FIND’s program for improving diagnosis of latent TB infections
An estimated one-third of the world’s population
is infected with tuberculosis. In
most high income countries, the diagnosis and
treatment of latent TB infection (LTBI) is an
integral part of TB control and strategies for its
elimination. However, a major limitation of
this approach has been the inadequacy of the
tuberculin skin test (TST) for diagnosis of LTBI
due to lack of specificity, particularly in BCG
vaccinated populations. Furthermore, the TST
requires a return visit to read the results and is
subject to errors in testing and interpretation of
results. Moreover, false-negative TST reactions
are common in immunosuppressed persons, and
more importantly, the test cannot discriminate
the 90% of persons with LTBI who will never
develop active TB from the 10% who will.
Thus, one of the greatest challenges in TB control
is to be able to predict accurately those who
are already infected and to treat them before
they develop “active” disease.
FIND Head of Product Evaluation, Dr. Richard O’Brien and FIND LTBI Consultant Dr. Madhukar Pai
lead FIND’s program for improving the diagnosis of LTBI.
The development of T cell-based, interferongamma
release assays (IGRAs) is a significant
breakthrough in diagnosis of LTBI. Current
evidence suggests that IGRAs have higher
specificity than the TST, better correlation
with surrogate markers of exposure to
Mycobacterium tuberculosis in low incidence
settings, and have less cross-reactivity in
BCG-vaccinated individuals compared to
TST. Thus, in industrialized countries, these
new tools may revolutionize the diagnosis and
management of LTBI.
One of these tests, the QuantiFERON-TB
Gold (QFT-G) assay produced by Cellestis,
Ltd. (Carnegie, Australia), has been recommended
by the U.S. Centers for Disease
Control as a replacement for TST whenever
the TST is indicated. However, in high incidence
settings, the diagnosis and treatment of
active TB cases is the first priority. This is why
FIND has chosen to initiate work in the development
and evaluation of newer LTBI diagnostics
focusing on IGRAs as promising options
for both diagnosis and prediction of disease.
Although IGRAs have shown promise, several
questions about their performance remain.
These include their accuracy in HIV-infected
persons and children, and the correlation of
positive test results with the likelihood of
future TB. An important question for FIND
and the global TB community is the relevance
of these tests in TB control in high-burden,
low-income settings.
FIND Head of Product Evaluation, Dr. Richard
O’Brien and FIND LTBI Consultant
Dr. Madhukar Pai lead FIND’s program for
improving the diagnosis of LTBI.
FIND and Cellestis Limited agreed to work
together to evaluate the QuantiFERON-TB
Gold assay in demonstration projects in
several developing countries to answer the
most pressing research questions.
Led by Dr. Richard O’Brien, Head of Product
Evaluation at FIND, and Dr. Madhukar Pai
(FIND Consultant for LTBI diagnostics),
FIND will support several important studies to
evaluate the utility of the QuantiFERON-TB
Gold In-Tube® method for the diagnosis of
LTBI in HIV-infected persons, in adult and
childhood contacts of TB patients, and for
active TB in young children. This will be done
through nested studies in two CREATE projects
in South Africa and Zambia (ZAMSTAR
project), in Brazil (THRio project), and in
vaccine studies of TB in infants in South
Africa and India, supported by the Aeras
Global TB Vaccine Foundation, as well as in a
study of IGRAs in HIV-infected and uninfected
children in South Africa (led by researchers
at the Case Western Reserve University and
Stellenbosch University).
These studies will provide useful data on the
key question of predictive value of IGRAs
among high-risk populations such as contacts
and HIV-infected persons, address the issue of
whether QFT-G can contribute to the diagnosis
of TB in infants, and assess the utility of
IGRAs among children under the age of 5
with TB/HIV co-infection in a high endemic,
resource-limited setting.
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