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Introduction The TriAD study will assess the Xpert MTB/XDR (Xpert XDR; Cepheid) assay to detect tuberculosis (TB) drug resistance in sputum testing positive for TB to rapidly triage and treat patients with a short all-oral treatment regimen.Methods and analysis In this study, approximately 4800 Xpert MTB/RIF or Ultra MTB-positive patients (irrespective of rifampicin (RIF) resistance (RR) status) from several clinical sites across South Africa, Nigeria and Ethiopia will be enrolled over 18–24 months and followed-up for approximately 6 months post-TB treatment completion. Participants will be enrolled into one of two cohorts based on Xpert MTB/RIF and Xpert XDR results: Mycobacterium tuberculosis (M.tb) positive participants with RR in Cohort 1 (n=880) and M.tb positive RIF susceptible TB patients with isoniazid mono-resistance irrespective of presence of resistance to fluoroquinolones, second-line injectable drugs or ethionamide in Cohort 2 (n=400). Cohort 1 will be compared with historical cohorts from each implementing sites. The primary study outcomes include time to initiation of an appropriate treatment regimen by resistance profile and the proportion of patients with favourable treatment outcomes compared with historical cohorts from each of the implementing sites. Secondary outcomes include feasibility, acceptability and cost-effectiveness of this approach to inform policies and guidelines for programmatic implementation of this triage and treat model for drug-resistant tuberculosis management. Utility of the tuberculosis molecular bacterial load assay (TB-MBLA) for real-time treatment response assessment will also be evaluated.Ethics and dissemination The University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and local research committees have provided ethical review and approval (BREC/00002654/2021, HREC 210805, NHREC/01/01/2007 and EPHI-IRB-459–2022). The South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval for the TRiAD Study (SAHPRA MD20211001). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry.Trial registration number Clinicaltrials.gov; Trial registration number: NCT05175794; South African National Clinical Trials Register (SANCTR DOH-27-012022-4720)

Abstract Background Highly effective, short-course, bedaquiline-containing treatment regimens for multidrug-resistant tuberculosis (MDR-TB) and integrase strand transfer inhibitor (INSTI)-containing fixed dose combination antiretroviral therapy (ART) have radically transformed treatment for MDR-TB and HIV. However, without advances in adherence support, we may not realize the full potential of these therapeutics. The primary objective of this study is to compare the effect of adherence support interventions on clinical and biological endpoints using an adaptive randomized platform. Methods This is a prospective, adaptive, randomized controlled trial comparing the effectiveness of four adherence support strategies on a composite clinical outcome in adults with MDR-TB and HIV initiating bedaquiline-containing MDR-TB treatment regimens and receiving ART in KwaZulu-Natal, South Africa. Trial arms include (1) enhanced standard of care, (2) psychosocial support, (3) mHealth using cellular-enabled electronic dose monitoring, and (4) combined mHealth and psychosocial support. The level of support will be titrated using a differentiated service delivery (DSD)-informed assessment of treatment support needs. The composite primary outcome will include survival, negative TB culture, retention in care, and undetectable HIV viral load at month 12. Secondary outcomes will include individual components of the primary outcome and quantitative evaluation of adherence on TB and HIV treatment outcomes. Discussion This trial will evaluate the contribution of different modes of adherence support on MDR-TB and HIV outcomes with WHO-recommended all-oral MDR-TB regimens and ART in a high-burden operational setting. We will also assess the utility of a DSD framework to pragmatically adjust levels of MDR-TB and HIV treatment support. Trial registration ClinicalTrials.gov NCT05633056. Registered on 1 December 2022

Abstract Background Lung cavitation is associated with heightened TB transmission and poor treatment outcomes. This study aimed to determine the relationship between systemic inflammation and lung cavitation in drug-resistant TB patients with and without HIV co-infection. Methods Plasma samples were obtained from 128 participants from the CAPRISA 020 Individualized M(X)drug-resistant TB Treatment Strategy Study (InDEX) prior to treatment initiation. Lung cavitation was present in 61 of the 128 drug-resistant TB patients with 93 being co-infected with HIV. The plasma cytokine and chemokine levels were measured using the 27-Plex Human Cytokine immunoassay. Modified Poisson regression models were used to determine the association between plasma cytokine/chemokine expression and lung cavitation in individuals with drug-resistant TB. Results Higher Interleukin-6 plasma levels (adjusted risk ratio [aRR] 1.405, 95% confidence interval [CI] 1.079–1.829, p = 0.011) were associated with a higher risk of lung cavitation in the multivariable model adjusting for age, sex, body mass index, HIV status, smoking and previous history of TB. Smoking was associated with an increased risk of lung cavitation (aRR 1.784, 95% CI 1.167–2.729, p = 0.008). An HIV positive status and a higher body mass index, were associated with reduced risk of lung cavitation (aRR 0.537, 95% CI 0.371–0.775, p = 0.001 and aRR 0.927, 95% CI 0.874–0.983, p = 0.012 respectively). Conclusion High plasma interleukin-6 levels are associated with an increased risk of cavitary TB highlighting the role of interleukin-6 in the immunopathology of drug-resistant TB.

Abstract Natural killer (NK) cells, key effector cells of the innate immune system, play an important role in the clearance and control of Mycobacterium tuberculosis and HIV infections. Here, we utilized peripheral blood specimens from the Improving Retreatment Success CAPRISA 011 study to characterize NK cell phenotypes during active TB in individuals with or without HIV co-infection. We further assessed the effects of TB treatment on NK cell phenotype, and characterized the effects of NK cell phenotypes during active TB on mycobacterial clearance and TB disease severity measured by the presence of lung cavitation. TB/HIV co-infection led to the expansion of functionally impaired CD56neg NK cell subset. TB treatment completion resulted in restoration of total NK cells, NK cell subset redistribution and downregulation of several NK cell activating and inhibitory receptors. Higher percentage of peripheral CD56bright cells was associated with longer time to culture conversion, while higher expression of NKp46 on CD56dim NK cells was associated with lower odds of lung cavitation in the overall cohort and the TB/HIV co-infected participants. Together these results provide a detailed description of peripheral NK cells in TB and TB/HIV co-infection and yield insights into their role in TB disease pathology.

Background: High-dose isoniazid is recommended in the 9–12 months short-course regimen for multidrug-resistant tuberculosis with inhA mutation. However, there is insufficient evidence to support the assumption of genotypic-phenotypic concordance. This study aimed to identify the genetic mutations associated with high-level phenotypic isoniazid resistance. Methods: Clinical isolates from patients with drug-resistant tuberculosis were profiled by whole-genome sequencing and subjected to minimum inhibitory concentration (MIC) testing using MGIT based-method. MICs were performed in concentration ranges based on the mutation present: isolates with no isoniazid resistance-conferring mutations and H37Rv, 0.016–0.256 µg/ml; inhA, 0.256–4.0 µg/ml, katG 1.0–16.0 µg/ml; and inhA + katG, 4.0–64.0 µg/ml. Isolates demonstrating resistance at the upper limit of the concentration range were tested up to the maximum of 64.0 µg/ml. Bootstrap of the mean MICs was performed to increase the robustness of the estimates and an overlap index was used to compare the distributions of the MICs for each mutation profile. Results: A total of 52 clinical isolates were included in this analysis. Bootstrap MIC means for inhA, katG and inhA + katG were 33.64 (95% CI, 9.47, 56.90), 6.79 (4.45, 9.70) and 52.34 (42.750, 61.66) µg/ml, respectively. There was high overlap between inhA and inhA + katG mutations (eta = 0.45) but not with inhA and katG (eta = 0.19). Furthermore, katG showed poor overlap with inhA + katG mutations (eta = 0.09). Unexpectedly, 4/8 (50.0%) of all InhA mutants demonstrated high-level resistance, while 20/24 (83.3%) of katG mutants demonstrated moderate-level resistance. Conclusions: InhA mutations demonstrated unexpectedly high MICs and showed high overlap with inhA + katG. Contrary to the common belief that katG mutants are associated with high-level resistance, this mutation primarily showed moderate-level resistance.

ABSTRACT: Objectives: The study aimed to describe the prevalence of and risk factors for post-COVID-19 condition (PCC). Methods: This was a prospective, longitudinal observational cohort study. Hospitalized and nonhospitalized adults were randomly selected to undergo telephone assessment at 1, 3, and 6 months. Participants were assessed using a standardized questionnaire for the evaluation of symptoms and health-related quality of life. We used negative binomial regression models to determine factors associated with the presence of ≥1 symptoms at 6 months. Results: A total of 46.7% of hospitalized and 18.5% of nonhospitalized participants experienced ≥1 symptoms at 6 months (P ≤0.001). Among hospitalized people living with HIV, 40.4% had persistent symptoms compared with 47.1% among participants without HIV (P = 0.108). The risk factors for PCC included older age, female sex, non-Black race, presence of a comorbidity, greater number of acute COVID-19 symptoms, hospitalization/COVID-19 severity, and wave period (lower risk of persistent symptoms for the Omicron compared with the Beta wave). There were no associations between self-reported vaccination status with persistent symptoms. Conclusion: The study revealed a high prevalence of persistent symptoms among South African participants at 6 months but decreased risk for PCC among participants infected during the Omicron BA.1 wave. These findings have serious implications for countries with resource-constrained health care systems.

Objectives: Critically ill patients with tuberculosis (TB) face a high mortality risk and require effective treatment. There is a paucity of data on rifampicin pharmacokinetics, the impact of continuous enteral feeding on drug absorption, and the potential of therapeutic drug monitoring (TDM) to optimize drug exposure in these patients. Methods: We performed a sequential pharmacokinetic study to determine the impact of feeding and TDM with rifampicin dose escalation in critically ill patients with TB. Noncompartmental pharmacokinetic analysis was performed. Results: Among 20 critically ill patients (40% were HIV-infected), median rifampicin Cmax (maximum serum concentration) in the fasted and fed states were 5.1 µg/ml versus 3.3 µg/ml, respectively (P

Summary: As COVID-19 evolves from a pandemic to an endemic disease, the already staggering number of people that have been or will be infected with SARS-CoV-2 is only destined to increase, and the majority of humanity will be infected. It is well understood that COVID-19, like many other viral infections, leaves a significant fraction of the infected with prolonged consequences. Continued high number of SARS-CoV-2 infections, viral evolution with escape from post-infection and vaccinal immunity, and reinfections heighten the potential impact of Long COVID. Hence, the impact of COVID-19 on human health will be seen for years to come until more effective vaccines and pharmaceutical treatments become available. To that effect, it is imperative that the mechanisms underlying the clinical manifestations of Long COVID be elucidated. In this article, we provide an in-depth analysis of the evidence on several potential mechanisms of Long COVID and discuss their relevance to its pathogenesis.

Long COVID is an emerging public health threat, following swiftly behind the surges of acute infection over the course of the COVID-19 pandemic. It is estimated that there are already approximately 100 million people suffering from Long COVID globally, 0.5 million of whom are South African, and for whom our incomplete understanding of the condition has forestalled appropriate diagnosis and clinical care. There are several leading postulates for the complex, multi-mechanistic pathogenesis of Long COVID. Patients with Long COVID may present with a diversity of clinical phenotypes, often with significant overlap, which may exhibit temporal heterogeneity and evolution. Post-acute care follow-up, targeted screening, diagnosis, a broad initial assessment and more directed subsequent assessments are necessary at the primary care level. Symptomatic treatment, self-management and rehabilitation are the mainstays of clinical care for Long COVID. However, evidence-based pharmacological interventions for the prevention and treatment of Long COVID are beginning to emerge. This article presents a rational approach for assessing and managing patients with Long COVID in the primary care setting.

Global tuberculosis (TB) eradication is undermined by increasing prevalence of emerging resistance to available drugs, fuelling ongoing demand for more complex diagnostic and treatment strategies. Early detection of TB drug resistance coupled with therapeutic decision making guided by rapid characterisation of pre-treatment and treatment emergent resistance remains the most effective strategy for averting Drug-Resistant TB (DR-TB) transmission, reducing DR-TB associated mortality, and improving patient outcomes. Solid- and liquid-based mycobacterial culture methods remain the gold standard for Mycobacterium tuberculosis (MTB) detection and drug susceptibility testing (DST). Unfortunately, delays to result return, and associated technical challenges from requirements for specialised resource and capacity, have limited DST use and availability in many high TB burden resource-limited countries. There is increasing availability of a variety of rapid nucleic acid-based diagnostic assays with adequate sensitivity and specificity to detect gene mutations associated with resistance to one or more drugs. While a few of these assays produce comprehensive calls for resistance to several first- and second-line drugs, there is still no endorsed genotypic drug susceptibility test assay for bedaquiline, pretomanid, and delamanid. The global implementation of regimens comprising these novel drugs in the absence of rapid phenotypic drug resistance profiling has generated a new set of diagnostic challenges and heralded a return to culture-based phenotypic DST. In this review, we describe the available tools for rapid diagnosis of drug-resistant tuberculosis and discuss the associated opportunities and challenges.

Post-Acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus – 2 (SARS-CoV-2) infection, or Long COVID, is a prevailing second pandemic with nearly 100 million affected individuals globally and counting. We propose a visual description of the complexity of Long COVID and its pathogenesis that can be used by researchers, clinicians, and public health officials to guide the global effort toward an improved understanding of Long COVID and the eventual mechanism-based provision of care to afflicted patients. The proposed visualization or framework for Long COVID should be an evidence-based, dynamic, modular, and systems-level approach to the condition. Furthermore, with further research such a framework could establish the strength of the relationships between pre-existing conditions (or risk factors), biological mechanisms, and resulting clinical phenotypes and outcomes of Long COVID. Notwithstanding the significant contribution that disparities in access to care and social determinants of health have on outcomes and disease course of long COVID, our model focuses primarily on biological mechanisms. Accordingly, the proposed visualization sets out to guide scientific, clinical, and public health efforts to better understand and abrogate the health burden imposed by long COVID.

Introduction Cotreatment of HIV and tuberculosis (TB) reduces morbidity and mortality in coinfected patients. Availability of antiretroviral treatment (ART) drug options, including within drug classes, is important, particularly in high HIV/TB burden low and middle-income countries.Methods and analysis This is a phase 2b, open-label, non-comparative randomised controlled trial to assess the antiretroviral activity of a fixed-drug, single tablet, combination of bictegravir (BIC) 50 mg/emtricitabine (FTC) 200 mg/tenofovir alafenamide (TAF) 25 mg (Biktarvy). The primary objective is to determine the efficacy, safety and pharmacokinetics of two times per day, coformulated BIC 50 mg/FTC 200 mg/TAF 25 mg in HIV-positive ART-naïve patients with TB who are receiving a rifampicin-based treatment regimen and to characterise viral suppression rates at week 24 through to week 48 in the BIC/FTC/TAF arm. We will enrol 120 patients randomised in a 2:1 ratio to the intervention or control arm of the study. A non-comparative contemporaneous control arm in which participants receive a dolutegravir-based regimen (standard of care) will also be enrolled.Ethics and dissemination The University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and the South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval (trial reference numbers: BREC/00001300/2020 and SAHPRA 20200810). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry.Trial registration number Clinicaltrials.gov; Trial registration number: NCT04734652; South African National Clinical Trials Register (SANCTR DOH-27-012021-6789)

Background: During magnetic resonance cholangiopancreatography (MRCP), the pancreatobiliary ducts can be obscured by the high-intensity signal from the stomach and duodenum. Pineapple juice may be an alternative to commercially available negative contrast agents, but has not been evaluated locally. Objectives: To evaluate the efficacy of a local, off-the-shelf pineapple juice preparation as a negative oral contrast agent for MRCP. Method: An observational, analytical study was conducted during January–December 2017. A 1.5 Tesla MRCP sequence was performed immediately before and after ingestion of 250 mL of a local, commercially-available pineapple juice preparation. Image evaluation was performed by two radiologists with independent, blind assessment of gastric/duodenal signal intensity and biliary /pancreatic duct visibility, before and after pineapple juice. Results: Fifty adult patients (F = 44, 88%) with median age 44 years (IQR: 34.75, 57) were included. After pineapple juice administration, there was significant measured (1661.51 vs. 1409.94, p 0.01) and perceived (2.16 vs. 2.72, p 0.01) duodenal signal reduction but no significant change in measured (1081.17 vs. 1044.38, p = 0.34) or perceived (2.73 vs. 2.84, p = 0.14) gastric signal intensity. Visibility of the common bile duct was significantly improved (3.67 vs. 3.86, p 0.01), whilst that of the main pancreatic duct showed no significant change (2.92 vs. 2.86, p = 0.44). Conclusion: The local pineapple juice preparation used in this study is an effective, affordable and natural negative oral contrast agent for enhancement of MRCP images, and specifically improves visualisation of the common bile duct.

Abstract Background The global predominance of tuberculosis in men has received significant attention. However, epidemiological studies now demonstrate that there is an increased representation of young women with tuberculosis, especially in high HIV burden settings where young women bear a disproportionate burden of HIV. The role of the HIV epidemic, as well as changes in behavioural, biological, and structural risk factors are explored as potential explanations for the increasing burden of tuberculosis in young women. Discussion As young women are particularly vulnerable to HIV infection in sub-Saharan Africa, it is unsurprising that the TB epidemic in this setting has become increasingly feminised. This age-sex trend of TB in South Africa is similar to WHO estimates for other countries with a high HIV prevalence where there are more female than male cases notified up to the age of 25 years. The high prevalence of anaemia of chronic disease in young women with HIV is an additional potential reason for their increased TB risk. The widespread use of injectable medroxyprogesterone acetate contraception, which has been shown to possess selective glucocorticoid effect and oestrogen suppression, in young women may be an important emerging biological risk factor for tuberculosis in young women. Behavioural factors such as alcohol use and tobacco smoking patterns are further factors which may be responsible for the narrowing of the sex gap in TB epidemiology. In comparison to the significantly higher alcohol consumption rates in men globally, there is a narrowing gap in alcohol consumption between the sexes in South Africa with alarming rates of alcohol abuse in young women. There is a similar narrowing of the tobacco smoking gap between the sexes in South Africa, with increasing smoking prevalence in young women. Conclusion With nearly 70% of all TB patients being co-infected with HIV in our setting, it is not surprising that the age and sex distribution of TB is increasingly resembling the distribution of HIV in this region of dual hyperendemicity. New TB service design must begin to reflect the presence of young women as a significant group burdened by the disease.

Background: Bronchoalveolar lavage (BAL) is indicated for medical evaluation of complex cases of lung disease. There is limited data on the performance of tuberculosis (TB) microbiologic tests on BAL in such patients, particularly in human immunodeficiency virus (HIV) and TB endemic areas. Methods: We evaluated the performance of Mycobacterium tuberculosis (Mtb) culture and up to two simultaneous Xpert MTB/RIF tests on BAL fluid against a consensus clinical diagnosis in 98 medically complex patients undergoing bronchoscopy over a two-year period in Durban, South Africa. Results: TB was the most frequently diagnosed lung disease, found in 19 of 98 participants (19%) and was microbiologically proven in 14 of these (74%); 9 (47%) were culture positive and 5 were positive on at least one Xpert MTB/RIF assay. Immunosuppression prevalence was high (26% HIV-infected, 29% on immunosuppressive therapy and 4% on chemotherapy). Xpert MTB/RIF had low sensitivity (45%) and high specificity (99%) when assessed against the consensus clinical diagnosis. Compared to TB culture, a single Xpert MTB/RIF increased the diagnostic yield by 11% and a second Xpert MTB/RIF by a further 16%. Conclusion: Although Xpert MTB/RIF had a low sensitivity, sending two tests improved the microbiologically-proven diagnostic yield of bronchoscopy from 47% to 74% compared to culture alone.

Medical education is evolving from a heavily hierarchical and paternalistic approach to a more developmental and student-centred paradigm. In addition, there has been a greater focus on decentralised medical education, taking medical students closer to the lowest tiers of the healthcare system and allowing for a more immersive experience within the communities of their patients. This paper presents the experience of an enlightening rural experience, in which the benefits of such a model to medical education are explored. Furthermore, it presents the highly personal and developmental journey that decentralised and, in particular, rural medical training can offer. A new concept of a ‘home-stay’ model has now been introduced as part of the rural medicine experience, where students are hosted by a family within the community in which they work. This is a transformative project in which the most fundamental principles of medical training and the art of medical practice can be honed. The convergence of clinical training, public health enlightenment, and family practice are highlighted.

Background: Higher education institutions (HEIs) the world over are beginning to recognise the importance of knowledge management; however, such institutions are still in their formative stages of addressing, evaluating and implementing the benefits of knowledge management with particular reference to human resource management (HRM). Knowledge management is a viable means through which HEIs could gainfully capitalise on their intellectual and social capital. Objectives: This study explores knowledge management as a strategic tool for HRM in HEIs. Specifically, the dimensions such as organisational culture, organisational performance, technology, management support and the institutions’ mission and vision will be evaluated to understand knowledge management within HEIs. Method: Using a cross-sectional survey design, a self-administered questionnaire was sent to 91 individuals representing senior, middle and junior human resource managers at selected HEIs in South Africa, Mauritius and India. The study investigated the impact of policies, systems and processes that the HEIs implemented in support of knowledge management and knowledge sharing. Results: A total of 91 human resource practitioners responded to the survey, the majority of whom were male (56%). Respondents from the different countries have similar perceptions regarding the issues that encourage knowledge generation and knowledge sharing (p = 0.209), and how characteristics of their institutions compare with those applicable to learning organisations (p = 0.422). Respondents disagreed to differing extents across countries that organisational or departmental structures, political interference, communication channels between employees and command and control procedures retarded knowledge generation and sharing (p = 0.001). Respondents from the different countries have differing perceptions regarding the speed at which knowledge is transferred (p = 0.000), the reliability of the knowledge that is transferred as well as the extent to which decisions can be made in using the available knowledge (p = 0.000), the ease with which knowledge is transferred in their context (p = 0.016), the transfer of tacit knowledge in their organisations (p = 0.000), whether individual employees use personal knowledge as a source of power (p = 0.025) and the role of the information and communications technology (ICT), infrastructure in knowledge creation and sharing (p = 0.000). Conclusion: The results provide convincing arguments to support the integration of HRM and knowledge management initiatives in HEIs. Whilst the HRM function at HEIs has demonstrated that it has the capability and resources to implement knowledge management initiatives, the results reflect that much ground needs to be covered to realise the full benefits of this endeavour. The study confirms that an effective knowledge management strategy for HRM that is aligned to the organisation’s strategic objectives is imperative for HEIs in South Africa.

Background: Process analysis and expert consultation help streamline and optimise processes, but these are underutilised. The World Health Organisation (WHO) recommends migration to electronic data collection by 2015, partly in response to multidrug-resistant tuberculosis (MDR-TB). We explore the influence of process analysis and iterative expert consultation, on shaping health information solutions to MDR-TB programmes. Methods: The study employs a two phase design. Phase one involves a process analysis of the South African National Tuberculosis Programme and an electronic medical records (EMR) solution and the generation of a detailed process model grounded in the fit between individual task and technology (FITT) theoretical framework using ‘business process modelling notation’. Phase two involves a two round Delphi study in the clinical management of tuberculosis and implementers of EMR solutions. Expert opinion is analysed according to emergent thematic content. Analyses and graphical model representation are performed using Microsoft Excel® and Visio® software. Results: A detailed process model is constructed which reveals 54 break points, 12 gaps, 3 risks, 5 wastes. Five participants are included in the Delphi study which support the findings of the process analysis. Thematic analysis identifies five themes: the individual, the process, technology, capacity, and collaboration. The opportunity to include synergistic relations across programmes emerges as a strong theme. Conclusions: Overall, the findings highlight inefficiencies, risk and gaps in the current process and the need for an operational excellence intervention. The study demonstrated the value of process engineering with iterative expert consultation toward developing a meaningful EMR solution consultation in a resource constrained, developing world context.