Revisiting FDA's 1995 Guidance on Bioequivalence Establishment of Topical Dermatologic Corticosteroids: New Research Based Recommendations.

Purpose: As per the US FDA guidance issued on June 2, 1995, the establishment of bioequivalence for topical dermatologic corticosteroids is based on comparing the pharmacodynamic (PD) effects of Test and Reference products at the dose duration corresponding to the population ED50, determined either by naïve pooled data or nonlinear mixed effect modeling (NLME). The guidance was introduced using a study case example where the expectation maximization (EM) NLME algorithm, as implemented in P-PHARM®, was used. Although EM methods are relatively common, other methods such as the First-Order Conditional Estimation (FOCE) as implemented in the NONMEM® software are even more common.

Immunogenicity of a Booster Dose of Quadrivalent Meningococcal Conjugate Vaccine in Previously Immunized HIV-Infected Children and Youth.

Background: The US Advisory Committee on Immunization Practices recommends a booster dose of quadrivalent meningococcal conjugate vaccine (MCV4) after initial immunization for patients at high risk for meningococcal infection.

Methods: The International Maternal Pediatric Adolescents AIDS Clinical Trials (IMPAACT) P1065 trial evaluated the use of MCV4 in human immunodeficiency virus (HIV)-infected children and youth. The final step of this trial was an open-label study of an MCV4 booster dose 3.

Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youths treated with tenofovir disoproxil fumarate.

Background: Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D-binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biological activity, and is elevated in individuals with higher plasma tenofovir concentrations.

Genetic associations with 25-hydroxyvitamin D deficiency in HIV-1-infected youth: fine-mapping for the GC/DBP gene that encodes the vitamin D-binding protein.

Serum 25-hydroxyvitamin D [25(OH)D] is often deficient (<12 ng/ml) or insufficient (<20 ng/ml) in youth living with human immunodeficiency virus type 1 infection (YLH). Based on evidence from multiple genome-wide association studies, we hypothesized that genetic factors associated with 25(OH)D deficiency should be readily detectable in YLH even when controlling for other known factors, including use of the antiretroviral drug efavirenz (EFV). Genotyping by bi-directional sequencing targeted 15 single nucleotide polymorphisms (SNPs) at the GC/DBP locus, with a focus on coding and regulatory variants, as well as those repeatedly reported in the literature.

Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency?

Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover.

Genetic variants in toll-like receptor 2 (TLR2), TLR4, TLR9, and FCγ receptor II are associated with antibody response to quadrivalent meningococcal conjugate vaccine in HIV-infected youth.

This study examined the association of host genetic variants with the antibody response to the quadrivalent meningococcal conjugate vaccine (MCV4) in HIV-infected youth. Genetic variants associated with severity of meningococcal disease, including the IgG Fc receptor (FCγRII)-A484T, interleukin-10 (IL-10)-A1082G, -C819T, and -C627A, IL-4-C589T, mannose binding lectin-2 (MBL2)-A/O, -H/L, -P/Q, and -X/Y, toll-like receptor 2 (TLR2)-G2408A, TLR4-A12874G and -C13174T, and TLR9-T1237C and -T1486C were determined by real-time PCR (RT-PCR) for 271 HIV-infected subjects (median, 17 years). Response was defined as a ≥4-fold increase from entry in bactericidal antibody titers to each serogroup.

Serum 25-hydroxyvitamin D response to vitamin D3 supplementation 50,000 IU monthly in youth with HIV-1 infection.

Context: Vitamin D deficiency and insufficiency occur frequently in youth with HIV infection, particularly among those receiving the antiretroviral drug efavirenz. Optimal vitamin D dosing for treatment is unclear.

Objective: Our objective was to evaluate safety and measure change in 25-hydroxyvitamin D (25-OHD) concentration from baseline to study wk 4 and 12 during treatment with vitamin D(3), 50,000 IU monthly.

Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus.

Objective: To compare the immunogenicity of 1 vs 2 doses of meningococcal polysaccharide conjugate vaccine (MCV4) in youth infected with human immunodeficiency virus (HIV).

Study Design: P1065 was a phase I/II immunogenicity and safety trial of MCV4 in 324 youth infected with HIV performed at 27 sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Group network in the US. At entry subjects received 1 dose of MCV4.

Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial.

Background: The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF).

Methods: This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18-25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo.

Safety and immunogenicity of quadrivalent meningococcal conjugate vaccine in 2- to 10-year-old human immunodeficiency virus-infected children.

Background: 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.

Methods: 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.

Medical decisional capacity among children with HIV.

Medical decisional capacity (DC) refers to the ability to understand, appreciate, and make meaningful decisions about one's health. This is an important construct for children living with HIV whose involvement in their medical care has important implications for disease management. In this study, we assessed the relationship among DC, developmental stage, intellectual ability, and social-emotional functioning of children with and without HIV infection (n=50).

Phase I/II, open-label trial of safety and immunogenicity of meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine in human immunodeficiency virus-infected adolescents.

Background: Quadrivalent meningococcal polysaccharide conjugate vaccine (MCV4) is routinely recommended for healthy youth in the United States, but there are no data about its use in HIV-infected people.

Methods: P1065 is a Phase I/II trial of MCV4 safety and immunogenicity in HIV-infected children and youth performed at 27 US sites of the IMPAACT network. All youth (11-24 years old) received 1 dose of open-label MCV4 at entry.

Clinical outcomes after an unstructured treatment interruption in children and adolescents with perinatally acquired HIV infection.

Objective: An unstructured treatment interruption in children with perinatally acquired HIV infection is an issue with unresolved significance. The objective of this study was to investigate the actual prevalence and clinical outcomes of a treatment interruption in children and adolescents with perinatally acquired HIV-1 infection.

Methods: Clinical data were analyzed for 72 children and adolescents who had HIV-1 infection and stopped their medications at 4 academic centers in the United States between January 2000 and September 2004.

Pediatric HIV infection: immune and viral evaluation.

Advances in laboratory methods have driven improvements in the management and treatment of HIV infection. The methods to accurately and rapidly diagnose HIV infection in infants and children have been outlined in the previous article. In this review, the laboratory evaluation of infected children is described and methods to monitor progression of disease and response to therapy outlined.

Pediatric HIV infection: diagnostic laboratory methods.

The diagnosis of HIV-1 infection in infants and children continues to present challenges. Currently available virologic assays are sensitive and specific and allow early detection of perinatally acquired HIV infection. Identification soon after birth allows for the rapid initiation of antiretroviral therapy and preservation of the infant's immune system.

Early vancomycin therapy and adverse outcomes in children with pneumococcal meningitis.

Background: Experts recommend that children with suspected pneumococcal meningitis should empirically receive combination therapy with vancomycin plus either ceftriaxone or cefotaxime. The relationship between timing of the first dose of vancomycin relative to other antibiotics and outcome in these children, however, has not been addressed.

Methods: Medical records of children with pneumococcal meningitis at a single institution from 1991-2001 were retrospectively reviewed.

Cushing syndrome with secondary adrenal insufficiency from concomitant therapy with ritonavir and fluticasone.

We present 2 cases of Cushing syndrome with secondary adrenal insufficiency from concomitant use of ritonavir and inhaled corticosteroids in children with human immunodeficiency virus infection. These cases highlight the need for special consideration when treatment with an inhaled/intranasal corticosteroid is indicated in children receiving antiretroviral therapy.

Safety and immunogenicity of intranasal murine parainfluenza virus type 1 (Sendai virus) in healthy human adults.

Human parainfluenza virus-type 1 (hPIV-1) is the most common cause of pediatric laryngotracheobronchitis (croup) and results in close to 30,000 US hospitalizations each year. No effective vaccine is available. We examined murine PIV-1 (Sendai virus, SeV) as a live, xenotropic vaccine for the closely related human PIV-1 in a phase I, dose escalation study in healthy adults.

Varicella zoster as a manifestation of immune restoration disease in HIV-infected children.

Background: Exacerbation of opportunistic infections in HIV-infected patients shortly after initiation of highly active antiretroviral therapy (HAART) has been named immune restoration disease (IRD). Thus far, IRD has not been reported in children.

Objective: We describe the clinical and immune characteristics of IRD in HIV-infected children treated with HAART.

Human immunodeficiency virus type 1 RNA polymerase chain reaction reasonably excludes infection in exposed infants.

A nucleic acid sequence-based amplification (NASBA) assay that detects HIV RNA may be helpful in excluding perinatal HIV infection. We reviewed the records of 190 infants born to HIV-infected mothers. The sensitivity and specificity of the NASBA assay were 100% when measured at two time periods in the first 9 months of life.