Impact of antiretroviral treatment on height evolution of HIV infected children.

BACKGROUND: Antiretroviral treatment (ART) has been shown to have a beneficial effect on the weight evolution but its effect on height remains unclear. We described patterns of height evolution and identified predictors of catch-up growth in HIV-infected children on ART. METHODS: To describe the height evolution from birth to adulthood, we developed a nonlinear mixed effect model using data from perinatally HIV-infected children who initiated ART from 1999 to 2013 in a prospective cohort study in Thailand. The main covariates of interest were: sex, ART regimen (dual nucleoside reverse-transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or protease inhibitor (PI)-based), baseline CD4 percentage, HIV-RNA load and CDC HIV Classification stage and occurrence of AIDS-defining events. RESULTS: A total 477 children (43% boys) contributed 18,596 height measurements over a median duration of 6.3 years on ART (interquartile range, 3.0 to 8.3). At ART initiation, median age was 6.2 years (1.8 to 9.6), 16% of children were underweight (weight-for-age z-score < - 2), 49% presented stunting (height-for-age z-score < - 2), and 7% wasting (weight-for-height z-score < - 2). The most frequent regimen at ART initiation was NNRTI-based (79%). A model with 4 components, birth length and 3 exponential functions of age accounting for the 3 growth phases was developed and show that the height-growth velocity was inversely associated with the age at ART initiation, the adult height was significantly lower in those who had experienced at least one AIDS-defining event while, as expected, the model found that adult height in females was lower than in males. Age at ART initiation, type of ART regimen, CDC stage, CD4 percentages, and HIV-RNA load were not associated with the final height. CONCLUSIONS: The younger the children at ART initiation, the greater the effect on height-growth velocity, supporting the World Health Organization's recommendation to start ART as early as possible. However, final adult height was not linked to the age at ART initiation.

Early-Onset Neonatal Sepsis and Antibiotic Use in Northeast Thailand.

OBJECTIVE: Antibiotics are commonly prescribed in neonatal intensive care units (NICUs) for suspected sepsis because of the nonspecific clinical symptoms of sepsis. The overuse of antibiotic is associated with adverse outcomes. This study aimed to determine the rate of early-onset sepsis (EOS) and antibiotic use in neonates admitted to three NICUs in Northeast Thailand STUDY DESIGN: This is a descriptive study using the data collected in the South East Asia-Using Research for Change in Hospital-acquired Infection in Neonates project. Neonates admitted within 3 days of life were included. EOS was defined as neonates who presented with three or more clinical signs or laboratory results suggested sepsis and received antibiotics for at least 5 days. Those with positive blood culture were culture-proven EOS. Antibiotic use within 3 days of life and up to 28 days was described. RESULTS: Among 1,897 neonates, 160 cases were classified as EOS (8.4%) with culture-proven EOS in 4 cases (0.2%). The median durations of antibiotic use in culture-proven and culture-negative EOSs were 15 and 8 days, respectively. CONCLUSION: The rate of culture-proven EOS was low, but there was a high rate of antibiotic use. Antibiotic stewardship should be emphasized.

Treatment Failure in HIV-Infected Children on Second-line Protease Inhibitor-Based Antiretroviral Therapy.

BACKGROUND: Human immunodeficiency virus (HIV)-infected children failing second-line antiretroviral therapy (ART) have no access to third-line antiretroviral drugs in many resource-limited settings. It is important to identify risk factors for second-line regimen failure. METHODS: HIV-infected children initiating protease inhibitor (PI)-containing second-line ART within the Program for HIV Prevention and Treatment observational cohort study in Thailand between 2002 and 2010 were included. Treatment failure was defined as confirmed HIV type 1 RNA load >400 copies/mL after at least 6 months on second-line regimen or death. Adherence was assessed by drug plasma levels and patient self-report. Cox proportional hazards regression analyses were used to identify risk factors for failure. RESULTS: A total of 111 children started a PI-based second-line regimen, including 59 girls (53%). Median first-line ART duration was 1.9 years (interquartile range [IQR], 1.4-3.3 years), and median age at second-line initiation was 10.7 years (IQR, 6.3-13.4 years). Fifty-four children (49%) experienced virologic failure, and 2 (2%) died. The risk of treatment failure 24 months after second-line initiation was 41%. In multivariate analyses, failure was independently associated with exposure to first-line ART for >2 years (adjusted hazard ratio [aHR], 1.8; P = .03), age >13 years (aHR, 2.9; P < .001), body mass index-for-age z score < -2 standard deviations at second-line initiation (aHR, 2.8; P = .03), and undetectable drug levels within 6 months following second-line initiation (aHR, 4.5; P < .001). CONCLUSIONS: Children with longer exposure to first-line ART, entry to adolescence, underweight, and/or undetectable drug levels were at higher risk of failing second-line ART and thus should be closely monitored.

D3/Penta 21 clinical trial design: A randomised non-inferiority trial with nested drug licensing substudy to assess dolutegravir and lamivudine fixed dose formulations for the maintenance of virological suppression in children with HIV-1 infection, aged 2 to 15 years.

BACKGROUND: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing. METHODS: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm. DISCUSSION: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial. TRIAL REGISTRATION: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57. CLINICALTRIALS: gov: NCT04337450.

A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz-Based Regimens.

Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral-naive children in Thailand, we assessed indirect response models to describe the evolution of high- and low-density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav ) according to their assumed status of "fast" or "slow" metabolizers of efavirenz were performed. At treatment initiation, children's median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z-score 0.01 (-1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in "fast" metabolizers and 97 mg/dL in "slow" metabolizers of efavirenz. The population pharmacokinetic-pharmacodynamic (PK-PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment.