Diagnostic accuracy of a low-cost, urine antigen, point-of-care screening assay for HIV-associated pulmonary tuberculosis before antiretroviral therapy: a descriptive study

Abstract

Background: The diagnostic accuracy of sputum smear microscopy and routine chest radiology for HIV-associated tuberculosis is poor, and culture-based diagnosis is slow, expensive, and is unavailable in most resource-limited settings. We assessed the diagnostic accuracy of a urine antigen test Determine TB-LAM Ag (Determine TB-LAM; Alere, Waltham, MA, USA) for screening for HIV-associated pulmonary tuberculosis before antiretroviral therapy (ART).

Methods: In this descriptive study, consecutive adults referred to a community-based ART clinic in Gugulethu township, South Africa, were all screened for tuberculosis by obtaining sputum samples for fluorescence microscopy, automated liquid culture (gold-standard test), and Xpert MTB/RIF assays (Cepheid, Sunnyvale, CA, USA) and urine samples for the Clearview TB-ELISA (TB-ELISA; Alere, Waltham, MA, USA) and Determine TB-LAM test. Patients with Mycobacterium tuberculosis cultured from one or more sputum samples were defined as cases of tuberculosis. The diagnostic accuracy of Determine TB-LAM used alone or combined with sputum smear microscopy was compared with that of sputum culture and the Xpert MTB/RIF assay for all patients and subgroups of patients stratified by CD4 cell count.

Findings: Patients were recruited between March 12, 2010, and April 20, 2011. Of 602 patients enrolled, 542 were able to provide one or more sputum samples, and 94 had culture-positive tuberculosis (prevalence 17·4%, 95% CI 14·2-20·8). Complete results from all tests were available for 516 patients (median CD4 count, 169·5 cells per μL; IQR 100-233), including 85 culture-positive tuberculosis, 24 of whom (28·2%, 95% CI 19·0-39·0) had sputum smear-positive disease. Determine TB-LAM test strips provided results within 30 min. Agreement was very high between two independent readers of the test strips (κ=0·97) and between the test strips and TB-ELISA (κ=0·84). Determine TB-LAM had highest sensitivity at low CD4 cell counts: 66·7% (95% CI 41·0-86·7) at <50 cells per μL, 51·7% (32·5-70·6) at <100 cells per μL, and 39·0% (26·5-52·6) at <200 cells per μL; specificity was greater than 98% for all strata. When combined with smear microscopy (either test positive), sensitivity was 72·2% (95% CI 46·5-90·3) at CD4 counts less than 50 cells per μL, 65·5% (45·7-82·1) at less than 100 cells per μL, and 52·5% (39·1-65·7) at less than 200 cells per μL, which did not differ statistically from the sensitivities obtained by testing a single sputum sample with the Xpert MTB/RIF assay.

Interpretation: Determine TB-LAM is a simple, low-cost, alternative to existing diagnostic assays for tuberculosis screening in HIV-infected patients with very low CD4 cell counts and provides important incremental yield when combined with sputum smear microscopy.

Funding: Wellcome Trust.

Figure 1

Study profile

Figure 2

Determine TB-LAM test strips from three patients in this study together with the reference reading card Positive control (upper) bands are seen in all three strips whereas positive test (lower) bands are only seen in the middle and right hand strips and the left strip is negative.

Figure 3

Venn diagrams showing the proportions of patients diagnosed by sputum culture, Xpert MTB/RIF (1 sample), sputum-smear microscopy (sputum acid-fast bacilli), and Determine TB-LAM Mutually exclusive proportions of patients shown in each of the compartments. Proportions of all patients with tuberculosis (A; n=85). Proportions of patients with CD4 cell counts less than 100 cells per μL (B; n=29). AFB=acid-fast bacilli.