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Background. IMPAACT P1066 is a Phase I/II open-label multicenter trial to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple raltegravir (RAL) formulations in human immunodeficiency virus (HIV)-infected youth. Methods. Dose selection of the oral suspension formulation for each cohort (IV: 6 months to <2 years and V: 4 weeks to <6 months) was based on review of short-term safety (4 weeks) and intensive PK evaluation. Safety data through Weeks 24 and 48 and Grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction from baseline at Week 24 (Success). For Cohort IV, optimized background therapy (OBT) could have been initiated with RAL either at study entry or after intensive PK sampling was completed at Day 5-12. An OBT was started when RAL was initiated for Cohort V subjects because they were not permitted to have received direct antiretroviral therapy before enrollment. Results. Total accrual was 27 subjects in these 2 cohorts, including 1 subject who was enrolled but never started study drug (excluded from the analyses). The targeted PK parameters (area under the curve [AUC]0-12hr and C12hr) were achieved for each cohort allowing for dose selection. Through Week 48, there were 10 subjects with Grade 3+ AEs. Two were judged related to study drug. There was 1 discontinuation due to an AE of skin rash, 1 event of immune reconstitution syndrome, and no drug-related deaths. At Week 48, for Cohorts IV and V, 87.5% of subjects achieved virologic success and 45.5%had HIV RNA <50 copies/mL. At Week 48, gains in CD4 cells of 527.6 cells/mm3 and 7.3% were observed. Conclusions. A total of 6 mg/kg per dose twice daily of RAL for oral suspensionwas well tolerated and showed favorable virologic and immunologic responses. [ABSTRACT FROM AUTHOR]

Novel, potent, and well-tolerated antiretroviral agents in appropriate formulations are acutely needed for HIV-infected pediatric patients of all ages. This study was designed to assess the safety and pharmacokinetics of raltegravir in HIV-infected children aged 4 weeks to <19 years.Background. IMPAACT P1066 is a phase I/II open-label multicenter trial to evaluate pharmacokinetics, safety, tolerability, and efficacy of multiple raltegravir formulations in human immunodeficiency virus (HIV)–infected youth.Methods. Dose selection for each cohort (I: 12 to <19 years; II: 6 to <12 years; and III: 2 to <6 years) was based on review of short-term safety (4 weeks) and intensive pharmacokinetic evaluation. Safety data through weeks 24 and 48, and grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction between baseline and week 24.Results. The targeted pharmacokinetic parameters (AUC0-12h and C12h) were achieved for each cohort, allowing dose selection for 2 formulations. Of 96 final dose subjects, there were 15 subjects with grade 3 or higher clinical AEs (1 subject with drug-related [DR] psychomotor hyperactivity and insomnia); 16 subjects with grade 3 or higher laboratory AEs (1 with DR transaminase elevation); 14 subjects with serious clinical AEs (1 with DR rash); and 1 subjects with serious laboratory AEs (1 with DR transaminase increased). There were no discontinuations due to AEs and no DR deaths. Favorable virologic responses at week 48 were observed in 79.1% of patients, with a mean CD4 increase of 156 cells/µL (4.6%).Conclusions. Raltegravir as a film-coated tablet 400 mg twice daily (6 to <19 years, and ≥25 kg) and chewable tablet 6 mg/kg (maximum dose 300 mg) twice daily (2 to <12 years) was well tolerated and showed favorable virologic and immunologic responses.Clinical Trials Registration NCT00485264. [ABSTRACT FROM PUBLISHER]

Background. The safety and immunogenicity of high-dose pandemic H1N1 (pH1N1) vaccination in perinatally human immunodeficiency virus type 1 (HIV-1)–infected children, adolescents, and young adults are unknown.Methods. Two 30-μg doses of 2009 Novartis pH1N1 monovalent vaccine (Fluvirin) were administered 21–28 days apart to perinatally HIV-1–infected children, adolescents, and young adults. Antibodies were measured by hemagglutination inhibition (HAI) assay at baseline, 21–28 days after first vaccination, 7–13 days after the second vaccination, and 7 months after the first vaccination.Results. Among the 155 participants, 54 were aged 4–8 years, 51 were aged 9–17 years, and 50 were aged 18–24 years. After 2 doses of Fluvirin, seroresponse (≥4-fold rise in HAI titers) was demonstrated in 79.6%, 84.8%, and 83% of participants in the aforementioned age groups, respectively, and seroprotection (HAI titers ≥40) was shown in 79.6%, 82.6%, and 85.1%, respectively. Of those lacking seroresponse (n = 43) or seroprotection (n = 37) after the first vaccination, 46.5% and 40.5% achieved seroresponse or seroprotection, respectively, after the second vaccination. Among participants who lacked seroprotection at entry, a “complete response” (both seroresponse and seroprotection) after first vaccination was associated with higher baseline log10 HAI titer and non-Hispanic ethnicity. No serious vaccine-related events occurred.Conclusion. Two doses of double-strength pH1N1 vaccine are safe and immunogenic and may provide improved protection against influenza in perinatally HIV-1–infected children and youth.Clinical Trials Registration. NCT00992836. [ABSTRACT FROM PUBLISHER]

Background: Early markers that predict immunologic long-term nonprogression in infants with perinatally acquired HIV infection might assist in subsequent antiretroviral treatment decisions. Objectives: We sought to identify early markers of immunologic long-term HIV disease nonprogression. Methods: We analyzed immunologic and virologic characteristics at 1 and 2 months of age in HIV-infected children who were enrolled in the Women and Infants Transmission Study and born before 1995, comparing immunologic long-term nonprogressors (ILTNPs; n=10) with non-ILTNPs (n=127). ILTNPs were children who survived to 8 years or older with CD4 percentages of 25% or greater and counts of 500 cells/mm3 or more without receiving highly active antiretroviral therapy. Non-ILTNPs were defined as all other HIV-infected children. Receiver operating characteristic curve analysis was used to assess combined sensitivity and specificity for each of these characteristics and to determine potential threshold values to discriminate between ILTNPs and non-ILTNPs. Results: Characteristics in the first 2 months of life associated with ILTNP status in univariate analysis included higher CD4 percentages, lower CD8+ percentages, lower CD8+HLA-DR+ percentages, and lower HIV-1 RNA PCR values. In receiver operating characteristic analysis CD8+HLA-DR+ percentage had the best combined sensitivity and specificity for discriminating between ILTNPs and non-ILTNPs. CD8+HLA-DR+ percentages of 5% or less predicted ILTNP status with 80% sensitivity and 80% specificity. In multivariate analysis CD8+HLA-DR+ percentage of 5% or less remained a significant predictor of ILTNP status after adjusting for CD3+CD4+ percentage and HIV-1 RNA PCR value (odds ratio, 15.4; 95% CI, 1.9-124.7). Conclusion: CD8+ HLA-DR+ T-lymphocyte percentage of less than 5% at 1 to 2 months of age might be predictive for ILTNP status but should not be used at this time to make treatment-deferral decisions. Immune activation in HIV-infected infants might herald more disease progression. Further study of the use of this subpopulation in early infancy to predict ILTNP status is warranted. [Copyright &y& Elsevier]