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

Virological failure, HIV-1 drug resistance, and early mortality in adults admitted to hospital in Malawi: an observational cohort study.

BACKGROUND: Antiretroviral therapy (ART) scale-up in sub-Saharan Africa combined with weak routine virological monitoring has driven increasing HIV drug resistance. We investigated ART failure, drug resistance, and early mortality among patients with HIV admitted to hospital in Malawi. METHODS: This observational cohort study was nested within the rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalised patients in Africa (STAMP) trial, which recruited unselected (ie, irrespective of clinical presentation) adult (aged ≥18 years) patients with HIV-1 at admission to medical wards. Patients were included in our observational cohort study if they were enrolled at the Malawi site (Zomba Central Hospital) and were taking ART for at least 6 months at admission. Patients who met inclusion criteria had frozen plasma samples tested for HIV-1 viral load. Those with HIV-1 RNA of at least 1000 copies per mL had drug resistance testing by ultra-deep sequencing, with drug resistance defined as intermediate or high-level resistance using the Stanford HIVDR program. Mortality risk was calculated 56 days from enrolment. Patients were censored at death, at 56 days, or at last contact if lost to follow-up. The modelling strategy addressed the causal association between HIV multidrug resistance and mortality, excluding factors on the causal pathway (most notably, CD4 cell count, clinical signs of advanced HIV, and poor functional and nutritional status). FINDINGS: Of 1316 patients with HIV enrolled in the STAMP trial at the Malawi site between Oct 26, 2015, and Sept 19, 2017, 786 had taken ART for at least 6 months. 252 (32%) of 786 patients had virological failure (viral load ≥1000 copies per mL). Mean age was 41·5 years (SD 11·4) and 528 (67%) of 786 were women. Of 237 patients with HIV drug resistance results available, 195 (82%) had resistance to lamivudine, 128 (54%) to tenofovir, and 219 (92%) to efavirenz. Resistance to at least two drugs was common (196, 83%), and this was associated with increased mortality (adjusted hazard ratio 1·7, 95% CI 1·2-2·4; p=0·0042). INTERPRETATION: Interventions are urgently needed and should target ART clinic, hospital, and post-hospital care, including differentiated care focusing on patients with advanced HIV, rapid viral load testing, and routine access to drug resistance testing. Prompt diagnosis and switching to alternative ART could reduce early mortality among inpatients with HIV. FUNDING: Joint Global Health Trials Scheme of the Medical Research Council, UK Department for International Development, and Wellcome Trust

A pragmatic approach to managing antiretroviral therapy-experienced patients diagnosed with HIV-associated cryptococcal meningitis: impact of antiretroviral therapy adherence and duration

Cryptococcal meningitis accounts for 15% of all HIV-related deaths [1]. The overall number of cryptococcal meningitis cases has remained relatively stable in many low-to-middle income countries (LMICs) despite increasing roll-out of antiretroviral therapy (ART). Increasing numbers of patients are at risk of developing cryptococcal meningitis following ART failure or discontinuation, offsetting declines in those presenting for the first time with advanced HIV [2–4]. Over half of patients diagnosed with cryptococcal meningitis in recent studies in sub-Saharan Africa are ART-experienced (i.e. currently receiving or previously received ART) [5,6]. Although there is robust evidence from prospective randomized trials that ART initiation should be delayed until 4–6 weeks after starting antifungal therapy in ART-naïve cryptococcal meningitis patients [7,8], the approach to ART management among ART-experienced cryptococcal meningitis patients lacks adequate evidence, with a paucity of published data

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

Cost-effectiveness of urine-based tuberculosis screening in hospitalised patients with HIV in Africa: a microsimulation modelling study.

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$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

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.

BackgroundThe 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 findingsA 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 ConclusionsThis 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 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