Despite being treatable, TB remains a major global public health problem. As Dr Mario Raviglione, Director Global Tuberculosis Programme of WHO, informed, in 2013, 9 million people fell ill with TB in; 1.5 million men, women and children died from it; 480,000 people developed multi drug resistant TB (MDR-TB), with 210,000 associated deaths. Also, 60% of all MDR-TB cases can be attributed to India, China, Russia, Pakistan and Ukraine.
With an estimated 26% of the global TB cases, India holds the dubious distinction of having the highest incidence of drug sensitive TB and multi MDR-TB cases globally. In 2014, an estimated 61000 MDR-TB cases were notified under the government’s Revised National TB Control programme (RNTCP) with another approximately 30000 cases in the private sector.
Early and improved case detection of TB, including MDR-TB, is therefore one of the global priorities for TB control. A recent multi centric demonstration study titled ‘Use of Xpert MTB/RIF in Decentralized Public Health Settings and Its Effect on Pulmonary TB and DR-TB Case Finding in India’, assessed the impact of up-front Xpert MTB/RIF (the first automated molecular test for diagnosing pulmonary TB and rifampicin-resistant pulmonary TB) testing in India.
Dr KS Sachdeva, Additional Deputy Director General, Central TB Division Ministry of Health & Family Welfare, Government of India, and lead author of the study informed that the key aim of this pilot study was to have an impact assessment of upfront testing for all TB presumptive cases, including those of MDR-TB, with Xpert MTB/RIF (instead of smear microscopy). The study was done at 18 decentralized Xpert MTB/RIF laboratories established at existing public sector microscopy centres in diverse geographic and demographic settings (8 in rural, 6 in urban and 4 in hard to reach tribal and hilly areas) covering a population of 8.8 million. A baseline phase in 14 centres captured programmatic baseline data, and an intervention phase in 18 centres offered Xpert MTB/RIF to all presumptive TB patients.
Results of the study
The study data shows that upfront Xpert MTB/RIF testing resulted in:
(i) An increment of 6-7% on TB detection rates-- baseline phase that tested on microscopy, showed a positivity of around 14%, whereas intervention phase that tested by Xpert showed a positivity of more than 20%. Thus an additional 7% were diagnosed due to Xpert.
(ii) An overall increase of 11% in TB case notification for all forms of pulmonary TB and an increase of 39% for bacteriologically confirmed TB cases.
(iii) A five-fold increase in Rifampicin resistant TB case detection
(iv) More than two fold increase in detection rates in PLHIV and in pediatric population
Also, nearly 33% of Rifampicin resistant TB cases were detected among Xpert MTB/RIF positive TB cases with no prior history of TB treatment.
Current diagnostic practice in India
When a patient presents with symptoms of pulmonary TB, sputum smear microscopy is the first point of care test performed to diagnose drug sensitive TB (smear microscopy cannot detect resistance). If the patient is smear-negative, subsequent diagnosis is based on repeated microscopy, radiology, and clinical judgment. On being tested positive, a 6 month treatment regimen for drug sensitive TB is initiated. A failed treatment results in a re treatment regimen for another 8 months, but drug resistance is still not tested. If treatment fails again, then test for drug resistance is done and patient is finally put on MDR-TB treatment after a delay of more than one year. Till recently, the only option available for Drug Susceptibility Test (DST) was, and still is in most cases, the solid culture test (and in some cases liquid culture) that takes around 4 months to give results.
Dr Sarabjit Chadha, Project Director, International Union Against TB and Lung Disease (The Union) lists some consequences of late diagnosis of MDR-TB: ‘Patient is given inappropriate treatment which prolongs avoidable suffering and morbidity; enhances severity of disease (and so increases mortality), especially if there are co-morbidities like HIV and diabetes; amplifies drug resistance, making it more difficult to treat the disease; and transmission to others continues thus spreading the disease. Apart from having an adverse affect on the patient’s mental health, it could also lead to treatment interruption.’
Most of these problems can be avoided if diagnosis of MDR-TB is made early and appropriate treatment given without delay, feels Dr Chadha. Newer rapid molecular diagnostic tests like, Xpert MTB/RIF and line probe assay (LPA), offer a solution to this problem. XpertMTB/RIF is an automated system that gives the results in less than 2 hours and can diagnose both TB and Rifampicin resistance. It does not require any laboratory or skilled human power.
The way forward
Realizing the huge impact of extending universal DST to all presumptive TB cases under routine programme conditions in improving case findings of TB as well as rifampicin-resistant TB, and thus helping India reach the goal of ending TB by diagnosing MDR-TB early on, Dr Chadha informs that: RNTCP has an ambitious plan for Universal DST for all TB cases by 2019—all TB cases tests for drug resistance at time of 1st diagnosis and all MDR-TB cases tested for second line drug testing.
It aims to (i) set up 120 culture and DST labs and 950 CBNAAT (Xpert or similar technology)—India currently has 69 labs with culture and DST facilities; 50 labs with Line Probe Assay (LPA) and 89 Xpert MTB/RIF (molecular diagnostic) sites; (ii) perform over 1 million DST annually and provide testing for second line drug resistance; (iii) Provide treatment to all those diagnosed with MDR-TB (at least 60,000 cases annually); (iv) Increase treatment outcomes from the current 50% to 65%.
Of course, the high cost of Xpert machine, at USD 20,000 and cost per test at USD 10, could be a stumbling block in achieving these targets. Moreover, diagnosing more people with MDR-TB at the 1st point of care will have to be matched with enhanced treatment capacity, because, as Dr Ravilgione has rightly said-- It is not ethical to diagnose and not treat.
Other challenges include ensuring treatment adherence by providing psycho/social/economic support and putting proper infection control methods in place, so that we not only treat drug sensitive and MDR-TB well but also prevent the spread of infection. Moreover, as Dr Chadha informs, there are no automated tests, like Xpert, for diagnosing resistance to 2nd line drugs, which is currently done by liquid culture that requires accredited labs and trained personnel.
One needs to do a cost benefit assessment to see what is a better option from public health point of view—short term savings on costs by going the conventional way and leaving MDR-TB patients undiagnosed and put on unappropriate treatment for a long period (thus not only playing with their lives but also increasing transmission to others); or nipping the problem in the bud by quickly and correctly diagnosing MDR-TB through the use of newer tools (like Xpert MTB/RIF and LPA) and then treating it- thus preventing spread of the disease and helping to realize the global dream of ending TB.
Dr Tim France, Managing Director, Inis Communication and a global health commentator, hits the nail on the wall--“Ending TB in India and elsewhere is possible only when we diagnose TB early; characterize the drug sensitivity of each case; treat the person with drugs that are most likely to work and address other issues, like help support the patient for treatment adherence, as well. Treating with drugs that do not work is not only dangerous for the individual patient, but also for broader public health as it may increase drug resistance”.
And as Dr Sachdeva said: “Decentralized deployment of Xpert could possibly help RNTCP achieve ‘early and complete’ detection of all TB and MDR-TB cases.” This will also be critical to implementing and achieving WHO’s End TB Strategy based upon the 3 pillars of (i) integrated, patient-centred care and prevention, (ii) bold policies and supportive systems, and (iii) intensified research and innovation.”