Rapid Urine-Based Screening for Tuberculosis to Reduce AIDS-Related Mortality in Hospitalized Patients in Africa (STAMP) Trial

Sub-Saharan Africa bears the brunt of the global HIV/AIDS epidemic, with 23.5 million people living with HIV and 1.2 million deaths in 2012. Tuberculosis (TB) is the leading cause of AIDS-related illness and deaths worldwide and 75% of this disease burden is in sub-Saharan Africa. Studies from across the continent have shown that 30%-67% of HIV-infected adult hospital in-patients who die have evidence of TB at post-mortem. Much of this disease is neither clinically suspected nor diagnosed before death. This indicates abject failure of current approaches to diagnosis, which is the key problem addressed by this trial.

The very large number of HIV-TB deaths means that Africa is not on track to meet the WHO TB control targets linked to the 2015 MDGs. This has therefore become a high-level strategic priority, with calls for action from WHO, UNAIDS, STOP-TB, PEPFAR and other agencies. We believe that recent advances in TB diagnosis can be harnessed to address this challenge in a fundamentally new way.

Background studies conducted by the PI in South Africa found that the burden of confirmed TB among unselected HIV-infected patients needing hospital admission was extremely high (32.6%). Symptoms were so poorly predictive for screening, however, that in day-to-day clinical practice, much of this disease remains 'under the radar' and undetected. We propose that, regardless of symptoms, all such patients should be investigated for TB on admission.
In these studies the diagnostic yield using the traditional approach of sputum-based testing was, however, very limited as fewer than half of the patients could produce sputum samples and much disease involved organs other than the lungs. In contrast, urine samples could be obtained from almost all patients and the yield of diagnoses from testing these with rapid diagnostics was far greater than that obtained from sputum. Urine was first tested using a simple 30-minute strip-test which is commercially available (Determine TB-LAM). Urine was also concentrated by simple centrifugation and tested using the new WHO-approved rapid Xpert MTB/RIF assay (Xpert). Compared to Xpert testing of sputum alone, addition of this urine-based testing strategy to the initial screen increased the early diagnostic yield of TB 3.0-fold - an extraordinary improvement.

Some recent studies have reported that implementation of new TB diagnostics with superior sensitivity did not improve patient outcomes. Thus, since use of new, costly tests might divert limited resources from other important healthcare needs, it is imperative that the impact, cost and cost-effectiveness of new diagnostic strategies such as this one are assessed in trials. This randomised controlled trial will enrol adult HIV-infected medical inpatients admitted to two regional referral hospitals in South Africa and Malawi. On admission, patients will be randomised to one of two TB screening strategies (1,300 patients in each arm), comparing TB diagnosis by Xpert testing of sputum (standard arm) with an intervention arm in which urine will in addition be screened with a combination of the two urine-based diagnostic tests. The care of patients provided by the routine medical team will not be otherwise altered.

The main study outcome will show whether additional urine-based screening results in greater survival due to improved yield and speed of TB diagnosis. To more fully assess the overall impact on patients and the efficiency of the healthcare received, a range of additional outcomes will be assessed. These include the total yield of TB diagnoses; times to diagnosis; the proportions starting TB treatment, other antibiotics and antiretrovirals; the length of hospital stay and the need for readmission. Implementation of this intervention will be further justified by comprehensive cost-effectiveness and budgetary impact analyses. If impact is demonstrated, this intervention could be readily implemented and scaled-up.

TB underlies 30%-67% of HIV/AIDS-related deaths among medical in-patients in hospitals across sub-Saharan Africa and much of this remains undiagnosed. Background studies in South Africa have shown major increases in diagnostic yield of TB are gained from rapid urine-based screening in such patients using a combination of the Determine TB-LAM lateral-flow assay and testing urine (40 ml concentrated by centrifugation) with the Xpert MTB/RIF assay. We hypothesize that urine-based screening will increase the yield and speed of TB diagnosis, accelerating appropriate medical management and reducing mortality risk. However, no studies have yet demonstrated improved clinical outcomes from use of new TB diagnostics with superior sensitivity. Thus, a trial is needed.

This pragmatic individually randomised controlled blinded trial will compare between arms the survival of medical in-patients admitted to two regional hospitals in South Africa and Malawi and randomised to one of two diagnostic TB screening strategies on day one of admission. Those in the standard arm will have sputum tested with Xpert whereas those in the intervention arm will, in addition, have urine-based screening using Determine TB-LAM and Xpert. The routine medical teams will be informed of laboratory results as soon as possible to inform treatment decisions but they will remain blinded to study arm allocation. Treatment for TB in the absence of microbiological confirmation will be at the discretion of the medical team. Clinical outcomes will be ascertained during hospital admission and during out-patient follow-up and the primary outcome is all-cause mortality at 56 days after randomization.

The findings will be of immediate relevance to public health policy both nationally and internationally and will be underpinned with economic analyses. Both diagnostic assays used are commercially available and Xpert is being widely implemented. Thus, implementation of this strategy is feasible and scalable.

Principal impact:
Reduction in mortality from HIV-associated TB.

Geographical location of beneficiaries:
HIV-associated TB is the leading cause of AIDS-related deaths worldwide, especially in sub-Saharan Africa where 75% of the global disease burden is concentrated. Countries in east and southern Africa are hardest hit. South Africa alone accounts for 30% of the global caseload and 88,000 deaths annually. Such countries will be the major beneficiaries.
A substantial disease burden also exists in other resource-limited settings (S. & S.E. Asia and S. America) and the diagnostic approach evaluated in this study is likely to be widely applicable. Post-mortem studies from India, for example, have documented very frequent renal involvement with TB among AIDS-related deaths, indicating the likely utility of urine-based TB diagnostics in this setting.

Patient and community beneficiaries:
TB/HIV in resource-limited settings disproportionately affects young adults who potentially have many years of economic productivity and often have multiple dependants in both the older and younger generations. TB is the leading cause of AIDS-related orphanhood. Increased survival derived from our intervention would have multiplied beneficial effects within families and the wider community. With widespread availability of free antiretrovirals, the prospects of long-term survival among HIV-infected patients are good. Thus, patients surviving in-patient admission may well return to long-term health, care for their families and remain economically productive.

Benefits to health-care provision:
This study seeks to generate evidence that would fundamentally alter the approach to investigation for TB in HIV-infected medical in-patients. Recommendations would include routine investigation of such patients regardless of symptoms and use of rapid urine-based diagnostics on the first day of admission. This would have major advantages over existing practice in terms of ease of obtaining clinical samples, high diagnostic yield, rapidity and simplicity for the laboratory service, and reduced reliance on obtaining sputum samples and associated risk of nosocomial TB transmission. Clinical management would be simplified through reductions in diagnostic delays and uncertainty, leading to shortened hospital in-patient admissions.

Policy maker beneficiaries: A key goal of this research is to influence national and international public health policy makers regarding guidelines for TB screening and diagnosis in HIV-infected medical in-patients in resource-limited settings. This is feasible as the tools are already available and WHO recommendations for use of Xpert MTB/RIF for diagnosis of extrapulmonary TB are already under development. Xpert MTB/RIF is being widely implemented through a discounted pricing scheme and is already implemented nationwide in South Africa and in many hospital settings in Malawi. The low-cost Determine TB-LAM assay is commercially available and will undergo WHO review in 2014. This study will further add to the evidence base for policy-makers to recommend use of these tools.

Economic beneficiaries:
Increased chances of return to health and long-term survival of young economically active adults will not only result in economic benefits for patients and their families but also the local, regional and national economies. Simple economic estimates suggest that if the new algorithm is associated with a significant reduction in mortality (25%), the cost per year of life saved would be extremely low (approximately USD $230 in diagnostic reagent costs per life saved). We anticipate that this will represent a highly cost-effective intervention for the national Ministries of Health, especially when taking into account the benefits derived from potential reductions in hospital stay and simplification of medical investigations.

Academic beneficiaries:
Multiple academic beneficiaries of this research are listed earlier.