Roland van Rensburg

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.

Regulatory limits on metformin co‐administered with dolutegravir (DTG) derive from healthy‐volunteer studies in which DTG increased metformin exposure by 79% through organic cation transporter 2 inhibition, prompting a 1,000 mg/day metformin dose restriction. Whether this applies to women with HIV and severe obesity, a clinically important and understudied population for metformin‐DTG coadministration, is unknown. In a secondary analysis of a reported cohort, we developed a population pharmacokinetic model of extended‐release (XR) metformin with a zero‐order‐release, first‐order‐absorption structure scaled by lean body mass (LBM). Estimated glomerular filtration rate and DTG exposure were evaluated as clearance covariates, including DTG as a time‐varying competitive inhibitor. We simulated steady‐state exposures across body mass index (BMI) 30–60 kg/m ² at 1000–3000 mg once daily compared to a DTG‐free reference model. Fifteen women contributed evaluable profiles (mean BMI 45.6 kg/m ² ). Apparent clearance was 70.2 L/h, approximately 40% higher than reported non‐obese values, and DTG exposure was approximately 54% lower than in volunteer studies. LBM dominated clearance and volume, while no DTG exposure‐dependent effect on metformin clearance was identifiable within the observed low DTG exposure range. Simulated exposures rose near‐proportionally with dose and minimally with BMI; the proportion exceeding the lactic acidosis‐associated maximum concentration of 5 mg/L was 4.4% at 2000 mg/day, 16.9% at 2500 mg/day and 37.9% at 3000 mg/day, whereas none exceeded the lactic acidosis‐associated average steady‐state concentration of 4 mg/L. Although an interaction at higher DTG exposures cannot be excluded, the low exposures observed suggest the 1,000 mg/day restriction may underdose this obese population, supporting investigation of doses up to 2000 mg/day as the maximum authorized daily dose for metformin XR.

Background Individualised pain management strategies rather than purely empiric analgesic escalation, has become a topic of importance in precision medicine. African populations carry the greatest global CYP2D6 genetic diversity, yet remain under-represented in pharmacogenetic studies. No prospective South African data exist evaluating CYP2D6 phenotype and tramadol analgesic response in postoperative settings. This study therefore aimed to determine the association between postoperative pain scores and CYP2D6 metaboliser status in South African participants receiving tramadol after total knee arthroplasty (TKA) or total hip arthroplasty (THA). Methods Fifty adults received immediate-release oral tramadol 50 mg according to a standardised institutional postoperative analgesic protocol after elective TKA or THA. Pain intensity was measured on an 11-point Numerical Rating Scale (NRS) immediately before, and two hours after the first postoperative tramadol dose. Genotyping from whole blood was performed using the Agena Bioscience Veridose and Copy Number Variation panels to determine CYP2D6 phenotype. Plasma tramadol and O-desmethyltramadol (M1) concentrations were quantified by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Results CYP2D6 phenotyping identified 36 normal metabolisers (72%), 11 intermediate metabolisers (22%), and 3 poor metabolisers (6%). Among participants who achieved a clinically significant analgesic response (≥3-point NRS reduction; n=25), 96% were normal metabolisers, 4% intermediate metabolisers, and none were poor metabolisers. (Fisher's exact p<0.001). M1 concentrations and M1:tramadol ratios differed significantly across phenotypes (p=0.010 and p<0.001, respectively). Conclusion A significant association was observed between tramadol analgesic response and metaboliser status. In resource-limited settings, the M1:tramadol ratio may reflect underlying CYP2D6 metaboliser status, potentially supporting more individualised analgesic prescribing.

Drug dosing recommendations derived from healthy volunteers and selected preregistration populations may not translate reliably to physiologically distinct or understudied groups, particularly in low‐ and middle‐income countries. Using a metformin–dolutegravir drug interaction study and colistin pharmacokinetic study from South Africa, we illustrate how body composition and disease severity, respectively, can alter dosing assumptions. Drug development and post‐registration programs should include explicit translation plans using target‐population data to confirm, refine, or revise dosing recommendations in understudied target populations.

Background: Despite effective antiretroviral therapy (ART), serious non-AIDS events (SNAEs), including cardiovascular disease and death, remain prevalent among people with HIV (PWH). Imperfect ART adherence despite viral suppression may contribute to this risk, underscoring the need to clarify the relationship between adherence, viral load dynamics, and SNAE development. Methods: We performed an analysis of deidentified data of participants in the prospective observational Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) A5001 and A5322 studies. The baseline was defined as the time at the first viral suppression to 90% versus ≤90% adherence. Data were primarily analyzed using inverse probability of censoring weights modeling. Results: Among 2940 participants followed for a median of 6.2 years, 237 SNAEs occurred, comprising 103 deaths and 134 cardiovascular events. Nearly all participants (95.9%) remained virally suppressed to 90% showed a protective effect on the development of all SNAEs: adjusted hazard ratio (aHR) 0.612 (95% confidence interval .390–.961). When only the development of the first SNAE was considered, the association remained substantially similar: aHR 0.641 (95% confidence interval .400–1.027). Conclusions: Adherence to ART >90% compared to ≤90% reduces SNAE risk even in virally suppressed PWH, underscoring the need for continued adherence support to improve long-term health outcomes for PWH.

Dolutegravir-based antiretroviral therapy (ART), a key component of HIV treatment in low- and middle-income countries, has been associated with weight gain and increased adiposity in people living with HIV (PLWH). This weight gain, along with fat redistribution, can elevate the risk of diabetes, hypertension, and cardiovascular disease. The South African Diabetes Prevention Program (SA-DPP) is a culturally tailored lifestyle intervention addressing nutrition, physical activity, and other risky behaviors, developed for resource-limited communities. We sought to evaluate the clinical experiences of PLWH and the acceptability and suitability of the SA-DPP intervention for this population. A qualitative study was conducted with PLWH and health staff from three primary health clinics in Cape Town (n = 35), selected through purposive sampling. The research included five focus groups and two individual interviews with PLWH, as well as five interviews (with healthcare staff (doctors, nurses (paired interview), and lay counselors; n = 6,). The discussions explored experiences regarding HIV treatment, lifestyle challenges, education, and support from clinics, and collected perspectives on the SA-DPP materials. All sessions were transcribed and thematically analyzed for insights into feasibility and acceptability. The SA-DPP curriculum was well received by both PLWH and healthcare staff, who found the content and structure comprehensive and relevant to nutrition and exercise needs. Participants valued the practicality of the booklets, with experts noting that the information and suggested activities were accessible in terms of cost and availability. Both groups indicated the material supported healthy behavior changes, though some experts suggested further adaptation to address unique challenges faced by PLWH, such as stigma and cultural perceptions of body image. The SA-DPP intervention was considered acceptable and relevant for addressing key lifestyle issues among PLWH. It has potential as a resource for managing various lifestyle-related diseases in this population, though further adaptation may be needed to enhance its relevance and address specific barriers in the context of HIV care. The online version contains supplementary material available at 10.1186/s12889-026-26991-4.

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.

Background: Tenofovir (TFV) is a key antiretroviral used in HIV pre-exposure prophylaxis (PrEP) and treatment, with efficacy contingent on adherence. Quantifying TFV concentrations in dried blood spots (DBS) as tenofovir diphosphate (TFV-DP) is a robust method for determining long-term adherence. However, standardised TFV-DP adherence thresholds in DBS have not been established. Objectives: To map the existing literature on TFV-DP concentration thresholds in DBS for assessing adherence to TFV-based HIV prevention and treatment, and to identify evidence gaps. Method: We conducted a scoping review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. Eight electronic databases were searched for studies reporting TFV-DP concentrations in DBS in relation to adherence thresholds or clinical outcomes for TFV-based PrEP or antiretroviral therapy (ART). Pharmacokinetic simulation or modelling studies used as reference benchmarks were included. Data were screened and extracted by two independent reviewers. We conducted descriptive analysis, tabulating findings. Results: Twenty-two studies were included. TFV-DP adherence thresholds for PrEP and treatment varied widely, from ≥ 650 fmol/punch to ≥ 1850 fmol/punch, reflecting differences in study design, populations and ART formulations. Reference studies defined adherence threshold as ≥ 700 fmol/punch for four doses/week. PrEP studies reported TFV-DP concentrations of 993–1173 fmol/punch for 4–7 doses/week, indicating that the reference threshold was conservative. In treatment studies, concentrations ≥ 1250 fmol/punch were associated with virological suppression, whereas concentrations < 800 fmol/punch were linked to an increased risk of viraemia. Conclusion: This review of TFV-DP in DBS for HIV PrEP and treatment supports purpose- and population-specific thresholds and highlights the need for further threshold validation to optimise PrEP and treatment strategies.

Objectives The glucose-lowering drug metformin has shown promise in non-diabetic conditions for improving endothelial dysfunction, but the literature of metformin’s effect on endothelial dysfunction and the biomarkers used to measure endothelial dysfunction have not yet been synthesised. We aimed to map the extent and nature of the existing research related to metformin for endothelial dysfunction in non-diabetic non-communicable diseases (NCDs). This scoping review was conducted following the methodological framework by Arksey and O’Malley and the recommendations from the Joanna Briggs Institute, and was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. Eligibility criteria We considered any peer-reviewed studies in adult humans on the use of metformin for endothelial dysfunction in non-diabetic NCDs. Narrative reviews, expert opinion, preclinical studies and qualitative studies were excluded. Sources of evidence An unrestricted search was conducted on four electronic databases and three registries from inception to October 2024. Charting methods Data charting was performed using predetermined data extraction headings. We used a systematic charting method and narrative synthesis to organise, synthesise and report the data. Results We identified 56 studies comprising 4620 participants (71.7% female). Polycystic ovarian syndrome was the most investigated NCD (57.1% of studies). 19 distinct biomarkers of endothelial dysfunction were identified, with flow-mediated dilation being the most frequently assessed (18 studies, 745 participants). Metformin showed a trend towards improvement for 7/19 (36.8%) biomarkers. Male participants were underrepresented in the literature and only five studies (9%) were conducted in the global south, potentially limiting the generalisability of repurposed metformin in diverse populations or settings. Studies with an active comparator reported a significant difference between the metformin and comparator groups in 20% (4/20), in contrast to studies without an active comparator (placebo or pre–post studies) reporting significant results favouring metformin in 83.3% (30/36). A knowledge gap also exists for metformin use in people with HIV, given that they are known to develop cardiovascular NCDs at a twofold higher rate than their HIV-negative counterparts. Conclusions While there is a growing evidence base supporting metformin as treatment for endothelial dysfunction in non-diabetic NCDs, our scoping review highlighted knowledge gaps in optimal biomarker selection and dosing strategies, and applications in a broader range of NCDs, including in people with HIV. More primary and secondary research using robust methodologies and study designs is needed to determine the quantitative effect of metformin on endothelial dysfunction.

The African Journal of Primary Health & Family Medicine welcomes submissions that encourage scholarly exchange between family medicine and primary health care researchers and practitioners across Africa and the developing world, whilst providing a contextual and holistic view of family medicine as practiced across the continent.