TUBERCULOSIS: WHO recommends against inaccurate tuberculosis tests

Kelly Morris
Misleading serology tests for tuberculosis could be worsening the epidemic in some high-burden countries. WHO will be issuing policy advice against their use in early 2011. Kelly Morris reports.
Although no international guideline recommends their use, scores of commercial serology tests for tuberculosis are being sold in high-burden countries. Some are laboratory-based tests, whereas others are rapid dipstick tests, which could fill a vital niche for a point-of-care tuberculosis diagnostic test. “If they worked, the problem of a gap in the pipeline for a point-of-care assay would have been solved decades ago”, comments Madhukar Pai, co-chair of the STOP-TB Partnership's new diagnostics working group. “The pity is that they don't work. In fact, they're inaccurate and useless.”
WHO is due to release a negative policy recommendation—the first of its kind for the organisation—on current commercial tuberculosis serodiagnostics. Results of several meta-analyses have indicated poor performance of these tests, and in 2008, an assessment of 19 commercial assays by TDR—the UN special programme for research and training in tropical diseases—found that none of the assays were good enough to replace sputum microscopy or as an add-on test to rule out tuberculosis. Manufacturers continue to claim that their tests are effective and fill a diagnostic niche, especially in sputum smear-negative patient groups.
Karin Weyer, WHO coordinator of TB diagnostics and laboratory strengthening, told The Lancet that “the negative policy process is a new concept in WHO”. But, she says, the process has been identical to that for positive recommendations, such as the endorsement announced on Dec 8 of a fully automated nucleic-acid amplification test (Xpert MTB/RIF, Cepheid) to improve tuberculosis diagnosis.
The available evidence on serodiagnostic kits has now been rigorously assessed, including meta-analyses when appropriate, and reviewed by an independent WHO expert group, says Weyer. “The expert group endorsed the findings from an updated systematic review since the TDR report in 2008 and essentially concluded that we should proceed with negative policy guidance based on the fact that the performance characteristics of these tests were way below what one would want and also because the quality of the data were so weak and so bad that it warranted a recommendation against the use of these tests”, she explains.
“Everyone is aware of the consequences of bad drugs and vaccines, but nobody really thinks about bad diagnostics and what impact they can have”, comments Pai. In their report, released at the end of December, the WHO Strategic and Technical Advisory Group for TB acknowledges “the adverse impact of misdiagnosis and wasted resources on patients and health services when using these tests for the diagnosis of active TB”, and recommends WHO to proceed with written guidance advising against current serodiagnostic kits. Further targeted research is strongly recommended since potential exists for research to develop accurate serologic assays, which could fill the point-of-care niche. WHO is being careful with preparation of the negative policy so as not to stifle innovation and research investment in tuberculosis diagnostics, says Weyer.
Commercial serodiagnostic kits are widely available, but the problem is probably greatest in India, where Pai estimates that serodiagnostic kits are used on at least 1·5 million people with suspected tuberculosis every year. Such testing is not done through the Revised National TB Control Programme (RNTCP) but through the unregulated private sector, which manages a substantial proportion of tuberculosis cases. Patients pay for serodiagnostic kits, and the market is estimated conservatively at over $US15 million in India alone, compared with $65 million for the entire RNTCP.
Despite country-wide DOTS coverage by the RNTCP, India continues to have more than 2 million new cases of tuberculosis every year. Ongoing transmission will not be reduced without intensified early case detection, which first relies on access to quality diagnosis. Writing in The New Yorker on Nov 15, journalist Michael Specter described how, in India, “for most patients, the choices are bleak”—overcrowded public hospitals versus unreliable tests at unregulated private laboratories or clinics.
Everyone in the private-sector chain gets a cut of patient fees—up to $10—30 per serodiagnostic kit—especially the referring doctors and private clinicians, who are often the same individual, Specter reports. Financial incentives perpetuate this system, Pai explains, since: “a private practitioner may not order sputum microscopy because you don't make much money out of a cheap test like sputum smears. The more expensive the test ordered, the more money you get back”, he explains.
The available evidence indicates that current tests lack either the necessary sensitivity or specificity or both to be an effective diagnostic test, and for many of these tests, false results far outnumber true results. Low sensitivity means increased false-negative results, which increase morbidity, mortality, and ongoing transmission of tuberculosis. Low specificity means more false-positive results; patients might then be given 6 months of potentially toxic treatment, while their underlying pathology remains uninvestigated and undiagnosed.
Many commercial tuberculosis serology kits are manufactured in China or India, but some are from western countries, such as France, the UK, Canada, and the USA. These manufacturers are selling high volumes of their test kits in countries such as India, although their tests are not licensed or used in the countries that make them.
During WHO's systematic review process, says Weyer, “we quickly discovered that manufacturers of these commercial serodiagnostics simply change the name of the test frequently and re-market and re-sell the same test under a new brand name. So, teasing out which test belonged to which brand name and updating the previous review by TDR proved to be a real challenge, as we wanted to be as solid as we could possibly be on the actual evidence.”
The key question is how much will the WHO guidance affect the sale and use of these tests in the private sector? “The ideal is that the public sector would be attractive enough and use state-of-the-art new tests, so that patients don't feel that they need to go to the private sector to get what they think may be a better diagnosis”, says Weyer.
However, given the extent of private-sector medicine, the concept of public—private mix (PPM) is being hailed in some quarters as the key to increasing efforts to tackle tuberculosis. The final report of WHO's subgroup on PPM for tuberculosis care and control advised earlier this year that countries need to scale up PPM, and involve provider groups outside national programmes to develop national strategic plans. Recommended approaches also include certification and accreditation of care providers and laboratories, and a system for mandatory notification of tuberculosis.
To achieve PPM recommendations, regulation of private-sector medicine will need to be developed and implemented in high-burden countries. What is absent from the PPM report is recognition that regulatory frameworks for diagnostic tests are also often weak or non-existent. WHO is helping countries establish regulatory systems to review the local relevance of diagnostics, and determine whether such tests should be marketed and sold, says Weyer. But, she foresees “a long-term difficult process”, as local expertise and capacity are often limited and regulatory frameworks need to be drawn up and passed through national legal systems country by country.
“Public-private partnership is the way to go”, asserts Camilla Rodrigues, a physician at the private Hinduja Hospital, in Mumbai, India, who has trialled the Xpert MTB/RIF system for diagnosis and drug-resistance testing of tuberculosis for more than 3 years. Rodrigues would like to see physician education on the unreliability of serology in endemic regions and laboratory accreditation encouraged. National governments need to provide guidelines for tuberculosis testing with “strict regulation in place for defaulters”, she says, adding that laboratories need diagnostic algorithms and strengthened capacity both for gold-standard tests, such as culture, and validated new molecular tests.
Weyer agrees, but notes that: “PPM alone will not overcome barriers presented by the lack of country regulatory frameworks for new diagnostics”. Nevertheless, market forces could play a part in developing and implementing better tuberculosis diagnostics. If Xpert MTB/RIF or other technologies are developed to become point-of-care tests, the private sector already has the infrastructure to deliver, and effective diagnostics could successfully replace inaccurate tests, says Pai.
The chief executive of a large private Indian diagnostic laboratory chain, Sanjeev Chaudhry, told The Lancet that Super Religare Laboratories strongly concurs in discouraging use of serodiagnostic kits in Indian settings. However, mere policy change might not be effective with the current magnitude of the challenge, he says, so, “instead of change in policy by private lab(s) in isolation or even as a consortium, we seriously feel that collective and dedicated efforts are required equally by the public- and private-sector service providers”.
As pathology service providers are expected to offer and satisfy the needs of the market, Chaudry continues that “we need to have an alternative cost-effective option along with appropriate awareness among clinicians and doctors”. Rodrigues notes that “the Indian diagnostic market is thriving. There is certainly potential for low-cost, accurate, and newer tests to be produced in India which will lower the cost.”
WHO guidance will be very clear, Weyer confirms, “to reflect the current commercial serodiagnostic tests but not to jeopardise future research and new antigen and biomarker discovery programmes that would guide and inform the development of point-of-care tests”.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60005-6/fulltext?rss=yes

TUBERCULOSIS: Immediate treatment for drug resistant tuberculosis possible with “while you wait” test

Geoff Watts An instrument developed in the US after the country’s anthrax contaminated letters scare of 2001 has now been endorsed by the World Health Organization as a more effective means of testing for tuberculosis.
Manufactured by the Californian company Cepheid, the Xpert MTB/RIF uses a disposable cartridge containing all the reagents required to perform the test. Results are available in about 90 minutes.
Sputum smear microscopy, the method commonly used for detecting tuberculosis, was developed 125 years ago. It misses many cases, especially in children and people who are HIV positive. The diagnosis of drug resistant tuberculosis relies on bacterial culture and drug susceptibility testing. These findings are not available for weeks or even months during which time a drug resistant strain can continue to spread.
The new test is fully automated, poses few biosafety hazards, can be operated in a non-specialist laboratory, and detects the presence of rifampicin drug resistance, an indicator of multiple drug resistance. Patients can be offered the appropriate treatment immediately.
Demonstrated this week at press conferences held in London and Geneva, journalists were able to see for themselves how straightforward the instrument is to use.
The operator first scans the bar code on a small lidded cartridge, a few centimetres square. The addition to the sputum sample of a prepared solution renders it non-infectious within 15 minutes. Using a pipette, 2 mL of this mixture are put into the cartridge which, after closing its lid, is slipped into the instrument. The results are displayed on a laptop computer.
Giorgio Roscigno, chief executive of the Foundation for Innovative New Diagnostics (FIND), the not-for-profit organisation that helped to develop its application to tuberculosis, said, “By changing the cartridges you could also use this instrument for other diseases.”
Explaining WHO’s decision to endorse the instrument Karin Weyer, of its Stop TB department, pointed to the accumulated data. “An expert group reviewed the evidence from around 12 000 patients evaluated in a variety of settings,” she said. “We are now recommending that we move as quickly as possible to provide policy guidance and a road map to countries to get this test working in the field.”
Multiple drug resistance poses a severe challenge to national tuberculosis programmes according to a recent editorial in the New England Journal of Medicine (2010;363:1070-1). “Globally,” say the authors, “fewer than two per cent of the estimated cases of multi-drug resistant disease are reported to the WHO and managed according to international guidelines.”
The new instrument costs $17 000 (£10 800; €12 900) and can perform 16-20 tests in eight hours. Each test costs $16.86, but will drop to $10.72 by 2014 if uptake proceeds as intended. South Africa and India are among countries that have plans to use the system, and many non-governmental bodies active in fighting tuberculosis have also expressed interest or said they will promote it.
http://www.bmj.com/content/341/bmj.c7132.full

TUBERCULOSIS: WHO urges roll-out of new TB test despite worries over cost

A test that can detect TB, including drug-resistant forms, in less than two hours could revolutionise treatment of the disease, according to the World Health Organisation, which is urging its roll-out across the globe.
Tuberculosis killed 4,700 people every day last year. The annual death toll of 1.7 million includes 380,000 people who are at particular risk because they have HIV, the virus that depresses the immune system and causes Aids.
The current diagnostic test for TB has been used for 125 years. It involves microscopic examination of a sputum sample and is not ideal because it doesn’t easily detect the growing number of strains that are resistant to antibiotics, or TB where the patient is also infected with HIV.
Some patients have to wait as long as three months to be diagnosed, which means their treatment is delayed and their prospects of recovery are reduced. The long wait also increases the chances they will infect others and, if they are given the wrong antibiotics for their particular strain of TB, drug resistance can worsen.
The new test delivers a result in 100 minutes. Dr. Mario Raviglione, Director of the WHO’s Stop TB department, said, “This new test represents a milestone for global TB diagnosis and care. It also represents new hope for the millions of people who are at the highest risk of TB and drug-resistant disease.”
He added, “We have the scientific evidence, we have defined the policy, and now we aim to support implementation for impact in countries.” The number of TB cases is set to rise as the test is rolled out. The WHO says drug-resistant cases could increase threefold and the number of cases where the patient is co-infected with HIV could double.
Trials and demonstration studies have been carried out over 18 months in a number of different countries, involving more than 8,000 patients. The test is a fully-automated nucleic acid amplification test, which the WHO says is simple and safe to use. It incorporates modern DNA technology that can be used outside of conventional laboratories - although the need for a constant electricity supply may be a problem in rural settings.
The major issue will now be cost. The market price for the equipment is $55,000 to $62,000, with an additional $55 to $82 for the cartridges it uses. The makers, Cepheid, have agreed to cut the price by 75 per cent for the poorest countries. However, at $16.86 per test, the cost is higher than the current system and the roll-out will depend on donor funding.
http://www.thehindu.com/health/medicine-and-research/article941615.ece

TUBERCULOSIS: DNA test developed by UMDNJ researcher may revolutionize tuberculosis diagnosis, treatment

December 10, 2010,
Seth Augenstein


William Perlman/The Star-Ledger:  (L-R) Danielle Amisano, research teaching specialist V along with Padmapriya Banada, Ph.D., research teaching specialist III work with test spit samples using the revolutionary new test (developed by a UMDNJ doctor) endorsed this week by WHO, at the UMDNJ-NJ Medical School Center for Emerging and Reemerging Pathogena Division of Infectious Diseases in Newark.

 NEWARK — The test used to detect for tuberculosis is basically the same today as it was for the past 100 years — slow. So slow that while patients waited up to three months for the results they spread their disease to others and even died — particularly in impoverished countries.
But on Wednesday the World Health Organization endorsed a new weapon in the fight against the disease: a two-hour automated DNA test which could slow the creeping contagion, and simply "revolutionize" treatment across the world.
The new test was developed by David Alland, the chief of the division of infectious diseases from the University of Medicine and Dentistry of New Jersey — New Jersey Medical School. It uses DNA analysis to provide a diagnosis in as little as two hours.
"This new test represents a major milestone for global TB diagnosis and care," said Mario Raviglione, director of the WHO’s Stop TB Department. "It also represents new hope for the millions of people who are at the highest risk of TB and drug-resistant disease."
Under the old testing method, a sample of a patient’s saliva is taken and brought to culture then examined under a microscope — a tedious and time consuming process. The initial screening for the TB bacteria often involves a skin test which may show that a patient is carrying the disease but only the saliva test shows it’s progressed to disease.
The DNA test is simpler, does not present any risk of infection, is more accurate – particularly in identifying drug-resistant TB, while also bringing the quicker results, Alland said.
"The test will say whether TB is there or not, and whether the TB is drug-resistant," Alland said. "Overall, the test picks up 98 percent of all TB … It picks up strains the microscope misses."
Patients still spit into a cup, but now they are mixed and shaken up with an agent that renders the sample safe. Then the mixture is transferred to a test cartridge and inserted into the DNA analysis machine. About 100 minutes later, the results are in – and with only two minutes of total hands-on time for health workers. Gone are the hours over the microscope, and weeks or months of waiting – and infecting others.
Alland developed the quicker, more accurate test in 1996 but getting it a stage in which it could be widely used on took years.
He said developing the technology for the test took four years, then he had to get funding for to help perfect it and finally he had to find a private company to take on its deployment around the world. Various experts predicted Thursday that the new test could save millions of lives over decades to come.
The test machines, cartridges and technology are manufactured by Cepheid, a California-based genetic testing company, with help from the international non-profit Foundation for Innovative New Diagnostics. The start-up money for the research came from the National Institutes of Health and the Bill and Melinda Gates Foundation, but it also came with a catch: that the cost of the machines be made affordable to the neediest parts of the world.


William Perlman/The Star-Ledger:  Dr. Padmapriya Banada, PhD, Research Teaching Specialist III work with test spit samples using revolutionary new test (developed by UMDNJ doctor, endorsed this week by WHO) at the UMDNJ-NJ Medical School Center for Emerging and Reemerging Pathogena Division of Infectious Diseases.

The test is a bit more expensive than the old microscope method. The machines alone cost between $55,000 and $62,000 and cartridges cost $55 apiece. But there are 116 countries around the world which will be considered preferred customers because of their current infection rate. As such, their tests will be reduced by 75 percent, down to just $16 per test, and that cost will be decreased down to $10 after the first 3 million tests worldwide, Alland said.
"I think that’s a really good business model," the doctor said.
The WHO plans to test with the machine quickly, reaching that 3 million test threshold by 2014. The test comes at a crucial stalemate in the fight against HIV and TB co-infection, according to experts. Approximately 2 billion people worldwide still carry the baccilus of the disease. Nine million develop the disease each year — mostly in Southeast Asia and Africa — and about 1.6 million die from it annually, according to the World Health Organization.
A report written in the journal Nature in 2006 estimated that an automated, quicker and reliable test – such as the one developed by Alland and Cepheid – would save the lives of 392,000 people around the world annually.
Lee Reichman, the executive director of UMDNJ’s Global Tuberculosis Institute, and a colleague of Alland’s, said the new test would easily save that many patients — and more.
"It revolutionizes TB diagnosis and treatment," Reichman said. "The fact that the WHO endorsed it is dynamite."
http://www.nj.com/news/index.ssf/2010/12/innovative_dna_test_developed.html