Elsevier

The Lancet

Volume 387, Issue 10024, 19–25 March 2016, Pages 1187-1197
The Lancet

Articles
Effect on mortality of point-of-care, urine-based lipoarabinomannan testing to guide tuberculosis treatment initiation in HIV-positive hospital inpatients: a pragmatic, parallel-group, multicountry, open-label, randomised controlled trial

https://doi.org/10.1016/S0140-6736(15)01092-2Get rights and content

Summary

Background

HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality.

Methods

We did a pragmatic, randomised, parallel-group, multicentre trial in ten hospitals in Africa—four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. Eligible patients were HIV-positive adults aged at least 18 years with at least one of the following symptoms of tuberculosis (fever, cough, night sweats, or self-reported weightloss) and illness severity necessitating admission to hospital. Exclusion criteria included receipt of any anti-tuberculosis medicine in the 60 days before enrolment. We randomly assigned patients (1:1) to either LAM plus routine diagnostic tests for tuberculosis (smear microscopy, Xpert-MTB/RIF, and culture; LAM group) or routine diagnostic tests alone (no LAM group) using computer-generated allocation lists in blocks of ten. All patients were asked to provide a urine sample of at least 30 mL at enrolment, and trained research nurses did the LAM test in patients allocated to this group using the Alere Determine tuberculosis LAM Ag lateral flow strip test (Alere, USA) at the bedside on enrolment. On the basis of a positive test result, the nurses made a recommendation for initiating anti-tuberculosis treatment. The attending physician made an independent decision about whether to start treatment or not. Neither patients nor health-care workers were masked to group allocation and test results. The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention). This trial is registered with ClinicalTrials.gov, number NCT01770730.

Findings

Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 patients and randomly assigned 2659 to treatment (1336 to LAM, 1323 to no LAM). 108 patients did not receive their allocated treatment, mainly because they did not meet the inclusion criteria, and 23 were excluded from analysis, leaving 2528 in the final modified intention-to-treat analysis (1257 in the LAM group, 1271 in the no LAM group). Overall all-cause 8-week mortality occurred in 578 (23%) patients, 261 (21%) in LAM and 317 (25%) in no LAM, an absolute reduction of 4% (95% CI 1–7). The risk ratio adjusted for country was 0·83 (95% CI 0·73–0·96), p=0·012, with a relative risk reduction of 17% (95% CI 4–28). With the time-to-event analysis, there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM (hazard ratio adjusted for country 0·82 [95% CI 0·70–0·96], p=0·015). No adverse events were associated with LAM testing.

Interpretation

Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital inpatients with suspected tuberculosis was associated with reduced 8-week mortality. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum.

Funding

The European & Developing Countries Clinical Trials Partnership, the South African Medical Research Council, and the South African National Research Foundation.

Introduction

Tuberculosis is the leading cause of death in people with HIV, accounting for about 360 000 deaths in 2013.1, 2 Case fatalities are significantly higher in individuals with tuberculosis plus HIV co-infection because of the increased disseminated extra-pulmonary tuberculosis, and more severe forms of disease associated with progressive immunosuppression.1 Hospitals in endemic countries are overwhelmed with HIV-positive individuals with suspected tuberculosis who consume a large proportion of restricted health-care budgets. This consumption is due to several factors, including missed and delayed diagnoses of tuberculosis, which is a major challenge in individuals with HIV co-infection.1 Indeed, post-mortem meta-analytical data suggest that tuberculosis is the cause of death in nearly 40% of HIV-positive patients, most being disseminated (>85%) and nearly half remaining undiagnosed at the time of death.3 Severely ill patients with tuberculosis and HIV co-infection are often unable to self-expectorate sputum, or have extra-pulmonary disease thus needing sputum induction or alternative invasive sampling to acquire material for tuberculosis diagnostic testing.4 Such resources are often unavailable in countries endemic for both tuberculosis and HIV.5 Furthermore, patients with tuberculosis and HIV co-infection with advanced immunosuppression often have low bacillary loads in sputum and other body cavity fluids—eg, pleural and pericardial fluid, thus reducing the sensitivity of both traditional diagnostic tests (smear and culture) and newer nucleic acid amplification-based diagnostics (eg Xpert MTB/RIF [Mycobacterium tuberculosis/resistance to rifampacin]).6, 7, 8 Because neither smear nor Xpert MTB/RIF provides immediate results at the point at which care is provided, a need remains for an affordable bedside diagnostic test for tuberculosis that can potentially minimise patient dropout, transmission, and mortality in hospital inpatients with advanced immunosuppression.

Research in context

Evidence before this study

We searched PubMed for English-language studies published up to Sept 10, 2015, that examined the use of urine lipoarabinomannan testing (LAM) at the point of care and its effect on important patient outcomes. We combined search terms for urine LAM (“LAM”, “lipoarabinomannan”, “urine LAM”, “urinary LAM”, “LAM lateral flow assay”, “LAM strip test”, and “urine lipoarabinomannan”) with those suggesting effect (“time to result”, “time to diagnosis”, “time to treatment”, “morbidity”, “mortality”, and “outcome”). We identified eight published studies associating urine LAM positivity with poor prognostic features or increased mortality, or both. One study had assessed the use of urine LAM for monitoring treatment outcomes. Thus, previous studies have assessed the diagnostic accuracy of LAM and reported on the potential association between LAM positivity and prognostic features. However, in view of its moderate sensitivity and CD4 cell count-associated niche usefulness, whether LAM can reduce mortality in settings endemic for tuberculosis and HIV remained unclear.

Added value of this study

Findings from our randomised trial suggest that a LAM-guided, prompt anti-tuberculosis treatment initiation strategy can reduce 8-week mortality in HIV-positive hospital inpatients.

Implications of all the available evidence

Our data inform clinical practice and the roll-out of new diagnostic modalities in settings endemic for tuberculosis and HIV. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum. Collectively, the data suggest that policy makers should consider implementation of this low-cost bedside tuberculosis test in hospital inpatients in resource-limited settings with high tuberculosis and HIV burdens while further data accumulate.

The Alere Determine tuberculosis lipoarabinomannan Ag lateral flow strip test (LAM; Alere, USA, www.alerehiv.com) is a commercially available bedside tuberculosis diagnostic instrument providing a result within 25 min, using about 60 μL of urine to detect lipoarabinomannan, a glycolipid antigen of the M tuberculosis cell wall.9 The diagnostic accuracy of the LAM test has been moderate overall. The best performance has been noted among HIV-positive hospital inpatients with advanced immunosuppression (CD4 cell count ≤200 cells/μL).10 In this subgroup, pooled sensitivity was 46% and specificity was 94%, respectively. Accurate assessment of the LAM-test specificity has been difficult in view of the limitations of diagnosis in patients with advanced immunosuppression and differences in LAM-test cutoffs used; with rigorous reference standard diagnosis and the updated cutoff, specificity is likely to be more than 95%.11 The urine LAM test has shown incremental yield over sputum-smear microscopy12, 13 and identifies patients with the most severe illness and the highest bacillary load and mortality,14, 15 and the persistence of LAM positivity at 2 months after treatment initiation has been shown to be a poor prognostic indicator.16

The suboptimum accuracy of existing diagnostic methods in this subgroup of severely ill HIV-positive hospital inpatients means that empirical anti-tuberculosis treatment is common. Thus, whether, and to what extent, LAM testing might improve patient-important clinical outcomes or merely displace empirical treatment in true positive cases is unclear.17 Indeed, large randomised controlled trials of Xpert MTB/RIF have not shown a significant effect on key clinical patient outcomes18, 19 because of the mitigating effect of empirical treatment practices.20 We postulated that, despite moderate overall sensitivity, the addition of adjunctive LAM testing to available sputum-based tuberculosis diagnostics to guide anti-tuberculosis treatment initiation would improve tuberculosis treatment-related outcomes including mortality, morbidity, and length of hospital stay for HIV-positive hospital inpatients, compared with use of available sputum-based tuberculosis diagnostics alone. Thus, we did a multicountry trial to assess these effects.

Section snippets

Study design and participants

We did a pragmatic, parallel-group, open-label, multicentre, randomised trial in ten urban or periurban hospitals in Africa—four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. The study was approved by the appropriate national regulatory authorities and by the ethics committee at each site. Additional methods are provided in the online appendix.

Patients admitted to the ten hospitals were screened for study inclusion. A detailed description of each hospital is in the

Results

Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 possible participants (figure 1). Most were screened 4–48 h after hospital admission, yet by this time 2569 (29%) had already been empirically started on anti-tuberculosis treatment and were excluded. An additional 1074 patients (12%) were too ill to provide informed consent and were thus also excluded from enrolment. After screening, we assigned 2659 eligible patients to study interventions, and included 2528 in the modified ITT analysis

Discussion

Adjunctive urine LAM tests reduced all cause 8-week mortality in hospital inpatients with HIV, symptoms of tuberculosis, and advanced immunosuppression. Use of LAM tests ensured that more patients initiated anti-tuberculosis treatment and this occurred earlier than patients not receiving LAM testing.

This is the first trial of any tuberculosis diagnostic test to show a mortality benefit. By contrast, two large diagnostic trials18, 19 of the Xpert MTB/RIF assay did not show either morbidity or

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