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1.  CD4/CD8 Ratio for Diagnosis of HIV-1 Infection in Infants: The Women and Infants Transmission Study 
Pediatrics  2008;122(2):331-339.
Early diagnosis of HIV infection in infants with perinatal HIV exposure is critical for clinical management decisions. Positive HIV nucleic acid detection represents the gold standard for the diagnosis of HIV infection status in infants prior to age 18 months, but this test is not universally available, especially in resource poor regions of the world. In this study we tested the hypothesis that the CD4/CD8 T cell ratio can predict HIV infection status in HIV-exposed infants.
CD4/CD8 T cell ratios were determined from data of live born, singleton infants who had been prospectively enrolled in the Women and Infants Transmission Study (WITS). Data from 2208 infants with known HIV infection status (179 HIV infected, 2029 uninfected) were analyzed.
Receiver Operating Characteristic (ROC) curves indicated that CD4/CD8 ratio performed better than CD4% for diagnosis of HIV infection as early as age 2 months (p=0.018), and this relationship was unaffected by adjusting for maternal race/ethnicity, infant birth weight, gestational age and gender. At age 4 mos., 90% specificity for HIV diagnosis was associated with 60% sensitivity. For ease of utilization, longitudinal LMS profile-based percentile curves were developed for sensitivity/specificity of CD4/CD8 ratios in HIV-infected and -uninfected infants until age 12 months. At age 6 months, a simplified equation that incorporated sequential CD4/CD8 ratios and hematocrit values resulted in improved ROCs with 94% positive predictive value (PPV) and 98% negative predictive value (NPV). The PPV and NPV remained above 90% in simulated infant populations over a wide range of prevalence of HIV infection.
In the absence of virologic diagnosis, a presumptive diagnosis of HIV- infection status may be made on the basis of CD4/CD8 ratios in HIV-1-exposed infants after age 2 months; sensitivity and specificity can be further improved at 6 months by using a discriminant analysis equation.
PMCID: PMC4699439  PMID: 18676551
HIV diagnosis; perinatal HIV transmission; HIV exposed infants; CD4/CD8 ratio
2.  Congenital Anomalies and in utero Antiretroviral Exposure in HIV-exposed Uninfected Infants 
JAMA pediatrics  2015;169(1):48-55.
Most studies examining the association of prenatal antiretroviral exposures with congenital anomalies (CAs) in children born to HIV-infected women have been reassuring, but some suggest increased risk with specific antiretrovirals.
To evaluate associations of in utero antiretroviral exposures with CAs in HIV-exposed uninfected children.
prospective cohort study, the Pediatric HIV/AIDS Cohort Study (PHACS) Surveillance Monitoring of ART Toxicities (SMARTT) study.
22 US medical centers
2580 HIV-exposed, uninfected children enrolled in SMARTT between 2007–2012.
First trimester exposure to any antiretroviral and to specific antiretroviral medications.
Main Outcome
The primary endpoint was a CA, based on clinician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate associations of CAs with first trimester antiretroviral exposures, adjusting for demographic and maternal characteristics.
CAs occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI: 5.85–7.82%); there were 242 confirmed major CAs (72 musculoskeletal, 55 cardiovascular). The prevalence of CAs increased significantly in successive birth cohorts (3.8% for children born <2002 up to 8.3% for 2008–2010). In adjusted models, there was no association of first trimester exposures to any antiretroviral, to combination antiretroviral regimens, or to any drug class with CAs. No individual antiretroviral in the reverse transcriptase inhibitor drug classes was associated with increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir (adjusted odds ratio (aOR)=1.93, 95% confidence interval (CI):1.23,3.03) and for ritonavir used as a booster (aOR=1.52, 95%CI: 1.08,2.14). With first trimester atazanavir, risks were highest for skin and musculoskeletal CAs (aORs=5.24 and 2.55, respectively).
Conclusions and Relevance
Few individual antiretrovirals and no drug classes were associated with increased risk of CAs after adjustment for calendar year and maternal characteristics. While the overall risk remained low, there was a relative increase in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV use during pregnancy still outweigh such risks, although further studies are warranted.
PMCID: PMC4286442  PMID: 25383770
3.  Combination Antiretroviral Use and Preterm Birth 
The Journal of Infectious Diseases  2012;207(4):612-621.
Background. Use of antiretroviral drugs (ARVs) during pregnancy has been associated with higher risk of preterm birth.
Methods. The Pediatric HIV/AIDS Cohort Study network's Surveillance Monitoring for ART Toxicities study is a US-based cohort of human immunodeficiency virus (HIV)–exposed uninfected children. We evaluated maternal ARV use during pregnancy and the risk of any type of preterm birth (ie, birth before 37 completed weeks of gestation), the risk of spontaneous preterm birth (ie, preterm birth that occurred after preterm labor or membrane rupture, without other complications), and the risk of small for gestational age (SGA; ie, a birth weight of <10th percentile for gestational age). Multivariable logistic regression models were used to evaluate the association of ARVs and timing of exposure, while adjusting for maternal characteristics.
Results. Among 1869 singleton births, 18.6% were preterm, 10.2% were spontaneous preterm, and 7.3% were SGA. A total of 89% used 3-drug combination ARV regimens during pregnancy. In adjusted models, the odds of preterm birth and spontaneous preterm birth were significantly greater among mothers who used protease inhibitors during the first trimester (adjusted odds ratios, 1.55 and 1.59, respectively) but not among mothers who used nonnucleoside reverse-transcriptase inhibitor or triple-nucleoside regimens during the first trimester. Combination ARV exposure starting later in pregnancy was not associated with increased risk. No associations were observed between SGA and exposure to combination ARV regimens.
Conclusions. Protease inhibitor use early in pregnancy may be associated with increased risk for prematurity.
PMCID: PMC3549601  PMID: 23204173
preterm birth; antiretrovirals; pregnancy; small for gestational age
4.  Safety of Tenofovir Use During Pregnancy: Early Growth Outcomes in HIV-Exposed Uninfected Infants 
AIDS (London, England)  2012;26(9):1151-1159.
To evaluate the association of tenofovir disoproxil fumarate (TDF) use during pregnancy with early growth parameters in HIV-exposed, uninfected (HEU) infants.
US-based prospective cohort study of HEU children to examine potential adverse effects of prenatal TDF exposure.
We evaluated the association of maternal TDF use during pregnancy with small for gestational age (SGA); low birth weight (LBW, <2.5kg); weight-for-age z-scores (WAZ), length-forage z-scores (LAZ) and head circumference-for-age (HCAZ) z-scores at newborn visit; and LAZ, HCAZ, and WAZ at age one year. Logistic regression models for LBW and SGA were fit, adjusting for maternal and sociodemographic factors. Adjusted linear regression models were used to evaluate LAZ, WAZ and HCAZ by TDF exposure.
Of 2029 enrolled children with maternal antiretroviral information, TDF was used by 449 (21%) HIV-infected mothers, increasing from 14% in 2003 to 43% in 2010. There was no difference between those exposed to combination regimens with versus without TDF for SGA, LBW, and newborn LAZ and HCAZ. However, at age one year, infants exposed to combination regimens with TDF had significantly lower adjusted mean LAZ and HCAZ than those without TDF (LAZ: −0.17 vs. −0.03, p=0.04; HCAZ: 0.17 vs. 0.42, p=0.02).
TDF use during pregnancy was not associated with increased risk for LBW or SGA. The slightly lower mean LAZ and HCAZ observed at age one year in TDF-exposed infants are of uncertain significance but underscore the need for additional studies of growth outcomes after TDF use during pregnancy.
PMCID: PMC3476702  PMID: 22382151
Tenofovir disoproxil fumarate; perinatal HIV exposure; infant growth; antiretroviral drugs; pregnancy
Immunoreconstitution of HIV-infected (HIV+) patients after treatment with highly antiretroviral therapy (HAART) appears to provoke inflammatory diseases.
Determine whether HIV+ children on HAART (HIV+ HAART+) have a higher incidence of asthma than HIV+ children not on HAART (HIV+ HAART−).
To investigate this possibility, 2,664 children (193 HIV+, 2,471 HIV−) born to HIV+ women were evaluated for the incidence and prevalence of asthma (i.e., asthma medication use), and change of CD4+ T cell percentage with time.
The HIV+ HAART+ children had higher CD4+ T cell percentages, lower CD8+ T cell percentages, and lower viral burdens than the HIV+ HAART− children (P≤0.05 to P≤0.01). The cumulative incidence of asthma medication use in HIV+ HAART+ children at 13.5 year rose to 33.5% vs. 11.5% in HIV+ HAART− children (hazard ratio=3.34, P=0.01) and was equal to that in the HIV− children. In children born prior to the HAART era, the prevalence of asthma medication use for HIV+ HAART+ children at 11 years of age was 10.4% vs. 3.8% for HIV+ HAART− children (odds ratio=3.38, P=0.02) and was equal to that of the HIV− children. The rate of change of CD4+ T cells (percent/year) around the time of first asthma medication for HIV+ HAART+ vs. HIV+ HAART− children was 0.81 vs. −1.43 (P=0.01).
The increased incidence of asthma in HIV+ HAART+ children may be driven by immunoreconstitution of CD4+ T cells.
This HIV model of pediatric asthma may yield clues to help explain the epidemic of asthma in the general pediatric population.
PMCID: PMC3246282  PMID: 18547627
pediatric HIV infection; CD4+ T cell mediated induction of asthma; HAART-produced immunoreconstitution
6.  Early Immunological Predictors of Neurodevelopmental Outcomes in HIV-Infected Children 
Background. A previous analysis of children infected with human immunodeficiency virus (HIV) in the Women and Infants Transmission Study showed a strong correlation between low activated CD8+ T lymphocytes in the first 2 months of life and good immunological prognosis. We sought to extend these observations to neurodevelopmental prognosis.
Methods. Ninety-eight HIV-infected children born before 1994 with flow cytometric data from the first 2 months of life and adequate neurodevelopmental testing through age 30 months were studied. Children were divided into those with low (⩽5% CD8+HLA-DR+ cells or ⩽25% CD8+CD38+ cells) or high (>5% CD8+HLA-DR+ cells or >25% CD8+CD38+ cells) immune activation at 1 and/or 2 months of age. Analysis was performed using survival analysis, Cox's proportional hazard regression, and longitudinal regression models.
Results. Absence of immune activation, measured as ⩽5% CD8+HLA-DR+ cells, was strongly associated with better performance on the psychomotor developmental index of the Bayley scales of infant development through the third year of life. This association persisted after adjustment for CD4 cell count, viral load, and progression to acquired immunodeficiency syndrome (P=.005). An association with the mental development index was also present (P=.048). Significant association between neurodevelopmental outcomes and ⩽25% CD8+CD38+ cells was not seen.
Conclusions. In this prospective cohort study of HIV-infected children, there was a significant favorable association of low immune activation in peripheral T cells at age 1 or 2 months, measured by a low percentage of CD8+HLA-DR+ cells, with subsequent psychomotor and mental development. This association was independent of other indices of severity and progression of HIV infection.
PMCID: PMC3671733  PMID: 19115969

Results 1-6 (6)