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Background: Identifying risk factors for respiratory syncytial virus (RSV)-associated severe acute respiratory illness (SARI) will assist with targeting vaccine interventions., Methods: Using surveillance data from South Africa (2012-2018), we compared the characteristics of individuals with RSV-associated influenza-like illness (ILI) (reference group) to those with RSV-associated SARI to describe factors associated with SARI using a multivariable analysis., Results: RSV was detected in 6% (483/7792) of ILI cases and 15% (844/5672) of SARI cases. Factors associated with SARI in children included age < 2 months, compared to age 2-4 years (adjusted odds ratio (aOR) 54.4; 95% confidence interval (CI) 23.5-125.8), malnutrition (aOR 1.9; 95% CI 1.2-3.2), prematurity (aOR 2.4; 95% CI 1.3-4.6) and living with HIV (LWH) (aOR 22.5; 95% CI 2.9-174.3). In individuals ≥ 5 years, factors associated with SARI included age ≥ 65 years compared to age 5-24 years (aOR 10.7; 95% CI 1.1-107.5), symptom duration ≥ 5 days (aOR 2.7; 95% CI 1.1-6.3), underlying illness (aOR 2.7; 95% CI 1.5-26.1) and LWH (aOR 16.8, 95% CI: 4.8-58.2)., Conclusion: Individuals at the extremes of age and those with identified risk factors might benefit most from RSV prevention interventions., Clinical Trial Number: Not applicable, this is not a clinical trial., (© 2024. The Author(s).)

Background: Tuberculosis (TB) preventive therapy (TPT) reduces the risk of TB disease in people with human immunodeficiency virus (HIV), yet uptake has been suboptimal in many countries. We assessed whether QuantiFERON Gold In-Tube (QGIT) during routine HIV care increased TB infection (TBI) testing and TPT prescriptions., Methods: This parallel-arm, 1:1 cluster-randomized controlled trial compared the standard-of-care tuberculin skin test to QGIT in South Africa. We enrolled consenting, TPT-eligible adults diagnosed with HIV ≤30 days prior and used intention-to-treat analyses for the outcomes: proportion of patients with documented TBI results, proportion with documented TPT, and time from enrollment to outcomes., Findings: We enrolled 2232 patients across 14 clinics from November 2014 to May 2017 (58% in intervention clinics). At 24 months of follow-up, more participants in intervention clinics had TBI results (69% vs 2%, P < .001) and TPT prescriptions (45% vs 30%, P = .13) than control clinics. Controlling for baseline covariates, intervention clinics had 60% (95% confidence interval, 51-68; P < .001) more participants with TBI results and 12% (95% confidence interval, -6 to 31; P = .18) more with TPT prescriptions. Among participants with results, those in intervention clinics received results and TPT faster (intervention: median of 6 and 29 days after enrollment vs control: 21 and 54 days, respectively)., Interpretation: In this setting, QGIT in routine HIV care resulted in more patients with TBI results. Clinicians also initiated more people with HIV on TPT in QGIT intervention clinics, and did so more quickly, than the control arm., Clinical Trials Registration: NCT02119130., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB., Methods: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed., Findings: Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17-3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%])., Interpretation: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments., Funding: TB Alliance., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: COVID-19 vaccine effectiveness (VE) studies leveraging systematic surveillance in sub-Saharan Africa are limited. We assessed the effectiveness of two vaccines (Pfizer BNT162b2 and Johnson & Johnson Ad26.COV2.S) against SARS-CoV-2-associated hospitalization in South African adults aged ≥18 years., Methods: We conducted a test-negative case-control study using pneumonia surveillance data in South Africa. Inpatients with physician-diagnosed lower respiratory tract infection or suspected COVID-19, testing SARS-CoV-2 positive or negative from June 2021-March 2022, were cases or controls, respectively. Fully vaccinated individuals received one Ad26.COV2.S dose or two BNT162b2 doses ≥14-days before enrollment. VE was estimated using multivariable logistic regression for Delta- and Omicron BA.1/BA.2-predominant periods, stratified by age and HIV status., Results: The study included 925 cases and 1890 controls; 38 (4%) cases and 186 (10%) controls were fully vaccinated with BNT162b2, and 30 (3%) cases and 94 (5%) controls with Ad26.COV2.S. The vaccine effectiveness of BNT162b2 against SARS-CoV-2-associated hospitalization over Delta and Omicron BA.1/BA.2 periods was 91% (95% CI: 52%, 98%) and 33% (-16%, 86%), respectively. The vaccine effectiveness of Ad26.COV2.S against hospitalization over Delta and Omicron BA.1/BA.2 periods was 72% (-36% ,94%), and -19% (-130%, 39%), respectively. The vaccine effectiveness of BNT162b2 against hospitalization over the Delta period was 94% (50%, 99%) and 89% (27%, 98%) among adults aged ≥60 years and HIV-uninfected, respectively., Conclusions: The BNT162b2 vaccine was effective against SARS-CoV-2-associated hospitalization during the Delta period for adults aged ≥18 years, ≥60 years and those HIV-uninfected. VE for Ad26.COV2.S was inconclusive, potentially due to limited sample size or residual confounding. These findings highlight the utility of sentinel surveillance for estimating VE., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing., Methods: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm., Discussion: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial., Trial Registration: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57., Clinicaltrials: gov: NCT04337450., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Twenty-three percent of people with human immunodeficiency virus (HIV, PWH) die within 6 months of hospital discharge. We tested the hypothesis whether a series of structured home visits could reduce mortality., Methods: We designed a disease neutral home visit package with up to 6 home visits starting 1-week post-hospitalization and every 2 weeks thereafter. The home visit team used a structured assessment algorithm to evaluate and triage social and medical needs of the participant and provide nutritional support. We compared all-cause mortality 6 months following discharge for the intervention compared to usual care in a pilot randomized trial conducted in South Africa. To inform potential scale-up we also included and separately analyzed a group of people without HIV (PWOH)., Results: We enrolled 125 people with HIV and randomized them 1:1 to the home visit intervention or usual care. Fourteen were late exclusions because of death prior to discharge or delayed discharge leaving 111 for analysis. The median age was 39 years, 31% were men; and 70% had advanced HIV disease. At 6 months among PWH 4 (7.3%) in the home visit arm and 10 (17.9%) in the usual care arm (P = .09) had died. Among the 70 PWOH enrolled overall 6-month mortality was 10.1%. Of those in the home visit arm, 91% received at least one home visit., Conclusions: We demonstrated feasibility of delivering post-hospital home visits and demonstrated preliminary efficacy among PWH with a substantial, but not statistically significant, effect size (59% reduction in mortality). Coronavirus disease 2019 (COVID-19) related challenges resulted in under-enrollment., Competing Interests: Potential conflicts of interest. J. E. G. reports the following grants or contracts unrelated to this work: NIH grant numbers R01AI150432, R01AI143748, and U01CA261626. N. A. M. reports a grant from Pfizer to conduct clinical research assessing incidence of pneumonia, paid to institution; unpaid participation on Scientific Advisory Board for TB Mate trial and DSMB for New Strat TB trial; role as non-executive board member for Setshaba Research Centre (fee paid per meeting approx. USD55 1 meeting per quarter). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Clofazimine is included in drug regimens to treat rifampicin/drug-resistant tuberculosis (DR-TB), but there is little information about its interaction with other drugs in DR-TB regimens. We evaluated the pharmacokinetic interaction between clofazimine and isoniazid, linezolid, levofloxacin, and cycloserine, dosed as terizidone. Newly diagnosed adults with DR-TB at Klerksdorp/Tshepong Hospital, South Africa, were started on the then-standard treatment with clofazimine temporarily excluded for the initial 2 weeks. Pharmacokinetic sampling was done immediately before and 3 weeks after starting clofazimine, and drug concentrations were determined using validated liquid chromatography-tandem mass spectrometry assays. The data were interpreted with population pharmacokinetics in NONMEM v7.5.1 to explore the impact of clofazimine co-administration and other relevant covariates on the pharmacokinetics of isoniazid, linezolid, levofloxacin, and cycloserine. Clofazimine, isoniazid, linezolid, levofloxacin, and cycloserine data were available for 16, 27, 21, 21, and 6 participants, respectively. The median age and weight for the full cohort were 39 years and 52 kg, respectively. Clofazimine exposures were in the expected range, and its addition to the regimen did not significantly affect the pharmacokinetics of the other drugs except levofloxacin, for which it caused a 15% reduction in clearance. A posteriori power size calculations predicted that our sample sizes had 97%, 90%, and 87% power at P < 0.05 to detect a 30% change in clearance of isoniazid, linezolid, and cycloserine, respectively. Although clofazimine increased the area under the curve of levofloxacin by 19%, this is unlikely to be of great clinical significance, and the lack of interaction with other drugs tested is reassuring., Competing Interests: The authors declare no conflict of interest.

Background: Elevated HIV-associated mortality persists, despite a notable decline with the expansion of antiretroviral therapy (ART). In South Africa, the relative majority of deaths occur in health facilities, providing an opportunity to track decedent characteristics., Setting: We analyzed data from 14,870 adult patients who died between 2008 and 2018 at Klerksdorp/Tshepong Hospital Complex in South Africa., Methods: Recorded data included demographics, causes of death, HIV status, ART, and tuberculosis (TB) history. We present summary statistics and results from linear, log-binomial, and multinomial regressions to quantify changes over time., Results: Over the study period, the median age of decedents with HIV in the hospital increased from 39.3 to 43.4 years, and there was a switch to male predominance (46%-54%). Those who died at a younger age (<40 years) remained more likely to be HIV-positive than the older age group, despite the overall proportion of HIV-positivity decreasing over time. The proportion of decedents with HIV ever started on ART increased from 21% to 67%. The proportion of HIV patients dying from TB and AIDS-defining illnesses decreased from 31% to 22%., Conclusions: We noted a shift in deaths over time to more men and older individuals, whereas the burden of HIV was heaviest on the younger age groups. Advanced HIV disease remained an important cause of mortality. We also observed an increase in less-traditional opportunistic illnesses among those with HIV, including malignancy, cardiovascular disease, and kidney disease. The high proportion of patients on ART who died prematurely requires further research and interventions., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The detection of respiratory syncytial virus (RSV) in upper airway samples does not necessarily infer causality of illness. We aimed to calculate the attributable fraction (AF) of RSV in clinical syndromes across age groups., Methods: Using unconditional logistic regression models, we estimated the AF of RSV-associated influenza-like illness (ILI) and severe acute respiratory illness (SARI) cases by comparing RSV detection prevalence among ILI and SARI cases to those of healthy controls in South Africa, 2012-2016. The analysis, stratified by HIV serostatus, was conducted in the age categories <1, 1-4, 5-24, 25-44, 45-64, and ≥65 years., Results: We included 12,048 individuals: 2687 controls, 5449 ILI cases, and 5449 SARI cases. RSV-AFs for ILI were significant in <1, 1-4, 5-and 24, 25-44-year age groups: 84.9% (95% confidence interval [CI] 69.3-92.6%), 74.6% (95% CI 53.6-86.0%), 60.8% (95% CI 21.4-80.5%) and 64.1% (95% CI 14.9-84.9%), respectively. Similarly, significant RSV-AFs for SARI were 95.3% (95% CI 91.1-97.5) and 83.4% (95% CI 70.9-90.5) in the <1 and 1-4-year age groups respectively. In HIV-infected persons, RSV was significantly associated with ILI cases vs controls in individuals aged 5-44 years., Conclusion: High RSV-AFs in young children confirm RSV detection is associated with severe respiratory illness in South African children, specifically infants. These estimates will assist with refining burden estimates and cost-effectiveness models., Competing Interests: Declarations of competing interest Prof Cheryl Cohen and Anne von Gottberg have received institutional funding support from US Centers for Disease Control (CDC) related to the present work and also received funding from Bill and Melinda Gates Foundation (BMGF), PATH, Sanofi, Wellcome Trust, and South African Medical Research Council of South Africa (MRC) outside of the submitted work. Dr Moyes received institutional funding from Sanofi and PATH for work outside of this present work. Dr Dawood reports personal fees from Sanofi-South Africa. In addition, she reports workshop attendance sponsorship from Biomieruex-South Africa., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Missing or undiagnosed patients with tuberculosis (TB) or coronavirus disease 2019 (COVID-19) are of concern. Identifying both infections in patients with no diagnosis prior to death contributes to understanding the burden of disease. To confirm reports of global reduction in TB incidence, a 2012 autopsy study of adults dying at home of natural causes in a high-TB-burden setting was repeated, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assessments after the first COVID-19 surge in South Africa., Methods: Adult decedents who died at home with insufficient information to determine cause of death, no recent hospitalization, and no current antemortem TB or COVID-19 diagnosis were identified between March 2019 and October 2020 with a 4-month halt during lockdown. A standardized verbal autopsy followed by minimally invasive needle autopsy (MIA) was performed. Biopsies were taken for histopathology from liver, bilateral brain and lung; bronchoalveolar lavage fluid was collected for Xpert (MTB/RIF) and mycobacterial culture, and blood for human immunodeficiency virus (HIV) polymerase chain reaction (PCR) testing. After the start of the COVID-19 pandemic, a nasopharyngeal swab and lung tissue were subjected to SARS-CoV-2 PCR testing., Results: Sixty-six MIAs were completed in 25 men and 41 women (median age, 60 years); 68.2% had antemortem respiratory symptoms and 30.3% were people with HIV. Overall, TB was diagnosed in 11 of 66 (16.7%) decedents, and 14 of 41 (34.1%) in the COVID-19 pandemic were SARS-CoV-2 positive., Conclusions: Undiagnosed TB in adults dying at home has decreased but remains unacceptably high. Forty percent of decedents had undiagnosed COVID-19, suggesting that estimates of excess deaths may underestimate the impact of SARS-CoV-2 on mortality., Competing Interests: Potential conflicts of interest. C. W. reports consulting fees from International Partnership for Microbicides. L. L. reports grants or contracts from Gilead Sciences (paid to institution). N. M. reports grants or contracts from Pfizer for an unrelated observational study of patients with pneumonia (paid to institution); reports participation on a data and safety monitoring board or advisory board for Strat TB for a clinical trial assessing treatment for TB meningitis; and was a board member of the Setshaba Research Center in Soshanguve, South Africa. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Despite a high (48%) prevalence of snuff use among women with HIV in South Africa, little is known of the attitudes and behaviors of use, strategies for cessation, and potential health risks., Methods: In a cross-sectional study, a questionnaire was administered to adults (≥18 years) with (HIV+) and without HIV (HIV-) who self-reported current snuff use to collect information on demographics, snuff use and cessation attempts, preferred strategies for cessation, other substance use, history of respiratory illness, and mental health., Results: 150 (74 HIV+, 76 HIV-) participants were enrolled; 115 (77%) were daily snuff users, 6 (4%) were current smokers, and 17 (11%) former smokers. Top reasons for current snuff use included improving health (n = 48, 32%), reducing stress (n = 26, 16%), and "being a habit" (n = 38, 25%). Participants believed snuff use to have mostly positive (n = 68, 46%) or no (n = 54, 36%) health impacts, and 57 (38%) participants believed snuff cures headaches. 103 (69%) participants reported a previous quit attempt, and 110 (73%) indicated high interest in quitting snuff. Although 105 (70%) participants indicated that advice from a healthcare provider would aid them in quitting snuff, only 30 (20%) reported ever receiving that advice. A majority of participants (n = 141, 94%) suffer from moderate to high levels of perceived stress, and overall few differences were seen by HIV status., Conclusions: Education on negative impacts of snuff, advice to quit from healthcare providers, and nicotine replacement therapy should be considered in the development of a snuff cessation program., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Aim: We compared soluble transferrin receptors (sTfR), serum ferritin, mean cell volume (MCV) of red cells and the sTfR-ferritin index with the intensive method bone marrow trephine (BMT) iron stores in the diagnosis of iron deficiency anaemia (IDA) in Human Immunodeficiency Virus (HIV)-positive hospitalised participants., Methods: In this cross-sectional study, we recruited hospitalised HIV-positive and coronavirus of 2019 (COVID-19)-negative adults with anaemia who required a bone marrow examination as part of their diagnostic workup. We measured the full blood count, ferritin, sTfR and assessed iron using the intensive method in Haemotoxylin and Eosin (H&E)-stained BMT core biopsies of consenting participants., Results: Of the 60 enrolled participants, 57 were evaluable. Thirteen (22.80%) had IDA on H&E BMT iron stores assessment, and 44 (77.19%) had anaemia of chronic diseases (ACD). The sTfR and the sTfR-ferritin index had sensitivities of 61.54% and 53.85%, respectively, for IDA diagnosis. The sensitivity and specificity of ferritin was 7.69% and 92.31%, respectively. The sTfR and sTfR-ferritin index's diagnostic specificity was relatively low at 46.15% and 38.46%, respectively., Conclusion: In this pilot study in HIV-positive participants, the prevalence of iron deficiency using the BMT assessment was low. Both the sTfR and the sTfR-ferritin index had a better quantitative correlation to bone marrow iron stores when compared with the MCV and ferritin and, may be more accurate surrogate markers of IDA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study aimed to understand the cost implications of managing people living with type 1 diabetes mellitus in the South African public healthcare system., Methods: A multicenter, noninterventional retrospective chart review study was performed. Data on healthcare resource consumption, demographics, risk factors, clinical history, and acute events were collected. Direct medical costs were collected over a 1-year period, stratified by controlled versus uncontrolled patients. In addition, the costs in people with controlled (glycated hemoglobin < 7%) versus uncontrolled glycated hemoglobin (≥ 7%) at time horizons of 1, 5, 10, and 25 years were modeled using the IQVIA Core Diabetes Model., Results: The costs based on the retrospective chart review were $630 versus $1012 (controlled versus uncontrolled population). The modeled costs at various time horizons were as follows: at 1 year, $900 versus $1331; at 5 years, $4163 versus $6423; at 10 years, $7759 versus $16 481; and at 25 years, $16 969 versus $66 268. The largest cost in the controlled population was severe hypoglycemia requiring nonmedical assistance, severe hypoglycemia requiring medical assistance, and treatment costs. In the uncontrolled population, the largest cost was the cost of diabetic ketoacidosis, severe hypoglycemia requiring nonmedical assistance, severe hypoglycemia requiring medical assistance, and foot complications., Conclusions: Strict glycemic control reduces healthcare resource use overall. Patients in the controlled group still experienced high resource use related to hypoglycemic events. The introduction of a structured patient education program and analog insulins may result in less episodes of hypoglycemia and potential cost savings., (Copyright © 2023 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: HIV and AIDS continues to impose substantial healthcare challenges in sub-Saharan Africa, but there are limited local data comparing inpatient outcomes between people with HIV (PLWH) and those uninfected., Objectives: To compare cause-specific mortality among hospitalised adolescents and adults, stratified by HIV-serostatus., Method: A cross-sectional analysis was performed, analysing cause-specific inpatient mortality data and total admissions, from 01 January 2017 to 30 June 2020, at Tshepong Hospital, North West province, South Africa., Results: The overall inpatient mortality rate decreased from 14.5% (95% confidence interval [CI]: 13.4-16.0) in 2017, to 11.3% (95% CI: 10.6-11.9) in 2020; P < 0.001. People living with HIV accounted for 53.9% ( n = 2342) of inpatient deaths, 22.6% ( n = 984) were HIV-seronegative patients and 23.5% ( n = 1020) patients with unknown HIV-serostatus. People with HIV died at younger ages (median: 44 years, interquartile range [IQR]: 35.8-54.2) compared to HIV-seronegative inpatients (median: 64.4 years, IQR: 55.5-73.9); P < 0.001. Leading causes of death were pneumonia (19.9%, n = 863), then pulmonary and extrapulmonary tuberculosis (15.0%, n = 654). People with HIV who had CD4+ counts < 350 cells/mL or viral load ≥ 1000 copies/mL had increased risk of death from tuberculosis compared to virally suppressed patients (adjusted relative risk: 2.10 [95% CI: 1.44-3.04, P < 0.009] and 1.56 [95% CI: 1.22-2.00, P < 0.001])., Conclusion: Our study, conducted in a regional hospital in South Africa, showed PLWH had higher mortality rates and died at younger ages compared to HIV-seronegative patients., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2023. The Authors.)

Background: Data on the economic burden of RSV-associated illness will inform decisions on the programmatic implementation of maternal vaccines and monoclonal antibodies. We estimated the cost of RSV-associated illness in fine age bands to allow more accurate cost-effectiveness models to account for a limited duration of protection conferred by short- or long-acting interventions., Methods: We conducted a costing study at sentinel sites across South Africa to estimate out-of-pocket and indirect costs for RSV-associated mild and severe illness. We collected facility-specific costs for staffing, equipment, services, diagnostic tests, and treatment. Using case-based data we calculated a patient day equivalent (PDE) for RSV-associated hospitalizations or clinic visits; the PDE was multiplied by the number of days of care to provide a case cost to the healthcare system. We estimated the costs in 3-month age intervals in children aged < 1 year and as a single group for children aged 1-4 years. We then applied our data to a modified version of the World Health Organization tool for estimating the mean annual national cost burden, including medically and non-medically attended RSV-associated illness., Results: The estimated mean annual cost of RSV-associated illness in children aged < 5 years was US dollars ($)137,204,393, of which 76% ($111,742,713) were healthcare system incurred, 6% ($8,881,612) were out-of-pocket expenses and 13% ($28,225,.801) were indirect costs. Thirty-three percent ($45,652,677/$137,204,393) of the total cost in children aged < 5 years was in the < 3-month age group, of which 52% ($71,654,002/$137,204,393) were healthcare system incurred. The costs of non-medically attended cases increased with age from $3,307,218 in the < 3-month age group to $8,603,377 in the 9-11-month age group., Conclusions: Among children < 5 years of age with RSV in South Africa, the highest cost burden was in the youngest infants; therefore, interventions against RSV targeting this age group are important to reduce the health and cost burden of RSV-associated illness., (© 2023. The Author(s).)

Background: Vaccines and monoclonal antibodies to protect the very young infant against the respiratory syncytial virus (RSV)-associated illness are effective for limited time periods. We aimed to estimate age-specific burden to guide implementation strategies and cost-effectiveness analyses., Methods: We combined case-based surveillance and ecological data to generate a national estimate of the burden of RSV-associated acute respiratory illness (ARI) and severe acute respiratory illness (SARI) in South African children aged < 5 years (2011-2016), including adjustment for attributable fraction. We estimated the RSV burden by month of life in the < 1-year age group, by 3-month intervals until 2 years, and then 12 monthly intervals to < 5 years for medically and non-medically attended illness., Results: We estimated a mean annual total (medically and non-medically attended) of 264,112 (95% confidence interval (CI) 134,357-437,187) cases of RSV-associated ARI and 96,220 (95% CI 66,470-132,844) cases of RSV-associated SARI (4.7% and 1.7% of the population aged < 5 years, respectively). RSV-associated ARI incidence was highest in 2-month-old infants (18,361/100,000 population, 95% CI 9336-28,466). The highest incidence of RSV-associated SARI was in the < 1-month age group 14,674/100,000 (95% CI 11,175-19,645). RSV-associated deaths were highest in the first and second month of life (110.8 (95% CI 74.8-144.5) and 111.3 (86.0-135.8), respectively)., Conclusions: Due to the high burden of RSV-associated illness, specifically SARI cases in young infants, maternal vaccination and monoclonal antibody products delivered at birth could prevent significant RSV-associated disease burden., (© 2023. The Author(s).)

Purpose: Despite evidence of myocardial infarct size reduction in animal studies, remote ischaemic conditioning (RIC) failed to improve clinical outcomes in the large CONDI-2/ERIC-PPCI trial. Potential reasons include that the predominantly low-risk study participants all received timely optimal reperfusion therapy by primary percutaneous coronary intervention (PPCI). Whether RIC can improve clinical outcomes in higher-risk STEMI patients in environments with poor access to early reperfusion or PPCI will be investigated in the RIC-AFRICA trial., Methods: The RIC-AFRICA study is a sub-Saharan African multi-centre, randomized, double-blind, sham-controlled clinical trial designed to test the impact of RIC on the composite endpoint of 30-day mortality and heart failure in 1200 adult STEMI patients without access to PPCI. Randomized participants will be stratified by whether or not they receive thrombolytic therapy within 12 h or arrive outside the thrombolytic window (12-24 h). Participants will receive either RIC (four 5-min cycles of inflation [20 mmHg above systolic blood pressure] and deflation of an automated blood pressure cuff placed on the upper arm) or sham control (similar protocol but with low-pressure inflation of 20 mmHg and deflation) within 1 h of thrombolysis and applied daily for the next 2 days. STEMI patients arriving greater than 24 h after chest pain but within 72 h will be recruited to participate in a concurrently running independent observational arm., Conclusion: The RIC-AFRICA trial will determine whether RIC can reduce rates of death and heart failure in higher-risk sub-optimally reperfused STEMI patients, thereby providing a low-cost, non-invasive therapy for improving health outcomes., (© 2021. The Author(s).)

The nicotine metabolite ratio (NMR) is associated with race/ethnicity but has not been evaluated among smokers in the African region. We conducted a cross-sectional analysis of baseline data from a large randomized, controlled trial for smoking cessation among people with HIV (PWH) in South Africa. Urine samples were analyzed for the NMR and evaluated as a binary variable using a cutoff value of the fourth quartile to determine the fastest metabolizers. The median NMR was 0.31 (IQR: 0.31, 0.32; range: 0.29, 0.57); the cut-point for fast metabolizers was ≥0.3174 ng/mL. A high NMR was not associated with the number of cigarettes per day (OR = 1.10, 95% CI: 0.71, 1.70, p = 0.66) but was associated with 40% lower odds of a quit attempt in the past year (OR = 0.69; 95% CI: 0.44, 1.07, p = 0.09) and alcohol use (OR = 0.59, 95% CI: 0.32, 1.06, p = 0.07). No association was seen with marijuana or HIV clinical characteristics. As we found only minimal variability in the NMR and minimal associations with intensity of smoking, NMR may be of limited clinical value in this population, although it may inform which individuals are less likely to make a quit attempt.

Background: Type 1 diabetes mellitus (T1DM) is less common than type 2 diabetes mellitus but is increasing in frequency in South Africa. It tends to affect younger individuals, and upon diagnosis, exogenous insulin is essential for survival. In South Africa, the health care system is divided into private and public health care systems. The private system is well resourced, whereas the public sector, which treats more than 80% of the population, has minimal resources. There are currently no studies in South Africa, and Africa at large, that have evaluated the immediate and long-term costs of managing people living with T1DM in the public sector., Objective: The primary objective was to quantify the cost of health care resource utilization over a 12-month period in patients with controlled and uncontrolled T1DM in the public health care sector. In addition, we will project costs for 5, 10, and 25 years and determine if there are cost differences in managing subsets of patients who achieve glycemic control (hemoglobin A 1c [HbA 1c ] <7%) and those who do not., Methods: The study was performed in accordance with Good Epidemiological Practice. Ethical clearance and institutional permissions were acquired. Clinical data were collected from 2 tertiary hospitals in South Africa. Patients with T1DM, who provided written informed consent, and who satisfied the inclusion criteria were enrolled in the study. Data collection included demographic and clinical characteristics, acute and chronic complications, hospital admissions, and so on. We plan to perform a cost-effectiveness analysis to quantify the costs of health care utilization in the preceding 12 months. In addition, we will estimate projected costs over the next 10 years, assuming that study participants maintain their current HbA 1c level. The cost-effectiveness analysis will be modeled using the IQVIA CORE Diabetes Model. The primary outcome measures are incremental quality-adjusted life years, incremental costs, incremental cost-effectiveness ratios, and incremental life years., Results: Ethical clearance and institutional approval were obtained (reference number 200407). Enrollment began on February 9, 2021, and was completed on August 24, 2021, with 224 participants. A database lock was performed on October 29, 2021. The statistical analysis and clinical study report were completed in January 2022., Conclusions: At present, there are no data assessing the short- and long-term costs of managing patients with T1DM in the South African public sector. It is hoped that the findings of this study will help policy makers optimally use limited resources to reduce morbidity and mortality in people living with T1DM., International Registered Report Identifier (irrid): RR1-10.2196/44308., (©Sindeep Bhana, Poobalan Naidoo, Somasundram Pillay, Ebrahim Variava, Kiolan Naidoo, Neeresh Rohitlall, Lauren Sekhuthe, Bruno Pauly. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 13.02.2023.)

Background: Data on risk factors for coronavirus disease 2019 (COVID-19)-associated hospitalization and mortality in high human immunodeficiency virus (HIV) prevalence settings are limited., Methods: Using existing syndromic surveillance programs for influenza-like-illness and severe respiratory illness at sentinel sites in South Africa, we identified factors associated with COVID-19 hospitalization and mortality., Results: From April 2020 through March 2022, severe acute respiratory syndrome coronavirus 2 was detected in 24.0% (660 of 2746) of outpatient and 32.5% (2282 of 7025) of inpatient cases. Factors associated with COVID-19-associated hospitalization included the following: older age (25-44 [adjusted odds ratio {aOR}= 1.8, 95% confidence interval (CI) = 1.1-2.9], 45-64 [aOR = 6.8, 95% CI = 4.2-11.0] and ≥65 years [aOR = 26.6, 95% CI = 14.4-49.1] vs 15-24 years); black race (aOR, 3.3; 95% CI, 2.2-5.0); obesity (aOR, 2.3; 95% CI, 1.4-3.9); asthma (aOR, 3.5; 95% CI, 1.4-8.9); diabetes mellitus (aOR, 5.3; 95% CI, 3.1-9.3); HIV with CD4 ≥200/mm 3 (aOR, 1.5; 95% CI, 1.1-2.2) and CD4 <200/mm 3 (aOR, 10.5; 95% CI, 5.1-21.6) or tuberculosis (aOR, 12.8; 95% CI, 2.8-58.5). Infection with Beta (aOR, 0.5; 95% CI, .3-.7) vs Delta variant and being fully vaccinated (aOR, 0.1; 95% CI, .1-.3) were less associated with COVID-19 hospitalization. In-hospital mortality was increased in older age (45-64 years [aOR, 2.2; 95% CI, 1.6-3.2] and ≥65 years [aOR, 4.0; 95% CI, 2.8-5.8] vs 25-44 years) and male sex (aOR, 1.3; 95% CI, 1.0-1.6) and was lower in Omicron-infected (aOR, 0.3; 95% CI, .2-.6) vs Delta-infected individuals., Conclusions: Active syndromic surveillance encompassing clinical, laboratory, and genomic data identified setting-specific risk factors associated with COVID-19 severity that will inform prioritization of COVID-19 vaccine distribution. Elderly people with tuberculosis or people with HIV, especially severely immunosuppressed, should be prioritized for vaccination., Competing Interests: Potential conflicts of interest. S. M. received an investigational grant from Sanofi Pasteur unrelated to this research. N. W. and A. v. G. received funding from Sanofi, and the Bill & Melinda Gates Foundation. C. C. has received funding from the Wellcome Trust and US CDC related to this work and PATH, South African Medical Research Council, Sanofi, and the Bill & Melinda Gates Foundation unrelated to this work. S. W. has received funding from US CDC related to this work. M. d. P. has received funding from the Bill & Melinda Gates foundation and the National Research Foundation, South Africa, unrelated to this work. J. M. has received grant funds from Pfizer, unrelated to this work., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Rapid switching from second-line to third-line antiretroviral therapy (TLART) is crucial for achieving viral suppression and reducing illness related to ART failure., Objectives: This retrospective cohort study quantified the waiting periods for TLART initiation after virological failure on second-line therapy was detected, assessed factors associated with delays and assessed the outcomes of patients started on TLART., Method: Data were abstracted from records of individuals eligible for TLART, and the time to TLART initiation was calculated. Reasons for delays were categorised according to patient, clinician and administrative processes., Results: Fifty-four patients were eligible for TLART. The median delay from the date of first viral load > 1000 copies/mL on second-line therapy to the start of TLART was 640 days (interquartile range [IQR]: 451-983 days). Of the patients that failed second-line and had an application for TLART, 41 (75.6%) were eventually initiated on TLART, and 11 (20.4%) died while waiting. Delays were primarily due to non-response to the first unsuppressed viral load while on second-line ART: 467 days (IQR: 232-803 days)., Conclusion: This study showed a prolonged waiting period for TLART initiation mainly between detected high viral load to requesting of resistance tests; many factors could have contributed, including clinicians' delayed responses to elevated viral loads. Mortality was high before TLART could be initiated. The process of TLART initiation needs to be made more efficient. Healthcare services should be strengthened to (1) recognise and manage virological failure early and identify those eligible for resistance testing, (2) ensure access to resistance testing and appropriately skilled clinicians, and (3) streamline approvals and delivery of TLART., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (© 2022. The Authors.)

Host genetic factors are known to modify the susceptibility, severity, and outcomes of COVID-19 and vary across populations. However, continental Africans are yet to be adequately represented in such studies despite the importance of genetic factors in understanding Africa's response to the pandemic. We describe the development of a research resource for coronavirus host genomics studies in South Africa known as COVIGen-SA-a multicollaborator strategic partnership designed to provide harmonised demographic, clinical, and genetic information specific to Black South Africans with COVID-19. Over 2,000 participants have been recruited to date. Preliminary results on 1,354 SARS-CoV-2 positive participants from four participating studies showed that 64.7% were female, 333 had severe disease, and 329 were people living with HIV. Through this resource, we aim to provide insights into host genetic factors relevant to African-ancestry populations, using both genome-wide association testing and targeted sequencing of important genomic loci. This project will promote and enhance partnerships, build skills, and develop resources needed to address the COVID-19 burden and associated risk factors in South African communities., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Andrew K. May et al.)

Background: The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear., Methods: We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated., Results: A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups., Conclusions: A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.)., (Copyright © 2022 Massachusetts Medical Society.)

Background: Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg., Methods: ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and <14 kg). Children weighing less than 14 kg starting first-line or second-line ART were enrolled in seven HIV treatment centres in South Africa, Uganda, and Zimbabwe. Randomisation, which was computer generated by the trial statistician, was stratified by first-line or second-line ART and three weight bands. Dispersible 5 mg dolutegravir was dosed according to WHO weight bands. The primary outcome was the Kaplan-Meier estimated proportion of children with virological or clinical failure by 96 weeks, defined as: confirmed viral load of at least 400 copies per mL after week 36; absence of virological suppression by 24 weeks followed by a switch to second-line or third-line ART; all-cause death; or a new or recurrent WHO stage 4 or severe WHO stage 3 event. The primary outcome was assessed by intention to treat in all randomly assigned participants. A primary Bayesian analysis of the difference in the proportion of children meeting the primary outcome between treatment groups incorporated evidence from the higher weight cohort (≥14 kg) in a prior distribution. A frequentist analysis was also done of the lower weight cohort (<14 kg) alone. Safety analyses are presented for all randomly assigned children in this study (<14 kg cohort). ODYSSEY is registered with ClinicalTrials.gov, NCT02259127., Findings: Between July 5, 2018, and Aug 26, 2019, 85 children weighing less than 14 kg were randomly assigned to receive dolutegravir (n=42) or standard of care (n=43; 32 [74%] receiving protease inhibitor-based ART). Median age was 1·4 years (IQR 0·6-2·0) and median weight 8·1 kg (5·4-10·0). 72 (85%) children started first-line ART and 13 (15%) started second-line ART. Median follow-up was 124 weeks (112-137). By 96 weeks, treatment failure occurred in 12 children in the dolutegravir group (Kaplan-Meier estimated proportion 31%) versus 21 (48%) in the standard-of-care group. The Bayesian estimated difference in treatment failure (dolutegravir minus standard of care) was -10% (95% CI -19% to -2%; p=0·020), demonstrating superiority of dolutegravir. The frequentist estimated difference was -18% (-36% to 2%; p=0·057). 15 serious adverse events were reported in 11 (26%) children in the dolutegravir group, including two deaths, and 19 were reported in 11 (26%) children in the standard-of-care group, including four deaths (hazard ratio [HR] 1·08 [95% CI 0·47-2·49]; p=0·86). 36 adverse events of grade 3 or higher were reported in 19 (45%) children in the dolutegravir group, versus 34 events in 21 (49%) children in the standard-of-care group (HR 0·93 [0·50-1·74]; p=0·83). No events were considered related to dolutegravir., Interpretation: Dolutegravir-based ART was superior to standard of care (mainly protease inhibitor-based) with a lower risk of treatment failure in infants and young children, providing support for global dispersible dolutegravir roll-out for younger children and allowing alignment of adult and paediatric treatment., Funding: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council., Competing Interests: Declaration of interests AT has received funding for her service on the Global Paediatrics Advisory Board between Oct 4, 2021, and Nov 14, 2021, with payments made to the MRC Clinical Trials Unit at University College London. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Rationale: Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to ∼6 months remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Objectives: To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB (i.e., without resistance to fluoroquinolones or aminoglycosides). Methods: Participants were randomly assigned (1:1 ratio) to a ∼6-month all-oral regimen that included levofloxacin, bedaquiline, and linezolid, or the standard-of-care (SOC) ⩾9-month World Health Organization (WHO)-approved injectable-based regimen. The primary endpoint was a favorable WHO-defined treatment outcome (which mandates that prespecified drug substitution is counted as an unfavorable outcome) 24 months after treatment initiation. The trial was stopped prematurely when bedaquiline-based therapy became the standard of care in South Africa. Measurements and Main Results: In total, 93 of 111 randomized participants (44 in the comparator arm and 49 in the interventional arm) were included in the modified intention-to-treat analysis; 51 (55%) were HIV coinfected (median CD4 count, 158 cells/ml). Participants in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome than participants in the SOC arm (51% [25 of 49] vs. 22.7% [10 of 44]; risk ratio, 2.2 [1.2-4.1]; P  = 0.006). Toxicity-related drug substitution occurred more frequently in the SOC arm (65.9% [29 of 44] vs. 34.7% [17 of 49]; P  = 0.001)], 82.8% (24 of 29) owing to kanamycin (mainly hearing loss; replaced by bedaquiline) in the SOC arm, and 64.7% (11 of 17) owing to linezolid (mainly anemia) in the interventional arm. Adverse event-related treatment discontinuation in the safety population was more common in the SOC arm (56.4% [31 of 55] vs. 32.1% [17 of 56]; P  = 0.007). However, grade 3 adverse events were more common in the interventional arm (55.4% [31 of 56] vs. 32.7 [18 of 55]; P  = 0.022). Culture conversion was significantly better in the intervention arm (hazard ratio, 2.6 [1.4-4.9]; P  = 0.003) after censoring those with bedaquiline replacement in the SOC arm (and this pattern remained consistent after censoring for drug replacement in both arms; P  = 0.01). Conclusions: Compared with traditional injectable-containing regimens, an all-oral 6-month levofloxacin, bedaquiline, and linezolid-containing MDR/RR-TB regimen was associated with a significantly improved 24-month WHO-defined treatment outcome (predominantly owing to toxicity-related drug substitution). However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB.Clinical trial registered with www.clinicaltrials.gov (NCT02454205).

Background: Estimates of the disease burden associated with different respiratory viruses are severely limited in low- and middle-income countries, especially in Africa., Methods: We estimated age-specific numbers and rates of medically and non-medically attended influenza-like illness (ILI) and severe respiratory illness (SRI) that were associated with influenza, respiratory syncytial virus (RSV), rhinovirus, human metapneumovirus, adenovirus, enterovirus and parainfluenza virus types 1-3 after adjusting for the attributable fraction (AF) of virus detection to illness in South Africa during 2013-2015. The base rates were estimated from five surveillance sites and extrapolated nationally., Results: The mean annual rates per 100,000 population were 51,383 and 4196 for ILI and SRI, respectively. Of these, 26% (for ILI) and 46% (for SRI) were medically attended. Among outpatients with ILI, rhinovirus had the highest AF-adjusted rate (7221), followed by influenza (6443) and adenovirus (1364); whereas, among inpatients with SRI, rhinovirus had the highest AF-adjusted rate (400), followed by RSV (247) and influenza (130). Rhinovirus (9424) and RSV (2026) had the highest AF-adjusted rates among children aged <5 years with ILI or SRI, respectively, whereas rhinovirus (757) and influenza (306) had the highest AF-adjusted rates among individuals aged ≥65 years with ILI or SRI, respectively., Conclusions: There was a substantial burden of ILI and SRI in South Africa during 2013-2015. Rhinovirus and influenza had a prominent disease burden among patients with ILI. RSV and influenza were the most prominent causes of SRI in children and the elderly, respectively., (© 2022 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19)., Methods: Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes., Findings: Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR., Interpretation: Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential., Funding: National Institute for Communicable Diseases of South Africa., Competing Interests: Declaration of interests NAI reports partial support from Janssen Pharmaceuticals to the institution for the consumables used for bedaquiline drug susceptibility testing. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: We aimed to describe the prevalence of human respiratory syncytial virus (HRSV) and evaluate associations between HRSV subgroups and/or genotypes and epidemiologic characteristics and clinical outcomes in patients hospitalized with severe respiratory illness (SRI)., Methods: Between January 2012 and December 2015, we enrolled patients of all ages admitted to two South African hospitals with SRI in prospective hospital-based syndromic surveillance. We collected respiratory specimens and clinical and epidemiological data. Unconditional random effect multivariable logistic regression was used to assess factors associated with HRSV infection., Results: HRSV was detected in 11.2% (772/6908) of enrolled patients of which 47.0% (363/772) were under the age of 6 months. There were no differences in clinical outcomes of HRSV subgroup A-infected patients compared with HRSV subgroup B-infected patients but among patients aged <5 years, children with HRSV subgroup A were more likely be coinfected with Streptococcus pneumoniae (23/208, 11.0% vs. 2/90, 2.0%; adjusted odds ratio 5.7). No significant associations of HRSV A genotypes NA1 and ON1 with specific clinical outcomes were observed., Conclusions: While HRSV subgroup and genotype dominance shifted between seasons, we showed similar genotype diversity as noted worldwide. We found no association between clinical outcomes and HRSV subgroups or genotypes., (© 2021 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Introduction: Sex workers in South Africa experience high levels of trauma and mental health issues, but little is known about their drug and alcohol use. This study assessed the prevalence of substance use and its key risk factors amongst female sex workers (FSWs) at two sites in South Africa., Methods: Two cross-sectional studies were conducted, in Soweto and Klerksdorp, South Africa. Using respondent-driven sampling (RDS) 508 FSWs in Soweto and 156 in Klerksdorp were enrolled. A study-specific survey was used to collect social and demographic information, substance use, mental ill-health, and HIV status. Raw and RDS-adjusted data were analyzed using Chi-squared tests of association. Weighted and unweighted Poisson regression models were used to assess key risk factors for alcohol and drug use at both univariate and multivariate levels., Results: Of the 664 FSWs, 56.2% were binge drinkers and 29.4% reported using drugs within the last year. Living in a home with regular food (RR: 1.2597, 95% CI: 1.1009-1.4413) and being HIV positive (RR: 1.1678, 95% CI: 1.0227-1.3334) were associated with a higher risk of binge drinking. Having symptoms suggestive of post-traumatic stress disorder (RR: 1.1803, 95% CI: 1.0025-1.3895) and past year physical/sexual abuse from either intimate (RR: 1.3648, 95% CI: 1.1522-1.6167) or non-intimate partners (RR: 1.3910, 95% CI: 1.1793-1.6407) were associated with a higher risk of drug use., Discussion: In conclusion, our findings demonstrate a high prevalence of alcohol and drug use among FSWs in Soweto and Klerksdorp with site-specific contextual dynamics driving substance use. Site differences highlight the importance of tailoring site-specific substance use harm mitigation for this key population., Competing Interests: The authors have declared that no competing interests exist.

Background: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART)., Methods: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed., Results: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01)., Conclusions: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.)., (Copyright © 2021 Massachusetts Medical Society.)

The global burden of the endemic mycoses (blastomycosis, coccidioidomycosis, emergomycosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and talaromycosis) continues to rise yearly and these infectious diseases remain a leading cause of patient morbidity and mortality worldwide. Management of the associated pathogens requires a thorough understanding of the epidemiology, risk factors, diagnostic methods and performance characteristics in different patient populations, and treatment options unique to each infection. Guidance on the management of these infections has the potential to improve prognosis. The recommendations outlined in this Review are part of the "One World, One Guideline" initiative of the European Confederation of Medical Mycology. Experts from 23 countries contributed to the development of these guidelines. The aim of this Review is to provide an up-to-date consensus and practical guidance in clinical decision making, by engaging physicians and scientists involved in various aspects of clinical management., Competing Interests: Declaration of Interests GRT received research funding from Amplyx Pharmaceuticals, Astellas, Basilea Pharmaceutica, Cidara Therapeutics, F2G, IMMY, Mayne Pharma, and Scynexis, and served as a consultant for Amplyx Pharmaceuticals, Astellas, Basilea Pharmaceutica, Cidara Therapeutics, F2G, IMMY, Mayne Pharma, Scynexis, and Pfizer. MJB is a founding partner and holds shares of Micología Molecular SL, she has received grant support from the Instituto de Salud Carlos III and has been paid for talks on behalf of United Medical LTDA. AA-I has received research grants to their institution from F2G and honoraria as a speaker from Gilead Sciences and Pfizer. DA-J holds share options in Pulmocide and has received grant support from Pulmocide, Astellas Pharma, Pfizer, and Gilead Sciences. He has received lecture honoraria from Astellas Pharma, Pfizer, Gilead Sciences, and AstraZeneca. JWB has served as a consultant for Pfizer. JFWC has received travel grants from Pfizer Corporation Hong Kong and Astellas Pharma Hong Kong, and was an invited speaker for Gilead Sciences Hong Kong and Luminex Corporation. OAC is funded by the German Federal Ministry of Education and Research, is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy (CECAD, EXC 2030—390661388), and has received research grants from Actelion, Amplyx Pharmaceuticals, Astellas Pharma, Basilea Pharmaceutica, Cidara Therapeutics, Da Volterra, F2G, Gilead Sciences, Janssen Pharmaceuticals, Medicines Company, MedPace, Melinta Therapeutics, Merck/MSD, Pfizer, and, Scynexis. OAC is also a consultant to Actelion, Allecra Therapeutics, Amplyx Pharmaceuticals, Astellas, Basilea Pharmaceutica, Biosys UK, Cidara Therapeutics, Da Volterra, Entasis, F2G, Gilead Sciences, Matinas BioPharma, MedPace, Menarini Ricerche, Roche Diagnostics, Merck/MSD, Nabriva Therapeutics, Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Scynexis, Seres Therapeutics, Tetraphase, and Vical, and received lecture honoraria from Astellas, Basilea Pharmaceutica, Gilead Sciences, Grupo Biotoscana, Merck/MSD, and Pfizer. NK received honoraria from Astellas, Gilead Sciences, Merck/MSD, and Pfizer, and received grants from Merck/MSD and Pfizer. NK was a speaker for Astellas, Gilead Sciences, Merck/MSD, and Pfizer and an adviser for Gilead Sciences, Merck/MSD, and Pfizer. DCMK has sat on advisory boards for Becton Dickinson and Merck/MSD, and received financial and travel support unrelated to the current work from Merck/MSD. MHM has received research support and served as a consultant for Astellas and Scynexis. ISS has served as an adviser to Avir Pharma. AS has received grant funding from Astellas and has consulted for Scynexis, Minnetronix Medical, Mayne Pharma, and Viamet Pharmaceuticals. J-PG has received research grant support from Pfizer. FQ-T has received research grants from Astellas, Merck/MSD, and Pfizer, and also received payments for presentations and continued medical education from Merck/MSD, Pfizer, United Medical, and Teva Brazil. PEV reported grants from Gilead Sciences, Merck/MSD, Pfizer, F2G, and Thermo Fisher Scientific, and travel support from OLM Systems and IMMY, outside of the submitted work. ACP has received research grant support on behalf of Pfizer, Gilead Sciences, Merck/MSD, and IMMY. He has also given paid talks for Pfizer, United Medical, Gilead Sciences, Merck/MSD, Astellas, and IMMY, and participated on the medical board of Pfizer, United Medical, Gilead Sciences, and Merck/MSD. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: HIV and tuberculosis (TB) independently cause an increased risk for venous thromboembolic disease (VTE): deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Data from high HIV and TB burden settings describing VTE are scarce. The Wells' DVT and PE scores are widely used but their utility in these settings has not been reported on extensively., Objectives: To evaluate new onset VTE, compare clinical characteristics by HIV status, and the presence or absence of TB disease in our setting. We also calculate the Wells' score for all patients., Methods: A prospective cohort of adult in-patients with radiologically confirmed VTE were recruited into the study between September 2015 and May 2016. Demographics, presence of TB, HIV status, duration of treatment, CD4 count, viral load, VTE risk factors, and parameters to calculate the Wells' score were collected., Results: We recruited 100 patients. Most of the patients were HIV-infected ( n =59), 39 had TB disease and 32 were HIV/TB co-infected. Most of the patients had DVT only ( n =83); 11 had PE, and 6 had both DVT and PE. More than a third of patients on antiretroviral treatment (ART) (43%; n =18/42) were on treatment for <6 months. Half of the patients (51%; n =20/39) were on TB treatment for <1 month. The median (interquartile range (IQR)) DVT and PE Wells' score in all sub-groups was 3.0 (1.0 - 4.0) and 3.0 (2.5 - 4.5), respectively., Conclusion: HIV/TB co-infection appears to confer a risk for VTE, especially early after initiation of ART and/or TB treatment, and therefore requires careful monitoring for VTE and early initiation of thrombo-prophylaxis., Competing Interests: Conflicts of interest: None.

Background: Policy recommendations on pertussis vaccination need to be guided by data, which are limited from low- and middle-income countries. We aimed to describe the epidemiology of pertussis in South Africa, a country with high human immunodeficiency virus (HIV) prevalence and routine pertussis vaccination for 6 decades including the acellular vaccine since 2009., Methods: Hospitalized patients of all ages were enrolled at 5 sentinel sites as part of a pneumonia surveillance program from January 2013 through December 2018. Nasopharyngeal specimens and induced sputum were tested by polymerase chain reaction (PCR) for Bordetella pertussis. In addition, demographic and clinical information were collected. Incidence rates were calculated for 2013-2016, and multivariable logistic regression performed to identify factors associated with pertussis., Results: Over the 6-year period 19 429 individuals were enrolled, of which 239 (1.2%) tested positive for B. pertussis. Detection rate was highest in infants aged <6 months (2.8%, 155/5524). Mean annual incidence was 17 cases per 100 000 population, with the highest incidence in children <1 year of age (228 per 100 000). Age-adjusted incidence was 65.9 per 100 000 in HIV-infected individuals compared to 8.5 per 100 000 in HIV-uninfected individuals (risk ratio 30.4, 95% confidence interval: 23.0-40.2). Ten individuals (4.2%) with pertussis died; of which 7 were infants aged <6 months and 3 were immunocompromised adults., Conclusions: Pertussis continues to be a significant cause of illness and hospitalization in South Africa, despite routine vaccination. The highest burden of disease and death occurred in infants; however, HIV-infected adults were also identified as an important group at risk of B. pertussis infection., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

BackgroundIn South Africa, COVID-19 control measures to prevent SARS-CoV-2 spread were initiated on 16 March 2020. Such measures may also impact the spread of other pathogens, including influenza virus and respiratory syncytial virus (RSV) with implications for future annual epidemics and expectations for the subsequent northern hemisphere winter.MethodsWe assessed the detection of influenza and RSV through facility-based syndromic surveillance of adults and children with mild or severe respiratory illness in South Africa from January to October 2020, and compared this with surveillance data from 2013 to 2019.ResultsFacility-based surveillance revealed a decline in influenza virus detection during the regular season compared with previous years. This was observed throughout the implementation of COVID-19 control measures. RSV detection decreased soon after the most stringent COVID-19 control measures commenced; however, an increase in RSV detection was observed after the typical season, following the re-opening of schools and the easing of measures.ConclusionCOVID-19 non-pharmaceutical interventions led to reduced circulation of influenza and RSV in South Africa. This has limited the country's ability to provide influenza virus strains for the selection of the annual influenza vaccine. Delayed increases in RSV case numbers may reflect the easing of COVID-19 control measures. An increase in influenza virus detection was not observed, suggesting that the measures may have impacted the two pathogens differently. The impact that lowered and/or delayed influenza and RSV circulation in 2020 will have on the intensity and severity of subsequent annual epidemics is unknown and warrants close monitoring.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed. METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa 200 MZ) or 4 months (4Pa 200 MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa 100 MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed. RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa 200 MZ, 4Pa 200 MZ, 4Pa 100 MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa 200 MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died. CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Host-directed therapies (HDTs) enhance the host response to tuberculosis (TB) infection to reduce disease severity. For instance, the manipulation of lipid mediator production diminishes the hyperactive immune response which is a known pathological feature of TB that generates lung tissue damage. Non-steroidal anti-inflammatory drugs (NSAIDs) and omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are examples of such HDTs. In this mini-review, we recapitulate the literature available on the effects of NSAIDs and n-3 LCPUFA in TB as well as the immunological pathways underpinning these effects. Many NSAIDs have a great deal of data describing their effects and safety and in many jurisdictions are inexpensive, and sold over the counter in neighborhood convenience stores and supermarkets. The potential benefits of NSAIDs in TB are well-documented in pre-clinical studies. The reduction of pro-inflammatory lipid mediator production by inhibiting cyclooxygenase (COX) pathways with NSAIDs has been found to improve lung histopathology, bacterial control, and survival. Additionally, n-3 LCPUFA and its novel bioactive metabolites produced by COX and lipoxygenase (LOX) have been identified as safe and effective pro-resolving and antibacterial pharmaconutrients. Nevertheless, heterogeneous results have been reported in pre-clinical TB studies. Recently, the importance of the correct timing of NSAIDs and n-3 LCPUFA administration in TB has also been highlighted. This mini-review will provide a better understanding of the potential contribution of these therapies toward reducing inflammatory lung damage and improving bactericidal activity, especially during later stages of TB infection. It further highlights that clinical trials are required to confirm benefit and safety in TB patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nienaber, Hayford, Variava, Martinson and Malan.)

Background: Tuberculosis is a top-10 cause of under-5 mortality, despite policies promoting tuberculosis preventive therapy (TPT). We previously conducted a cluster randomized trial to evaluate the effectiveness of symptom-based versus tuberculin skin-based screening on child TPT uptake. Symptom-based screening did not improve TPT uptake and nearly two-thirds of child contacts were not identified or not linked to care. Here we qualitatively explored healthcare provider perceptions of factors that impacted TPT uptake among child contacts., Methods: Sixteen in-depth interviews were conducted with key informants including healthcare providers and administrators who participated in the trial in Matlosana, South Africa. The participants' experience with symptom-based screening, study implementation strategies, and ongoing challenges with child contact identification and linkage to care were explored. Interviews were systematically coded and thematic content analysis was conducted., Results: Participants' had mixed opinions about symptom-based screening and high acceptability of the study implementation strategies. A key barrier to optimizing child contact screening and evaluation was the supervision and training of community health workers., Conclusions: Symptom screening is a simple and effective strategy to evaluate child contacts, but additional pediatric training is needed to provide comfort with decision making. New clinic-based child contact files were highly valued by providers who continued to use them after trial completion. Future interventions to improve child contact management will need to address how to best utilize community health workers in identifying and linking child contacts to care., Trial Registration: The results presented here were from research related to NCT03074799 , retrospectively registered on 9 March 2017.

Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development., Methods: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks., Results: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls., Conclusions: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children., Trial Registration: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.

South Africa processes 5.1 million HIV CD4, viral load (VL), and tuberculosis (TB) tests annually. This pilot non-randomized trial in South Africa explored an intervention ("MatlaMobile") to deliver laboratory results via mobile phone. Adults completing CD4, VL, and/or TB laboratory tests were enrolled-either receiving results by returning to clinic (control, n = 174) or mobile phone (intervention, n = 226). Study staff instructed control participants to return within 6 days (standard-of-care). MatlaMobile instructed intervention participants with clinically actionable results requiring intervention or treatment change (i.e., < 200 CD4 cells per milliliter, ≥ 400 viral copies per milliliter, or TB positive) to return immediately. A greater proportion of intervention participants than controls saw their results within 7 days of enrollment (73% vs. 8.6%, p < 0.001). Among participants instructed to return, more intervention participants (20%, n = 14/70) returned than controls (8.6%, n = 15/174, p = 0.02). MatlaMobile demonstrated that patients can quickly receive and respond appropriately to digital delivery of health information.

Background: Data on influenza economic burden in risk groups for severe influenza are important to guide targeted influenza immunization, especially in resource-limited settings. However, this information is limited in low- and middle-income countries., Methods: We estimated the cost (from a health system and societal perspective) and years of life lost (YLL) for influenza-associated illness in South Africa during 2013-2015 among (i) children aged 6-59 months, (ii) individuals aged 5-64 years with HIV, pulmonary tuberculosis (PTB) and selected underlying medical conditions (UMC), separately, (iii) pregnant women and (iv) individuals aged ≥65 years, using publicly available data and data collected through laboratory-confirmed influenza surveillance and costing studies. All costs were expressed in 2015 prices using the South Africa all-items Consumer Price Index., Results: During 2013-2015, the mean annual cost of influenza-associated illness among the selected risk groups accounted for 52.1% ($140.9/$270.5 million) of the total influenza-associated illness cost (for the entire population of South Africa), 45.2% ($52.2/$115.5 million) of non-medically attended illness costs, 43.3% ($46.7/$107.9 million) of medically-attended mild illness costs and 89.3% ($42.0/$47.1 million) of medically-attended severe illness costs. The YLL among the selected risk groups accounted for 86.0% (262,069 /304,867 years) of the total YLL due to influenza-associated death., Conclusion: In South Africa, individuals in risk groups for severe influenza accounted for approximately half of the total influenza-associated illness cost but most of the cost of influenza-associated medically attended severe illness and YLL. This study provides the foundation for future studies on the cost-effectiveness of influenza immunization among risk groups., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: All people with HIV who screen negative for active tuberculosis (TB) should receive isoniazid preventive therapy (IPT). IPT implementation remains substantially below the 90% WHO target. This study sought to further understanding of IPT prescription by piloting a simplified prescribing approach., Setting: Primary care clinics in Matlosana, South Africa., Design: This was a mixed-methods implementation study., Methods: Nine providers were recruited and underwent training on 2018 WHO guidelines. A simplified prescribing tool containing antiretroviral therapy (ART) and IPT prescriptions was introduced into the workflow for 2 weeks. Prescription data were collected from file review. Interviews were conducted with prescribers., Results: During the study period, 41 patients were evaluated for ART initiation; 34 (83%) files used the simplified prescribing tool. Thirty-seven (90%) patients were eligible for same-day ART and IPT initiation, of whom 36 (97%) received IPT prescription. Qualitative interviews identified the following barriers to IPT prescription: cognitive burden, extensive documentation, limited management support, paucity of training, stock-outs, and patient-related factors. Provider acceptability of the tool was favorable, with unanimous recommendation to colleagues on the basis of streamlining documentation and reminding to prescribe., Conclusions: This simplified prescribing device for IPT was feasible to implement. Streamlining documentation and reminding providers to prescribe can reduce work-flow barriers to IPT provision., Competing Interests: Conflicts of interest: none declared., (© 2020 The Union.)

Background: In acute sepsis, reduced lipid and lipoprotein levels occur in HIV negative patients, in particular, low high-density lipoprotein cholesterol (HDL-c) levels are inversely correlated with sepsis severity and increased mortality. However, due to the limited data describing lipid and lipoprotein levels in septic HIV-infected individuals we aimed to investigate the changes in this subgroup., Materials and Methods: A prospective cross-sectional observational study of HIV-infected patients comparing admitted HIV - infected patients with sepsis to healthy controls from the antiretroviral therapy (ART) clinic. Non fasting - lipograms, ART use, diagnosis of tuberculosis (TB), markers of infection, renal function and mortality outcome to 3 months post discharge were reviewed., Results: Total cholesterol (TC), low-density lipoprotein (LDL-c) and HDL-c were all significantly lower in the sepsis group (p < 0.001). HDL-c was significantly associated with a higher white cell count (p = 0.018), higher C- reactive protein (p = 0.036) and low serum albumin (p < 0.001). In those with active TB (55%) HDL-c was reduced even further (0.55 vs. 0.72mmol/L, p = 0.013). Acute kidney injury (p = 0.560) and mortality at discharge (p = 0.097) or 3 months follow up (p = 0.953) was not associated with reduced HDL-c., Conclusion: Septic HIV-infected patients had significantly reduced lipid and lipoprotein levels at admission. Of note however, a low HDL-c was associated with markers of infection and reductions in HDL-c was more marked in those with active TB., (Copyright: © 2020 Afr. J. Infect. Diseases.)

Background: Data on influenza burden in risk groups for severe influenza are important to guide targeted influenza immunization, especially in resource limited settings. However, this information is limited overall and in particular in low- and middle-income countries. We sought to assess the mean annual national burden of medically and non-medically attended influenza-associated mild, severe-non-fatal and fatal illness among potential target groups for influenza immunization in South Africa during 2013-2015., Methods: We used published mean national annual estimates of mild, severe-non-fatal, and fatal influenza-associated illness in South Africa during 2013-2015 and estimated the number of such illnesses occurring among the following risk groups: (i) children aged 6-59 months; (ii) individuals aged 5-64 years with HIV, and/or pulmonary tuberculosis (PTB), and/or selected underlying medical conditions (UMC); (iii) pregnant women; and (iv) individuals aged ≥65 years. We also estimated the number of individuals among the same risk groups in the population., Results: During 2013-2015, individuals in the selected risk groups accounted for 45.3% (24,569,328/54,086,144) of the population and 43.5% (4,614,763/10,598,138), 86.8% (111,245/128,173) and 94.5% (10,903/11,536) of the mean annual estimated number of influenza-associated mild, severe-non-fatal and fatal illness episodes, respectively. The rates of influenza-associated illness were highest in children aged 6-59 months (23,983 per 100,000 population) for mild illness, in pregnant women (930 per 100,000 population) for severe-non-fatal illness and in individuals aged ≥65 years (138 per 100,000 population) for fatal illness., Conclusion: Influenza immunization of the selected risk groups has the potential to prevent a substantial number of influenza-associated severe illness. Nonetheless, because of the high number of individuals at risk, South Africa, due to financial resources constrains, may need to further prioritize interventions among risk populations. Cost-burden and cost-effectiveness estimates may assist with further prioritization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Rifampicin-resistant (RR) tuberculosis (TB) on X-pert Mycobacterium tuberculosis/rifampicin (MTB/Rif) is assumed to be a surrogate for multi-drug resistant (MDR) TB. Following an RR result, a second specimen was taken for confirmatory culture and drug-susceptibility testing (DST). This study compared the initial diagnostic X-pert MTB/RIF result with the confirmatory DST in a high human immunodeficiency virus (HIV) seroprevalence setting., Design: Records analysing demographics, HIV serostatus, prior TB treatments, and DST results were retrospectively reviewed., Results: Of 604 patients with X-pert MTB/RIF RR, 374 (61.9%) had DST and were included. The mean age was 36.9 years and 82% were HIV infected. Following DST, MDR was confirmed in 49% and Rif mono-resistant (RMR) TB in 36%. Amongst RMR TB, 84% were HIV-infected, and amongst those with CD4 < 50 versus those 50-350 cells/mm 3 RMR TB was noted in 51% versus 33%, respectively (P = 0.012). Primary DR was diagnosed in 43% (61% MDR and 33% RMR)., Conclusion: Rifampicin resistance detected on a diagnostic X-pert MTB/Rif assay did not always predict MDR. Rifampicin mono-resistance is emerging amongst those with HIV co-infection and low CD4 counts (<50 cells/mm 3 ). Research is needed to reduce the number of drugs and treatment durations for RMR TB., (Copyright © 2019 International Society for Antimicrobial Chemotherapy. Published by Elsevier Ltd. All rights reserved.)

Background: Tuberculosis preventive therapy (TPT) is highly effective at preventing tuberculosis disease in household child contacts (<5 years), but is poorly implemented worldwide. In 2006, the World Health Organization recommended symptom-based screening as a replacement for tuberculin skin testing (TST) to simplify contact evaluation and improve implementation. We aimed to determine the effectiveness of this recommendation., Methods: We conducted a pragmatic, cluster-randomized trial to determine whether contact evaluation using symptom screening improved the proportion of identified child contacts who initiated TPT, compared to TST-based screening, in Matlosana, South Africa. We randomized 16 clinics to either symptom-based or TST-based contact evaluations. Outcome data were abstracted from customized child contact management files., Results: Contact tracing identified 550 and 467 child contacts in the symptom and TST arms, respectively (0.39 vs 0.32 per case, respectively; P = .27). There was no significant difference by arm in the adjusted proportion of identified child contacts who were screened (52% in symptom arm vs 60% in TST arm; P = .39). The adjusted proportion of identified child contacts who initiated TPT or tuberculosis treatment was 51.5% in the symptom clinics and 57.1% in the TST clinics (difference -5.6%, 95% confidence interval -23.7 to 12.6; P = .52). Based on the district's historic average of 0.7 child contacts per index case, 14% and 15% of child contacts completed 6 months of TPT in the symptom and TST arms, respectively (P = .89)., Conclusions: Symptom-based screening did not improve the proportion of identified child contacts evaluated or initiated on TPT, compared to TST-based screening. Further research is needed to identify bottlenecks and evaluate interventions to ensure all child contacts receive TPT., Clinical Trials Registration: NCT03074799., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Introduction: Household contacts of patients with active pulmonary tuberculosis (TB) often have latent TB infection, and are at risk of progression to disease. We set out to investigate whether index TB case HIV status was linked to a higher probability of latent TB infection among household contacts., Materials and Methods: Data were collected prospectively from participants in the intervention arm of a household cluster-randomised trial in two South Africa provinces (Mangaung, Free State, and Capricorn, Limpopo). In intervention group households, TB contacts underwent HIV testing and tuberculin skin testing (TST). TST induration was estimated at two cut-offs (≥5mm, ≥10mm). Multilevel Bayesian regression models estimated posterior distributions of the percentage of household contacts with TST induration ≥5mm and ≥10mm by age group, and compared the odds of latent TB infection by key risk factors including HIV status index case age and study province., Results: A total of 2,985 household contacts of 924 index cases were assessed, with most 2,725 (91.3%) undergoing TST. HIV prevalence in household contacts was 14% and 10% in Mangaung and Capricorn respectively. Overall, 16.8% (458/2,725) had TST induration of ≥5mm and 13.1% (359/2,725) ≥10mm. In Mangaung, children aged 0-4 years had a high TST positivity prevalence compared to their peers in Capricorn (22.0% vs. 7.6%, and 20.5% vs. 2.3%, using TST thresholds of ≥5mm and ≥10mm respectively). Compared to contacts from Capricorn, household contacts living in Mangaung were more likely to have TST induration ≥5mm (odds ratio [OR]: 3.08, 95% credibility interval [CI]: 2.13-4.58) and ≥10mm (OR: 4.52, 95% CI: 3.03-6.97). There was a 90% and 92% posterior probability that the odds of TST induration ≥5mm (OR: 0.79, 95% CI: 0.56-1.14) and ≥10mm (OR: 0.77, 95% CI: 0.53-1.10) respectively were lower in household contacts of HIV-positive compared to HIV-negative index cases., Conclusions: High TST induration positivity, especially among young children and people living in Mangaung indicates considerable TB transmission despite high antiretroviral therapy coverage. Household contact of HIV-positive index TB cases were less likely to have evidence of latent TB infection than contacts of HIV-negative index cases., Competing Interests: The authors have declared that no competing interests exist

Understanding of the burden of HIV infection and comorbid conditions in older adults is limited, especially in low- and middle-income countries. Antiretroviral therapy (ART) has increased longevity of HIV-positive individuals, making age-related comorbidities more likely. This study aimed to compare the demographic and disease profiles, including chronic comorbid conditions of inpatients, at least 50 years of age, by HIV status, admitted to a regional hospital in South Africa. Adults, 50 years of age and older, admitted to internal medicine wards from November 2015 to February 2016 were approached to participate. Sociodemographic data, laboratory results, anthropometric data, discharge diagnoses, and HIV status were collected and compared by HIV serostatus. Overall, 151 participants were enrolled. Their median age was 61 years (IQR: 56-68 years); 89 (58.9%) were women. Overall, 47 (31.1%) were HIV positive, of whom 10 (6.6%) were first diagnosed during the admission. HIV-positive inpatients were younger than HIV-negative patients. The leading discharge diagnoses of all participants were acute gastroenteritis (11.5%) and community-acquired pneumonia (11.5%). Hypertension and type 2 diabetes mellitus (T2DM) were the leading comorbidities in both HIV-negative and HIV-positive participants. Prevalence of hypertension was 75.0% in seronegative, 59.5% in those with a prior diagnosis of HIV, and 40.0% in newly diagnosed; similarly, prevalence of T2DM was 22.1% in HIV-negative and 24.3% in known HIV-positive participants. Similar proportions died during admission; 11.3% of HIV-negative and 12.7% of HIV-positive admitted inpatients died. Almost one third of patients admitted were HIV positive. In HIV-positive older admitted to hospital, the leading cause for hospitalization was coinfections. In the ART era, irrespective of HIV status, older patients have similar age-related chronic illnesses and similar mortality rates, despite younger age at admission.