As I have noted in past posts, the need for diagnostic tests (Dx) for tuberculosis (TB) is immense and immediate (“ReDuX,” 1/6/11, and “ReDuX Part II,” 1/13/11). TB is a major problem in the developing world (8.8 million people are infected each year) and a growing one in the developed world with the emergence of drug-resistant strains (Stop TD Fast Facts). While the bacterial infection is easily treated in the early stages (with a six-month course of antibiotics), the most common diagnostic test in the high-TB-burden countries (HBC) misses about half of the cases tested, including during the earliest but still contagious stages, and the tests for determining drug resistance are expensive. Better TB diagnostics may save 400,000 lives yearly, according to a 2006 forum (Nature: Diagnostics for the Developing World). As for the market for TB Dx, a 2006 study by WHO and Foundation for Innovative New Diagnostics (FIND) reported that the global annual number of tests needed for detection and monitoring was about 275 million administered at a cost of more than $1 billion (TB Dx Global Demand).
The big story in TB diagnostics in 2011 has been the launch of the Gene Xpert® MTB/RIF system that was developed by Cepheid Corp. with funding through FIND and the NIH (FIND press release). In my post of 1/13/11, I wondered if FIND had a strong case for its cost-effectiveness and if Cepheid was really interested in promoting the product in the HBC. The good news is that the systems are in use; TB labs in 47 countries have purchased or ordered the system for a total 460 readers and 600,000 cartridges through the end of 2011 (WHO Roll Out). And Cepheid is promoting the system through a website (Cepheid Cares) even though it is not now a major product for it. Based on the 75% discounted prices negotiated by FIND at the start of the co-development process (Prices), I estimate HBC sales of the Xpert system and reagents have been about $18 million, or 6% of their $277 million 2011 revenue (Cepheid 2010 4Q Report). As for the effect of the Xpert system on TB diagnosis and treatment, it is apparently still too early in its implementation to measure. I found one study that reported the system worked well in real world settings and reduced the delay in starting treatment ten-fold (5 vs. 56 days), but did not measure outcomes such as reduction in morbidity and mortality (Boehme et al 2011), leaving some of the many TB experts still concerned about its cost-effectiveness (Vassell et al 2011) and feasibility for wide use (Kranzer 2011). Given the Xpert system’s requirements for electricity, lab facilities, training, and expensive reagents, the need still exists for a rapid test that is affordable, sensitive, specific, user-friendly, equipment-lite, and useful in adults and children.
Through its Grand Challenges grant program, the Bill & Melinda Gates Foundation has been feeding the TB diagnostics pipeline by supporting discovery-phase, mostly academic, work and several weeks ago announced the awarding of $7.7 million in funding to ten projects to find markers for early diagnosis (Gates press release). The main theme of the projects, which are described briefly at TB Biomarkers, TB Biomarkers, is to use new and sophisticated technology to find makers in very low concentration in accessible samples. Evidently there is either a lack of companies interested in the TB Dx Challenge or lack of qualified applicants, since only one awardee was a company and two awards went to academics working with company partners. Since my bias is that a test a company is working on is more likely to get into use sooner than an academic project, here my a quick summary of those Gates projects and one sponsored by FIND with my guess of how well the test may fit the above criteria and when the test may be ready for field trials:
|Company||Partner||Technology||POC Dx Fit||Yrs to Trial|
|Global Biodiagnostics||FIND||Reporter enzyme fluorescence||Low||3+|
|Advantageous Systems||Alland, UMDNJ||Paramagnetic nanoparticles conjugated with capture antibodies||Low||5+|
|SomaLogic||NA||Aptamer with microarray detection||Low||5+|
|Quanterix||Pollock, BIDMC||Femto-scale ELISA||Good||2|
In addition to these four, there are about fifteen other products in development in companies according to the BIO Ventures for Global Health Primer (Primer), and my next project may be to try ranking these tests by their fit with the “ideal” TB Dx criteria. I should note that there are a bunch of marketed TB diagnostics based on the standard immunochemistry (ELISA) format, 19 of which were evaluated by the WHO in 2008 (WHO RTD evaluation). The WHO concluded that, although there was an increase in case-finding from 75% to 89% when some of the RTDs were used with the standard microscopy test, the false positive rate of 64% was too high for recommending use. Back to the drawing board.