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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.

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.

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.

Background: ARIEL (Darunavir in treatment-experienced pediatric population) was a phase II, open-label study assessing safety and antiviral activity of darunavir/ritonavir twice daily with an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected pediatric patients (3 to <6 years, weighing 10 to <20 kg)., Methods: The study consisted of an initial 4-week screening period, 48 weeks of treatment and a 4-week follow-up period. Patients initially received darunavir/ritonavir 20/3 mg/kg twice-daily for 2 weeks. Following review of pharmacokinetic, safety and antiviral data, the doses of darunavir/ritonavir were adjusted to 25/3 mg/kg twice-daily for patients <15 kg, and 375/50 mg twice-daily for patients 15 to <20 kg., Results: Of the 34 patients screened, 21 were treated (median treatment duration 48.6 weeks). Darunavir plus an OBR was well tolerated over 48 weeks, with no new safety concerns, and a comparable safety profile to that seen in older children and adults. All treatment-emergent lipid-related and glucose-related laboratory abnormalities were grade 1 or 2. At week 48, 17 of 21 patients (81.0%) had a confirmed virologic response (intent-to-treat, time-to-loss of virologic response). Improvements in height and weight were seen during the study., Conclusions: No new safety concerns were observed over a 48 week period. These results led to lowering the age to 3 years at which darunavir/ritonavir is indicated for use in treatment-experienced pediatric patients. This study also established doses of darunavir to use in treatment-experienced, HIV-1-infected patients aged 3 to <6 years. A high virologic response was observed with this dose. No development of resistance was observed in patients who experienced virologic failure.

Background: Untreated syphilis during pregnancy is associated with spontaneous abortion, stillbirth, prematurity and infant mortality. Syphilis may facilitate HIV transmission, which is especially concerning in low- and middle-income countries where both diseases are common., Methods: We performed an analysis of data available from NICHD/HPTN 040 (P1043), a study focused on the prevention of intrapartum HIV transmission to 1684 infants born to 1664 untreated HIV-infected women. This analysis evaluates risk factors and outcomes associated with a syphilis diagnosis in this cohort of HIV-infected women and their infants., Results: Approximately, 10% of women (n=171) enrolled had serological evidence of syphilis without adequate treatment documented and 1.4% infants (n=24) were dually HIV and syphilis infected. Multivariate logistic analysis showed that compared with HIV-infected women, co-infected women were significantly more likely to self-identify as non-white (adjusted odds ratio [AOR] 2.5, 95% CI: 1.5-4.2), to consume alcohol during pregnancy (AOR 1.5, 95% CI: 1.1-2.1) and to transmit HIV to their infants (AOR 2.1, 95% CI: 1.3-3.4), with 88% of HIV infections being acquired in utero. As compared with HIV-infected or HIV-exposed infants, co-infected infants were significantly more likely to be born to mothers with venereal disease research laboratory titers≥1:16 (AOR 3, 95% CI: 1.1-8.2) and higher viral loads (AOR 1.5, 95% CI: 1.1-1.9). Of 6 newborns with symptomatic syphilis, 2 expired shortly after birth, and 2 were HIV-infected., Conclusion: Syphilis continues to be a common co-infection in HIV-infected women and can facilitate in utero transmission of HIV to infants. Most infants are asymptomatic at birth, but those with symptoms have high mortality rates.

Background: There are no previous data describing nelfinavir and lamivudine pharmacokinetics in neonates treated with weight-band dosing regimens., Design: Pharmacokinetic study of nelfinavir and lamivudine pharmacokinetics in infants during the first 2 weeks of life treated with weight-band dosing regimens., Methods: Intensive 12-hour pharmacokinetic profiles were performed between either days 4-7 or days 10-14 of life in 26 Brazilian infants., Results: Pharmacokinetic data were obtained from 26 infants who received median (range) per kg doses of 58.8 (48.4-79.0) mg/kg for nelfinavir and 2.0 (1.5-3.2) mg/kg for lamivudine. Median nelfinavir 12-hour AUC (AUC0-12) was 25.5 (1.7-183.5) μg*h/mL and median 12-hour concentration (C12h) was 1.09 (<0.04-14.44) μg/mL. AUC0-12 was less than 15 μg*h/mL (the 10% for adults) in 12 infants (46%). Median lamivudine AUC0-12 was 7.8 (2.7-15.6) μg*h/mL and median C12h was 0.23 (<0.04-0.74) μg/mL., Conclusions: : Lamivudine pharmacokinetic parameters observed in this study were consistent with those seen in other studies of neonates. While median nelfinavir AUC and C12h in these neonates were above the exposure targets, interindividual variability in nelfinavir exposure was large and nelfinavir exposure failed to meet the exposure targets in 46% of infants.