Urine-Xpert Ultra for the diagnosis of tuberculosis in people living with HIV: a prospective, multicentre, diagnostic accuracy study

Abstract

Background: Diagnostic delays for tuberculosis are common, with high resultant mortality. Urine-Xpert Ultra (Cepheid) could improve time to diagnosis of tuberculosis disease and rifampicin resistance. We previously reported on lot-to-lot variation of the Fujifilm SILVAMP TB LAM. In this prespecified secondary analysis of the same cohort, we aimed to determine the diagnostic yield and accuracy of Urine-Xpert Ultra for tuberculosis in people with HIV, compared with an extended microbiological reference standard (eMRS) and composite reference standard (CRS) and also compared with Determine TB LAM Ag (AlereLAM, Abbott).

Methods: In this prospective, multicentre, diagnostic accuracy study, we recruited consecutive inpatients and outpatients (aged ≥18 years) with HIV from 13 hospitals and clinics in seven countries (Malawi, South Africa, Tanzania, Thailand, Uganda, Viet Nam, and Zambia). Patients with no isoniazid preventive therapy in the past 6 months and fewer than three doses of tuberculosis treatment in the past 60 days were included. Reference and index testing was performed in real time. The primary outcome of this secondary analysis was the diagnostic yield and accuracy of Urine-Xpert Ultra compared with the eMRS and CRS. Diagnostic accuracy was compared with AlereLAM and diagnostic yield was compared with both AlereLAM and Sputum-Xpert Ultra. This study was registered with ClinicalTrials.gov, NCT04089423, and is complete.

Findings: Between Dec 13, 2019, and Aug 5, 2021, 3528 potentially eligible individuals were screened and 1731 were enrolled, of whom 1602 (92·5%) were classifiable by the eMRS (median age 40 years [IQR 33-48], 838 [52·3%] of 1602 were female, 764 [47·7%] were male, 937 [58·5%] were outpatients, 665 [41·5%] were inpatients, median CD4 count was 374 cells per μL [IQR 138-630], and 254 [15·9%] had microbiologically confirmed tuberculosis). Against eMRS as reference, sensitivities of Urine-Xpert Ultra and AlereLAM were 32·7% (95% CI 27·2-38·7) and 30·7% (25·4-36·6) and specificities were 98·0% (97·1-98·6) and 90·4% (88·7-91·8), respectively. Against CRS as reference, sensitivities of Urine-Xpert Ultra and AlereLAM were 21·1% (95% CI 17·6-25·1), and 30·5% (26·4-34·9), and specificities were 99·1% (98·3-99·6) and 95·1% (93·5-96·3), respectively. The combination of Sputum-Xpert Ultra with AlereLAM or Urine-Xpert Ultra diagnosed 202 (77·1%) and 204 (77·9%) of 262 eMRS-positive participants, respectively, in incompletely overlapping groups; combining all three tests diagnosed 214 (81·7%) of 262 eMRS-positive participants INTERPRETATION: Urine-Xpert Ultra could offer promising clinical utility in addition to AlereLAM and Sputum-Xpert Ultra. In inpatient settings where both AlereLAM and Urine-Xpert Ultra are possible, both should be offered to support rapid diagnosis and treatment.

Funding: Global Health Innovative Technology Fund, KfW Development Bank, Commonwealth of Australia represented by the Department of Foreign Affairs and Trade, and the Netherlands Enterprise Agency.

Figure 1

Study flow diagram 1797 were deemed ineligible per protocol for the following reasons: due to already having had three doses antituberculosis treatment in the past 60 days, having received isoniazid prophylaxis therapy in the past 6 months, being outpatients who had no symptoms of tuberculosis, or being unwilling to attend trial follow-up; exact numbers were not captured. CRS=composite reference standard. eMRS=extended microbiological reference standard.

Figure 2

Sensitivity and specificity of AlereLAM and Urine-Xpert Ultra in the overall cohort versus the eMRS and CRS, and in subgroups defined by CD4 count and setting Error bars are Wilson's 95% CIs. Numbers of true positives, false positives, true negatives, and false negatives for each subgroup are in appendix 1 (p 11). CRS=composite reference standard. eMRS=extended microbiological reference standard.

Figure 3

Diagnostic yield per rapid test in all participants (A), only inpatients (B), those with CD4 counts of ≤200 cells per μL (C), and among those who died within 10 weeks of enrolment (D) compared with the eMRS-positive group eMRS=extended microbiological reference standard.

Figure 4

Urine-Xpert Ultra positivity and mortality (A) Overall and country-specific conditional average effect of positive urine Xpert Ultra on death, determined with a multilevel logistic regression model. (B) Predicted probability of death by CD4 count, conditional on antiretroviral status and tuberculosis extended microbiological reference standard results. (C) Predicted conditional probability of death by age and CD4 count by Urine-Xpert Ultra results; white dots are individual participants and colour segments are model predictions. ART=antiretroviral therapy.

Figure 4

Urine-Xpert Ultra positivity and mortality (A) Overall and country-specific conditional average effect of positive urine Xpert Ultra on death, determined with a multilevel logistic regression model. (B) Predicted probability of death by CD4 count, conditional on antiretroviral status and tuberculosis extended microbiological reference standard results. (C) Predicted conditional probability of death by age and CD4 count by Urine-Xpert Ultra results; white dots are individual participants and colour segments are model predictions. ART=antiretroviral therapy.