Xpert MTB/RIF Ultra newer technology DIAGNOSIS OF TUBERCULOSIS

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Xpert MTB/RIF Ultra newer technology past to future DIAGNOSIS OF TUBERCULOSIS By Dr.T.V.Rao MD

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Xpert MTB/RIF Ultra newer technology past to future DIAGNOSIS OF TUBERCULOSIS :

Xpert MTB/RIF Ultra newer technology past to future DIAGNOSIS OF TUBERCULOSIS Dr.T.V.Rao MD 4/1/2017 Dr.T.V.Rao @ tuberculosis 1

TB Kills many in the World, Now emerging resistance is a concern :

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 4/1/2017 Dr.T.V.Rao @ tuberculosis 2

Limitations with Direct Microscopy with Ziehl–Neelsen staining;:

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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 3

Detection of AFB with Fluorescence microscopy :

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 4/1/2017 Dr.T.V.Rao @ tuberculosis 4

Culture remains the gold standard with Many Limitations :

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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 5

Tuberculin skin dependent on Immunological status of Infected patient :

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 4/1/2017 Dr.T.V.Rao @ tuberculosis 6

Drug Resistance is concern in Tuberculosis :

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 4/1/2017 Dr.T.V.Rao @ tuberculosis 7

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WHO RECOMMENDS A NEW MOLECULAR BASED METHOD :

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 4/1/2017 Dr.T.V.Rao @ tuberculosis 10

WHAT IS Xpert MTB/RIF :

WHAT IS Xpert MTB/RIF 4/1/2017 Dr.T.V.Rao @ tuberculosis 2

Xpert MTB/RIF:

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). 4/1/2017 Dr.T.V.Rao @ tuberculosis 12

Xpert MTB/RIF Detects the Rifampicin resistance and presence of Tuberculosis :

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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 13

About GeneXpert Systems and Xpert Tests:

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 . 4/1/2017 Dr.T.V.Rao @ tuberculosis 14

WHO recommends testing with Xpert MTB/RIF :

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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 15

WHO’s 2013 policy recommendations:

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 ). 4/1/2017 Dr.T.V.Rao @ tuberculosis 16

Changing Recommendation on Tuberculosis Diagnosis :

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). 4/1/2017 Dr.T.V.Rao @ tuberculosis 17

Xpert MTB/RIF Preferred than Microscopy :

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). 4/1/2017 Dr.T.V.Rao @ tuberculosis 18

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 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). 4/1/2017 Dr.T.V.Rao @ tuberculosis 19

The world is benefited with MTB/RIF Tests:

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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 20

Need for New Generation of Testing methods :

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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 21

LAUNCH OF NEW TB TEST ULTRA BACKED BY WHO RECOMMENDATION 2017 Xpert® MTB/RIF Ultra :

LAUNCH OF NEW TB TEST ULTRA BACKED BY WHO RECOMMENDATION 2017 Xpert ® MTB/RIF Ultra 4/1/2017 Dr.T.V.Rao @ tuberculosis 2

Xpert® MTB/RIF Ultra :

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 . 4/1/2017 Dr.T.V.Rao @ tuberculosis 23

Xpert® MTB/RIF Ultra (Ultra), :

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 settin gs 4/1/2017 Dr.T.V.Rao @ tuberculosis 24

Current Recommendation of WHO:

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 4/1/2017 Dr.T.V.Rao @ tuberculosis 25

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 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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 26

Xpert® MTB/RIF Ultra (Ultra), performance assessment :

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,. 4/1/2017 Dr.T.V.Rao @ tuberculosis 27

Xpert MTB/RIF Ultra assay proving to be a better technology :

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 4/1/2017 Dr.T.V.Rao @ tuberculosis 28

Xpert® MTB/RIF Ultra (Ultra), has higher sensitivity :

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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 29

Xpert® MTB/RIF Ultra (Ultra), higher performance :

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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 30

Increased sensitivity causes False Positives :

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 4/1/2017 Dr.T.V.Rao @ tuberculosis 31

Opinion of WHO Expert Group :

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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 32

Observation of WHO:

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. 4/1/2017 Dr.T.V.Rao @ tuberculosis 33

WHO CAUTIONS ON NEWER TECHNOLOGY :

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.” 4/1/2017 Dr.T.V.Rao @ tuberculosis 34

WE ALL CAN WORK TO STOP TUBERCULOSIS :

WE ALL CAN WORK TO STOP TUBERCULOSIS 4/1/2017 Dr.T.V.Rao @ tuberculosis 35

Reference and Adopted from :

Reference and Adopted from 2017 LAUNCH OF NEW TB TEST ULTRA BACKED BY WHO RECOMMENDATION FIND WHO RESOURCES ON TUBERCULOSIS AND NEWER CHALLENGES 4/1/2017 Dr.T.V.Rao @ tuberculosis 4

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 :

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 4/1/2017 Dr.T.V.Rao @ tuberculosis 37

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