The document discusses the development and recommendation of a new tuberculosis diagnostic test called Xpert MTB/RIF Ultra. It notes that while previous tests like Xpert MTB/RIF were a breakthrough, Ultra offers higher sensitivity especially in difficult cases like children and HIV patients. A WHO expert group evaluated Ultra and recommended its use as an improved alternative to existing tests for TB diagnosis and rifampin resistance detection in all settings. However, the increased sensitivity of Ultra may also increase false positives which will require adjustments to diagnostic algorithms.

1. Xpert MTB/RIF Ultra
newer technology
past to future
DIAGNOSIS OF TUBERCULOSIS
Dr.T.V.Rao MD
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2. TB Kills many in the World,
Now emerging resistance is a
concern
•TB killed 1.8 million people in 2015 and caused TB
disease in 10.4 million.2 An estimated 580,000 TB
patients were also resistant to rifampicin, a critical
first-line TB drug. However, less than 70% of new TB
cases and only 25% of drug-resistant cases were
diagnosed or treated in 2015, leaving significant
gaps in our understanding of the disease and its
global effect on the population
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3. Limitations with Direct
Microscopy with
Ziehl–Neelsen
staining;
• Direct microscopic examination is
a fast and inexpensive method to
identify acid-fast bacilli
through the use of Ziehl–
Neelsen staining; however, it is
limited by poor sensitivity and the
inability to discriminate between
mycobacterial species, which can
be a relevant issue especially
among children and
immunocompromised individuals.
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4. Detection of AFB with Fluorescence
microscopy
• Fluorescence or light-
emitting diode
microscopy may be an
alternative to traditional
microscopy with a
moderate improvement
in sensitivity (+10%) but
also slightly higher costs
and the need for well-
trained technicians
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5. Culture remains the
gold standard with
Many Limitations
• Culture remains the gold standard
technique for the diagnosis of TB, even
though its large-scale use is limited by the
long waiting time due to the slow growth
rate of mycobacteria (~2–6 weeks in liquid
media) with consequent diagnostic delays;
furthermore, the need for biosafety
level 3 laboratory infrastructures
and highly skilled laboratory technicians
who are often lacking especially in
resource-constrained settings is another
significant limitation.
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6. Tuberculin skin dependent on
Immunological status of Infected
patient
• Tuberculin skin test and
interferon-gamma release
assay are currently
recommended for the
diagnosis of LTBI, but have a
marginal role in the detection
of TB cases, as they cannot
distinguish between active
and latent infection and may
be influenced by the patient’s
immune statue
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7. Drug Resistance is concern in
Tuberculosis
• The emergence and spread of
multidrug-resistant strains is
currently among the greatest
concerns, which may hinder the
achievement of future goals to
ensure early case detection and
prompt referral to specialised
centres for treatment initiation
and follow-up
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10. WHO RECOMMENDS A NEW
MOLECULAR BASED METHOD
• WHO currently recommends a
biomolecular test as the initial
diagnostic tool in case of TB
suspect. Among the several
commercially available nucleic
acid amplification tests, Xpert
MTB/Rif (Cepheid,
Sunnyvale, CA, USA)
is the most efficient
and suitable for
implementation in
resource-constrained settings
(at the point-of-care level), as it
does not require any
sophisticated laboratory facility,
is fully automated and provides
the results in <2 h
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11. WHAT IS
Xpert MTB/RIF
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12. Xpert MTB/RIF
• The Xpert MTB/RIF is a cartridge based nucleic acid
amplification test, automated diagnostic test that can
identify Mycobacterium tuberculosis (MTB) DNA and
resistance to rifampicin (RIF) by nucleic acid
amplification test (NAAT). It was co-developed by the
laboratory of Professor David Alland at the University of
Medicine and Dentistry of New Jersey (UMDNJ).] Cepheid
Inc. and Foundation for Innovative New Diagnostics, with
additional financial support from the US National
Institutes of Health (NIH).
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13. Xpert MTB/RIF Detects the
Rifampicin resistance and presence
of Tuberculosis
•The existing test,
Xpert MTB/RIF, was
introduced in 2010
and transformed the
landscape of TB
diagnosis by offering
rapid, sensitive
diagnosis of TB and
rifampicin resistance.
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14. About GeneXpert
Systems and Xpert
Tests
• With more than 10,000 systems in
182 countries, the GeneXpert
System is the world’s most popular
molecular diagnostics’ instrument.
The GeneXpert System’s modular
configuration means that the
system is the most scalable
available, offering the ability to
perform from one to eighty Xpert
tests at the same time.
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15. WHO recommends
testing with Xpert
MTB/RIF
• In December 2010, the World
Health Organization (WHO)
endorsed the Xpert MTB/RIF for
use in TB endemic countriesThis
test, and others that are likely to
follow, could have the potential to
improve the diagnosis of TB in
those that are likely to be missed
by traditional tests.
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16. WHO’s 2013 policy
recommendations
• Using Xpert MTB/RIF to diagnose
pulmonary TB and rifampicin resistance
in adults and children Xpert MTB/RIF
should be used rather than conventional
microscopy, culture and DST as the
initial diagnostic test in adults suspected
of having MDR-TB or HIV-associated TB
(strong recommendation, high-quality
evidence).
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17. Changing
Recommendation on
Tuberculosis Diagnosis
• Xpert MTB/RIF should be
used rather than
conventional microscopy,
culture and DST as the initial
diagnostic test in children
suspected of having MDR-TB
or HIV-associated TB).
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18. Xpert MTB/RIF Preferred
than Microscopy
• Xpert MTB/RIF may be used
rather than conventional
microscopy and culture as
the initial diagnostic test in
all adults suspected of having
TB (conditional
recommendation
acknowledging resource
implications, high-quality
evidence).
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19. Xpert MTB/RIF may be used as a
follow-on test to microscopy
• Xpert MTB/RIF may be used as a
follow-on test to microscopy in
adults suspected of havingTB
who are not at risk of MDR-TB or
HIV-associated TB, especially
when further testing of smear-
negative specimens is necessary
(conditional recommendation
acknowledging resource
implications, high-quality
evidence).
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20. The world is benefited with MTB/RIF
Tests
• As of 2016, more than 23 million Xpert MTB/RIF
tests have been procured in 130 countries and
multidrug-resistant TB (MDR-TB) detection has
more than tripled.4,5 However, sensitivity of Xpert
MTB/RIF is imperfect in smear-negative and HIV-associated
TB, and some limitations also remain in the determination
of rifampicin-resistance status using the existing test. Ultra
is a second-generation test that was designed to overcome
the sensitivity limitations of Xpert MTB/RIF.
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21. Need for New Generation of Testing
methods
• However, sensitivity of Xpert
MTB/RIF is imperfect in smear-
negative and HIV-associated TB,
and some limitations also
remain in the determination of
rifampicin-resistance status
using the existing test. Ultra is
a second-generation test
that was designed to
overcome the sensitivity
limitations of Xpert
MTB/RIF.
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22. LAUNCH OF NEW TB TEST
ULTRA BACKED BY WHO
RECOMMENDATION
2017
Xpert® MTB/RIF Ultra
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23. Xpert® MTB/RIF Ultra
• It was developed by Cepheid in
collaboration with Rutgers, with
additional support from the U.S.
National Institute of Allergy and
Infectious Diseases (NIAID), and
FIND, with support from funders
including the Governments of
Australia and the Netherlands,
and UK Aid from the British
People.
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24. Xpert® MTB/RIF Ultra
(Ultra),
• Sunnyvale, CA, USA; New Brunswick, NJ, USA; Geneva,
Switzerland – 24 March 2017 – On World TB Day, Cepheid,
Rutgers New Jersey Medical School and FIND
announced a new version of the Xpert
MTB/RIF test, the Xpert® MTB/RIF Ultra
(Ultra), for the diagnosis of TB and rifampicin resistance.
The World Health Organization (WHO) earlier today issued a
recommendation that Ultra can be used as an alternative to
the existing Xpert MTB/RIF test for the diagnosis of TB and
detection of rifampicin resistance in all settings
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25. Current Recommendation of
WHO
• The World Health
Organization (WHO) earlier
today issued a
recommendation that Ultra
can be used as an
alternative to the existing
Xpert MTB/RIF test for the
diagnosis of TB and
detection of rifampicin
resistance in all settings
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26. The WHO expert evaluation concluded that the new Ultra
test showed better performance than Xpert MTB/RIF
• The WHO expert evaluation
concluded that the new Ultra
test showed better performance
than Xpert MTB/RIF in detecting
TB in difficult-to-diagnose and
vulnerable populations, such as
children and people living with
HIV, and in those with extra-
pulmonary TB.
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27. Xpert® MTB/RIF Ultra (Ultra),
performance assessment
• Ultra’s performance was
assessed in 2016 in a multi-
centre non-inferiority study
at ten sites in eight low-
and middle-income
countries. The study was
coordinated by FIND, and
conducted by FIND and the
NIAID-sponsored
Tuberculosis Clinical
Diagnostics Research
Consortium,.
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28. Xpert MTB/RIF Ultra assay proving
to be a better technology
• The Xpert MTB/RIF Ultra
assay was redesigned to boost
analytical sensitivity more than
ten-fold and to improve
reliability of detecting
mutations associated with
rifampin resistance. The latter
was accomplished by
introducing a new and powerful
feature, automated post-PCR
melt curve analysis, to the
GeneXpert System
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29. Xpert® MTB/RIF Ultra (Ultra), has
higher sensitivity
• The study found that Ultra sensitivity was up to 17%
higher than Xpert MTB/RIF, with the greatest
sensitivity gains seen among patients that
would have been missed in microscopy centres
(smear-negative, culture-positive patients) and HIV-
positive TB patients. In addition, several retrospective
studies conducted in parallel to the main study
demonstrated significant increases in sensitivity of TB
detection in children and patients with extrapulmonary TB.
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30. Xpert® MTB/RIF Ultra (Ultra),
higher performance
• Ultra performance
approaches that of
liquid culture, but is
faster and easier to use
at the point of care,”,
Rutgers New Jersey
Medical School, whose
research laboratory
contributed to the
development of the test.
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31. Increased
sensitivity causes
False Positives
• As a result of its increased
sensitivity, the use of Ultra
also resulted in a higher
rate of false positives
compared to Xpert
MTB/RIF, possibly due to
the detection of non-viable
TB bacteria that are present
in people with a recent
history of TB
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32. Opinion of
WHO Expert
Group• The WHO expert group
noted the need for
further discussion on the
implementation
challenges this presents
and the willingness to
balance increased test
sensitivity with
decreased specificity in
different settings.
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33. Observation of
WHO
• Our expert group consultation
found that Ultra performs
better than its predecessor in
the most difficult cases, such
as in children and in
patients with HIV co-
infection or extra-
pulmonary TB.
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34. WHO CAUTIONS
ON NEWER
TECHNOLOGY
• “The decreased
specificity of the test
will require a more
nuanced approach in
diagnostic algorithms,
and we encourage
additional research on
Ultra to inform its
introduction and use.”
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35. WE ALL CAN WORK
TO STOP
TUBERCULOSIS
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36. Reference and Adopted from
• 2017 LAUNCH OF NEW TB TEST ULTRA BACKED BY WHO RECOMMENDATION FIND
• WHO RESOURCES ON TUBERCULOSIS AND NEWER CHALLENGES

37. Program created by Dr.T.V.Rao MD for
benefit of Medical and paramedical
professionals on global education on health
care matters
Email
doctortvrao@gmail.com
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