Availability and stock-outs of paediatric antiretroviral treatment formulations at health facilities in Kenya and Uganda.

INTRODUCTION: The large number of deaths among children with HIV is driven by poor antiretroviral treatment (ART) coverage among this cohort. The aim of the study was to assess the availability and stock-outs of paediatric and adult ART formulations in Kenya and Uganda across various regions and types of health facilities. METHODS: A survey on availability and stock-outs of paediatric ART at health facilities was adapted from the standardized Health Action International-WHO Medicine Availability Monitoring Tool. All preferred and limited-use formulations, and three phased-out formulations according to the 2021 WHO optimal formulary list were included in the survey, as well as a selection of adult ART formulations suitable for older children, adolescents, and adults. Availability data were collected in June-July 2022 and stock-out data were obtained over the previous year from randomly selected public and private-not-for-profit (PNFP) facilities registered to dispense paediatric ART across six districts per country. All data were analysed descriptively. RESULTS: In total, 144 health facilities were included (72 per country); 110 were public and 34 PNFP facilities. Overall availabilities of preferred paediatric ART formulations were 52.2% and 63.5% in Kenya and Uganda, respectively, with dolutegravir (DTG) 10 mg dispersible tablets being available in 70.2% and 77.4% of facilities, respectively, and abacavir/lamivudine dispersible tablets in 89.8% and 98.2% of facilities. Of note, availability of both formulations was low (37.5% and 62.5%, respectively) in Kenyan PNFP facilities. Overall availabilities of paediatric limited-use products were 1.1% in Kenya and 1.9% in Uganda. At least one stock-out of a preferred paediatric ART formulation was reported in 40.0% of Kenyan and 74.7% of Ugandan facilities. Nevirapine solution stock-outs were reported in 43.1% of Ugandan facilities, while alternative formulations for postnatal HIV prophylaxis were not available. CONCLUSIONS: Recommended DTG-based first-line ART for children across all ages was reasonably available at health facilities in Kenya and Uganda, with the exception of Kenyan PNFP facilities. Availability of paediatric ART formulations on the limited-use list was extremely low across both countries. Stock-outs were reported regularly, with the high number of reported stock-outs of neonatal ART formulations in Uganda being most concerning.

Twice-Daily Dosing of Dolutegravir in Infants on Rifampicin Treatment: A Pharmacokinetic Substudy of the EMPIRICAL Trial.

BACKGROUND: We evaluated dolutegravir pharmacokinetics in infants with human immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) without rifampicin. METHODS: Infants with HIV aged 1-12 months, weighing ≥3 kg, and receiving dolutegravir BID with rifampicin or OD without rifampicin were eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse events (AEs) were reported. RESULTS: Twenty-seven of 30 enrolled infants had evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 months (6.1-9.9), weight was 6.3 kg (5.6-7.2), 21 (78%) received rifampicin, and 11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with rifampicin versus OD without rifampicin were area under curve (AUC)0-24h 0.91 (95% confidence interval, .59-1.42), Ctrough 0.95 (0.57-1.59), Cmax 0.87 (0.57-1.33). One infant (5%) receiving rifampicin versus none without rifampicin had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. The dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. Five of 82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB treatment completion, HIV viral load was <1000 copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of infants with and without rifampicin, respectively. CONCLUSIONS: Dolutegravir BID in infants receiving rifampicin resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV-TB coinfection.

First-Line Antituberculosis Drug Concentrations in Infants With HIV and a History of Recent Admission With Severe Pneumonia.

Optimal antituberculosis therapy is essential for favorable clinical outcomes. Peak plasma concentrations of first-line antituberculosis drugs in infants with living HIV receiving WHO-recommended dosing were low compared with reference values for adults, supporting studies on increased doses of first-line TB drugs in infants.

Lamivudine and Emtricitabine Dosing Proposal for Children with HIV and Chronic Kidney Disease, Supported by Physiologically Based Pharmacokinetic Modelling.

Dose recommendations for lamivudine or emtricitabine in children with HIV and chronic kidney disease (CKD) are absent or not supported by clinical data. Physiologically based pharmacokinetic (PBPK) models have the potential to facilitate dose selection for these drugs in this population. Existing lamivudine and emtricitabine compound models in Simcyp® (v21) were verified in adult populations with and without CKD and in non-CKD paediatric populations. We developed paediatric CKD population models reflecting subjects with a reduced glomerular filtration and tubular secretion, based on extrapolation from adult CKD population models. These models were verified using ganciclovir as a surrogate compound. Then, lamivudine and emtricitabine dosing strategies were simulated in virtual paediatric CKD populations. The compound and paediatric CKD population models were verified successfully (prediction error within 0.5- to 2-fold). The mean AUC ratios in children (GFR-adjusted dose in CKD population/standard dose in population with normal kidney function) were 1.15 and 1.23 for lamivudine, and 1.20 and 1.30 for emtricitabine, with grade-3- and -4-stage CKD, respectively. With the developed paediatric CKD population PBPK models, GFR-adjusted lamivudine and emtricitabine dosages in children with CKD resulted in adequate drug exposure, supporting paediatric GFR-adjusted dosing. Clinical studies are needed to confirm these findings.

Neural network algorithm for detection of erosions and ankylosis on CT of the sacroiliac joints: multicentre development and validation of diagnostic accuracy.

OBJECTIVES: To evaluate the feasibility and diagnostic accuracy of a deep learning network for detection of structural lesions of sacroiliitis on multicentre pelvic CT scans. METHODS: Pelvic CT scans of 145 patients (81 female, 121 Ghent University/24 Alberta University, 18-87 years old, mean 40 ± 13 years, 2005-2021) with a clinical suspicion of sacroiliitis were retrospectively included. After manual sacroiliac joint (SIJ) segmentation and structural lesion annotation, a U-Net for SIJ segmentation and two separate convolutional neural networks (CNN) for erosion and ankylosis detection were trained. In-training validation and tenfold validation testing (U-Net-n = 10 × 58; CNN-n = 10 × 29) on a test dataset were performed to assess performance on a slice-by-slice and patient level (dice coefficient/accuracy/sensitivity/specificity/positive and negative predictive value/ROC AUC). Patient-level optimisation was applied to increase the performance regarding predefined statistical metrics. Gradient-weighted class activation mapping (Grad-CAM++) heatmap explainability analysis highlighted image parts with statistically important regions for algorithmic decisions. RESULTS: Regarding SIJ segmentation, a dice coefficient of 0.75 was obtained in the test dataset. For slice-by-slice structural lesion detection, a sensitivity/specificity/ROC AUC of 95%/89%/0.92 and 93%/91%/0.91 were obtained in the test dataset for erosion and ankylosis detection, respectively. For patient-level lesion detection after pipeline optimisation for predefined statistical metrics, a sensitivity/specificity of 95%/85% and 82%/97% were obtained for erosion and ankylosis detection, respectively. Grad-CAM++ explainability analysis highlighted cortical edges as focus for pipeline decisions. CONCLUSIONS: An optimised deep learning pipeline, including an explainability analysis, detects structural lesions of sacroiliitis on pelvic CT scans with excellent statistical performance on a slice-by-slice and patient level. CLINICAL RELEVANCE STATEMENT: An optimised deep learning pipeline, including a robust explainability analysis, detects structural lesions of sacroiliitis on pelvic CT scans with excellent statistical metrics on a slice-by-slice and patient level. KEY POINTS: • Structural lesions of sacroiliitis can be detected automatically in pelvic CT scans. • Both automatic segmentation and disease detection yield excellent statistical outcome metrics. • The algorithm takes decisions based on cortical edges, rendering an explainable solution.

Brief Report: Suboptimal Lopinavir Exposure in Infants on Rifampicin Treatment Receiving Double-dosed or Semisuperboosted Lopinavir/Ritonavir: Time for a Change.

BACKGROUND: Although super-boosted lopinavir/ritonavir (LPV/r; ratio 4:4 instead of 4:1) is recommended for infants living with HIV and receiving concomitant rifampicin, in clinical practice, many different LPV/r dosing strategies are applied due to poor availability of pediatric separate ritonavir formulations needed to superboost. We evaluated LPV pharmacokinetics in infants with HIV receiving LPV/r dosed according to local guidelines in various sub-Saharan African countries with or without rifampicin-based tuberculosis (TB) treatment. METHODS: This was a 2-arm pharmacokinetic substudy nested within the EMPIRICAL trial (#NCT03915366). Infants aged 1-12 months recruited into the main study were administered LPV/r according to local guidelines and drug availability either with or without rifampicin-based TB treatment; during rifampicin cotreatment, they received double-dosed (ratio 8:2) or semisuperboosted LPV/r (adding a ritonavir 100 mg crushed tablet to the evening LPV/r dose). Six blood samples were taken over 12 hours after intake of LPV/r. RESULTS: In total, 14/16 included infants had evaluable pharmacokinetic curves; 9/14 had rifampicin cotreatment (5 received double-dosed and 4 semisuperboosted LPV/r). The median (IQR) age was 6.4 months (5.4-9.8), weight 6.0 kg (5.2-6.8), and 10/14 were male. Of those receiving rifampicin, 6/9 infants (67%) had LPV Ctrough <1.0 mg/L compared with 1/5 (20%) in the control arm. LPV apparent oral clearance was 3.3-fold higher for infants receiving rifampicin. CONCLUSION: Double-dosed or semisuperboosted LPV/r for infants aged 1-12 months receiving rifampicin resulted in substantial proportions of subtherapeutic LPV levels. There is an urgent need for data on alternative antiretroviral regimens in infants with HIV/TB coinfection, including twice-daily dolutegravir.

Pharmacokinetic interaction between raltegravir and rifampicin in an infant with HIV exposed to active TB: a case report.

We report a case of an infant with HIV receiving raltegravir granules for oral suspension and rifampicin-based TB prophylaxis. Raltegravir trough levels remained subtherapeutic and viral load increased during concurrent rifampicin therapy despite using double-dosed raltegravir. Even after rifampicin therapy, a higher dose was needed. This highlights the importance of therapeutic drug monitoring and dose adjustments of raltegravir in infants with rifampicin as comedication.

What babies need: accelerating access to current and novel antiretroviral drugs in neonates through pharmacokinetic studies.

Although 23 antiretroviral drugs are approved for use in adults, only six are approved by regulatory authorities for use in term neonates born to women with HIV, with even fewer options for preterm neonates. A major hurdle for approvals is the delay in the generation of pharmacokinetic and safety data for antiretrovirals in neonates. The median time between the year of approval from the US Food and Drug Administration of an antiretroviral agent for adults and the first publication date for pharmacokinetic data in neonates less than 4 weeks old is 8 years (range 2-23 years). In this Viewpoint, we address pharmacokinetic research gaps and priorities for current and novel antiretroviral use in neonates. We also consider the challenges and provide guidance on neonatal clinical pharmacology research on antiretroviral agents with the goal of stimulating research and expediting the availability of safe medications for the prevention and treatment of HIV in this vulnerable population.

Raltegravir-based Postnatal HIV Prophylaxis Therapy in a Neonate After in Utero Dolutegravir Exposure.

We present a case report of a neonate receiving raltegravir-based postnatal HIV prophylaxis after in utero dolutegravir exposure. High levels of raltegravir and dolutegravir can potentially cause bilirubin toxicity as they compete for albumin binding and follow the same metabolic pathway through UGT1A1. This case suggests delaying initiation of raltegravir-based postnatal prophylaxis by 24-48 hours after in utero dolutegravir exposure.

Dexamethasone is a dose-dependent perpetrator of drug-drug interactions: implications for use in people living with HIV.

Global use of dexamethasone in COVID-19 patients has revealed a poor understanding of the drug-drug interaction (DDI) potential of dexamethasone, particularly with antiretroviral agents (ARVs). Dexamethasone is both a substrate and a dose-dependent inducer of cytochrome P450 3A4 (CYP3A4). As many ARVs are substrates and/or inhibitors or inducers of CYP3A4, there is concern about DDIs with dexamethasone either as a perpetrator or a victim. Assessment of DDIs that involve dexamethasone is complex as dexamethasone is used at a range of daily doses (generally 0.5 up to 40 mg) and a treatment course can be short, long, or intermittent. Moreover, DDIs with dexamethasone have been evaluated only for a limited number of drugs. Here, we summarize the available in vitro and in vivo data on the interaction potential of dexamethasone and provide recommendations for the management of DDIs with ARVs, considering various dexamethasone dosages and treatment durations.

Packaging of a Pediatric Weight Management Intervention and Implementation Blueprint for Rural and Micropolitan Communities: The Nebraska CORD 3.0 Project.

Pediatric weight management interventions (PWMIs) have resulted in positive changes among family members and, if widely disseminated, could have an impact on pediatric weight management in rural communities. The purpose of this article is to describe a backward design approach taken to create an online packaged program and implementation blueprint for building healthy families (BHF), an effective PWMI for implementation in rural communities. The backward design process included the identification of end users: primary (facilitators to be trained through the packaged program and implementation blueprint), secondary (researchers and evaluators), terminal (caregivers and children impacted by PWMI participation), tertiary (community support organizations, funding agency promoting widespread PWMI, and payors), as well as, key outcomes for respective end user groups based on the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework. This process resulted in the BHF Online Training Resources and Program package and implementation blueprint that included a modular approach encompassing the interplay of training modules for program facilitators, knowledge checks to ensure mastery of program components, recruitment resources for school and clinical settings, all program materials, embedded fidelity assessments for quality assurance, and a data portal to track participant success. Next steps include preliminary product testing with potential facilitators and a type 3 effectiveness implementation trial to determine the utility of the BHF Online Training Resources and Program package with and without participation in a learning collaborative to support implementation and sustainability.

JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate.

The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid ß lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future.

Bayesian pooling versus sequential integration of small preclinical trials: a comparison within linear and nonlinear modeling frameworks.

Bayesian sequential integration is an appealing approach in drug development, as it allows to recursively update posterior distributions as soon as new data become available, thus considerably reducing the computation time. However, preclinical trials are often characterized by small sample sizes, which may affect the estimation process during the first integration steps, particularly when complex PK-PD models are used. In this case, sequential integration would not be practicable, and trials should be pooled together. This work is aimed at comparing simple Bayesian pooling with sequential integration through a simulation study. The two techniques are compared under several scenarios using linear as well as nonlinear models. The results of our simulation study encourage the use of Bayesian sequential integration with linear models. However, in the case of nonlinear models several caveats arise. This paper outlines some important recommendations and precautions in that respect.

Pharmacokinetics of antiretroviral and tuberculosis drugs in children with HIV/TB co-infection: a systematic review.

INTRODUCTION: Management of concomitant use of ART and TB drugs is difficult because of the many drug-drug interactions (DDIs) between the medications. This systematic review provides an overview of the current state of knowledge about the pharmacokinetics (PK) of ART and TB treatment in children with HIV/TB co-infection, and identifies knowledge gaps. METHODS: We searched Embase and PubMed, and systematically searched abstract books of relevant conferences, following PRISMA guidelines. Studies not reporting PK parameters, investigating medicines that are not available any longer or not including children with HIV/TB co-infection were excluded. All studies were assessed for quality. RESULTS: In total, 47 studies met the inclusion criteria. No dose adjustments are necessary for efavirenz during concomitant first-line TB treatment use, but intersubject PK variability was high, especially in children <3 years of age. Super-boosted lopinavir/ritonavir (ratio 1:1) resulted in adequate lopinavir trough concentrations during rifampicin co-administration. Double-dosed raltegravir can be given with rifampicin in children >4 weeks old as well as twice-daily dolutegravir (instead of once daily) in children older than 6 years. Exposure to some TB drugs (ethambutol and rifampicin) was reduced in the setting of HIV infection, regardless of ART use. Only limited PK data of second-line TB drugs with ART in children who are HIV infected have been published. CONCLUSIONS: Whereas integrase inhibitors seem favourable in older children, there are limited options for ART in young children (<3 years) receiving rifampicin-based TB therapy. The PK of TB drugs in HIV-infected children warrants further research.

Unexpected air quality impacts from implementation of green infrastructure in urban environments: A Kansas City case study.

Green infrastructure (GI) implementation can benefit an urban environment by reducing the impacts of urban stormwater on aquatic ecosystems and human health. However, few studies have systematically analyzed the biophysical effects on regional meteorology and air quality that are triggered by changes in the urban vegetative coverage. In this study we use a state-of-the-art high-resolution air quality model to simulate the effects of a hypothetically feasible vegetation-focused GI implementation scenario in Kansas City, MO/KS on regional meteorology and air quality. Full year simulations are conducted for both the base case and GI land use scenarios using two different land surface models (LSMs) schemes inside the meteorological model. While the magnitudes of the changes in air quality due to the GI implementation differ using the two LSMs, the model outputs consistently showed increases in summertime PM2.5 (1.1 µg m-3, approximately 10% increase using NOAH LSM), which occurred mostly during the night and arose from the primary components, due to the cooler surface temperatures and the decreased planetary boundary layer height (PBLH). Both the maximum daily 8-hour average ozone and 1 h daily maximum O3 during summertime, decreased over the downtown areas (maximum decreases of 0.9 and 1.4 ppbv respectively). The largest ozone decreases were simulated to happen during the night, mainly caused by the titration effect of increased NOx concentration from the lower PBLH. These results highlight the region-specific non-linear process feedback from GI on regional air quality, and further demonstrate the need for comprehensive coupled meteorological-air quality modeling systems and necessity of accurate land surface model for studying these impacts.

Identifying Implementation Science Characteristics for a Prenatal Oral Health eHealth Application.

Background. Oral health is a significant public health issue; yet barriers to implementing the prenatal oral health guidelines into practice remain. This formative research aimed to identify key implementation science characteristics to inform the development of an eHealth application (app) to assist providers in implementing the prenatal oral health guidelines during prenatal visits. Method. Guided by the Consolidated Framework for Implementation Research, the clinic's infrastructure, workflow, and contextual factors were assessed via clinic observation, technology assessment, prenatal provider interviews (n = 4), clinic staff interviews (n = 8), and two focus groups with oral health providers (n = 16). Results. System-level factors influencing future implementation were identified regarding structural characteristic, networks/communication, culture, external policy/incentives, relative advantage, complexity, design quality/packaging, knowledge/beliefs, and personal attributes. Discussion. Findings provided vital information and will directly inform the design and implementation of an eHealth app that aims to facilitate the translation of the interprofessional prenatal oral health guidelines into clinical prenatal oral health practices.