2017 launch of new TB test ultra backed by WHO recommendation

• Xpert MTB/RIF Ultra can better diagnose TB in children and people living with HIV

Sunnyvale, CA, USA; New Brunswick, NJ, USA; Geneva, Switzerland – 24 March 2017 – On World TB Day, Cepheid, Rutgers New Jersey Medical School and FIND today 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.¹

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. 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.³

“The Xpert MTB/RIF Ultra assay was redesigned to boost analytical sensitivity more than ten-fold and to improve the 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,” said David H. Persing, MD, Ph.D., Cepheid’s Chief Medical and Technology Officer.

”Ultra performance approaches that of liquid culture, but is faster and easier to use at the point of care,” said Dr David Alland, Professor of Medicine and Director of the Center of Emerging Pathogens, Rutgers New Jersey Medical School, whose research laboratory contributed to the development of the test.

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. 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, the 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. 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.

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, which is led by Dr Susan Dorman of Johns Hopkins University School of Medicine and Dr Jerrold Ellner at Boston Medical Center and Boston University School of Medicine. 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.

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. 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.

“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. WHO plans to release implementation guidance on the use of the test in the next few weeks,” said Dr Karin Weyer, Coordinator, Laboratories, Diagnostics and Drug Resistance at WHO. “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.”

“The commercialization of Ultra will have immediate impact for children, HIV/TB co-infected patients and other difficult-to-diagnose groups by enabling rapid TB diagnosis,” said Dr Catharina Boehme, CEO of FIND. “While the reduced specificity of the test presents a challenge, we expect this trade-off to emerge with most next-generation molecular TB tests. We are now assessing how we can most effectively leverage the benefits of Ultra in the global effort to find the missing 4 million TB cases.”

About Cepheid
Based in Sunnyvale, Calif., Cepheid (Nasdaq: CPHD) is a leading molecular diagnostics company that is dedicated to improving healthcare by developing, manufacturing, and marketing accurate yet easy-to-use molecular systems and tests. By automating highly complex and time-consuming manual procedures, the company’s solutions deliver a better way for institutions of any size to perform sophisticated genetic testing for organisms and genetic-based diseases. Through its strong molecular biology capabilities, the company is focusing on those applications where accurate, rapid, and actionable test results are needed most, such as managing infectious diseases and cancer. For more information, visit www.cepheid.com.

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. As a result, the GeneXpert System meets the throughput requirements of customers of all sizes – from lower volume point-of-care settings to higher volume reference laboratories – enabling accurate, fast and cost effective test results.

GeneXpert Systems run proprietary Xpert test cartridges. The Xpert test menu spans healthcare-associated infections, sexual health, critical infectious disease, and oncology, and today offers 25 tests outside the US, and 20 tests in the US. More information on the GeneXpert System and the Xpert tests is available on our website at www.cepheid.com.

About Rutgers New Jersey Medical School 
Founded in 1954, Rutgers New Jersey Medical School is the oldest school of medicine in the state. Today it is part of Rutgers, The State University of New Jersey, and graduates approximately 170 physicians a year. In addition to providing the MD degree, the school offers MD/PhD, MD/MPH and MD/MBA degrees through collaborations with other institutions of higher education. Dedicated to excellence in education, research, clinical care and community outreach, the medical school comprises 22 academic departments and works with several healthcare partners, including its principal teaching hospital, The University Hospital. Its faculty consists of numerous world-renowned scientists and many of the region’s “top doctors.” Home to the nation’s oldest student-run clinic, New Jersey Medical School hosts more than 50 centers and institutes, including the Public Health Research Institute Center, the Global Tuberculosis Institute and the Neurological Institute of New Jersey. For more information please visit: njms.rutgers.edu.

About the Tuberculosis Clinical Diagnostics Research Consortium (TB CDRC)
The TB CDRC is an inter-disciplinary consortium of scientists and clinicians whose mission is to provide data on the performance of investigational diagnostics and their potential impact on TB management in TB-endemic settings. TB CDRC was established in 2009 through a contract from the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health (HHSN272200900050C/N01-AI-90050).

About FIND 
FIND was established in 2003 as a global non-profit dedicated to accelerating the development, evaluation and delivery of high-quality, affordable diagnostic tests for poverty-related diseases, including tuberculosis, malaria, HIV/AIDS, Ebola, sleeping sickness, hepatitis C, leishmaniasis, Chagas disease and Buruli ulcer, and for fighting antimicrobial resistance and supporting outbreak preparedness Over the last decade, FIND has partnered in the delivery of 20 new diagnostic tools, including ten for tuberculosis, and created an enabling environment for numerous others through the provision of specimen banks, reagent development and better market visibility. FIND also supports better access to new diagnostics through price negotiations, implementation, quality assurance and lab strengthening work. FIND has over 100 partners globally, including research institutes and laboratories, ministries of health and national disease control programmes, commercial partners, bilateral and multilateral organizations, especially WHO, and clinical trial sites.

[1] WHO Meeting Report of a Technical Expert Consultation: Non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF. Available at: http://apps.who.int/iris/handle/10665/254792
[2] WHO Global Tuberculosis Report 2016. Available at: http://www.who.int/tb/publications/factsheet_global.pdf
[3] WHO Meeting Report of a Technical Expert Consultation: Non-inferiority analysis of Xpert MTB/RIF Ultra compared to Xpert MTB/RIF. Available at: http://apps.who.int/iris/handle/10665/254792
[4] World Health Organization website. WHO monitoring of Xpert MTB/RIF roll-out. Accessed March 13, 2017.  http://www.who.int/tb/areas-of-work/laboratory/status_xpert_rollout_dec_2016.pdf
[5] Albert H, Nathavitharana RR, Isaacs C, Pai M, Denkinger CM, and Boehme C. Development, roll-out and impact of Xpert MTB/RIF for tuberculosis: what lessons have we learnt and how can we do better? Eur Resp J. 2016 Aug; 48(2): 516–525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967565/