Pharmacokinetic targets of antiretroviral therapy in children and adolescents

Large populations of HIV-infected and exposed infants, children and adolescents are increasingly exposed to antiretroviral therapy throughout dramatic changes of the body composition and maturation process in utero, perinatally and during the later growth and development throughout childhood and puberty. The majority of HIV-infected children live in the resource-limited setting where the presence of other significant co-morbidities such as malnutrition, tuberculosis and malaria complicates the selection of the most effective, safe and least toxic combination of antiretroviral drug therapy. This review focuses on the role of the pharmacokinetic factors including clinically important drug-drug interactions on the therapeutic targets of antiretroviral therapy throughout childhood and adolescence.   Proceedings of the 9th International Workshop on Neonatology · Cagliari (Italy) · October 23rd-26th, 2013 · Learned lessons, changing practice and cutting-edge researc

Mechanistic Modeling of Placental Drug Transfer in Humans: How Do Differences in Maternal/Fetal Fraction of Unbound Drug and Placental Influx/Efflux Transfer Rates Affect Fetal Pharmacokinetics?

Background: While physiologically based pharmacokinetic (PBPK) models generally predict pharmacokinetics in pregnant women successfully, the confidence in predicting fetal pharmacokinetics is limited because many parameters affecting placental drug transfer have not been mechanistically accounted for. Objectives: The objectives of this study were to implement different maternal and fetal unbound drug fractions in a PBPK framework; to predict fetal pharmacokinetics of eight drugs in the third trimester; and to quantitatively investigate how alterations in various model parameters affect predicted fetal pharmacokinetics. Methods: The ordinary differential equations of previously developed pregnancy PBPK models for eight drugs (acyclovir, cefuroxime, diazepam, dolutegravir, emtricitabine, metronidazole, ondansetron, and raltegravir) were amended to account for different unbound drug fractions in mother and fetus. Local sensitivity analyses were conducted for various parameters relevant to placental drug transfer, including influx/efflux transfer clearances across the apical and basolateral membrane of the trophoblasts. Results: For the highly-protein bound drugs diazepam, dolutegravir and ondansetron, the lower fraction unbound in the fetus vs. mother affected predicted pharmacokinetics in the umbilical vein by ≥10%. Metronidazole displayed blood flow-limited distribution across the placenta. For all drugs, umbilical vein concentrations were highly sensitive to changes in the apical influx/efflux transfer clearance ratio. Additionally, transfer clearance across the basolateral membrane was a critical parameter for cefuroxime and ondansetron. Conclusion: In healthy pregnancies, differential protein binding characteristics in mother and fetus give rise to minor differences in maternal-fetal drug exposure. Further studies are needed to differentiate passive and active transfer processes across the apical and basolateral trophoblast membrane

The Mental Health Effects and Experiences of Breastfeeding Decision-Making Among Postpartum Women Living with HIV

Prior to January 2023, women living with HIV (WLWH) in the United States (US) were discouraged from breastfeeding due to the potential risk of mother-to-child HIV transmission through breastfeeding. Lack of breastfeeding decision-making and experience among WLWH may negatively affect maternal mental health. We implemented a quality improvement initiative to screen WLWH for postpartum depression (PPD), evaluate their attitudes toward breastfeeding, and assess their experience with breastfeeding decision-making. We collected quantitative data from WLWH using a voluntary, self-administered 6-item breastfeeding decision-making and experience survey (administered 1 month postpartum) and a 10-item Edinburgh Postnatal Depression Scale (EPDS, negative = 0-9; administered 1 and 4 months postpartum) tool. We conducted descriptive statistics and cross tabulation analysis. We analyzed 106 WLWH (93.4% non-Hispanic Black/African American; mean age 33.1 years; 82.1% HIV RNA \u3c 200 copies/mL). One in five (19.1%) WLWH had a positive baseline EPDS screen, with the mean EPDS scores decreasing from 5.3 ± 5.4 (baseline) to 4.6 ± 4.8 (follow-up). Among 55 WLWH who provided baseline and follow-up EPDS scores, only 3/13 with a positive baseline EPDS screen had resolved depressive symptoms at follow-up. Over one-third (37.7%) of WLWH indicated feeling sadness when asked whether lack of breastfeeding negatively affected their feelings or emotions. Over half of WLWH (51.9%) were aware of the US breastfeeding recommendations, but the majority (60.4%) had never discussed breastfeeding options with a medical provider. Improved provider-patient discussions on infant feeding options among WLWH is needed to increase awareness of breastfeeding choices and promote informed, autonomous breastfeeding decision-making among WLWH

Outcomes of Dual Versus Triple Antiretroviral Drug Regimens Among Virally Suppressed Adults in the DC Cohort

This study explored virological outcomes of two-drug (2DRs) and three-drug (3DRs) antiretroviral regimens in adults with HIV in the DC Cohort. We analyzed 310 treatment-experienced adults with sustained HIV RNA ≤50 copies/mL at baseline, 53 of whom switched to 2DRs and 257 continued 3DRs. Adults on 2DRs and 3DRs had similar demographics (median age 53.3 years, 76.8% cisgender male, 76.1% Black). Adults on 2DRs had more participants with ≥2 comorbidities (62.3% vs. 42.8%,  = .019), had a longer time since HIV diagnosis (median years 20.4 vs. 13.2,  = .017), and received the regimen of interest for a shorter duration (median years 1.3 vs. 3.3,  \u3c .001) compared with adults on 3DRs. Adults receiving 2DRs had a higher, although nonsignificant, risk for virological failure (two consecutive HIV RNA ≥50 copies/mL) at 24 months follow-up than adults on 3DRs (6.7% vs. 1.7%, respectively;  = .10). Future analysis of the effectiveness of 2DRs is needed

Integrase Strand Transfer Inhibitors and Weight Gain in Children and Youth With Perinatal Human Immunodeficiency Virus in the DC Cohort.

We conducted a retrospective analysis of 38 children and youth with human immunodeficiency virus (aged 0–19 years) in the United States and report an increased rate of change of BMI-for-age z score after initiating integrase strand transfer inhibitors (+0.19 z score units/year [95% confidence interval, .01–.37]; P = .036) for a median follow-up of 527.5 days

Can therapeutic drug monitoring improve pharmacotherapy of hiv infection in adolescents?

Currently, therapeutic drug monitoring (TDM) of antiretroviral therapy (ART) is not performed in the US as part of routine clinical care of an HIV-infected adolescent patient. TDM is recommended to rule out subtherapeutic drug concentrations and to differentiate between malabsorption, drug interactions, poor adherence, or increased drug metabolism or clearance as possible causes of decreased drug exposure. The use of TDM is also considered to assist in finding the optimal dose of a drug in patients in patients whose virus has shown a reduced susceptibility to that drug. The dosing of antiretroviral (ARV) drugs in adolescent patients with HIV infection depends on the chronological age, weight, height and the stage of sexual maturation. Due to the limited data on the pharmacokinetics (PK) of ART during puberty the transition of a dosing regimen from higher pediatric (weight and surface-based) to adult (fixed) range is not well defined. Developmental PK differences contribute to high variability in pediatric and adolescent patients and an increased frequency of suboptimal ARV exposure than in adults. Individualized, concentration-targeted optimal dosing of ARV medications can be beneficial to patients for whom only limited dosing guidelines are available. This manuscript describes 3 cases of the application of TDM in treatment experienced adolescent patients whose ART was optimized using of ARV TDM. TDM of ARV drugs is useful in managing the pharmacotherapy of HIV in adolescent patients and is well received by the adolescent patients with HIV and their families. Among others, the benefits of TDM provide evidence for adherence interventions and create grounds for enhanced education of the adolescent patient and involved adult caregivers about ART. Finally, TDM in adolescents provides valuable information about the clinical pharmacology of ART during puberty

Prevention of Perinatal HIV Transmission in an Area of High HIV Prevalence in the United States

Objective: To evaluate the uptake of perinatal HIV preventive interventions by the risk of perinatal HIV transmission in mother–infant pairs in a high–HIV prevalence area in the US. Study design: This was a retrospective cohort study of mother–infant pairs with perinatal HIV exposure during 2013-2017 managed at a subspecialty pediatric HIV program in Washington, DC. We collected demographic data, maternal HIV history, delivery mode, maternal and infant antiretroviral drug (ARV) use, and infant HIV test results. We compared the uptake of recommended preventive interventions in low-risk (ie, mothers on antiretroviral therapy [ART] with viral suppression) and high-risk (mothers without ART or viral suppression) mother–infant pairs using the Pearson chi-square, Fisher exact, and Wilcoxon rank-sum tests and logistic regression. Results: We analyzed 551 HIV-exposed infants (HEIs) and 542 mothers living with HIV. The majority of mothers received ARVs (95.5%), had HIV RNA ≤1000 copies/mL before delivery (81.9%), and received intrapartum zidovudine (ZDV; 65.5%). The majority of all HEIs were low risk (82.6%) and received postpartum ARVs (98.9%). Among the low-risk infants, 53.2% were delivered via cesarean delivery (CD), and 62.9% and 96.5% were administered intrapartum and postpartum ZDV, respectively. Among high-risk infants, 84.4% were delivered via CD, 78.1% received intrapartum ZDV, and 62.5% received combination ART. Nine high-risk infants acquired HIV perinatally. Conclusion: In an area of high HIV prevalence in the US, a large proportion of low-risk HEIs received intrapartum ZDV and were delivered via CD. We also observed missed opportunities for the prevention of perinatal HIV transmission

Physiologically Based Pharmacokinetic Modeling Framework to Predict Neonatal Pharmacokinetics of Transplacentally Acquired Emtricitabine, Dolutegravir, and Raltegravir

Background and objectiveLittle is understood about neonatal pharmacokinetics immediately after delivery and during the first days of life following intrauterine exposure to maternal medications. Our objective was to develop and evaluate a novel, physiologically based pharmacokinetic modeling workflow for predicting perinatal and postnatal disposition of commonly used antiretroviral drugs administered prenatally to pregnant women living with human immunodeficiency virus.MethodsUsing previously published, maternal-fetal, physiologically based pharmacokinetic models for emtricitabine, dolutegravir, and raltegravir built with PK-Sim/MoBi®, placental drug transfer was predicted in late pregnancy. The total drug amount in fetal compartments at term delivery was estimated and subsequently integrated as initial conditions in different tissues of a whole-body, neonatal, physiologically based pharmacokinetic model to predict drug concentrations in the neonatal elimination phase after birth. Neonatal elimination processes were parameterized according to published data. Model performance was assessed by clinical data.ResultsNeonatal physiologically based pharmacokinetic models generally captured the initial plasma concentrations after delivery but underestimated concentrations in the terminal phase. The mean percentage error for predicted plasma concentrations was - 71.5%, - 33.8%, and 76.7% for emtricitabine, dolutegravir, and raltegravir, respectively. A sensitivity analysis suggested that the activity of organic cation transporter 2 and uridine diphosphate glucuronosyltransferase 1A1 during the first postnatal days in term newborns is ~11% and ~30% of that in adults, respectively.ConclusionsThese findings demonstrate the general feasibility of applying physiologically based pharmacokinetic models to predict washout concentrations of transplacentally acquired drugs in newborns. These models can increase the understanding of pharmacokinetics during the first postnatal days and allow the prediction of drug exposure in this vulnerable population