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Background: Hydroxychloroquine (HCQ) has proved ineffective in treating patients hospitalised with Coronavirus Disease 2019 (COVID-19), but uncertainty remains over its safety and efficacy in chemoprevention. Previous chemoprevention randomised controlled trials (RCTs) did not individually show benefit of HCQ against COVID-19 and, although meta-analysis did suggest clinical benefit, guidelines recommend against its use., Methods and Findings: Healthy adult participants from the healthcare setting, and later from the community, were enrolled in 26 centres in 11 countries to a double-blind, placebo-controlled, randomised trial of COVID-19 chemoprevention. HCQ was evaluated in Europe and Africa, and chloroquine (CQ) was evaluated in Asia, (both base equivalent of 155 mg once daily). The primary endpoint was symptomatic COVID-19, confirmed by PCR or seroconversion during the 3-month follow-up period. The secondary and tertiary endpoints were: asymptomatic laboratory-confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection; severity of COVID-19 symptoms; all-cause PCR-confirmed symptomatic acute respiratory illness (including SARS-CoV-2 infection); participant reported number of workdays lost; genetic and baseline biochemical markers associated with symptomatic COVID-19, respiratory illness and disease severity (not reported here); and health economic analyses of HCQ and CQ prophylaxis on costs and quality of life measures (not reported here). The primary and safety analyses were conducted in the intention-to-treat (ITT) population. Recruitment of 40,000 (20,000 HCQ arm, 20,000 CQ arm) participants was planned but was not possible because of protracted delays resulting from controversies over efficacy and adverse events with HCQ use, vaccine rollout in some countries, and other factors. Between 29 April 2020 and 10 March 2022, 4,652 participants (46% females) were enrolled (HCQ/CQ n = 2,320; placebo n = 2,332). The median (IQR) age was 29 (23 to 39) years. SARS-CoV-2 infections (symptomatic and asymptomatic) occurred in 1,071 (23%) participants. For the primary endpoint the incidence of symptomatic COVID-19 was 240/2,320 in the HCQ/CQ versus 284/2,332 in the placebo arms (risk ratio (RR) 0.85 [95% confidence interval, 0.72 to 1.00; p = 0.05]). For the secondary and tertiary outcomes asymptomatic SARS-CoV-2 infections occurred in 11.5% of HCQ/CQ recipients and 12.0% of placebo recipients: RR: 0.96 (95% CI, 0.82 to 1.12; p = 0.6). There were no differences in the severity of symptoms between the groups and no severe illnesses. HCQ/CQ chemoprevention was associated with fewer PCR-confirmed all-cause respiratory infections (predominantly SARS-CoV-2): RR 0.61 (95% CI, 0.42 to 0.88; p = 0.009) and fewer days lost to work because of illness: 104 days per 1,000 participants over 90 days (95% CI, 12 to 199 days; p < 0.001). The prespecified meta-analysis of all published pre-exposure RCTs indicates that HCQ/CQ prophylaxis provided a moderate protective benefit against symptomatic COVID-19: RR 0.80 (95% CI, 0.71 to 0.91). Both drugs were well tolerated with no drug-related serious adverse events (SAEs). Study limitations include the smaller than planned study size, the relatively low number of PCR-confirmed infections, and the lower comparative accuracy of serology endpoints (in particular, the adapted dried blood spot method) compared to the PCR endpoint. The COPCOV trial was registered with ClinicalTrials.gov; number NCT04303507., Interpretation: In this large placebo-controlled, double-blind randomised trial, HCQ and CQ were safe and well tolerated in COVID-19 chemoprevention, and there was evidence of moderate protective benefit in a meta-analysis including this trial and similar RCTs., Trial Registration: ClinicalTrials.gov NCT04303507; ISRCTN Registry ISRCTN10207947., Competing Interests: NJW and LvS are members of the PLOS Medicine Editorial Board. The rest of the authors have declared that no competing interests exist., (Copyright: © 2024 Schilling et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: To evaluate diagnostic yield and feasibility of integrating testing for TB and COVID-19 using molecular and radiological screening tools during community-based active case-finding (ACF)., Methods: Community-based participants with presumed TB and/or COVID-19 were recruited using a mobile clinic. Participants underwent simultaneous point-of-care (POC) testing for TB (sputum; Xpert Ultra) and COVID-19 (nasopharyngeal swabs; Xpert SARS-CoV-2). Sputum culture and SARS-CoV-2 RT-PCR served as reference standards. Participants underwent ultra-portable POC chest radiography with computer-aided detection (CAD). TB infectiousness was evaluated using smear microscopy, cough aerosol sampling studies (CASS), and chest radiographic cavity detection. Feasibility of POC testing was evaluated via user-appraisals., Results: Six hundred and one participants were enrolled, with 144/601 (24.0%) reporting symptoms suggestive of TB and/or COVID-19. 16/144 (11.1%) participants tested positive for TB, while 10/144 (6.9%) tested positive for COVID-19 (2/144 [1.4%] had concurrent TB/COVID-19). Seven (7/16 [43.8%]) individuals with TB were probably infectious. Test-specific sensitivity and specificity (95% CI) were: Xpert Ultra 75.0% (42.8-94.5) and 96.9% (92.4-99.2); Xpert SARS-CoV-2 66.7% (22.3-95.7) and 97.1% (92.7-99.2). Area under the curve (AUC) for CAD4TB was 0.90 (0.82-0.97). User appraisals indicated POC Xpert to have 'good' user-friendliness., Conclusions: Integrating TB/COVID-19 screening during community-based ACF using POC molecular and radiological tools is feasible, has a high diagnostic yield, and can identity probably infectious persons., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

One quarter of the world's population is estimated to be infected with Mycobacterium tuberculosis. Identifying recent TB infection (TBI) offers an avenue to targeted TB preventative therapy provision, and prevention to disease progression. However, detecting recent TBI remains challenging. The QuantiFERON-TB Gold Plus assay (QFT-Plus) claims to have improved sensitivity in detecting recent TBI, by the addition of the TB2 antigen tube to the TB1 tube used in previous tests. TB2 detects CD8-mediated interferon gamma response, a potential marker of recent infection. We compared QFT-Plus TB1 and TB2 responses in individuals with recent and remote infection in high-burden settings. The Tuberculosis Reduction through Expanded Antiretroviral Treatment and TB Screening (TREATS) Project followed a cohort of adolescents and young people (AYP) aged 15-24 years in Zambia and South Africa to determine TBI incidence measured by QFT-Plus over 24 months. We categorised individuals with QTF-Plus positive result into recent and remote infection. We compared their TB1 and TB2 responses and the antigen tube differential [TB2-TB1], an indicator of CD8-activity, using logistic regression. At baseline, 3876 AYP, 1852/3876 (47.8%) were QFT-Plus positive whilst 2024/3876 (52.2%) QFT-Plus negative. Of the QFT-Plus baseline positives, 1069/1852 (57.7%) tested positive at both 12 and 24 months-remote infection. Of the QFT-Plus baseline negatives, 274/2024(13.3%) converted within a 12-month period- recent infection. TB1 and TB2 responses were higher in remote than recent infection. In recent infection, TB2 responses were greater than TB1 responses. The mean differential was 0.01 IU/ml in recent and -0.22 IU/ml in remote infection, (p = 0.145). The quantitative QFT-Plus results did not appear to reflect a marked distinction between recent and remote infection. Further analysis of the responses of infected individuals who developed disease is required to determine whether any signal in QFT-Plus results may predict progression to disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Amofa-Sekyi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Tuberculosis (TB) continues to be a major cause of death across sub-Saharan Africa (SSA). In parallel, non-communicable disease and especially cardiovascular disease (CVD) burden has increased substantially in the region. Cardiac manifestations of TB are well-recognised but the extent to which they co-exist with pulmonary TB (PTB) has not been systematically evaluated. The aim of this study is to improve understanding of the burden of cardiac pathology in PTB in those living with and without HIV in a high-burden setting., Methods: This is a cross-sectional and natural history study to evaluate the burden and natural history of cardiac pathology in participants with PTB in Lusaka, Zambia, a high burden setting for TB and HIV. Participants with PTB, with and without HIV will be consecutively recruited alongside age- and sex-matched TB-uninfected comparators on a 2:1 basis. Participants will undergo baseline assessments to collect clinical, socio-demographic, functional, laboratory and TB disease impact data followed by point-of-care and standard echocardiography. Participants with PTB will undergo further repeat clinical and functional examination at two- and six months follow-up. Those with cardiac pathology at baseline will undergo repeat echocardiography at six months., Discussion: The outcomes of the study are to a) determine the burden of cardiac pathology at TB diagnosis, b) describe its association with patient-defining risk factors and biochemical markers of cardiac injury and stretch and c) describe the natural history of cardiac pathology during the course of TB treatment., (© 2024. The Author(s).)

Background: From 2018-2021 the TB Reduction through Expanded Antiretroviral Treatment and TB Screening (TREATS) project took place in 21 Zambian and South African communities. The TREATS Incidence of TB Infection Cohort Study was conducted in adolescents and young people (AYP), aged 15-24 years in 14 communities. We describe the baseline prevalence and risk factors of Mycobacterium tuberculosis (M. tuberculosis) infection among this cohort and explore the quantitative QFT-Plus interferon gamma (IFN-γ) responses., Methods and Findings: A random sample of approximately 300 AYP per community were recruited and information on TB/HIV risk factors, TB symptoms and social mixing patterns collected. QuantiFERON TB Gold Plus assay (QFT-Plus) was used to detect M. tuberculosis infection, following manufacturer's instructions. Logistic regression was used to determine factors associated with infection. 5577 eligible AYP were invited to participate across both countries, with 4648 enrolled. QFT-Plus results were available for 4529: 2552(Zambia) and 1977(South Africa). Overall, 47.6% (2156/4529) AYP had positive QFT-Plus results, the prevalence of infection in South Africa being twice that in Zambia (64.7% (1280/1977) vs 34.3% (867/2552) p<0.001). Infection was associated with age, household contact with TB and alcohol in Zambia but showed no associations in South Africa. The antigen tube differential (TB2-TB1>0.6 IU/ml) of the assay at baseline showed no evidence of association with recent TB exposure., Conclusion: The high prevalence of infection in AYP warrants urgent action to address TB control, especially in South Africa. Further research is required to delineate antigen tube responses of the QFT-Plus assay more precisely to fully realise the benefit of the additional TB2 tube in high TB/HIV burden settings., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Amofa-Sekyi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: HPTN071 (PopART) was a cluster randomized trial conducted in Zambian and South African (SA) communities, between 2013-2018. The PopART intervention (universal HIV-testing and treatment (UTT) combined with population-level TB symptom screening) was implemented in 14 communities. The TREATS study (2017-2021) was conducted to evaluate the impact of the PopART intervention on TB outcomes. We report on the impact of the combined TB/HIV intervention on the incidence of TB infection in a cohort of adolescents and young adults (AYA) aged 15-24 years., Methods: A random sample of AYA was enrolled between July 2018 and July 2019 in 7 intervention vs 7 standard-of-care communities. We collected questionnaire data on risk factors for TB, and blood for measuring TB infection using QuantiFERON (QFT) Plus. AYA were seen at months 12 and 24 with all procedures repeated. Primary outcome was incidence of TB infection comparing intervention and standard-of-care communities. An incident case was defined as a participant with QFT interferon-gamma response of < 0.2 IU/ml plasma ('negative') at baseline and a QFT interferon-gamma response of > = 0.7 IU/ml ('positive') at follow up., Results: We enrolled 4,648 AYA, 2,223 (47.8%) had a negative QFT-plus result at baseline, 1,902 (85.6%) had a follow up blood sample taken at 12 months or 24 months. Among the 1,902 AYA, followed for 2,987 person-years, 213 had incident TB infection giving (7.1 per 100 person-years). TB infection incidence rates were 8.7 per 100 person-years in intervention communities compared to 6.0 per 100 person-years in standard-of-care communities. There was no evidence the intervention reduced the transmission of TB (incidence-rate-ratio of 1.45, 95%CI 0.97-2.15, p = 0.063)., Conclusion: In our trial setting, we found no evidence that UTT combined with TB active case finding reduced the incidence of TB infection at population level. Our data will inform future modelling work to better understand the population level dynamics of HIV and TB., Competing Interests: The authors have declared that no competing interest exist., (Copyright: © 2023 Shanaube et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Female genital schistosomiasis (FGS) has been associated with prevalent HIV-1. We estimated the incidence of HIV-1 infection in Zambian women with and without FGS., Methods: Women (aged 18-31, nonpregnant, sexually active) were invited to participate in this study in January-August 2018 at the final follow-up of the HPTN 071 (PopART) Population Cohort. HIV-1-negative participants at enrollment (n = 492) were included in this analysis, with testing to confirm incident HIV-1 performed in HPTN 071 (PopART). The association of incident HIV-1 infection with FGS ( Schistosoma DNA detected by polymerase chain reaction [PCR] in any genital specimen) was assessed with exact Poisson regression., Results: Incident HIV-1 infections were observed in 4.1% (20/492) of participants. Women with FGS were twice as likely to seroconvert as women without FGS but with no statistical evidence for a difference (adjusted rate ratio, 2.16; 95% CI, 0.21-12.30; P = .33). Exploratory analysis suggested an association with HIV-1 acquisition among women with ≥2 positive genital PCR specimens (rate ratio, 6.02; 95% CI, 0.58-34.96; P = .13)., Conclusions: Despite higher HIV seroconversion rates in women with FGS, there was no statistical evidence of association, possibly due to low power. Further longitudinal studies should investigate this association in a setting with higher schistosomiasis endemicity., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)