Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please can you give a brief introduction to tuberculosis (TB)?
TB is an infectious disease caused by Mycobacterium tuberculosis. Nearly 9 million people develop TB every year, and TB kills nearly 1.4 million individuals each year. While the incidence of TB has steadily declined in the west, it remains a huge public health problem in many developing countries, with India having the highest burden.
Although many countries have met the Stop TB Partnership's targets of 70% case detection and 85% cure rate by 2005 (70/85 targets), TB incidence is still not falling as quickly as expected. One important reason is that TB patients are not diagnosed and cured quickly enough. When TB patients are not diagnosed and cured quickly, they may unknowingly spread their infection to their families and communities – further exacerbating the epidemic. Without early and better TB diagnosis, we are unlikely to achieve TB elimination.
What methods have previously been used to test for TB?
In most high TB incidence countries, sputum smear microscopy is the most widely used test for TB. It is inexpensive and can be done even in peripheral laboratories. This test has been used for nearly a century. Sputum is smeared on a glass slide, stained with dyes, and read under a microscope by a trained technician.
Sputum smears detect highly infectious patients and have high specificity. However, sensitivity of the test is modest (about 50 – 60%), although higher sensitivity can be obtained by performing fluorescence (e.g. auramine) staining and with the use of light-emitting diode microscopy. Sputum microscopy generally performs poorly in HIV-infected persons. It is of lesser value in young children (who often cannot produce sputum) and in extrapulmonary TB.
There are better tests for TB such as liquid culture and nucleic acid amplification tests (NAATs). However, these technologies, until recently, have been challenging to scale-up in resource-limited settings. They are expensive and require sophisticated laboratories and expertise that is often lacking in developing countries.
What factors are important in a TB test?
An ideal TB test will have high sensitivity and specificity, and will produce results rapidly. It should also be simple enough to be implemented in primary health care settings, and in peripheral laboratories and clinics. If the TB test can also detect drug-resistance simultaneously, that will be a big advantage. Cost is obviously a critical consideration – TB is a disease of poverty and expensive solutions are hard to scale-up.
Please can you outline the Xpert® MTB/RIF test that you recently reviewed?
The biggest recent advance in TB diagnosis is the development and WHO endorsement of Xpert® MTB/RIF (Cepheid Inc, Sunnyvale, CA, USA), an automated, cartridge-based nucleic acid amplification test that can detect TB, as well as drug-resistance. The technology can potentially be performed in peripheral laboratories that have uninterrupted power and temperature control. Since the test is automated, minimal training is sufficient. The test takes around 90 minutes, with minimal hands-on technical time required. Thus, this NAAT can be implemented outside of the conventional reference/centralized laboratory.
While Xpert MTB/RIF has many advantages, high cost was a big concern for its widespread use. In August 2012, several international donors provided funding to reduce the cost of Xpert MTB/RIF cartridges from $16.86 to $9.98. This reduced price is available for the public sector in 145 high-burden and developing countries.
What did your review of the Xpert® MTB/RIF test find?
Our recent Cochrane systematic review showed that this test is highly accurate [Steingart KR et al. Cochrane Library 2013 http://doi.wiley.com/10.1002/14651858.CD009593.pub2]. When compared to culture, Xpert has about 88% sensitivity and 98% specificity. In smear-negative patients with TB, Xpert had a sensitivity of 67%. For rapid detection of rifampicin resistance, the sensitivity is about 94% and specificity is 98%. So, this test is substantially more sensitive than sputum smear microscopy, and has great potential to increase the case detection rate.
Although not covered in our Cochrane review, there is growing evidence than Xpert MTB/RIF is quite helpful for rapid diagnosis of extrapulmonary and childhood TB, and WHO is expected to release a policy on this in 2013. Also, this technology has greatly stimulated resurgent interest in using molecular tests for rapid diagnosis of active TB and drug-resistance and has inspired new players to enter the field of TB diagnostics.
How does this test differ from previous TB tests?
The Xpert test is more sensitive than sputum smears and is less operator-dependent. While thousands of TB bacteria must be present in each millilitre of sputum sample for TB to be detected under the microscope, Xpert can detect TB bacteria at much lower concentrations. In addition, the conventional microscopy approach does not detect drug resistance, while Xpert can rapidly detect resistance to rifampicin, the most important first-line TB drug.
While there are many TB NAATs on the market, Xpert is the only completely automated NAAT and the only molecular test that can be done outside of sophisticated, reference laboratories.
Why is it important to be able to detect drug-resistant TB strains?
Multidrug-resistant TB refers to TB that is resistant to isoniazid and rifampicin, two of the most important first-line antibiotics used to treat TB. Multidrug-resistant TB requires extensive treatment (2 years or longer) with multiple drugs (with high toxicity), and outcomes are usually poor. Treatment of drug-resistant TB is very expensive because of the high cost of second-line TB drugs.
Ideally, all patients diagnosed to have TB must also have a drug susceptibility test done, to check if the TB strains are sensitive to the commonly used first-line drugs. If drug-resistance is identified, then second-line drug treatment for MDR-TB must be initiated. While TB patients in developed countries routinely get drug susceptibility testing, this does not happen in poor countries because of resource and infrastructure constraints.
How much of a problem is multidrug-resistant TB?
Drug resistance develops when patients do not complete their full course of treatment; when doctors prescribe the wrong treatment, the wrong dose, or length of time for taking the drugs; when the supply of drugs is not continuous; or when poor quality drugs are used.
About 3.7% of new TB patients in the world have MDR-TB. In TB patients who have been previously treated for TB, nearly 20% have MDR-TB. The WHO estimates that between 220,000 and 400,000 MDR-TB cases occurred among all the TB cases notified in the world in 2011. Much of the MDR-TB burden is in the BRICS (Brazil, Russia, India, China and South Africa).
What impact do you think your study will have?
Early case detection and rapid treatment continues to remain the most important TB control strategy, and acceleration of the uptake of new TB diagnostic technologies is critical for ensuring early diagnosis and reduced TB transmission. Several efforts are now underway to scale-up the Xpert technology in many high TB burden countries. As countries are actively making their policies on this test, we hope the evidence in our Cochrane review will inform such policies and inform roll-out decisions.
How do you think the future of TB testing will develop?
Already, fast-follower, next-generation NAATs have emerged, after the Xpert technology. In many ways, the Xpert test has become the pathfinder for wider use of rapid, accurate molecular tests for TB, and for showing that it is possible to think beyond the century-old microscopy test. These next-generation NAATs will help further scale-up molecular testing in resource-limited settings and eventually replace sputum smears in peripheral laboratories. But there is widespread agreement that we need a much simpler, point-of-care solution that can be implemented in the most decentralized manner. This will require investments in basic biomarker research.
The TB field needs many more companies to develop good products. Several companies are now interested in TB, but they have unanswered questions. To help advance the field, a new website resource has been created (www.tbfaqs.org) to identify and answer major frequently asked questions (FAQs) by test developers.
Do you think it will be possible to eliminate TB?
Not with the current portfolio of TB diagnostics, drugs and vaccines. TB incidence is declining too slowly for us to reach the elimination target by 2050. We need much better tests, drugs and vaccines to really drive down the incidence of TB rapidly. Thankfully, some progress has already been made with new TB diagnostics and Xpert is one example. Recently, the US FDA approved a drug called bedaquiline, as part of combination therapy to treat adults with MDR-TB when other alternatives are not available. This is the first new TB drug approved in over 40 years. Other new TB drugs or combinations are expected within the next 2 – 3 years. What we desperately need is a new TB vaccine that is substantially more efficacious than the 90-year old BCG vaccine. Funding agencies such as the Bill & Melinda Gates Foundation are doing a lot to support vaccine development, but progress has been slow.
Where can readers find more information?
For free access to our Cochrane review on Xpert MTB/RIF test:
Steingart KR, Sohn H, Schiller I, Kloda LA, Boehme CC, Pai M, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD009593. DOI: 10.1002/14651858.CD009593.pub2. - http://doi.wiley.com/10.1002/14651858.CD009593.pub2 (open access)
For the WHO policy on Xpert MTB/RIF and progress on the global roll-out of this test, please see: http://www.who.int/tb/laboratory/mtbrifrollout/en/index.html
For a comprehensive landscape report on TB diagnostics, please see: Tuberculosis Diagnostic Technology Landscape by UNITAID, available at: http://www.unitaid.eu/marketdynamics/tuberculosis-diagnostic-landscape
The website “Evidence-based TB Diagnosis” offers guidelines on TB diagnostics, systematic reviews, training materials, and landscape reports: http://tbevidence.org/
For market analyses of TB diagnostics, please see: http://tbevidence.org/resource-center/market-analyses/
For test developers and diagnostics manufacturers, a new website has been launched: http://www.tbfaqs.org/
Website of the Stop TB Partnership’s New Diagnostics Working Group: http://www.stoptb.org/wg/new_diagnostics/
About Professor Madhukar Pai
Madhukar Pai did his medical training in India. He completed his PhD in epidemiology at the University of California, Berkeley, and a postdoctoral fellowship at the University of California, San Francisco. He is currently an associate professor of epidemiology at McGill University in Montreal.
In addition, he serves as a Consultant for the Bill & Melinda Gates Foundation. He has served as co-chair of the Stop TB Partnership's Working Group on New Diagnostics and served as a member of the Stop TB Partnership's Coordinating Board.
He holds honorary professorship positions at the Christian Medical College, Vellore, India; University of Cape Town, South Africa; and Stellenbosch University, South Africa. He serves on the editorial boards of the Lancet Infectious Diseases, PLoS Medicine, International Journal of TB and Lung Disease, and PLoS One.
Dr Pai’s research is mainly focused on improving the diagnosis of TB, especially in high-burden countries like India and South Africa. His research is supported by grant funding from the Bill & Melinda Gates Foundation, Grand Challenges Canada, and Canadian Institutes of Health Research.
He has more than 150 peer-reviewed publications. For his research contributions, he received the 2007 Union Scientific Prize from the International Union Against Tuberculosis and Lung Disease. In 2011, he received the Canadian Rising Star in Global Health award from Grand Challenges Canada. In 2012, he received the Chanchlani Global Health Research Award from McMaster University, Canada.