Relative Bioavailability of Dolutegravir (DTG) and Emtricitabine/Tenofovir Alafenamide Fumarate (F/TAF) Administered as Paediatric Tablet Formulations in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together. METHODS: Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (Cmax) of each compound were within 0.70-1.43, we considered this as no clinically relevant PK interaction. RESULTS: A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC0-∞ and Cmax fell outside our acceptance criteria of 0.70-1.43. CONCLUSIONS: Although TAF AUC and Cmax 90% CIs fell outside the pre-defined criteria (0.62-1.11 and 0.65-1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.

Negative impact of a health insurer-mandated de-simplification from a single-tablet regimen to a two-tablet regimen.

OBJECTIVES: Antiretroviral therapy (ART) accounts for a considerable proportion of HIV care expenses. In June 2021, a Dutch healthcare insurer implemented a mandatory policy to de-simplify branded RPV/TDF/FTC (Eviplera®) into a two-tablet regimen containing rilpivirine (Edurant®) plus generic TDF/FTC as part of cost-saving measures. The objectives of this study were to evaluate (1) the acceptance of this policy, (2) the trends in antiretroviral therapy dispensation, and (3) cost developments. DESIGN: A retrospective database study. METHODS: In this study, medication dispensation data were obtained from the Dutch Foundation for Pharmaceutical Statistics (SFK). This database covers 98% of all medication dispensations from Dutch pharmacies including people with HIV who receive ART. We received pseudonymized data exclusively from individuals insured by the insurer for the years 2020-2022. Costs were calculated using Dutch drug prices for each year. RESULTS: In June 2021, 128 people with HIV were on branded RPV/TDF/FTC. Following the policy implementation, 59 (46%) had switched to RPV + generic TDF/FTC, but after 1.5 years, only 17/128 individuals (13%) used the proposed two-tablet regimen. The other 111/128 used RPV/TDF/FTC with prescriptions for 'medical necessity' (n = 29), switched to RPV/TAF/FTC (n = 51), or other ART (n = 31). Despite expectations of cost-savings, costs increased from €72,988 in May 2021 to €75,649 in May 2022. CONCLUSIONS: A mandatory switch from an STR to a TTR in people with HIV proved unsuccessful, marked by low acceptance, and increased costs after one year. This underscores the necessity of incorporating patient and prescriber involvement in changing medication policies.

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.

Efficacy and Safety of Bariatric Surgery in Dutch People Living with HIV: a Retrospective Matched Cohort Analysis.

PURPOSE: Obesity is rising among people with HIV (PLWH), sparking interest in bariatric surgery (BS) for this group. Yet, large-scale comparative research on BS outcomes in PLWH is lacking. METHODS: We performed a retrospective, matched cohort analysis in PLWH and HIV uninfected controls. Subjects were retrieved from the Dutch Audit for Treatment of Obesity (DATO) registry. Matching (1:7 ratio) included age (± 5-years), sex, body-mass index (BMI) of ± 3 kg/m2, surgery type, and associated health problems (AHPs) at baseline. The primary endpoint was total weight loss percentage (%TWL) ≥ 20% achieved at 1-year post-BS. Secondary endpoints were cumulative %TWL achieved at 2-years post-BS, a reported remission or improvement in AHPs post-BS, and surgical complications, both at 1-year post-BS. Comparisons were performed using conditional logistic regression. RESULTS: Twenty-seven PLWH and 168 controls were included. At 1-year post-BS, 89% PLWH achieved ≥ 20%TWL, compared to 94% of controls (p = 0.4). Cumulative %TWL at 2-years post-BS were 82% and 92% in PLWH and controls, respectively (p = 0.2). Improvement rates in hypertension and type 2 diabetes mellitus were 50% and 86% in PLWH, versus 87% and 87% in controls. Full remission occurred in 20% and 71% of PLHIV, versus 49% and 44% of controls, respectively. No improvement or remission was observed for dyslipidaemia in PLHIV compared to 54% improvement and 29% remission in controls. Surgical complications were 0% in PLHIV and 13% (n = 21) in controls. CONCLUSION: Efficacy and safety outcomes of BS were similar between PLWH and controls except for the lack of improvement in dyslipidaemia in PLWH.

Outcomes of Drug Interactions Between Antiretrovirals and Co-Medications, Including Over-the-Counter Drugs: A Real-World Study.

INTRODUCTION: The objective was to characterize real-world outcomes of drug-drug interactions (DDIs) between antiretrovirals (ARVs) and other drugs, including over-the-counter medications (OTC), and treatment outcomes in clinical practice. METHODS: www.clinicalcasesDDIs.com is an open-access website for healthcare providers to consult and briefly describe real-world clinical cases on DDI with ARVs. We reviewed all the clinical cases reported to the website between March 2019 and May 2023. RESULTS: A total of 139 cases were reported, mostly involving ritonavir or cobicistat (boosters; 74 cases), unboosted integrase inhibitors (InSTI; 29 cases), and non-nucleoside reverse transcriptase inhibitors (NNRTI; 23 cases). Central nervous system drugs (29 cases) and cardiovascular drugs (19 cases) were the most frequently described co-medications. Notably, OTC medications were implicated in 27 cases, including mineral supplements (11 cases), herbals (8 cases), weight loss drugs (4 cases), anabolic steroids (3 cases), and recreational drugs (1 case). OTC acted as the perpetrator drug in 21 cases, leading to loss of ARV efficacy in 17 instances (mineral supplements in 10 cases, weight loss drugs in 4 cases, herbals in 3 cases). Additionally, toxicity was reported in 4 out of 6 cases where OTC was considered the victim drug of the DDI (anabolic steroids in 3 cases, MDMA in 1 case). CONCLUSIONS: Frequent unwanted outcomes resulting from DDIs between ARVs and OTC medications underscore the importance of integrating non-prescription drugs into medication reconciliation. The real-world data available through www.clinicalcasesDDIs.com serves as a valuable resource for assessing the clinical relevance of DDIs.

Virological failure after switch to long-acting cabotegravir and rilpivirine injectable therapy: an in-depth analysis.

BACKGROUND: Long-acting (LA) injectable therapy with cabotegravir (CAB) and rilpivirine (RPV) is currently used as maintenance treatment for HIV-1, and has a low risk for virological failure (VF). Although the risk is low, the circumstances and impact of VF in the real-world setting merits further evaluation. METHODS: We performed an in-depth clinical, virological and pharmacokinetic analysis on the reasons behind, and the impact of VF during LA CAB/RPV therapy in five cases from the Netherlands. Genotypic resistance testing was performed after the occurrence of VF and drug plasma (trough) concentrations were measured after VF was established and on any other samples to assess on-treatment drug levels. CAB and RPV drug levels that were below the first quartile of the population cut-off (

Comparison of dolutegravir- and efavirenz on depression, anxiety and sleep disorders in pregnant and postpartum women living with HIV; a DolPHIN2 substudy.

BACKGROUND: Both dolutegravir and efavirenz are known to be effective in pregnancy and post-partum to prevent vertical transmission of HIV and to maintain maternal health. Both drugs have also been associated with neuropsychiatric symptoms. To what extent these symptoms occur in pregnant and post-partum women, however, is not yet known. METHODS: This was a secondary analysis of the DolPHIN2 study, a multicenter randomized trial among women presenting late in pregnancy with untreated HIV- who received either a dolutegravir- or efavirenz- containing regimen. Longitudinal measures of depression, anxiety and sleep quality were analyzed during pregnancy and up to 48 weeks post-partum. RESULTS: Among 268 women median (IQR) Edinburgh Post Natal depression score (EPDS) scores were 8 (3-11) and highest at enrolment. In the dolutegravir -and efavirenz arm, respectively, 23.7% and 25.6% had an EPDS score above 9, indicating possible or probable depression. Abnormal Hospital Anxiety Depression scores (HADS) (above 11) were seen at least once during follow up in 42 of patients (15.7%), although no differences were seen between treatment arms. No association was found between EPDS, suicidality and HADS scores and the assigned regimen (p = 0.93, 0.97 and 0.18 respectively). Median (IQR) Pittsburgh Sleep Quality index (PSQI) scores for dolutegravir- and efavirenz were 6 (5-7) and 5 (5-6.5) respectively, p = 0.70. CONCLUSIONS: No statistically significant differences were observed between efavirenz- or dolutegravir containing regimens. Rates of depression were high, but decreased over the course of time and confirm the need for psychological support after initial HIV diagnosis in pregnancy.

The impact of obesity on doravirine exposure in people with HIV.

Obesity incidence is increasing among people with HIV. Doravirine is a recommended first-line antiretroviral drug in many countries with no data from people with obesity. This study investigates the exposure of doravirine 100 mg standard dose in obese versus normal weight patients using clinical data combined with physiologically based pharmacokinetic modelling. Results from both approaches showed an elevated doravirine exposure during obesity, yet within the safety range of doravirine with no need for dose modification.

Twice-daily dosing of dolutegravir in infants on rifampicin treatment: a pharmacokinetic substudy of the EMPIRICAL trial.

INTRODUCTION: We evaluated dolutegravir pharmacokinetics in infants with HIV receiving dolutegravir twice-daily with rifampicin-based TB-treatment compared to once-daily without rifampicin. METHODS: This pharmacokinetic substudy was nested in the EMPIRICAL trial for infants with HIV admitted with severe pneumonia. Infants aged 1-12 months, weighing ≥3 kg, and receiving dolutegravir twice-daily with rifampicin or once-daily without rifampicin were eligible. Six bloodsamples were taken over 12 (twice-daily dosing) or 24 hours (once-daily dosing). Dolutegravir pharmacokinetic parameters were calculated and compared for infants with and without rifampicin, and HIV viral load data and adverse events (AEs) were reported descriptively. RESULTS: 27/30 enrolled infants on dolutegravir had evaluable pharmacokinetic curves. The median (IQR) age was 7.1 (6.1-9.9) months, weight was 6.3 (5.6-7.2) kilograms, 21/27 (78%) received rifampicin, and 11/27 (41%) were female. Geometric mean ratios comparing dolutegravir twice-daily with rifampicin versus once-daily without rifampicin were AUC0-24h 0.91 (95%CI 0.59-1.42); Ctrough 0.95 (0.57-1.59); Cmax 0.87 (0.57-1.33). 1/21 infants receiving rifampicin versus 0/6 without rifampicin had dolutegravir Ctrough <0.32 mg/L, and none had Ctrough <0.064 mg/L. Dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. 5/82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB-treatment completion, HIV viral load was <1,000 copies/mL in 76% and 100% of infants, and undetectable in 35% and 20% of infants with and without rifampicin, respectively. CONCLUSION: Dolutegravir twice-daily in infants receiving rifampicin-based TB-treatment 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.

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.

Outcomes of Bariatric Surgery in People With Human Immunodeficiency Virus: A Retrospective Analysis From the ATHENA Cohort.

BACKGROUND: The implications of bariatric surgery (BS) on virologic and metabolic outcomes in people with human immunodeficiency virus (HIV; PWH) on antiretroviral therapy (ART) are unknown. METHODS: Here, we report a retrospective analysis up to 18 months post-BS in PWH from the AIDS Therapy evaluation in The Netherlands (ATHENA) cohort with data from all dutch HIV treating Centers. Primary end points were a confirmed virologic failure (2 consecutive HIV-RNA measurements >200 copies/mL) and the percentage of patients who achieved >20% total body weight loss up to 18 months post-BS. Switches from baseline ART and trough plasma concentrations of antiretrovirals were also reported post-BS. Metabolic parameters and medication usage were compared pre- and post-BS. RESULTS: Fifty-one patients were included. One case of confirmed virologic failure and 3 cases with viral blips were detected in this cohort up to 18 months post-BS. Eighty-five percent of patients achieved >20% total body weight loss at 18 months post-BS, with a mean difference from baseline (95% confidence interval) of -33.5% (-37.7% to -29.3%). Trough plasma concentrations of measured antiretroviral agents were all above minimum effective concentrations, except for 1 sample of darunavir. Lipid profiles, but not serum creatinine and blood pressure, improved significantly (P < .01) post-BS. Total medications and obesity-related comedications declined from 203 to 103 and from 62 to 25, respectively, at 18 months post-BS. CONCLUSIONS: BS was an effective intervention for weight loss and lipid control in PWH using ART in this cohort with no clear link to poor virologic outcomes.

Pharmacokinetic Data of Dolutegravir in Second-line Treatment of Children With Human Immunodeficiency Virus: Results From the CHAPAS4 Trial.

BACKGROUND: Dolutegravir (DTG), combined with a backbone of 2 nucleoside reverse transcriptase inhibitors, is currently the preferred first-line treatment for human immunodeficiency virus (HIV) in childhood. CHAPAS4 is an ongoing randomized controlled trial investigating second-line treatment options for children with HIV. We did a nested pharmacokinetic (PK) substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food as part of their second-line treatment. METHODS: Additional consent was required for children on DTG enrolled in the CHAPAS4 trial to participate in this PK substudy. Children weighing 14-19.9 kg took 25 mg DTG as dispersible tablets and children ≥20 kg took 50 mg film-coated tablets. Steady-state 24-hour DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 hours after observed DTG intake with food. Reference adult PK data and pediatric data from the ODYSSEY trial were used primarily for comparison. The individual target trough concentration (Ctrough) was defined as 0.32 mg/L. RESULTS: Thirty-nine children on DTG were included in this PK substudy. The geometric mean (GM) area under the concentration-time curve over the dosing interval (AUC0-24h) was 57.1 hours × mg/L (coefficient of variation [CV%], 38.4%), which was approximately 8% below the average AUC0-24h in children in the ODYSSEY trial with comparable dosages, but above the adult reference. The GM (CV%) Ctrough was 0.82 mg/L (63.8%), which was comparable to ODYSSEY and adult reference values. CONCLUSIONS: This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY trial and adult references. Clinical Trials Registration.ISRCTN22964075.

First Pharmacokinetic Data of Tenofovir Alafenamide Fumarate and Tenofovir With Dolutegravir or Boosted Protease Inhibitors in African Children: A Substudy of the CHAPAS-4 Trial.

BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3-15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)-recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults. RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. CONCLUSIONS: In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. CLINICAL TRIALS REGISTRATION: ISRCTN22964075.

Potential drug-drug interactions in males living with HIV who use drugs to treat lower urinary tract symptoms.

OBJECTIVE: Lower urinary tract symptoms (LUTS) are becoming more prevalent in the ageing population of males living with HIV. Drugs to treat LUTS are known for both their potential role as victims in drug-drug interactions (DDIs) and their side effects. We aimed to evaluate the current use of drugs to treat LUTS and to assess potential DDIs in our cohort of adult males living with HIV. DESIGN: This was a retrospective review of pharmacy records. METHODS: We recorded the combination antiretroviral therapy (cART) regimen and any use of drugs to treat LUTS (anatomical therapeutic chemical codes G04CA/CB/CX and G04BD). Potential DDIs were assessed using the interaction checker developed by the University of Liverpool (https://www.hiv-druginteractions.org/checker). RESULTS: A total of 411 adult males living with HIV were included in this analysis. The median (interquartile range [IQR]) age was 53 (41-62) years. Nineteen (4.6%) patients used one or more drugs to treat LUTS. As expected, older patients were more likely to be receiving treatment for LUTS: Q1 (20-40 years) = 0%; Q2 (41-52 years) = 2%; Q3 (53-61 years) = 7%; Q4 (62-79 years) = 10%. Seven potential DDIs between cART and LUTS treatment were noted in six of the 19 (32%) patients. Following medication reviews of these six patients, the following interventions were proposed: evaluate safe use of alpha-blocker (n = 4), change in cART (n = 2), and dose reduction of the anticholinergic agent (n = 1). CONCLUSION: Treatment for LUTS coincided with cART in 7%-10% of patients aged above the median age of 53 years in our cohort. Improvements in DDI management appeared to be possible in this growing cohort of males living with HIV and with LUTS.

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.

Exploring the Breastfeeding Desires and Decision-Making of Women Living with HIV in the Netherlands: Implications for Perinatal HIV Management in Developed Countries.

Introduction: Guidelines in high-income countries recommend women living with human immunodeficiency virus (HIV) to formula feed their newborns, because the possibility of mother-to-child-transmission of HIV during breastfeeding cannot be ruled out. It is an ongoing debate if the possible transmission risk outweighs the medical, cultural, psychological, and social importance of breastfeeding in women stable on current first-line suppressive antiretroviral regimens. The study aim was to explore breastfeeding desires and decision-making of immigrant and nonimmigrant women living with HIV in the Netherlands. Method: A questionnaire was administered orally or online to 82 women living with HIV in the Netherlands. The breastfeeding desires of the participants were collected as categorical data, and breastfeeding decision-making and willingness to adhere to additional monitoring were collected on a 5-point Likert scale. Categorical data were presented as proportions, and Likert scale data were presented in Likert scale bar plots. Results: Seventy-one percent of the participants expressed a desire to breastfeed in the future. The most important factors influencing decision-making to breastfeed were the chance of transmission of HIV to the infant and the advice by the doctor or nurse practitioner. Of the participants, 42% expressed their interest in breastfeeding with a <1/100 transmission risk. More than half of the participants expressed their interest to breastfeed with additional monitoring. Conclusions: A substantial proportion of the women living with HIV in the Netherlands has a desire to breastfeed, of which the majority are willing to adhere to additional monitoring to do so.