Tuberculosis continues to be a major health problem in India. But the unveiling of a new test to diagnose TB and drug resistance on World Tuberculosis Day (March 24) brings some hope into a bleak scenario.

Last Thursday, on World Tuberculosis Day, for the first time since the 1880s there was probably some justifiable cause for jubilation. After centuries of grappling with sputum smear microscopy, developed way back in the 1880s, there was finally a new test — a rapid one at that — available for the diagnosis of tuberculosis. And wait, it gets better; a single test to indicate drug resistance.

In his foreword to the TB India 2010 Status Report, Union Health Minister Ghulam Nabi Azad, said in 2009, the programme had reached the 70 per cent case detection and 85 per cent cure of new smear positive patients. “The ultimate goal of the programme remains a ‘TB-free India', with reduction of TB burden till it is no longer a major public health problem in India.” However, he acknowledged, that there was a long way to go to reach that goal.

Cent per cent detection

It is essential to reach a 100 per cent detection rate, emphasised Madhukar Pai, Assistant Professor, McGill University, Department of Epidemiology and Biostatistics. “Unless we are able to do that, we will not be able to cut off the epidemic's legs. Tuberculosis has suffered from a century of neglect. In terms of primary tools for diagnosis. The sputum smear microscopy test has remained unchanged for years.”

Though India's own drug-delivery model — the Directly Observed Treatment, Short Course (DOTS) strategy — was a huge success, there continued to be two million new cases in India, according to the WHO report. Why? “Clearly because the underlying problem has not been corrected: cases are not being diagnosed quickly or even correctly. By the time a patient is identified and put under treatment, he has infected a whole bunch of other people,” Dr. Pai explained.

The sputum smear microscopy test, most commonly used in public health settings to detect pulmonary TB, is reputed to have roughly 50 per cent chance of detection. Also, a significant number of people is outside the public health sector, where the most common test is the serological (blood) antibody test “that is expensive and means nothing,” according to Dr. Pai.

In fact, last September, the WHO Strategic and Technical Advisory Group for Tuberculosis actually made a “negative recommendation” for the use of serological tests for TB, in consideration of the ‘compelling evidence base and large body of work demonstrating the poor performance of commercial serodiagnostics and the adverse impact of misdiagnosis and wasted resources on patients and health services.”

New testing tool

It was in this scenario that Xpert MTB/RIF was sprung on the world. It is a simple two-hour test, which can be performed outside a lab setting, can simultaneously test for the TB bacillus and identify resistance to rifampicin, a key anti-tuberculosis drug.  Over 1,700 patients were screened at five sites across the world, including in Mumbai, using this PCR diagnostic kit developed through a partnership between Cepheid and Foundation for Innovative New Diagnostics (FIND), the University of Medicine and Dentistry of New Jersey, the Bill and Melinda Gates Foundation and the National Institutes of Health (U.S.).The study demonstrated high sensitivity and specificity, identifying 98 per cent of patients with TB and correctly identifying 98 per cent of bacteria resistant to rifampin. Results were impressive enough to elicit a dramatic recommendation from Mario Raviglione, Director of WHO's Stop TB department. “This new test represents a major milestone for global TB diagnosis and care. It also represents new hope for the millions of people who are at the highest risk of TB and drug-resistant disease.”

The WHO said its endorsement of the rapid test followed 18 months of rigorous assessment of its field effectiveness in the early diagnosis of TB, MDR-TB and TB complicated by HIV infection. It also released recommendations and guidance for countries to incorporate this test in their programmes.  Peter Small, senior programme officer, TB, Global Health Programme, Bill and Melinda Gates Foundation, and Dr. Pai, in the New England Journal of Medicine (NEJM) in September 2010 also recorded the promise this new ‘automated nucleic acid–amplification test that may allow a relatively unskilled health care worker to diagnose tuberculosis and detect resistance to a key antibiotic within 90 minutes' held for the world. The test was also easy to perform with minimal training, was not prone to cross-contamination, and required minimal bio-safety facilities.In a systematic review in the November 2010 Lancet Infectious Diseases issue, Jamie Rylance et al concluded that the test could revolutionise TB care and control by providing an accurate diagnosis for many patients in about 100 minutes, compared to current tests that can take up to three months to have results.

The biggest advantage of the test, if it were to be introduced in India, would be its ability to detect drug resistance at the first instance of testing for TB, according to pulmonologists. Under the current Revised National Tuberculosis Control Programme (RNTCP), there is no testing for drug resistance until the patient has had over six to 10 months of treatment, said Ramya Ananthakrishnan, medical director of REACH, Chennai-based NGO.

However, in order to know the prevalence of resistance among new cases and re-treatment cases, surveys were carried out in Gujarat and Maharashtra. According to the RNTCP Status Report, these surveys estimated the prevalence of MDR-TB to be less than three per cent in new cases and 14-17 per cent in re-treatment cases. In terms of sheer numbers, that could be staggering. In 2007, India topped the list of nations with high MDR TB cases, with 1,31,000 cases.

Dr. Ananthakrishnan added, “Any test that would identify drug resistance early is a boon. When patients develop drug resistance to TB, and remain untreated, they begin to spread these resistant strains of the bacillus, thereby infecting new patients with MDR TB.” The conventional culture test takes a minimum of six weeks to confirm resistance. Yet, she pointed out, the key issue is the costs involved in adopting such a tool, in a country where “everything is based on the sputum smear test for pulmonary TB. This means we have to invest heavily in new infrastructure though we have an established network of laboratories in place.”

P.R. Narayanan, former director of the ICMR institution in Chennai, Tuberculosis Research Centre (TRC) is very clear that there are going to be problems associated with the change. “The challenge is to make it available to those who need it.”

Affordability

Acknowledging that affordability has been a key concern in the assessment process, co-developer FIND announced that it has negotiated with manufacturer Cepheid, a 75 per cent reduction in the market price for countries most affected by TB. Preferential pricing will be granted to 116 low- and middle- income countries where TB is endemic, with additional reduction in price once there is significant volume of demand.

For Dr. Sowmya Swaminathan, co-ordinator, Research on Neglected Priorities, WHO, and Deputy Director, TRC, the technology seems very promising, but unless costs come down, access would be an issue. Monopoly production is also an issue: Currently, there is only manufacturer of the tool. She suggested that the technology transfer options be explored, especially for countries with a huge burden of the disease. On the lines of allowing Indian companies to manufacture anti-retro virals in order to bring down costs for the country.

The NEJM article was probably hinting at similar opportunities, when it said it was optimistic of the role of governments, product developers, and companies in emerging economies with high tuberculosis burdens, such as China, India, Brazil, and South Africa. “These countries now have the capacity to develop low-cost generic or novel assays adapted to local contexts and incorporate their scale-up in both national tuberculosis-control programs and private laboratories, supported by successful public–private partnerships.”

The RNTCP itself has acknowledged the need to look at newer and rapid technologies that would enhance the diagnostic capacity for MDR-TB and cut short the turnaround times. It also claimed to have initiated new projects to validate and demonstrate newer TB diagnostic technologies in collaboration with FIND, India.

As Dr. Swaminathan asked, “We have the science, the technology and the resources. What do we do to see a reduction in new cases in the next five years?” Perhaps, the answer to that would be a commitment towards deploying better technologies in a manner that would enable universal access.

Keywords: TuberculosisTB