Anti-tuberculosis (TB) treatment guided by the results of a new urine TB test reduced mortality among HIV-positive patients in 10 sub-Saharan African hospitals. An article in The Lancet reported on the clinical findings of this study.
HIV-associated TB is a primary cause of HIV- or AIDS-related deaths among adults in areas with scarce resources. The disease presents challenges in that it has a poor survival rate and isn’t always easy to diagnose. “Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy,” the study’s authors explained.
The investigators conducted a randomized trial at multiple hospital locations in South Africa, Tanzania, Zambia, and Zimbabwe to test the efficacy of an inexpensive urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and whether it could guide treatments to reduce TB-related mortality in HIV patients. The advantage of this test is “it requires neither laboratory infrastructure, nor equipment and costs far less per test (<US$3) than the Xpert MTB/RIF assay (around $10),” noted authors Andrew Kerkhoff, MD, of the University of California San Francisco School of Medicine, and Stephen D. Lawn, PhD, of the London School of Hygiene and Tropical Medicine, in a related commentary.
The World Health Organization has recommended the urine LAM test to screen for TB among hospital inpatients showing signs of TB and also for the sickest and most immune-compromised HIV-positive patients.
The researchers enlisted and screened more than 8,700 HIV-positive adults with TB symptoms, randomly assigning treatment to 2,659 patients.
After accounting for certain exclusions, 2,528 patients took part in the analysis: 1,257 who underwent LAM testing and routine diagnostic tests (Xpert-MTB/RIF, smear microscopy, and culture), and 1,271 who had just the routine tests. Participants contributed a urine sample of 30mL. The investigators used the Alere Determine tuberculosis LAM Ag lateral flow strip test to evaluate patients in the LAM group. Health care providers made recommendations and decisions on anti-TB treatment when test results were positive.
“The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention),” the study indicated. Overall, a larger proportion in the LAM group received treatment for TB and also received treatment in the first 3 days, compared with those in the non-LAM cohort.
Eight-week mortality rates were noticeably lower in the LAM groups. Among the 578 deaths that occurred, 317 were in the non-LAM group, versus 261 in the LAM group. Looking at the results in a “time-to-event” analysis, “there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM,” the study’s authors reported. Mortality reduction was especially prominent among those patients with the most compromised immune systems.
The researchers concluded that LAM-guided treatment had an effect on reducing 8-week mortality of HIV patients in hospitals.
“This is the first trial of any diagnostic test for tuberculosis to show a reduction in the number of deaths. 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 early,” said the study’s senior author and project supervisor, Keertan Dheda, PhD, professor of respiratory medicine at the University of Cape Town in South Africa, in a statement.
The authors noted that LAM testing might be most useful in hospitals that lack diagnostic resources and house the most severely ill patients who are unable to self-expectorate sputum.
The study was able to prove the LAM’s overall effectiveness in quickly and inexpensively diagnosing HIV-associated TB, Kerkhoff and Lawn wrote in their commentary on the findings. However, Kerkhoff and Lawn also raised some concerns about these findings. The study’s authors “report on the diagnostic accuracy of urine LAM testing even though the study was not primarily designed a priori to rigorously assess this. 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 observed.
The researchers also used a weak reference standard: just one sputum culture or Xpert test to measure the LAM’s diagnostic prowess, Kerkoff and Lawn noted. They mention that in a similar study conducted in Cape Town, the LAM’s specificity reached almost 100% “when compared with a rigorous microbiological reference standard that incorporated sampling of sputum, blood, and urine, for which we did a mean of 5.6 reference standard tests per patient.”