Parallel use of low-complexity automated nucleic acid amplification tests and lateral flow urine lipoarabinomannan assays to detect tuberculosis disease in adults and adolescents living with HIV.

Background: Low-complexity automated nucleic acid amplification tests (LC-aNAATs) are molecular World Health Organization (WHO)-recommended rapid diagnostic tests (also known as mWRDs) widely used to diagnose tuberculosis disease. The lateral flow urine lipoarabinomannan assay (LF-LAM) is recommended by the WHO to assist in diagnosing tuberculosis disease amongst people with HIV. Previous systematic reviews have assessed the diagnostic accuracy of LC-aNAATs and LF-LAM used in isolation for the detection of tuberculosis, but in clinical practice the tests may be used in parallel (i.e. LC-aNAAT in combination with LF-LAM).

Objectives: To compare the diagnostic accuracy of the parallel use of LC-aNAAT on respiratory samples and LF-LAM on urine versus LC-aNAATs on respiratory samples alone for detection of tuberculosis disease in adults and adolescents with HIV who present with presumptive tuberculosis.

Search Methods: We searched Cochrane CENTRAL, MEDLINE, Embase, Science Citation Index-Expanded, Biosis Previews, Conference Proceedings Citation Index - Science, Scopus, WHO Global Index Medicus, ProQuest Dissertations & Theses, ClinicalTrial.gov, and the WHO International Clinical Trials Registry up to 3 November 2023.

Selection Criteria: We included studies that allowed assessment of the diagnostic accuracy of parallel testing and LC-aNAAT on respiratory samples in the same study group. Participants were adults and adolescents (defined as 10 years of age and older) with HIV who presented with presumptive tuberculosis. The reference standards we used for the detection of tuberculosis disease were microbiological or composite. As well as published studies, we included unpublished data if the data provided by study authors on request were the final data and could be used to compare diagnostic accuracy of parallel testing to one of the component tests.

Data Collection And Analysis: Two review authors independently extracted data using a standardised form and assessed methodological quality using QUADAS-2 and QUADAS-C tools. We performed bivariate random-effects meta-analysis using a Bayesian approach to estimate sensitivity, specificity, and absolute differences between index tests. We performed subgroup analyses based on the presence of signs and symptoms, CD4 cell count, and clinical setting, as well as separate analyses for those with a positive screen for tuberculosis, advanced HIV, or serious illness.

Main Results: In 27 studies involving 12,651 participants, of whom 2368 (19%) had tuberculosis based on a microbiological reference standard, the parallel use of respiratory LC-aNAAT and urine LF-LAM had a pooled sensitivity of 77.5% (95% credible interval (CrI) 73.4 to 81.3) and specificity of 89.4% (95% CrI 85.8 to 92.3). Compared to respiratory LC-aNAAT alone, parallel testing had 6.7 (95% CrI 3.8 to 10.7) percentage points higher sensitivity (low certainty) and -6.8 (95% CrI -9.5 to -4.7) percentage points difference in specificity (low-certainty evidence), using a microbiological reference standard. In 23 studies, 11,109 participants, of whom 3723 (34%) had tuberculosis based on a composite reference standard, parallel testing had a pooled sensitivity of 67.6% (95% CrI 59.9 to 74.6) and a pooled specificity of 96.2% (95% CrI 92.8 to 98.1). Compared to respiratory LC-aNAAT alone, parallel testing had 16.0 (10.7 to 22.9) percentage points higher sensitivity (low-certainty evidence) and -3.5 (95% CrI -6.6 to -1.7) percentage points difference in specificity (very low certainty evidence), using a composite reference standard.

Authors' Conclusions: In the diagnosis of tuberculosis disease in people with HIV who present with presumptive tuberculosis, parallel testing (LC-aNAAT on respiratory samples and LF-LAM on urine) improves sensitivity at the cost of reduced specificity compared to LC-aNAAT on respiratory samples alone. The gain in sensitivity should be weighed against the loss of specificity, taking into consideration the varying tuberculosis prevalence in different settings. For low-prevalence settings, using the tests in parallel may lead to a large increase in false-positive results. In settings with high tuberculosis prevalence, the benefit of identifying additional patients with tuberculosis at the point-of-care likely outweighs the relatively lower risk of overtreatment of those without tuberculosis.

Funding: Internal sources: Liverpool School of Tropical Medicine, UK External sources: Foreign, Commonwealth and Development Office (FCDO), UK. Project number 300342-104; WHO, TB Prevention, Diagnosis, Treatment, Care & Innovation (PCI), Global TB Programme REGISTRATION: Protocol available via https://doi.org/10.1002/14651858.CD016070, version published 13 May 2024.