Jorge Lujan-Zilbermann

Respiratory Virus Infections in Pediatric Hematopoietic Stem Cell Transplantation

Respiratory virus infections (RVI) have become an increasingly appreciated problem in the hematopoietic stem cell transplant (HSCT) population. A retrospective analysis of 274 patients undergoing 281 HSCT at St. Jude Childrens Research Hospital from January 1994 through December 1997 was performed. Medical and clinical laboratory records were reviewed beginning at the onset of conditioning through the year following each HSCT, and the analysis was done for the first RVI only. Thirty-two (11%) of 281 HSCT cases developed a RVI during the first year post-HSCT. The most frequent cause of RVI was human parainfluenza virus type 3. Univariate analysis was performed to determine the association between risk factors and the cumulative incidence of RVI. Respiratory viruses are frequent causes of infections in the first year post-HSCT in the pediatric population. Only allogeneic transplant and the degree of acute or chronic graft versus host disease were found to be statistically significant risk factors for RVI.

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. RESULTS At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, -7.9 and -6.2 pg/mL; P = .031 and .053, respectively). CONCLUSIONS In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration. CLINICAL TRIALS REGISTRATION NCT00490412.

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. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomized double-blind, placebo-controlled multicenter trial of HIV-infected youth ages 18-24 yr, with viral load below 5000 copies/ml, on stable antiretroviral therapy. INTERVENTION INTERVENTION included vitamin D(3), 50,000 IU (n = 102), or matching placebo (n = 101) administered in three directly observed oral doses at monthly intervals. RESULTS At baseline, mean (sd) age was 20.9 (2.0) yr; 37% were female and 52% African-American, and 54% were vitamin D deficient/insufficient (25-OHD < 20 ng/ml), with no randomized group differences. Of evaluable participants vitamin D deficient/insufficient at baseline who were administered vitamin D, 43 of 46 (93%) had sufficient 25-OHD by wk 12. Vitamin D supplementation increased 25-OHD serum concentration from a baseline of 21.9 (13.3) to 35.9 (19.1) ng/ml at wk 12 (P < 0.001) with no change for placebo. Although use of the antiretroviral efavirenz was associated with lower baseline 25-OHD concentration, efavirenz did not diminish the response to vitamin D supplementation. There was no treatment-related toxicity. CONCLUSIONS Supplementation with vitamin D(3) 50,000 IU monthly for three doses was safe. Increases in 25-OHD occurred in treated participants regardless of antiretroviral regimen.

Pneumococcal meningitis in children: relationship of antibiotic resistance to clinical characteristics and outcomes.

Background. The relationship of antibiotic susceptibility to clinical outcome in children with pneumococcal meningitis is uncertain. Previous studies have been limited by inclusion of relatively few patients infected with nonsusceptible pneumococci and inconsistent use of empiric vancomycin. Methods. Medical records of 86 children with culture-confirmed pneumococcal meningitis at a single institution from October, 1991, to October, 1999, were retrospectively reviewed, and differences in presentation and outcome based on antibiotic susceptibility of pneumococcal isolates were assessed. Results. Of 86 isolates 34 were nonsusceptible to penicillin (12 resistant). Of 60 isolates for which cefotaxime susceptibility data were available, 17 were nonsusceptible (12 resistant). Antibiotic susceptibility was not significantly associated with death, intensive care unit admission, mechanical ventilation, focal neurologic deficits, seizures, secondary fever, abnormal neuroimaging studies or hospital days. Children with penicillin-resistant isolates had significantly higher median blood leukocyte counts (24 100/&mgr;l vs. 15 700/&mgr;l, P = 0.03) and lower median CSF protein concentrations (85 mg/dl vs. 219 mg/dl, P = 0.04), were more likely to have a CSF glucose concentration of ≥50 mg/dl (7 of 11 vs. 15 of 68, P = 0.009) and had lower rates of sensorineural hearing loss (1 of 8 vs. 25 of 40, P = 0.02) than children with isolates that were not resistant to penicillin. Children with cefotaxime-nonsusceptible isolates had an increased median duration of primary fever compared with those with nonsusceptible strains (6 days vs. 3.5 days, P = 0.02). Conclusions. In children with pneumococcal meningitis, penicillin resistance was associated with a reduced risk of hearing loss, while cefotaxime resistance was associated with a longer duration of fever. Other outcome measures were not significantly influenced by the antibiotic susceptibility of pneumococcal isolates.

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. Standardized questionnaires were used to evaluate safety. Baseline protective immunity was defined as rabbit serum bactericidal antibody (rSBA) titer ≥1:128. Immunogenic response was defined as a ≥4-fold rise in rSBA against each meningococcal serogroup. Multivariable logistic regression analysis was used to evaluate the association of demographic and clinical characteristics on immunogenic response to serogroup C. Results: Among 319 subjects who received MCV4, 10 (3.1%) reported immediate adverse events which were local and mild, and 7 (2.2%) experienced Grade ≥3 adverse events, unrelated to vaccine. The 305 subjects with serologic data had a median age of 17 years and were 59% male, 50% Black, and 38% Latino. Subjects were stratified by entry CD4%: 12%, CD4 <15%; 40%, 15% to 24%; and 48%, ≥25%. Baseline protective immunity varied by serogroup: A, 41%; C, 11%; W-135, 15%; Y, 35% The immunogenic response rates to serogroups A, C, W-135, and Y were 68%, 52%, 73%, and 63%, respectively. In multivariable logistic regression models, lower entry CD4%, higher entry viral load, and CDC Class B/C diagnosis were associated with significantly lower odds of response to serogroup C. Conclusion: Many HIV-infected youth naturally acquire meningococcal immunity. MCV4 is safe and immunogenic in HIV-infected youth, but response rates are lower than in healthy youth, particularly for those with more advanced HIV clinical, immunologic, and virologic status.

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?

ABSTRACT 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. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. IMPORTANCE (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.)

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. RESULTS. Among 405 patients with perinatal HIV-1 infection, 72 (17.8%) experienced a treatment interruption during the observation period. The mean age of patients at the time of the treatment interruption was 12.8 years, and the mean length of the treatment interruption was 14 months. Medication fatigue was the most common reason for a treatment interruption. The CD4+ T-cell percentage nadir before the treatment interruption did not predict CD4+ T-cell percentage declines during the treatment interruption; however, the CD4+ T-cell percentage gain from nadir to the time of the treatment interruption predicted CD4+ T-cell percentage declines during the treatment interruption. During the median follow-up of 19 months (range: 6–48 months), 48 (67%) patients resumed antiretroviral medications. As expected, there was a continuous CD4+ T-cell percentage decrease and plasma HIV-1 RNA increase during the observation period. Overall, 7 (10%) patients were admitted to the hospital; 2 (3%) patients experienced an AIDS-defining illness. CONCLUSIONS. An unstructured treatment interruption seems to be a major issue for youth with perinatally acquired HIV-1 infection. Patients who experienced the greatest rise in CD4+ T-cell percentage on treatment had the largest CD4+ T-cell percentage decline after the treatment interruption. Close monitoring is required when a treatment interruption occurs in children and adolescents with HIV infection.

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. Vancomycin start time was defined as the number of hours from initiation of cefotaxime or ceftriaxone therapy until the administration of vancomycin therapy. Outcome variables were death, sensorineural hearing loss, and other neurologic deficits at discharge. Associations between independent variables and outcome variables were assessed in univariate and multiple logistic regression analyses. RESULTS. Of 114 subjects, 109 received empiric vancomycin therapy in combination with cefotaxime or ceftriaxone. Ten subjects (9%) died, whereas 37 (55%) of 67 survivors who underwent audiometry had documented hearing loss, and 14 (13%) of 104 survivors were discharged with other neurologic deficits. Subjects with hearing loss had a significantly shorter median vancomycin start time than did those with normal hearing (<1 vs 4 hours). Vancomycin start time was not significantly associated with death or other neurologic deficits in univariate or multivariate analyses. Multiple logistic regression revealed that hearing loss was independently associated with vancomycin start time <2 hours, blood leukocyte count <15000/μL, and cerebrospinal fluid glucose concentration <30 mg/dL. CONCLUSIONS. Early empiric vancomycin therapy was not clinically beneficial in children with pneumococcal meningitis but was associated with a substantially increased risk of hearing loss. It may be prudent to consider delaying the first dose of vancomycin therapy until ≥2 hours after the first dose of parenteral cephalosporin in children beginning therapy for suspected or confirmed pneumococcal meningitis.

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. Adverse events were assessed for 6 weeks after each MCV4 dose. Results: 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 load <400 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%) (P < 0.0001) 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. Conclusions: 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.

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. At 24 weeks, those with screening cluster of differentiation 4 (CD4)% ≥ 15 were randomized to receive a second dose or not, and all with screening CD4% <15 received a second dose. Immunogenicity was evaluated as the proportion of subjects with a ≥ 4-fold rise from entry in serum bactericidal antibody against each meningococcal serogroup (SG) at weeks 28 and 72. Logistic regression models adjusting for HIV disease severity were used to evaluate the effect of 1 vs 2 MCV4 doses among those with screening CD4% ≥ 15. RESULTS Subjects randomized to receive 2 vs 1 MCV4 dose had significantly higher response rates to all SGs at week 28 and to all except Neisseria meningitidis SG Y at week 72, with adjusted ORs of 2.5-5.6. In 31 subjects with screening CD4% <15 who received 2 MCV4 doses, response rates ranged from 22%-55% at week 28 and 6%-28% at week 72. CONCLUSION In youth infected with HIV with a CD4% ≥ 15, a second dose of MCV4 given 6 months after the initial dose significantly improves response rates at 28 and 72 weeks. Subjects with CD4% <15 at entry had lower response rates despite 2 doses of MCV4.