Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial.

BACKGROUND: HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. METHODS: This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. DISCUSSION: Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986.

Prediction of tuberculosis clusters in the riverine municipalities of the Brazilian Amazon with machine learning.

OBJECTIVE: Tuberculosis (TB) is the second most deadly infectious disease globally, posing a significant burden in Brazil and its Amazonian region. This study focused on the "riverine municipalities" and hypothesizes the presence of TB clusters in the area. We also aimed to train a machine learning model to differentiate municipalities classified as hot spots vs. non-hot spots using disease surveillance variables as predictors. METHODS: Data regarding the incidence of TB from 2019 to 2022 in the riverine town was collected from the Brazilian Health Ministry Informatics Department. Moran's I was used to assess global spatial autocorrelation, while the Getis-Ord GI* method was employed to detect high and low-incidence clusters. A Random Forest machine-learning model was trained using surveillance variables related to TB cases to predict hot spots among non-hot spot municipalities. RESULTS: Our analysis revealed distinct geographical clusters with high and low TB incidence following a west-to-east distribution pattern. The Random Forest Classification model utilizes six surveillance variables to predict hot vs. non-hot spots. The machine learning model achieved an Area Under the Receiver Operator Curve (AUC-ROC) of 0.81. CONCLUSION: Municipalities with higher percentages of recurrent cases, deaths due to TB, antibiotic regimen changes, percentage of new cases, and cases with smoking history were the best predictors of hot spots. This prediction method can be leveraged to identify the municipalities at the highest risk of being hot spots for the disease, aiding policymakers with an evidenced-based tool to direct resource allocation for disease control in the riverine municipalities.

[Progress in lipoarabinomannan antigen detection for tuberculosis diagnosis in people living with HIV/AIDS].

Tuberculosis (TB) is the leading cause of death among people living with HIV/AIDS (PLWHA), posing a significant disease burden. Early TB screening in PLWHA is a key intervention to reduce transmission and control disease progression. ​Lipoarabinomannan (LAM) is a glycolipid of Mycobacterium tuberculosis (MTB) that can be detected in the urine of tuberculosis patients. LAM is useful for the rapid and accurate diagnosis of tuberculosis. This article reviews LAM and its application and limitations in the diagnosis of PLWHA, hoping to provide a reference for the diagnosis of tuberculosis in PLWHA.

[Retrospective analysis of diagnosis and treatment of tuberculosis in designated medical institutions in China from 2017 to 2022].

Objective: To understand the status of tuberculosis diagnosis and treatment capacity and the development and changes of tuberculosis diagnosis and treatment in provincial and municipal designated medical institutions in China from 2017 to 2022, so as to provide a basis for the formulation of relevant policies for the improvement and development of designated medical institutions for tuberculosis and the tuberculosis prevention and treatment service system, and to provide reasonable support for further strengthening the capacity of designated medical institutions for tuberculosis. Methods: This study was initiated and carried out by Beijing Chest Hospital affiliated to Capital Medical University/Clinical Center for Tuberculosis Prevention and Control of China CDC (hereinafter referred to as "Clinical Center") by means of questionnaire survey, and the investigation was carried out from March to November 2023. During this period, the clinical center distributed questionnaires to the hospital member units of "Beijing Tuberculosis Diagnosis and Treatment Technology Innovation Alliance", retrospectively collected their tuberculosis-related diagnosis and treatment data from 2017 to 2022, and used descriptive statistical methods to analyze the number of tuberculosis beds, outpatients and hospitalizations in medical institutions. The results were expressed in absolute numbers (percentages), and three-line tables, bar charts and line charts were drawn to describe the analysis results and changing trends. Results: The 54 medical institutions surveyed in this survey included 21 provincial-level designated medical institutions and 33 prefecture-level designated medical institutions. Most medical institutions have set up clinical departments, auxiliary departments and functional departments to undertake public health tasks of infectious diseases. The tuberculosis laboratory in the hospital has a comprehensive ability and has the detection technology needed for most tuberculosis diagnosis; The number of tuberculosis beds, children's tuberculosis beds and ICU beds all showed an increasing trend from 2017 to 2022. The proportion of tuberculosis beds in the hospital decreased slightly, from 39.31% in 2017 to 34.76% in 2022, showing a slight downward trend. Compared with the hospital surveyed, the number of tuberculosis outpatients in 2019 was 562 029, and the number of outpatients in 2020-2022 was 462 328, 519 630 and 424 069 respectively, which was significantly lower than that in 2019. The number of tuberculosis outpatients in medical institutions decreased significantly from 2020 to 2022. By analyzing the proportion of patients with different types of tuberculosis, the proportion of sensitive tuberculosis outpatients in 2017-2022 decreased from 84.49% in 2017 to 78.05% in 2022, showing a downward trend year by year. The proportion of patients with multidrug-resistant/ rifampin-resistant tuberculosis increased from 2.03% in 2017 to 7.18% in 2022. From 2017 to 2019, the total number of inpatients with tuberculosis showed an upward trend. Compared with 2019, the number of inpatients in 2020, 2021 and 2022 showed a downward trend, and the decline in 2020 was large (down 14.94% compared with 2019). Among the inpatients, the absolute number and proportion of patients with sensitive pulmonary tuberculosis remained relatively stable, and the number and proportion of inpatients with multidrug-resistant/rifampin-resistant pulmonary tuberculosis increased year by year. Conclusions: Most medical institutions have the capacity to carry out routine diagnosis and treatment of tuberculosis, but the public health function needs to be strengthened. The transformation of medical institutions requires proper guidance and adequate support. During 2019-2022, most medical institutions were affected by the COVID-19 epidemic, and their tuberculosis diagnosis and treatment work also changed to varying degrees. During this period, hospitals took various measures to overcome difficulties and tried their best to maintain the normal development of tuberculosis diagnosis and treatment, and the tuberculosis diagnosis and treatment work of various institutions gradually resumed in 2022.

Granulomatous meningoencephalitis and blindness associated with Mycobacterium tuberculosis complex infection in a senile female chimpanzee (Pan troglodytes).

A 40-year old female chimpanzee (Pan troglodytes) developed hyporexia, weight loss, followed by progressive and complete blindness. Tomography demonstrated an intracranial mass in the rostroventral brain involving the optic chiasm, with a presumptive diagnosis of neoplasm. However, histopathology revealed a granulomatous meningoencephalitis, and tissue samples tested positive for Mycobacterium tuberculosis.

Evaluation of serological assays for the diagnosis of childhood tuberculosis disease: a study protocol.

BACKGROUND: Tuberculosis (TB) poses a major public health challenge, particularly in children. A substantial proportion of children with TB disease remain undetected and unconfirmed. Therefore, there is an urgent need for a highly sensitive point-of-care test. This study aims to assess the performance of serological assays based on various antigen targets and antibody properties in distinguishing children (0-18 years) with TB disease (1) from healthy TB-exposed children, (2) children with non-TB lower respiratory tract infections, and (3) from children with TB infection. METHODS: The study will use biobanked plasma samples collected from three prospective multicentric diagnostic observational studies: the Childhood TB in Switzerland (CITRUS) study, the Pediatric TB Research Network in Spain (pTBred), and the Procalcitonin guidance to reduce antibiotic treatment of lower respiratory tract infections in children and adolescents (ProPAED) study. Included are children diagnosed with TB disease or infection, healthy TB-exposed children, and sick children with non-TB lower respiratory tract infection. Serological multiplex assays will be performed to identify M. tuberculosis antigen-specific antibody features, including isotypes, subclasses, Fc receptor (FcR) binding, and IgG glycosylation. DISCUSSION: The findings from this study will help to design serological assays for diagnosing TB disease in children. Importantly, those assays could easily be developed as low-cost point-of-care tests, thereby offering a potential solution for resource-constrained settings. GOV IDENTIFIER: NCT03044509.

Extracellular vesicles in mycobacteria: new findings in biogenesis, host-pathogen interactions, and diagnostics.

Since the discovery of extracellular vesicles (EVs) in mycobacterial species 15 years back, we have learned that this phenomenon is conserved in the Mycobacterium genus and has critical roles in bacterial physiology and host-pathogen interactions. Mycobacterium tuberculosis (Mtb), the tuberculosis (TB) causative agent, produces EVs both in vitro and in vivo including a diverse set of biomolecules with demonstrated immunomodulatory effects. Moreover, Mtb EVs (MEVs) have been shown to possess vaccine properties and carry biomarkers with diagnostic capacity. Although information on MEV biogenesis relative to other bacterial species is scarce, recent studies have shed light on how MEVs originate and are released to the extracellular space. In this minireview, we discuss past and new information about the vesiculogenesis phenomenon in Mtb, including biogenesis, MEV cargo, aspects in the context of host-pathogen interactions, and applications that could help to develop effective tools to tackle the disease.

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

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

Increased tuberculosis case detection in Tanzanian children and adults using African giant pouched rats.

BACKGROUND: African giant pouched rats, trained by Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO), have demonstrated their ability to detect tuberculosis (TB) from sputum. We assessed rat-based case detection and compared the mycobacterium bacillary load (MTB-load) in children versus adults. METHODS: From January-December 2022, samples were collected prospectively from 69 Directly Observed Therapy (DOT) facilities' presumed TB patients. Using an average of five rats, APOPO re-evaluated patients with bacteriologically negative (sputum-smear microscopy or Xpert MTB/RIF) results. Rat-positive samples were tested using concentrated smear light-emitting diode microscopy to confirm TB detection before treatment initiation. The rats' identification of pulmonary TB is based on smelling TB-specific volatile organic compounds (VOCs) in sputum. Using STATA, Chi-square for odds ratio and confidence interval was calculated and evaluated: (1) the yield of rat-based TB detection compared to that of the health facilities; (2) rat-based TB detection in children versus adults; and (3) rats' ability to detect TB across MTB-loads and between children and adults. RESULTS: From 35,766 patients, 5.3% (1900/35,766) were smear-positive and 94.7% (33,866/35,766) were smear or Xpert-negatives at DOTS facility. Of those with negative results, 2029 TB cases were detected using rats, contributing to 52% (2029/3929 of total TB identified), which otherwise would have been missed. Compared to DOT facilities, rats were six-fold more likely to detect TB among Acid Fast Bacilli (AFB) 1+/scanty [90% (1829/2029) versus 60% (1139/1900), odds ratio, OR = 6.11, 95% confidence interval, CI: 5.14-7.26]; twice more likely to identify TB cases among children [71% (91/129) versus 51% (1795/3542), OR = 2.3, 95% CI: 1.59-3.42]; and twice more likely to identify TB cases among children with AFB 1+/scanty than adults with the same MTB-load [5% (86/1703) versus 3% (28/1067), OR = 2.0, 95% CI: 1.28-3.03]. CONCLUSIONS: Rats contributed over half of the TB cases identified in program settings, and children, especially those with a lower MTB-load, were more likely to be diagnosed with TB by rats. The chemical signatures, VOCs, were only available for adults, and further research describing the characteristics of VOCs in children versus adults may pave the way to enhance TB diagnosis in children.

Impact of the COVID-19 pandemic on the real-world diagnostic infrastructure for tuberculosis-An ESGMYC collaborative study.

We determined the impact of the COVID-19 pandemic on mycobacterial diagnostic services. 40 laboratories from 22 countries completed an online questionnaire covering the redeployment of the laboratory infrastructure and/or staff for SARS-CoV-2 testing, staff shortages and supply chain disruptions. 28 laboratories reported monthly numbers of samples processed for mycobacterial investigations and monthly numbers of M. tuberculosis complex (MTBC) PCRs performed between October 1st 2018 and October 31st 2020. More than half (23/40) of the participating TB laboratories reported having performed COVID-19 diagnostics in the early phase of the pandemic, in part with negative impact on the mycobacterial service activities. All participating laboratories reported shortages of consumables and laboratory equipment due to supply chain issues. Average monthly sample numbers decreased by 24% between January 2020 and October 2020 compared to pre-pandemic averages. At the end of the study period, most participating laboratories had not returned to pre-pandemic average MTBC PCR throughput.

Implementation of a rapid diagnostic assay package for cryptococcosis, histoplasmosis and tuberculosis in people living with HIV in Paraguay.

BACKGROUND: Opportunistic infections (OIs) are common causes of mortality among people living with HIV (PLHIV). We determined prevalence and 30-day mortality due to histoplasmosis, cryptococcosis, and TB in PLHIV with advanced HIV disease (AHD). METHODS: PLHIV 18 years and older, with a CD4 + T-cell count of less than 350 cells/mm3 newly diagnosed with HIV infection or re-engaged in care after being without ART for more than 90 days (Group A). The second group included symptomatic PLHIV regardless of ART status or CD4 + T-cell count (Group B); all followed for 30 days. Detection of Histoplasma Ag (HisAg) in urine was done by enzyme immunoassay (EIA), Cryptococcus antigen (CrAg) was detected in serum and cerebrospinal fluid (CSF) specimens by lateral flow assay (LFA), and lipoarabinomannan (LAM) detection in urine was by LFA (TB LAM) and in sputum by GeneXpert for diagnosis of Mycobacterium infections. RESULTS: From August 2021 to June 2022, 491 PLHIV were enrolled; 482 (98%) had a CD4 + T-cell result, and 381 patients (79%) were classified with AHD according to CD4 + T-cell count (< 200 CD4/mm3). Frequency of an OI was 38% (n = 145/381). Antigen test positivity rate was 16% (72/467) for TB-LAM, 9% (43/464) for HisAg, and 11% (51/484) for CrAg. Twenty-one of 34 (62%) patients receiving CSF CrAg tests were positive, confirming meningitis. Significant differences in 30-day mortality were observed in patients with an OI (16%) vs. no OI (7%) (p = 0.002). Mortality was highest in patients with histoplasmosis (25%), co-infection (22%), cryptococcosis (18% overall; 19% for cryptococcal meningitis), and TB (10%). CONCLUSIONS: TB and fungal OIs, including co-infection, were common in PLHIV in Paraguay and had high associated mortality. Laboratories and health facilities need access to CD4 + T-cell testing and rapid diagnostic assays.

Global analysis of an age-structured tuberculosis model with an application to Jiangsu, China.

Diagnostic delay for TB infected individuals and the lack of TB vaccines for adults are the main challenges to achieve the goals of WHO by 2050. In order to evaluate the impacts of diagnostic delay and vaccination for adults on prevalence of TB, we propose an age-structured model with latent age and infection age, and we incorporate Mycobacterium TB in the environment and vaccination into the model. Diagnostic delay is indicated by the age of infection before receiving treatment. The threshold dynamics are established in terms of the basic reproduction number R 0 . When R 0 < 1 , the disease-free equilibrium is globally asymptotically stable, which means that TB epidemic will die out; When R 0 = 1 , the disease-free equilibrium is globally attractive; there exists a unique endemic equilibrium and the endemic equilibrium is globally attractive when R 0 > 1 . We estimate that the basic reproduction number R 0 = 0.5320 (95% CI (0.3060, 0.7556)) in Jiangsu Province, which means that TB epidemic will die out. However, we find that the annual number of new TB cases by 2050 is 1,151 (95%CI: (138, 8,014)), which means that it is challenging to achieve the goal of WHO by 2050. To this end, we evaluate the possibility of achieving the goals of WHO if we start vaccinating adults and reduce diagnostic delay in 2025. Our results demonstrate that when the diagnostic delay is reduced from longer than four months to four months, or 20% adults are vaccinated, the goal of WHO in 2050 can be achieved, and 73,137 (95%CI: (23,906, 234,086)) and 54,828 (95%CI: (15,811, 206,468)) individuals will be prevented from being infected from 2025 to 2050, respectively. The modeling approaches and simulation results used in this work can help policymakers design control measures to reduce the prevalence of TB.

Point-of-care ultrasound for diagnosing extrapulmonary TB.

Despite the high morbidity and mortality globally, standard microbiologic diagnosis for TB requires laboratory infrastructure inaccessible in many resource-limited areas and may be insufficient for identifying extrapulmonary disease. Point-of-care (POC) ultrasound facilitates visualization of extrapulmonary manifestations, permitting laboratory-independent diagnosis, but its diagnostic utility remains unclear.We conducted a systematic review of five online databases for studies reporting ultrasound findings among cases with and without extrapulmonary TB (EPTB). A minimum of two authors independently screened and reviewed each article, and extracted data elements of interest. We conducted a series of univariate meta-analyses using a random-effects model to calculate the pooled effect estimate and 95% confidence interval (CI) for each outcome: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).Of 279 articles identified, 6 were included. There were 699 cases of EPTB among 1,633 participants. The pooled sensitivity estimate was 0.72 (95% CI 0.57-0.88). The pooled specificity estimate was 0.77 (95% CI 0.63-0.90). The pooled PPV and NPV estimates were respectively 0.67 (95% CI 0.47-0.87) and 0.85 (95% CI 0.77-0.93).POC ultrasound showed modest test characteristics for diagnosing EPTB, which may constitute an improvement over some currently available diagnostics..

Guidelines for tuberculosis screening and preventive treatment among pregnant and breastfeeding women living with HIV in PEPFAR-supported countries.

BACKGROUND: Tuberculosis (TB) preventive treatment (TPT) is recommended by the World Health Organization (WHO) for persons living with HIV, including pregnant and breastfeeding women. Given the President's Emergency Plan for AIDS Relief (PEPFAR)'s investment in TPT services for persons living with HIV as a strategy to prevent TB as well as uncertainty in guidelines and policy regarding use of TPT during pregnancy and the postpartum period, we conducted a review of current relevant national guidelines among PEPFAR-supported countries. METHODS: Our review included 44/49 PEPFAR-supported countries to determine if TB screening and TPT are recommended specifically for pregnant and breastfeeding women living with HIV (WLHIV). National guidelines reviewed and abstracted included TB, HIV, prevention of vertical HIV transmission, TPT, and any other relevant guidelines. We abstracted information regarding TB screening, including screening tools and frequency; and TPT, including timing, regimen, frequency, and laboratory monitoring. RESULTS: Of 44 PEPFAR-supported countries for which guidelines were reviewed, 66% were high TB incidence countries; 41% were classified by WHO as high TB burden countries, and 43% as high HIV-associated TB burden countries. We found that 64% (n = 28) of countries included TB screening recommendations for pregnant WLHIV in their national guidelines, and most (n = 35, 80%) countries recommend TPT for pregnant WLHIV. Fewer countries included recommendations for breastfeeding as compared to pregnant WLHIV, with only 32% (n = 14) mentioning TB screening and 45% (n = 20) specifically recommending TPT for this population; most of these recommend isoniazid-based TPT regimens for pregnant and breastfeeding WLHIV. However, several countries also recommend isoniazid combined with rifampicin (3RH) or rifapentine (3HP). CONCLUSIONS: Despite progress in the number of PEPFAR-supported countries that specifically include TB screening and TPT recommendations for pregnant and breastfeeding WLHIV in their national guidelines, many PEPFAR-supported countries still do not include specific screening and TPT recommendations for pregnant and breastfeeding WLHIV.

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

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