low antibody responses of HEUs may contribute to increased morbidity and mortality.
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http://dx.doi.org/10.1097/QAD.0000000000001393DOI Listing
March 2017

Characterizing human cytomegalovirus reinfection in congenitally infected infants: an evolutionary perspective.

Mol Ecol 2017 Apr 8;26(7):1980-1990. Epub 2017 Feb 8.

School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Given the strong selective pressures often faced by populations when colonizing a novel habitat, the level of variation present on which selection may act is an important indicator of adaptive potential. While often discussed in an ecological context, this notion is also highly relevant in our clinical understanding of viral infection, in which the novel habitat is a new host. Thus, quantifying the factors determining levels of variation is of considerable importance for the design of improved treatment strategies. Here, we focus on such a quantification of human cytomegalovirus (HCMV) - a virus which can be transmitted across the placenta, resulting in foetal infection that can potentially cause severe disease in multiple organs. Recent studies using genomewide sequencing data have demonstrated that viral populations in some congenitally infected infants diverge rapidly over time and between tissue compartments within individuals, while in other infants, the populations remain highly stable. Here, we investigate the underlying causes of these extreme differences in observed intrahost levels of variation by estimating the underlying demographic histories of infection. Importantly, reinfection (i.e. population admixture) appears to be an important, and previously unappreciated, player. We highlight illustrative examples likely to represent a single-population transmission from a mother during pregnancy and multiple-population transmissions during pregnancy and after birth.
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http://dx.doi.org/10.1111/mec.13953DOI Listing
April 2017

High Levels of Chemokine C-C Motif Ligand 20 in Human Milk and Its Production by Oral Keratinocytes.

Breastfeed Med 2017 03 2;12:116-121. Epub 2016 Dec 2.

1 Department of Pediatrics, Ribeirão Preto School of Medicine, University of São Paulo , São Paulo, Brazil .

Background: Chemokine C-C motif ligand 20 (CCL20) is implicated in the formation and function of mucosal lymphoid tissues. Although CCL20 is secreted by many normal human tissues, no studies have evaluated the presence of CCL20 in human milk or its production by oral keratinocytes stimulated by human milk.

Objective: To evaluate the presence of CCL20 in breast milk and verify CCL20 secretion in vitro by oral keratinocytes stimulated with human and bovine milk, as well as its possible association with breast milk lactoferrin levels.

Materials And Methods: The levels of CCL20 and lactoferrin were measured by enzyme-linked immunosorbent assay in human milk at three different stages of maturation from 74 healthy breastfeeding mothers. In vitro, oral keratinocytes were stimulated with human and bovine milk, and CCL20 was measured in their supernatant.

Results: High concentrations of CCL20 were detected in the human breast milk samples obtained during the first week (1,777.07 pg/mL) and second week postpartum (1,523.44 pg/mL), with a significantly low concentration in samples at 3-6 weeks postpartum (238.42 pg/mL; p < 0.0001). Human breast milk at different weeks postpartum stimulated higher CCL20 secretion by oral keratinocytes compared with bovine milk (p < 0.05). Such stimulation had no association with breast milk lactoferrin concentration.

Conclusion: CCl20 is present at high levels in human milk, predominantly in the first and second week postpartum, but at significantly lower levels at 3-6 weeks postpartum. Human milk is capable of stimulating CCL20 secretion by oral keratinocytes, and this induction had no association with breast milk lactoferrin concentration.
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http://dx.doi.org/10.1089/bfm.2016.0067DOI Listing
March 2017

Severe Vitamin D Deficiency in Human Immunodeficiency Virus-Infected Pregnant Women is Associated with Preterm Birth.

Am J Perinatol 2017 04 7;34(5):486-492. Epub 2016 Oct 7.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Maternal and Pediatric Infectious Disease Branch, Bethesda, Maryland.

 Low maternal vitamin D has been associated with preterm birth (PTB). Human immunodeficiency virus (HIV)-infected pregnant women are at risk for PTB, but data on maternal vitamin D and PTB in this population are scarce.  In a cohort of Latin American HIV-infected pregnant women from the National Institute of Child Health and Human Development International Site Development Initiative protocol, we examined the association between maternal vitamin D status and PTB. Vitamin D status was defined as the following 25-hydroxyvitamin D levels: severe deficiency (< 10 ng/mL), deficiency (10-20 ng/mL), insufficiency (21-29 ng/mL), and sufficiency (≥30 ng/mL). PTB was defined as delivery at < 37 weeks' gestational age (GA). Logistic regression was used to assess the association between maternal vitamin D status and PTB.  Of 715 HIV-infected pregnant women, 13 (1.8%) were severely vitamin D deficient, 224 (31.3%) were deficient, and 233 were (32.6%) insufficient. Overall, 23.2% (166/715) of pregnancies resulted in PTB (median GA of PTBs = 36 weeks [interquartile range: 34-36]). In multivariate analysis, severe vitamin D deficiency was associated with PTB (odds ratio = 4.7, 95% confidence interval: 1.3-16.8]).  Severe maternal vitamin D deficiency is associated with PTB in HIV-infected Latin American pregnant women. Further studies are warranted to determine if vitamin D supplementation in HIV-infected women may impact PTB.
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http://dx.doi.org/10.1055/s-0036-1593536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367960PMC
April 2017

Chlamydia trachomatis and Neisseria gonorrhoeae in HIV-infected Pregnant Women and Adverse Infant Outcomes.

Pediatr Infect Dis J 2016 Aug;35(8):894-900

From the *David Geffen UCLA School of Medicine, Los Angeles, California; †UCLA Fielding School of Public Health, Department of Epidemiology, Los Angeles, California; ‡Westat, Rockville, Maryland; §Fundacao Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil; ¶Office of the Global AIDS Coordinator, US Department of State, Washington DC; ‖Cepheid, Sunnyvale, California; **Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; ††Hospital Geral de Nova Iguaçu, DST/AIDS, Nova Iguaçu, Rio de Janeiro, Brazil; ‡‡Hospital Federal dos Servidores do Estado, Rio de Janeiro, Brazil; §§SAMRC and Perinatal HIV Research Unit, University of Witwatersrand, Cape Town, South Africa; ¶¶Department of Obstetrics and Gynecology, Stellenbosch University/Tygerberg Hospital, Cape Town, South Africa; ‖‖Serviço de Infectologia, Hospital Conceicao, Porto Alegre, Rio Grande do Sul, Brazil; ***Hospital Femina, Porto Alegre, Rio Grande do Sul, Brazil; †††Irmandade da Santa Casa de Misericordia de Porto Alegre, Rio Grande do Sul, Brazil; ‡‡‡Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; §§§Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil; ¶¶¶Foundation for Maternal and Infant Health (FUNDASAMIN), Buenos Aires, Argentina; and ‖‖‖Escola Paulista de Medicina-Universidade Federal de São Paulo, São Paulo, Brazil.

Background: Sexually transmitted infections (STIs) in pregnancy such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) may lead to adverse infant outcomes.

Methods: Individual urine specimens from HIV-infected pregnant women diagnosed with HIV during labor were collected at the time of infant birth and tested by polymerase chain reaction for CT and NG. Infant HIV infection was determined at 3 months with morbidity/mortality assessed through 6 months.

Results: Of 1373 maternal urine samples, 277 (20.2%) were positive for CT and/or NG; 249 (18.1%) for CT, 63 (4.6%) for NG and 35 (2.5%) for both CT and NG. HIV infection was diagnosed in 117 (8.5%) infants. Highest rates of adverse outcomes (sepsis, pneumonia, congenital syphilis, septic arthritis, conjunctivitis, low birth weight, preterm delivery and death) were noted in infants of women with CT and NG (23/35, 65.7%) compared with NG (16/28, 57.1%), CT (84/214, 39.3%) and no STI (405/1096, 37%, P = 0.001). Death (11.4% vs. 3%, P = 0.02), low birth weight (42.9% vs. 16.9%, P = 0.001) and preterm delivery (28.6% vs. 10.2%, P = 0.008) were higher among infants of CT and NG-coinfected women. Infants who had any adverse outcome and were born to women with CT and/or NG were 3.5 times more likely to be HIV infected after controlling for maternal syphilis (odds ratio: 3.5, 95% confidence interval: 1.4-8.3). By adjusted multivariate logistic regression, infants born to mothers with any CT and/or NG were 1.35 times more likely to have an adverse outcome (odds ratio, 1.35; 95% confidence interval, 1.03-1.76).

Conclusions: STIs in HIV-infected pregnant women are associated with adverse outcomes in HIV-exposed infected and uninfected infants.
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http://dx.doi.org/10.1097/INF.0000000000001199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945428PMC
August 2016

Neurologic Outcomes in HIV-Exposed/Uninfected Infants Exposed to Antiretroviral Drugs During Pregnancy in Latin America and the Caribbean.

AIDS Res Hum Retroviruses 2016 Apr;32(4):349-56

8 Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.

To evaluate antiretroviral (ARV) drug exposure and other factors during pregnancy that may increase the risk of neurologic conditions (NCs) in HIV-exposed/uninfected (HEU) infants. A prospective cohort study was conducted at 24 clinical sites in Latin America and the Caribbean. Data on maternal demographics, health, HIV disease status, and ARV use during pregnancy were collected. Infant data included measurement of head circumference after birth and reported medical diagnoses at birth, 6-12 weeks, and 6 months. Only infants with maternal exposure to combination ARV therapy (cART) (≥3 drugs from ≥2 drug classes) during pregnancy were included. Microcephaly, defined as head circumference for age z-score less than -2, and NC were evaluated for their association with covariates, including individual ARVs, using bivariable and logistic regression analyses. From 2002 to 2009, 1,400 HEU infants met study inclusion criteria. At least one NC was reported in 134 (9.6%; 95% confidence interval [CI]: 8.1-11.2), microcephaly in 105 (7.5%; 95% CI: 6.2-9.0), and specific neurologic diagnoses in 33 (2.4%; 95% CI: 1.6-3.3) HEU infants. Microcephaly and NC were not significantly associated with any specific ARV analyzed (p > 0.05). Covariates associated with increased odds of NC included male sex (odds ratio [OR] = 1.9; 95% CI: 1.3-2.8), birth weight <2.5 kg (OR = 3.1; 95% CI: 2.1-4.8), 1-min Apgar score <7 (OR = 2.5; 95% CI: 1.4-4.4), and infant infections (OR = 2.5; 95% CI: 1.5-4.1). No ARV investigated was associated with adverse neurologic outcomes. Continued investigation of such associations may be warranted as new ARVs are used during pregnancy and cART exposure during the first trimester becomes increasingly common.
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http://dx.doi.org/10.1089/AID.2015.0254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817559PMC
April 2016

Limits and patterns of cytomegalovirus genomic diversity in humans.

Proc Natl Acad Sci U S A 2015 Jul 6;112(30):E4120-8. Epub 2015 Jul 6.

Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655; Immunology and Virology Program, University of Massachusetts Medical School, Worcester, MA 01655

Human cytomegalovirus (HCMV) exhibits surprisingly high genomic diversity during natural infection although little is known about the limits or patterns of HCMV diversity among humans. To address this deficiency, we analyzed genomic diversity among congenitally infected infants. We show that there is an upper limit to HCMV genomic diversity in these patient samples, with ∼ 25% of the genome being devoid of polymorphisms. These low diversity regions were distributed across 26 loci that were preferentially located in DNA-processing genes. Furthermore, by developing, to our knowledge, the first genome-wide mutation and recombination rate maps for HCMV, we show that genomic diversity is positively correlated with these two rates. In contrast, median levels of viral genomic diversity did not vary between putatively single or mixed strain infections. We also provide evidence that HCMV populations isolated from vascular compartments of hosts from different continents are genetically similar and that polymorphisms in glycoproteins and regulatory proteins are enriched in these viral populations. This analysis provides the most highly detailed map of HCMV genomic diversity in human hosts to date and informs our understanding of the distribution of HCMV genomic diversity within human hosts.
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http://dx.doi.org/10.1073/pnas.1501880112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522815PMC
July 2015

Low vitamin D status among pregnant Latin American and Caribbean women with HIV Infection.

Int J Gynaecol Obstet 2015 Jul 11;130(1):54-8. Epub 2015 Apr 11.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Maternal and Pediatric Infectious Disease Branch, Bethesda, MD, USA.

Objective: To evaluate the prevalence and predictors of low vitamin D status among pregnant women with HIV infection.

Methods: The present cross-sectional study analyzed repository specimens collected at 12-34 weeks of pregnancy among women enrolled across 17 sites in Latin America and the Caribbean between 2002 and 2009. Logistic regression modeling was used to identify factors associated with low vitamin D status (25-hydroxyvitamin D <30 ng/mL).

Results: Among 715 women, 218 (30.5%) were vitamin D deficient (<20 ng/mL) and 252 (35.2%) were insufficient (21- /mL). Factors associated with low vitamin D status included residence in subtropical latitudes (adjusted odds ratio [aOR] 1.97, 95% confidence interval [CI] 1.35-2.88), assessment during non-summer seasons (autumn: aOR 1.85, 95% CI 1.20-2.86; spring: 4.3, 2.65-6.95; winter: 10.82, 5.74-20.41), employment (aOR 1.56, 95% CI 1.06-2.38), and assessment before 20 weeks of pregnancy (aOR 1.89, 95% CI 1.18-3.06). Factors protective against low vitamin D status were CD4 count below 200 cells per mm(3) (aOR 0.45, 95% CI 0.26-0.77) and protease inhibitors (aOR 0.62, 95% CI 0.40-0.95).

Conclusion: Low vitamin D status was prevalent among pregnant women with HIV infection. Further studies are warranted to identify the impact of low maternal vitamin D status.
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http://dx.doi.org/10.1016/j.ijgo.2015.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461462PMC
July 2015

Normal Growth of Healthy Infants Born from HIV+ Mothers Fed a Reduced Protein Infant Formula Containing the Prebiotics Galacto-Oligosaccharides and Fructo-Oligosaccharides: A Randomized Controlled Trial.

Clin Med Insights Pediatr 2015 9;9:37-47. Epub 2015 Mar 9.

Nestlé Clinical Development Unit, Vevey, Switzerland.

Objective: The aim of the current study was to evaluate the safety of a new reduced protein (2.1 g/100 kcal) infant formula containing 4 g/L of 90% galacto-oligosaccharides (GOS) and 10% fructo-oligosaccharides (FOS).

Methods: Healthy term infants from Brazil were enrolled. Those born to human immunodeficiency virus (HIV)-positive mothers were randomized to a test (n = 65) or control (n = 63) formula group. Infants born to HIV-negative mothers were either exclusively breast-fed (n = 79) or received a mixed diet (breast milk and test formula, n = 65). Between 2 weeks and 4 months of age, infants were exclusively fed according to their assigned group. Anthropometric measurements were taken at baseline, 1, 2, 3, 4, 6, 8, 10, and 12 months. Digestive tolerance was evaluated during the first 4 months. The primary outcome was mean daily weight gain between 2 weeks and 4 months in the test formula and breast-fed groups.

Results: Data from all infants (N = 272) were used in the intention-to-treat (ITT) analysis and data from 230 infants were used in the per-protocol (PP) analysis. The difference in mean daily weight gain between 2 weeks and 4 months in the test formula and breast-fed groups was 1.257 g/day (one-sided 95% confidence interval [CI]: -0.705 to inf, P < 0.001) in the PP analysis, showing that the lower bound of the 95% CI was above the -3.0 g/day non-inferiority margin. Results were similar in the ITT analysis. Symptoms of digestive tolerance and frequency of adverse events were similar in the two groups.

Conclusions: The formula containing 2.1 g/100 kcal protein and GOS and FOS was safe and tolerated well.
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http://dx.doi.org/10.4137/CMPed.S17841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357629PMC
October 2015

Undervaccination of perinatally HIV-infected and HIV-exposed uninfected children in Latin America and the Caribbean.

Pediatr Infect Dis J 2013 Aug;32(8):845-50

Escola Paulista de Medicina, Universidade Federal de São Paulo, UNIFESP, São Paulo, Brazil.

Background: Perinatally HIV-infected (PHIV) children may be at risk of undervaccination. Vaccination coverage rates among PHIV and HIV-exposed uninfected (HEU) children in Latin America and the Caribbean were compared.

Methods: All PHIV and HEU children born from 2002 to 2007 who were enrolled in a multisite observational study conducted in Latin America and the Caribbean were included in this analysis. Children were classified as up to date if they had received the recommended number of doses of each vaccine at the appropriate intervals by 12 and 24 months of age. Fisher's exact test was used to analyze the data. Covariates potentially associated with a child's HIV status were considered in multivariable logistic regression modeling.

Results: Of 1156 eligible children, 768 (66.4%) were HEU and 388 (33.6%) were PHIV. HEU children were significantly (P < 0.01) more likely to be up to date by 12 and 24 months of age for all vaccines examined. Statistically significant differences persisted when the analyses were limited to children enrolled before 12 months of age. Controlling for birth weight, sex, primary caregiver education and any use of tobacco, alcohol or illegal drugs during pregnancy did not contribute significantly to the logistic regression models.

Conclusions: PHIV children were significantly less likely than HEU children to be up to date for their childhood vaccinations at 12 and 24 months of age, even when limited to children enrolled before 12 months of age. Strategies to increase vaccination rates in PHIV are needed.
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http://dx.doi.org/10.1097/INF.0b013e31828bbe68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717191PMC
August 2013
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