Rapid TB test gets nod of approval from WHO

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A Zambian clinical worker tests for TB using a sputum smear microscopy, which routinely misses about 50 percent of all TB cases.

The World Health Organization announced Wednesday its support of the Xpert MTB/RIF for rapid diagnosis of tuberculosis, multidrug resistant TB and TB in HIV-infected individuals. The results of the test demonstration study were announced in September of this year in the New England Journal of Medicine, producing results for many patients in approximately 100 minutes. Current test could take up to three months.

“The Xpert MTB/RIF is a revolutionary technology that could allow TB programs in resource-limited settings to leapfrog from 19th century microscopic techniques to 21st century rapid molecular assays,” said Celine Gounder, MD, ScM, from the Center for Tuberculosis Research at Johns Hopkins University. “The archaic tests that are still the mainstay of TB diagnosis in most of the world miss a large proportion of cases, and the best tests that we had until now were slow, expensive and had high human resource and infection control requirements.”

Approximately 1.7 million people die every year from tuberculosis, including 380,000 people with HIV, and TB is responsible for more than a quarter of deaths of people living with HIV. More than nine million people developed active TB last year.

The automated nucleic acid–amplification test was co-developed by the Foundation for Innovative New Diagnostics (FIND), Cepheid Inc. (the manufacturer), and the University of Medicine and Dentistry of New Jersey. The National Institute of Allergy and Infectious Diseases at the National Institutes of Health and the Bill & Melinda Gates Foundation contributed funding to the test demonstration study.

“After 125 years of stagnation, diagnostic technology for TB has finally moved into the molecular age and an entirely new paradigm has been created,” said Richard E. Chaisson, MD, Professor of Medicine, Epidemiology and International Health also at the Hopkins Center for Tuberculosis Research.

The coffee-maker-sized Xpert machine tests sputum samples in specially designed, single-use cartridges and is fully automated, making it easy and safe to use. According to the WHO, the ‘while you wait’ test incorporates modern DNA technology that can be used outside of conventional laboratories.

Most developing countries use sputum microscopy to diagnose TB, but it only detects about 20 percent of TB cases among those living with HIV and less than half of TB cases overall. Sputum microscopy is also not useful for detecting TB in children or drug resistant TB.  Using a solid or liquid culture, another method of TB diagnosis, can take several weeks and requires sophisticated bio-safety procedures.

The approval from WHO is big news for areas facing a large epidemic of HIV-TB co-infection as well as drug resistant TB. “HIV-associated TB is the leading cause of death among people living with HIV in the Africa region,” U.S. Global AIDS Coordinator Eric Goosby, MD, said today in a statement.  The benefits are enormous:  use of Xpert MTB-RIF can significantly increase TB case-finding (by roughly 30%) and significantly increase MDR case-finding (roughly three-fold).

“We look forward to further partnering with Ministries of Health [in Africa], WHO, FIND and other partners to ensure that we use the platform established through PEPFAR to facilitate the rapid uptake of this critical new technology,” Dr. Goosby said.

But the new test is not cheap, and even the newly negotiated lower prices for countries in need are still exclusionary.

During the demonstration study, the price per cartridge was $18.40, but Cepheid agreed to drop the price even further $16.86 for low-income and middle-income countries facing a large epidemic. As demand for cartridges increases over time, the company has agreed to continually lower the cartridge price to an eventual $10.72 by 2014. But the machine itself is also costly – and the FIND-negotiated cost is still $17,000. The machines also must be calibrated annually, which could cost anywhere from $500 to $1800 depending on the Xpert machine model.

“The Xpert MTB/RIF remains expensive even at the FIND-negotiated concessionary prices,” said Dr. Gounder.  “Research is needed on the clinical impact of the Xpert MTB/RIF on TB- and HIV-related outcomes, and the cost-effectiveness of scaling-up the test in various settings.”

However, while the cost of the machine is greater than sputum microscopy, the initial capital costs of the Xpert are lower than for culture.  In addition, the cost of running the test is similar to that of culture.  The benefits are enormous:  use of Xpert MTB-RIF can significantly increase TB case-finding (by roughly 30%) and significantly increase MDR case-finding (roughly three-fold).

“The GeneXpert platform will have a transformational impact on TB and MDR-TB control around the world, and will challenge clinicians, TB programs and funding agencies to keep pace with dramatically increased numbers of diagnosed patients,” Dr. Chaisson said.  “It is important that this wonderful technological advance is matched by improved treatment of patients who are diagnosed with both susceptible and drug-resistant TB.”

The WHO analysis found that using Xpert MTB/RIF to meet diagnostic targets for MDR-TB will require less than one percent of current funding for TB control.  And WHO found that the cost of testing all HIV-positive individuals suspected of having TB will amount to less than one percent of current expenditure on HIV care in several high TB-HIV burden countries.

“The rapid test will be critical for programs supported by the U.S. Government, primarily through the bilateral programs of U.S. Agency for International Development (USAID) and in high HIV-prevalence contexts benefitting from PEPFAR support,” according to a statement posted Wednesday to the PEPFAR website. “The U.S. Government agencies contributing to global TB control, namely USAID, PEPFAR, and the U.S. Centers for Disease Control and Prevention (CDC), are committed to working together to support the rapid scale-up and appropriate use of this new technology.”

The test is not FDA-approved, and the WHO’s roadmap for rolling out the Xpert implies that approval in wealthy countries would be helpful to boost economies of scale and get a substantial test cost reduction by 2014.

The Xpert MTB/RIF is a tremendous advance, however, more funding is urgently needed for research into inexpensive technologies that can be used at the level of the health post, where most people seek care and where there can be few lab workers and an inconsistent supply of electricity and clean water.  The Treatment Action Group has documented that only 10 percent of all TB research funding is being spent on development of new diagnostics.