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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. [ABSTRACT FROM AUTHOR]

We determined total and unbound concentrations of doravirine (DOR) in cerebrospinal fluid and blood plasma. Total and unbound DOR concentrations in cerebrospinal fluid exceeded the half-maximal effective concentration against wild-type virus (5.1 ng/mL) in all patients, suggesting that DOR may contribute to inhibit viral replication in this compartment. [ABSTRACT FROM AUTHOR]

Introduction: Sub‐dermal hormone implants, such as levonorgestrel (LNG), are a safe and desirable form of long‐acting contraception, but their use among HIV‐positive women on antiretroviral therapy (ART) may be compromised given the potential for a cytochrome P450 3A‐mediated drug–drug interaction. Our study aimed to characterize the pharmacokinetics of LNG released from a sub‐dermal implant over six months in HIV‐positive Ugandan women on nevirapine (NVP)‐ or efavirenz (EFV)‐based ART. Material and Methods: This non‐randomized, parallel group study compared LNG pharmacokinetics between HIV‐positive Ugandan women not yet eligible for ART (control group, n=18) and those on stable NVP‐ (n=20) or EFV‐ (n=20) based ART. The two‐rod (75 mg/rod) LNG sub‐dermal implant was inserted at study enrolment. LNG sampling was obtained pre‐implant and at weeks 1, 4, 12 and 24 post‐insertion. LNG concentrations were analyzed using a validated LC‐MS/MS method, with an assay calibration range of 50–1500 pg/mL. Safety monitoring, including a pregnancy test, was conducted at each study visit. Results: At enrolment, participants had a mean age of 31 years; CD4+ cell counts were similar between the control, NVP and EFV groups (758, 645 and 568 cells/mm[sup.3], respectively; p=0.09); all women in the NVP and EFV groups had an undetectable HIV‐RNA. Women in the control group had a higher baseline body weight (73 kg) compared to those in the NVP (63 kg; p=0.03) or EFV groups (60 kg; p Conclusions: Over a 24‐week period, LNG concentrations were 40–54% lower in women on EFV‐based ART, despite their having a significantly lower body weight, compared to those not on ART. In women on NVP‐based ART, LNG concentrations were 32–39% higher than those observed in the control group, a difference partially explained by body weight. These data confirm a significant drug interaction occurs between the LNG implant and EFV, adding to growing concern for reduced contraceptive efficacy with their combined use. In contrast, these data support use of the LNG implant with NVP‐based ART., Table 1: LNG concentrations shown as geometric mean (GM) with 90% confidence intervals (CIs) Control group; pg/mL NVP group; pg/mL NVP:control GM ratio (90% CI) EFV group; pg/mL EFV:control GM [...]

We determined total and unbound concentrations of bictegravir (BIC) in cerebrospinal fluid (CSF) in 15 asymptomatic, virologically suppressed patients. The median plasma and CSF total BIC concentrations were 1837.1 ng/mL (interquartile range [IQR], 1237.2-2586.7) and 6.9 (IQR, 4.8-10.9), respectively. Median unbound BIC concentration was 2.48 ng/mL (IQR, 1.6-3.7). Total and unbound BIC CSF concentrations were above the half-maximal effective concentration value in all patients, and all subjects had human immunodeficiency virus viral suppression in plasma and CSF. Bictegravir may contribute to inhibit viral replication in this compartment. [ABSTRACT FROM AUTHOR]

Background: Different antiretroviral therapies (ARTs) may have differing effects on central nervous system (CNS) function. We assessed CNS pharmacodynamic effects of switching integrase inhibitors in people-with-HIV (PWH). Methods: PWH on tenofovir-DF/emtricitabine plus raltegravir 400 mg twice daily with suppressed plasma HIV RNA and without overt neuropsychiatric symptoms were randomly allocated on a 1:2 basis to remain on raltegravir or switch to dolutegravir 50 mg once daily for 120 days. Pharmacodynamic parameters assessed included cognitive function ( z -score of 7 domains), patient-reported outcome measures (PROMs; PHQ-9 and Beck's depression questionnaires), cerebral metabolite ratios measured by proton magnetic resonance spectroscopy (H 1 -MRS) and plasma and cerebrospinal fluid (CSF) HIV RNA. Pharmacokinetic parameters were also assessed in plasma and CSF. Changes and factors associated with changes in pharmacodynamics parameters were assessed. Results: In 20 subjects (19 male, 14 white ethnicity, median age 43 years (IQR: 11.5) and CD4 + count 717 (SD: 298) cells/µL), over 120 days there were no statistically significant changes in cognitive function [mean z -score difference (95%CI) -0.004 (-0.38/0.37); p  = 0.98], PROMs [PHQ-9 median score change: 0 in control arm, -0.5 switch arm ( p  = 0.57); Beck's depression questionnaire: -1.5 control arm, -1.0 switch arm ( p  = 0.38)], nor cerebral metabolite ratios between study arms. CSF HIV RNA was <5 copies/mL at baseline and day 120 in all subjects. Geometric mean pre-dose CSF dolutegravir concentration was 7.6 ng/mL (95% CI: 5.2-11.1). Conclusions: Switching integrase inhibitor in virologically suppressed PWH without overt neuropsychiatric symptoms resulted in no significant changes in an extensive panel of CNS pharmacodynamics parameters.