GeneXpert: A Game-Changer for Tuberculosis elimination

Is this the breakthrough that TB control has been waiting for?

Tuberculosis (TB) kills more people than any other single infection, the global burden of TB cases and drug resistance are increasing   and most patients still only have access to an inadequate diagnostic test developed more than a century ago. Recent evaluations of a desktop machine called the GeneXpert MTB/RIF that in less than two hours simultaneously detects Mycobacterium tuberculosis and tests for drug resistance have stimulated tremendous enthusiasm . Is this the breakthrough that TB control has been waiting for?

The GeneXpert MTB/RIF Test

The MTB/RIF test offers a potential solution for improving TB diagnosis . Molecular testing enables speed, and the MTB/RIF test is feasible for use in peripheral labs and clinics by unskilled personnel . In two multi-centre studies, a single MTB/RIF test detected almost all smear-positive TB patients and about three-quarters of the smear-negative TB patients whilst concurrently testing for rifampicin resistance, thus identifying patients who need second-line drug treatment . By enabling TB diagnosis and drug resistance testing almost anywhere without requiring the specialised laboratories and technicians needed for other rapid tests  this new MTB/RIF test has the capacity to be a “game-changer” in TB diagnosis.

What about Accuracy?

The MTB/RIF test enables TB detection and rifampicin resistance testing near the point of care, facilitating rapid screening for TB and drug resistance. However, the accuracy issues described above suggest that access to confirmatory culture-based testing will still be required in many settings. Rifampicin-resistant TB is usually MDRTB and always requires second-line drug therapy, so this has immediate treatment implications. Patients found by the MTB/RIF test to have rifampicin-resistant TB still require specialist laboratory facilities for more extensive drug resistance testing. Paradoxically, the benefit of MTB/RIF test implementation through identifying more rifampicin-resistant TB is likely to actually increase the demand for specialist reference laboratories to indicate how those patients infected with rifampicin-resistant TB should be treated.

Limitations of the Test

The MTB/RIF test is a major advance in TB diagnostic testing, but has limitations, including the limited shelf-life of the diagnostic cartridges, some operating temperature and humidity restrictions, requirement for electricity supply, unknown long-term robustness, and the need for annual servicing and calibration of each machine. Laboratories in low-income countries are littered with expensive equipment that no longer functions because it was inappropriate to the setting to which it was donated. Ensuring sustainable systems for long-term provision of servicing and consumables may be more important and challenging than initial implementation of the diagnostic equipment itself.

Impact in Low and Middle Income Settings

While effectiveness analysis and feasibility studies are necessary, they are poor surrogates for predicting the impact of the MTB/RIF test in programmatic use . More broadly, lab-based accuracy data are not sufficient to judge the contribution of new diagnostic tools for case finding, treatment, cure, and ultimately TB control. Despite numerous microbiological studies of improved TB diagnostic technologies, we remain remarkably ignorant of how best to implement better tests to improve patient care, of who should receive the limited capacity for better tests to maximise health impact, of how these tests may impact patient-relevant outcomes, and of how these issues vary between settings . The impact of better diagnostic tests on the equity of care is largely unstudied and we don't know yet how this novel technology will affect the delays and costs faced by patients in their journey towards a cure for this archetypal disease of poverty.

The Ongoing Toll of Drug Resistance

TB drug resistance prevalence is increasing , and of the estimated 500,000 people annually who develop MDRTB, less than 7% are diagnosed and only one in five of these receive effective treatment . The introduction of a new diagnostic test, no matter how good, doesn't necessarily imply clinical benefit because better TB tests only lead to better health if populations can afford to access them and act effectively upon their results. Indeed, studies frequently report success diagnosing MDRTB and XDRTB cases that then remain untreated  despite the demonstrated achievability of effective MDRTB care . Clearly, the current widespread failure to adequately manage the great majority of the MDRTB that is already diagnosed is no justification for failing to diagnose the rest. To be sure, increasing universal rapid MDRTB diagnosis is important for meeting the human rights and public health needs for universal access to MDRTB treatment and the MTB/RIF test has the capacity to greatly facilitate this process. However, six-months curative treatment for a TB patient costs a few tens to a few hundreds of dollars, but MDRTB treatment costs ten to a hundred times more, several thousands of dollars .Thus, in many settings, the costs of MTB/RIF testing are likely to be dwarfed by the cost of treating the drug-resistant TB that it will diagnose.

Furthermore, MDRTB management requires skills and specialist drug supply.  Consequently, the greatest challenges concerning MTB/RIF screening of new TB patients for drug resistance will likely be to ensure rapidly expanded capacity to manage drug-resistant TB. The early diagnosis of drug-resistant TB can be cost-effective , but risk factors for TB drug resistance have poor predictive value, especially in high-prevalence settings , so universal drug resistance testing of all new TB patients by the MTB/RIF or other rapid tests is a priority in many settings. Despite these challenges, the global public health community will be wise to take the opportunity offered by rapid MDRTB tests, including the MTB/RIF test, to urgently invest in preventing the global increase in drug-resistant TB.

An important limitation of the MTB/RIF test is its cost, which may be prohibitive for a disease that principally affects poor people in poor communities . With tiered pricing for low-income countries, each MTB/RIF test machine currently costs US$17,000–$62,000. More importantly, each disposable test-cartridge costs US$17–$120 , which is comparable with the per capita annual health expenditure in the countries with the highest TB burdens. Although much more expensive than smear microscopy, affordability varies greatly between settings, these costs are expected to fall, and they appear to be comparable with the total costs of providing other rapid TB tests . Furthermore, experiences with HIV viral load and CD4 cell counting tests have demonstrated that advocacy can convince donors to fund the rapid implementation of relatively expensive diagnostic technologies when needs and benefits are clear, and the MTB/RIF test may be such a test. Thus, costliness may not prevent the roll-out of this test to the limited numbers of TB patients requiring drug resistance testing, but may severely restrict the availability of this assay for the much larger numbers of people needing testing for suspected TB. Despite the fact that funding for TB control in high-burden countries has more than doubled between 2002 and 2009, large funding gaps remain, and many countries are currently struggling to sustain basic diagnostic and treatment services.

The MTB/RIF test should make rapid drug resistance testing more widely achievable and, in selected groups, may strengthen TB case finding. Its impact will inevitably be limited by its expense, but it may be cost-effective and useful for rapidly screening TB patients for drug resistance if funding for increased MDR TB treatment also becomes available.

Whilst this advance should be celebrated and funding for it should be prioritised, this must be viewed within the shameful context that almost 2 million people die each year from TB, and very few of them would have been saved by any diagnostic test.

Specifically, these deaths occur in mainly HIV-negative people, almost all of whom die from drug-susceptible TB, principally because of the inadequacy of basic, inexpensive health care provision for this curable infectious disease.

Funding should be identified to make the MTB/RIF test available in suitable settings, but the current financial crisis coupled with the huge unmet needs in other health areas will make the competition for resources even more intense .

This new test must not divert resources from preventive efforts and well-established TB diagnostic and treatment systems that already have the potential to have considerable impact upon TB morbidity and mortality.

TB control programs have “averted millions of deaths, but their effects on TB transmission and incidence rates are not yet widely detectable”  Poverty and social factors remain the principal determinants of global TB rates, not TB control efforts  There is increasing consensus that tools such as the new MTB/RIF test must be integrated with interventions that address the socioeconomic determinants of TB if they are to help current achievements in TB care to result in TB control.

Dr.Javeed Kakroo,  Microbiologist Certified infection control Auditor Kidney Hospital, Srinagar

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