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
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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Systematic review of the determine TB LAM Ag lateral flow urine lipoarabinomannan assay for active TB in people living with HIV: preliminary findings
The global HIV response has made tremendous progress but is entering a new phase with additional challenges. Scientific innovations have led to multiple safe, effective, and durable options for treatment and prevention, and long-acting formulations for 2-monthly and 6-monthly dosing are becoming available with even longer dosing intervals possible on the horizon. The scientific agenda for HIV cure and remission strategies is moving forward but faces uncertain thresholds for success and acceptability. Nonetheless, innovations in prevention and treatment have often failed to reach large segments of the global population (eg, key and marginalised populations), and these major disparities in access and uptake at multiple levels have caused progress to fall short of their potential to affect public health. Moving forward, sharper epidemiologic tools based on longitudinal, person-centred data are needed to more accurately characterise remaining gaps and guide continued progress against the HIV epidemic. We should also increase prioritisation of strategies that address socio-behavioural challenges and can lead to effective and equitable implementation of existing interventions with high levels of quality that better match individual needs. We review HIV epidemiologic trends; advances in HIV prevention, treatment, and care delivery; and discuss emerging challenges for ending the HIV epidemic over the next decade that are relevant for general practitioners and others involved in HIV care.
Over 4 million adults are living with advanced HIV disease with approximately 650 000 fatalities from HIV reported in 2021. People with advanced HIV disease have low immunity and can present to health services in two ways: those who are well but at high risk of developing severe disease, and those who are severely ill. These two groups require specific management approaches that place different demands on the health system. The first group can generally be supported in primary care settings but require differentiated care to meet their needs. The second group are at high risk of death and need focused diagnostics and clinical care, and possibly hospitalisation. Investments in high-quality clinical management of patients with advanced HIV disease who are seriously ill at primary care or hospital level (often only for a brief period of time during their acute illness) improves the likelihood that their condition will stabilise and that they will recover. Providing high-quality and safe clinical care that is accessible to these groups of people living with HIV who are at risk of severe illness and death is a key priority for reaching the global target of zero AIDS deaths.
Sputum is the most widely used sample to diagnose active tuberculosis, but many people living with HIV are unable to produce sputum. Urine, in contrast, is readily available. We hypothesised that sample availability influences the diagnostic yield of various tuberculosis tests.
In this systematic review and meta-analysis of individual participant data, we compared the diagnostic yield of point-of-care urine-based lipoarabinomannan tests with that of sputum-based nucleic acid amplification tests (NAATs) and sputum smear microscopy (SSM). We used microbiologically confirmed tuberculosis based on positive culture or NAAT from any body site as the denominator and accounted for sample provision. We searched PubMed, Web of Science, Embase, African Journals Online, and clinicaltrials.gov from database inception to Feb 24, 2022 for randomised controlled trials, cross-sectional studies, and cohort studies that assessed urine lipoarabinomannan point-of-care tests and sputum NAATs for active tuberculosis detection in participants irrespective of tuberculosis symptoms, HIV status, CD4 cell count, or study setting. We excluded studies in which recruitment was not consecutive, systematic, or random; provision of sputum or urine was an inclusion criterion; less than 30 participants were diagnosed with tuberculosis; early research assays without clearly defined cutoffs were tested; and humans were not studied. We extracted study-level data, and authors of eligible studies were invited to contribute deidentified individual participant data. The main outcomes were the tuberculosis diagnostic yields of urine lipoarabinomannan tests, sputum NAATs, and SSM. Diagnostic yields were predicted using Bayesian random-effects and mixed-effects meta-analyses. This study is registered with PROSPERO, CRD42021230337.
We identified 844 records, from which 20 datasets and 10 202 participants (4561 [45%] male participants and 5641 [55%] female participants) were included in the meta-analysis. All studies assessed sputum Xpert (MTB/RIF or Ultra, Cepheid, Sunnyvale, CA, USA) and urine Alere Determine TB LAM (AlereLAM, Abbott, Chicago, IL, USA) in people living with HIV aged 15 years or older. Nearly all (9957 [98%] of 10 202) participants provided urine, and 82% (8360 of 10 202) provided sputum within 2 days. In studies that enrolled unselected inpatients irrespective of tuberculosis symptoms, only 54% (1084 of 1993) of participants provided sputum, whereas 99% (1966 of 1993) provided urine. Diagnostic yield was 41% (95% credible interval [CrI] 15–66) for AlereLAM, 61% (95% Crl 25–88) for Xpert, and 32% (95% Crl 10–55) for SSM. Heterogeneity existed across studies in the diagnostic yield, influenced by CD4 cell count, tuberculosis symptoms, and clinical setting. In predefined subgroup analyses, all tests had higher yields in symptomatic participants, and AlereLAM yield was higher in those with low CD4 counts and inpatients. AlereLAM and Xpert yields were similar among inpatients in studies enrolling unselected participants who were not assessed for tuberculosis symptoms (51% vs 47%). AlereLAM and Xpert together had a yield of 71% in unselected inpatients, supporting the implementation of combined testing strategies.
AlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples.
Human immunodeficiency virus (HIV) infection is transmitted through sex, vertically from mother to child or through sharing of needles by intravenous drug users. Untreated, the infection results in progressive depletion of CD4 T lymphocytes resulting in progression to the acquired immunodeficiency syndrome (AIDS) on average 8–10 years after initial infection. Individuals with AIDS are susceptible to opportunistic infections and malignancies. Tuberculosis is the most frequent cause of hospitalization and death in people living with HIV in lower- and middle-income countries. Combination antiretroviral therapy (ART) is highly effective at suppressing viral replication when taken with optimal adherence. This results in the maintenance or restoration of immune function and prevention of opportunistic infections. International guidelines now recommend that all patients diagnosed with HIV initiate ART at the time of diagnosis regardless of CD4 count. This is of benefit to individual health, restoring life expectancy to approximate that of HIV-negative people in the same setting and very effectively reduces the risk of onward transmission.