All-cause
8-week mortality is reduced by rapid point-of-care urine-based testing for
tuberculosis (TB), using a test for detection of mycobacterial lipoarabinomannan
(LAM) to guide rapid treatment initiation in hospitalised HIV-positive people
with signs and symptoms of TB, according to a late-breaker study presented by
Dr Jonny Peter of the University of Cape Town, and colleagues, at the 46th Union World Conference on Lung Health in Cape Town from 2 to 6
December 2015.
Those
who received LAM testing in addition to standard of care diagnostics were 18%
less likely to die at 8 weeks (aHR = 0.82; 95% CI: 0.70-0.96, p = 0.015).
The LAM strip test
measures for the presence of lipoarabinomannan in urine. The test has
shown variable sensitivity and specificity in different populations, and has
performed best in studies of hospitalised patients with HIV infection and
advanced immunosuppression (CD4 count below 150 cells/mm3). The test
is not considered suitable for outpatient screening. (Lawn 2012)
Speeding up diagnosis by using a point-of-care test in
addition to laboratory diagnostic tests such as TB culture or Xpert MTB/RIF has
the potential to speed up the initiation of treatment and to increase the
number of people receiving treatment.
The
randomised controlled trial studied whether the LAM strip test, in combination
with current available TB diagnostics, would improve TB-related mortality,
morbidity and length of hospital stay in HIV-positive people. TB mortality is
high, especially in people living with HIV with extensive immune damage, where a TB diagnosis
is already difficult.
The study
was conducted in South Africa, Tanzania, Zambia and Zimbabwe.
Of
the 8728 patients with presumed HIV/TB co-infection from secondary and tertiary
hospitals 2659 were randomised to be included in the study, made up of 1336 people
in the LAM arm and 1323 in the non-LAM arm. Patients in the LAM arm were
allocated LAM in addition to routine TB diagnostics (minimum of two sputum
smear specimens and culture and one Xpert MTB/RIF, if available).
A total of 1257
patients were included in the modified intention to treat analysis and 59 were
lost to follow-up.1198 patients were analysed per protocol analysis, after 70
did not receive the LAM test, 47 did not meet the inclusion criteria and nine
were excluded from the analysis due to withdrawing consent and missing hard
copy documents.
A total of 1323
people were allocated to the non-LAM arm where routine TB diagnostics were used
to detect TB. 1271 patients were included in the modified intention to treat
analysis after 38 did not receive diagnostic tests, 23 did not meet the
inclusion criteria and 14 were excluded from the analysis. An additional 58 people
were lost to follow-up resulting in 1213 patients being included in the per
protocol analysis.
Of the
2528 people included in the study, the median age was 37 (IQR: 30-44) and 51%
(n = 1300) were women. 27 % (n = 682) had previously had TB. The median CD4 count
was 84 cells/mm3 (IQR: 26 – 208 cells/mm3), with 2%
(n = 59) at WHO clinical Stage 1, 27%(n = 671) at Stage 2, 53% (n = 1331) at Stage 3
and 17 % (n = 438) at Stage 4. Almost half (48%, n = 1224) were on ART at study
entry and 73% (n = 615/848) of eligible patients were initiated on ART at 8-week
follow up.
Of the
total number of people started on anti-TB treatment, 52% (n = 648) of people who
were diagnosed using LAM compared to 48% (598) in the non-LAM arm (p = 0.024). The
time-to-treatment analysis showed significant differences in the cumulative
proportion of people receiving TB treatment and the number of deaths for
patients who started treatment by the end of Day 1 (55.1 % vs 40.3%); end of
Day 2 (71.1% vs 60.5%); end of Day 3 (79.2% vs 69.1%) and the end of Day 4
(84.0 % vs 75.6%) between the LAM and non-LAM arm respectively (p < 0.001 for
all of these).
The
study also showed that there was no significant difference between the two
groups in the hospital length of stay from enrolment or change in TB morbidity
as measured by Karnofsky score in patients on TB treatment.
Despite
overall suboptimal test sensitivity even for people with low CD4 counts, as shown
in a study published in July this year by the same group, the ability of LAM to identify
patients at high risk of death or lost-to-follow-up offers important prognostic
value.
Sensitivity
measures the percentage of results that will be (correctly)
positive when a disease is actually present. Lower rates of sensitivity will
produce more false negative results.
This previous study of outpatients with HIV showed
that among 583
participants with signs and symptoms of TB that had HIV or refused
testing, the overall LAM sensitivity was 22.7 % (95% CI: 16.6 - 28.7; n = 41/181)
and 30.4 % (95% CI: 17.1 - 43.7; n = 14/46) in the CD4 ≤ 100 cells/mm3
sub-group. Among culture-positive TB cases, adjunctive LAM testing did not
improve the sensitivity of either sputum Xpert-MTB/RIF [78.2 % (95% CI: 69.8 - 86.7)
versus 76.1 % (95% CI: 67.4-84.8, p = 0.7] or smear-microscopy [56.2 % (95% CI:
45.9 - 66.5) versus 43.8 % (95% CI: 33.5 - 54.1, p = 0.1).