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. 2021 Aug 20;8(8):CD014641.
doi: 10.1002/14651858.CD014641.

Impact of diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people living with HIV

Ruvandhi R Nathavitharana  1 , Philip Lederer  2 , Marty Chaplin  3 , Stephanie Bjerrum  4 , Karen R Steingart  5 , Maunank Shah  6
Affiliations

Impact of diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people living with HIV

Ruvandhi R Nathavitharana et al. Cochrane Database Syst Rev. .

Abstract

Background: Tuberculosis is the primary cause of hospital admission in people living with HIV, and the likelihood of death in the hospital is unacceptably high. The Alere Determine TB LAM Ag test (AlereLAM) is a point-of-care test and the only lateral flow lipoarabinomannan assay (LF-LAM) assay currently commercially available and recommended by the World Health Organization (WHO). A 2019 Cochrane Review summarised the diagnostic accuracy of LF-LAM for tuberculosis in people living with HIV. This systematic review assesses the impact of the use of LF-LAM (AlereLAM) on mortality and other patient-important outcomes.

Objectives: To assess the impact of the use of LF-LAM (AlereLAM) on mortality in adults living with HIV in inpatient and outpatient settings. To assess the impact of the use of LF-LAM (AlereLAM) on other patient-important outcomes in adults living with HIV, including time to diagnosis of tuberculosis, and time to initiation of tuberculosis treatment.

Search methods: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); Science Citation Index Expanded (Web of Science), BIOSIS Previews, Scopus, LILACS; ProQuest Dissertations and Theses; ClinicalTrials.gov; and the WHO ICTRP up to 12 March 2021.

Selection criteria: Randomized controlled trials that compared a diagnostic intervention including LF-LAM with diagnostic strategies that used smear microscopy, mycobacterial culture, a nucleic acid amplification test such as Xpert MTB/RIF, or a combination of these tests. We included adults (≥ 15 years) living with HIV.

Data collection and analysis: Two review authors independently assessed trials for eligibility, extracted data, and analysed risk of bias using the Cochrane tool for assessing risk of bias in randomized studies. We contacted study authors for clarification as needed. We used risk ratio (RR) with 95% confidence intervals (CI). We used a fixed-effect model except in the presence of clinical or statistical heterogeneity, in which case we used a random-effects model. We assessed the certainty of the evidence using GRADE.

Main results: We included three trials, two in inpatient settings and one in outpatient settings. All trials were conducted in sub-Saharan Africa and assessed the impact of diagnostic strategies that included LF-LAM on mortality when the test was used in conjunction with other tuberculosis diagnostic tests or clinical assessment for clinical decision-making in adults living with HIV. Inpatient settings In inpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy likely reduces mortality in people living with HIV at eight weeks compared to routine tuberculosis diagnostic testing without LF-LAM (pooled RR 0.85, 95% CI 0.76 to 0.94; 5102 participants, 2 trials; moderate-certainty evidence). That is, people living with HIV who received LF-LAM had 15% lower risk of mortality. The absolute effect was 34 fewer deaths per 1000 (from 14 fewer to 55 fewer). In inpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy probably results in a slight increase in the proportion of people living with HIV who were started on tuberculosis treatment compared to routine tuberculosis diagnostic testing without LF-LAM (pooled RR 1.26, 95% CI 0.94 to 1.69; 5102 participants, 2 trials; moderate-certainty evidence). Outpatient settings In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may reduce mortality in people living with HIV at six months compared to routine tuberculosis diagnostic testing without LF-LAM (RR 0.89, 95% CI 0.71 to 1.11; 2972 participants, 1 trial; low-certainty evidence). Although this trial did not detect a difference in mortality, the direction of effect was towards a mortality reduction, and the effect size was similar to that in inpatient settings. In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may result in a large increase in the proportion of people living with HIV who were started on tuberculosis treatment compared to routine tuberculosis diagnostic testing without LF-LAM (RR 5.44, 95% CI 4.70 to 6.29, 3022 participants, 1 trial; low-certainty evidence). Other patient-important outcomes Assessment of other patient-important and implementation outcomes in the trials varied. The included trials demonstrated that a higher proportion of people living with HIV were able to produce urine compared to sputum for tuberculosis diagnostic testing; a higher proportion of people living with HIV were diagnosed with tuberculosis in the group that received LF-LAM; and the incremental diagnostic yield was higher for LF-LAM than for urine or sputum Xpert MTB/RIF.

Authors' conclusions: In inpatient settings, the use of LF-LAM as part of a tuberculosis diagnostic testing strategy likely reduces mortality and probably results in a slight increase in tuberculosis treatment initiation in people living with HIV. The reduction in mortality may be due to earlier diagnosis, which facilitates prompt treatment initiation. In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may reduce mortality and may result in a large increase in tuberculosis treatment initiation in people living with HIV. Our results support the implementation of LF-LAM to be used in conjunction with other WHO-recommended tuberculosis diagnostic tests to assist in the rapid diagnosis of tuberculosis in people living with HIV.

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Conflict of interest statement

RRN has no known conflicts of interest. She serves voluntarily as Chair of a tuberculosis advocacy organisation, TB Proof, based in South Africa. Although TB Proof has not directly led advocacy efforts related to urine LAM, the organisation has supported calls to improve access to urine LAM based on WHO guidance.

PL has no known conflicts of interest.

MC has no known conflicts of interest.

SB has no known conflicts of interest.

KRS has received financial support from Cochrane Infectious Diseases, UK; McGill University, Canada; and USAID, USA, administered by the World Health Organization Global TB Programme, Switzerland for the preparation of systematic reviews and educational materials. She has also received consultancy fees from Foundation for Innovative New Diagnostics (FIND), Switzerland (for the preparation of systematic reviews and GRADE tables); honoraria; and travel support to attend WHO guideline meetings.

MS has no known conflicts of interest.

Figures

1
1
Study flow diagram. The literature search for this review was conducted in conjunction with the search for a Cochrane Review on the diagnostic accuracy of LF‐LAM (AlereLAM) (Bjerrum 2019). We initially identified 189 studies for title and abstract screening, of which 41 were selected for full‐text review. Fifteen studies were identified for Bjerrum 2019, and two studies were identified for this review. Updated literature searches on 12 November 2019 and 12 March 2021 identified one additional study. *In this study, the standard‐of‐care arm utilized a diagnostic strategy that did not include any of the tuberculosis tests described in our protocol as criteria for inclusion, and the study was not used to guide clinical decision‐making, precluding comparison of the impact of LF‐LAM compared to other diagnostic strategies (Blanc 2020).
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias domain for each included study.
4
4
Forest plot comparing the risk ratios for mortality in participants in inpatient settings who received a diagnostic intervention including LAM compared to those who received standard of care (SoC). Mortality was assessed at eight weeks in Gupta‐Wright 2018 and Peter 2016. Between brackets are the 95% confidence intervals (CI) for the risk ratios. The figure shows the estimated mortality risk ratio for each study (blue square) and its 95% CI (black horizontal line) and the pooled estimated mortality risk ratio combining results (black diamond).
5
5
Forest plot comparing the risk ratios for mortality at eight weeks in participants in inpatient settings who received a diagnostic intervention including LAM compared to those who received standard of care (SoC), sensitivity analysis with 25% mortality in missing participants receiving LAM and 0% mortality in missing participants receiving SoC. Between brackets are the 95% confidence intervals (CI) for the risk ratios. The figure shows the estimated mortality risk ratio for each study (blue square) and its 95% CI (black horizontal line) and the pooled estimated mortality risk ratio combining results from both studies (black diamond).
6
6
Forest plot comparing the risk ratios for mortality at eight weeks in participants in inpatient settings who received a diagnostic intervention including LAM compared to those who received standard of care (SoC), sensitivity analysis with 0% mortality in missing participants receiving LAM and 25% mortality in missing participants receiving SoC. Between brackets are the 95% confidence intervals (CI) for the risk ratios. The figure shows the estimated mortality risk ratio for each study (blue square) and its 95% CI (black horizontal line) and the pooled estimated mortality risk ratio combining results from both studies (black diamond).
7
7
Forest plot reporting the risk ratio for mortality at six months in participants in outpatient settings who received a diagnostic intervention including LAM compared to those who received standard of care (SoC). Between brackets are the 95% confidence intervals (CI) for the risk ratios. The figure shows the estimated mortality risk ratio for each study (blue square) and its 95% CI (black horizontal line) and the pooled estimated mortality risk ratio combining results (black diamond).
8
8
Forest plot comparing the risk ratios for mortality in inpatients who received a diagnostic intervention including LAM compared to those who received standard of care (SoC), mortality at eight weeks, by CD4 strata ≤ 100 cells/µL versus > 100 cells/µL. Between brackets are the 95% confidence intervals (CI) for the risk ratios. The figure shows the estimated mortality risk ratio for each study (blue square) and its 95% CI (black horizontal line) and the pooled estimated mortality risk ratio combining results from both studies (black diamond).
9
9
Forest plot comparing the risk ratios for mortality in inpatients who received a diagnostic intervention including LAM compared to those who received standard of care (SoC), mortality at eight weeks, by CD4 strata ≤ 200 cells/µL versus > 200 cells/µL. Between brackets are the 95% confidence intervals (CI) for the risk ratios. The figure shows the estimated mortality risk ratio for each study (blue square) and its 95% CI (black horizontal line) and the pooled estimated mortality risk ratio combining results from both studies (black diamond).
10
10
Forest plot comparing the risk ratios for proportion of participants in inpatient settings treated for tuberculosis who received a diagnostic intervention including LAM compared to those who received standard of care (SoC). Between brackets are the 95% confidence intervals (CI) for the risk ratios. The figure shows the proportion for each study (blue square) and its 95% CI (black horizontal line) and the pooled estimated mortality risk ratio combining results from both studies (black diamond).
11
11
Forest plot reporting the risk ratio for proportion of participants in outpatient settings treated for tuberculosis who received a diagnostic intervention including LAM compared to those who received standard of care (SoC). Between brackets are the 95% confidence intervals (CI) for the risk ratios. The figure shows the proportion for the study (blue square) and its 95% CI (black horizontal line).
1.1
1.1. Analysis
Comparison 1: Meta‐analyses comparing mortality for LAM versus standard of care, Outcome 1: Mortality at 8 weeks, inpatient settings
1.2
1.2. Analysis
Comparison 1: Meta‐analyses comparing mortality for LAM versus standard of care, Outcome 2: Sensitivity analysis ‐ 25% mortality in missing participants (LAM) and 0% in missing participants (standard of care)
1.3
1.3. Analysis
Comparison 1: Meta‐analyses comparing mortality for LAM versus standard of care, Outcome 3: Sensitivity analysis ‐ 0% mortality in missing participants (LAM) and 25% in missing participants (standard of care)
1.4
1.4. Analysis
Comparison 1: Meta‐analyses comparing mortality for LAM versus standard of care, Outcome 4: Mortality at 6 months, outpatient settings
2.1
2.1. Analysis
Comparison 2: Meta‐analyses comparing mortality for LAM versus standard of care, stratified by CD4 strata, Outcome 1: Mortality at 8 weeks, inpatients ‐ stratified by CD4 ≤ 100 versus > 100 cells/µL
2.2
2.2. Analysis
Comparison 2: Meta‐analyses comparing mortality for LAM versus standard of care, stratified by CD4 strata, Outcome 2: Mortality at 8 weeks, inpatients ‐ stratified by CD4 ≤ 200 versus > 200 cells/µL
2.3
2.3. Analysis
Comparison 2: Meta‐analyses comparing mortality for LAM versus standard of care, stratified by CD4 strata, Outcome 3: Mortality at 6 months, outpatients ‐ stratified by CD4 count < 50 cells/µL versus ≥ 50 cells/µL
3.1
3.1. Analysis
Comparison 3: Meta‐analyses comparing proportion of participants treated for tuberculosis for LAM versus standard of care, Outcome 1: Proportion of participants treated for tuberculosis, inpatient settings
3.2
3.2. Analysis
Comparison 3: Meta‐analyses comparing proportion of participants treated for tuberculosis for LAM versus standard of care, Outcome 2: Proportion of participants treated for tuberculosis, outpatient settings
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