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Objective The aim of the study was to compare the yields of newly diagnosed cases of HIV infection and advanced immunodeficiency between individuals attending a mobile HIV counselling and testing (HCT) service as participants in a population-based HIV seroprevalence survey and those accessing the same service as volunteers for routine testing. Methods The study was conducted in a peri-urban township within the Cape Metropolitan Region, South Africa. Survey participants (recruited testers) were randomly selected, visited at home and invited to attend the mobile HCT service. They received 70 South African Rand food vouchers for participating in the survey, but could choose to test anonymously. The yield of HIV diagnoses was compared with that detected in members of the community who voluntarily attended the same HIV testing facility prior to the survey and did not receive incentives (voluntary testers). Results A total of 1813 individuals were included in the analysis (936 recruited and 877 voluntary testers). The prevalence of newly diagnosed HIV infection was 10.9% [95% confidence interval (CI) 9.0-13.1%] among recruited testers and 5.0% (3.7-6.7%) among voluntary testers. The prevalence of severe immune deficiency (CD4 count ≤200 cells/μL) among recruited and voluntary testers was 17.8% (10.9-26.7%) and 4.6% (0.0-15.4%), respectively. Linkage to HIV care in recruited testers with CD4 counts ≤350 cells/μL was 78.8%. Conclusion Compared with routine voluntary HCT, selection and invitation in combination with incentives doubled the yield of newly diagnosed HIV infections and increased the yield almost fourfold of individuals needing antiretroviral therapy. This may be an important strategy to increase community-based HIV diagnosis and access to care. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is the most common opportunistic disease in HIV-infected patients during the initial months of antiretroviral therapy (ART) and presents a great challenge to ART programs in resource-limited settings. The mechanisms underlying development of TB in this period are complex. Some cases may represent progression of undiagnosed subclinical disease present before starting ART, emphasizing the importance of careful screening strategies for TB. It has been suggested that progression in such cases is due to immune reconstitution disease-a phenomenon in which dysregulated restoration of pathogen-specific immune responses triggers the presentation of subclinical disease. However, whereas some cases have exaggerated or overtly inflammatory manifestations consistent with existing case definitions for IRD, many others do not. Moreover, since ART-induced immune recovery is a time-dependent process, active TB may develop as a consequence of persisting immunodeficiency. All these mechanisms are likely to be important, representing a spectrum of complex interactions between mycobacterial burden and changing host immune response. We propose that the potential range of effects of ART includes (1) shortening of the time for subclinical TB to become symptomatic (a phenomenon often referred to as "unmasking"), (2) increased rapidity of initial onset of TB symptoms, and (3) heightened intensity of clinical manifestations. We suggest that the term "ART-associated TB" be used to refer collectively to all cases of TB presenting during ART and that "immune reconstitution disease" be used to refer to the subset of ART-associated TB cases in which the effect on disease severity results in exaggerated and overtly inflammatory disease. [ABSTRACT FROM AUTHOR]

Background: Although failure of tuberculosis (TB) control in sub-Saharan Africa is attributed to the HIV epidemic, it is unclear why the directly observed therapy short-course (DOTS) strategy is insufficient in this setting. We conducted a cross-sectional survey of pulmonary TB (PTB) and HIV infection in a community of 13,000 with high HIV prevalence and high TB notification rate and a well-functioning DOTS TB control program.Methods: Active case finding for PTB was performed in 762 adults using sputum microscopy and Mycobacterium tuberculosis culture, testing for HIV, and a symptom and risk factor questionnaire. Survey findings were correlated with notification data extracted from the TB treatment register.Results: Of those surveyed, 174 (23%) tested HIV positive, 11 (7 HIV positive) were receiving TB therapy, 6 (5 HIV positive) had previously undiagnosed smear-positive PTB, and 6 (4 HIV positive) had smear-negative/culture-positive PTB. Symptoms were not a useful screen for PTB. Among HIV-positive and -negative individuals, prevalence of notified smear-positive PTB was 1,563/100,000 and 352/100,000, undiagnosed smear-positive PTB prevalence was 2,837/100,000 and 175/100,000, and case-finding proportions were 37 and 67%, respectively. Estimated duration of infectiousness was similar for HIV-positive and HIV-negative individuals. However, 87% of total person-years of undiagnosed smear-positive TB in the community were among HIV-infected individuals.Conclusions: PTB was identified in 9% of HIV-infected individuals, with 5% being previously undiagnosed. Lack of symptoms suggestive of PTB may contribute to low case-finding rates. DOTS strategy based on passive case finding should be supplemented by active case finding targeting HIV-infected individuals. [ABSTRACT FROM AUTHOR]

Central nervous system involvement in HIV infection leads to neurobehavioural sequelae. Although apathy is a well-recognised symptom in adults living with HIV linked to alterations in brain structure, there is scarce research examining motivation in children living with HIV (CLWH). We used the Children's Motivation Scale (CMS; normative mean = 50, SD = 10) to assess motivation levels in 76 CLWH aged 6-16 years (63 on antiretroviral therapy [ART]; 13 ART-naïve slow progressors) in South Africa. Overall, CLWH scored low on the CMS (mean = 35.70 [SD = 5.87]). Motivation levels were significantly reduced in children taking ART compared to ART-naïve slow progressors (p = 0.02), but were not correlated with markers of HIV disease (CD4 + cell count or viral load), or neurocognitive function (p > 0.05). CMS scores were correlated with diffusion tensor imaging metrics of white matter microstructure in specific frontostriatal brain regions (p < 0.05). On multiple regression, associations with the anterior limb of the internal capsule, a subcortical white matter region, remained significant after adjusting for potential confounders. These findings suggest that reduced motivation may be an important neurobehavioural symptom in CLWH and may reflect changes in white matter microstructure of frontostriatal brain regions., (© 2024. The Author(s).)

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., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Determine TB-LAM is the first point-of-care test (POC) for HIV-associated tuberculosis (TB) and rapidly identifies TB in those at high-risk for short-term mortality. While the relationship between urine-LAM and mortality has been previously described, the outcomes of those undergoing urine-LAM testing have largely been assessed during short follow-up periods within diagnostic accuracy studies. We therefore sought to assess the relationship between baseline urine-LAM results and subsequent hospitalization and mortality under real-world conditions among outpatients in the first year of ART., Methods: Consecutive, HIV-positive adults with a CD4 count < 100 cells/uL presenting for ART initiation were enrolled. TB diagnoses and outcomes (hospitalization, loss-to-follow and mortality) were recorded during the first year following enrolment. Baseline urine samples were retrospectively tested using the urine-LAM POC assay. Kaplan Meier survival curves were used to assess the cumulative probability of hospitalization or mortality in the first year of follow-up, according to urine-LAM status. Cox regression analyses were performed to determine independent predictors of hospitalization and mortality at  three months and one year of follow-up., Results: 468 patients with a median CD4 count of 59 cells/uL were enrolled. There were 140 patients (29.9%) with newly diagnosed TB in the first year of follow-up of which 79 (56.4%) were microbiologically-confirmed. A total of 18% (n = 84) required hospital admission and 12.2% (n = 57) died within a year of study entry. 38 out of 468 (8.1%) patients retrospectively tested urine-LAM positive - including 19.0% of those with microbiologically-proven TB diagnoses (n = 15/79) and 23.0% (n = 14/61) of those with clinical-only TB diagnoses; 9 of 38 (23.7%) of patients retrospectively testing LAM positive were never diagnosed with TB under routine program conditions. Among all patients (n = 468) in the first year of follow-up, a positive urine-LAM result was strongly associated with all-cause hospitalization and mortality with a corresponding adjusted hazard ratio (aHR) of 3.7 (95%CI, 1.9-7.1) and 2.6 (95%, 1.2-5.7), respectively., Conclusions: Systematic urine-LAM testing among ART-naïve HIV-positive outpatients with CD4 counts < 100 cells/uL detected TB cases that were missed under routine programme conditions and was highly predictive for subsequent hospitalization and mortality in the first year of ART.

Background: In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death., Methods: We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization., Results: A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses. At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78). Serious adverse events were more common with systematic treatment., Conclusions: Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events. (Funded by the Agence Nationale de Recherches sur le Sida et les Hépatites Virales; STATIS ANRS 12290 ClinicalTrials.gov number, NCT02057796.)., (Copyright © 2020 Massachusetts Medical Society.)

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., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: KD has obtained speaker fees at industry-sponsored symposia and non-financial support from Alere in the form of kits and test strips, outside the submitted work. No other authors declare competing interests.

Background: Testing urine improves the number of tuberculosis diagnoses made among patients in hospital with HIV. In conjunction with the two-country randomised Rapid Urine-based Screening for Tuberculosis to Reduce AIDS-related Mortality in Hospitalised Patients in Africa (STAMP) trial, we used a microsimulation model to estimate the effects on clinical outcomes and the cost-effectiveness of adding urine-based tuberculosis screening to sputum screening for hospitalised patients with HIV., Methods: We compared two tuberculosis screening strategies used irrespective of symptoms among hospitalised patients with HIV in Malawi and South Africa: a GeneXpert assay (Cepheid, Sunnyvale, CA, USA) for Mycobacterium tuberculosis and rifampicin resistance (Xpert) in sputum samples (standard of care) versus sputum Xpert combined with a lateral flow assay for M tuberculosis lipoarabinomannan in urine (Determine TB-LAM Ag test, Abbott, Waltham, MA, USA [formerly Alere]; TB-LAM) and concentrated urine Xpert (intervention). A cohort of simulated patients was modelled using selected characteristics of participants, tuberculosis diagnostic yields, and use of hospital resources in the STAMP trial. We calibrated 2-month model outputs to the STAMP trial results and projected clinical and economic outcomes at 2 years, 5 years, and over a lifetime. We judged the intervention to be cost-effective if the incremental cost-effectiveness ratio (ICER) was less than US$750/year of life saved (YLS) in Malawi and $940/YLS in South Africa. A modified intervention of adding only TB-LAM to the standard of care was also evaluated. We did a budget impact analysis of countrywide implementation of the intervention., Findings: The intervention increased life expectancy by 0·5-1·2 years and was cost-effective, with an ICER of $450/YLS in Malawi and $840/YLS in South Africa. The ICERs decreased over time. At lifetime horizon, the intervention remained cost-effective under nearly all modelled assumptions. The modified intervention was at least as cost-effective as the intervention (ICERs $420/YLS in Malawi and $810/YLS in South Africa). Over 5 years, the intervention would save around 51 000 years of life in Malawi and around 171 000 years of life in South Africa. Health-care expenditure for screened individuals was estimated to increase by $37 million (10·8%) and $261 million (2·8%), respectively., Interpretation: Urine-based tuberculosis screening of all hospitalised patients with HIV could increase life expectancy and be cost-effective in resource-limited settings. Urine TB-LAM is especially attractive because of high incremental diagnostic yield and low additional cost compared with sputum Xpert, making a compelling case for expanding its use to all hospitalised patients with HIV in areas with high HIV burden and endemic tuberculosis., Funding: UK Medical Research Council, UK Department for International Development, Wellcome Trust, US National Institutes of Health, Royal College of Physicians, Massachusetts General Hospital., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

HIV-associated disseminated TB (tuberculosis) has been under-recognised and poorly characterised. Blood culture is the gold-standard diagnostic test, but is expensive, slow, and may under-diagnose TB dissemination. In a cohort of hospitalised HIV patients, we aimed to report the prevalence of TB-blood-culture positivity, performance of rapid diagnostics as diagnostic surrogates, and better characterise the clinical phenotype of disseminated TB. HIV-inpatients were systematically investigated using sputum, urine and blood testing. Overall, 132/410 (32.2%) patients had confirmed TB; 41/132 (31.1%) had a positive TB blood culture, of these 9/41 (22.0%) died within 90-days. In contrast to sputum diagnostics, urine Xpert and urine-lipoarabinomannan (LAM) combined identified 88% of TB blood-culture-positive patients, including 9/9 who died within 90-days. For confirmed-TB patients, half the variation in major clinical variables was captured on two principle components (PCs). Urine Xpert, urine LAM and TB-blood-culture positive patients clustered similarly on these axes, distinctly from patients with localised disease. Total number of positive tests from urine Xpert, urine LAM and MTB-blood-culture correlated with PCs (p < 0.001 for both). PC1&PC2 independently predicted 90-day mortality (ORs 2.6, 95%CI = 1.3-6.4; and 2.4, 95%CI = 1.3-4.5, respectively). Rather than being a non-specific diagnosis, disseminated TB is a distinct, life-threatening condition, which can be diagnosed using rapid urine-based tests, and warrants specific interventional trials.

Primary health care workers (HCWs) in low- and middle-income settings (LMIC) often work in challenging conditions in remote, rural areas, in isolation from the rest of the health system and particularly specialist care. Much attention has been given to implementation of interventions to support quality and performance improvement for workers in such settings. However, little is known about the design of such initiatives and which approaches predominate, let alone those that are most effective. We aimed for a broad understanding of what distinguishes different approaches to primary HCW support and performance improvement and to clarify the existing evidence as well as gaps in evidence in order to inform decision-making and design of programs intended to support and improve the performance of health workers in these settings. We systematically searched the literature for articles addressing this topic, and undertook a comparative review to document the principal approaches to performance and quality improvement for primary HCWs in LMIC settings. We identified 40 eligible papers reporting on interventions that we categorized into five different approaches: (1) supervision and supportive supervision; (2) mentoring; (3) tools and aids; (4) quality improvement methods, and (5) coaching. The variety of study designs and quality/performance indicators precluded a formal quantitative data synthesis. The most extensive literature was on supervision, but there was little clarity on what defines the most effective approach to the supervision activities themselves, let alone the design and implementation of supervision programs. The mentoring literature was limited, and largely focused on clinical skills building and educational strategies. Further research on how best to incorporate mentorship into pre-service clinical training, while maintaining its function within the routine health system, is needed. There is insufficient evidence to draw conclusions about coaching in this setting, however a review of the corporate and the business school literature is warranted to identify transferrable approaches. A substantial literature exists on tools, but significant variation in approaches makes comparison challenging. We found examples of effective individual projects and designs in specific settings, but there was a lack of comparative research on tools across approaches or across settings, and no systematic analysis within specific approaches to provide evidence with clear generalizability. Future research should prioritize comparative intervention trials to establish clear global standards for performance and quality improvement initiatives. Such standards will be critical to creating and sustaining a well-functioning health workforce and for global initiatives such as universal health coverage., (© The Author 2016. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine.)

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.

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.

Compared with smear microscopy, the Xpert MTB/RIF assay (Xpert), with superior accuracy and capacity to diagnose rifampicin resistance, has advanced TB diagnostic capability. However, recent trials of Xpert impact have not demonstrated reductions in patient morbidity and mortality. We conducted a narrative review of Xpert impact trials to summarize which patient-relevant outcomes Xpert has improved and explore reasons for no observed morbidity or mortality reductions. We searched PubMed, Google Scholar, Cochrane Library and Embase and identified eight trials meeting inclusion criteria: three individually randomized, three cluster-randomized, and two pre-post trials. In six trials Xpert increased diagnostic yield of bacteriologically-confirmed TB from sputa and in four trials Xpert shortened time to TB treatment. However, all-cause mortality was similar between arms in all six trials reporting this outcome, and the only trial to assess Xpert impact on morbidity reported no impact. Trial characteristics that might explain lack of observed impact on morbidity and mortality include: higher rates of empiric TB treatment in microscopy compared with Xpert arms, enrollment of study populations not comprised exclusively of populations most likely to benefit from Xpert, and health system weaknesses. So far as equipoise exists, future trials that address past limitations are needed to inform Xpert use in resource-limited settings., (© Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: The size and concentration of exhaled bioaerosols may influence TB transmission risk. This study piloted bioaerosol measurement in patients with TB and assessed variability in bioaerosol production during normal tidal breathing. Understanding this may provide a tool for assessing heterogeneity in infectivity and may inform mathematical models of TB control practices and policies., Methods: Optical particle counter technology was used to measure aerosol size and concentration in exhaled air (range 0.3-20 µm in diameter) during 15 tidal breaths across four groups over time: healthy/uninfected, healthy/Mycobacterium tuberculosis-infected, patients with extrathoracic TB and patients with intrathoracic TB. High-particle production was defined as any 1-5 µm sized bioaerosol count above the median count among all participants (median count=2 counts/L)., Results: Data from 188 participants were obtained pretreatment (baseline). Bioaerosol production varied considerably between individuals. Multivariable analysis showed intrathoracic TB was associated with a 3½-fold increase in odds of high production of 1-5 µm bioaerosols (adjusted OR: 3.5; 95% CI 1.6 to 7.8; p=0.002) compared with healthy/uninfected individuals., Conclusions: We provide the first evidence that intrathoracic TB increases bioaerosol production in a particle size range that could plausibly transport M. tuberculosis. There is substantial variation in production within patients with TB that may conceivably relate to the degree of infectivity. Further data is needed to determine if high bioaerosol production during tidal breathing is associated with infectiousness., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Rapid detection of tuberculosis (TB) among people living with human immunodeficiency virus (HIV) is a global health priority. HIV-associated TB may have different clinical presentations and is challenging to diagnose. Conventional sputum tests have reduced sensitivity in HIV-positive individuals, who have higher rates of extrapulmonary TB compared with HIV-negative individuals. The lateral flow urine lipoarabinomannan assay (LF-LAM) is a new, commercially available point-of-care test that detects lipoarabinomannan (LAM), a lipopolysaccharide present in mycobacterial cell walls, in people with active TB disease., Objectives: To assess the accuracy of LF-LAM for the diagnosis of active TB disease in HIV-positive adults who have signs and symptoms suggestive of TB (TB diagnosis).To assess the accuracy of LF-LAM as a screening test for active TB disease in HIV-positive adults irrespective of signs and symptoms suggestive of TB (TB screening)., Search Methods: We searched the following databases without language restriction on 5 February 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE (PubMed,1966); EMBASE (OVID, from 1980); Science Citation Index Expanded (SCI-EXPANDED, from 1900), Conference Proceedings Citation Index-Science (CPCI-S, from 1900), and BIOSIS Previews (from 1926) (all three using the Web of Science platform; MEDION; LILACS (BIREME, from 1982); SCOPUS (from 1995); the metaRegister of Controlled Trials (mRCT); the search portal of the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); and ProQuest Dissertations & Theses A&l (from 1861)., Selection Criteria: Eligible study types included randomized controlled trials, cross-sectional studies, and cohort studies that determined LF-LAM accuracy for TB against a microbiological reference standard (culture or nucleic acid amplification test from any body site). A higher quality reference standard was one in which two or more specimen types were evaluated for TB, and a lower quality reference standard was one in which only one specimen type was evaluated for TB. Participants were HIV-positive people aged 15 years and older., Data Collection and Analysis: Two review authors independently extracted data from each included study using a standardized form. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We evaluated the test at two different cut-offs: (grade 1 or 2, based on the reference card scale of five intensity bands). Most analyses used grade 2, the manufacturer's currently recommended cut-off for positivity. We carried out meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and estimated the models using a Bayesian approach. We determined accuracy of LF-LAM combined with sputum microscopy or Xpert® MTB/RIF. In addition, we explored the influence of CD4 count on the accuracy estimates. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Main Results: We included 12 studies: six studies evaluated LF-LAM for TB diagnosis and six studies evaluated the test for TB screening. All studies were cross-sectional or cohort studies. Studies for TB diagnosis were largely conducted among inpatients (median CD4 range 71 to 210 cells per µL) and studies for TB screening were largely conducted among outpatients (median CD4 range 127 to 437 cells per µL). All studies were conducted in low- or middle-income countries. Only two studies for TB diagnosis (33%) and one study for TB screening (17%) used a higher quality reference standard.LF-LAM for TB diagnosis (grade 2 cut-off): meta-analyses showed median pooled sensitivity and specificity (95% credible interval (CrI)) of 45% (29% to 63%) and 92% (80% to 97%), (five studies, 2313 participants, 35% with TB, low quality evidence). The pooled sensitivity of a combination of LF-LAM and sputum microscopy (either test positive) was 59% (47% to 70%), which represented a 19% (4% to 36%) increase over sputum microscopy alone, while the pooled specificity was 92% (73% to 97%), which represented a 6% (1% to 24%) decrease from sputum microscopy alone (four studies, 1876 participants, 38% with TB). The pooled sensitivity of a combination of LF-LAM and sputum Xpert® MTB/RIF (either test positive) was 75% (61% to 87%) and represented a 13% (1% to 37%) increase over Xpert® MTB/RIF alone. The pooled specificity was 93% (81% to 97%) and represented a 4% (1% to 16%) decrease from Xpert® MTB/RIF alone (three studies, 909 participants, 36% with TB). Pooled sensitivity and specificity of LF-LAM were 56% (41% to 70%) and 90% (81% to 95%) in participants with a CD4 count of less than or equal to 100 cells per µL (five studies, 859 participants, 47% with TB) versus 26% (16% to 46%) and 92% (78% to 97%) in participants with a CD4 count greater than 100 cells per µL (five studies, 1410 participants, 30% with TB).LF-LAM for TB screening (grade 2 cut-off): for individual studies, sensitivity estimates (95% CrI) were 44% (30% to 58%), 28% (16% to 42%), and 0% (0% to 71%) and corresponding specificity estimates were 95% (92% to 97%), 94% (90% to 97%), and 95% (92% to 97%) (three studies, 1055 participants, 11% with TB, very low quality evidence). There were limited data for additional analyses.The main limitations of the review were the use of a lower quality reference standard in most included studies, and the small number of studies and participants included in the analyses. The results should, therefore, be interpreted with caution., Authors' Conclusions: We found that LF-LAM has low sensitivity to detect TB in adults living with HIV whether the test is used for diagnosis or screening. For TB diagnosis, the combination of LF-LAM with sputum microscopy suggests an increase in sensitivity for TB compared to either test alone, but with a decrease in specificity. In HIV-positive individuals with low CD4 counts who are seriously ill, LF-LAM may help with the diagnosis of TB.

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.

TB is the leading cause of HIV/AIDS-related deaths globally. New diagnostic tools are urgently needed to avert deaths from undiagnosed HIV-associated TB. Although simple assays that detect lipoarabinomannan (LAM) in urine have been commercially available for years, their specific role and utility were initially misunderstood, such that they have been slower to emerge from the diagnostics pipeline than otherwise might have been expected. In this article, we review and explain how urine-LAM assays should be understood as diagnostics for disseminated TB in HIV-positive patients with advanced immunodeficiency, in whom haematogenous TB dissemination to the kidneys serves as the primary mechanism by which LAM enters the urine. These insights are critical for the appropriate design of studies to evaluate these assays and to understand how they might be most usefully implemented. This understanding also supports the 2015 WHO recommendations on the restricted use of these assays in sick HIV-positive patients with advanced immunodeficiency., (© The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Background: Anaemia commonly complicates both human immunodeficiency virus (HIV) infection and tuberculosis (TB), contributing substantially to morbidity and mortality. The mechanisms underlying anaemia and corresponding treatments in co-infected patients are poorly defined., Objective: To determine the relative contributions of anaemia of chronic disease (ACD) and iron deficiency to anaemia in patients with HIV-associated TB., Design: Consecutively recruited hospitalised (n = 102) and matched ambulatory patients (n = 51) with microbiologically confirmed HIV-associated TB in Cape Town, South Africa, were included. Haemoglobin levels, iron status markers, hepcidin and pro-inflammatory cytokines in blood were measured. We determined the prevalence of ACD and iron-deficiency anaemia (IDA) using seven different published definitions of IDA., Results: More than 80% of enrolled HIV-associated TB patients were anaemic, and anaemia was more severe among in-patients. Over 95% of anaemic HIV-associated TB patients had ACD, whereas the proportion with IDA using a range of seven different definitions was low overall (median <3%, range 0-32.6) in both patient groups. The proportion with IDA and hepcidin concentration ⩿ 20.0 ng/ml (predictive of responsiveness to oral iron supplementation) was also very low (median <3%, range 0-15.1)., Conclusions: ACD was the predominant cause underlying anaemia in HIV-associated TB patients, and IDA was very uncommon in this setting. The majority of anaemic HIV-associated TB patients were unlikely to benefit from oral iron supplementation.

Background: Anemia is very common in patients with human immunodeficiency virus (HIV)-associated tuberculosis, and hepcidin may be key in mediating this. We explored the relationship between blood hepcidin concentrations and anemia severity, mycobacterial burden and mortality in patients with HIV-associated tuberculosis., Methods: Consecutive unselected HIV-infected adults in South Africa were systematically investigated for tuberculosis. Three groups were studied: 116 hospitalized inpatients with HIV infection and tuberculosis (hereafter, "hospitalized patients"), 58 ambulatory outpatients with HIV infection and newly diagnosed tuberculosis (hereafter, "ambulatory patients with tuberculosis"), and 58 ambulatory outpatients with HIV infection and without tuberculosis (hereafter, "ambulatory patients without tuberculosis"). Blood hepcidin concentrations were determined for all patients. Vital status at 3 months was determined, and independent predictors of mortality were identified., Results: Median hepcidin concentrations were 38.8 ng/mL among hospitalized patients, 19.1 ng/mL among ambulatory patients with tuberculosis, and 5.9 ng/mL among ambulatory patients without tuberculosis (P < .001). In both groups with HIV-associated tuberculosis, hepcidin concentrations were strongly associated with greater anemia severity. Additionally, strong, graded associations were observed between hepcidin and composite indices of mycobacterial burden and dissemination. Patients dying within 3 months had significantly higher hepcidin concentrations, which independently predicted mortality., Conclusions: High hepcidin concentrations were strongly associated with disseminated disease, anemia, and poor prognosis in patients with HIV-associated tuberculosis. Hepcidin may be a mechanistically important mediator underlying the high prevalence of severe anemia in these patients., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

The public sector scale-up of antiretroviral therapy (ART) in South Africa commenced in 2004. We aimed to describe the hospital-level disease burden and factors contributing to morbidity and mortality among hospitalized HIV-positive patients in the era of widespread ART availability. Between June 2012 and October 2013, unselected patients admitted to medical wards at a public sector district hospital in Cape Town were enrolled in this cross-sectional study with prospective follow-up. HIV testing was systematically offered and HIV-infected patients were systematically screened for TB. The spectrum of admission diagnoses among HIV-positive patients was documented, vital status at 90 and 180 days ascertained and factors independently associated with death determined. Among 1018 medical admissions, HIV status was ascertained in 99.5%: 60.1% (n = 609) were HIV-positive and 96.1% (n = 585) were enrolled. Of these, 84.4% were aware of their HIV-positive status before admission. ART status was naive in 35.7%, current in 45.0%, and interrupted in 19.3%. The most frequent primary clinical diagnoses were newly diagnosed TB (n = 196, 33.5%), other bacterial infection (n = 100, 17.1%), and acquired immunodeficiency syndrome (AIDS)-defining illnesses other than TB (n = 64, 10.9%). By 90 days follow-up, 175 (29.9%) required readmission and 78 (13.3%) died. Commonest causes of death were TB (37.2%) and other AIDS-defining illnesses (24.4%). Independent predictors of mortality were AIDS-defining illnesses other than TB, low hemoglobin, and impaired renal function. HIV still accounts for nearly two-thirds of medical admissions in this South African hospital and is associated with high mortality. Strategies to improve linkage to care, ART adherence/retention and TB prevention are key to reducing HIV-related hospitalizations in this setting., Competing Interests: The authors have no conflicts of interest to disclose.

Antiretroviral therapy (ART) is the main intervention needed to reduce morbidity and mortality and to prevent tuberculosis in adults living with HIV. However, in most resource-limited countries, especially in sub-Saharan Africa, ART is started too late to have an effect with substantial early morbidity and mortality, and in high tuberculosis burden settings ART does not reduce the tuberculosis risk to that reported in individuals not infected with HIV. Co-trimoxazole preventive therapy started before or with ART, irrespective of CD4 cell count, reduces morbidity and mortality with benefits that continue indefinitely. Isoniazid preventive therapy as an adjunct to ART prevents tuberculosis in high-exposure settings, with long-term treatment likely to be needed to sustain this benefit. Unfortunately, both preventive therapies are underused in low-income and high-burden settings. ART development has benefited from patient-centred simplification with several effective regimens now available as a one per day pill. We argue that co-trimoxazole and isoniazid should also be combined into a single fixed-dose pill, along with pyridoxine (vitamin B6), that would be taken once per day to help with individual uptake and national scale-up of therapies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background.  Morbidity and mortality remain high among hospitalized patients infected with human immunodeficiency virus (HIV) in sub-Saharan Africa despite widespread availability of antiretroviral therapy. Severe anemia is likely one important driver, and some evidence suggests that blood transfusions may accelerate HIV progression and paradoxically increase short-term mortality. We investigated the relationship between anemia, blood transfusions, and mortality in a South African district hospital. Methods.  Unselected consecutive HIV-infected adults requiring acute medical admission to a Cape Town township district hospital were recruited. Admission hemoglobin concentrations were used to classify anemia severity according to World Health Organization/AIDS Clinical Trials Group criteria. Vital status was determined at 90 days, and Cox regression analyses were used to determine independent predictors of mortality. Results.  Of 585 HIV-infected patients enrolled, 578 (98.8%) were included in the analysis. Anemia was detected in 84.8% of patients and was severe (hemoglobin, 6.5-7.9 g/dL) or life-threatening (hemoglobin, <6.5 g/dL) in 17.3% and 13.3%, respectively. Within 90 days of the date of admission, 13.5% (n = 78) patients received at least 1 blood transfusion with red cell concentrate and 77 (13.3%) patients died. In univariable analysis, baseline hemoglobin and receipt of blood transfusion were associated with increased mortality risk. However, in multivariable analysis, neither hemoglobin nor receipt of a blood transfusion were independently associated with greater mortality risk. Acquired immune deficiency syndrome-defining illnesses other than tuberculosis and impaired renal function independently predicted mortality. Conclusions.  Newly admitted HIV-infected adults had a high prevalence of severe or life-threatening anemia and blood transfusions were frequently required. However, after adjustment for confounders, blood transfusions did not confer an increased mortality risk.

Objectives: Tuberculosis (TB) is estimated to be the leading cause of HIV-related deaths globally. However, since HIV-associated TB frequently remains unascertained, we systematically reviewed autopsy studies to determine the true burden of TB at death., Methods: We systematically searched Medline and Embase databases (to end 2013) for literature reporting on health facility-based autopsy studies of HIV-infected adults and/or children in resource-limited settings. Using forest plots and random-effects meta-analysis, we summarized the TB prevalence found at autopsy and used meta-regression to explore variables associated with autopsy TB prevalence., Results: We included 36 eligible studies, reporting on 3237 autopsies. Autopsy TB prevalence was extremely heterogeneous (range 0-64.4%), but was markedly higher in adults [pooled prevalence 39.7%, 95% confidence interval (CI) 32.4-47.0%] compared to children (pooled prevalence 4.5%, 95% CI 1.7-7.4%). Post-mortem TB prevalence varied by world region, with pooled estimates in adults of 63.2% (95% CI 57.7-68.7%) in South Asia (n = 2 studies); 43.2% (95% CI 38.0-48.3) in sub-Saharan Africa (n = 9 studies); and 27.1% (95% CI 16.0-38.1%) in the Americas (n = 5 studies). Autopsy prevalence positively correlated with contemporary estimates of national TB prevalence. TB in adults was disseminated in 87.9% (82.2-93.7%) of cases and was considered the cause of death in 91.4% (95% CI 85.8-97.0%) of TB cases. Overall, TB was the cause of death in 37.2% (95% CI 25.7-48.7%) of adult HIV/AIDS-related deaths. TB remained undiagnosed at death in 45.8% (95% CI 32.6-59.1%) of TB cases., Conclusions: In resource-limited settings, TB accounts for approximately 40% of facility-based HIV/AIDS-related adult deaths. Almost half of this disease remains undiagnosed at the time of death. These findings highlight the critical need to improve the prevention, diagnosis and treatment of HIV-associated TB globally.

Background: Autopsy studies of HIV/AIDS-related hospital deaths in sub-Saharan Africa reveal frequent failure of pre-mortem diagnosis of tuberculosis (TB), which is found in 34-64 % of adult cadavers. We determined the overall prevalence and predictors of TB among consecutive unselected HIV-positive adults requiring acute hospital admission and the comparative diagnostic yield obtained by screening urine and sputum samples obtained on day 1 of admission with Xpert MTB/RIF (Xpert)., Methods: To determine overall TB prevalence accurately, comprehensive clinical sampling (sputum, urine, blood plus other relevant samples) was done and TB was defined by detection of Mycobacterium tuberculosis in any sample using Xpert and/or mycobacterial liquid culture. To evaluate a rapid screening strategy, we compared the diagnostic yield of Xpert testing sputum samples and urine samples obtained with assistance from a respiratory study nurse in the first 24 h of admission., Results: Unselected HIV-positive acute adult new medical admissions (n = 427) who were not receiving TB treatment were enrolled irrespective of clinical presentation or symptom profile. From 2,391 cultures and Xpert tests done (mean, 5.6 tests/patient) on 1,745 samples (mean, 4.1 samples/patient), TB was diagnosed in 139 patients (median CD4 cell count, 80 cells/μL). TB prevalence was very high (32.6 %; 95 % CI, 28.1-37.2 %; 139/427). However, patient symptoms and risk factors were poorly predictive for TB. Overall, ≥1 non-respiratory sample(s) tested positive in 115/139 (83 %) of all TB cases, including positive blood cultures in 41/139 (29.5 %) of TB cases. In the first 24 h of admission, sputum (spot and/or induced samples) and urine were obtainable from 37.0 % and 99.5 % of patients, respectively (P <0.001). From these, the proportions of total TB cases (n = 139) that were diagnosed by Xpert testing sputum, urine or both sputum and urine combined within the first 24 h were 39/139 (28.1 %), 89/139 (64.0 %) and 108/139 (77.7 %) cases, respectively (P <0.001)., Conclusions: The very high prevalence of active TB and its non-specific presentation strongly suggest the need for routine microbiological screening for TB in all HIV-positive medical admissions in high-burden settings. The incremental diagnostic yield from Xpert testing urine was very high and this strategy might be used to rapidly screen new admissions, especially if sputum is difficult to obtain.

Approximately one-third of the global burden of tuberculosis (TB) remains undiagnosed each year and the vast majority of cases of multidrug-resistant TB remain undetected. Many countries still place heavy reliance on outdated technologies that are blunt and ineffective tools for controlling this epidemic. However, during the past 10 years, there has been substantial progress within the TB diagnostics developmental pipeline. Old technologies have been reviewed and improved and new technologies have been developed and evaluated and are now being implemented. This review summarizes these developments and describes the currently available diagnostic tools. Consideration is given to the requirements of future diagnostic tests and how these should be evaluated not only with regard to their diagnostic accuracy and operational feasibility, but ultimately in terms of whether they impact clinical outcomes cost effectively, especially for those most in need., (Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.)

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.

Background: Although the evidence base regarding the use of the Xpert MTB/RIF assay for diagnosis of pulmonary tuberculosis (TB) when testing respiratory samples is well established, the evidence base for its diagnostic accuracy for extrapulmonary and sputum-scarce pulmonary TB when testing non-respiratory samples is less clearly defined., Methods: A systematic literature search of 7 electronic databases (Medline, EMBASE, ISI Web of Science, BIOSIS, Global Health Database, Scopus and Cochrane Database) was conducted to identify studies of the diagnostic accuracy of the Xpert assay when testing non-respiratory samples compared with a culture-based reference standard. Data were extracted and study quality was assessed using the QUADAS-2 tool. Sensitivities and specificities were calculated on a per-sample basis, stratified by sample type and smear microscopy status and summarised using forest plots. Pooled estimates were calculated for groups with sufficient data., Results: Twenty-seven studies with a total of 6,026 non-respiratory samples were included. Among the 23 studies comparing Xpert and culture done on the same samples, sensitivity was very heterogeneous with a median sensitivity of 0.83 (IQR, 0.68-0.94) whereas specificities were typically very high (median, 0.98; IQR, 0.89-1.00). The pooled summary estimates of sensitivity when testing smear-positive and smear-negative samples were 0.95 (95% CI 0.91-1.00) and 0.69 (95% CI 0.60-0.80), respectively. Pooled summary estimates of sensitivity varied substantially between sample types: lymph node tissue, 0.96 (95% CI, 0.72-0.99); tissue samples of all types, 0.88 (95% CI, 0.76-0.94); pleural fluid, 0.34 (95% CI, 0.24-0.44); gastric aspirates for diagnosis of sputum-scarce pulmonary TB, 0.78 (IQR, 0.68 - 0.85). Median sensitivities when testing cerebrospinal fluid and non-pleural serous fluid samples were 0.85 (IQR, 0.75-1.00) and 0.67 (IQR, 0.00-1.00), respectively., Conclusion: Xpert detects with high specificity the vast majority of EPTB cases with smear-positive non-respiratory samples and approximately two-thirds of those with smear-negative samples. Xpert is a useful rule-in diagnostic test for EPTB, especially when testing cerebrospinal fluid and tissue samples. In addition, it has a high sensitivity for detecting pulmonary TB when using gastric aspirate samples. These findings support recent WHO guidelines regarding the use of Xpert for TB diagnosis from non-respiratory samples.

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.

The role of Xpert(®) MTB/RIF for tuberculosis (TB) diagnosis remains to be clearly delineated in high-resource settings. At a London hospital, we evaluated a policy of selective assay use, with testing restricted to defined sub-groups of patients. Management was directly influenced in 30% of patients studied, including 'ruling-in' a TB diagnosis (leading to initiation of treatment for TB or for potential multidrug-resistant TB); negative assay results also helped support decisions for cessation of empirical anti-tuberculosis treatment or the safe initiation of other treatments such as immunosuppressant drugs. The benefits and pitfalls of this assay's use within high-resource settings are discussed.