Enhanced tuberculosis diagnosis with computer-aided chest X-ray and urine LAM in adults with HIV admitted to hospital (CASTLE study): A cluster randomised trial.

BACKGROUND: People with HIV (PHIV) admitted to hospital have high mortality, with tuberculosis (TB) being the major cause of death. Systematic use of new TB diagnostics could improve TB diagnosis and might improve outcomes. METHODS: We conducted a cluster randomised trial among adult PHIV admitted to Zomba Central Hospital, Malawi. Admission-days were randomly assigned to: enhanced TB diagnostics using urine lipoarabinomannan (LAM) antigen tests (SILVAMP-LAM, Fujifilm, Japan and Determine-LAM, Alere/Abbot, USA), digital chest X-ray with computer aided diagnosis (dCXR-CAD, CAD4TBv6, Delft, Netherlands), plus usual care ("enhanced TB diagnostics"); or usual care alone ("usual care"). The primary outcome was TB treatment initiation during admission. Secondary outcomes were 56-day mortality, TB diagnosis within 24-hours, and undiagnosed TB at discharge, ascertained by culture of one admission sputum sample. FINDINGS: Between 2 September 2020 and 15 February 2022, we recruited 419 people. Four people were excluded post-recruitment, leaving 415 adults recruited during 207 randomly assigned admission-days in modified intention-to-treat analysis. At admission, 90.8% (377/415) were taking antiretroviral therapy (ART) with median (IQR) CD4 cell count 240 cells/mm3. In the enhanced diagnostic arm, median CAD4TBv6 score was 60 (IQR: 51-71), 4.4% (9/207) had SILVAMP-LAM-positive and 14.4% (29/201) had Determine-LAM positive urine with three samples positive by both urine tests. TB treatment was initiated in 46/208 (22%) in enhanced TB diagnostics arm and 24/207 (12%) in usual care arm (risk ratio [RR] 1.92, 95% CI 1.20-3.08). There was no difference in mortality by 56 days (enhanced TB diagnosis: 54/208, 26%; usual care: 52/207, 25%; hazard ratio 1.05, 95% CI 0.72-1.53); TB treatment initiation within 24 hours (enhanced TB diagnosis: 8/207, 3.9%; usual care: 5/208, 2.4%; RR 1.61, 95% CI 0.53-4.71); or undiagnosed microbiological-confirmed TB at discharge (enhanced TB diagnosis, 0/207 (0.0%), usual care arm 2/208 (1.0%) (p = 0.50). INTERPRETATION: Urine SILVAMP-LAM/Determine-LAM plus dCXR-CAD diagnostics identified more hospitalised PHIV with TB than usual care. The increase in TB treatment appeared mainly due to greater use of Determine-LAM, rather than SILVAMP-LAM or dCXR-CAD. Poor concordance between Determine-LAM and SILVAMP-LAM urine tests requires further investigation. Inpatient mortality for adults with HIV remains unacceptability high.

Blazing the trail for innovative tuberculosis diagnostics.

The COVID-19 pandemic brought diagnostics into the spotlight in an unprecedented way not only for case management but also for population health, surveillance, and monitoring. The industry saw notable levels of investment and accelerated research which sparked a wave of innovation. Simple non-invasive sampling methods such as nasal swabs have become widely used in settings ranging from tertiary hospitals to the community. Self-testing has also been adopted as standard practice using not only conventional lateral flow tests but novel and affordable point-of-care molecular diagnostics. The use of new technologies, including artificial intelligence-based diagnostics, have rapidly expanded in the clinical setting. The capacity for next-generation sequencing and acceptance of digital health has significantly increased. However, 4 years after the pandemic started, the market for SARS-CoV-2 tests is saturated, and developers may benefit from leveraging their innovations for other diseases; tuberculosis (TB) is a worthwhile portfolio expansion for diagnostics developers given the extremely high disease burden, supportive environment from not-for-profit initiatives and governments, and the urgent need to overcome the long-standing dearth of innovation in the TB diagnostics field. In exchange, the current challenges in TB detection may be resolved by adopting enhanced swab-based molecular methods, instrument-based, higher sensitivity antigen detection technologies, and/or artificial intelligence-based digital health technologies developed for COVID-19. The aim of this article is to review how such innovative approaches for COVID-19 diagnosis can be applied to TB to have a comparable impact.

Target product profiles: tests for tuberculosis treatment monitoring and optimization.

The World Health Organization has developed target product profiles containing minimum and optimum targets for key characteristics for tests for tuberculosis treatment monitoring and optimization. Tuberculosis treatment optimization refers to initiating or switching to an effective tuberculosis treatment regimen that results in a high likelihood of a good treatment outcome. The target product profiles also cover tests of cure conducted at the end of treatment. The development of the target product profiles was informed by a stakeholder survey, a cost-effectiveness analysis and a patient-care pathway analysis. Additional feedback from stakeholders was obtained by means of a Delphi-like process, a technical consultation and a call for public comment on a draft document. A scientific development group agreed on the final targets in a consensus meeting. For characteristics rated of highest importance, the document lists: (i) high diagnostic accuracy (sensitivity and specificity); (ii) time to result of optimally ≤ 2 hours and no more than 1 day; (iii) required sample type to be minimally invasive, easily obtainable, such as urine, breath, or capillary blood, or a respiratory sample that goes beyond sputum; (iv) ideally the test could be placed at a peripheral-level health facility without a laboratory; and (v) the test should be affordable to low- and middle-income countries, and allow wide and equitable access and scale-up. Use of these target product profiles should facilitate the development of new tuberculosis treatment monitoring and optimization tests that are accurate and accessible for all people being treated for tuberculosis.

L'Organisation mondiale de la santé a élaboré des profils de produits cibles contenant des cibles minimales et optimales pour les caractéristiques principales des essais destinés au suivi et à l'optimisation du traitement de la tuberculose. L'optimisation du traitement de la tuberculose fait référence à l'instauration d'un régime de traitement efficace de la tuberculose ou à l'adoption d'un tel régime, avec une probabilité élevée d'obtenir de bons résultats thérapeutiques. Les profils de produits cibles couvrent également les essais de guérison effectués à l'issue du traitement. Les profils de produits cibles ont été élaborés sur la base d'un sondage auprès des parties prenantes, d'une analyse coût-efficacité et d'une analyse du parcours de soins du patient. Des retours supplémentaires des parties prenantes ont été obtenus au moyen d'un processus créé selon la méthode Delphi, d'une consultation technique et d'un appel à commentaires publics sur un projet de document. Un groupe d'élaboration scientifique s'est mis d'accord sur les objectifs finaux lors d'une réunion de concertation. En ce qui concerne les caractéristiques jugées les plus importantes, le document énumère ce qui suit: (i) une grande précision diagnostique (sensibilité et spécificité); (ii) un délai idéal d'obtention des résultats ≤ 2 heures et au maximum de 1 jour; (iii) le type d'échantillon requis doit être peu invasif et facile à obtenir, comme l'urine, l'haleine ou le sang capillaire, ou bien un échantillon respiratoire au-delà des expectorations; (iv) idéalement, l'essai pourrait avoir lieu dans un établissement de santé périphérique sans laboratoire ; et (v) l'essai devrait être abordable pour les pays à revenu faible et intermédiaire et permettre un accès large et équitable ainsi qu'une mise à l'échelle. L'utilisation de ces profils de produits cibles devrait faciliter la mise au point de nouveaux essais de surveillance et d'optimisation du traitement de la tuberculose qui soient précis et accessibles à toutes les personnes suivant un traitement pour la tuberculose.

La Organización Mundial de la Salud ha elaborado perfiles de productos objetivo que contienen objetivos mínimos y óptimos para las características principales de las pruebas de seguimiento y optimización del tratamiento de la tuberculosis. La optimización del tratamiento de la tuberculosis consiste en iniciar o cambiar a un régimen eficaz de tratamiento de la tuberculosis que ofrezca una alta probabilidad de un buen resultado terapéutico. Los perfiles de productos objetivo también abarcan las pruebas de curación realizadas al final del tratamiento. La elaboración de los perfiles de los productos objetivo se basó en una encuesta a las partes interesadas, un análisis de rentabilidad y un análisis de la vía de atención al paciente. Se obtuvo información adicional de las partes interesadas mediante un proceso tipo Delphi, una consulta técnica y una convocatoria de comentarios públicos sobre un borrador del documento. Un grupo de desarrollo científico acordó los objetivos finales en una reunión de consenso. Para las características clasificadas de mayor importancia, el documento enumera: (i) alta precisión diagnóstica (sensibilidad y especificidad); (ii) tiempo hasta el resultado de óptimamente ≤ 2 horas y no más de 1 día; (iii) el tipo de muestra requerida debe ser mínimamente invasiva, fácil de obtener, como orina, aliento o sangre capilar, o una muestra respiratoria que vaya más allá del esputo; (iv) idealmente la prueba podría realizarse en un centro sanitario periférico sin laboratorio; y (v) la prueba debe ser asequible para los países de ingresos bajos y medios y permitir un acceso amplio y equitativo y su expansión. El uso de estos perfiles de producto objetivo debería facilitar el desarrollo de pruebas nuevas de seguimiento y optimización del tratamiento de la tuberculosis que sean precisas y accesibles para todas las personas que reciben tratamiento antituberculoso.

Cost-effectiveness of a Novel Lipoarabinomannan Test for Tuberculosis in Patients With Human Immunodeficiency Virus.

BACKGROUND: A novel urine lipoarabinomannan assay (FujiLAM) has higher sensitivity and higher cost than the first-generation AlereLAM assay. We evaluated the cost-effectiveness of FujiLAM for tuberculosis testing among hospitalized people with human immunodeficiency virus (HIV), irrespective of symptoms. METHODS: We used a microsimulation model to project clinical and economic outcomes of 3 testing strategies: (1) sputum Xpert MTB/RIF (Xpert), (2) sputum Xpert plus urine AlereLAM (Xpert+AlereLAM), (3) sputum Xpert plus urine FujiLAM (Xpert+FujiLAM). The modeled cohort matched that of a 2-country clinical trial. We applied diagnostic yields from a retrospective study (yields for Xpert/Xpert+AlereLAM/Xpert+FujiLAM among those with CD4 <200 cells/µL: 33%/62%/70%; among those with CD4 ≥200 cells/µL: 33%/35%/47%). Costs of Xpert/AlereLAM/FujiLAM were US$15/3/6 (South Africa) and $25/3/6 (Malawi). Xpert+FujiLAM was considered cost-effective if its incremental cost-effectiveness ratio (US$/year-of-life saved) was <$940 (South Africa) and <$750 (Malawi). We varied key parameters in sensitivity analysis and performed a budget impact analysis of implementing FujiLAM countrywide. RESULTS: Compared with Xpert+AlereLAM, Xpert+FujiLAM increased life expectancy by 0.2 years for those tested in South Africa and Malawi. Xpert+FujiLAM was cost-effective in both countries. Xpert+FujiLAM for all patients remained cost-effective compared with sequential testing and CD4-stratified testing strategies. FujiLAM use added 3.5% (South Africa) and 4.7% (Malawi) to 5-year healthcare costs of tested patients, primarily reflecting ongoing HIV treatment costs among survivors. CONCLUSIONS: FujiLAM with Xpert for tuberculosis testing in hospitalized people with HIV is likely to increase life expectancy and be cost-effective at the currently anticipated price in South Africa and Malawi. Additional studies should evaluate FujiLAM in clinical practice settings.

Tuberculosis in Hospitalized Patients With Human Immunodeficiency Virus: Clinical Characteristics, Mortality, and Implications From the Rapid Urine-based Screening for Tuberculosis to Reduce AIDS Related Mortality in Hospitalized Patients in Africa.

BACKGROUND: Tuberculosis (TB) is the major killer of people living with human immunodeficiency virus (HIV) globally, with suboptimal diagnostics and management contributing to high case-fatality rates. METHODS: A prospective cohort of patients with confirmed TB (Xpert MTB/RIF and/or Determine TB-LAM Ag positive) identified through screening HIV-positive inpatients with sputum and urine diagnostics in Malawi and South Africa (Rapid urine-based Screening for Tuberculosis to reduce AIDS Related Mortality in hospitalized Patients in Africa [STAMP] trial). Urine was tested prospectively (intervention) or retrospectively (standard of care arm). We defined baseline clinical phenotypes using hierarchical cluster analysis, and also used Cox regression analysis to identify associations with early mortality (≤56 days). RESULTS: Of 322 patients with TB confirmed between October 2015 and September 2018, 78.0% had ≥1 positive urine test. Antiretroviral therapy (ART) coverage was 80.2% among those not newly diagnosed, but with median CD4 count 75 cells/µL and high HIV viral loads. Early mortality was 30.7% (99/322), despite near-universal prompt TB treatment. Older age, male sex, ART before admission, poor nutritional status, lower hemoglobin, and positive urine tests (TB-LAM and/or Xpert MTB/RIF) were associated with increased mortality in multivariate analyses. Cluster analysis (on baseline variables) defined 4 patient subgroups with early mortality ranging from 9.8% to 52.5%. Although unadjusted mortality was 9.3% lower in South Africa than Malawi, in adjusted models mortality was similar in both countries (hazard ratio, 0.9; P = .729). CONCLUSIONS: Mortality following prompt inpatient diagnosis of HIV-associated TB remained unacceptably high, even in South Africa. Intensified management strategies are urgently needed, for which prognostic indicators could potentially guide both development and subsequent use.

Risk score for predicting mortality including urine lipoarabinomannan detection in hospital inpatients with HIV-associated tuberculosis in sub-Saharan Africa: Derivation and external validation cohort study.

BACKGROUND: The prevalence of and mortality from HIV-associated tuberculosis (HIV/TB) in hospital inpatients in Africa remains unacceptably high. Currently, there is a lack of tools to identify those at high risk of early mortality who may benefit from adjunctive interventions. We therefore aimed to develop and validate a simple clinical risk score to predict mortality in high-burden, low-resource settings. METHODS AND FINDINGS: A cohort of HIV-positive adults with laboratory-confirmed TB from the STAMP TB screening trial (Malawi and South Africa) was used to derive a clinical risk score using multivariable predictive modelling, considering factors at hospital admission (including urine lipoarabinomannan [LAM] detection) thought to be associated with 2-month mortality. Performance was evaluated internally and then externally validated using independent cohorts from 2 other studies (LAM-RCT and a Médecins Sans Frontières [MSF] cohort) from South Africa, Zambia, Zimbabwe, Tanzania, and Kenya. The derivation cohort included 315 patients enrolled from October 2015 and September 2017. Their median age was 36 years (IQR 30-43), 45.4% were female, median CD4 cell count at admission was 76 cells/µl (IQR 23-206), and 80.2% (210/262) of those who knew they were HIV-positive at hospital admission were taking antiretroviral therapy (ART). Two-month mortality was 30% (94/315), and mortality was associated with the following factors included in the score: age 55 years or older, male sex, being ART experienced, having severe anaemia (haemoglobin < 80 g/l), being unable to walk unaided, and having a positive urinary Determine TB LAM Ag test (Alere). The score identified patients with a 46.4% (95% CI 37.8%-55.2%) mortality risk in the high-risk group compared to 12.5% (95% CI 5.7%-25.4%) in the low-risk group (p < 0.001). The odds ratio (OR) for mortality was 6.1 (95% CI 2.4-15.2) in high-risk patients compared to low-risk patients (p < 0.001). Discrimination (c-statistic 0.70, 95% CI 0.63-0.76) and calibration (Hosmer-Lemeshow statistic, p = 0.78) were good in the derivation cohort, and similar in the external validation cohort (complete cases n = 372, c-statistic 0.68 [95% CI 0.61-0.74]). The validation cohort included 644 patients between January 2013 and August 2015. Median age was 36 years, 48.9% were female, and median CD4 count at admission was 61 (IQR 21-145). OR for mortality was 5.3 (95% CI 2.2-9.5) for high compared to low-risk patients (complete cases n = 372, p < 0.001). The score also predicted patients at higher risk of death both pre- and post-discharge. A simplified score (any 3 or more of the predictors) performed equally well. The main limitations of the scores were their imperfect accuracy, the need for access to urine LAM testing, modest study size, and not measuring all potential predictors of mortality (e.g., tuberculosis drug resistance). CONCLUSIONS: This risk score is capable of identifying patients who could benefit from enhanced clinical care, follow-up, and/or adjunctive interventions, although further prospective validation studies are necessary. Given the scale of HIV/TB morbidity and mortality in African hospitals, better prognostic tools along with interventions could contribute towards global targets to reduce tuberculosis mortality.

Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial.

BACKGROUND: Current diagnostics for HIV-associated tuberculosis are suboptimal, with missed diagnoses contributing to high hospital mortality and approximately 374 000 annual HIV-positive deaths globally. Urine-based assays have a good diagnostic yield; therefore, we aimed to assess whether urine-based screening in HIV-positive inpatients for tuberculosis improved outcomes. METHODS: We did a pragmatic, multicentre, double-blind, randomised controlled trial in two hospitals in Malawi and South Africa. We included HIV-positive medical inpatients aged 18 years or more who were not taking tuberculosis treatment. We randomly assigned patients (1:1), using a computer-generated list of random block size stratified by site, to either the standard-of-care or the intervention screening group, irrespective of symptoms or clinical presentation. Attending clinicians made decisions about care; and patients, clinicians, and the study team were masked to the group allocation. In both groups, sputum was tested using the Xpert MTB/RIF assay (Xpert; Cepheid, Sunnyvale, CA, USA). In the standard-of-care group, urine samples were not tested for tuberculosis. In the intervention group, urine was tested with the Alere Determine TB-LAM Ag (TB-LAM; Alere, Waltham, MA, USA), and Xpert assays. The primary outcome was all-cause 56-day mortality. Subgroup analyses for the primary outcome were prespecified based on baseline CD4 count, haemoglobin, clinical suspicion for tuberculosis; and by study site and calendar time. We used an intention-to-treat principle for our analyses. This trial is registered with the ISRCTN registry, number ISRCTN71603869. FINDINGS: Between Oct 26, 2015, and Sept 19, 2017, we screened 4788 HIV-positive adults, of which 2600 (54%) were randomly assigned to the study groups (n=1300 for each group). 13 patients were excluded after randomisation from analysis in each group, leaving 2574 in the final intention-to-treat analysis (n=1287 in each group). At admission, 1861 patients were taking antiretroviral therapy and median CD4 count was 227 cells per µL (IQR 79-436). Mortality at 56 days was reported for 272 (21%) of 1287 patients in the standard-of-care group and 235 (18%) of 1287 in the intervention group (adjusted risk reduction [aRD] -2·8%, 95% CI -5·8 to 0·3; p=0·074). In three of the 12 prespecified, but underpowered subgroups, mortality was lower in the intervention group than in the standard-of-care group for CD4 counts less than 100 cells per µL (aRD -7·1%, 95% CI -13·7 to -0·4; p=0.036), severe anaemia (-9·0%, -16·6 to -1·3; p=0·021), and patients with clinically suspected tuberculosis (-5·7%, -10·9 to -0·5; p=0·033); with no difference by site or calendar period. Adverse events were similar in both groups. INTERPRETATION: Urine-based tuberculosis screening did not reduce overall mortality in all HIV-positive inpatients, but might benefit some high-risk subgroups. Implementation could contribute towards global targets to reduce tuberculosis mortality. FUNDING: Joint Global Health Trials Scheme of the Medical Research Council, the UK Department for International Development, and the Wellcome Trust.

Diagnostic accuracy, incremental yield and prognostic value of Determine TB-LAM for routine diagnostic testing for tuberculosis in HIV-infected patients requiring acute hospital admission in South Africa: a prospective cohort.

BACKGROUND: We previously reported that one-third of HIV-positive adults requiring medical admission to a South African district hospital had laboratory-confirmed tuberculosis (TB) and that almost two-thirds of cases could be rapidly diagnosed using Xpert MTB/RIF-testing of concentrated urine samples obtained on the first day of admission. Implementation of urine-based, routine, point-of-care TB screening is an attractive intervention that might be facilitated by use of a simple, low-cost diagnostic tool, such as the Determine TB-LAM lateral-flow rapid test for HIV-associated TB. METHODS: Sputum, urine and blood samples were systematically obtained from unselected HIV-positive adults within 24 hours of admission to a South African township hospital. Additional clinical samples were obtained during hospitalization as clinically indicated. TB was defined by the detection of Mycobacterium tuberculosis in any sample using Xpert MTB/RIF or liquid culture. The diagnostic yield, accuracy and prognostic value of urine-lipoarabinomannan (LAM) testing were determined, but urine-LAM results did not inform treatment decisions. RESULTS: Consecutive HIV-positive adult acute medical admissions not already receiving TB treatment (n = 427) were enrolled regardless of clinical presentation or symptoms. TB was diagnosed in 139 patients (TB prevalence 32.6%; median CD4 count 80 cells/µL). In the first 24 hours of admission, sputum (spot and/or induced) samples were obtained from 37.0% of patients and urine samples from 99.5% of patients (P < 0.001). The diagnostic yields from these specimens were 19.4% (n = 27/139) for sputum-microscopy, 26.6% (n = 37/139) for sputum-Xpert, 38.1% (n = 53/139) for urine-LAM and 52.5% (n = 73/139) for sputum-Xpert/urine-LAM combined (P < 0.01). Corresponding yields among patients with CD4 counts <100 cells/µL were 18.9%, 24.3%, 55.4% and 63.5%, respectively (P < 0.01). The diagnostic yield of urine-LAM was unrelated to respiratory symptoms, and LAM assay specificity (using a grade-2 cut-off) was 98.9% (274/277; 95% confidence interval [CI] 96.9-99.8). Among TB cases, positive urine-LAM status was strongly associated with mortality at 90 days (adjusted hazard ratio 4.20; 95% CI 1.50-11.75). CONCLUSIONS: Routine testing for TB in newly admitted HIV-positive adults using Determine TB-LAM to test urine provides major incremental diagnostic yield with very high specificity when used in combination with sputum testing and has important utility among those without respiratory TB symptoms and/or unable to produce sputum. The assay also rapidly identifies individuals with a poor prognosis.

Detection of lipoarabinomannan (LAM) in urine is an independent predictor of mortality risk in patients receiving treatment for HIV-associated tuberculosis in sub-Saharan Africa: a systematic review and meta-analysis.

BACKGROUND: Simple immune capture assays that detect mycobacterial lipoarabinomannan (LAM) antigen in urine are promising new tools for the diagnosis of HIV-associated tuberculosis (HIV-TB). In addition, however, recent prospective cohort studies of patients with HIV-TB have demonstrated associations between LAM in the urine and increased mortality risk during TB treatment, indicating an additional utility of urinary LAM as a prognostic marker. We conducted a systematic review and meta-analysis to summarise the evidence concerning the strength of this relationship in adults with HIV-TB in sub-Saharan Africa, thereby quantifying the assay's prognostic value. METHODS: We searched MEDLINE and Embase databases using comprehensive search terms for 'HIV', 'TB', 'LAM' and 'sub-Saharan Africa'. Identified studies were reviewed and selected according to predefined criteria. RESULTS: We identified 10 studies eligible for inclusion in this systematic review, reporting on a total of 1172 HIV-TB cases. Of these, 512 patients (44 %) tested positive for urinary LAM. After a variable duration of follow-up of between 2 and 6 months, overall case fatality rates among HIV-TB cases varied between 7 % and 53 %. Pooled summary estimates generated by random-effects meta-analysis showed a two-fold increased risk of mortality for urinary LAM-positive HIV-TB cases compared to urinary LAM-negative HIV-TB cases (relative risk 2.3, 95 % confidence interval 1.6-3.1). Some heterogeneity was explained by study setting and patient population in sub-group analyses. Five studies also reported multivariable analyses of risk factors for mortality, and pooled summary estimates demonstrated over two-fold increased mortality risk (odds ratio 2.5, 95 % confidence interval 1.4-4.5) among urinary LAM-positive HIV-TB cases, even after adjustment for other risk factors for mortality, including CD4 cell count. CONCLUSIONS: We have demonstrated that detectable LAM in urine is associated with increased risk of mortality during TB treatment, and that this relationship remains after adjusting for other risk factors for mortality. This may simply be due to a positive test for urinary LAM serving as a marker of higher mycobacterial load and greater disease dissemination and severity. Alternatively, LAM antigen may directly compromise host immune responses through its known immunomodulatory effects. Detectable LAM in the urine is an independent risk factor for mortality among patients receiving treatment for HIV-TB. Further research is warranted to elucidate the underlying mechanisms and to determine whether this vulnerable patient population may benefit from adjunctive interventions.

Rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalized patients in Africa (the STAMP trial): study protocol for a randomised controlled trial.

BACKGROUND: HIV-associated tuberculosis (TB) co-infection remains an enormous burden to international public health. Post-mortem studies have highlighted the high proportion of HIV-positive adults admitted to hospital with TB. Determine TB-LAM and Xpert MTB/RIF assays can substantially increase diagnostic yield of TB within one day of hospital admission. However, it remains unclear if this approach can impact clinical outcomes. The STAMP trial aims to test the hypothesis that the implementation a urine-based screening strategy for TB can reduce all cause-mortality among HIV-positive patients admitted to hospital when compared to current, sputum-based screening. METHODS: The trial is a pragmatic, individually randomised, multi-country (Malawi and South Africa) clinical trial with two study arms (1:1 recruitment). Unselected HIV-positive patients admitted to medical wards, irrespective of presentation, meeting the inclusion criteria and giving consent will be randomized to screening for TB using either: (i) 'standard of care'- testing of sputum using the Xpert MTB/RIF assay (Xpert) or (ii) 'intervention'- testing of sputum using Xpert and testing of urine using (a) Determine TB-LAM lateral-flow assay and (b) Xpert following concentration of urine by centrifugation. Patients will be excluded if they have received TB treatment in the previous 12 months, if they have received isoniazid preventive therapy in the last 6 months, if they are aged <18 years or they live outside the pre-specified geographical area. Results will be provided to the responsible medical team as soon as available to inform decisions regarding TB treatment. Both the study and routine medical team will be masked to study arm allocation. 1300 patients will be enrolled per arm (equal numbers at the two trial sites). The primary endpoint is all-cause mortality at 56 days. An economic analysis will be conducted to project long-term outcomes for shorter-term trial data, including cost-effectiveness. DISCUSSION: This pragmatic trial assesses an intervention to reduce the high mortality caused by HIV-associated TB, which could feasibly be scaled up in high-burden settings if shown to be efficacious and cost-effective. We discuss the challenges of designing a trial to assess the impact on mortality of laboratory-based TB screening interventions given frequent initiation of empirical treatment and a failure of several previous clinical trials to demonstrate an impact on clinical outcomes. We also elaborate on the practical and ethical issues of 'testing a test' in general. TRIAL REGISTRATION: ISRCTN Registry ( ISRCTN71603869 ) prospectively registered 08 May 2015; the South African National Controlled Trials Registry (DOH-27-1015-5185) prospectively registered October 2015.

The predictive value of current haemoglobin levels for incident tuberculosis and/or mortality during long-term antiretroviral therapy in South Africa: a cohort study.

BACKGROUND: Low haemoglobin concentrations may be predictive of incident tuberculosis (TB) and death in HIV-infected patients receiving antiretroviral therapy (ART), but data are limited and inconsistent. We examined these relationships retrospectively in a long-term South African ART cohort with multiple time-updated haemoglobin measurements. METHODS: Prospectively collected clinical data on patients receiving ART for up to 8 years in a community-based cohort were analysed. Time-updated haemoglobin concentrations, CD4 counts and HIV viral loads were recorded, and TB diagnoses and deaths from all causes were ascertained. Anaemia severity was classified using World Health Organization criteria. TB incidence and mortality rates were calculated and Poisson regression models were used to identify independent predictors of incident TB and mortality, respectively. RESULTS: During a median follow-up of 5.0 years (IQR, 2.5-5.8) of 1,521 patients, 476 cases of incident TB and 192 deaths occurred during 6,459 person-years (PYs) of follow-up. TB incidence rates were strongly associated with time-updated anaemia severity; those without anaemia had a rate of 4.4 (95%CI, 3.8-5.1) cases/100 PYs compared to 10.0 (95%CI, 8.3-12.1), 26.6 (95%CI, 22.5-31.7) and 87.8 (95%CI, 57.0-138.2) cases/100 PYs in those with mild, moderate and severe anaemia, respectively. Similarly, mortality rates in those with no anaemia or mild, moderate and severe time-updated anaemia were 1.1 (95%CI, 0.8-1.5), 3.5 (95%CI, 2.7-4.8), 11.8 (95%CI, 9.5-14.8) and 28.2 (95%CI, 16.5-51.5) cases/100 PYs, respectively. Moderate and severe anaemia (time-updated) during ART were the strongest independent predictors for incident TB (adjusted IRR = 3.8 [95%CI, 3.0-4.8] and 8.2 [95%CI, 5.3-12.7], respectively) and for mortality (adjusted IRR = 6.0 [95%CI, 3.9-9.2] and adjusted IRR = 8.0 [95%CI, 3.9-16.4], respectively). CONCLUSIONS: Increasing severity of anaemia was associated with exceptionally high rates of both incident TB and mortality during long-term ART. Patients receiving ART who have moderate or severe anaemia should be prioritized for TB screening using microbiological assays and may require adjunctive clinical interventions.

Resolution of anaemia in a cohort of HIV-infected patients with a high prevalence and incidence of tuberculosis receiving antiretroviral therapy in South Africa.

BACKGROUND: Anaemia is frequently associated with both HIV-infection and HIV-related tuberculosis (TB) in antiretroviral therapy (ART)-naïve patients in sub-Saharan Africa and is strongly associated with poor prognosis. However, the effect of ART on the resolution of anaemia in patient cohorts with a high prevalence and incidence of tuberculosis is incompletely defined and the impact of TB episodes on haemoglobin recovery has not previously been reported. We therefore examined these issues using data from a well-characterised cohort of patients initiating ART in South Africa. METHODS: Prospectively collected clinical and haematological data were retrospectively analysed from patients receiving ART in a South African township ART service. TB diagnoses and time-updated haemoglobin concentrations, CD4 counts and HIV viral loads were recorded. Anaemia severity was classified according to WHO criteria. Multivariable logistic regression analysis was used to determine factors independently associated with anaemia after 12 months of ART. RESULTS: Of 1,140 patients with baseline haemoglobin levels, 814 were alive in care and had repeat values available after 12 months of ART. The majority of patients were female (73%), the median CD4 count was 104 cells/uL and 30.5% had a TB diagnosis in the first year of ART. At baseline, anaemia (any severity) was present in 574 (70.5%) patients and was moderate/severe in 346 (42.5%). After 12 months of ART, 218 (26.8%) patients had anaemia of any severity and just 67 (8.2%) patients had moderate/severe anaemia. Independent predictors of anaemia after 12 months of ART included greater severity of anaemia at baseline, time-updated erythrocyte microcytosis and receipt of an AZT-containing regimen. In contrast, prevalent and/or incident TB, gender and baseline and time-updated CD4 cell count and viral load measurements were not independent predictors. CONCLUSIONS: Although anaemia was very common among ART-naive patients, the anaemia resolved during the first year of ART in a large majority of patients regardless of TB status without routine use of additional interventions. However, approximately one-quarter of patients remained anaemic after one year of ART and may require additional investigations and/or interventions.

Tuberculosis treatment monitoring tests during routine practice: study design guidance.

SCOPE: The current tools for tuberculosis (TB) treatment monitoring, smear microscopy and culture, cannot accurately predict poor treatment outcomes. Research into new TB treatment monitoring tools (TMTs) is growing, but data are unreliable. In this article, we aim to provide guidance for studies investigating and evaluating TB TMT for use during routine clinical care. Here, a TB TMT would guide treatment during the course of therapy, rather than testing for a cure at the regimen's end. This article does not cover the use of TB TMTs as surrogate endpoints in the clinical trial context. METHODS: Guidelines were initially informed by experiences during a systematic review of TB TMTs. Subsequently, a small content expert group was consulted for feedback on initial recommendations. After revision, feedback from substantive experts across sectors was sought. QUESTIONS ADDRESSED BY THE GUIDELINE AND RECOMMENDATIONS: The proposed considerations and recommendations for studies evaluating TB TMTs for use during the treatment in routine clinical care fall into eight domains. We provide specific recommendations regarding study design and recruitment, outcome definitions, reference standards, participant follow-up, clinical setting, study population, treatment regimen reporting, and index tests and data presentation. Overall, TB TMTs should be evaluated in a manner similar to diagnostic tests, but TB TMT accuracy must be assessed at multiple timepoints throughout the treatment course, and TB TMTs should be evaluated in study populations who have already received a diagnosis of TB. Study design and outcome definitions must be aligned with the developmental phase of the TB TMT under evaluation. There is no reference standard for TB treatment response, so different reference standards and comparator tests have been proposed, the selection of which will vary depending on the developmental phase of the TMT under assessment. The use of comparator tests can assist in generating evidence. Clarity is required when reporting of timepoints, TMT read-outs, and analysis results. Implementing these recommendations will lead to higher quality TB TMT studies that will allow data to be meaningfully compared, thereby facilitating the development of novel tools to guide individual TB therapy and improve treatment outcomes.

Evaluation of the Xpert MTB Host Response assay for the triage of patients with presumed pulmonary tuberculosis: a prospective diagnostic accuracy study in Viet Nam, India, the Philippines, Uganda, and South Africa.

BACKGROUND: Non-sputum-based triage tests for tuberculosis are a priority for ending tuberculosis. We aimed to evaluate the diagnostic accuracy of the late-prototype Xpert MTB Host Response (Xpert HR) blood-based assay. METHODS: We conducted a prospective diagnostic accuracy study among outpatients with presumed tuberculosis in outpatient clinics in Viet Nam, India, the Philippines, Uganda, and South Africa. Eligible participants were aged 18 years or older and reported cough lasting at least 2 weeks. We excluded those receiving tuberculosis treatment in the preceding 12 months and those who were unwilling to consent. Xpert HR was performed on capillary or venous blood. Reference standard testing included sputum Xpert MTB/RIF Ultra and mycobacterial culture. We performed receiver operating characteristic (ROC) analysis to identify the optimal cutoff value for the Xpert HR to achieve the target sensitivity of 90% or more while maximising specificity, then calculated diagnostic accuracy using this cutoff value. This study was prospectively registered with ClinicalTrials.gov, NCT04923958. FINDINGS: Between July 13, 2021, and Aug 15, 2022, 2046 adults with at least 2 weeks of cough were identified, of whom 1499 adults (686 [45·8%] females and 813 [54·2%] males) had valid Xpert HR and reference standard results. 329 (21·9%) had microbiologically confirmed tuberculosis. Xpert HR had an area under the ROC curve of 0·89 (95% CI 0·86-0·91). The optimal cutoff value was less than or equal to -1·25, giving a sensitivity of 90·3% (95% CI 86·5-93·3; 297 of 329) and a specificity of 62·6% (95% CI 59·7-65·3; 732 of 1170). Sensitivity was similar across countries, by sex, and by subgroups, although specificity was lower in people living with HIV (45·1%, 95% CI 37·8-52·6) than in those not living with HIV (65·9%, 62·8-68·8; difference of 20·8%, 95% CI 13·0-28·6; p<0·0001). Xpert HR had high negative predictive value (95·8%, 95% CI 94·1-97·1), but positive predictive value was only 40·1% (95% CI 36·8-44·1). Using the Xpert HR as a triage test would have reduced confirmatory sputum testing by 57·3% (95% CI 54·2-60·4). INTERPRETATION: Xpert HR did not meet WHO minimum specificity targets for a non-sputum-based triage test for pulmonary tuberculosis. Despite promise as a rule-out test that could reduce confirmatory sputum testing, further cost-effectiveness modelling and data on acceptability and usability are needed to inform policy recommendations. FUNDING: National Institute of Allergy and Infectious Diseases of the US National Institutes of Health. TRANSLATIONS: For the Vietnamese and Tagalog translations of the abstract see Supplementary Materials section.

Head-to-head comparison of diagnostic accuracy of TB screening tests: Chest-X-ray, Xpert TB host response, and C-reactive protein.

Background: Accessible, accurate screening tests are necessary to advance tuberculosis (TB) case finding and early detection in high-burden countries. We compared the diagnostic accuracy of available TB triage tests. Methods: We prospectively screened consecutive adults with ≥2 weeks of cough presenting to primary health centers in the Philippines, Vietnam, South Africa, Uganda, and India. All participants received the index tests: chest-X-ray (CXR), venous or capillary Cepheid Xpert TB Host Response (HR) testing, and point-of-care C-reactive protein (CRP) testing (Boditech iChroma II). CXR images were processed using computer-aided detection (CAD) algorithms. We assessed diagnostic accuracy against a microbiologic reference standard (sputum Xpert Ultra, culture). Optimal cut-points were chosen to achieve sensitivity ≥90% and maximize specificity. Two-test screening algorithms were considered, using two approaches: 1) sequential negative serial screening in which the second screening test is conducted only if the first is negative and positive is defined as positive on either test and 2) sequential positive serial screening, in which the second screening test is conducted only if the first is positive and positive is defined as positive on both tests. Results: Between July 2021 and August 2022, 1,392 participants with presumptive TB had valid results on index tests and the reference standard, and 303 (22%) had confirmed TB. In head-to-head comparisons, CAD4TB v7 showed the highest specificity when using a cut-point that achieves 90% sensitivity (70.3% vs. 65.1% for Xpert HR, difference 95% CI 1.6 to 8.9; 49.7% for CRP, difference 95% CI 17.0 to 24.3). Among the possible two-test screening algorithms, three met WHO target product profile (TPP) minimum accuracy thresholds and had higher accuracy than any test alone. At 90% sensitivity, the specificity was 79.6% for Xpert HR-CAD4TB [sequential negative], 75.9% for CRP-CAD4TB [sequential negative], and 73.7% for Xpert HR-CAD4TB [sequential positive]. Conclusions: CAD4TB achieves TPP targets and outperforms Xpert HR and CRP. Combining screening tests further increased accuracy. Cost and feasibility of two-test screening algorithms should be explored. Registration: NCT04923958.

Diagnostic yield as an important metric for the evaluation of novel tuberculosis tests: rationale and guidance for future research.

Better access to tuberculosis testing is a key priority for fighting tuberculosis, the leading cause of infectious disease deaths in people. Despite the roll-out of molecular WHO-recommended rapid diagnostics to replace sputum smear microscopy over the past decade, a large diagnostic gap remains. Of the estimated 10·6 million people who developed tuberculosis globally in 2022, more than 3·1 million were not diagnosed. An exclusive focus on improving tuberculosis test accuracy alone will not be sufficient to close the diagnostic gap for tuberculosis. Diagnostic yield, which we define as the proportion of people in whom a diagnostic test identifies tuberculosis among all people we attempt to test for tuberculosis, is an important metric not adequately explored. Diagnostic yield is particularly relevant for subpopulations unable to produce sputum such as young children, people living with HIV, and people with subclinical tuberculosis. As more accessible non-sputum specimens (eg, urine, oral swabs, saliva, capillary blood, and breath) are being explored for point-of-care tuberculosis testing, the concept of yield will be of growing importance. Using the example of urine lipoarabinomannan testing, we illustrate how even tests with limited sensitivity can diagnose more people with tuberculosis if they enable increased diagnostic yield. Using tongue swab-based molecular tuberculosis testing as another example, we provide definitions and guidance for the design and conduct of pragmatic studies that assess diagnostic yield. Lastly, we show how diagnostic yield and other important test characteristics, such as cost and implementation feasibility, are essential for increased effective population coverage, which is required for optimal clinical care and transmission impact. We are calling for diagnostic yield to be incorporated into tuberculosis test evaluation processes, including the WHO Grading of Recommendations, Assessment, Development, and Evaluations process, providing a crucial real-life implementation metric that complements traditional accuracy measures.

Interventions to reduce deaths in people living with HIV admitted to hospital in low- and middle-income countries: A systematic review.

People living with HIV (PLHIV) admitted to hospital have a high risk of death. We systematically appraised evidence for interventions to reduce mortality among hospitalised PLHIV in low- and middle-income countries (LMICs). Using a broad search strategy with terms for HIV, hospitals, and clinical trials, we searched for reports published between 1 Jan 2003 and 23 August 2021. Studies of interventions among adult HIV positive inpatients in LMICs were included if there was a comparator group and death was an outcome. We excluded studies restricted only to inpatients with a specific diagnosis (e.g. cryptococcal meningitis). Of 19,970 unique studies identified in search, ten were eligible for inclusion with 7,531 participants in total: nine randomised trials, and one before-after study. Three trials investigated systematic screening for tuberculosis; two showed survival benefit for urine TB screening vs. no urine screening, and one which compared Xpert MTB/RIF versus smear microscopy showed no difference in survival. One before-after study implemented 2007 WHO guidelines to improve management of smear negative tuberculosis in severely ill PLHIV, and showed survival benefit but with high risk of bias. Two trials evaluated complex interventions aimed at overcoming barriers to ART initiation in newly diagnosed PLHIV, one of which showed survival benefit and the other no difference. Two small trials evaluated early inpatient ART start, with no difference in survival. Two trials investigated protocol-driven fluid resuscitation for emergency-room attendees meeting case-definitions for sepsis, and showed increased mortality with use of a protocol for fluid administration. In conclusion, ten studies published since 2003 investigated interventions that aimed to reduce mortality in hospitalised adults with HIV, and weren't restricted to people with a defined disease diagnosis. Inpatient trials of diagnostics, therapeutics or a package of interventions to reduce mortality should be a research priority. Trial registration: PROSPERO Number: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019150341.

Novel FujiLAM assay to detect tuberculosis in HIV-positive ambulatory patients in four African countries: a diagnostic accuracy study.

BACKGROUND: Development of rapid biomarker-based tests that can diagnose tuberculosis using non-sputum samples is a priority for tuberculosis control. We aimed to compare the diagnostic accuracy of the novel Fujifilm SILVAMP TB LAM (FujiLAM) assay with the WHO-recommended Alere Determine TB-LAM Ag test (AlereLAM) using urine samples from HIV-positive patients. METHODS: We did a diagnostic accuracy study at five outpatient public health facilities in Uganda, Kenya, Mozambique, and South Africa. Eligible patients were ambulatory HIV-positive individuals (aged ≥15 years) with symptoms of tuberculosis irrespective of their CD4 T-cell count (group 1), and asymptomatic patients with advanced HIV disease (CD4 count <200 cells per µL, or HIV clinical stage 3 or 4; group 2). All participants underwent clinical examination, chest x-ray, and blood sampling, and were requested to provide a fresh urine sample, and two sputum samples. FujiLAM and AlereLAM urine assays, Xpert MTB/RIF Ultra assay on sputum or urine, sputum culture for Mycobacterium tuberculosis, and CD4 count were systematically carried out for all patients. Sensitivity and specificity of FujiLAM and AlereLAM were evaluated against microbiological and composite reference standards. FINDINGS: Between Aug 24, 2020 and Sept 21, 2021, 1575 patients (823 [52·3%] women) were included in the study: 1031 patients in group 1 and 544 patients in group 2. Tuberculosis was microbiologically confirmed in 96 (9·4%) of 1022 patients in group 1 and 18 (3·3%) of 542 patients in group 2. Using the microbiological reference standard, FujiLAM sensitivity was 60% (95% CI 51-69) and AlereLAM sensitivity was 40% (31-49; p<0·001). Among patients with CD4 counts of less than 200 cells per µL, FujiLAM sensitivity was 69% (57-79) and AlereLAM sensitivity was 52% (40-64; p=0·0218). Among patients with CD4 counts of 200 cells per µL or higher, FujiLAM sensitivity was 47% (34-61) and AlereLAM sensitivity was 24% (14-38; p=0·0116). Using the microbiological reference standard, FujiLAM specificity was 87% (95% CI 85-89) and AlereLAM specificity was 86% (95 CI 84-88; p=0·941). FujiLAM sensitivity varied by lot number from 48% (34-62) to 76% (57-89) and specificity from 77% (72-81) to 98% (93-99). INTERPRETATION: Next-generation, higher sensitivity urine-lipoarabinomannan assays are potentially promising tests that allow rapid tuberculosis diagnosis at the point of care for HIV-positive patients. However, the variability in accuracy between FujiLAM lot numbers needs to be addressed before clinical use. FUNDING: ANRS and Médecins Sans Frontières.