Angela Colbers

Introduction: Pregnancy is associated with physiological changes, resulting in altered pharmacokinetics, which may impact antiretroviral drug exposure. To assure health and prevent vertical transmission of HIV, it is imperative to reach adequate drug exposure. This study aims to determine the impact of pregnancy on bictegravir pharmacokinetics, examine mechanisms responsible for lower exposure, report on placental transfer, safety, and efficacy. Materials and methods: This open-label pharmacokinetic study, included women living with HIV who used bictegravir, emtricitabine with tenofovir alafenamide. Plasma samples were obtained in third trimester, as well as 4–6 weeks postpartum. If feasible, cord blood and maternal plasma at delivery were obtained. Results: Sixteen participants were included. Geometric mean area under the curve for total bictegravir was 48.8 mg*h/L (coefficient of variation (CV) 25.9%) in third trimester and 99.2 mg*L/h (CV 32.9%) postpartum, with a geometric mean ratio (90% CI) of 0.49 (0.44–0.55); 24 h post-dosing, median (IQR) unbound fractions were 0.15 (0.13–0.18)% and 0.11 (0.10–0.13) during pregnancy and postpartum, respectively. Median (IQR) ratio between pregnancy and postpartum was 173.7% (127.8–305.7) for glucuronidation-metabolite (M15) and 200.7% (150.0–224.9) for sulfation-metabolite (M20). Low-level viraemia was noted in several participants, but no vertical transmission occurred. Cord blood maternal plasma ratio (IQR) was 1.3 (1.0–1.4). No congenital anomalies were reported. Conclusion: Although bictegravir exposure is decreased during pregnancy, mainly due to altered protein binding and increased glucuronidation and sulfation, trough levels remained above the PA-IC95. No vertical transmission occurred and no congenital anomalities were observed. Bictegravir was shown to have profound placental transfer.

Background: The impact of in utero exposure to specific antiretroviral therapy (ART), particularly integrase strand transfer inhibitors, on early brain development, remains poorly understood. We used magnetic resonance imaging (MRI) to compare brain structure in children who are HIV-exposed and uninfected (CHEU) with prenatal dolutegravir (DTG) vs efavirenz (EFV) exposure. Methods: DolPHIN-2 was a randomized trial of pregnant women initiating DTG- vs EFV-based ART in the third trimester. At 3-4 years of age, a subgroup of their children from the South African cohort, along with HIV-unexposed (CHU) children, underwent T1-weighted MRI (DolPHIN-2 PLUS). Measurements of brain structure, including volume, cortical thickness, and surface area, were extracted using Freesurfer. Associations between ART /HIV exposure and child brain structure were examined using multiple linear regression. Results: This analysis included 58 children (25 CHEU [13 DTG, 12 EFV] and 33 CHU, mean age 46.35 months, 51.7% male). Demographic characteristics were similar across groups. Significant differences in global or regional brain volumes, cortical thickness, or surface area were not detected between DTG- and EFV-exposed children or between CHEU and CHU. Conclusion: Among this small sample of children at 3-4 years, statistically significant differences in global or regional brain structure were not detected between those exposed in the third trimester of pregnancy to DTG or EFV and CHU. Given the modest sample size, the study had limited power to detect small-to-moderate differences. Further longitudinal studies with larger sample sizes are needed to assess the effects of specific ART in the context of new regimens and better maternal HIV disease control on CHEU brain structure.

Introduction: Risk of transmission of HIV through breastfeeding is minimal in case of maternal viral suppression due to antiretroviral therapy. However, to what extent antiretroviral drugs transfer into breastmilk is not fully understood. Data are especially lacking for relatively newer drugs—such as bictegravir—that only recently was approved to use in pregnancy. Therefore, the aim of this study is to determine infant exposure to bictegravir through breastmilk. Materials and methods: Concentrations of bictegravir were measured in plasma and breastmilk of healthy, lactating women without HIV after a single dose of bictegravir 50 mg (co-formulated with tenofovir alafenamide 25 mg and emtricitabine 200 mg). Concentrations were measured using validated LC-MS/MS assays and pharmacokinetic parameters were calculated using non-compartmental analysis. Breastmilk to maternal plasma ratio, daily infant dosage and relative infant dose were established to determine infant exposure to bictegravir through breastmilk. Results: Twelve volunteers participated in the study. The geometric mean (CV%) area under the curve based on the last measured concentration was 52.17 (22.6) mg*h/L in plasma and 0.44 (32.0) mg*h/L in breastmilk, resulting in a geometric mean (CV%) breastmilk to maternal plasma ratio of 0.009 (26.6). The median (IQR) daily infant and relative infant doses with an intake of 150 or 200 mL/kg/day were 0.034 mg/kg/day (0.026–0.060) and 0.046 (0.035–0.080) mg/kg/day and 0.68 (0.53–1.00) % and 0.90% (0.71–1.33), respectively. Conclusion: Exposure to bictegravir through breastmilk is very low, with a relative infant dose below 1%. Even though metabolizing capacity in newborns is not yet fully developed, it is not expected to cause infant toxicity.

Background: In 2019, the World Health Organization (WHO) changed its recommendations for pregnant women living with HIV from efavirenz-based to dolutegravir-based therapy due to its superior efficacy, tolerability and resistance profile. Perinatal exposure to antiretrovirals may influence infant growth, but limited data exist on the effects of specific regimens over time. Aim: This study aimed to compare growth trajectories over the first 72 weeks of life among infants exposed to dolutegravir-based versus efavirenz-based therapy during late pregnancy. Methods: The DolPHIN-2 trial was a randomized, open-label trial conducted in South Africa and Uganda, researching the efficacy of dolutegravir-based versus efavirenz-based therapy in pregnant women living with HIV, initiating treatment in the third trimester. In this secondary analysis, we compared growth trajectories until 72 weeks postpartum between HIV-exposed uninfected infants perinatally exposed to dolutegravir-based versus efavirenz-based therapy. Measures of infant weight, length and head circumference were converted to WHO-defined weight-for-age, weight-for-length, length-for-age and head circumference-for-age Z-scores. Subsequently, Z-scores were compared across treatment arms, using linear mixed-effect models. Results: After exclusions, 232 infants remained (dolutegravir: n = 116; efavirenz: n = 116). In both crude models and models adjusted for study site and maternal height, length-for-age Z-scores were 0.277 units higher in the dolutegravir arm. No statistically significant impact of treatment was observed for other outcomes. In both study arms, a decline in mean length-for-age Z-scores occurred over the first 72 weeks, while mean weight-for-age Z-scores declined between weeks 48 and 72. Conclusion: Our data support the WHO in recommending dolutegravir-based therapy over efavirenz-based therapy in pregnant women living with HIV.

Background: Isoniazid (INH) remains a first-line drug for the treatment of tuberculosis (TB) in young children. In 2010, the WHO recommended an increase in the daily dose of INH up to 10 (7–15) mg/kg. Currently, there are no INH suspensions available in Europe. Methods: We aimed to characterize the pharmacokinetics of a licensed INH suspension (10 mg/mL, Pharmascience Inc., Montreal, QC, Canada) in children receiving INH daily at 10 mg/kg in a single-center, open-label, non-randomized, phase IIa clinical trial (EudraCT Number: 2016-002000-31) in Barcelona (Spain). Samples were analyzed using a validated UPLC-UV assay. The N-acetyltransferase 2 gene was examined to determine the acetylation status. A non-compartmental pharmacokinetic analysis was conducted. Results: Twenty-four patients (12 females) were included (primary chemoprophylaxis, n = 12; TB treatment, n = 9; and TB infection preventive treatment, n = 3). The acetylator statuses were homozygous fast (n = 3), heterozygous intermediate (n = 18), and homozygous slow (n = 2; unavailable in one patient). The INH median (IQR) C_max and AUC_0–24h values were 6.1 (4.5–8.2) mg/L and 23.0 (11.2–35.4) h∙mg/L; adult targets (>3 mg/L and 11.6–26.3 h∙mg/L) were not achieved in three and six cases, respectively. Gender, age at assessment (2 years), and INH monotherapy (vs. combined TB treatment) had no impact on pharmacokinetic parameters. Significant differences in C_max (p = 0.030) and AUC_0–24h (p = 0.011) values were observed based on acetylator status. Treatment was well tolerated, and no severe adverse events were observed; three patients developed asymptomatic mildly elevated alanine aminotransferase levels. Conclusions: In infants and children receiving a daily INH suspension at 10 mg/kg, no safety concerns were raised, and the target adult levels were reached in the majority of patients.

Darunavir is a potent HIV protease inhibitor with a high barrier to resistance. We conducted a nested pharmacokinetic sub-study within CHAPAS-4 to evaluate darunavir exposure in African children with HIV, taking once-daily darunavir/ritonavir for second-line treatment. We used data from the CHAPAS-4 pharmacokinetic sub-study treating children with once-daily darunavir/ritonavir (600/100 mg if 14–24.9 kg and 800/100 mg if ≥25 kg) with either tenofovir alafenamide fumarate (TAF)/emtricitabine (FTC), abacavir/lamivudine or zidovudine/lamivudine. Steady-state pharmacokinetic sampling was done at 0, 1, 2, 4, 6, 8, 12 and 24 hours after observed darunavir/ritonavir intake. Non-compartmental and population pharmacokinetic analyses were used to describe the data and identify significant covariates. Reference adult pharmacokinetic data were used for comparison. We simulated the World Health Organization (WHO) recommended 600/100 mg darunavir/ritonavir dose for the 25–34.9 kg weight band. Data from 59 children with median age and weight 10.9 (range 3.8–14.7) years and 26.0 (14.5–47.0) kg, respectively, were available. A two-compartment disposition model with transit absorption compartments and weight-based allometric scaling of clearance and volume best described darunavir data. Our population achieved geometric mean (%CV) darunavir AUC_0–24h, 94.3(50) mg·h/L and C_max, 9.1(35) mg/L, above adult reference values and C_trough, 1.5(111) mg/L, like adult values. The nucleoside reverse-transcriptase inhibitor backbone was not found to affect darunavir concentrations. Simulated WHO-recommended darunavir/ritonavir doses showed exposures equivalent to adults. Higher alpha-1-acid glycoprotein increased binding to darunavir and decreased apparent clearance of darunavir. Darunavir exposures achieved in our trial are within safe range. Darunavir/ritonavir can safely be co-administered with TAF/FTC. Both WHO-recommended 600/100 mg and CHAPAS-4 800/100 mg darunavir/ritonavir doses for the 25–34.9 kg weight band offer favourable exposures. The choice between them can depend on tablet availability.

We characterized population pharmacokinetics in 42 African children receiving once-daily 25 mg (14 to 20 kg) dolutegravir. Coadministration with emtricitabine and tenofovir alafenamide reduced dolutegravir bioavailability by 19.6% (95% confidence interval: 8.13%–30.8%) compared with zidovudine or abacavir with lamivudine. Nevertheless, concentrations remained above efficacy targets, confirming current dosing recommendations.

Background: We investigated the impact of Drug–Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs. Methods: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure. Results: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%–13.9%) and iron (4%–6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (−21%; P = 0.0271) and C24 (−53%; P = 0.0028). Conclusions: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.