The tuberculosis diagnostics pipeline
By Colleen Daniels
Accurate diagnosis of tuberculosis (TB) is the gateway to treatment and—it is hoped—cure for people with latent TB infection (LTBI) or active TB disease. According to the Stop TB Partnership and the World Health Organization (WHO), 3 million of the 9 million people who develop TB disease every year are not recorded as diagnosed or treated. 
Sputum smear microscopy is still the most widely used TB diagnostic test, despite its lack of sensitivity, most notably among children and people living with HIV. There is still no simple, instrument-free, point-of-care diagnostic test for active TB. Products moving forward are listed in table 1.
|Genedrive MTB/RIF ID||Epistem, United Kingdom||Real-time PCR for TB and rifampin (RIF) resistance||Sponsor claims field trials under way |
|Line probe assay (LiPA)||Nipro Corporation, Japan||LiPA kit to detect pncA mutations associated with pyrazinamide-resistant TB||Evaluated at two centralized labs by FIND [3, 4]|
|FluoroType MTB||Hain Lifescience, Germany||Semi-automated NAAT for detection of Mycobacterium tuberculosis complex in clinical specimens||Study results published.  The assay is marketed in Europe and will be made available globally in 2014|
|FluoroType MTB RNA||Hain Lifescience, Germany||Molecular therapy monitoring of people with Mycobacterium tuberculosis (MTB) who are on treatment||First clinical data will become available in 2014 |
|LATE-PCR with Lights-On/Lights-Off Probes and PrimeSafe technology ||Stellenbosch University, South Africa; Brandeis University, United States; Hain Lifescience, Germany||PCR test for simultaneous detection of MTB and resistance to isoniazid, rifampin, ethambutol, and injectables. Technology licensed from Brandeis University for development by Hain Lifescience to detect MDR- and XDR-TB in a single-tube PCR assay||The technology will be presented at validation sites throughout Q3 of 2014. Due to be CE-marked (European Union accreditation for medical devices) by Q2 of 2015 [8, 9]|
|Pure LAMP||Eiken Chemical Company, Japan||Manual TB detection based on loop-mediated isothermal amplification (LAMP) using a nucleic acid amplification method||Published study  from microscopy centers in China. Now on path for WHO review |
|Alere Determine TB-LAM Ag lipoarabinomannan (LAM) lateral flow test||Alere, United States||Lateral flow urine test detects TB LAM in adults with HIV and advanced immunosuppression||On the market; independent field studies completed; additional studies under way [12, 13]|
|TB Scope ||CellScope Mobile Microscopy/Fletcher Lab, University of California, Berkeley, United States||Automated imaging using sensitive fluorescence method||Currently being tested in Hanoi, Vietnam, as part of a WHO study to provide TB diagnosis at peripheral levels of the health care system |
|TREK Sensititre MYCOTB MIC plate||Trek Diagnostic Systems/Thermo Fisher Scientific, United States||A dry microdilution plate containing lyophilized antibiotics for determination of minimum inhibitory concentrations of first- and second-line TB drugs (except pyrazinamide)||In field studies |
*Unlike with the phase designations for drug development (i.e., phase I, IIa, IIb, III), there are no global standard definitions for the stages or definitions for diagnostics development. The European Union (E.U.), the U.S. Food and Drug Administration (FDA), [17, 18] and the WHO  each uses different definitions and terminology.
Only technologies with documented progress—data published in peer-reviewed journals —since the 2013 Pipeline Report are shown in table 1. Several sponsors claim that they have additional tests in development, but these have made no visible progress since 2012. After the approval of Xpert MTB/RIF by the WHO in 2010, the diagnostics pipeline for molecular technologies expanded. TB experts spoke hopefully of “fast followers,” hoping that these tests might be cheaper, faster, or easier to use than Xpert MTB/RIF. No such test has yet been validated by the WHO or a stringent regulatory authority.
Xpert MTB/RIF Implementation Science Moves Forward
Cepheid’s GeneXpert system was recommended by the WHO in 2010. It uses a rapid, automated, cartridge-based nucleic acid amplification test (NAAT) platform that detects the TB organism and some common rifampin-resistance mutations. The Xpert MTB/RIF assay is more accurate than smear microscopy and much faster than TB culture. Data from the implementation of Xpert MTB/RIF may have helped persuade more countries to use it. 
A 2013 Cochrane Review  analysis focusing on 18 studies reported a “pooled sensitivity of 88% and specificity of 98%” when Xpert MTB/RIF replaced smear microscopy as an initial test, and pooled sensitivity of “67% and specificity of 98%” when used as a follow-up test after a smear-negative culture result. The authors concluded that Xpert MTB/RIF can be used as an “initial diagnostic test for TB detection and [rifampin] resistance” and would be “valuable” as an add-on test.  In 2014, the Cochrane Review published an updated analysis of Xpert (27 studies), with highly consistent results. 
The WHO updated its policy guidance on Xpert MTB/RIF in October 2013, recommending that the assay be used for initial diagnosis in individuals suspected of having MDR-TB or HIV-associated TB. It added conditional recommendations regarding the assay’s use as a follow-up to microscopy, in “adults who are suspected of having TB but not at risk of MDR-TB or HIV-associated TB.”  The update provided recommendations on using Xpert MTB/RIF to detect TB in children. 
A systematic review and meta-analysis  determined that Xpert MTB/RIF performed well compared with culture and a composite reference standard in the detection of certain types of extrapulmonary TB. The WHO recommends using Xpert MTB/RIF rather than conventional tests for “diagnosis of TB in lymph nodes and other tissues, and as the preferred initial test for diagnosis of TB meningitis [tuberculous meningitis].” 
One of the many studies published in the past year and a half on Xpert MTB/RIF showed that nurses can administer the assay effectively in primary health care settings.  Rapid diagnosis allows more patients to start treatment the same day. Hanrahan and colleagues found that those who received an Xpert MTB/RIF–positive test at a primary health clinic had a median time of zero days time to treatment initiation.  In a study done in South Korea, the median turnaround time for the Xpert MTB/RIF assay was 0 and 6 days; the median time to treatment was 7 days compared with 21 days in those who did not have a diagnosis with Xpert MTB/RIF. 
In some of these studies, Xpert MTB/RIF was used to diagnose tuberculous meningitis; one in Vietnam showed that diagnosis was possible: Xpert MTB/RIF had a sensitivity of 59.3% when compared with microscopy (78.6%) and the Mycobacterial Growth Indicator Tube (MGIT) liquid culture system (66.5%).  Several studies also tried using samples other than sputum to detect TB using Xpert MTB/RIF. [32, 33] Among people with HIV, exhaled breath condensate, urine, saliva, and blood samples did not allow TB detection using Xpert MTB/RIF.  Another study found that Xpert MTB/RIF can be used as the initial diagnostic for HIV-associated lymph node tuberculosis. A single Xpert test had a 88.2% and a sensitivity of 93.3%, though this improved with decreasing CD4 cell count. All patients who had a positive Xpert MTB/RIF result initiated treatment within one day compared with those without an Xpert MTB/RIF result.  A study with Xpert using stool as a specimen for the diagnosis of pulmonary TB in HIV-positive children found that Xpert detected “8/17 (47%) culture-confirmed tuberculosis cases, including 4/5 (80%) HIV-infected and 4/12 (33%) HIV-uninfected children.” 
Many studies showed that Xpert MTB/RIF increased detection of TB, both drug-resistant and drug-susceptible. An active case-finding study in Phnom Penh, Cambodia, increased detection of drug-susceptible and drug-resistant TB by using a symptom screening followed by smear microscopy and targeted use of Xpert MTB/RIF.  At health centers in Adama Town and the Oromia region of Ethiopia, Xpert MTB/RIF was found to increase the TB detection rate by 47.4% (64 cases) compared with smear microscopy, especially in patients with advanced immunosuppression.  Results from the implementation of Xpert MTB/RIF in nine TB REACH projects show that Xpert MTB/RIF detected TB in a large number of people with TB that routine services failed to detect. In Kenya, Malawi, the Democratic Republic of Congo, and Nepal, diagnostic interventions that included Xpert MTB/RIF to test people who were sputum smear–negative found 2,833 people that would previously have been unidentified. 
Some published data suggest that Xpert MTB/RIF has not demonstrated a clear effect in improving patient outcomes. [40, 41] The TB NEAT  and TB Extend  studies concluded that Xpert MTB/RIF does not necessarily increase the number of people treated, but does increase the number of people diagnosed with microbiologically confirmed TB. In many countries, including South Africa, Xpert MTB/RIF testing is done through a laboratory service rather than in community clinics. If Xpert MTB/RIF was implemented at more peripheral levels of the health system, it would be possible for people to have a single visit to a health facility and start treatment the same day, thereby reducing loss to follow-up, morbidity, and mortality.
Current operational research studies on Xpert MTB/RIF listed on ClinicalTrials.gov focus on achieving the best clinical outcomes and reducing TB in HIV-positive adults and children, using Xpert MTB/RIF in mobile units, assessing Xpert MTB/RIF diagnosis at the point of treatment, and intensifying case finding with a package of diagnostic tools including Xpert MTB/RIF.
Xpert MTB/RIF is a major advance in TB diagnostics. Among the short-term priorities should be understanding how best to implement Xpert MTB/RIF in order to improve individual and public health, increasing the ruggedness of the instrument in order to ensure that it operates reliably in a variety of climates and settings, determining specimen processing and testing procedures that optimize yield from Xpert MTB/RIF testing of nonrespiratory specimens, and increasing the assay’s sensitivity to enable it to detect a greater proportion of paucibacillary TB.
Alere Determine LAM – A Useful Test in Advanced Immunosuppression
An important advance in assays over the past year is the Alere Determine TB LAM (lipoarabinomannan) lateral flow test. Several studies are assessing its ability to detect TB in severely immunosuppressed people with HIV, who are among the hardest to diagnose.
One of the key findings, presented at the Conference for Retroviruses and Opportunistic Infections in Boston, Massachusetts, in February 2014, is the importance of the Determine LAM urinary test as an add-on rather than a stand-alone test. Steven Lawn presented data showing an increase in detection from 26.6% to 80.6%, when the Determine LAM test was added to an Xpert MTB/RIF test. When combined, Determine TB LAM and Xpert MTB/RIF detected 69.1% of culture-confirmed cases, enabling them to find MTB infection in 85% of people with CD4 cell counts below 100/mm3.  In Uganda, a study showed that the sensitivity of Xpert MTB/RIF and Determine LAM, used together, is superior to that of either test alone. 
A study conducted in Ethiopia in people with HIV found that the Determine TB LAM assay worked best in those who had a CD4 cell count ≤100/mm3 and that it could be used with sputum microscopy in this group.  A study conducted in hospital and outpatient settings in Uganda and South Africa found that in HIV-positive adults with symptoms of TB who had a CD4 cell count ≤100/mm3, the assay detected over half of culture-positive tuberculosis samples in less than 30 minutes.  Getting sputum samples from children is difficult, so for them a urinary LAM test would be best for TB detection; however, a study in South Africa showed that the test has insufficient sensitivity and specificity to diagnose TB in children, whether they have HIV or not. 
Determine TB LAM tests can also be used to rule in TB in patients with advanced HIV-induced immunosuppression and lead to early treatment initiation.  The test is cheap, produces results in less than 30 minutes, and can be used at the point of care. The WHO must review available evidence on Determine TB LAM, and provide guidance so that this test, if appropriate, can be used widely in people with HIV and low CD4 counts, and possible TB.
Other Diagnostics Progressing
New additions to the 2014 table are the LiPA (Nipro), the FluoroType MTB (Hain Lifescience), the FluoroType MTB RNA (Hain Lifescience), and the Pure LAMP (Eiken Chemical). The LiPA is a drug susceptibility test (DST). A recent study found no difference between conventional DST and LiPA for rifampin, pyrazinamide, and levofloxacin, but it did find a difference in isoniazid susceptibility.  FIND is evaluating LiPA at two centralized laboratories. The FluoroType MTB is a semi-automated nucleic acid amplification test to detect MTB. A study evaluated the test in a laboratory in Germany and found it had a sensitivity of 99.2% (smear-positive 100%; smear-negative 56.3%) and a specificity of 98.9%. The authors concluded that the test results were comparable to non-nucleic acid amplification tests on the market. The FluoroType MTB RNA is a molecular platform that monitors therapy of people with TB. The assay is in development, and Hain Lifescience intends to publish its first clinical data this year.  There is a need for additional well-designed, quality-monitored studies to ensure the reproducibility of these results. The Pure LAMP is a manual TB detection tool based on loop-mediated isothermal amplification (LAMP) using a nucleic acid amplification method. A study at county-level TB laboratories in China found 92.12% sensitivity in smear-positive, culture-positive TB patients and 53.81% in smear-negative, culture-positive patients. Specificity was 98.32%. The study found that there was a lower contamination rate than in solid culture. 
The linear-after-the-exponential PCR (LATE-PCR) with Lights-On/Lights-Off probes is a test that can detect MTB and resistance to isoniazid, rifampin, ethambutol, fluoroquinolones, amikacin, kanamycin, and capreomycin in less than three hours.  Brandeis University licensed this technology to Hain Lifescience. Hain will work to develop assay versions to detect MDR and XDR-TB in one single-tube PCR assay.
The TREK Sensititre MYCOTB MIC plate is a culture-based technology for DST. A study conducted in the Republic of Korea and Uganda assessed the performance and feasibility compared to the agar proportion method (APM). Results between the MYCOTB and APM showed ≥92% for 7 of 12 drugs with respect to susceptible or resistant TB isolates when assessed with a strict definition.  Minimum inhibitory concentration (MIC) results are used to optimize therapy in a number of infectious diseases other than TB. The availability of a simple, commercially produced MIC plate for MTB testing that shows what drugs the person’s strain of TB is resistant to could facilitate individualized approaches to the management of highly drug-resistant TB.
Other studies currently under way are assessing the use of interferon gamma release assays (IGRAs), primarily Quantiferon TB Gold (QFT), for diagnosis of latent TB infection in health care workers in high- and middle-income countries and in children. Two studies (NCT00982969 and NCT00962676) are assessing the clinical use of QFT in the diagnosis of active TB in immunosuppressed and immunocompetent patients. The WHO recommends against the use of IGRAs for the detection of active TB in any setting. 
Three studies (NCT01301144, NCT01748357, NCT01379066) are looking at the efficacy of volatile organic compounds (VOC), with one study assessing the Siemens VOC breath analyzer. No published data on these studies were available in 2013.
Diagnostics from the 2013 Pipeline with No Reported Progress
The following tests from the 2013 Pipeline Report are not included in this year’s table, as no new data have been published: the Alere Q, B-Smart GeneXpert XDR cartridge, GenoType MTBDRsl, iCubate, Infiniti MTB, Loopamp TB detection, GenoType MTBDRplus 2.0, NATeasy, TruArray, Truenat, TB rapid screen, TBDx, BNP Middlebrook, MDR/XDR-TB Color Test, BreathLink, and the breathalyzer prototype. Of these, the GenoType MTBDRplus 2.0, iCubate System, EasyNAT TB Diagnostic Kit, and the Truenat MTB test are now available on the market. The GenoType MTBDRplus 2.0 and the Truenat had data published in 2007–2012 and 2012, respectively. The Truenat is currently included in a study (NCT01589289) on predictors of tropical diseases in neurological disorders in the Democratic Republic of the Congo. FIND and Applied Visual Life Sciences (Leesburg, Virginia) recently announced a collaboration to evaluate the TBDx automated platform.
The developer of Truenat, Bigtec Laboratories, states that it has tested the assay’s performance against Xpert MTB/RIF, is now evaluating the test in the public sector in India to inform national TB policy, is attempting to validate the Truenat MTB test for detection of TB in extrapulmonary samples, and is developing a resistance assay for detection of MDR-TB. Truenat said that it is developing a multicenter trial in collaboration with FIND. 
Basic Science and Biomarkers
Current limits on our understanding of the biology of TB infection and disease limit scientific approaches to developing better diagnostic tests. There is simply not enough research being funded and conducted in basic science and biomarker discovery for TB. A ClinicalTrials.gov search found only three studies (NCT01269268, NCT00023439, and NCT00212498) investigating potential TB biomarkers. 
Funding for TB diagnostic R&D remains grossly insufficient; there was a 23.4% decline in spending between 2011 and 2012 according to our most recent report on TB R&D resource tracking.  In 2012, US$42,429,160 was spent globally when the Global Plan to Stop TB 2011–2015 called for annual spending of US$340 million.  This serious inadequacy of funding is one of the main reasons for the lack of movement in the diagnostics pipeline.
Whole-Genome Sequencing: The Final Frontier?
Whole-genome sequencing is becoming cheaper and more widely used for a variety of scientific investigations, including disease diagnosis, staging, and response to therapy.  Current technologies available from Illumina, Oxford Nanopore Technologies, Life Technologies, and Integrated Nano-Technologies can be used for whole-genome sequencing for TB. South Africa uses whole-genome sequencing as part of its TB drug-resistance surveillance, and the United Kingdom uses it for management of patients with very difficult XDR-TB cases. If the technology can be developed,  there is potential to use whole-genome sequencing to manage patients with MDR- and XDR-TB. Whole-genome sequencing has the potential to help guide clinicians in the selection of regimens to which a patient’s TB organism is susceptible. However, additional basic-science research is needed to more fully delineate the mechanisms of resistance and the spectrum of genetic determinants of resistance for certain drugs.
Identifying High-Priority Target Product Profiles and Market Size Estimation
While much of the current activity is centered around scale-up of Xpert MTB/RIF and evaluation of newer molecular tests, there are many other gaps in TB diagnostics, including a simple, low-cost triage test to identify patients who need further testing; a simple, biomarker-based TB test for nonsputum samples; a molecular or nonmolecular smear replacement test at the microscopy-center level; and tests for systematic screening.
Kik and colleagues published a study  in which the greatest needs were identified using several criteria, with the engagement of stakeholder groups. A rapid, sputum-based, molecular test for microscopy centers (with the option of an add-on DST cartridge) ranked highest, followed by a rapid biomarker-based, instrument-free test for nonsputum samples (which also detects childhood and extrapulmonary TB).
Parallel efforts to estimate potential markets for new TB tests are ongoing. This information will be most helpful to product developers and could catalyze new investments. Kik and colleagues estimated that the potential market size for a smear replacement molecular test (costing US$5) to be 30.8 million tests annually, with a potential market value of US$154 million per year in 22 high-burden countries. 
An expert consensus group convened by the WHO, the Global Laboratory Initiative, the Stop TB Partnership, and FIND met in Geneva, Switzerland, in May 2014 to develop, review, and agree on the minimum requirements for products most urgently needed; a report is expected in late 2014.
The TB diagnostics pipeline is at a standstill. Several potentially promising technologies are stuck in early development with little funding and no cohesive strategy to develop and evaluate them faster and more effectively. The TB diagnostics pipeline needs to be coordinated, prioritized, and funded by the TB and research communities together.
- Public- and private-sector R&D funders and research institutes must include more clinicians as researchers in the development process to ensure that basic science and biomarker research prioritizes needs based product development.
- Public- and private-sector R&D funders, investigators, and civil-society must prioritize and fully fund the development of an accurate, fast, cheap, point-of-care diagnostic for TB.
- Public- and private-sector R&D funders and investigators must prioritize and fully fund basic science, biomarker research, in order to gain a better understanding of TB disease.
- Public- and private-sector R&D funders and policy makers setting the agenda for R&D must create new opportunities for investigators and developers to be able to translate findings from biomarker research into technologies.
- Public- and private-sector R&D funders must fully fund specimen- and strain banks to increase their capacity and investigators’ access to them, and to facilitate technology development and early testing. They must develop standard operating procedures across initiatives so that samples and information can be shared.
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