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Objective The SENTINEL1 observational study characterized confirmed respiratory syncytial virus hospitalizations (RSVH) among U.S. preterm infants born at 29 to 35 weeks' gestational age (wGA) not receiving respiratory syncytial virus (RSV) immunoprophylaxis (IP) during the 2014 to 2015 and 2015 to 2016 RSV seasons. Study Design All laboratory-confirmed RSVH at participating sites during the 2014 to 2015 and 2015 to 2016 RSV seasons (October 1–April 30) lasting ≥24 hours among preterm infants 29 to 35 wGA and aged Results Results were similar across the two seasons. Among infants with community-acquired RSVH (N = 1,378), 45% were admitted to the intensive care unit (ICU) and 19% required invasive mechanical ventilation (IMV). There were two deaths. Infants aged Conclusion Among U.S. preterm infants 29 to 35 wGA not receiving RSV IP, RSVH are often severe with almost one-half requiring ICU admission and about one in five needing IMV.

Rationale: Active immunization is needed to protect infants and young children against respiratory syncytial virus (RSV). Rationally designed live-attenuated RSV vaccines are in clinical developmen...

Ketamine is an N-methyl D-aspartate receptor antagonist used off label to facilitate dissociative anesthesia in children undergoing invasive procedures. Available for both intravenous and intramuscular administration, ketamine is commonly used when vascular access is limited. Pharmacokinetic (PK) data in children are sparse, and the bioavailability of intramuscular ketamine in children is unknown. We performed 2 prospective PK studies of ketamine in children receiving either intramuscular or intravenous ketamine, and combined the data to develop a pediatric population PK model using nonlinear mixed effects methods. We applied our model by performing dosing simulations targeting plasma concentrations previously associated with analgesia (>100 ng/mL) and anesthesia awakening (750 ng/mL). A total of 113 children (50 intramuscular and 63 intravenous ketamine) with a median age of 3.3 years (range: 0.02 to 17.6 years), and median weight of 14 kg (2.4 to 176.1) contributed 275 plasma samples (149 after intramuscular, 126 after intravenous ketamine). A 2-compartment model with first-order absorption following intramuscular administration and first-order elimination described the data best. Allometrically scaled weight was included in the base model for central and peripheral volume of distribution (exponent 1), and for clearance and intercompartmental clearance (exponent 0.75). Model estimated bioavailability of intramuscular ketamine was 41%. Dosing simulations suggest that doses of 2 mg/kg intravenously and 8mg/kg or 6 mg/kg intramuscularly depending on age provide adequate sedation (plasma ketamine concentrations >750 ng/mL) for procedures lasting up to 20 minutes.

BackgroundNonspecific clinical signs and suboptimal diagnostic tests limit accurate identification of late onset sepsis (LOS) and necrotizing enterocolitis (NEC) in premature infants, resulting in significant morbidity and antibiotic overuse. An infant’s systemic inflammatory response may be identified earlier than clinical suspicion through analysis of multiple vital signs by a computerized algorithm (RALIS).AimTo evaluate the revised RALIS algorithm for detection of LOS and NEC in preterm infants.MethodsIn this nested case-control study, VS data (heart rate, respiratory rate, temperature, desaturations, bradycardias) were extracted from medical records of infants 23-32 weeks gestation. RALIS generated an output, with score >5 triggering an alert. Patient episodes were classified based on culture, radiograph, and antibiotic data into categories: LOS, expanded LOS, NEC, and controls. Paired t-tests, linear regression and cross-validation analyses were used to evaluate the relationship between RALIS alert and LOS/NEC.ResultsAmong 155 infants with 161 episodes, there were 41 expanded LOS (+ blood, CSF, urine, respiratory culture), 31 LOS (+ blood, CSF, urine), 9 NEC, and 93 controls. RALIS alert was 43.1+/-79 hours before culture in LOS (p=0.012). There was a significant association between RALIS alert and LOS/NEC (β=0.72, pConclusionsFor infants

BACKGROUND Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. METHODS An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. RESULTS A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CONCPlasma (eCONCPlasma) was derived using (CONCDBS - 3.223)/0.51. The median bias and geometric mean ratio improved to -11% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONCPlasma to CONCPlasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (-11 to 50) and -8% (-34 to 11), respectively, when eCONCPlasma was used. CONCLUSIONS After transformation, DBS sampling accurately predicted ampicillin exposure in neonates.

The purpose of this study was to perform a multisite evaluation to establish the performance characteristics of the BD Max extended enteric bacterial panel (xEBP) assay directly from unpreserved or Cary-Blair-preserved stool specimens for the detection of Yersinia enterocolitica , enterotoxigenic Escherichia coli (ETEC), Vibrio , and Plesiomonas shigelloides . The study included prospective, retrospective, and prepared contrived specimens from 6 clinical sites. BD Max xEBP results were compared to the reference method, which included standard culture techniques coupled with alternate PCR and sequencing, except for ETEC, for which the reference method was two alternate PCRs and sequencing. Alternate PCR was also used to confirm the historical results for the retrospective specimens and for discrepant result analysis. A total of 2,410 unformed, deidentified stool specimens were collected. The prevalence in the prospective samples as defined by the reference method was 1.2% ETEC, 0.1% Vibrio , 0% Y. enterocolitica , and 0% P. shigelloides . Compared to the reference method, the positive percent agreement (PPA) (95% confidence interval [CI]), negative percent agreement (NPA) (95% CI), and kappa coefficient (95% CI) for the BD Max xEBP assay for all specimens combined were as follows: ETEC, 97.6% (87.4 to 99.6), 99.8% (99.5 to 99.9), and 0.93 (0.87 to 0.99); Vibrio , 100% (96.4 to 100), 99.7% (99.4 to 99.8), and 0.96 (0.93 to 0.99); Y. enterocolitica , 99.0% (94.8 to 99.8), 99.9% (99.8 to 99.9), and 0.99 (0.98 to 1); P. shigelloides , 100% (96.4 to 100), 99.8% (99.5 to 99.9), and 0.98 (0.95 to 1), respectively. In this multicenter study, the BD Max xEBP showed a high correlation (kappa, 0.97; 95% CI, 0.95 to 0.98) with the conventional methods for the detection of ETEC, Vibrio , Y. enterocolitica , and P. shigelloides in stool specimens from patients suspected of acute gastroenteritis, enteritis, or colitis.

Supplemental Digital Content is available in the text., Background: Infants with premature birth ≤35 weeks gestational age, chronic lung disease of prematurity and congenital heart disease are at an increased risk for lower respiratory tract infections and hospitalization from respiratory syncytial virus (RSV), which has been shown in randomized trials to be prevented by palivizumab. However, palivizumab effectiveness (PE) has not been studied in a large clinical setting. Methods: A multicenter study among high-risk US and Canadian children younger than 24 months hospitalized with lower respiratory tract infection and whose nasopharyngeal aspirates were tested for human metapneumovirus (HMPV) and RSV were the subjects of the trial. We conducted a test-negative case–control study in these subjects to determine PE. We used an inverse propensity score weighted (IPSW) multiple logistic regression model to adjust PE. Results: Palivizumab was used in 434 (51%) of 849 eligible children. RSV was identified in 403 (47%) children. The unadjusted PE was 43% [95% confidence interval (CI), 34%–51%)]. After IPSW adjustment, the adjusted PE was 58% (95% CI, 43%–69%). Palivizumab prevented intensive care unit admissions (PE, 62%; 95% CI, 35%–78%). PE for 29–35 weeks gestational age and ≤6 months of chronologic age without chronic lung disease of prematurity or congenital heart disease was 74% (95% CI, 56%–85%). Conclusions: Using a test-negative case–control design with RSV molecular detection, palivizumab is shown to prevent RSV hospitalizations and intensive care unit admissions in high-risk infants.

Milrinone is a type 3 phosphodiesterase inhibitor used to improve cardiac output in critically ill infants and children. Milrinone is primarily excreted unchanged in the urine, raising concerns for toxic accumulation in the setting of renal dysfunction of critical illness. We developed a population pharmacokinetic model of milrinone using nonlinear mixed-effects modeling in NONMEM to perform dose-exposure simulations in children with variable renal function. We included children aged

BACKGROUND Rilpivirine (RPV), a recently developed, once daily human immunodeficiency virus non-nucleoside reverse transcriptase inhibitor, is not currently approved for pediatric patients, but is sometimes prescribed for adolescents with multiple treatment failures, for regimen simplification or to minimize toxicity. Darunavir/ritonavir (DRV/r) administered once daily is also increasingly used in adolescents and may alter RPV pharmacokinetics (PK). We evaluated the PK interactions between RPV and DRV/r once daily in adolescents and young adults. METHODS Human immunodeficiency virus-infected subjects 12 to

Among 234 US youths with perinatal human immunodeficiency virus, 75% had antiretroviral resistance, substantially higher than that of the reference laboratory overall (36%-44%). Resistance to newer antiretrovirals and to all antiretrovirals in a class was uncommon. The only factor independently associated with future resistance was a higher peak viral load.

Current efforts to fi nd a cure for HIV disease require that viral load assays be available to accurately detect and measure viral load in compartments other than peripheral blood. Over the years, HIV viral load assays have been adapted to measure viral presence in cerebral spinal fl uid (CSF), genital secretions and various other compartments.

BackgroundPersons who are infected with human immunodeficiency virus (HIV) are at high risk of human papillomavirus (HPV)-associated cancers. The objectives are to compare antibody titers to HPV 6, 11, 16, and 18 and rate of abnormal cytology between perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth.MethodsThis is a prospective observational cohort study of HPV4 vaccinated youth performed as part of the multicenter Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. Seroconversion and geometric mean titer (GMT) against HPV types 6, 11, 16, and 18 were calculated. Vaccine effectiveness included rates of abnormal cervical cytology and genital warts.ResultsSeroconversion to HPV 6, 11, 16, and 18 occurred in 83%, 84%, 90%, and 62% of 310 vaccinated PHIV youth compared to 94%, 96%, 99%, and 87% of 148 vaccinated PHEU youth, respectively (P < .05 for all comparisons). GMTs were lower in the PHIV vs PHEU within each category of HPV4 doses received. Higher GMTs were associated with younger age, lower HIV type 1 RNA viral load, and higher CD4% at first HPV4 vaccination, as well as shorter duration between last vaccine dose and antibody specimen. Abnormal cytology occurred in 33 of 56 PHIV and 1 of 7 PHEU sexually active vaccinated females, yielding incidence rates per 100 person-years of 15.0 (10.9 to 20.6) and 2.9 (0.4 to 22.3), respectively.ConclusionAntibody titers to HPV4 were lower for all serotypes in PHIV compared to PHEU youth. Protection against abnormal cytology was also diminished in sexually active PHIV females.

Trimethoprim (TMP)-sulfamethoxazole (SMX) is used to treat various types of infections, including community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) and Pneumocystis jirovecii infections in children. Pharmacokinetic (PK) data for infants and children are limited, and the optimal dosing is not known. We performed a multicenter, prospective PK study of TMP-SMX in infants and children. Separate population PK models were developed for TMP and SMX administered by the enteral route using nonlinear mixed-effects modeling. Optimal dosing was determined on the basis of the matching adult TMP exposure and attainment of the surrogate pharmacodynamic (PD) target for efficacy, a free TMP concentration above the MIC over 50% of the dosing interval. Data for a total of 153 subjects (240 samples for PK analysis) with a median postnatal age of 8 years (range, 0.1 to 20 years) contributed to the analysis for both drugs. A one-compartment model with first-order absorption and elimination characterized the TMP and SMX PK data well. Weight was included in the base model for clearance (CL/ F ) and volume of distribution ( V / F ). Both TMP and SMX CL/ F increased with age. In addition, TMP and SMX CL/ F were inversely related to the serum creatinine and albumin concentrations, respectively. The exposure achieved in children after oral administration of TMP-SMX at 8/40 mg/kg of body weight/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 320/1,600 mg/day divided into administration every 12 h and achieved the PD target for bacteria with an MIC of 0.5 mg/liter in >90% of infants and children. The exposure achieved in children after oral administration of TMP-SMX at 12/60 and 15/75 mg/kg/day divided into administration every 12 h matched the exposure achieved in adults after administration of TMP-SMX at 640/3,200 mg/day divided into administration every 12 h in subjects 6 to

Evidence of high efficacy of live attenuated influenza vaccine (LAIV) from randomized controlled trials is strong for children 2-6 years of age, but fewer data exist for older school-age children. We reviewed the published data on efficacy and effectiveness of LAIV in children ≥5 years. QUOSA (Elsevier database) was searched for articles published from January 1990 to June 2014 that included 'FluMist', 'LAIV', 'CAIV', 'cold adapted influenza vaccine', 'live attenuated influenza vaccine', 'live attenuated cold adapted' or 'flu mist'. Studies evaluated included randomized controlled trials, effectiveness and indirect protection studies. This review demonstrates that LAIV has considerable efficacy and effectiveness in school-age children.

Background. Fetal bone effects of maternal tenofovir use have not been well studied. We sought to compare whole-body bone mineral content (BMC) of newborns exposed vs not exposed to tenofovir in utero. Methods. We enrolled participants from April 2011 to June 2013 at 14 US clinical sites. Singleton infants of women with human immunodeficiency virus (HIV) infection who took tenofovir in late pregnancy (tenofovir-exposed) or no tenofovir during pregnancy (tenofovir-unexposed) were enrolled during late pregnancy or within 72 hours of birth. Infants born before 36 weeks gestation or with confirmed HIV infection were excluded. Whole-body BMC was measured in the first month of life and compared with that of the tenofovir-exposed and tenofovir-unexposed newborns, unadjusted and adjusted for covariates. Results. Seventy-four tenofovir-exposed and 69 tenofovir-unexposed infants had evaluable BMC measurements. Tenofovir-exposed mothers were more likely to be married (31% vs 22%; P = .04) and to use boosted protease inhibitors (84% vs 62%; P = .004). Tenofovir-exposed newborns did not differ from unexposed newborns on mean gestational age (38.2 vs 38.1 weeks) or mean length (−0.41 vs −0.18) or weight (−0.71 vs −0.48) Z-scores. The mean (standard deviation) BMC of tenofovir-exposed infants was 12% lower than for unexposed infants (56.0 [11.8] vs 63.8 [16.6] g; P = .002). The adjusted mean bone mineral content was 5.3 g lower (95% confidence interval, −9.5, −1.2; P = .013) in the tenofovir-exposed infants. Conclusions. Maternal tenofovir use is associated with significantly lower neonatal BMC. The duration and clinical significance of this finding should be evaluated in longitudinal studies. Clinical Trials Registration. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01310023","term_id":"NCT01310023"}}NCT01310023.

Background: Trimethoprim-sulfamethoxazole (TMP-SMX) is an antimicrobial drug combination commonly prescribed in children and adults. The study objectives were to validate and apply an HPLC–MS/MS method to quantify TMP-SMX in dried plasma spots (DPS) and dried urine spots (DUS), and perform a comparability analysis with liquid matrices. Results: For TMP the validated range was 100–50,000 ng/ml for DPS and 500–250,000 ng/ml for DUS; for SMX, the validated range was 1000–500,000 ng/ml for both DPS and DUS. Good agreement was noted between DPS/DUS and liquid plasma and urine samples for TMP, while only modest agreement was observed for SMX in both matrices. Conclusion: A precise, accurate and reproducible method was developed to quantify TMP-SMX in DPS and DUS samples.

We aimed to describe temporal changes in substance use among HIV-infected pregnant women in the United States from 1990 to 2012.Data came from two prospective cohort studies (Women and Infants Transmission Study and Surveillance Monitoring for Antiretroviral Therapy Toxicities Study).Women were classified as using a substance during pregnancy if they self-reported use or had a positive biological sample. To account for correlation between repeated pregnancies by the same woman, generalized estimating equation models were used to test for temporal trends and evaluate predictors of substance use.Over the 23-year period, substance use among the 5451 HIV-infected pregnant women sharply declined; 82% of women reported substance use during pregnancy in 1990, compared with 23% in 2012. Use of each substance decreased significantly (P 0.001 for each substance) in an approximately linear fashion, until reaching a plateau in 2006. Multivariable models showed substance use was inversely associated with receiving antiretroviral therapy. Among the subset of 824 women with multiple pregnancies under observation, women who used a substance in their previous pregnancy were at elevated risk of substance use during their next pregnancy (risk ratio, 5.71; 95% confidence interval, 4.63-7.05).A substantial decrease in substance use during pregnancy was observed between 1990 and 2012 in two large US cohorts of HIV-infected women. Substance use prevalence in these cohorts became similar to that of pregnant women in the general US population by the mid-2000s, suggesting that the observed decrease may be due to an epidemiological transition of the HIV epidemic among women in the United States.

Amiodarone is a first-line antiarrhythmic for life-threatening ventricular fibrillation or ventricular tachycardia in children, yet little is known about its pharmacokinetics (PK) in this population. We developed a population PK (PopPK) model using samples collected via an opportunistic study design of children receiving amiodarone per standard of care supplemented by amiodarone PK data from the literature. Both study data and literature data were predominantly from infants

BACKGROUND: Respiratory syncytial virus (RSV) is the most important viral cause of severe respiratory illness in young children and lacks a vaccine. RSV cold-passage/stabilized 2 (RSVcps2) is a modification of a previously evaluated vaccine candidate in which 2 major attenuating mutations have been stabilized against deattenuation. METHODS: RSV-seronegative 6–24-month-old children received an intranasal dose of 10(5.3) plaque-forming units (PFU) of RSVcps2 (n = 34) or placebo (n = 16) (International Maternal Pediatric Adolescent AIDS Clinical Trials protocol P1114 and companion protocol CIR285). RSV serum neutralizing antibody titers before and 56 days after vaccination, vaccine virus infectivity (defined as vaccine virus shedding detectable in nasal wash and/or a ≥4-fold rise in serum antibodies), reactogenicity, and genetic stability were assessed. During the following RSV transmission season, participants were monitored for respiratory illness, with serum antibody titers measured before and after the season. RESULTS: A total of 85% of vaccinees were infected with RSVcps2 (median peak titer, 0.5 log(10) PFU/mL by culture and 2.9 log(10) copies/mL by polymerase chain reaction analysis); 77% shed vaccine virus, and 59% developed a ≥4-fold rise in RSV-serum neutralizing antibody titers. Respiratory tract and/or febrile illness occurred at the same rate (50%) in the vaccine and placebo groups. Deattenuation was not detected at either of 2 stabilized mutation sites. CONCLUSIONS: RSVcps2 was well tolerated and moderately immunogenic and had increased genetic stability in 6–24-month-old RSV-seronegative children. CLINICAL TRIALS REGISTRATION: NCT01852266 and NCT01968083.

The direct impact of vaccines on children is well described, but the major public health impact of indirect protection provided to the community by vaccines is underappreciated. Community protection occurs when vaccinated persons block the chain of transmission, protecting undervaccinated or unvaccinated susceptible community members by preventing exposure and limiting the spread of the pathogen through the community. Substantial declines in disease incidence have occurred shortly after implementing new childhood vaccines, including declines among vaccine-ineligible children, adolescents, and adults. Protection of susceptible community members depends on maintaining high vaccination rates. Improved recognition of community protection will strengthen childhood vaccination strategies that will protect our communities into the future.

BACKGROUND: Live respiratory syncytial virus (RSV) candidate vaccine LIDΔM2-2 is attenuated by deletion of the RSV RNA regulatory protein M2-2, resulting in upregulated viral gene transcription and antigen expression but reduced RNA replication. METHODS: RSV-seronegative children ages 6–24 months received a single intranasal dose of 10(5) plaque forming units (PFU) of LIDΔM2-2 (n = 20) or placebo (n = 9) (NCT02237209, NCT02040831). RSV serum antibodies, vaccine infectivity, and reactogenicity were assessed. During the following RSV season, participants were monitored for respiratory illness and pre- and post-RSV season serum antibodies. RESULTS: Vaccine virus was shed by 95% of vaccinees (median peak titers of 3.8 log(10) PFU/mL by quantitative culture and 6.3 log(10) copies/mL by PCR); 90% had ≥4-fold rise in serum neutralizing antibodies. Respiratory symptoms and fever were common in vaccine (95%) and placebo (78%). One vaccinee had grade 2 rhonchi concurrent with vaccine shedding, rhinovirus, and enterovirus. Eight of 19 vaccinees versus 2 of 9 placebo recipients had substantially increased RSV antibody titers after the RSV season without medically attended RSV disease, indicating anamnestic vaccine responses to wild-type RSV without significant illness. CONCLUSION: LIDΔM2-2 had excellent infectivity and immunogenicity, encouraging further study of vaccine candidates attenuated by M2-2 deletion. CLINICAL TRIALS REGISTRATION: NCT02237209, NCT02040831.

Despite improved survival due to combination antiretroviral therapy (cART), youth with perinatally-acquired HIV (PHIV) show cognitive deficits and developmental delay at increased rates. HIV affects the brain during critical periods of development, and the brain may be a persistent reservoir for HIV due to suboptimal blood brain barrier penetration of cART. We conducted structural magnetic resonance imaging (sMRI) and cognitive testing in 40 PHIV youth (mean age=16.7 years) recruited from the NIH Pediatric HIV/AIDS Cohort Study (PHACS) who are part of the first generation of PHIV youth surviving into adulthood. Historical and current HIV disease severity and substance use measures were also collected. Total and regional cortical grey matter brain volumes were compared to a group of 334 typically-developing, HIV-unexposed and uninfected youth (frequency-matched for age and sex) from the Pediatric Imaging, Neurocognition, and Genetics (PING) study (mean age=16.1 years). PHIV youth had smaller (2.8 – 5.1%) total and regional grey matter volumes than HIV-unexposed and uninfected youth, with smallest volumes seen among PHIV youth with higher past peak viral load (VL) and recent unsuppressed VL. In PHIV youth, worse cognitive performance correlated with smaller volumes. This pattern of smaller grey matter volumes suggests that PHIV infection may influence brain development and underlie cognitive dysfunction seen in this population. Among PHIV youth, smaller volumes were also linked to substance use (alcohol use: 9.0 – 13.4%; marijuana use: 10.1 – 16.0%). In this study, collection of substance use information was limited to the PHIV cohort; future studies should also collect substance use information in controls to further address interactions between HIV and substance use on brain volume.

Current efforts to fi nd a cure for HIV disease require that viral load assays be available to accurately detect and measure viral load in compartments other than peripheral blood. Over the years, HIV viral load assays have been adapted to measure viral presence in cerebral spinal fl uid (CSF), genital secretions and various other compartments. In this study we describe our efforts to quantitatively recover HIV-1 from pooled pediatric bone marrow plasma spiked with known concentrations of HIV-1 virus using the Abbott RealTime HIV-1 assay and the m2000 platform. We focused on nucleic acid extraction, sample dilution, viral copy recovery, linearity and limit of detection.

The study by Farber et al1 on the retrospective effectiveness of palivizumab for late preterm infants contains critical design flaws that call into question many of its conclusions. The study is a retrospective cohort study of infants born at 29 to 36 weeks’ gestation from 9 Texas Medicaid managed care programs. The study was funded by managed care organizations with a financial interest in justifying cost reductions associated with palivizumab approvals. Among infants born at 29 to 32 weeks’ gestation, those with ≥1 insurance claim for palivizumab had a 38% lower rate of hospitalization for respiratory syncytial virus (RSV) (5.0% vs 3.1%, P = .04). For the infants born at 33 to 36 weeks’ … E-mail: boyce.thomas{at}mayo.edu

Monthly doses of palivizumab, an RSV-specific monoclonal antibody, reduce RSV-related hospitalizations (RSVH) in high-risk children; however, no specific palivizumab level has been correlated with disease severity in humans. A post hoc analysis of a previous randomized, placebo-controlled trial evaluated the relationship between serum palivizumab level at the time of RSVH and disease severity. Pediatric intensive care unit (PICU) admission was the primary severity marker. Relationships were evaluated between disease severity and gestational age, age at enrollment, age at RSVH, presence of bronchopulmonary dysplasia, sex, race, multiple birth, household smoking, daycare attendance, sibling(s), family history of atopy, duration between most recent palivizumab dose and RSVH, and palivizumab level at RSVH. Forty-two (87.5%) of 48 palivizumab recipients with RSVH had palivizumab levels drawn; 11 were admitted to the PICU. Mean palivizumab levels were lower in PICU-admitted subjects (47.2 μg/mL) vs. non-PICU subjects (98.7 μg/mL; P < 0.0001); there were no statistically significant differences in other variables examined. The probability of PICU admission declined with higher palivizumab levels; there were no PICU admissions with levels ≥ 92 μg/mL. In multivariate analyses, palivizumab level was the only independent predictor of PICU admission (P = 0.009). Palivizumab level also correlated with duration of RSVH and PICU stay, supplemental oxygen use and duration, and mechanical ventilation use and duration (P < 0.05). Higher palivizumab level was associated with decreased disease severity in high-risk infants with RSVH. Findings suggest that palivizumab level has clinical relevance, and adherence to timely monthly dosing may confer additional protection among high-risk children receiving palivizumab.

Clindamycin is commonly prescribed to treat children with skin and skin structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus [CA-MRSA]), yet little is known about the pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving intravenous clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. Median age (range) was 3.3 years (0–20). Median dosing was 9.9 mg/kg/dose (3.8–15.1). A 1-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (L/h)=13.7*(weight/70)0.75*(PMA3.1/(43.63.1+PMA3.1)); V (L)=61.8*(weight/70). Maturation reached 50% adult CL values at ~44 weeks PMA. Our findings support age-based dosing.

SUMMARY The prevalence of HIV-associated neurocognitive impairment in perinatally HIV-infected children has declined sincethe introduction of combination antiretroviral therapy (cART). Early initiation of cART in infancy has been shown topositively impact neurodevelopment; however, children continue to be diagnosed with HIVoutside of the early infancyperiod and can experience subtle to severe neurocognitive deficits despite cART. The causes of these neurocognitivedeficits despite effective cART are multifactorial and likely include continued viral replication in the CNS, ongoingneuroinflammation, irreversible CNS injury prior to cART initiation, neurotoxic effects of cART, and socioeconomicand psychosocial effects. Manyaspects of our understanding of HIV-associated neurocognitive disorders have emergedfrom research in adult patients, but perinatally HIV-infected children represent a very different population. Thesechildren were exposed to HIV during a period of rapid brain development and have lifelong infection and potentiallifelong cARTexposure. HIVis no longer a rapidly fatal disease, and most HIV-infected children in resource-rich coun-tries are living into adulthood. It is therefore critical to optimize neurocognitive outcomes of these youth. This reviewsummarizes current understanding of the pathogenesis of HIV-associated CNS infection and the impact of cART onneurocognitive function in children and adolescents and discusses important areas for future research. Copyright ©2014 John Wiley & Sons, Ltd.Received: 29 January 2014; Revised: 23 March 2014; Accepted: 24 March 2014

Human parainfluenza virus type 3 (HPIV3) is a common cause of upper and lower respiratory tract illness in infants and young children. Live-attenuated cold-adapted HPIV3 vaccines have been evaluated in infants but a suitable interval for administration of a second dose of vaccine has not been defined.HPIV3-seronegative children between the ages of 6 and 36 months were randomized 2:1 in a blinded study to receive two doses of 10⁵ TCID₅₀ (50% tissue culture infectious dose) of live-attenuated, recombinant cold-passaged human PIV3 vaccine (rHPIV3cp45) or placebo 6 months apart. Serum antibody levels were assessed prior to and approximately 4-6 weeks after each dose. Vaccine virus infectivity, defined as detection of vaccine-HPIV3 in nasal wash and/or a≥4-fold rise in serum antibody titer, and reactogenicity were assessed on days 3, 7, and 14 following immunization.Forty HPIV3-seronegative children (median age 13 months; range 6-35 months) were enrolled; 27 (68%) received vaccine and 13 (32%) received placebo. Infectivity was detected in 25 (96%) of 26 evaluable vaccinees following doses 1 and 9 of 26 subject (35%) following dose 2. Among those who shed virus, the median duration of viral shedding was 12 days (range 6-15 days) after dose 1 and 6 days (range 3-8 days) after dose 2, with a mean peak log₁₀ viral titer of 3.4 PFU/mL (SD: 1.0) after dose 1 compared to 1.5 PFU/mL (SD: 0.92) after dose 2. Overall, reactogenicity was mild, with no difference in rates of fever and upper respiratory infection symptoms between vaccine and placebo groups.rHPIV3cp45 was immunogenic and well-tolerated in seronegative young children. A second dose administered 6 months after the initial dose was restricted in those previously infected with vaccine virus; however, the second dose boosted antibody responses and induced antibody responses in two previously uninfected children.

BACKGROUND: Prevention-of-mother-to-child-transmission (PMTCT) programs have made it possible to achieve dramatic reductions in the rate of vertical HIV transmission. However high attrition particularly after delivery has limited the impact of these interventions for HIV-exposed infants who remain at risk through the end of breastfeeding. DESIGN AND METHODS: A review of current literature on early infant diagnosis (EID) testing and country experience in low-and middle-income countries. RESULTS: While PMTCT programs report reduced rates of infection among infants tested at 2 months of age too few services are focused on retention of HIV-exposed infants in care. An unacceptably large proportion of HIV-exposed and HIV-infected infants remain unidentified. While the complexities of EID have been simplified with the development of optimized commodities and tools to improve service delivery the inaccessibility and inadequate uptake of EID services has resulted in lag of care for the millions of HIV-exposed infants who remain unidentified. Coverage of EID testing remains low and there are many HIV- infected infants or at risk of infection who may not enter the health system through PMTCT programs. Waiting for HIV-infected children to present sick is not an adequate strategy for identifying and linking infants to treatment. Several interventions suggest a potential to expand access to EID testing while more aggressive testing strategies may ensure children can be captured at any point of contact with the health system. CONCLUSIONS: Programs focused on preventing vertical transmission need to increase their commitment to child-centric interventions and broaden their measure of success to reflect infants who test negative at the end of the exposure period. This paper argues that EID is a key strategy to retaining HIV-exposed infants through the end of the exposure period as it provides an opportunity to offer early clinical care and continuous follow up. It is imperative that maternal and child survival programs become sensitized to the urgency of early identification of HIV in infants and their retention in care.

Background Pediatric vaccination has resulted in declines in disease in unvaccinated individuals through decreasing pathogen circulation in the community. About 2 years after implementation of pediatric rotavirus vaccination in the United States, dramatic declines in rotavirus disease were observed in both vaccinated and unvaccinated children. Whether this protection extends to adults is unknown. Methods The prevalence of rotavirus, as determined by Rotaclone enzyme immunoassay, in adults who had stools submitted for bacterial stool culture (BSC) between February to May to Northwestern Memorial Hospital, Chicago, was compared between the prepediatric impact era (2006-2007) and the pediatric impact era (2008-2010). Isolates were genotyped and clinical characteristics of those with rotavirus were compared. Results Of the 5788 BSC sent, 4725 met inclusion criteria and 3530 of these (74.7%) were saved for rotavirus testing. The prevalence of rotavirus among adults who had stool sent for BSC declined from 4.35% in 2006-2007 to 2.24% in 2008-2010 (a relative decline of 48.4%; P = .0007). The decline in the prevalence of rotavirus was of similar significant magnitude in both outpatients and inpatients. Marked year-to-year variability was observed in circulating rotavirus genotypes, with strain G2P[4] accounting for 24%; G1P[8], 22%; G3P[8], 11%; and G12P[6], 10% overall. About 30% of adults from whom rotavirus was isolated were immunocompromised and this remained constant. Conclusions Pediatric rotavirus vaccination correlated with a relative decline of almost 50% in rotavirus identified from adult BSC during the peak rotavirus season, suggesting that pediatric rotavirus vaccination protects adults from rotavirus.

We retrospectively reviewed 14 children with active blastomycosis. Pulmonary disease occurred in 86% of the cohort and extrapulmonary dissemination was noted in 46%. Urine blastomycosis or histoplasmosis antigens were positive in all tested patients. Acute kidney injury was common in patients who were treated with amphotericin. Mortality tended to be associated with a delay in diagnosis.

Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size. The final model included TBW and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (liters/hour) = 13.8 × (TBW/70) 0.75 × [PMA 2.83 /(39.5 2.83 +PMA 2.83 )]; volume of distribution ( V ) was associated with TBW, albumin (ALB), and alpha-1 acid glycoprotein (AAG): V (liters) = 63.6 × (TBW/70) × (ALB/3.3) −0.83 × (AAG/2.4) −0.25 . After accounting for differences in TBW, obesity status did not explain additional interindividual variability in model parameters. Our findings support TBW-based dosing for obese and nonobese children.

Background Increased incidence and prevalence of asthma have been documented for perinatally HIV-infected youth 10 to 21 years of age compared with HIV-exposed uninfected (HEU) youth. Objective We sought to perform objective pulmonary function tests (PFTs) in HIV-infected and HEU youth with and without diagnosed asthma. Method Asthma was determined in 370 participants (218 HIV-infected and 152 HEU participants) by means of chart review and self-report at 13 sites. Interpretable PFTs (188 HIV-infected and 132 HEU participants) were classified as obstructive, restrictive, or normal, and reversibility was determined after bronchodilator inhalation. Values for HIV-1 RNA, CD4 and CD8 T cells, eosinophils, total IgE, allergen-specific IgE, and urinary cotinine were measured. Adjusted prevalence ratios (PRs) of asthma and PFT outcomes were determined for HIV-infected participants relative to HEU participants, controlling for age, race/ethnicity, and sex. Results Current asthma was identified in 75 (34%) of 218 HIV-infected participants and 38 (25%) of 152 HEU participants (adjusted PR, 1.33; P = .11). The prevalence of obstructive disease did not differ by HIV status. Reversibility was less likely in HIV-infected youth than in HEU youth (17/183 [9%] vs 21/126 [17%]; adjusted PR, 0.47; P = .020) overall and among just those with obstructive PFT results (adjusted PR, 0.46; P = .016). Among HIV-infected youth with current asthma, serum IgE levels were inversely correlated with CD8 T-cell counts and positively correlated with eosinophil counts and not associated with CD4 T-cell counts. HIV-infected youth had lower association of specific IgE levels to several inhalant and food allergens compared with HEU participants and significantly lower CD4/CD8 T-cell ratios (suggesting immune imbalance). Conclusion Compared with HEU youth, HIV-infected youth demonstrated decreased reversibility of obstructive lung disease, which is atypical of asthma. This might indicate an early stage of chronic obstructive pulmonary disease. Follow-up into adulthood is warranted to further define their pulmonary outcomes.

BACKGROUND Combination antiretroviral therapy has led to increased survival among youth with perinatally acquired HIV (PHIV). However, cognitive deficits continue to be common. Histopathological studies in adults have found HIV concentrated in subcortical structures, which are involved in sensory processing, movement, and higher-order cognition that emerges with development. METHODS We conducted magnetic resonance imaging and cognitive testing in 40 youth with PHIV at one site of the Adolescent Master Protocol of the Pediatric HIV/AIDS Cohort Study. We collected HIV disease-severity measures and substance-use reports. Subcortical volume and shape deformation were generated with FreeSurfer-Initiated Large Deformation Diffeomorphic Metric Mapping. Inward shape deformation was defined as negative displacement. We evaluated associations of subcortical shape deformation with past HIV severity after adjustment for sex, age at neuroimaging, age at HIV severity marker, and substance use. We examined associations between subcortical deformation and cognitive function. RESULTS Negative correlations between shape deformation and peak HIV viral load (VL) were found in clusters in the caudate tail, globus pallidus, lateral putamen, and anterior and medial thalamus. Positive correlations between shape deformation and nadir CD4-positive T-lymphocyte percentage (CD4%) were found in clusters in the medial and posterior thalamus. Inward deformation in caudate and thalamic clusters correlated with worse cognition. CONCLUSIONS Youth with PHIV have demonstrable subcortical shape deformation related to past HIV severity and cognition; inward deformation was associated with higher peak VL, lower nadir CD4%, and worse cognition. Identifying subcortical deformation may inform clinical practice for early intervention to help improve cognitive outcomes and assess the neuroefficacy of combination antiretroviral therapy in youth with PHIV.

Dalbavancin is a novel lipoglycopeptide antibiotic that has potent in vitro activity against Gram-positive microorganisms.We performed a phase 1, open-label, multicenter study to investigate the pharmacokinetics (PK) and safety of a single dose of intravenous dalbavancin in hospitalized pediatric subjects 3 months to 11 years of age. We combined these data with previously collected adolescent PK data and performed a population PK analysis.Model development was performed using 311 dalbavancin plasma concentrations from 43 subjects. The median age was 5.9 years (range: 0.3-16.9). A 3-compartment, linear PK model was developed. Based on simulations, the following age-dependent dosing regimen was found to achieve similar dalbavancin exposure to that in adults administered a 2-dose regimen: children 6 to18 years of age, 12 mg/kg (1000 mg maximum) on day 1 and 6 mg/kg (500 mg maximum) on day 8 and children 3 months to6 years of age, 15 mg/kg (1000 mg maximum) on day 1 and 7.5 mg/kg (500 mg maximum) on day 8. Similarly, the following age-dependent regimen was found to match adult exposure after a single-dose (1500 mg): 6 to18 years of age, 18 mg/kg (1500 mg maximum) on day 1 and 3 months to6 years of age, 22.5 mg/kg (1500 mg maximum) on day 1. Nineteen subjects experienced 36 treatment-emergent adverse events. Five of 36 adverse events were assessed as possibly or probably related to treatment.Dalbavancin pediatric dosing that matched adult exposure was identified. Overall, dalbavancin was well tolerated in our study population.

OBJECTIVES Identification of HIV infection in exposed infants facilitates early therapy, which may limit viral reservoirs that maintain HIV infection under HAART. METHODS The dynamics of the resting CD4 T-cell latent HIV reservoir was determined over the first 2 years of life in 17 HIV-infected infants initiating lopinavir/ritonavir-based HAART at a median age of 8.1 weeks and achieving adequate suppression of plasma viral load by 24 weeks. RESULTS The resting CD4 T-cell latent HIV reservoir was detected in 12 of 14 (86%) infants tested at 24 weeks of HAART [median frequency 1.88 infectious units per million (IUPM); range

Human metapneumovirus (HMPV) is a significant cause of respiratory tract infections. Little is known about HMPV in children who are at high risk for lower respiratory tract infection (LRTI).To determine the prevalence of HMPV in high-risk children and to identify HMPV risk factors, children ≤24 months with prematurity, chronic lung disease, and/or congenital cardiac disease who were hospitalized with LRTI were prospectively enrolled. Nasopharyngeal aspirates were tested for HMPV, respiratory syncytial virus (RSV), influenza A and B, and parainfluenza types 1-3. Demographics, medical history, and outcomes for those with HMPV and RSV were compared. A multivariate analysis was performed to determine HMPV risk factors.Over 4 years, 1126 eligible children were enrolled. Pathogens were identified in 61% of subjects. HMPV was identified in 9.0%, second to RSV (45%). Coinfection with HMPV and RSV occurred in1% of subjects. Subjects infected with HMPV were older (8.2 vs 4.0 months, P .001), were born more prematurely (27 vs 33 weeks, P .001), and more commonly had chronic lung disease (59.3% vs 21.8%, P .001) compared with subjects infected with RSV. In a multivariate analysis that compared children infected with HMPV to all others, increasing age and household exposure to children ages 6-12 were associated with an increased risk, whereas birth at older gestational age and exposure to children age12 were associated with a decreased risk.HMPV was detected in 9% of high-risk children who were hospitalized with lower respiratory tract disease, representing the second most common virus in this population. Compared with all other subjects (including RSV-infected), subjects infected with HMPV were older but were born more prematurely.

Since the discovery of HIV 30 years ago, we have learned much about HIV in children and adolescents. Dramatic declines have occurred in mother-to-child transmission of HIV in resource-rich countries. Resource-poor countries struggle with improving prevention of mother-to-child transmission due to the lack of universal antiretroviral treatment for pregnant and nursing mothers. In children infected with HIV, pharmacokinetic, safety and efficacy data have been determined for many of the older drugs. Data are lacking for the newer, safer and more effective currently available drugs, resulting in the pediatric guidelines lagging behind adult recommendations. Although guidelines for prevention and treatment are helpful, the way they are created causes them to lag behind new scientific evidence, and in some situations they will be confusing or only based on expert opinion. Improving prevention of HIV infection in adolescents and young adults and in treating those who become HIV infected is crucially important. The next 10 years hold tremendous opportunities for improvements in prevention and treatment of HIV in children, adolescents and young adults.

A novel swine-origin influenza A subtype H1N1 virus, designated 2009 H1N1 influenza A, was identified as the cause of pandemic febrile respiratory illnesses [1–4]. Although individuals of all ages were affected, the greatest increase in severe morbidity and mortality occurred in young children, pregnant women, and the morbidly obese [5]. In human immunodeficiency virus type 1 (HIV-1)–infected patients, influenza infection is more severe than that typical of age-matched uninfected people [6, 7]. HIV-1–nfected patients also may shed virus for greater periods of time, prolonging the need for isolation in the clinic or hospital [8]. Because of the increased severity of this pandemic in children and young adults, knowledge of the safety and immunogenicity of the pandemic influenza A (pH1N1) 2009 monovalent vaccine in this population is critically important. Antibody responses to seasonal trivalent influenza vaccine (TIV) are blunted in HIV-1–infected children and adults who are not receiving antiretroviral therapy (ART) [9–11] but improved in patients who do not have progressive HIV-1 disease and/or are receiving combination ART (cART) [12–16]. Still, the immunological response is poorer compared to that of HIV-uninfected cohorts [15, 16]. Studies evaluating the effect of antigen dosage on the immune responses to TIV performed over the past 35 years demonstrate dose-related increases in serum and mucosal antibody responses [17–25]. Higher vaccine dosages are also associated with the development of higher levels of serum antibodies that recognize antigenically distinct drift variants [23] and can overcome suboptimal responses in immunologically impaired vaccinees, such as elderly patients [22, 24, 25]. However, higher dosages of hemagglutinin are also associated with more frequent adverse events. We hypothesized that 2 doses of influenza vaccine would be necessary to achieve protection in perinatally HIV-1–infected children and youth who had no prior exposure to pH1N1. In addition, because of blunted response to TIV in HIV-1–infected persons, we investigated a 30-μg dose of antigen, double the 15-μg dose proposed for healthy children.

Human immunodeficiency virus (HIV)-infected children are at increased risk of meningococcal infection and poor response to quadrivalent meningococcal conjugate vaccine (MCV4), but MCV4 has not been studied in preadolescent HIV-infected children.The P1065 trial enrolled 2- to 10-year-old HIV-infected children with CD4 ≥ 25% to receive MCV4 at entry and at week 24. Rates of response (≥ 4-fold increase in rabbit serum bactericidal antibody) against each meningococcal serogroup (A, C, Y, W-135), geometric mean titers, and rates of seroprotection (rabbit serum bactericidal antibody titer ≥ 1:128) were determined from sera obtained at entry and weeks 4, 24, 28, and 72. Adverse events were assessed for 6 weeks after each MCV4 dose.At entry, 47% of the 59 participants were male, 56% black, 31% Latino, median age was 6 years, 88% were receiving antiretroviral therapy, and 75% had viral load400 copies/mL. There were no serious adverse events within 6 weeks after MCV4 doses; all vaccination reactions were mild. Response after a single MCV4 dose was high to serogroup A (92%) and W-135 (98%); responses improved after a second dose for serogroup C (43%-80%) (P0.0001) and Y (76%-84%) (P = 0.38). By week 72, seroprotection rates were 93%, 91%, 78%, and 46% for serogroups W-135, Y, A, and C, respectively.Two doses of MCV4 were safe and immunogenic in 2- to 10-year-old HIV-infected children. The second dose increased the proportion of children who made a response to serogroup C. Seroprotection waned substantially for serogroups A and C within 1 year of last MCV4 dose.

Data on the combination of darunavir/ritonavir and etravirine both given twice daily in adolescents/young adults are lacking. In this study, we assessed the pharmacokinetics of darunavir/ritonavir 600/100 mg with etravirine 200 mg twice daily in 36 treatment-experienced human immunodeficiency virus-infected adolescents and young adults and found that exposures were comparable to those reported in adults.

Early in theHIVepidemic,patientswithAIDSwerenotalways diagnosed as having the disease, in some cases because their opportunistic infections (eg, disseminated histoplasmosis) were not yet recognized as AIDS-defining conditions. Sincethen,therehavebeenremarkableadvances inboththediagnosticcapabilitiesandtherapeuticoptions inthetreatmentofHIVdisease.Thisprogresshas resulted in restorationof severely ill patients’ immune systems and previously lethal HIV infection becoming a chronic disease. There has seldom been such successful and rapid progress for adiseasewithhighmorbidity and short life expectancy (eg, in the 1980s,>40%ofperinatally infectedchildrendiedbefore 4 years of age, whereas today, with optimal care

Improved antiretroviral therapies are needed for the treatment of HIV-infected infants, given the rapid progression of the disease and drug resistance resulting from perinatal exposure to antiretrovirals. We examined longitudinal pharmacokinetics (PK) data from a clinical trial of lopinavir/ritonavir (LPV/r) in HIV-infected infants in whom therapy was initiated at less than 6 months of age. A population PK analysis was performed using NONMEM to characterize changes in lopinavir (LPV) PK relating to maturational changes in infants, and to assess dosing requirements in this population. We also investigated the relationship between LPV PK and viral dynamic response. Age and ritonavir concentrations were the only covariates found to be significant. Population PK of LPV was characterized by high apparent clearance (CL/F) in young infants, which decreased with increasing age. Although younger infants had lower LPV concentrations, the viral dynamics did not correlate with initial LPV exposure. Monte Carlo simulations demonstrated that WHO weight band-based dosing recommendations predicted therapeutic LPV concentrations and provided drug exposure levels comparable to those resulting from US Food and Drug Administration (FDA)-suggested dosing regimens.

Background Alternatives to the available stavudine-containing paediatric fixed-dose combination (FDC) tablets are rapidly needed due to concerns regarding the cumulative toxicity of long-term stavudine exposure. We report the bioavailability and short-term safety of a novel paediatric FDC tablet of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP; 30/15/28 mg) in HIV-infected children. Methods In this Phase I/II open-label pharmacokinetic study, 42 children weighing 6–30 kg treated with NVP-based HAART for ≥4 weeks were randomized to receive the FDC tablets (GPO-VIR Z30) or the liquid formulations. Dosing was weight-based. Intensive 12-h blood sampling was performed after 2 weeks; subjects then crossed-over to the alternate formulation at equal doses and sampling repeated 2 weeks later. Pharmacokinetic parameters were determined by non-compartmental analysis. Buccal-swab samples were collected for cytochrome P450 ( CYP)2B6 polymorphism analysis. Results With the FDC tablet, the geometric mean (90% CI) area under the curve (AUC) for ZDV, 3TC and NVP was 1.58 (1.49-1.68), 7.78 (7.38-8.19) and 68.88 (62.13-76.36) μg•h/ml, respectively. Rules for NVP therapeutic inadequacy were defined a priori, and despite lower NVP exposure with the tablet ( P Conclusions Disparities in drug exposure between formulations were observed; however, the FDC tablet delivered therapeutically adequate exposures of each drug and could well play an important role in simplifying antiretroviral treatment for children.