Population Pharmacokinetics of Milrinone in Infants, Children, and Adolescents.

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 <21 years who received intravenous milrinone per clinical care. Plasma milrinone concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay (range 1-5000 ng/mL). We performed dose-exposure simulations targeting steady-state therapeutic concentrations of 100-300 ng/mL previously established in adults and children with cardiac dysfunction. We simulated concentrations over 48 hours in typical subjects with decreasing creatinine clearance (CrCl), estimated using the updated bedside Schwartz equation. Seventy-four patients contributed 111 plasma samples (concentration range, 4-634 ng/mL). The median (range) postmenstrual age (PMA) was 3.7 years (0-18), and median weight (WT) was 13.1 kg (2.6-157.7). The median serum creatinine and CrCl were 0.5 mg/dL (0.1-3.1) and 117.2 mL/min/1.73 m2 (13.1-261.3), respectively. A 1-compartment model characterized the pharmacokinetic data well. The final model parameterization was: Clearance (L/h) = 15.9*(WT [kg] / 70)0.75 * (PMA1.12 / (67.71.12 +PMA1.12 )*(CrCl / 117)0.522 ; and Volume of Distribution (L) = 32.2*(WT [kg] / 70). A loading dose of 50 µg/kg followed by a continuous infusion of 0.5 µg/kg/min resulted in therapeutic concentrations, except when CrCl was severely impaired at ≤30 mL/min/1.73 m2 . In this setting, a 25 µg/kg loading dose and 0.25 µg/kg/min continuous infusion resulted in therapeutic exposures.

Early viral suppression improves neurocognitive outcomes in HIV-infected children.

OBJECTIVE: To estimate the association of age of viral suppression and central nervous system penetration effectiveness (CPE) score with neurocognitive functioning among school-age children with perinatally acquired HIV infection (PHIV+). DESIGN: We analyzed data from two US-based multisite prospective cohort studies. METHODS: Multivariable general linear regression models were used to evaluate associations of age at viral suppression and CPE scores (of initial antiretroviral therapy regimen and weighted average) with the Wechsler Intelligence Scale for Children, Third or Fourth Edition neurocognitive assessments [Full-Scale Intelligence Quotient (FSIQ); Performance IQ/Perceptual Reasoning Index (PIQ/PRI); and Verbal IQ/Verbal Comprehension Index (VIQ/VCI)], adjusted for demographic and clinical covariates. Sensitivity analyses were stratified by birth cohort (before versus after 1996). RESULTS: A total of 396 PHIV+ children were included. Estimated differences in mean FSIQ (comparing virally suppressed versus unsuppressed children) by each age cutoff were 3.7, 2.2, 3.2, 4.4, and 3.9 points at ages 1, 2, 3, 4, and 5, respectively. For PIQ/PRI, estimated mean differences were 3.7, 2.4, 2.2, 4.6, and 4.5 at ages 1 through 5, respectively. In both cases, these differences were significant only at the age 4 and 5 thresholds. After stratifying by birth cohort, the association between age at suppression and cognitive function persisted only among those born after 1996. Age at viral suppression was not associated with VIQ/VCI; CPE score was not associated with FSIQ, verbal comprehension, or perceptual reasoning indices. CONCLUSION: Virologic suppression during infancy or early childhood is associated with improved neurocognitive outcomes in school-aged PHIV+ children. In contrast, CPE scores showed no association with neurocognitive outcomes.

Serum palivizumab level is associated with decreased severity of respiratory syncytial virus disease in high-risk infants.

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.

Long-term highly suppressed HIV-infected children and adolescents with negative rapid HIV tests due to significant antibody loss.

BACKGROUND: Rapid HIV test devices are widely used throughout the world and are important as diagnostic tools with relatively high sensitivity and specificity. Loss of HIV specific antibodies in late-stage AIDS patients has previously been reported in patients with advanced disease (i.e., AIDS). OBJECTIVE: To study rate of antibody loss that may lead to false negative HIV-antibodies results in children and adolescents who received long term antiretroviral (ARV) treatment with persistently undetectable viral loads. STUDY DESIGN: Five FDA approved rapid HIV test kits including Trinity Uni-Gold Recombigen HIV-1, OraQuick Advance HIV-1/2, Reveal G3 HIV-1, Clearview STAT-PAK HIV-1/2, and Clearview COMPLETE HIV-1/2 were used to test 98 stored samples from 27 patients. Samples were tested at baseline and at least twice in 6-14 years post initiation of ARV treatment and full viral load suppression. RESULTS: Of the 403 tests, 43 (10.7%) were found to be false-negative using rapid HIV kits. Loss of positivity was correlated with decrease of HIV antibody titer. CONCLUSIONS: There is a slow but persistent loss of HIV specific antibodies in highly suppressed HIV infected children and adolescents that may lead to false-negative results in rapid HIV antibody tests. The temporal loss of signal is dependent on the baseline level of antibodies and the type of HIV rapid test kit used.

The glory of guidelines and the twilight of reality: controversies and challenges in the prevention and treatment of HIV in children.

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.

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

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

Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children.

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<0.001), the levels remained therapeutically adequate. ZDV AUC was similar between formulations. 3TC exposure was significantly higher with the tablet but comparable to historical data in adults and children taking branded tablets. While receiving the tablet, NVP AUC in children with CYP2B 516 GG (45%), GT (45%) and TT (10%) genotypes were 67.0, 74.5 and 106.4 µg•h/ml, respectively (P=0.04). 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.

Correlation of HIV-specific immunity, viral control, and diversification following planned multiple exposures to autologous HIV in a pediatric population.

Repeated controlled exposure to autologous virus was previously shown to result in increased CD8 T lymphocyte response to HIV antigens and accompanying reduction in viremia. We attempted to see if this immunity contributed to virologic control by correlating the immune response with quasispecies envelope diversification, an indicator of immune selection. The greatest diversification was seen in those with the greatest reduction in viremia but was unrelated to the frequency of Env-specific gamma interferon-producing cells. There was a trend toward correlation between the response to multiple HIV antigens and diversification.

Neuroschistosomiasis due to Schistosoma haematobium presenting as spinal cord tumor.

Schistosomiasis is rarely encountered in the United States, but immigration and travel to endemic areas make it important to know its various presentations to improve diagnosis and treatment. We present our experience with a child with Schistosoma haematobium pseudotumor, initially diagnosed as a cord neoplasm.

Substance use in HIV-Infected women during pregnancy: self-report versus meconium analysis.

We evaluated prenatal substance use in a cohort of 480 HIV-infected women and their uninfected children. Substance use was reported by 29%; the most common substances reported were tobacco (18%), alcohol (10%), and marijuana (7.2%). Fewer than 4% of women reported cocaine or opiate use. Substance use was more common in the first trimester (25%) than the second (17%) and third (15%) (trend p-value <0.01), and was associated with race/ethnicity, education, birthplace, age and marital status. For 264 mother/infant pairs with meconium results, sensitivity of self-report was 86% for tobacco, 80% for marijuana and 67% for cocaine. Higher discordance between self-report and urine/blood toxicology was observed for cocaine, marijuana and opiates in a non-random subset of mothers/infants with these tests. Findings suggest reasonably complete self-reporting of substance use as confirmed by meconium analysis. Illicit substance use was low and substantially less than that reported in earlier studies of HIV-infected women, but alcohol and tobacco exposure was prevalent.

Shedding and immunogenicity of live attenuated influenza vaccine virus in subjects 5-49 years of age.

BACKGROUND: Live attenuated influenza vaccine (LAIV) is indicated for influenza prevention in persons 2-49 years of age. This study describes the incidence and duration of vaccine virus shedding and serum immune responses after receipt of LAIV. METHODS: A single open-label dose of trivalent LAIV was administered intranasally to 344 subjects in 3 age cohorts: 5-8, 9-17, and 18-49 years of age. Shedding was determined by culture of nasal swabs (on days 1-7, daily; days 9-25, every other day; and day 28). Immunogenicity was measured as serum strain-specific hemagglutinin inhibition (HAI) titers (days 0, 28). RESULTS: Among subjects aged 5-8 years, 9-17 years, and 18-49 years, 44%, 27%, and 17% of subjects, respectively, shed vaccine virus after vaccination, and the mean number of positive samples per subject was 2.2, 1.8, and 1.5, respectively. Shedding occurred on days 1-11 postvaccination. Shedding incidence peaked on day 2, and maximum observed titers were highest on days 2-3 (<5, <4, and <3 log(10)TCID(50)/mL, respectively, by age group). Despite positive cultures, all titers were <1 log(10)TCID(50)/mL after days 10, 6, and 6, respectively, by age group. Shedding incidence was inversely correlated to age and baseline serum HAI titer. The seroresponse rate (4-fold rise in HAI) to at least 1 strain was 59% (68%, 64%, and 47%, respectively, by age group), and strain-specific rates were higher in baseline seronegative/serosusceptible subjects. Reactogenicity, most commonly runny nose, headache, and sore throat, was not associated with shedding or seroresponse. CONCLUSIONS: This is the first study to comprehensively evaluate nasal shedding of LAIV in individuals 5-49 years of age. Shedding was generally of short duration and at low titers. Study findings support the current recommendation of the Advisory Committee on Immunization Practices that LAIV recipients should only avoid contact with severely immunosuppressed persons (e.g., hematopoietic stem cell transplant recipients) for 7 days after vaccination.

Planned multiple exposures to autologous virus in HIV type 1-infected pediatric populations increases HIV-specific immunity and reduces HIV viremia.

We tested to determine if planned multiple exposures to autologous HIV in pediatric patients with HIV-1 infection will induce cellular immunity that controls viremia. A prospective multicenter study of aviremic pediatric patients on highly active antiretroviral therapy who underwent progressively longer antiretroviral treatment interruptions in cycles starting with 3 days, increasing by 2 days in length each consecutive cycle, was conducted. Eight individuals became viremic and reached Cycle 13 or greater with an "off-therapy" interval of >or=27 days. HIV-specific interferon-gamma (IFN-gamma) production to inactivated HIV and vaccinia vectors expressing gag, env, nef, and pol increased (>10-fold) from baseline in six of eight subjects. The HIV-specific lymphoproliferative response as measured by the median stimulation index (SI) increased in the treatment group from 1 at baseline to 16, 12, 4, and 3 at Cycles 7, 10, 13, and 17, respectively. Median plasma RNA levels peaked at Cycle 7 (4.45 log) and declined to levels <10(4) cp/ml after Cycle 10 (4.1, 3.5, and 3.4 at Cycles 10, 13, and 17). In a subset of five patients who reached Cycle 17, HIV-specific IFN-gamma frequencies were 4- to 30-fold higher and median RNA levels were 0.32-2.10 (median 1.3) log lower than at comparable days off treatment at Cycle 8 (17 days off therapy). A second group of children, not undergoing drug interruption, did not develop significant increases in either HIV-specific IFN-gamma production or SI. Increased HIV-specific immune responses and decreased HIV RNA were seen in those children who have had >10 cycles of antiretroviral discontinuations of increasing durations acting as autologous virus vaccinations. Other studies may have failed due to an insufficient number of exposures to HIV; most of the studies had fewer than six drug interruptions.

Rapid human immunodeficiency virus decay in highly active antiretroviral therapy (HAART)-experienced children after starting mega-HAART.

Increasing numbers of patients are treated with mega-highly active antiretroviral therapy (HAART), or multiple-combination antiretroviral therapy, in an attempt to overcome the viral resistance that has contributed to treatment failure. Studies of human immunodeficiency virus (HIV) viral dynamics are used to quantify the potency of a given regimen. While mega-HAART is expected to provide potent therapy, its potency among heavily experienced HIV-infected children who have failed previous treatment is untested. HIV dynamics studies performed in children have provided minimal information on viral dynamics during mega-HAART. The present study estimates first- and second-phase viral dynamics in six children on mega-HAART, following failure of combination therapy. The first phase of viral decay was rapid, relative to rates reported in previous pediatric studies (median delta = 0.778d(-1), range = 0.583 to 1.088, half-life 1 [t1(1/2)] = 0.894d), while the second phase revealed results similar to those of previous studies (median mu = 0.026d(-1), range = -0.005 to 0.206, t2(1/2) = 9.316d). This indicates that mega-HAART can provide potent therapy among heavily experienced pediatric patients.

Pneumococcal endocarditis in children.

Endocarditis due to Streptococcus pneumoniae is unusual in children, accounting for 3%-7% of all cases of childhood endocarditis. The US Pediatric Multicenter Pneumococcal Surveillance Group has prospectively identified patients with invasive disease at 8 children's hospitals. During the period of 1 September 1993 through 28 February 2003, a total of 11 children with pneumococcal endocarditis were seen. Seven (64%) were 3-36 months old; 8 (73%) were boys. Ten (91%) had preexisting structural heart disease; 5 had undergone previous heart surgery. Concomitant sites of infection were noted in 6 patients (55%), including 3 patients with meningitis. One patient (9%) died during hospitalization, and 5 others (45%) experienced serious complications. Only 2 patients remained hospitalized for their entire course of parenteral antibiotic therapy. Eight of 10 pneumococcal isolates tested were vaccine or vaccine-related serotypes included in the currently licensed 7-valent conjugated pneumococcal vaccine. Pneumococcal endocarditis in children is unusual but often has serious complications.

Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study.

BACKGROUND: Peripheral blood lymphocyte subsets need to be determined in a large, urban, minority-predominant cohort of healthy children to serve as suitable control subjects for the interpretation of the appearance of these cells in several disease conditions, notably pediatric HIV-1 infection. OBJECTIVE: We sought to determine the distribution of lymphocyte subsets in healthy urban-dwelling infants, children, and adolescents in the United States. METHODS: Lymphocyte subsets were determined by means of 3-color flow cytometry in a cross-sectional study of 807 HIV-unexposed children from birth through 18 years of age. RESULTS: Cell-surface marker analysis demonstrated that age was an extremely important variable in 24 lymphocyte subset distributions measured as percentages or absolute counts--eg, the CD4 (helper) T cell, CD8 (cytotoxic) T cell, CD19 B cell, CD4CD45RACD62L (naive helper) T cell, CD3CD4CD45RO (memory helper) T cell, CD8HLA-DRCD38 (activated cytotoxic) T cell, and CD8CD28 (activation primed cytotoxic) T cell. The testing laboratory proved to be an important variable, indicating the need for using the same laboratory or group of laboratories to assay an individual's blood over time and to assay control and ill or treated populations. Sex and race-ethnicity were much less important. CONCLUSION: The results of this study provide a control population for assessment of the effects of HIV infection on the normal development and distribution of lymphocyte subsets in children of both sexes, all races, and all ethnic backgrounds from birth through 18 years of age in an urban population. This study's findings will also prove invaluable in interpreting the immune changes in children with many other chronic diseases, such as primary immunodeficiency, malignancy, rheumatoid arthritis, and asthma.

Recombinant glycoprotein vaccines for human immunodeficiency virus-infected children and their effects on viral quasispecies.

In individuals infected with human immunodeficiency virus type 1 (HIV-1), specific immunity is associated with a more diverse viral repertoire and slower disease progression. Attempts to enhance antiviral immunity with therapeutic vaccination have shown that recombinant glycoprotein (RGP) vaccines are safe, well tolerated, and immunogenic, but the effect of RGP vaccines on the viral repertoire is unknown. We evaluated diversification of the viral envelope in 12 HIV-infected children who received placebo or RGP vaccines. At baseline, 11 of 12 patients had multiple viral variants. On follow-up 6 months later, children who had a strong vaccine-associated lymphoproliferative immune response showed less viral diversification than those in whom the immune response was weak or absent. These results suggest that the immune response elicited by RGP vaccines does not exert a significant selection pressure on the viral quasispecies and therefore may not be helpful in changing the course of the disease.