Predictors of adverse pregnancy outcomes in women infected with HIV in Latin America and the Caribbean: a cohort study.

OBJECTIVE: To examine maternal characteristics associated with adverse pregnancy outcomes among women infected with HIV. DESIGN: Prospective cohort study. SETTING: Multiple sites in Latin America and the Caribbean. POPULATION: Women infected with HIV enrolled in the Perinatal (2002-2007) and the Longitudinal Study in Latin American Countries (LILAC; 2008-2012) studies of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI). METHODS: Frequencies of adverse pregnancy outcomes assessed among pregnancies. Risk factors investigated by logistic regression analysis. MAIN OUTCOME MEASURES: Adverse pregnancy outcomes, including preterm delivery (PT), low birthweight (LBW), small for gestational age (SGA), stillbirth (SB), and neonatal death. RESULTS: Among 1512 women, 1.9% (95% confidence interval, 95% CI, 1.3-2.7) of singleton pregnancies resulted in a stillbirth and 32.9% (95% CI 30.6-35.4) had at least one adverse pregnancy outcome. Of 1483 singleton live births, 19.8% (95% CI 17.8-21.9) were PT, 14.2% (95% CI 12.5-16.1) were LBW, 12.6% (95% CI 10.9-14.4) were SGA, and 0.4% (95% CI 0.2-0.9) of infants died within 28 days of birth. Multivariable logistic regression modelling indicated that the following risk factors increased the probability of having one or more adverse pregnancy outcomes: lower maternal body mass index at delivery (odds ratio, OR, 2.2; 95% CI 1.4-3.5), hospitalisation during pregnancy (OR 3.3; 95% CI 2.0-5.3), hypertension during pregnancy (OR 2.7; 95% CI 1.5-4.8), antiretroviral use at conception (OR 1.4; 95% CI 1.0-1.9), and tobacco use during pregnancy (OR 1.7; 95% CI 1.3-2.2). The results of fitting multivariable logistic regression models for PT, LBW, SGA, and SB are also reported. CONCLUSIONS: Women infected with HIV had a relatively high occurrence of adverse pregnancy outcomes, and some maternal risk factors were associated with these adverse pregnancy outcomes. Interventions targeting modifiable risk factors should be evaluated further.

Ethical tradeoffs in trial design: case study of an HPV vaccine trial in HIV-infected adolescent girls in lower income settings.

The Declaration of Helsinki and the Council of the International Organization of Medical Sciences provide guidance on standards of care and prevention in clinical trials. In the current and increasingly challenging research environment, the ethical status of a trial design depends not only on protection of participants, but also on social value, feasibility, and scientific validity. Using the example of a study assessing efficacy of a vaccine to prevent human papilloma virus in HIV-1 infected adolescent girls in low resource countries without access to the vaccine, we compare several trial designs which rank lower on some criteria and higher on others, giving rise to difficult trade-offs. This case demonstrates the need for developing more nuanced guidance documents to help researchers balance these often conflicting criteria.

Metabolic abnormalities and viral replication are associated with biomarkers of vascular dysfunction in HIV-infected children.

OBJECTIVES: HIV-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction in HIV-infected children (with and without hyperlipidaemia) with those in HIV-exposed, uninfected (HEU) children enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers. METHODS: A prospective cohort study was carried out. Biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP1)], coagulant dysfunction (fibrinogen and P-selectin), endothelial dysfunction [soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM) and E-selectin], and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded. RESULTS: The median ages of the children were 12.3 years in the HIV-infected group and 10.1 years in the HEU group. Body mass index (BMI) z-scores, waist and hip circumferences, and percentage body fat were lower in the HIV-infected children. Total and non-high-density lipoprotein (HDL) cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children also had higher MCP-1, fibrinogen, sICAM and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavourable lipid profiles were positively associated with IL-6, MCP-1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP-1 and CRP) and endothelial dysfunction (sICAM and sVCAM). CONCLUSIONS: HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavourable lipid levels and active HIV replication.

Newborn Hearing Screenings in Human Immunodeficiency Virus-Exposed Uninfected Infants.

Perinatal HIV infection and congenital cytomegalovirus (CMV) infection may increase the risk for hearing loss. We examined 1,435 infants enrolled in the Surveillance Monitoring of ART Toxicities (SMARTT) study of the Pediatric HIV/AIDS Cohort Study (PHACS) network, a prospective study of the safety of in utero antiretroviral (ARV) exposures. We determined the proportion of perinatally HIV-exposed uninfected (HEU) newborns who were referred for additional hearing testing, and evaluated the association between in utero ARV exposures and newborn hearing screening results. Using a nested case-control design, we also examined congenital CMV infection in infants with and without screening referral. Congenital CMV infection was determined based on CMV DNA detection using a nested PCR assay in peripheral blood mononuclear cells obtained within 14 days of birth. Among the 1,435 infants (70% black, 31% Hispanic, 51% male), 45 (3.1%) did not pass the hearing screen and were referred for further hearing testing. Based on exact logistic regression models controlling for maternal use of tobacco and ototoxic medications, first trimester exposure to Tenofovir was associated with lower odds of a newborn hearing screening referral [adjusted odds ratio (aOR) = 0.41, 95% confidence interval (CI): 0.14-1.00]. Exposure to Atazanavir was linked to higher odds of newborn screening referral, although not attaining significance [aOR = 1.84, 95% CI: 0.92-3.56]. Maternal ARV use may have varying effects on newborn hearing screenings. These results highlight the importance for audiologists to be knowledgeable of in utero ARV exposures in HEU children because of the possibility of higher referrals in these children.

Cutaneous polyarteritis nodosa. Reports of two cases in children and review of the literature.

BACKGROUND: Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small- and medium-sized arteries that most often affects the kidneys, heart, and liver but can affect any organ system. A cutaneous form of PAN without visceral involvement, which follows a benign but often chronic course, has also been described. Both forms are rare in children. OBSERVATIONS: We describe two children with cutaneous PAN who were admitted to The Johns Hopkins Children's Center, Baltimore, Md, within a 1-week period. Both girls, aged 2 and 6 years old, presented with multiple, red, painful, edematous nodules on the extremities, face, and trunk. Dermatologic findings were accompanied by fever, arthralgias, and arthritis, but neither child had evidence of severe systemic disease. Skin biopsy specimens revealed necrotic small- and medium-sized muscular arteries with neutrophilic and eosinophilic infiltrate and fibrin thrombi. Both patients responded to treatment with prednisone. CONCLUSIONS: In children with cutaneous PAN, systemic symptoms may be present, but the lack of life-threatening complications distinguishes this relatively benign disease from systemic PAN.

Analysis of the optimal cut-point for HIV-p24 antigen testing to diagnose HIV infection in HIV-exposed children from resource-constrained settings.

BACKGROUND: Nucleic-acid-testing (NAT) to diagnose HIV infection in children under age 18 months provides a barrier to HIV-testing in exposed children from resource-constrained settings. The ultrasensitive HIV-p24-antigen (Up24) assay is cheaper and easier to perform and is sensitive (84-98%) and specific (98-100%). The cut-point optical density (OD) selected for discriminating between positive and negative samples may need assessment due to regional differences in mother-to-child HIV-transmission rates. OBJECTIVES: We used receiver operator characteristics (ROC) curves and logistic regression analyses to assess the effect of various cut-points on the diagnostic performance of Up24 for HIV-infection status among HIV-exposed children. Positive and negative predictive values at different rates of disease prevalence were also estimated. STUDY DESIGN: A study of Up24 testing on dried blood spot (DBS) samples collected from 278 HIV-exposed Haitian children, 3-24-months of age, in whom HIV-infection status was determined by NAT on the same DBS card. RESULTS: The sensitivity and specificity of Up24 varied by the cut-point-OD value selected. At a cut-point-OD of 8-fold the standard deviation of the negative control (NCSD), sensitivity and specificity of Up24 were maximized [87.8% (95% CI, 83.9-91.6) and 92% (95% CI, 88.8-95.2), respectively]. In lower prevalence settings (5%), positive and negative predictive values of Up24 were maximal (75.9% and 98.8%, respectively) at a cut-point-OD that was 15-fold the NCSD. CONCLUSIONS: In low prevalence settings, a high degree of specificity can be achieved with Up24 testing of HIV-exposed children when a higher cut-point OD is used; a feature that may facilitate more frequent use of Up24 antigen testing for HIV-exposed children.

Differential mortality by measles vaccine titer and sex.

Mortality was evaluated in 1972 children who had received measles vaccines at 6-11 months of age that were 10-fold (medium titer) or 100-fold (high titer) greater than standard titer. Mortality among boys did not differ by vaccine titer and was similar to mortality in children who received standard-titer vaccine. Girl recipients of high-titer vaccine had somewhat greater mortality than girls who received medium-titer vaccine (risk ratio = 1.71, 95% confidence interval = 0.91-3.24). Increased mortality was associated with high-titer vaccine for girls but not for boys (P = .04). There was no evidence of selection bias or preferential health care by sex that might explain the differential mortality. This mortality pattern has been noted in two other populations with high background infant and childhood mortality. The biologic basis for this effect on mortality has not been determined. Data from this and other studies have resulted in discontinuation of the use of high-titer measles vaccines.