In the JournalsPerspective

Urine-based TB test lowers mortality

Results from a randomized controlled trial suggest that an adjunctive, low-cost urine test could help reduce tuberculosis-related mortality among patients living with HIV, particularly those with advanced disease.

Postmortem data from 2015 indicate that TB is the leading cause of death in adults with HIV (37.2%), and almost half (45.8%) of these cases go undiagnosed. Although the point-of-care urine test only led to a modest decrease in death in the study, this method of screening could potentially save thousands of lives, according to Keertan Dheda, MD, PhD, professor of respiratory medicine and head of the lung infection and immunity unit at the University of Cape Town.

Keertan Dheda

Keertan Dheda

“This is the first trial of any diagnostic test for tuberculosis to show a reduction in the number of deaths,” Dheda said in a press release. “The reduction in mortality is likely to be because urine-testing, in conjunction with routine testing, resulted in a greater proportion of patients starting tuberculosis treatment earlier.”

LAM’s effect on mortality

Dheda and colleagues assessed the impact of the Alere Determine TB lipoarabinomannan Ag lateral flow strip test (Alere; LAM) on TB mortality among adults with HIV in sub-Saharan Africa. The LAM test uses approximately 60 µL of urine to detect the glycolipid antigen lipoarabinomannan, which is present in Mycobacterium tuberculosis cell walls. The method produces results within 25 minutes and costs approximately $2.66 for each test.

The study included 2,528 patients in 10 hospitals across four TB-endemic countries: South Africa, Tanzania, Zambia and Zimbabwe. Patients were screened for TB using either routine testing with smear, Xpert MTB/RIF test (Cepheid) and culture in addition to LAM urine testing (n = 1,257), or routine testing alone (n = 1,271).

Eight-week mortality — the study’s primary endpoint — was 21% in the LAM group vs. 25% in the non-LAM group, an absolute reduction in mortality of 4% (95% CI, 1–7), according to the researchers.

The improvement in survival appeared to be driven primarily by the number of people who started therapy, and started it earlier, after their diagnosis. For example, more patients who were screened using the LAM test were started on anti-TB therapy compared with those who underwent routine screening alone (52% vs. 47%; P = .024), and more patients in the LAM group were treated in the first 4 days (84% vs. 76%; P = .0002).

Concern over test specificity

According to the researchers, the LAM test had an overall sensitivity of 45.6% (95% CI, 40.4-50.9) and a specificity of 88.7% (95% CI, 86.3-90.7). The highest sensitivity was found in coinfected patients with advanced immunosuppression (CD4 cell counts of 50/µL or fewer) — at 63.7% (95% CI, 55.6-71.1). These patients often are the most difficult to diagnose, the researchers noted.

“Importantly, we found that the test was particularly effective in identifying tuberculosis among patients with advanced HIV infection who are most vulnerable to TB disease,” Dheda said in the release.

In a related editorial, Andrew Kerkhoff, MD, MSc, a resident physician at the University of California, San Francisco, and Stephen D. Lawn, MD, a professor of infectious diseases and tropical medicine at the London School of Hygiene & Tropical Medicine, expressed concern over the specificity of the LAM test reported in the study by Dheda and colleagues.

“If their finding that urine-LAM specificity was less than 90% is taken at face value, these data would raise serious concerns about the potential of the assay to generate large numbers of false-positive diagnoses,” they wrote.

Kerkhoff and Lawn said the Xpert test and sputum culture are insufficient reference standards, and that the specificity of the same test exceeded 99% in a 2015 study comparing LAM with the combination of sputum, blood and urine sampling. However, the reduced specificity could be due to several factors, Dheda said, including the presence of non-TB organisms, which can cause the strip test to be misread. Additionally, he noted that the 2015 study was conducted under ideal research conditions, whereas their trial was performed under real-world conditions.

Nevertheless, Kerkhoff and Lawn said the findings were “remarkable” and “provide key evidence that urine-LAM testing is an effective means of rapid, low-cost, ante-mortem diagnosis for the large burden of HIV-associated tuberculosis.”

Future of urine-based TB tests

According to the researchers, urine-based screening has several advantages over the collection of sputum, particularly among severely ill patients with TB and HIV coinfection who have difficulty producing such samples, and among those with advanced immunosuppression who have low bacillary loads in sputum and other body cavity fluids, which can reduce the sensitivity of routine tests and even the more advanced diagnostics like the Xpert test.

Since November, WHO has recommended LAM urine testing for the diagnosis of active TB in patients living with HIV. “However, the recommendation was conditional,” Dheda said in the release, “meaning it is up to the doctor or health system to decide whether or not to use the test. These data make the test more compelling and suggest that scale up and rollout of the test is now required.”

The researchers suggested that LAM testing will offer the greatest benefit in hospitals with limited resources and in patients with the most severe illness. – by John Schoen

References:

Gupta RK, et al. AIDS. 2015;doi:10.1097/QAD.0000000000000802.

Kerkhoff AD, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)00146-X.

Lawn SD, et al. J Acquir Immune Defic Syndr. 2015;doi:10.1097/QAI.0000000000000672.

Peter JG, et al. Lancet. 2016;doi:10.1016/S0140-6736(15)01092-2.

WHO. The use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screening of active tuberculosis in people living with HIV. 2015. http://apps.who.int/iris/bitstream/10665/193633/1/9789241509633_eng.pdf?ua=1&ua=1. Accessed March 9, 2016.

Disclosures: Dheda reports receiving speaker fees at industry-sponsored symposia and nonfinancial support from Alere in the form of kits and test strips, outside the submitted work. Kerkhoff and Lawn report no relevant financial disclosures.

Results from a randomized controlled trial suggest that an adjunctive, low-cost urine test could help reduce tuberculosis-related mortality among patients living with HIV, particularly those with advanced disease.

Postmortem data from 2015 indicate that TB is the leading cause of death in adults with HIV (37.2%), and almost half (45.8%) of these cases go undiagnosed. Although the point-of-care urine test only led to a modest decrease in death in the study, this method of screening could potentially save thousands of lives, according to Keertan Dheda, MD, PhD, professor of respiratory medicine and head of the lung infection and immunity unit at the University of Cape Town.

Keertan Dheda

Keertan Dheda

“This is the first trial of any diagnostic test for tuberculosis to show a reduction in the number of deaths,” Dheda said in a press release. “The reduction in mortality is likely to be because urine-testing, in conjunction with routine testing, resulted in a greater proportion of patients starting tuberculosis treatment earlier.”

LAM’s effect on mortality

Dheda and colleagues assessed the impact of the Alere Determine TB lipoarabinomannan Ag lateral flow strip test (Alere; LAM) on TB mortality among adults with HIV in sub-Saharan Africa. The LAM test uses approximately 60 µL of urine to detect the glycolipid antigen lipoarabinomannan, which is present in Mycobacterium tuberculosis cell walls. The method produces results within 25 minutes and costs approximately $2.66 for each test.

The study included 2,528 patients in 10 hospitals across four TB-endemic countries: South Africa, Tanzania, Zambia and Zimbabwe. Patients were screened for TB using either routine testing with smear, Xpert MTB/RIF test (Cepheid) and culture in addition to LAM urine testing (n = 1,257), or routine testing alone (n = 1,271).

Eight-week mortality — the study’s primary endpoint — was 21% in the LAM group vs. 25% in the non-LAM group, an absolute reduction in mortality of 4% (95% CI, 1–7), according to the researchers.

The improvement in survival appeared to be driven primarily by the number of people who started therapy, and started it earlier, after their diagnosis. For example, more patients who were screened using the LAM test were started on anti-TB therapy compared with those who underwent routine screening alone (52% vs. 47%; P = .024), and more patients in the LAM group were treated in the first 4 days (84% vs. 76%; P = .0002).

Concern over test specificity

According to the researchers, the LAM test had an overall sensitivity of 45.6% (95% CI, 40.4-50.9) and a specificity of 88.7% (95% CI, 86.3-90.7). The highest sensitivity was found in coinfected patients with advanced immunosuppression (CD4 cell counts of 50/µL or fewer) — at 63.7% (95% CI, 55.6-71.1). These patients often are the most difficult to diagnose, the researchers noted.

“Importantly, we found that the test was particularly effective in identifying tuberculosis among patients with advanced HIV infection who are most vulnerable to TB disease,” Dheda said in the release.

In a related editorial, Andrew Kerkhoff, MD, MSc, a resident physician at the University of California, San Francisco, and Stephen D. Lawn, MD, a professor of infectious diseases and tropical medicine at the London School of Hygiene & Tropical Medicine, expressed concern over the specificity of the LAM test reported in the study by Dheda and colleagues.

“If their finding that urine-LAM specificity was less than 90% is taken at face value, these data would raise serious concerns about the potential of the assay to generate large numbers of false-positive diagnoses,” they wrote.

Kerkhoff and Lawn said the Xpert test and sputum culture are insufficient reference standards, and that the specificity of the same test exceeded 99% in a 2015 study comparing LAM with the combination of sputum, blood and urine sampling. However, the reduced specificity could be due to several factors, Dheda said, including the presence of non-TB organisms, which can cause the strip test to be misread. Additionally, he noted that the 2015 study was conducted under ideal research conditions, whereas their trial was performed under real-world conditions.

Nevertheless, Kerkhoff and Lawn said the findings were “remarkable” and “provide key evidence that urine-LAM testing is an effective means of rapid, low-cost, ante-mortem diagnosis for the large burden of HIV-associated tuberculosis.”

Future of urine-based TB tests

According to the researchers, urine-based screening has several advantages over the collection of sputum, particularly among severely ill patients with TB and HIV coinfection who have difficulty producing such samples, and among those with advanced immunosuppression who have low bacillary loads in sputum and other body cavity fluids, which can reduce the sensitivity of routine tests and even the more advanced diagnostics like the Xpert test.

Since November, WHO has recommended LAM urine testing for the diagnosis of active TB in patients living with HIV. “However, the recommendation was conditional,” Dheda said in the release, “meaning it is up to the doctor or health system to decide whether or not to use the test. These data make the test more compelling and suggest that scale up and rollout of the test is now required.”

The researchers suggested that LAM testing will offer the greatest benefit in hospitals with limited resources and in patients with the most severe illness. – by John Schoen

References:

Gupta RK, et al. AIDS. 2015;doi:10.1097/QAD.0000000000000802.

Kerkhoff AD, et al. Lancet. 2016;doi:10.1016/S0140-6736(16)00146-X.

Lawn SD, et al. J Acquir Immune Defic Syndr. 2015;doi:10.1097/QAI.0000000000000672.

Peter JG, et al. Lancet. 2016;doi:10.1016/S0140-6736(15)01092-2.

WHO. The use of lateral flow urine lipoarabinomannan assay (LF-LAM) for the diagnosis and screening of active tuberculosis in people living with HIV. 2015. http://apps.who.int/iris/bitstream/10665/193633/1/9789241509633_eng.pdf?ua=1&ua=1. Accessed March 9, 2016.

Disclosures: Dheda reports receiving speaker fees at industry-sponsored symposia and nonfinancial support from Alere in the form of kits and test strips, outside the submitted work. Kerkhoff and Lawn report no relevant financial disclosures.

    Perspective
    David L. Cohn

    David L. Cohn

    This is an important study. LAM testing has been around for a while, and it certainly has held promise, most importantly for patients with possible TB, coinfected with HIV, and who have low CD4 cell counts. The added value has been for patients who are the most immunocompromised, often with disseminated TB, and in whom the usual ways of diagnosing TB are suboptimal, such as sputum smears and cultures or the Xpert-MTB/RIF test. This has always been a challenging group to accurately diagnose TB.

    We have known for years that HIV-infected patients in sub-Saharan Africa with low CD4 cell counts have very high mortality. Many studies, both pre- and post-mortem, have assessed the role of TB in mortality. It is the most common opportunistic infection in AIDS patients on a global basis, and the most common cause of death.

    In this study, the bottom line was, use of the LAM test compared with relying on the standard of care for the diagnosis of TB resulted in a relative risk reduction of 17% in mortality after 8 weeks. This is a modest effect, but still highly significant. If you multiply that times hundreds of thousands of patients with HIV and possible TB, then this finding is a home run in terms of potential impact. That this study was conducted in multiple countries and different settings with a large sample size is also relevant. The LAM test is easy to perform as a point-of-care test, and urine is a relatively easy sample to obtain. It is often difficult to get sputum from sick patients because they are so moribund and/or cannot cough, and yet almost everyone can produce a urine specimen. That was shown in the study — patients were able to provide urine more often than sputum (> 99% vs. 93%).

    Another important point is that the LAM test can be used in not just large tertiary centers, where a lot of TB is diagnosed, but also in district hospitals and community centers, where they are less likely to have accurate sputum diagnosis on site, often with delays in diagnosis.

    The test appeared to benefit the sickest patients. In stratified analyses, for those with CD4 cell counts of 50/µL or less, the HR for death was 0.71, a 29% reduction, whereas for those with CD4 cell counts greater than 50/µL, the HR was 0.95, a 5% reduction. This is precisely the population in which we want to use this test: patients with HIV-related TB, low CD4 cell counts with high mortality, and for whom one might save a life by finding a positive LAM test, and thereby starting anti-TB treatment and ART early. We know from previous studies that patients who have CD4 cell counts less than 50/µL are those who benefit the most from immediate ART (ie, within 2 weeks of starting anti-TB treatment).

    It is also important to point out that in recent studies, the use of the Xpert-MTB/RIF test, although a major breakthrough in diagnosing TB, has not been shown to improve mortality, whereas the LAM test does. The reason that it does is because it worked best in the patients who needed it the most.

    • David L. Cohn, MD
    • Infectious Disease News Editorial Board member Professor of medicine, division of infectious diseases, University of Colorado

    Disclosures: Cohn reports no relevant financial disclosures.