[Show abstract][Hide abstract] ABSTRACT: Resistance to antiretroviral drugs is an increasingly prevalent challenge affecting both the adult and pediatric HIV-infected populations. Though data on the safety, pharmacokinetics, and efficacy of newer antiretroviral agents in children typically lags behind adult data, newer agents are becoming available for use in HIV-infected children who are failing to respond to or are experiencing toxicities with traditional antiretroviral regimens. Integrase strand transfer inhibitors are one such new class of antiretrovirals. Raltegravir has been US Food and Drug Administration (FDA) approved for use in patients over the age of 4 weeks. Elvitegravir is a second member of this class, and has the potential for use in children but does not yet have a Pediatric FDA indication. Dolutegravir, a second-generation integrase inhibitor, is approved for those older than 12 years. This review summarizes the use of integrase inhibitors in children and adolescents, and highlights the results of recent clinical trials.
[Show abstract][Hide abstract] ABSTRACT: To assess thepharmacokinetic (PK), safety and efficacy of dolutegravir plus optimized background regimen (OBR) in HIV infected treatment-experienced adolescents.
Children ≥12 to < 18 yearsreceived dolutegravir weight-based fixed doses at ~1.0 mg/kg once daily in a Phase I/II multicenter open-label 48 week study. Intensive PK evaluation was done at steady state after dolutegravir was added to a failing regimen or started at the end of a treatment interruption. Safety and HIV RNA and CD4 cell count assessments were performed through Week 48.
Twenty three adolescents, were enrolled and 22 (96%) completed the 48 week study visit. Median age and weight were 15 years and 52 kg, respectively. Median (IQR) baseline CD4+ cell count was 466 cells/µL (297, 771). Median (IQR) baseline HIV-1 RNA log10 was 4.3 log10 copies/mL (3.9, 4.6). Dolutegravir geometric mean AUC(0-24) and C24 were 46.0 µg.h/mL and 0.90 µg/mL, respectively, which were within the study targets based on adult PK ranges. Virologic success with an HIV RNA < 400 copies/mL was achieved in 74 % (95% CI: 52% to 90%) at Week 48. Additionally, 61% (95% CI: 39% to 80%) had an HIV RNA < 50 copies/mL at Week 48. Median (IQR) gain in CD4 cell count at Week 48 was 84 cells/µL (-81, 238). Dolutegravir was well tolerated, with no Grade 4 AEs, SAEs or discontinuations due to AEs.
Dolutegravir achieved target PK exposures in adolescents. Dolutegravir was safe and well tolerated, providing good virologic efficacy through Week 48.
Full-text · Article · Aug 2015 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Objective:
This study compared 12-month CD4 and viral load outcomes in HIV-infected children and adolescents with virological failure, managed with four treatment switch strategies.
This observational study included perinatally HIV-infected (PHIV) children in the Pediatric HIV/AIDS Cohort Study (PHACS) and Pediatric AIDS Clinical Trials (PACTG) Protocol 219C.
Treatment strategies among children with virologic failure were compared: continue failing combination antiretroviral therapy (cART); switch to new cART; switch to drug-sparing regimen; and discontinue all ART. Mean changes in CD4% and viral load from baseline (time of virologic failure) to 12 months follow-up in each group were evaluated using weighted linear regression models.
Virologic failure occurred in 939 out of 2373 (40%) children. At 12 months, children switching to new cART (16%) had a nonsignificant increase in CD4% from baseline, 0.59 percentage points [95% confidence interval (95% CI) -1.01 to 2.19], not different than those who continued failing cART (71%) (-0.64 percentage points, P = 0.15) or switched to a drug-sparing regimen (5%) (1.40 percentage points, P = 0.64). Children discontinuing all ART (7%) experienced significant CD4% decline -3.18 percentage points (95% CI -5.25 to -1.11) compared with those initiating new cART (P = 0.04). All treatment strategies except discontinuing ART yielded significant mean decreases in log10VL by 12 months, the new cART group having the largest drop (-1.15 log10VL).
In PHIV children with virologic failure, switching to new cART was associated with the best virological response, while stopping all ART resulted in the worst immunologic and virologic outcomes and should be avoided. Drug-sparing regimens and continuing failing regimens may be considered with careful monitoring.
Full-text · Article · Jul 2015 · AIDS (London, England)
[Show abstract][Hide abstract] ABSTRACT: This study describes sexual health knowledge in perinatally HIV-infected (PHIV+) and perinatally exposed uninfected (PHIV−) ethnic-minority youth, aged 9–16 years, residing in New York City (N = 316). Data on youth sexual health knowledge (e.g., pregnancy, sexually transmitted diseases, birth control) and caregiver–adolescent communication about sexual health were examined. Participants in both groups answered only 35% of the sexual health knowledge questions correctly (mean = 6.6 of 19). Higher scores were found among youth who reported more communication about sex with caregivers (vs. those who did not report talking about sex with caregivers; 8.54 vs. 5.84, p < .001) and among PHIV+ youth who were aware of their status (vs. PHIV+ youth who were not; 7.27 vs. 4.70, p < .001). Age was positively correlated with sexual health knowledge (β = .489, p < .001). Both PHIV+ and PHIV− youth had poor sexual health knowledge, suggesting a need for sexual health education for both groups. Data suggest that interventions focused on caregiver–child risk communication may be important for prevention.
No preview · Article · Jul 2015 · Journal of HIV/AIDS & Social Services
[Show abstract][Hide abstract] ABSTRACT: Some perinatally infected children do not regain normal CD4 T-cell counts despite suppression of HIV-1 plasma viremia by antiretroviral therapy (ART). The frequency, severity and significance of these discordant treatment responses remain unclear.
We examined the persistence of CD4 lymphocytopenia despite virologic suppression in 933 children (≥5 years of age) in the USA, Latin America and the Caribbean.
CD4 T-cell trajectories were examined and Kaplan-Meier methods used to estimate median time to CD4 T-cell count at least 500 cells/μl.
After 1 year of virologic suppression, most (99%) children achieved a CD4 T-cell count of at least 200 cells/μl, but CD4 T-cell counts remained below 500 cells/μl after 1 and 2 years of virologic suppression in 14 and 8% of children, respectively. Median times to first CD4 T-cell count at least 500 cells/μl were 1.29, 0.78 and 0.46 years for children with less than 200, 200-349 and 350-499 cells/μl at the start of virologic suppression. New AIDS-defining events occurred in nine children, including four in the first 6 months of virologic suppression. Other infectious and HIV-related diagnoses occurred more frequently and across a wide range of CD4 cell counts.
ART improved CD4 cell counts in most children, but the time to CD4 cell count of at least 500 cells was highly dependent upon baseline immunological status. Some children did not reach a CD4 T-cell count of 500 cells/μl despite 2 years of virologic suppression. AIDS-defining events occurred in 1% of the population, including children in whom virologic suppression and improved CD4 T-cell counts were achieved.
[Show abstract][Hide abstract] ABSTRACT: P1066 is an open-label study of raltegravir in HIV+ youth, ages 4 weeks-18 years. Here we summarize P1066 pharmacokinetic (PK) data and a population PK model for the pediatric chewable tablet and oral granules. Raltegravir PK parameters were calculated using non-compartmental analysis. A two-compartment model was developed using data from P1066 and an adult study of the pediatric formulations. Inter-individual variability was described by an exponential error model, and residual variability was captured by an additive/proportional error model. Twelve-hour concentrations (C12hr ) were calculated from the model-derived elimination rate constant and 8-hour observed concentration. Simulated steady-state concentrations were analyzed by non-compartmental analysis. Target area-under-the-curve (AUC0-12hr ) and C12hr were achieved in each cohort. For the pediatric formulations, geometric mean AUC0-12hr values were 18.0-22.6 µM*hr across cohorts, and C12hr values were 71-130 nM, with lower coefficients of variation vs the film-coated tablet. A two-compartment model with first-order absorption adequately described raltegravir plasma PK in pediatric and adult patients. Weight was a covariate on clearance and central volume, and incorporated using allometric scaling. Raltegravir chewable tablets and oral granules exhibited PK parameters consistent with those from prior adult studies and older children in P1066, as well as lower variability than the film-coated tablet. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Mar 2015 · The Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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/mm(3) and 7.3% were observed.
A total of 6 mg/kg per dose twice daily of RAL for oral suspension was well tolerated and showed favorable virologic and immunologic responses.
[Show abstract][Hide abstract] ABSTRACT: Background Limited data are available for once-daily (QD) darunavir (DRV)/ritonavir (r) in the pediatric population. Coadministration
of etravirine (ETR) may alter the pharmacokinetics (PK) of DRV. We evaluated the PK interactions between DRV/r (QD) and ETR
QD or twice-daily (BID) in children, adolescents, and young adults.
[Show abstract][Hide abstract] ABSTRACT: Abstract We examined youth-caregiver adherence report concordance and association of different adherence self-report items with HIV RNA viral load (VL) in perinatally HIV-infected adolescents assessed in 2003-2008. Youth (n=194; 9-19 years) and their caregivers completed a multi-step 2-day recall, one item on last time medications were missed, and one item on responsibility for managing youths' medications. Across early (9-12 years), middle (13-15 years), and late (16+years) adolescence, both youth and caregivers reported having primary responsibility for youths' medication regimens and demonstrated poor to moderate youth-caregiver concordance on adherence items. Responses to the last-time-missed item had greater association with VL than did the 2-day recall, particularly for longer times (e.g., past month). By age group, significant associations with VL were found for caregiver reports in early adolescence, caregiver and youth reports in middle adolescence, and youth reports in late adolescence, suggesting that caregivers offer better reports of youth adherence during early adolescence, but by later adolescence, youth are better informants. Although design limitations preclude definitive conclusions about the reliability and validity of specific adherence items, this study suggests important issues related to age group, caregiver vs. youth informants of adherence, and recall periods for child adherence assessment that warrant further research.
No preview · Article · Nov 2014 · AIDS PATIENT CARE and STDs
[Show abstract][Hide abstract] ABSTRACT: Background. IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate safety, pharmacokinetics (PK), tolerability and efficacy of multiple raltegravir (RAL) formulations in 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 (PK) evaluation. Safety data through Weeks 24 and 48, and Grade >3 or serious adverse events (AE) 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 PK parameters (AUC0-12 hr and C12 hr) were achieved for each cohort allowing dose selection for two formulations. Of 96 final dose subjects, there were 15 subjects with Grade 3+ clinical AEs (1 subject with drug related [DR] psychomotor hyperactivity and insomnia); 16 subjects with Grade 3+ laboratory AEs (1 with DR transaminase elevation); 15 subjects with serious clinical AEs (1 with DR rash); 2 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 78.9%, with a mean CD4 increase of 156 cells/uL (4.6%). Conclusions. 400 mg BID of RAL film-coated tablet (6 to <19 years, and ≥25 kg) and 6 mg/kg BID (maximum dose 300 mg) of RAL chewable tablet (2 to<12 years) were well-tolerated and showed favorable virologic and immunologic responses.
Preview · Article · Oct 2013 · Clinical Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Background: P1093 is an ongoing Phase I/II multicenter open-label PK, safety, dose finding study of DTG plus optimized background regimen (OBR) in children and adolescents in age defined cohorts. The pediatric weight band dosing of ~1 mg/kg once a day achieved PK exposure in adolescents comparable to those observed at 50 mg once daily in adults.
Methods: HIV infected treatment experienced children >12 to < 18 yrs on a failing antiretroviral (ARV) regimen with an HIV RNA of ≥1000 copies/mL (c/mL) were enrolled in Stage 1 (intensive PK) or Stage 2 (extended follow up). DTG was added to a stable, failing ARV regimen in Stage 1, with an OBR added after intensive PK (~Day5-10), or DTG was started with an OBR in Stage 2. Safety, tolerability, CD4 cell count and HIV-1 RNA were evaluated at Week 24. Virologic success was defined as achieving an HIV-1 RNA < 400 c/mL by Week 24 based on the FDA snapshot algorithm, with an additional secondary endpoint of HIV-1 RNA <50 c/mL.
Results: Twenty three adolescents (Stage 1, n=10; Stage 2, n=13) were enrolled and completed the 24 week study visit. Demographics were as follows: 78% (18/23) female, 52% (12/23) African American, 35% (8/23) Caucasian, 26% (6/23) were of Hispanic ethnicity. Mean (SD) age 14 yrs (±1.8) and weight= 55.1 kg (±15.6). Median (IQR) baseline CD4+ cell count and % were 466 cells/µL (297, 771) and 22% (18.4, 29.2) respectively. Median (IQR) baseline HIV-1 RNA log10 was 4.3 log10 c/mL (3.9, 4.6). Virologic success with an HIV RNA < 400 c/mL was achieved in 82.6 % (19/23 ; 95% CI: 61.2 % to 95%) at Week 24. Additionally, 69.6% (16/23 ; 95% CI: 47.1% to 86.8%) had an HIV RNA load < 50 c/mL at Week 24. Median (IQR) gain in CD4 cell count and % at Week 24 was 63 cells/µL (-56, 180) and 4.9% (1, 8) respectively. DTG was well tolerated, with 2 subjects experiencing Grade 3 laboratory abnormalities; one developed unconjugated bilirubin elevation while on atazanavir as part of the OBR, and another subject developed asymptomatic lipase elevation, which was deemed treatment unrelated. There were no Grade 4 AEs, SAEs or discontinuations due to AEs.
Conclusion: DTG plus OBR was safe and well tolerated in HIV infected adolescents. In addition, DTG treatment as part of an OBR provided high virologic efficacy through Week 24.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: In adults, nucleoside reverse transcriptase inhibitor-only antiretroviral regimens (NOARs) with ≥3 nucleoside reverse transcriptase inhibitors are less potent than highly active antiretroviral therapy (HAART). Published pediatric experience with NOARs is limited; thus, we wished to better define the virological, immunological and toxicological effects of NOARs in children and adolescents.
METHODS: We analyzed data from NOAR-treated participants in LEGACY, a multicenter observational cohort study of HIV-infected children and adolescents. NOAR-treated case-participants were matched to participants without prior NOAR who initiated HAART during the same year for comparison.
RESULTS: Of 575 participants with data from time of HIV diagnosis through 2006, 67 (12%) received NOARs for at least 24 weeks; most (46%) received the fixed dose combination of zidovudine/lamivudine/abacavir. NOAR use peaked in 2001 to 2002. NOAR-treated participants were significantly older and more treatment experienced than HAART-treated participants. Virologic outcomes, including the percentage of participants with a plasma HIV RNA viral load <400 copies/mL at week 24 (47% versus 34%) and the mean 24-week change in log10 plasma HIV RNA viral load from baseline (-0.63 versus -1.02), were similar between NOAR- and HAART-treated participants, but virologic rebound was more likely in NOAR-treated participants (77% versus 54%, P = 0.02). Increase in CD4 percentage points from baseline to 24 weeks was negligible in NOAR-treated participants compared with HAART-treated participants (0.95% versus 10.1%, P < 0.001). Anemia and leukopenia were more commonly reported with NOARs than HAART.
DISCUSSION: Week 24 virologic outcomes were similar between NOAR- and HAART-treated participants, but NOAR durability was poorer and their use was associated with less immunologic reconstitution. NOARs should play a limited role in pediatric and adolescent antiretroviral therapy.
No preview · Article · Sep 2013 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract] ABSTRACT: Abstract
Atopic sensitization to aeroallergens in early life has been found to be a strong risk factor for the development of persisting asthma in young children with recurrent wheeze.
To assess the yield of skin prick test (SPT) compared with allergen specific serum IgE (sIgE) testing at identifying aeroallergen sensitization in atopic children younger than 4 years.
Concordance between SPT and allergen-specific sIgE testing for 7 common aeroallergens was analyzed in 40 atopic inner-city children 18 to 48 months of age (mean [SD], 36  months) with recurrent wheezing and family history of asthma and/or eczema.
In 80% of children one or more allergen sensitizations would have been missed if only SPT had been performed, and in 38% of children one or more sensitizations would have been missed if only sIgE testing had been performed. Agreement between the SPT and sIgE test was fair for most allergens (κ = −0.04 to 0.50), as was correlation between sIgE levels and SPT grade (ρ = 0.21 to 0.55). Children with high total sIgE (≥300 kU/L) were more likely to have positive sIgE test results, with negative corresponding SPT results (P = .02).
Our study revealed a significant discordance between allergen-specific SPT and sIgE testing results for common aeroallergens, suggesting that both SPT and sIgE testing should be performed when diagnosing allergic sensitization in young children at high risk of asthma.
No preview · Article · Jun 2013 · Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Atopic sensitization to aeroallergens in early life has been found to be a strong risk factor for the development of persisting asthma in young children with recurrent wheeze. OBJECTIVE: To assess the yield of skin prick test (SPT) compared with allergen specific serum IgE (sIgE) testing at identifying aeroallergen sensitization in atopic children younger than 4 years. METHODS: Concordance between SPT and allergen-specific sIgE testing for 7 common aeroallergens was analyzed in 40 atopic inner-city children 18 to 48 months of age (mean [SD], 36  months) with recurrent wheezing and family history of asthma and/or eczema. RESULTS: In 80% of children one or more allergen sensitizations would have been missed if only SPT had been performed, and in 38% of children one or more sensitizations would have been missed if only sIgE testing had been performed. Agreement between the SPT and sIgE test was fair for most allergens (κ = -0.04 to 0.50), as was correlation between sIgE levels and SPT grade (ρ = 0.21 to 0.55). Children with high total sIgE (≥300 kU/L) were more likely to have positive sIgE test results, with negative corresponding SPT results (P = .02). CONCLUSION: Our study revealed a significant discordance between allergen-specific SPT and sIgE testing results for common aeroallergens, suggesting that both SPT and sIgE testing should be performed when diagnosing allergic sensitization in young children at high risk of asthma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01028560.
No preview · Article · Jun 2013 · Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology
[Show abstract][Hide abstract] ABSTRACT: APOBEC3 proteins mediate potent antiretroviral activity by hypermutating the retroviral genome during reverse transcription.
To counteract APOBEC3 and gain a replicative advantage, lentiviruses such as human immunodeficiency virus type 1 (HIV-1) and
simian immunodeficiency virus (SIV) have evolved the Vif protein, which targets APOBEC3 proteins for proteasomal degradation.
However, the proteasome plays a critical role in the generation of T cell peptide epitopes. Whether Vif-mediated destruction
of APOBEC3 proteins leads to the generation and presentation of APOBEC3-derived T cell epitopes on the surfaces of lentivirus-infected
cells remains unknown. Here, using peptides derived from multiple Vif-sensitive APOBEC3 proteins, we identified APOBEC3-specific
T cell responses in both HIV-1-infected patients and SIV-infected rhesus macaques. These results raise the possibility that
these T cell responses may be part of the larger antiretroviral immune response.
Full-text · Article · Mar 2013 · Journal of Virology
[Show abstract][Hide abstract] ABSTRACT: The introduction of combination antiretroviral therapy has resulted in improved survival and quality of life for individuals infected with the human immunodeficiency virus (HIV). There is, as expected, a growing population of perinatally HIV-infected women who are, have been, or will become pregnant. We describe a large cohort of perinatally infected women, compare it with a similar age-matched behaviorally HIV-infected group, and examine factors affecting maternal and infant health.
We reviewed the records of 30 perinatally infected women who gave birth at two hospitals between January 2000 and December 2011. The comparison group comprised behaviorally infected women who delivered at these hospitals during the same period. The outcome measures were differences in CD4 counts and viral load between the cohorts, and comparisons of maternal morbidity, mortality, and mother-to-child HIV transmission.
Median CD4 counts were significantly lower in the perinatal group before, during, and after pregnancy. The median viral load was significantly higher in the perinatal group. Interval prepregnancy to post partum viral load decline was also greater in the behavioral group. Viral load decreases in the perinatal population were not sustained in the post partum period, at which time viral load trended back to prepregnancy levels. There was one mother-to-child HIV transmission in a perinatally infected woman. Over an extended 4 years of follow-up, there were four deaths in the perinatal group and none in the behavioral group.
After delivery, the differences between perinatally and behaviorally infected mothers accentuate, with immunologic deterioration in the former group. The perinatal population may require novel management strategies to ensure outcomes comparable with those observed in the behavioral group.
Preview · Article · Feb 2013 · Adolescent Health, Medicine and Therapeutics
[Show abstract][Hide abstract] ABSTRACT: Allergy immunotherapy during early childhood may have potential benefits for the prevention of asthma and allergy morbidity. However, subcutaneous immunotherapy has not yet been prospectively researched in children younger than 4 years, primarily because of safety concerns, including the fear and psychological distress young children may experience with repeated needle injections.
To quantify fear in atopic children younger than 4 years with a history of wheezing who are receiving subcutaneous immunotherapy.
Fear of injection was graded during a total of 788 immunotherapy injection visits in 18 children (age, 37 months; SD, 9 months) receiving subcutaneous allergy immunotherapy. The parent and the injection nurse assigned fear scores on a scale of 0 to 10 after each injection visit.
At the time of analysis, children had a median of 49 injection visits (range, 12-88) during a median study period of 81.5 weeks (range, 15-165 weeks). Fifteen children (83%) lost their fear of injections during the study. A fear score of 0 was achieved after a mean of 8.4 visits (SD, 7.4). The more injection visits were missed, the more likely children were to retain fear of injections (hazard ratio, 0.13; 95% confidence interval, 0.02-1.02; P=.05). Age, adverse events, number of injections at each visit, and change of injection personnel were not associated with increased fear.
Our analysis suggests that most children receiving weekly subcutaneous immunotherapy lose their fear of injections during the treatment course. Children with increased intervals between visits may be at higher risk of experiencing fear of injections.
clinicaltrial.gov identifier NCT01028560.
No preview · Article · Dec 2012 · Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology