Interest in tuberculosis research is high, but a quantum leap in funding must follow.
doi:10.1038/nindia.2018.54 Published online 30 April 2018
It is heartening to note the heightened political interest and engagement on TB in the past year. What started at the Berlin G20 meeting was followed by the Moscow Declaration to End TB: a promise to increase multisectoral action as well as track progress, and build accountability. The first UN General Assembly High-Level Meeting on TB in September 2018 will seek further commitment from heads of state, which some, like the Prime Minister of India, have already made. At the recent End TB Summit in Delhi, PM Modi announced an ambitious plan to eliminate TB, with a slew of new interventions, including a social support scheme for all TB patients.
Modi also pointed out that the fight against TB must start in communities, villages and towns — a true people’s movement.
The World Health Organization’s End TB Strategy adopted by all member states in May 2014 aims to reduce TB deaths globally by 95%, and to cut new cases by 90% between 2015 and 2035, and to ensure that no family is burdened with catastrophic expenses due to the disease.
Tuberculosis still kills more people than any other infectious disease and the growing burden of multidrug resistant (MDR) TB is a challenge. Seven countries account for 64% of the total burden. India leads the count, followed by Indonesia, China, Philippines, Pakistan, Nigeria, and South Africa. In fact, India accounts for a quarter of the world’s TB cases and a third of its deaths. For the year 2015, the updated estimate of incidence (new and relapse TB cases per year) is 2.8 million cases, of which the RNTCP diagnosed and notified 1.7 million incident TB patients, leaving approximately 1.1 million presumptive patients whose fate was unknown. The 2015 estimate of the number of TB deaths is 478 000 — making it one of the leading causes of death in India. Of the estimated 79,000 cases of multidrug resistant (MDR) TB, about 31,000 were diagnosed and the majority put on treatment, leaving a large number of patients undetected with the possibility of further transmission.
While the disease is caused by a bacterium Mycobacterium tuberculosis, socio-economic determinants are important and the incidence rate of TB among people in the lowest socioeconomic quintile is at least three times higher than those in the highest quintile. A recent systematic review found that the total cost of TB for patients and affected families on average represented more than half their yearly income. Major drivers of TB in Asia include poverty, overcrowding and under-nutrition, while HIV is the main risk factor in sub-Saharan Africa. Other risk factors include diabetes, smoking and exposure to indoor air pollution, and alcohol consumption.
In Europe, TB rates began to decline in the 1920’s, well before any effective vaccine or drug was available, mainly due to living standards improvements.
Tuberculosis infects people mostly via the respiratory route and establishes a nidus of infection, where the organism can survive in a dormant or latent form for many years or decades. An imbalance in the immune control system allows the infection to progress to active disease and the infection progresses faster and is more severe/ widespread in young infants and children, those with HIV infection and other immunosuppressive conditions.
There have been great advances in genomics, proteomics and immunology in recent years, but major gaps remain in understanding of pathogenesis of some forms of TB. There is much to learn about the interaction between mycobacterial lineage and host genetics, determinants of virulence and transmission, biomarkers that can predict progression from latent to active disease and correlates of protective immunity. This has slowed down the development of a newer, more effective vaccine for TB, as well as tests that can easily identify individuals most at risk of disease progression who could be targeted for treatment of latent infection. Ultimately, for elimination, latent TB treatment would have to be scaled up, in addition to identification and treatment of active cases.
Major challenges in India include the disparity of treatment providers, many of whom do not follow standard diagnostic or treatment algorithms, the lack of awareness about TB symptoms, and the fact that free diagnosis and treatment are available at government health centres, causing stigma which prevents people from seeking care.
“The total cost of TB for patients and families represents half their annual income.”
The National Strategic Plan 2017- 2025 addresses many of these challenges and provides cash incentives for TB patients who are regular with therapy as well as for physicians who report TB. A national prevalence survey is planned in 2018 to provide a baseline prevalence rate — ideally, complete notification of TB by private and public providers will negate the need for such surveys and enable the programme to monitor progress.
After relying on sputum smear microscopy for diagnosis for more than a hundred years, a cartridge based nucleic acid amplification test has become the standard of care, enabling rapid diagnosis and detection of Rifampicin resistance simultaneously. There are more affordable diagnostics on the horizon, mainly from India and China, and it is now possible to imagine that every patient with suspected TB could have a molecular diagnostic test, with susceptibility testing for at least Rifampcin, even at a remote primary health centre, with no electricity or highly qualified staff.
After a gap of 40 years, there are now two new drugs to treat TB, though currently these are reserved for multidrug resistant cases. There is a small pipeline of novel molecules that must undergo further clinical development.
More data are likely to become available on the combination of Bedaquiline and Delamanid in treating extensively drug-resistant TB. In the case of TB, it is novel drug combinations (rather than individual drugs) that need to be tested for safety, efficacy, affordability and convenience. This will require the involvement of research institutes, pharmaceutical companies, regulatory agencies and funders, including middle-income countries. The paradigm of drug development needs to be different for diseases like TB, which predominantly affect the poor and do not have a market in the West.
Research to identify specific immune cell core regulatory pathway disruptions caused by pathogens must be increased to efficiently develop new host directed therapies for treatment and prevention. Already, some host directed therapies like the antidiabetic drug, Metformin, and leukotriene antagonists are being tested as adjunct therapies. There needs to be a quantum increase in investment in research in TB — right from basic science to better understand biology and transmission dynamics, to translational research on biomarkers, clinical trials of new drug combinations, and operational research to address blocks in programme delivery. The India TB Research Consortium was launched in 2017 by the Indian Council of Medical Research, in partnership with the Department of Biotechnology and other science ministries, international agencies, and WHO, to undertake translational research to develop and validate new tools (diagnostics, drug combinations and vaccines) needed to fulfill the TB elimination goals.
A national mission to end TB has been launched in India. A concerted effort by all stakeholders — government, private sector, and the patient community — is required, with regular surveillance. The ministry of health has developed a seven-year national strategic plan. Additional investments in research through the India TB Research Consortium will hopefully deliver new and better tools to prevent, detect and treat TB.
The author is deputy director-general of programmes, World Health Organization.
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