Population Pharmacokinetic Modeling of Dolutegravir to Optimize Pediatric Dosing in HIV-1-Infected Infants, Children, and Adolescents.

BACKGROUND AND OBJECTIVE: HIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated. METHODS: A population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure-safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events. RESULTS: A total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure-safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events. CONCLUSIONS: The dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization.

Etravirine in treatment-experienced HIV-1-infected children 1 year to less than 6 years of age.

OBJECTIVE: To describe the pharmacokinetics, safety, and efficacy of etravirine (ETR) in HIV-infected children 1 to less than 6 years of age. DESIGN: Phase I/II, open-label, multicenter, dose-finding study. METHODS: Antiretroviral therapy (ART)-experienced children in two age cohorts (I: 2 to <6 years; II: 1 to less than 2 years) received weight-based ETR, swallowed whole or dispersed in liquid, with optimized ART including a ritonavir-boosted protease inhibitor. Intensive pharmacokinetics occurred 7-18 days after starting ETR. Participants with ETR AUC12h less than 2350 ng h/ml had a dose increase and repeat pharmacokinetics. RESULTS: Twenty-six children enrolled and 21 (15 in cohort I and 6 in cohort II) had evaluable intensive pharmacokinetics sampling at the final weight-based dose. On the final dose, the geometric mean ETR AUC12h was 3823 ng h/ml for cohort I and 3328 ng h/ml for cohort II. Seven children (33.3%) on the final dose, all taking ETR dispersed, had an AUC12  h less than 2350 ng h/ml and underwent a dose increase. ETR AUC12  h was 3.8-fold higher when ETR was swallowed whole vs. dispersed, P less than 0.0001. On the final dose, 75 and 33.3% in cohorts I and II, respectively, had HIV-1 RNA 400 copies/ml or less or at least 2 log reductions from baseline at week 48. Three children (11.5%) experienced a grade at least 3 adverse event related to ETR but only 1 discontinued. CONCLUSION: ETR was well tolerated. Predefined pharmacokinetics targets were met but overall exposures were low vs. historical data in adults, particularly in young children taking dispersed tablets. A high rate of viral efficacy was observed among those aged 2 to more than 6 years but not in those less than 2 years.

Long-Term Safety and Efficacy of Dolutegravir in Treatment-Experienced Adolescents With Human Immunodeficiency Virus Infection: Results of the IMPAACT P1093 Study.

BACKGROUND: P1093 is an ongoing phase I/II multicenter open-label study of dolutegravir plus an optimized background regimen in age-defined pediatric cohorts; here we report the long-term safety and virologic efficacy outcomes for the oldest cohort. METHODS: The study enrolled human immunodeficiency virus type 1 (HIV-1)-infected treatment-experienced adolescents aged 12 to <18 years, with an HIV-1 RNA level ≥1000 copies/mL . Cumulative safety and HIV-1 RNA outcomes were assessed once the last enrolled participant reached 144 weeks of follow-up. RESULTS: Among 23 adolescents enrolled, 16 remained in the study at least 144 weeks; the median follow-up was 153 weeks (range, 55-193 weeks). Dolutegravir was well tolerated, with grade 3 clinical adverse events in 5 participants, grade 3 laboratory abnormalities in 3, and grade 4 laboratory abnormalities in 1; none of the adverse events or abnormalities were judged to be treatment related. In an-intent-to-treat analysis, an HIV-1 RNA level <400 copies/mL at week 144 was achieved in 43% (10 of 23 participants; 95% confidence interval, 23.2%-65.5%); in addition, 35% (8 of 23; 16.4%-57.3%) had an HIV-1 RNA level <50 copies/mL. Nine participants (39%) discontinued study treatment before 144 weeks, but none because of adverse events or drug intolerance. All participants with sustained virologic control had excellent adherence; most who experienced virologic failure had adherence levels <90%. HIV-1 genotypic drug resistance testing was available at time of failure from 6 participants; 1 had evolution in integrase resistance with E138T, S147G, and R263K mutations at week 192 and phenotypic dolutegravir resistance of a 5.1-fold change. CONCLUSIONS: Dolutegravir plus an optimized background regimen seemed safe, well tolerated, and efficacious in this cohort of treatment-experienced HIV-1-infected adolescents. Adherence remains problematic in this population. CLINICAL TRIALS REGISTRATION: NCT01302847.

Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-randomised, multicentre trial.

BACKGROUND: Raltegravir is an integrase inhibitor approved for use in adults and children with HIV-1 infection, but there are no data on the long-term use of this medication in children. We aimed to assess the long-term safety, tolerability, pharmacokinetics, and efficacy of multiple raltegravir formulations in children aged 4 weeks to 18 years with HIV-1 infection. METHODS: In this phase 1/2 open-label multicentre trial (IMPAACT P1066), done in 43 IMPAACT network sites in the USA, South Africa, Brazil, Botswana, and Argentina, eligible participants were children aged 4 weeks to 18 years with HIV-1 infection who had previously received antiretroviral therapy (ART), had HIV-1 RNA higher than 1000 copies per mL, and no exposure to integrase inhibitors. Participants were separated into five age groups and enrolled in six cohorts. Three formulations of open-label raltegravir-adult tablets, chewable tablets, and granules for oral suspension-were added to individualised optimised background therapy, according to the age and weight of participants. The primary outcome at 48 weeks has been previously reported. In the 240-week follow-up, outcomes of interest included graded clinical and laboratory safety of raltegravir formulations during the study and virological efficacy (with virological success defined as HIV-1 RNA reduction of >1 log10 from baseline or HIV-1 RNA <400 copies per mL) at week 240. The primary analysis group for safety and efficacy comprised patients treated only with the final selected dose of raltegravir. This trial is registered with ClinicalTrials.gov, number NCT00485264. FINDINGS: Between August, 2007, and December, 2012, 220 patients were assessed for eligibility, and 153 were enrolled and treated. Of these patients, 122 received only the final selected dose of raltegravir (63 received adult tablets, 33 chewable tablets, and 26 oral granules), and one was not treated. There were few serious clinical or laboratory safety events noted, with two patients having a drug-related adverse event (skin rash), which led one patient to discontinue the study treatment. The addition of raltegravir to an individually optimised ART regimen resulted in virological success at week 240 in 19 (44·2%, 95% CI 29·1-60·1) of 43 patients receiving 400 mg tablets, 24 (77·4%, 58·9-90·4) of 31 patients receiving the chewable tablets, and 13 (86·7%, 59·5-98·3) of 15 patients receiving oral granules. Among patients with virological failure, raltegravir resistance was noted in 19 (38%) of 50 patients who had virological rebound after initial suppression and had samples at virological failure available for testing. INTERPRETATION: Our study suggests that raltegravir can be used for the treatment of HIV-1 infection in children as young as 4 weeks, with the expectation of long-term safety and efficacy, but should be used with caution among older children who had previous extensive antiretroviral therapy. FUNDING: National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Mental Health, and Merck.

Development and Validation of the PREMM5 Model for Comprehensive Risk Assessment of Lynch Syndrome.

Purpose Current Lynch syndrome (LS) prediction models quantify the risk to an individual of carrying a pathogenic germline mutation in three mismatch repair (MMR) genes: MLH1, MSH2, and MSH6. We developed a new prediction model, PREMM5, that incorporates the genes PMS2 and EPCAM to provide comprehensive LS risk assessment. Patients and Methods PREMM5 was developed to predict the likelihood of a mutation in any of the LS genes by using polytomous logistic regression analysis of clinical and germline data from 18,734 individuals who were tested for all five genes. Predictors of mutation status included sex, age at genetic testing, and proband and family cancer histories. Discrimination was evaluated by the area under the receiver operating characteristic curve (AUC), and clinical impact was determined by decision curve analysis; comparisons were made to the existing PREMM1,2,6 model. External validation of PREMM5 was performed in a clinic-based cohort of 1,058 patients with colorectal cancer. Results Pathogenic mutations were detected in 1,000 (5%) of 18,734 patients in the development cohort; mutations included MLH1 (n = 306), MSH2 (n = 354), MSH6 (n = 177), PMS2 (n = 141), and EPCAM (n = 22). PREMM5 distinguished carriers from noncarriers with an AUC of 0.81 (95% CI, 0.79 to 0.82), and performance was similar in the validation cohort (AUC, 0.83; 95% CI, 0.75 to 0.92). Prediction was more difficult for PMS2 mutations (AUC, 0.64; 95% CI, 0.60 to 0.68) than for other genes. Performance characteristics of PREMM5 exceeded those of PREMM1,2,6. Decision curve analysis supported germline LS testing for PREMM5 scores ≥ 2.5%. Conclusion PREMM5 provides comprehensive risk estimation of all five LS genes and supports LS genetic testing for individuals with scores ≥ 2.5%. At this threshold, PREMM5 provides performance that is superior to the existing PREMM1,2,6 model in the identification of carriers of LS, including those with weaker phenotypes and individuals unaffected by cancer.

Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer.

BACKGROUND: Recent guidelines recommend the Lynch Syndrome prediction models MMRPredict, MMRPro, and PREMM1,2,6 for the identification of MMR gene mutation carriers. We compared the predictive performance and clinical usefulness of these prediction models to identify mutation carriers. METHODS: Pedigree data from CRC patients in 11 North American, European, and Australian cohorts (6 clinic- and 5 population-based sites) were used to calculate predicted probabilities of pathogenic MLH1, MSH2, or MSH6 gene mutations by each model and gene-specific predictions by MMRPro and PREMM1,2,6. We examined discrimination with area under the receiver operating characteristic curve (AUC), calibration with observed to expected (O/E) ratio, and clinical usefulness using decision curve analysis to select patients for further evaluation. All statistical tests were two-sided. RESULTS: Mutations were detected in 539 of 2304 (23%) individuals from the clinic-based cohorts (237 MLH1, 251 MSH2, 51 MSH6) and 150 of 3451 (4.4%) individuals from the population-based cohorts (47 MLH1, 71 MSH2, 32 MSH6). Discrimination was similar for clinic- and population-based cohorts: AUCs of 0.76 vs 0.77 for MMRPredict, 0.82 vs 0.85 for MMRPro, and 0.85 vs 0.88 for PREMM1,2,6. For clinic- and population-based cohorts, O/E deviated from 1 for MMRPredict (0.38 and 0.31, respectively) and MMRPro (0.62 and 0.36) but were more satisfactory for PREMM1,2,6 (1.0 and 0.70). MMRPro or PREMM1,2,6 predictions were clinically useful at thresholds of 5% or greater and in particular at greater than 15%. CONCLUSIONS: MMRPro and PREMM1,2,6 can well be used to select CRC patients from genetics clinics or population-based settings for tumor and/or germline testing at a 5% or higher risk. If no MMR deficiency is detected and risk exceeds 15%, we suggest considering additional genetic etiologies for the cause of cancer in the family.

Pharmacokinetics and 48-Week Safety and Efficacy of Raltegravir for Oral Suspension in Human Immunodeficiency Virus Type-1-Infected Children 4 Weeks to 2 Years of Age.

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/mm(3) and 7.3% were observed. CONCLUSIONS: 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.

Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week Results from IMPAACT P1093.

OBJECTIVE: To assess the pharmacokinetics (PK), safety and efficacy of dolutegravir plus optimized background regimen in HIV-infected treatment-experienced adolescents. METHODS: Children older than 12 to younger than 18 years received dolutegravir weight-based fixed doses at approximately 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. RESULTS: 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 [interquartile range (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 of the area under the plasma concentration-time curve from time of administration to 24 hours after dosing (AUC0-24) and 24 hour postdose concentration (C24) were 46.0 µg hours/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% confidence interval (CI): 52-90%] at week 48. Additionally, 61% (95% CI: 39-80%) 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 adverse events, serious adverse events or discontinuations because of serious adverse events. CONCLUSIONS: Dolutegravir achieved target PK exposures in adolescents. Dolutegravir was safe and well tolerated, providing good virologic efficacy through week 48.

Pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in HIV-1-infected children aged 2 through 18 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.

Dynamics of the resting CD4(+) T-cell latent HIV reservoir in infants initiating HAART less than 6 months of age.

OBJECTIVES: Identification of HIV infection in exposed infants facilitates early therapy, which may limit viral reservoirs that maintain HIV infection under HAART. METHODS: The dynamics of the resting CD4 T-cell latent HIV reservoir was determined over the first 2 years of life in 17 HIV-infected infants initiating lopinavir/ritonavir-based HAART at a median age of 8.1 weeks and achieving adequate suppression of plasma viral load by 24 weeks. RESULTS: The resting CD4 T-cell latent HIV reservoir was detected in 12 of 14 (86%) infants tested at 24 weeks of HAART [median frequency 1.88 infectious units per million (IUPM); range <0.22 to 81.7), and remained measurable (median IUPM = 0.32; range <0.22 to 3.25) in six of 10 (60%) children retested at 96 weeks. The reservoir declined, from 24 to 96 weeks of HAART, at an estimated mean rate of 0.028 log10 IUPM/month, corresponding to a half-life of 11 months (95% confidence interval 6-30 months]. A strong relationship was found between the frequency of latently infected CD4 T cells at 96 weeks of HAART and time to first undetectable plasma viral load (Spearman r = 0.91, P < 0.001). CONCLUSION: Although the resting CD4 T-cell latent reservoir remains detectable over the first 2 years of HAART in a substantial proportion of infants, its size is associated with time to first undetectable viral load. To minimize HIV reservoirs in infants, rapid curtailment of viremia may limit HIV reservoirs and should be a therapeutic goal of early HAART in infants.

Long-term outcomes for HIV-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral therapy.

OBJECTIVE: To investigate the longitudinal pharmacokinetics, safety and efficacy of lopinavir/ritonavir (LPV/r) in HIV-infected infants initiating combination antiretroviral therapy (cART) between 2 weeks and 6 months of age. METHOD: A prospective, open-label, multicenter Phase I/II study of LPV/r-based cART at a dose of 300/75 mg/m(2)/dose LPV/r twice daily. Intensive pharmacokinetic sampling at 12 months of age and quarterly predose LPV concentrations were collected and safety, virologic and immunologic responses were monitored every 4-12 weeks up to 252 weeks. RESULTS: Thirty-one HIV-infected infants enrolled into two age cohorts, 14 days to <6 weeks and 6 weeks to <6 months; 29 completed ≥48 weeks of follow-up (median = 123 weeks, range 4-252). At 12 months of age, median LPV area under the curve was comparable for both age cohorts and similar to older children and adults. At week 48, 22 of 31 patients (71%) had HIV-1 RNA <400 copies/ml and 11 of 15 (73%) had <50 copies/ml; 29 of 31 achieved HIV-1 RNA <400 copies/ml on study treatment and 19 (66%) remained durably suppressed until the end of study; viral suppression correlated with a higher percentage of predose time points exceeding the LPV target of 1 µg/ml (92 vs. 71%, P = 0.002). CONCLUSION: LPV/r at 300/75 mg/m(2)/dose as part of a cART regimen resulted in viral suppression through 96 weeks of treatment in >65% of young infants. Due to initially low LPV exposure in infants <6 weeks of age, frequent dose adjustment for weight gain is advisable and consideration should be given to studying a higher dose for very young infants.

Associations of proinflammatory cytokine levels with lipid profiles, growth, and body composition in HIV-infected children initiating or changing antiretroviral therapy.

OBJECTIVES: To measure proinflammatory cytokines (PIC) in HIV-infected children beginning or changing antiretroviral therapy (ART), evaluating associations with virologic, immunologic, serum lipid, growth, and body composition measures, markers of growth hormone action and glucose metabolism. METHODS: Forty-nine prepubertal HIV-infected children had measurements of viral load (VL), CD4 lymphocyte count and percentage, serum lipids, apolipoprotein AI/B, IGF-1, IGFBP-1, and IGFBP-3, anthropometry, bioelectrical impedance analysis, TNF-α, IL-1 ß, and IL-6 at baseline and 48 weeks of ART. RESULTS: Baseline levels were detectable (>0.1 pg/mL) for IL-1 ß in 28 of 48, and for TNF-α and Il-6 in all 49 children. TNF-α decreased with ART (P < 0.001) and IL-6 demonstrated a similar trend (P = 0.065). Children with 48-week VL <400 copies/mL had greater declines in TNF-α (mean 45%) than subjects with higher VL (5%; P = 0.009). Each 10% improvement in CD4% was associated with 26% lower TNF-α (P = 0.002) and 31% lower IL-6 (P = 0.016). Greater reductions in TNF-α were associated with lower total/HDL cholesterol ratio (P = 0.003) at week 48. CONCLUSIONS: In HIV-infected children initiating or changing ART, PIC were detectable at baseline and decreased over 48 weeks. Better immunologic responses were associated with greater reductions in TNF-α and IL-6. Reductions in TNF-α were associated with improved total/HDL cholesterol ratio.

Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy.

BACKGROUND: With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r). METHODS: A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m twice daily plus 2 nucleoside analogs in HIV-1-infected infants > or =14 days to <6 weeks of age. Intensive 12-hour PK evaluations were performed after 2 weeks of LPV/r therapy, and doses were modified to maintain LPV predose concentrations >1 microg/mL and area under the curve (AUC) <170 microg hr/mL. RESULTS: Ten infants enrolled [median age 5.7 (range, 3.6-5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7-7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246-305) mg/m q12 hours; median measures were AUC = 36.6 (range, 27.9-62.6) microg hr/mL; predose concentration = 2.2 (range, 0.99-4.9) microg/mL; maximum concentration = 4.76 (range, 2.84-7.28) microg/mL and apparent clearance (L/h/m) = 6.75 (range, 2.79-12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure. CONCLUSIONS: Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.

Insulin-like growth factor-1 and lean body mass in HIV-infected children.

OBJECTIVES: To describe insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-1-binding protein-1 (IGFBP-1) and IGFBP-3 in HIV+ children before and after initiating or changing antiretroviral therapy and to evaluate association of growth and body composition to growth factors at baseline and over time. METHODS: Ninety-seven prepubertal HIV+ children aged 1 month to younger than 13 years were observed over 48 weeks after beginning or changing antiretroviral therapy. Serum IGF-1, IGFBP-1, and IGFBP-3 were measured and compared with age- and sex-specific norms. Anthropometric measures were compared as follows: subjects vs matched children from (a) the National Health and Nutrition Examination Survey to generate z scores and (b) HIV-exposed, uninfected children from Women and Infants Transmission Study; and subjects with normal vs abnormal IGF-1 and IGFBP concentrations at baseline. Anthropometric changes were compared for children whose IGF-1 level normalized vs remaining subjects. Multivariate analysis adjusting for sex, race, and baseline age evaluated associations between anthropometry and IGF-1 and IGFBP concentrations. RESULTS: In multivariate analysis, lower baseline IGF-1 and IGFBP-3 were associated with lower mean weight, height, mid-arm muscle circumference, and mid-thigh circumference z scores. Twenty-four percent of children had a low IGF-1 level at baseline, 50% of whom normalized IGF-1 on study. Children whose IGF-1 normalized had greater increases in mean mid-arm muscle circumference z score (1.00 vs -0.03, P = 0.029), but a trend toward lesser mean height increase (P = 0.082) than remaining subjects. Likewise, in comparison to controls from Women and Infants Transmission Study, mean mid-arm muscle circumference also increased more in children whose IGF-1 normalized (P = 0.024) but mean height changed less (P = 0.003). Fifty-five percent of children had elevated IGFBP-1 at baseline, 69% of whom normalized. CONCLUSIONS: IGF-1 increases and IGFBP-1 decreases in HIV-infected children upon initiation or change in antiretroviral therapy. Improved muscle mass, but not linear growth, is associated with normalized IGF-1 concentration. These findings suggest that IGF-1 may merit evaluation as a potential therapeutic strategy to improve lean body mass in HIV-infected children.

Pharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitors.

Human immunodeficiency virus (HIV)-infected children and adolescents who are failing antiretrovirals may have a better virologic response when drug exposures are increased, using higher protease inhibitor doses or ritonavir boosting. We studied the pharmacokinetics and safety of high-dose lopinavir-ritonavir (LPV/r) in treatment-experienced patients, using an LPV/r dose of 400/100 mg/m(2) orally every 12 h (p.o. q12h) (without nonnucleoside reverse transcriptase inhibitor [NNRTI]), or 480/120 mg/m(2) p.o. q12h (with NNRTI). We calculated the LPV inhibitory quotient (IQ), and when the IQ was <15, saquinavir (SQV) 750 mg/m(2) p.o. q12h was added to the regimen. We studied 26 HIV-infected patients. The median age was 15 years (range, 7 to 17), with 11.5 prior antiretroviral medications, 197 CD4 cells/ml, viral load of 75,577 copies/ml, and a 133-fold change in LPV resistance. By treatment week 2, 14 patients had a viral-load decrease of >0.75 log(10), with a median maximal decrease in viral load of -1.57 log(10) copies/ml at week 8. At week 2, 19 subjects showed a median LPV area under the concentration-time curve (AUC) of 157.2 (range, 62.8 to 305.5) microg x h/ml and median LPV trough concentration (C(trough)) of 10.8 (range, 4.1 to 25.3) microg/ml. In 16 subjects with SQV added, the SQV median AUC was 33.7 (range, 4.4 to 76.5) microg x h/ml and the median SQV C(trough) was 2.1 (range, 0.2 to 4.1) microg/ml. At week 24, 18 of 26 (69%) subjects remained in the study. Between weeks 24 and 48, one subject withdrew for nonadherence and nine withdrew for persistently high virus load. In antiretroviral-experienced children and adolescents with HIV, high doses of LPV/r with or without SQV offer safe options for salvage therapy, but the modest virologic response and the challenge of adherence to a regimen with a high pill burden may limit the usefulness of this approach.

Lipid and glucose alterations in HIV-infected children beginning or changing antiretroviral therapy.

OBJECTIVE: The objective of this study was to describe lipid profiles and glucose homeostasis in HIV-positive children after initiating or changing antiretroviral therapy and their associations with viral, immune, antiretroviral therapy, and growth factor parameters. METHODS: Ninety-seven prepubertal HIV-positive children aged 1 month to <13 years were observed for 48 weeks after beginning or changing antiretroviral therapy. Fasting lipid panels, serum glucose, insulin, insulin-like growth factor-1 and binding proteins-1 and -3, plasma viral load, and CD4% were measured. Each child was matched on age, gender, and race/ethnicity to children from the National Health and Nutrition Examination Survey, used to give z scores for each child's lipid values. Multivariate regression was used to evaluate the association of changes in z scores over 48 weeks with suppression of HIV-1 RNA, change in CD4% and growth factors, and antiretroviral therapy, adjusted for entry z score, CD4%, log(10) HIV-1 RNA, Centers for Disease Control and Prevention category, and total fat and cholesterol dietary intake. RESULTS: Lipid, apolipoprotein, and insulin levels all increased significantly by 48 weeks. Multivariate analysis of changes demonstrated that increased HDL and decreased total-HDL cholesterol ratio were associated with CD4% increase and with insulin-like growth factor-1, which increased to normal (versus remained stable or became low) over 48 weeks. Total cholesterol levels increased among children who achieved HIV-1 RNA of <400 copies per mL. Antiretroviral therapy regimens that included both a protease inhibitor and a non-nucleoside reverse transcriptase inhibitor were associated with greater increases in total-HDL cholesterol ratio than regimens that contained a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor but not both. CONCLUSIONS: In these HIV-positive children with predominantly mild-to-moderate disease, initiation or change in antiretroviral therapy was associated with significant increases in multiple lipid measures and insulin resistance. Favorable lipid changes were associated with CD4% increases, suggesting a protective effect of immune reconstitution on atherosclerosis, and with increased insulin-like growth factor-1 levels, supporting the theory that reduced growth hormone resistance may be a mechanism by which lipid profiles are improved. Finally, antiretroviral therapy regimens that contain both a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor are associated with worse lipid profiles than regimens that contain 1 but not both of these drug classes.

Impact of nucleoside reverse transcriptase inhibitors on mitochondria in human immunodeficiency virus type 1-infected children receiving highly active antiretroviral therapy.

Mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTIs) has been reported to be responsible for various adverse effects. The relative impact of NRTIs on the mitochondria of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected children receiving highly active antiretroviral therapy (HAART) is unknown. Mitochondrial DNA (mtDNA) levels were quantified longitudinally from peripheral blood mononuclear cells (PBMCs) in 31 HIV-1-infected children from Pediatric AIDS Clinical Trial Group Study 382 who were receiving HAART, including nelfinavir, efavirenz, and different NRTIs, and who had had undetectable plasma HIV-1 RNA levels for >2 years. The median mtDNA levels in PBMCs increased from 137 copies/cell at the baseline to 179 copies/cell at week 48 (P = 0.01) and 198 copies/cell at week 104 (P < 0.001). Before the initiation of HAART, children who received regimens containing didanosine had mtDNA levels persistently lower than those in children not receiving didanosine (106 versus 140 copies/cell; P = 0.008). During HAART, the median increase in the mtDNA level from the baseline to week 104 was the lowest in children who received regimens containing didanosine (+26 copies/cell) compared to those in children who received other regimens (+79 copies/cell) (P = 0.02). A multivariate analysis also demonstrated that didanosine, as part of HAART, was the only NRTI associated with the change in mtDNA levels (P = 0.007). Children receiving didanosine-containing antiretroviral regimens have the lowest mtDNA levels in PBMCs and may be at greater risk for long-term adverse effects due to mitochondrial toxicity. This may be of particular importance in resource-limited countries where didanosine is widely used for the treatment of HIV-infected children.

Efavirenz pharmacokinetics in HIV-1-infected children are associated with CYP2B6-G516T polymorphism.

BACKGROUND: The CYP2B6-G516T polymorphism has been shown to alter plasma efavirenz (EFV) concentrations in adults. The impact of CYP2B6-G516T polymorphisms on EFV concentrations may be different in children because of differences in liver maturation and drug dosage. METHODS: The CYP2B6-G516T polymorphisms were analyzed in 71 HIV-1-infected children receiving highly active antiretroviral therapy (HAART) containing EFV for >or=6 months. EFV pharmacokinetics, toxicity profiles, and viral resistance data were also evaluated. RESULTS: The median oral clearance (CL/F) rate was significantly lower in children with the CYP2B6-516-T/T genotype (3.0 L/h/m2, n=13) than in children with the G/T genotype (5.7 L/h/m2, n=30; P=0.02) or the G/G genotype (7.0 L/h/m2, n=31; P=0.003). In children with the CYP2B6-516-G/G genotype, which is associated with higher expression of hepatic CYP2B6, the clearance rate was significantly higher in younger children (<5 years of age) than in older children (>or=5 years of age) (9.7 L/h/m2 vs. 6.6 L/h/m2; P=0.03). No association was found between CYP2B6-G516T polymorphisms and virologic or immunologic responses, toxicity, or the development of viral resistance against EFV. CONCLUSIONS: CYP2B6-G516T polymorphisms significantly affect the CL/F rate of EFV in children. Changes in hepatic enzyme activity by age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.