Tracy Kellermann

Background: People with HIV (PWH) experience excess cardiovascular disease risk with persistent inflammation considered a key driver, despite antiretroviral therapy. Low-level viremia (LLV) may contribute to inflammation and vascular injury, but data in sub-Saharan Africa are limited. We assessed correlates of endothelial function among Black African PWH with a history of viremia despite antiretroviral therapy use. Methods: We conducted a cross-sectional substudy within the South African UTRA trial (NCT05333679). Endothelial function was measured with EndoPAT using the natural log-transformed Reactive Hyperemia Index (LnRHI); endothelial dysfunction was defined as LnRHI ≤ 0.51. The primary exposure was 12-month cumulative HIV viral load (VL) area under the curve. Body mass index, waist-to-hip ratio, and Body Roundness Index were modeled using adjusted natural cubic splines with robust standard errors. We evaluated associations of various covariates, including these body composition metrics, with LnRHI via multivariable regression. Results: Of 120 participants (median age 46 years, 69% women), 26% met criteria for endothelial dysfunction despite low 10-year cardiovascular disease risk. Median LnRHI was 0.69 (interquartile range 0.50–0.94). Mean cumulative VL area under the curve was 1.55 log ₁₀ copy-yr/mL (interquartile range 1.30–2.20), consistent with LLV. Cumulative VL was not associated with endothelial function after adjustment. By contrast, LnRHI varied significantly and nonlinearly across body mass index, waist-to-hip ratio, and Body Roundness Index, with an overall downward trend with increasing adiposity. Conclusions: In this cross-sectional analysis of Black African PWH with LLV, no association between cumulative VL and endothelial dysfunction was observed. However, higher adiposity was consistently associated with declining endothelial function. Our data add to the growing evidence on the importance of addressing body composition as a multifactorial risk determinant and important correlate of early vascular risk in PWH.

Background: Breast cancer is a leading cause of cancer-related mortality in women globally. Breast cancer patients treated with tamoxifen demonstrate interpatient variability, with adherence challenges affecting up to 50% of patients by year 5, directly impacting the concentrations of the active metabolite of tamoxifen, namely endoxifen, and clinical outcomes. This pilot study evaluated the use of tamoxifen and endoxifen therapeutic drug monitoring (TDM) using liquid chromatography-tandem mass spectrometry in South African women. Methods: The authors enrolled 20 women with estrogen receptor–positive breast cancer who were treated with tamoxifen; performed TDM on them, and assessed their adherence using objective and subjective methods. Objective nonadherence was defined as tamoxifen plasma concentration P = 0.322). Based on a therapeutic threshold of 5.97 ng/mL, 20% (95% CI: 8.1%–41.6%) had subtherapeutic endoxifen concentrations. Conclusions: A liquid chromatography-tandem mass spectrometry method was developed and fully validated according to the ICH M10 guidelines to simultaneously provide objective adherence measurements and TDM in a pilot study. This method enables clinicians to verify medication compliance and determine therapeutic concentrations by quantifying both tamoxifen adherence and endoxifen concentration in a single analysis.

Objectives: To determine the PK of the pro-drug colistimethate sodium (CMS) and colistin in adult patients admitted to a South African critical care unit and to compare the PK with historical data. Materials and methods: We conducted a prospective, observational, PK study in critically ill adult patients receiving intravenous colistin as part of standard of care. CMS was administered as a loading dose of either 9 million units (MU) or 12 MU followed by maintenance doses dependent on creatinine clearance (CrCl) at either 12- or 8-hourly. PK samples were collected at 1, 2, 4, 8, 12, 24 and 48 hours post-loading dose. CMS and colistin concentrations were analysed using liquid chromatography–tandem mass spectrometry. The PK of CMS and colistin were described using non-compartmental analysis in Phoenix WinNonlin. Results: We enrolled 24 participants, 50% (12/24) were admitted with burns. Mean age was 42 years (SD ± 16.3) and mean CrCl was 140 mL/min (SD ± 58.7). The PK parameters following a loading dose of 9 MU were comparable to published data. Colistin AUC showed a negative correlation with white cell count (r = −0.63) and eGFR (r = −0.44). Probability of target attainment was acceptable at Acinetobacter baumannii minimum inhibitory concentrations <1 mg/L. Conclusion: Our results are comparable to previously published literature. Notably, increasing eGFR and WCC decreased colistin AUC. Future work will adopt a population pharmacokinetic modelling approach to quantify and account for sources of variability, with the aim of informing individualized dosing strategies for this South African population.

Tuberculous meningitis (TBM) treatment outcomes are poor, partly due to suboptimal drug penetration into the cerebrospinal fluid (CSF). Little is known about the CSF pharmacokinetics of many TB drugs, both established and new. This study investigated the CSF penetration of cycloserine (administered as terizidone) and clofazimine, two core second-line drugs for drug-resistant tuberculosis (TB). We recruited participants with pulmonary drug-resistant TB, but without TBM, receiving terizidone and/or clofazimine for at least 2 weeks and collected serial plasma samples and a single CSF sample. Drug concentrations were quantified with validated liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were determined using noncompartmental analysis, and population pharmacokinetic modeling was used to estimate the partition coefficient and equilibration half-life. Data were available from 27 participants, with a median age of 36 (range 20–60) and a weight of 52 kg (30–73 kg), who contributed 216 plasma and 27 CSF samples. The plasma pharmacokinetics of both drugs was in line with previous reports. Terizidone, measured as cycloserine, achieved CSF exposure of 69% relative to plasma, with plasma and CSF concentrations equilibrating with a half-life of 4.7 hours. Clofazimine CSF penetration was 0.13% of plasma exposure, with an equilibration half-life of 55.4 hours. Cycloserine and clofazimine concentrations in CSF approximated their estimated unbound (active) concentration in plasma, thus suggesting good penetration of the unbound drug into the CSF, supporting their potential use in TBM regimens. This study demonstrates a feasible and reproducible method for effective assessment of CSF drug penetration for CNS infections.

Background: Sertraline (SER) is a selective serotonin reuptake inhibitor (SSRI) prescribed for depression, including during pregnancy. Existing literature suggests a potential association between gestational SER use and cardiac and neurodevelopmental anomalies in exposed offspring. This study evaluated the relative impacts of SER and its metabolite desmethylsertraline (DES) on the proteome during early development. Methods: Zebrafish embryos and larvae were exposed to individual treatments of translated umbilical cord-blood equivalent concentrations of SER or DES during early developmental stages. Quantified activity tracking and protein expression levels of serotonin transporter (SERT) were used to confirm a significant SSRI effect in exposed larvae. A whole-larvae proteomic analysis was conducted using a label-free quantitative liquid chromatography-mass spectrometry approach. Protein identification was performed using zebrafish and human protein databases. Results: Apparent therapeutic SSRI effect of exposure doses of SER and DES was confirmed in zebrafish larvae, by reduced activity levels, as well as decreased SERT. DES, but not SER, resulted in several differentially regulated proteins, identified in both the zebrafish and human databases. The results from the two databases correlated and aligned with an increased risk for cardiovascular and neurodevelopmental dysregulation. Conclusion: Proteomic data suggest that DES, rather than SER, at physiologically relevant doses, may be responsible for adverse clinical outcomes reported after gestational SSRI use. Current data positions larval zebrafish as a possible tool for assessment of long-term risk after gestational SER use, as well as a drug development tool in this context. Clinical trial number: N/A.

Background: Scalable strategies to detect and address inadequate adherence to antiretroviral therapy (ART) are a high priority towards meeting UNAIDS 95-95-95 targets. A urine tenofovir rapid assay (UTRA) at the point-of-care improves adherence among pre-exposure prophylaxis recipients and virologic suppression (VS) in a pre-post study of people with HIV (PWH). Here, we conducted the first randomized trial of UTRA-enhanced adherence support vs standard of care among PWH. Methods: Participants receiving dolutegravir (DTG)– or protease inhibitor (PI)–based ART were randomized to UTRA-enhanced adherence support (n = 100) vs standard of care (n = 100). The primary outcome was VS, HIV-1 RNA <50 copies/mL, at 12-months and secondary outcome was VS at 6 months. To explore ART adherence over the preceding 6–8 weeks, tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) was quantified. C-reactive protein (CRP) was measured as an inflammatory marker. Results: At the 12-month visit, 59/80 (74%) in the intervention and 48/75 (64%) in the control arm achieved VS (the same proportion as at 6 months; P = .2); TFV-DP concentrations (median, IQR) in DBS were significantly higher in the intervention arm: 884 (491–1296) vs 598 (239–964) fmol/3-mm DBS punch in the control arm (P < .01). Higher TFV-DP DBS concentrations correlated with a slight decrease in CRP (Spearman's rho = −0.19; P = .02). Conclusions: UTRA-enhanced adherence support did not result in a significantly higher VS rate but was associated with increased TFV-DP in DBS—in turn, associated with lower CRP levels—suggesting that UTRA-enhanced adherence support improves long-term drug exposure and could also reduce HIV-associated inflammation. Clinical Trials Registration: clinicaltrials.gov (https://clinicaltrials.gov/study/NCT05333679).

Background: Obesity among women with human immunodeficiency virus (WWH) is nearly 2-fold higher than in men. Obesity is closely associated with dysglycemia, and frequently necessitates the coadministration of dolutegravir and metformin. A pharmacokinetic study in 15 nonobese healthy volunteers determined that dolutegravir increased metformin plasma exposure by 79%, prompting regulatory and guideline recommendations to limit metformin to 1000 mg/day when coadministered with dolutegravir. Obesity has been linked to lower metformin exposures, and our study aimed to verify the metformin pharmacokinetic exposure in the increasing population of obese WWH. Methods: We conducted intensive plasma sampling in virally suppressed WWH receiving metformin extended-release 1000 mg once daily with concomitant dolutegravir 50 mg once daily. Dual-energy X-ray absorptiometry was performed to quantify body fat composition. Noncompartmental analysis of metformin and dolutegravir concentrations was performed, and our findings were compared to the reference study. Results: We enrolled 15 participants with a mean body mass index of 45.6 kg/m2. Metformin area under the concentration-time curve over the 24-hour dosing interval (AUC0–24) was 40.9% lower and dolutegravir AUC0–24 was 54.4% lower in obese WWH compared to the reference study. Metformin and dolutegravir clearance were 1.7- and 2.2-fold higher, respectively. Linear regression did not show associations between body fat composition and metformin or dolutegravir exposures. Conclusions: Limiting metformin to 1000 mg daily is likely to lead to underdosing in obese WWH on dolutegravir. Lower metformin exposure appears to be due to the reduced inhibitory effect of lower dolutegravir concentrations on metformin clearance and increased volume of distribution due to obesity. Our data support the revision of the current maximum dose restriction of metformin in the target population of obese WWH.