South African Medical Research Council Research Articles

Cognitive performance, neuropsychiatric symptoms, and cerebrospinal fluid viral control following programmatic switch from efavirenz-based to dolutegravir-based antiretroviral therapy in South Africa (CONNECT): a prospective cohort study

Both efavirenz and dolutegravir have been associated with neuropsychiatric side-effects and cognitive impairment. Furthermore, cerebrospinal fluid (CSF) HIV RNA escape has not been comprehensively studied in African populations. We aimed to examine changes in cognition, neuropsychiatric symptoms, and CSF viral control associated with the widespread switch from efavirenz-based to dolutegravir-based antiretroviral therapy (ART). This prospective cohort study of people with HIV and people without HIV recruited adults with HIV (aged 18-55 years) from the Gugulethu Community Health Centre in a low-income periurban area of Cape Town, South Africa. Eligible participants had been receiving efavirenz-based ART for at least 1 year and were identified by the clinic to switch to dolutegravir-based ART as part of the national programmatic switch. Participants were studied at baseline and followed up at 1 year after switch to dolutegravir. People without HIV were recruited from the same area, matched for age and gender, and followed up at the same time interval. People with HIV and people without HIV underwent comprehensive cognitive testing over seven domains and measures of functioning, mood, anxiety, and sleep. People with HIV had CSF sampling for HIV RNA quantification. Between Aug 12, 2019, and Sept 16, 2022, we recruited 178 people with HIV and 95 people without HIV. 145 (81%) of 178 people with HIV and 40 (66%) of 60 people without HIV who were offered underwent follow-up. Global cognitive performance was 2·57 T score points lower in people with HIV than in people without HIV at baseline (p=0·0008). At follow-up, cognition in people with HIV improved more than practice effects observed in people without HIV (coefficient 1·40, 95% CI 0·48-2·32, p=0·0028) and no significant difference in cognitive performance between groups was apparent (51·43 vs 52·73; p=0·22). Sleep quality improved following the switch (risk ratio 0·90, 95% CI 0·84-0·95; p=0·0002), driven mainly by indicators of disturbed sleep. There were nine incident cases of depression, although baseline differences were present. There was one case (1%) of CSF escape at baseline and three cases (4%) at follow-up; all were at low levels or resolved with repeated sampling. Improvements in cognition and sleep are probably related to switching from efavirenz. However, the possible increase in depression warrants further examination. Cognitive performance in virally supressed African people with HIV receiving dolutegravir-based therapy is similar to people without HIV. CSF escape is uncommon on both efavirenz-based and dolutegravir-based therapy. South African Medical Research Council and UK Medical Research Council, Newton Fund.

Diagnostic accuracy of Truenat MTB Plus, Truenat MTB Ultima and Xpert MTB/RIF Ultra for the diagnosis of pulmonary TB in an HIV-endemic setting.

Truenat MTB Plus (MTB Plus) and MTB Ultima (Ultima) are World Health Organization-endorsed low-complexity tuberculosis (TB) tests, however, performance data are scarce. Adults (≥18 years; n=498) self-presenting with symptoms to primary care clinics in Cape Town, South Africa (19/02/2016-22/02/2023) provided sputa. We evaluated the accuracy of MTB Plus and Ultima, with Xpert MTB/RIF Ultra (Ultra) as a comparator, vs. a single culture (TB reference standard) or MTBDRplus on an isolate (rifampicin susceptibility reference standard). The proportion of MTB Plus and Ultima unsuccessful results was 20% (95% confidence interval 17, 23) and 14 (11, 16), respectively, with ≥half resolving upon retesting the same eluate. In a three-way analysis, MTB Plus, Ultima and Ultra had sensitivities of 84% (78, 88), 90% (85, 93), and 92% (87, 95), and specificities of 95% (92, 97), 85% (80, 88) and 95% (92, 97) for TB. The proportion of unsuccessful results for MTB-RIF Dx done the same day as DNA extraction was 9% (3, 16; MTB Plus-positives) and 18% (10, 26; Ultima-positives) [if after day-of-extraction, these were 27% (18, 35) and 44% (35, 51)]. Same-day rifampicin susceptibility testing was often unsuccessful in samples with "very low" load [73% (58, 89) MTB Plus, 75% (65, 86) Ultima] but had 100% (40, 100) sensitivity and 99% (96, 100) specificity (for both MTB Plus- or Ultima-positive DNA). Lot variation in unsuccessful and false-positive results was observed. Ultima showed comparable sensitivity to Ultra but specificity, lot variation, and, like MTB-RIF Dx, unsuccessful result rates were suboptimal. European & Developing Countries Clinical Trials Partnership, and South African Medical Research Council.

Critical assessment of infants born to mothers with drug resistant tuberculosis

There have been no detailed descriptions of infants born to mothers treated for drug resistant TB in pregnancy. Critical case history assessment is important to identify risks and guide clinical practice. In a cohort of pregnant women with multidrug or rifampicin resistant (MDR/RR)-TB enrolled between 1 January 2013 and 31 December 2022, we followed mother-infant pairs until the infant was 12 months old. We performed critical case history assessments to explore potential mechanisms of Mycobacterium tuberculosis transmission to the infant, and to describe the clinical presentation and disease trajectories observed in infants diagnosed with TB. Among 101 mother-infant pairs, 23 (23%) included infants diagnosed with TB disease; 16 were clinically diagnosed and seven had microbiological confirmation (five MDR/RR-TB, two drug-susceptible TB). A positive maternal sputum culture at the time of delivery was significantly associated with infant TB risk (p=0.023). Of the 12 infants diagnosed with TB in the first three months of life, seven (58%) of the mothers were culture positive at delivery; of whom four reported poor TB treatment adherence. However, health system failures, including failing to diagnose and treat maternal MDR/RR-TB, inadequate screening of newborns at birth, not providing appropriate TB preventive therapy (TPT), and M.tuberculosis transmission from non-maternal sources also contributed to TB development in infants. Infants born to mothers with MDR/RR-TB are at greatest risk if maternal adherence to MDR/RR-TB treatment or antiretroviral therapy (ART) is sub-optimal. In a high TB incidence setting, infants are also at risk of non-maternal household and community transmission. Ensuring maternal TB diagnosis and appropriate treatment, together with adequate TB screening and prevention in all babies born to mothers or households with TB will minimise the risk of infant TB disease development. South African Medical Research Council.

Evaluating the impact of the global evidence, local adaptation (GELA) project for enhancing evidence-informed guideline recommendations for newborn and young child health in three African countries: a mixed-methods protocol

BackgroundPoverty-related diseases (PRD) remain amongst the leading causes of death in children under-5 years in sub-Saharan Africa (SSA). Clinical practice guidelines (CPGs) based on the best available evidence are key to strengthening health systems and helping to enhance equitable health access for children under five. However, the CPG development process is complex and resource-intensive, with substantial scope for improving the process in SSA, which is the goal of the Global Evidence, Local Adaptation (GELA) project. The impact of research on PRD will be maximized through enhancing researchers and decision makers’ capacity to use global research to develop locally relevant CPGs in the field of newborn and child health. The project will be implemented in three SSA countries, Malawi, South Africa and Nigeria, over a 3-year period. This research protocol is for the monitoring and evaluation work package of the project. The aim of this work package is to monitor the various GELA project activities and evaluate the influence these may have on evidence-informed decision-making and guideline adaptation capacities and processes. The specific project activities we will monitor include (1) our ongoing engagement with local stakeholders, (2) their capacity needs and development, (3) their understanding and use of evidence from reviews of qualitative research and, (4) their overall views and experiences of the project.MethodsWe will use a longitudinal, mixed-methods study design, informed by an overarching project Theory of Change. A series of interconnected qualitative and quantitative data collections methods will be used, including knowledge translation tracking sheets and case studies, capacity assessment online surveys, user testing and in-depth interviews, and non-participant observations of project activities. Participants will comprise of project staff, members of the CPG panels and steering committees in Malawi, South Africa and Nigeria, as well as other local stakeholders in these three African countries.DiscussionOngoing monitoring and evaluation will help ensure the relationship between researchers and stakeholders is supported from the project start. This can facilitate achievement of common goals and enable researchers in South Africa, Malawi and Nigeria to make adjustments to project activities to maximize stakeholder engagement and research utilization. Ethical approval has been provided by South African Medical Research Council Human Research Ethics Committee (EC015-7/2022); The College of Medicine Research and Ethics Committee, Malawi (P.07/22/3687); National Health Research Ethics Committee of Nigeria (01/01/2007).

Treatment adherence and clinical outcomes amongst in people with drug-susceptible tuberculosis using medication monitor and differentiated care approach compared with standard of care in South Africa: a cluster randomized trial

Poor treatment adherence contributes to lower treatment completion and higher loss to follow-up among people with tuberculosis (PWTB). Medication monitors have shown some evidence of improved adherence. We conducted a cluster randomised trial in 18 primary health clinics in South Africa between May 2019-February 2022. Persons (aged ≥ 2 years) with drug-sensitive tuberculosis (DS-TB) were enrolled. All participants were provided with monitors which were silent in the standard of care (SoC) arm. In the intevention arm, weekly adherence reports were reviewed and participants received intensified support as appropriate (text, phone call, home visit, motivational counselling). The primary outcome was adherence, which was calculated as days box was opened (proxy for drug taken)/total expected treatment days as a binary variable (<80% versus ≥80%). Analysis took into account clustered design. The trial was registered with the Pan African Trial Registry PACTR20190268115772. We enrolled 2727 participants (38% women, median age 36 (IQR 27-45 years), of whom 2584 had available adherence data. The primary outcome (measured as ≥80% adherence) was higher in intervention versus SoC arm (81.0% versus 50.8%, adjusted risk ratio (ARR) 1.51 (1.36-1.66). Similarly, overall percentage adherence was higher in intervention versus SoC arm (88.5% versus 69.7%, adjusted risk difference 16.8% (13.3%-20.4%)). People with DS-TB had improved treatment adherence in the intervention arm. We believe the effect on adherence is important and warrants continued use and evaluation of these technologies. The study is funded by Bill & Melinda Gates Foundation, Uinted States, the Stop TB Partnership, Switzerland, and the South African Medical Research Council, South Africa.

The nasopharyngeal microbiome in South African children with lower respiratory tract infection: a nested case-control study of the Drakenstein Child Health Study.

Lower respiratory tract infection (LRTI) is a leading cause of infant morbidity and mortality globally. LRTI may be caused by viral or bacterial infections, individually or in combination. We investigated associations between LRTI and infant nasopharyngeal (NP) viruses and bacteria in a South African birth cohort. In a case-control study of infants enrolled in the Drakenstein Child Health Study (DCHS), LRTI cases were identified prospectively and age-matched with controls from the cohort. NP swabs were tested using quantitative real-time polymerase chain reaction (qPCR) and 16S rRNA gene amplicon sequencing. We calculated adjusted Conditional Odds Ratios (aORs) for qPCR targets and used mixed effects models to identify differentially abundant taxa between LRTI cases and controls and explore viral-bacterial interactions. Respiratory Syncytial Virus (RSV) [aOR: 5.69, 95% CI: 3.03-10.69], human rhinovirus (HRV) [1.47, 1.03-2.09], parainfluenza virus [3.46, 1.64-7.26], adenovirus [1.99, 1.08-3.68], enterovirus [2.32, 1.20-4.46], Haemophilus influenzae [1.72, 1.25-2.37], Klebsiella pneumoniae [2.66, 1.59-4.46], or high-density (> 6.9 log10 copies/mL) Streptococcus pneumoniae [1.53, 1.01-2.32] were associated with LRTI. Using 16S sequencing, LRTI was associated with increased relative abundance of Haemophilus (q = 0.0003) and decreased relative abundance of Dolosigranulum (q = 0.001), Corynebacterium (q = 0.091) and Neisseria (q = 0.004). In samples positive for RSV, Staphylococcus and Alloprevotella were present at lower relative abundance in cases than controls. In samples positive for parainfluenza virus or HRV, Haemophilus was present at higher relative abundance in cases. The associations between bacterial taxa and LRTI are strikingly similar to those identified in high-income countries, suggesting a conserved phenotype. RSV was the major virus associated with LRTI. H. influenzae appears to be the major bacterial driver of LRTI, acting synergistically with viruses. The Gram-positive bacteria Dolosigranulum and Corynebacteria may protect against LRTI, while Staphylococcus was associated with reduced risk of RSV-related LRTI. National Institutes of Health of the USA, Bill and Melinda Gates Foundation, National Research Foundation South Africa, South African Medical Research Council, L'Oréal-UNESCO For Women in Science South Africa, Australian National Health and Medical Research Council.

Child abuse and neglect-related murders in South Africa: a comparison of two national surveys in 2009 and 2017

Population-based statistics on deaths from child abuse and neglect are only routinely available in countries that have reliable national statistics on child murder. For low-income and middle-income countries, relatively little is known about prevalence trends of child murder. South Africa is an exception, having conducted dedicated national studies on child murders for 2009 and 2017 to provide data on child murders overall and on child abuse and neglect-related murders. We aimed to compare child abuse and neglect-related murders in South Africa across two surveys to determine any change between 2009 and 2017. We conducted two retrospective national mortuary-based surveys on murder of children aged 0-17 years for 2009 and 2017 from a proportionate random sample of medico-legal laboratories in South Africa. A sampling frame of medico-legal laboratories for each study year was prepared with stratification by medico-legal laboratory size. A minimum of 2 years after the crime was allowed before data collection to enable progression of the investigation process. Child abuse and neglect-related murders were identified using both medico-legal laboratory post-mortem autopsy reports and police data. To identify a child abuse and neglect-related murder, we primarily used the framework of abuse happening within the context of responsibility of care arrangements but broadened this to include all perpetrators and abuse identified from the data. We stratified age into 0-4, 5-9, 10-14, and 15-17 years and further stratified children younger than 5 years into early neonates (newborns killed within 6 days of birth), 7 days to 11 months, and 1-4 years. We calculated incidence rate ratios (IRR) with 95% CIs to compare rates between 2009 and 2017. An estimated 458 (95% CI 377-539) children in 2009 and 213 (179-247) children in 2017 were murdered in circumstances of child abuse and neglect. The percentage of all child murders that were child abuse and neglect-related declined from 2009 to 2017 (458 [45·0%] of 1018 in 2009 vs 213 [25·0%] of 851 in 2017), with the overall age-standardised rate decreasing from 2·6 to 1·1 per 100 000 children aged 0-17 years (IRR 0·43 [95% CI 0·35-0·54]). Girls represented 276 (60·3%) of 458 murders in 2009, which declined to 96 (45·1%) of 213 murders in 2017, and boys represented 178 (38·9%) of 458 murders in 2009 and 109 (51·4%) of 213 murders in 2017. The decrease was statistically significant for girls in the 0-4 year (IRR 0·33 [0·22-0·49]) and 5-9 year (0·33 [0·15-0·73]) age groups and for boys in the 0-4 year age group (0·49 [0·33-0·71]). Among early neonates (within 6 days of birth), the decrease in child abuse and neglect-related murders was more pronounced among girls than among boys (IRR 0·33 [95% CI 0·19-0·56] vs 0·46 [0·28-0·77]). Child abuse and neglect-related murders are common in South Africa but our study shows that they can be reduced. The high rate of these murders points to the need to continue research and monitoring to inform priority targeted interventions and to better understand the impact of child support policies. Ford Foundation and South African Medical Research Council.

Investigating molecular interactions between SARS-CoV-2 spike protein variants and glucose metabolic dysregulation in beta-cells

The severity of COVID-19 disease onset is strongly linked to co-morbidities such as diabetes, with hyperglycemia an independent risk factor for mortality. Additionally, hyperglycemia alters intracellular mechanisms to induce oxidative stress and subsequently dysregulate glucose metabolic pathways such as the hexosamine biosynthetic pathway (HBP) and the formation of advanced glycation end-products (AGEs). The emergence of new-onset hyperglycemia following SARS-CoV-2 infection is a cause for concern. One possible explanation is the direct infection of the pancreas leading to damage of β-cells. Binding of SARS-CoV-2 spike (S)-protein to its primary receptor, ACE2, can be enhanced via glycosylation and/or glycation of the receptor, rendering it more susceptible to S-protein interactions. The interplay between hyperglycemia and SARS-CoV-2 infection, however, remains to be fully elucidated. The primary objective of this study is therefore to investigate the effects of hyperglycemia and SARS-CoV-2 binding on pancreatic β-cells. More specifically, we aim to determine the role(s) of AGE production and HBP-mediated O-GlcNAcylation in modulation of SARS-CoV-2 entry and accessory proteins, S-protein binding, and downstream molecular effects in cultured INS-1 β-cells under hyperglycemic conditions. We hypothesize that hyperglycemia primes host cells for SARS-CoV-2 S-protein variants via glycation (AGE) and O-GlcNAcylation (HBP) pathways to promote binding to INS-1 β-cells. INS-1 cells were exposed to 1) high glucose, glucosamine (increases HBP), and methylglyoxal (AGE precursor) and 2) recombinant S-protein (Wild type, β and δ-variants) in separate experiments. Metabolic activity (WST-1 assays) and Western blot analyses were performed to assess markers of mitochondrial oxidative phosphorylation, the AGE (RAGE) and HBP (OGT and O-GlcNAc), SARS-CoV-2 entry (ACE2, DPP4, Basigin, EEA1, VCP) and accessory proteins (TMPRSS2, ADAM10, ADAM17, Cathepsin B, CD13). Glucose-stimulated insulin response was determined using an insulin ELISA. Metabolic activity was increased by high glucose (p&lt;0.0001), glucosamine (p&lt;0.0001) and methylglyoxal (p&lt;0.05) versus controls. Recombinant S-protein variants increased metabolic activity in a time, concentration and variant-dependent manner. Here, the lower (10 ng/ml) concentration showed a &gt;4-fold increase for the β- and δ-variants (p&lt;0.0001 versus control, respectively), while the wild type had a similar response with higher concentrations (100 and 1000 ng/ml). The endosomal protein EEA1 was significantly increased (p&lt;0.05 versus control) in response to AGE modulation. We conclude that hyperglycemia and modulation of the HBP and AGE pathways exert differential β-cell metabolic effects and AGE induction may prime endosomal entry mechanisms for SARS-CoV-2 spike protein. The spike variants significantly stimulate metabolic activity, modulating β-cell function in an acute manner. This project is funded by the National Research Foundation (NRF) of South Africa and the South African Medical Research Council (SAMRC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Navigating ethical challenges of integrating genomic medicine into clinical practice: Maximising beneficence in precision oncology

The development of gene expression profiling and next-generation sequencing technologies have steered oncogenomics to the forefront of precision medicine. This created a need for harmonious cooperation between clinicians and researchers to increase access to precision oncology, despite multiple implementation challenges being encountered. The aim is to apply personalised treatment strategies early in cancer management, targeting tumour subtypes and actionable gene variants within the individual’s broader clinical risk profile and wellbeing. A knowledge-generating database linked to the South African Medical Research Council’s Genomic Centre has been created for the application of personalised medicine, using an integrated service and research approach. Insights gained from patient experiences related to tumour heterogeneity, access to targeted therapies and incidental findings of pathogenic germline variants in tumour DNA, provided practice-changing evidence for the implementation of a cost-minimisation pathology-supported genetic testing strategy. Integrating clinical care with genomic research through data sharing advances personalised medicine and maximises precision oncology benefits.

Research ethics and artificial intelligence for global health: perspectives from the global forum on bioethics in research

BackgroundThe ethical governance of Artificial Intelligence (AI) in health care and public health continues to be an urgent issue for attention in policy, research, and practice. In this paper we report on central themes related to challenges and strategies for promoting ethics in research involving AI in global health, arising from the Global Forum on Bioethics in Research (GFBR), held in Cape Town, South Africa in November 2022.MethodsThe GFBR is an annual meeting organized by the World Health Organization and supported by the Wellcome Trust, the US National Institutes of Health, the UK Medical Research Council (MRC) and the South African MRC. The forum aims to bring together ethicists, researchers, policymakers, research ethics committee members and other actors to engage with challenges and opportunities specifically related to research ethics. In 2022 the focus of the GFBR was “Ethics of AI in Global Health Research”. The forum consisted of 6 case study presentations, 16 governance presentations, and a series of small group and large group discussions. A total of 87 participants attended the forum from 31 countries around the world, representing disciplines of bioethics, AI, health policy, health professional practice, research funding, and bioinformatics. In this paper, we highlight central insights arising from GFBR 2022.ResultsWe describe the significance of four thematic insights arising from the forum: (1) Appropriateness of building AI, (2) Transferability of AI systems, (3) Accountability for AI decision-making and outcomes, and (4) Individual consent. We then describe eight recommendations for governance leaders to enhance the ethical governance of AI in global health research, addressing issues such as AI impact assessments, environmental values, and fair partnerships.ConclusionsThe 2022 Global Forum on Bioethics in Research illustrated several innovations in ethical governance of AI for global health research, as well as several areas in need of urgent attention internationally. This summary is intended to inform international and domestic efforts to strengthen research ethics and support the evolution of governance leadership to meet the demands of AI in global health research.

Determinants of lung function development from birth to age 5 years: an interrupted time series analysis of a South African birth cohort

Early life is a key period that determines long-term health. Lung development in childhood predicts lung function attained in adulthood and morbidity and mortality across the life course. We aimed to assess the effect of early-life lower respiratory tract infection (LRTI) and associated risk factors on lung development from birth to school age in a South African birth cohort. We prospectively followed children enrolled in a population-based cohort from birth (between March 5, 2012 and March 31, 2015) to age 5 years with annual lung function assessment. Data on multiple early-life exposures, including LRTI, were collected. The effect of early-life risk factors on lung function development from birth to age 5 years was assessed using the Generalised Additive Models for Location, Scale and Shape and Interrupted Time Series approach. 966 children (475 [49·2%] female, 491 [50·8%] male) had lung function measured with oscillometry, tidal flow volume loops, and multiple breath washout. LRTI occurred in 484 (50·1%) children, with a median of 2·0 LRTI episodes (IQR 1·0-3·0) per child. LRTI was independently associated with altered lung function, as evidenced by lower compliance (0·959 [95% CI 0·941-0·978]), higher resistance (1·028 [1·016-1·041]), and higher respiratory rate (1·018 [1·063-1·029]) over 5 years. Additional impact on lung function parameters occurred with each subsequent LRTI. Respiratory syncytial virus (RSV) LRTI was associated with lower expiratory flow ratio (0·97 [0·95-0·99]) compared with non-RSV LRTI. Maternal factors including allergy, smoking, and HIV infection were also associated with altered lung development, as was preterm birth, low birthweight, female sex, and coming from a less wealthy household. Public health interventions targeting LRTI prevention, with RSV a priority, are vital, particularly in low-income and middle-income settings. UK Medical Research Council Grant, The Wellcome Trust, The Bill & Melinda Gates Foundation, US National Institutes of Health Human Heredity and Health in Africa, South African Medical Research Council, Hungarian Scientific Research Fund, and European Respiratory Society.

Blood RNA biomarkers for tuberculosis screening in people living with HIV before antiretroviral therapy initiation: a diagnostic accuracy study

Undiagnosed tuberculosis remains a major threat for people living with HIV. Multiple blood transcriptomic biomarkers have shown promise for tuberculosis diagnosis. We sought to evaluate their diagnostic accuracy and clinical utility for systematic pre-antiretroviral therapy (ART) tuberculosis screening. We enrolled consecutive adults (age ≥18 years) referred to start ART at a community health centre in Cape Town, South Africa, irrespective of symptoms. Sputa were obtained (using induction if required) for two liquid cultures. Whole-blood RNA samples underwent transcriptional profiling using a custom Nanostring gene panel. We measured the diagnostic accuracy of seven candidate RNA signatures (one single gene biomarker [BATF2] and six multigene biomarkers) for the reference standard of Mycobacterium tuberculosis culture status, using area under the receiver-operating characteristic curve (AUROC) analysis, and sensitivity and specificity at prespecified thresholds (two standard scores above the mean of healthy controls; Z2). Clinical utility was assessed by calculating net benefit in decision curve analysis. We compared performance with C-reactive protein (CRP; threshold ≥5 mg/L), WHO four-symptom screen (W4SS), and the WHO target product profile for tuberculosis triage tests. A total of 707 people living with HIV (407 [58%] female and 300 [42%] male) were included, with median CD4 count 306 cells per mm3 (IQR 184-486). Of 676 participants with available sputum culture results, 89 (13%) had culture-confirmed tuberculosis. The seven RNA signatures were moderately to highly correlated (Spearman rank coefficients 0·42-0·93) and discriminated tuberculosis culture positivity with similar AUROCs (0·73-0·80), but none statistically better than CRP (AUROC 0·78, 95% CI 0·72-0·83). Diagnostic accuracy was similar across CD4 count strata, but lower among participants with negative W4SS (AUROCs 0·56-0·65) compared with positive (AUROCs 0·75-0·84). The RNA biomarker with the highest AUROC point estimate was a four-gene signature (Suliman4; AUROC 0·80, 95% CI 0·75-0·86), with sensitivity 83% (95% CI 74-90) and specificity 59% (55-63) at the Z2 threshold. In decision curve analysis, Suliman4 and CRP had similar clinical utility to guide confirmatory tuberculosis testing, but both had higher net benefit than W4SS. In exploratory analyses, an approach combining CRP (≥5 mg/L) and Suliman4 (≥Z2) had sensitivity of 80% (70-87), specificity of 70% (66-74), and higher net benefit than either biomarker alone. RNA biomarkers showed better clinical utility to guide confirmatory tuberculosis testing for people living with HIV before ART initiation than symptom-based screening, but their performance did not exceed that of CRP and fell short of WHO recommended targets. Interferon-independent approaches might be required to improve accuracy of host-response biomarkers to support tuberculosis screening before ART initiation. South African Medical Research Council, European and Developing Countries Clinical Trials Partnership 2, National Institutes of Health National Institute of Allergy and Infectious Diseases, The Wellcome Trust, National Institute for Health and Care Research, Royal College of Physicians London.

Point-of-care C-reactive protein and Xpert MTB/RIF Ultra for tuberculosis screening and diagnosis in unselected antiretroviral therapy initiators: a prospective, cross-sectional, diagnostic accuracy study

Tuberculosis, a major cause of death in people living with HIV, remains challenging to diagnose. Diagnostic accuracy data are scarce for promising triage and confirmatory tests such as C-reactive protein (CRP), sputum and urine Xpert MTB/RIF Ultra (Xpert Ultra), and urine Determine TB LAM Ag (a lateral flow lipoarabinomannan [LF-LAM] test), without symptom selection. We evaluated novel triage and confirmatory tests in ambulatory people with HIV initiating antiretroviral therapy (ART). 897 ART-initiators were recruited irrespective of symptoms and sputum induction offered. For triage (n=800), we evaluated point-of-care blood-based CRP testing, compared with the WHO-recommended four-symptom screen (W4SS). For sputum-based confirmatory testing (n=787), we evaluated Xpert Ultra versus Xpert MTB/RIF (Xpert). For urine-based confirmatory testing (n=732), we evaluated Xpert Ultra and LF-LAM. We used a sputum culture reference standard. 463 (52%) of 897 participants were female. The areas under the receiver operator characteristic curves for CRP was 0·78 (95% CI 0·73-0·83) and for number of W4SS symptoms was 0·70 (0·64-0·75). CRP (≥10 mg/L) had similar sensitivity to W4SS (77% [95% CI 68-85; 80/104] vs 77% [68-85; 80/104]; p>0·99] but higher specificity (64% [61-68; 445/696] vs 48% [45-52; 334/696]; p<0·0001]; reducing unnecessary confirmatory testing by 138 (95% CI 117-160) per 1000 people and number-needed-to-test from 6·91 (95% CI 6·25-7·81) to 4·87 (4·41-5·51). Sputum samples with Xpert Ultra, which required induction in 49 (31%) of 158 of people (95% CI 24-39), had higher sensitivity than Xpert (71% [95% CI 61-80; 74/104] vs 56% [46-66; 58/104]; p<0·0001). Of the people with one or more confirmatory sputum or urine test results that were positive, the proportion detected by Xpert Ultra increased from 45% (26-64) to 66% (46-82) with induction. Programmatically done haemoglobin, triage test combinations, and urine tests showed comparatively worse results. CRP is a more specific triage test than W4SS in those initiating ART. Sputum induction improves diagnostic yield. Sputum samples with Xpert Ultra is a more accurate confirmatory test than with Xpert. South African Medical Research Council, EDCTP2, US National Institutes of Health-National Institute of Allergy and Infectious Diseases.

1498. Geographic differences in weight change on dolutegravir: a prospective cohort study

Abstract Background People with HIV (PWH) on integrase inhibitors may be at increased risk of excess weight gain, but it is unclear if this risk is consistent across settings. Our study objective was to compare weight change over 48 weeks among PWH in Uganda and South Africa.Figure 1.Mean weight change (kg) over 48 weeks among DISCO participants overall (A), among men (B), and among women (C). Methods The Population Effectiveness of Dolutegravir Implementation in Sub-Saharan Africa (DISCO) study is a prospective observational cohort of PWH in routine clinical care at public-sector HIV clinics in Uganda and South Africa. Inclusion criteria were as follows: PWH &amp;gt;18 years old, on NNRTI-based first-line ART for &amp;gt;6 months, and switched to tenofovir disoproxil fumarate, lamivudine, and dolutegravir) by clinic staff. We measured the primary outcomes of weight (in kilograms [kg]) and waist circumference (WC, in centimeters [cm]) at enrollment, 24 weeks, and 48 weeks after switch. The primary outcomes were (1) weight change (kg) and (2) change in WC (cm). We used a linear mixed-effect regression model, adjusted for age, sex, education, duration on ART, and the interaction of study site and visit, to estimate weight. Results 428 individuals in Uganda and 387 in South Africa had data available. The mean weight change over 48 weeks was 0.6 kg [95% CI: 0.1-1.0] in Uganda compared to 2.9 kg [2.4-3.4] in South Africa (p&amp;lt; 0.001); men had significantly smaller mean weight changes than women did in both countries (Figure 1). After adjustment, PWH in South Africa gained significantly more weight than those in Uganda. In participants with available waist data (277 in Uganda and 402 in South Africa), the mean change in WC was significantly greater among those in South Africa (2.3 cm [1.4-3.2]) than those in Uganda (0.8 cm [0.0-1.5]) (p&amp;lt; 0.017). Conclusion PWH in South Africa experienced greater weight gain than in Uganda, suggesting substantial heterogeneity in this risk across settings. Strategies to address obesity risk in PWH should account for regionality. Disclosures W D Francois Venter, MD, FCP, PhD, Gilead Sciences: Grant/Research Support|South African Medical Research Council: Grant/Research Support|Unitaid: Grant/Research Support|USAID: Grant/Research Support|ViiV Healthcare: Grant/Research Support Mark J Siedner, MD, MPH, Viiv Healthcare: Grant/Research Support

Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study

Bedaquiline is a life-saving tuberculosis drug undergoing global scale-up. People at risk of weak tuberculosis drug regimens are a priority for novel drug access despite the potential source of Mycobacterium tuberculosis-resistant strains. We aimed to characterise bedaquiline resistance in individuals who had sustained culture positivity during bedaquiline-based treatment. We did a retrospective longitudinal cohort study of adults (aged ≥18 years) with culture-positive pulmonary tuberculosis who received at least 4 months of a bedaquiline-containing regimen from 12 drug-resistant tuberculosis treatment facilities in Cape Town, South Africa, between Jan 20, 2016, and Nov 20, 2017. Sputum was programmatically collected at baseline (ie, before bedaquiline initiation) and each month to monitor treatment response per the national algorithm. The last available isolate from the sputum collected at or after 4 months of bedaquiline was designated the follow-up isolate. Phenotypic drug susceptibility testing for bedaquiline was done on baseline and follow-up isolates in MGIT960 media (WHO-recommended critical concentration of 1 μg/mL). Targeted deep sequencing for Rv0678, atpE, and pepQ, as well as whole-genome sequencing were also done. In total, 40 (31%) of 129 patients from an estimated pool were eligible for this study. Overall, three (8%) of 38 patients assessable by phenotypic drug susceptibility testing for bedaquiline had primary resistance, 18 (47%) gained resistance (acquired or reinfection), and 17 (45%) were susceptible at both baseline and follow-up. Several Rv0678 and pepQ single-nucleotide polymorphisms and indels were associated with resistance. Although variants occurred in Rv0676c and Rv1979c, these variants were not associated with resistance. Targeted deep sequencing detected low-level variants undetected by whole-genome sequencing; however, none were in genes without variants already detected by whole-genome sequencing. Patients with baseline fluoroquinolone resistance, clofazimine exposure, and four or less effective drugs were more likely to have bedaquiline-resistant gain. Resistance gain was primarily due to acquisition; however, some reinfection by resistant strains occurred. Bedaquiline-resistance gain, for which we identified risk factors, was common in these programmatically treated patients with sustained culture positivity. Our study highlights risks associated with implementing life-saving new drugs and shows evidence of bedaquiline-resistance transmission. Routine drug susceptibility testing should urgently accompany scale-up of new drugs; however, rapid drug susceptibility testing for bedaquiline remains challenging given the diversity of variants observed. Doris Duke Charitable Foundation, US National Institute of Allergy and Infectious Diseases, South African Medical Research Council, National Research Foundation, Research Foundation Flanders, Stellenbosch University Faculty of Medicine Health Sciences, South African National Research Foundation, Swiss National Science Foundation, and Wellcome Trust.

Alcohol policy framing in South Africa during the early stages of COVID-19: using extraordinary times to make an argument for a new normal

IntroductionPublic health and alcohol industry actors compete to frame alcohol policy problems and solutions. Little is known about how sudden shifts in the political context provide moments for policy actors to re-frame alcohol-related issues. South Africa’s temporary bans on alcohol sales during the COVID-19 pandemic offered an opportunity to study this phenomenon.MethodsWe identified Professor Charles Parry from the South African Medical Research Council as a key policy actor. Parry uses a Twitter account primarily to comment on alcohol-related issues in South Africa. We harvested his tweets posted from March 18 to August 31, 2020, coinciding with the first two alcohol sales bans. We conducted a thematic analysis of the tweets to understand how Parry framed alcohol policy evidence and issues during these ‘extraordinary times.’ResultsParry underlined the extent of alcohol-related harm during ‘normal times’ with scientific evidence and contested industry actors’ efforts to re-frame relevant evidence in a coherent and well-constructed argument. Parry used the temporary sales restrictions to highlight the magnitude of the health and social harms resulting from alcohol consumption, particularly trauma, rather than the COVID-19 transmission risks. Parry portrayed the sales ban as a policy learning opportunity (or ‘experiment’) for South Africa and beyond.ConclusionsCrisis conditions can provide new openings for public health (and industry) actors to make salient particular features of alcohol and alcohol policy evidence.

The met and unmet health needs for HIV, hypertension, and diabetes in rural KwaZulu-Natal, South Africa: analysis of a cross-sectional multimorbidity survey

The convergence of infectious diseases and non-communicable diseases in South Africa is challenging to health systems. In this analysis, we assessed the multimorbidity health needs of individuals and communities in rural KwaZulu-Natal and established a framework to quantify met and unmet health needs for individuals living with infectious and non-communicable diseases. We analysed data collected between May 25, 2018, and March 13, 2020, from participants of a large, community-based, cross-sectional multimorbidity survey (Vukuzazi) that offered community-based HIV, hypertension, and diabetes screening to all residents aged 15 years or older in a surveillance area in the uMkhanyakude district in KwaZulu-Natal, South Africa. Data from the Vukuzazi survey were linked with data from demographic and health surveillance surveys with a unique identifier common to both studies. Questionnaires were used to assess the diagnosed health conditions, treatment history, general health, and sociodemographic characteristics of an individual. For each condition (ie, HIV, hypertension, and diabetes), individuals were defined as having no health needs (absence of condition), met health needs (condition that is well controlled), or one or more unmet health needs (including diagnosis, engagement in care, or treatment optimisation). We analysed met and unmet health needs for individual and combined conditions and investigated their geospatial distribution. Of 18 041 participants who completed the survey (12 229 [67·8%] were female and 5812 [32·2%] were male), 9898 (54·9%) had at least one of the three chronic diseases measured. 4942 (49·9%) of these 9898 individuals had at least one unmet health need (1802 [18·2%] of 9898 needed treatment optimisation, 1282 [13·0%] needed engagement in care, and 1858 [18·8%] needed a diagnosis). Unmet health needs varied by disease; 1617 (93·1%) of 1737 people who screened positive for diabetes, 2681 (58·2%) of 4603 people who screened positive for hypertension, and 1321 (21·7%) of 6096 people who screened positive for HIV had unmet health needs. Geospatially, met health needs for HIV were widely distributed and unmet health needs for all three conditions had specific sites of concentration; all three conditions had an overlapping geographical pattern for the need for diagnosis. Although people living with HIV predominantly have a well controlled condition, there is a high burden of unmet health needs for people living with hypertension and diabetes. In South Africa, adapting current, widely available HIV care services to integrate non-communicable disease care is of high priority. Fogarty International Center and the National Institutes of Health, the Bill & Melinda Gates Foundation, the South African Department of Science and Innovation, the South African Medical Research Council, the South African Population Research Infrastructure Network, and the Wellcome Trust. For the isiZulu translation of the abstract see Supplementary Materials section.

Safety of COVID-19 booster dose: is the juice worth the squeeze?

Safety of COVID-19 booster dose: is the juice worth the squeeze?

Effect of compensatory evolution in the emergence and transmission of rifampicin-resistant Mycobacterium tuberculosis in Cape Town, South Africa: a genomic epidemiology study

Experimental data show that drug-resistance-conferring mutations are often associated with a decrease in the replicative fitness of bacteria in vitro, and that this fitness cost can be mitigated by compensatory mutations; however, the role of compensatory evolution in clinical settings is less clear. We assessed whether compensatory evolution was associated with increased transmission of rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa. We did a genomic epidemiological study by analysing available M tuberculosis isolates and their associated clinical data from individuals routinely diagnosed with rifampicin-resistant tuberculosis in primary care and hospitals in Khayelitsha, Cape Town, South Africa. Isolates were collected as part of a previous study. All individuals diagnosed with rifampicin-resistant tuberculosis and with linked biobanked specimens were included in this study. We applied whole-genome sequencing, Bayesian reconstruction of transmission trees, and phylogenetic multivariable regression analysis to identify individual and bacterial factors associated with the transmission of rifampicin-resistant M tuberculosis strains. Between Jan 1, 2008, and Dec 31, 2017, 2161 individuals were diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa. Whole-genome sequences were available for 1168 (54%) unique individual M tuberculosis isolates. Compensatory evolution was associated with smear-positive pulmonary disease (adjusted odds ratio 1·49, 95% CI 1·08-2·06) and a higher number of drug-resistance-conferring mutations (incidence rate ratio 1·38, 95% CI 1·28-1·48). Compensatory evolution was also associated with increased transmission of rifampicin-resistant disease between individuals (adjusted odds ratio 1·55; 95% CI 1·13-2·12), independent of other patient and bacterial factors. Our findings suggest that compensatory evolution enhances the in vivo fitness of drug-resistant M tuberculosis genotypes, both within and between patients, and that the in vitro replicative fitness of rifampicin-resistant M tuberculosis measured in the laboratory correlates with the bacterial fitness measured in clinical settings. These results emphasise the importance of enhancing surveillance and monitoring efforts to prevent the emergence of highly transmissible clones capable of rapidly accumulating new drug resistance mutations. This concern becomes especially crucial at present, because treatment regimens incorporating novel drugs are being implemented. Funding for this study was provided by a Swiss and South Africa joint research award (grant numbers 310030_188888, CRSII5_177163, and IZLSZ3_170834), the European Research Council (grant number 883582), and a Wellcome Trust fellowship (to HC; reference number 099818/Z/12/Z). ZS-D was funded through a PhD scholarship from the South African National Research Foundation and RMW was funded through the South African Medical Research Council.

An intergenerational life-course approach to address early childhood obesity and adiposity: the Healthy Life Trajectories Initiative (HeLTI)

BackgroundInteractions between genes and early-life exposures during conception, fetal life, infancy, and early childhood have been shown to affect an individual's health later in life. Maternal undernutrition and obesity, gestational diabetes, and impaired growth in utero and in early life are associated with adiposity and overweight and obesity in childhood, which are risk factors for poor health trajectories and non-communicable diseases. In Canada, China, India, and South Africa, 10–30% of children aged 5–16 years are overweight or obese. MethodsThe application of developmental origins of health and disease principles offers a novel approach to prevention of overweight and obesity and reduction of adiposity by delivering integrated interventions across the life course, starting before conception and continuing through early childhood. The Healthy Life Trajectories Initiative (HeLTI) was established in 2017 through a unique collaboration between national funding agencies in Canada, China, India, South Africa, and WHO. The aim of HeLTI is to evaluate the effect of an integrated four-phase intervention starting preconceptionally and continuing through pregnancy, infancy, and early childhood on reducing childhood adiposity (fat mass index) and overweight and obesity, and optimising early child development, nutrition, and other healthy behaviours. FindingsApproximately 22 000 women are being recruited in Shanghai (China), Mysore (India), Soweto (South Africa), and across various provinces of Canada. Women who conceive (an expected 10 000) and their children will be followed up until the child reaches the age of 5 years. InterpretationHeLTI has harmonised the intervention, measures, tools, biospecimen collection, and analysis plans for the trial to be run across four countries. HeLTI will help establish whether an intervention aimed at addressing maternal health behaviours, nutrition, and weight; providing psychosocial support to reduce maternal stress and prevent mental illness; optimising infant nutrition, physical activity, and sleep; and promoting parenting skills can reduce the intergenerational risk of excess childhood adiposity and overweight and obesity across diverse settings. FundingCanadian Institutes of Health Research; National Science Foundation of China; Department of Biotechnology, India; and South African Medical Research Council.