Search

Background Clinical pediatric tuberculosis (TB) diagnosis may lead to overdiagnosis particularly among children with human immunodeficiency virus (CHIV). We assessed the performance of monocyte-lymphocyte ratio (MLR) as a diagnostic biomarker and constructed a clinical prediction score to improve specificity of TB diagnosis in CHIV with limited access to microbiologic testing. Methods We pooled data from cohorts of children aged ≤13 years from Vietnam, Cameroon, and South Africa to validate the use of MLR ≥0.378, previously found as a TB diagnostic marker among CHIV. Using multivariable logistic regression, we created an internally validated prediction score for diagnosis of TB disease in CHIV. Results The combined cohort had 601 children (median age, 1.9 [interquartile range, 0.9–5.3] years); 300 (50%) children were male, and 283 (47%) had HIV. Elevated MLR ≥0.378 had sensitivity of 36% (95% confidence interval [CI], 23%–51%) and specificity of 79% (95% CI, 71%–86%) among CHIV in the validation cohort. A model using MLR ≥0.28, age ≥4 years, tuberculin skin testing ≥5 mm, TB contact history, fever >2 weeks, and chest radiograph suggestive of TB predicted active TB disease in CHIV with an area under the receiver operating characteristic curve of 0.85. A prediction score of ≥5 points had a sensitivity of 94% and specificity of 48% to identify confirmed TB, and a sensitivity of 82% and specificity of 48% to identify confirmed and unconfirmed TB groups combined. Conclusions Our score has comparable sensitivity and specificity to algorithms including microbiological testing and should enable clinicians to rapidly initiate TB treatment among CHIV when microbiological testing is unavailable. [ABSTRACT FROM AUTHOR]

Background: Pregnancy is a risk factor for progression from latent tuberculosis infection to symptomatic tuberculosis. However, how pregnancy influences T-cell responses to Mycobacterium tuberculosis is unknown.Methods: We measured M. tuberculosis-specific cytokines, T-cell memory markers, and overall CD4+ and CD8+ T-cell activation by flow cytometry from 49 women (18 with and 31 without HIV) who became pregnant while enrolled in a randomized controlled trial of preexposure prophylaxis for HIV. We analyzed data using COMPASS, an established statistical method for evaluating overall antigen-specific T-cell responses.Results: Pregnant women with latent tuberculosis infection demonstrated significantly diminished M. tuberculosis-specific CD4+ cytokine responses in the third trimester (COMPASS polyfunctional score [PFS], 0.07) compared before (PFS, 0.15), during (PFS, 0.13 and 0.16), and after pregnancy (PFS, 0.14; P = .0084, Kruskal-Wallis test). Paradoxically, M. tuberculosis-specific CD8+ cytokines and nonspecifically activated T-cells increased during late pregnancy. Nonspecific T-cell activation, a validated biomarker for progression from latent tuberculosis infection to tuberculosis disease, increased in latent tuberculosis infection-positive women postpartum, compared with latent tuberculosis infection-negative women.Conclusions: Pregnancy-related functional T-cell changes were most pronounced during late pregnancy. Both M. tuberculosis-specific T-cell changes during pregnancy and increases in immune activation postpartum may contribute to increased risk for tuberculosis progression.Clinical Trials Registration: NCT0557245. [ABSTRACT FROM AUTHOR]

Background Trials of mass drug administration (MDA) of azithromycin (AZM) report reductions in child mortality in sub-Saharan Africa. AZM targeted to high-risk children may preserve benefit while minimizing antibiotic exposure. We modeled the cost-effectiveness of MDA to children 1–59 months of age, MDA to children 1–5 months of age, AZM administered at hospital discharge, and the combination of MDA and postdischarge AZM. Methods Cost-effectiveness was modeled from a payer perspective with a 1-year time horizon, and was presented as cost per disability-adjusted life-year (DALY) averted and death averted, with probabilistic sensitivity analyses. The model included parameters for macrolide resistance, adverse events, hospitalization, and mortality sourced from published data. Results Assuming a base-case 1.64% mortality risk among children 1–59 months old, 3.1% among children 1–5 months old, 4.4% mortality risk postdischarge, and 13.5% mortality reduction per trial data, MDA would avert ~267 000 deaths at a cost of $14.26/DALY averted (95% uncertainty interval [UI], 8.72–27.08). MDA to only children 1–5 months old would avert ~186 000 deaths at a cost of $4.89/DALY averted (95% UI, 2.88–11.42), and postdischarge AZM would avert ~45 000 deaths, at a cost of $2.84/DALY (95% UI, 1.71–5.57) averted. Cost-effectiveness decreased with presumed diminished efficacy due to macrolide resistance. Conclusions Targeting AZM to children at highest risk of death may be an antibiotic-sparing and highly cost-effective, or even cost-saving, strategy to reduce child mortality. However, targeted AZM averts fewer absolute deaths and may not reach all children who would benefit. Any AZM administration decision must consider implications for antibiotic resistance. [ABSTRACT FROM AUTHOR]

Despite diagnostic performance limitations, urine lipoarabinomannan (LAM) predicts death in human immunodeficiency virus (HIV)-infected adults with tuberculosis. Pediatric data are limited. Among 137 hospitalized HIV-infected children, mortality was 4.9-fold higher among those with positive LAM (127 vs 31 per 100 person-years; adjusted hazard ratio, 4.92; 95% confidence interval [CI], 1.79-13.49; P = .002). Lipoarabinomannan identifies HIV-infected children at risk for death potentially missed by respiratory sampling. [ABSTRACT FROM AUTHOR]

Background. Treatment of human immunodeficiency virus (HIV)-infected women to prevent cervical cancer may stimulate HIV RNA cervical shedding and risk HIV transmission. Methods. From 2011 to 2014, 400 HIV-infected women diagnosed with cervical intraepithelial neoplasia 2/3 in Kenya were randomized to loop electrosurgical excision procedure (LEEP) or cryotherapy. Cervical samples were collected at baseline and 3 weekly intervals. Samples were tested for HIV RNA using the Gen-Probe Aptima HIV assay with a minimum detection level of 60 copies/swab and analyzed using generalized estimating equations. Results. Women who received LEEP had significantly higher cervical HIV RNA levels than those who received cryotherapy at weeks 2 (adjusted incident rate ratio [aIRR], 1.07; P = .038) and 3 (aIRR, 1.08; P = .046). Within LEEP, significantly higher cervical shedding was found at weeks 2 (2.03 log10 copies/swab; P < .001) and 3 (2.04 log10 copies/swab; P < .001) compared to baseline (1.80 log10 copies/swab). Cervical HIV RNA was significantly higher following LEEP for up to 3 weeks among women on antiretroviral treatment (ART) (0.18 log10 copies/swab increase; P = .003) and in ART-naive women (1.13 log10 copies/swab increase; P < .001) compared to baseline. Within cryotherapy, cervical shedding increased in ART-naive women (0.72 log10 copies/swab increase; P = 0.004) but did not increase in women on ART. Conclusions. Women randomized to LEEP had a larger increase in post-procedural cervical HIV shedding than cryotherapy. Benefits of cervical cancer prevention outweigh the risk of HIV sexual transmission; our findings underscore the importance of risk-reduction counseling. [ABSTRACT FROM AUTHOR]

It is common in longitudinal studies for scheduled visits to be accompanied by as-needed visits due to medical events occurring between scheduled visits. If the timing of these as-needed visits is related to factors that are associated with the outcome but are not among the regression model covariates, naively including these as-needed visits in the model yields biased estimates. In this paper, the authors illustrate and discuss the key issues pertaining to inverse intensity rate ratio (IIRR)-weighted generalized estimating equations (GEE) methods in the context of a study of Kenyan mothers infected with human immunodeficiency virus type 1 (1999–2005). The authors estimated prevalences and prevalence ratios for morbid conditions affecting the women during a 1-year postpartum follow-up period. Of the 484 women under study, 62% had at least 1 as-needed visit. Use of a standard GEE model including both scheduled and unscheduled visits predicted a pneumonia prevalence of 2.9% (95% confidence interval: 2.3%, 3.5%), while use of the IIRR-weighted GEE predicted a prevalence of 1.5% (95% confidence interval: 1.2%, 1.8%). The estimate obtained using the IIRR-weighted GEE approach was compatible with estimates derived using scheduled visits only. These results highlight the importance of properly accounting for informative follow-up in these studies. [ABSTRACT FROM PUBLISHER]

Background. There are limited data regarding the relative merits of biomarkers as predictors of mortality or time to initiation of antiretroviral therapy (ART). Methods. We evaluated the usefulness of the CD4 cell count, CD4 cell percentage (CD4%), human immunodeficiency virus type 1 (HIV-1) load, total lymphocyte count (TLC), body mass index (BMI), and hemoglobin measured at 32 weeks' gestation as predictors of mortality in a cohort of HIV-1-infected women in Nairobi, Kenya. Sensitivity, specificity, positive predictive value (PPV), and area under the receiver operating characteristic (ROC) curve (AUC) were determined for each biomarker separately, as well as for the CD4 cell count and the HIV-1 load combined. Results. Among 489 women with 10,150 person-months of follow-up, mortality rates at 1 and 2 years postpartum were 2.1% (95% confidence interval [CI], 0.7%-3.4%) and 5.5% (95% CI, 3.0%-8.0%), respectively. CD4 cell count and CD4% had the highest AUC value (>0.9). BMI, TLC, and hemoglobin were each associated with but poorly predictive of mortality (PPV, <7%). The HIV-1 load did not predict mortality beyond the CD4 cell count. Conclusions. The CD4 cell count and CD4% measured during pregnancy were both useful predictors of mortality among pregnant women. TLC, BMI, and hemoglobin had a limited predictive value, and the HIV-1 load did not predict mortality any better than did the CD4 cell count alone. [ABSTRACT FROM AUTHOR]

Background. Breast-feeding by infants exposed to human immunodeficiency virus type 1 (HIV-1) provides an opportunity to assess the role played by repeated HIV-1 exposure in eliciting HIV-1-specific immunity and in defining whether immune responses correlate with protection from infection. Methods. Breast-feeding infants born to HIV-1-seropositive women were assessed for HLA-selected HIV-1 peptide-specific cytotoxic T lymphocyte interferon (IFN)-γ responses by means of enzyme-linked immunospot (ELISpot) assays at 1, 3, 6, 9, and 12 months of age. Responses were deemed to be positive when they reached ⩾50 HIV-1-specific sfu/1 × 106 peripheral blood mononuclear cells (PBMCs) and were at least twice those of negative controls. Results. A total of 807 ELISpot assays were performed for 217 infants who remained uninfected with HIV-1 at ~12 months of age; 101 infants (47%) had at least 1 positive ELISpot result (median, 78-170 sfu/1 × 106 PBMCs). The prevalence and magnitude of responses increased with age (P = .01 and P = .007, respectively); the median log10 value for HIV-1-specific IFN-γ responses increased by 1.0 sfu/1 × 106 PBMCs/month (P > .001) between 1 and 12 months of age. Of 141 HIV-1-uninfected infants with 1-month ELISpot results, 10 (7%) acquired HIV-1 infection (0/16 with positive vs. 10/125 [8%] with negative ELISpot results; P = .6). Higher values for log10 HIV-1-specific spot-forming units at 1 month of age were associated with a decreased risk of HIV-1 infection, adjusted for maternal HIV-1 RNA level (adjusted hazard ratio, 0.09 [95% confidence interval, 0.01- 0.72]). Conclusions. Breast-feeding HIV-1-exposed uninfected infants frequently had HIV-1-specific IFN-γ responses. Greater early HIV-1-specific IFN-γ responses were associated with decreased HIV-1 acquisition. [ABSTRACT FROM AUTHOR]

Background. Clinical signs and symptoms of acute human immunodeficiency virus (HIV) infection in infants are not well characterized. Methods. Serial clinical assessments and HIV PCR assays were conducted in a cohort of children born to HIV-seropositive mothers from birth to 2 years of age. Acute HIV infection visits were defined as those up to 3 months prior to and including the visit at which HIV DNA was first detected. Noninfection visits included all visits at which the child had test results negative for HIV, including the last visit at which a test result negative for HIV DNA was obtained in children who later acquired HIV infection. Differences in the prevalence of symptoms at acute infection versus noninfection visits were determined overall and were stratified by age at infection (<2 months vs. ⩾2 months). HIV RNA was measured serially in infected infants and was compared between infants with and infants without symptoms of acute HIV infection. Results. There were 125 acute infection visits (among 56 infants) and 3491 noninfection visits (among 306 infants). Acute HIV infection was associated with rash (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.1- 2.8), failure to thrive (OR, 1.9; 95% CI, 1.0-3.5), and lymphadenopathy (OR, 2.5; 95% CI, 1.4-4.8). Acute HIV infection was associated with lymphadenopathy (OR, 2.6; 95% CI, 1.3-5.0) in infants <2 months of age and with pneumonia (OR, 3.2; 95% CI, 1.1-9.3) and dehydration (OR, 6.0; 95% CI, 1.9-18.5) in infants ⩾2 months of age. Infant peak viral load and mortality were not associated with symptoms of acute HIV infection. However, infants with symptoms had higher viral levels later in the course of infection than did those without symptoms (P = .05). Conclusions. Infants may manifest symptoms early during the course of HIV infection, and symptoms of acute HIV infection may correlate with poor viral control. Rash, failure to thrive, lymphadenopathy, pneumonia, and dehydration may signify acute HIV infection in infants. [ABSTRACT FROM AUTHOR]

Background. There is conflicting evidence regarding the effects of breast-feeding on maternal mortality from human immunodeficiency virus type 1 (HIV-1) infection, and little is known about the effects of breast-feeding on markers of HIV-1 disease progression. Methods. HIV-1-seropositive women were enrolled during pregnancy and received short-course zidovudine. HIV-1 RNA levels and CD4 cell counts were determined at baseline and at months 1, 3, 6, 12, 18, and 24 postpartum and were compared between breast-feeding and formula-feeding mothers. Results. Of 296 women, 98 formula fed and 198 breast-fed. At baseline, formula-feeding women had a higher education level and prevalence of HIV-1-related illness than did breast-feeding women; however, the groups did not differ with respect to CD4 cell counts and HIV-1 RNA levels. Between months 1 and 24 postpartum, CD4 cell counts decreased 3.9 cells/μL/month (P < .001), HIV-1 RNA levels increased 0.005 log10 copies/mL/month (P = .03), and body mass index (BMI) decreased 0.03 kg/m²/month (P < .001). The rate of CD4 cell count decline was higher in breast-feeding mothers (7.2 cells/μL/month) than in mothers who never breast-fed (4.0 cells/μL/ month) (P = .01). BMI decreased more rapidly in breast-feeding women (P = .04), whereas HIV-1 RNA levels and mortality did not differ significantly between breast-feeding and formula-feeding women. Conclusions. Breast-feeding was associated with significant decreases in CD4 cell counts and BMI. HIV-1 RNA levels and mortality were not increased, suggesting a limited adverse impact of breast-feeding in mothers receiving extended care for HIV-1 infection. [ABSTRACT FROM AUTHOR]

The prevalence of human immunodeficiency virus (HIV)-1-infected cells and HIV-1 RNA levels in genital secretions and breast milk and the risk of mother-to-child transmission of HIV-1 were compared among subtypes A, C, and D in a Kenyan cohort. Pregnant women infected with subtype C were significantly more likely to shed HIV-1-infected vaginal cells than were those infected with subtype A or D (odds ratio [OR], 3.6 [95% confidence interval {CI}, 1.4-8.8]; P = .006). This relationship held after adjusting for age, CD4 cell count, and plasma HIV-1 RNA load (OR, 3.1 [95% CI, 1.1-8.6]; P = .03). These observations suggest that HIV-1 subtype influences mucosal shedding of HIV-1. [ABSTRACT FROM AUTHOR]

Understanding how the level of human immunodeficiency virus type 1 (HIV-1)-infected breast milk cells (BMCs) affects HIV transmission via breast-feeding can shed light on the mechanism of infection and aid in establishing effective interventions. The proportion of infected cells to total cells was measured in serial breast milk samples collected from 291 HIV-1-infected women in Nairobi, Kenya, by use of real-time DNA polymerase chain reaction amplification of BMCs. The number of infected BMCs per million cells was associated with levels of cell-free viral RNA in breast milk (R=.144; P=.032), levels of cell-free virus in blood plasma (R=.365; P<.001), and the detection of proviral DNA in cervical and vaginal secretions (P<.001 and P = .030, respectively). The number of infected BMCs per million cells was lower in colostrum or early milk than in mature milk (P<.001). Previous studies demonstrated that the concentration of BMCs varies throughout lactation, and we used these data to transform infected BMCs per million cells to infected BMCs per milliliter. The estimated concentration of infected BMCs per milliliter was higher in colostrum or early milk than in mature milk (P<.001). Each log10 increase in infected BMCs per milliliter was associated with a 3.19-fold-increased risk of transmission (P=.002), after adjustment for cell-free virus in plasma (hazard ratio [HR], 2.09; P=.03) and breast milk (HR, 1.01; P=1.00). This suggests that infected BMCs may play a more important role in transmission of HIV via breast-feeding than does cell-free virus. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus type 1 (HIV-1) is transmitted through blood, genital secretions, and breast milk. The probability of heterosexual transmission of HIV-1 per sex act is .0003-.0015, but little is known regarding the risk of transmission per breast-milk exposure. We evaluated the probability of breast-milk transmission of HIV-1 per liter of breast milk ingested and per day of breast-feeding in a study of children born to HIV-l-infected mothers. The probability of breast-milk transmission of HIV-1 was .00064 per liter ingested and .00028 per day of breast-feeding. Breast-milk infectivity was significantly higher for mothers with more-advanced disease, as measured by prenatal HIV-1 RNA plasma levels and CD4 cell counts. The probability of HIV-1 infection per liter of breast milk ingested by an infant is similar in magnitude to the probability of heterosexual transmission of HIV-1 per unprotected sex act in adults. [ABSTRACT FROM AUTHOR]

Transmission of human immunodeficiency virus type 1 (HIV-1) via breast-feeding can occur throughout lactation. Defining both fluctuation in breast-milk virus level over time and how breast-milk virus correlates with mother-to-child transmission is important for establishing effective interventions. We quantified breastmilk HIV-1 RNA levels in serial samples collected from 275 women for up to 2 years after delivery. Higher maternal plasma virus load, lower maternal CD4 T cell count, and detection of HIV-1 DNA in maternal genital secretions were significantly associated with elevated breast-milk HIV-1 RNA. Within women who breast-fed, median virus load in colostrum/early milk was significantly higher than that in mature breast milk collected 14 days after delivery (P ≤ .004). Breast-feeding mothers who transmitted HIV-1 to their infants had both significantly higher breast-milk viral RNA throughout lactation and more-consistent viral shedding, compared with mothers who did not transmit HIV-1. In breast-feeding women, a 2-fold-increased risk of transmission was associated with every 10-fold increase in breast-milk virus load (95% confidence interval, 1.3-3.0; P< .001). These results indicate that the risk of infant infection from breast-feeding is influenced by breast-milk virus load, which is highest early after delivery. [ABSTRACT FROM AUTHOR]

Secretory leukocyte protease inhibitor (SLPI), a protein found in saliva, breast milk, and genital secretions, is capable of inhibiting human immunodeficiency virus (HIV) type 1 in vitro. The aim of this study was to determine whether SLPI in infant saliva provides protection against mother-to-child HIV-1 transmission. In total, 602 saliva specimens were collected from 188 infants at birth and at ages 1, 3, and 6 months. Infants' median salivary SLPI concentrations were higher at birth than at 6 months (341 vs. 219 ng/mL; P = .001). There was no association between SLPI concentration and HIV-1 transmission overall. However, among 122 breast-fed infants who were HIV-1 uninfected at 1 month, higher salivary SLPI levels were associated with a decreased risk of HIV-1 transmission through breast milk (hazard ratio, 0.5; 95% confidence interval, 0.3-0.9; P = .03). These results suggest that SLPI plays an important role in reducing HIV-1 transmission through breast milk. [ABSTRACT FROM AUTHOR]

In this article the author discusses the study which examines the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus type 1 (HIV-1). She stresses that incremental steps to prevent HIV-1 infections in infants need to be accelerated by the PMTCT programs. She is critical of the cell count testing and integration of highly active antiretroviral therapy for the improvement of the logistics of cluster of differentiation 4 (CD4) and increase the effectiveness of PMTCT.