The TB battle: How well are we fighting the bug?
[Nature India Special Volume: Biotechnology — An agent for sustainable socio-economic transformation]
doi:10.1038/nindia.2016.29 Published online 29 February 2016
The year 2015 is a milestone year in the worldwide war against TB — it is the last year of the Stop TB Strategy before adoption of the 20-year End TB Strategy, whose goal is to end the global TB epidemic by the year 20351. In the Indian context, this is certainly a daunting task, considering that India figures in WHO’s three new High Burden Country Lists for TB, TB/HIV and MDR-TB.
India’s fight against TB control was initiated in 1906 with the establishment of the Mary Wilson TB sanatorium in Tilaunia, Rajasthan. Treatment modalities changed with the advent of chemotherapy and evolved over close to 90 years into the present day DOTS treatment strategy that is incorporated into the Revised National TB Control Programme (RNTCP)2. The RNTCP covered the entire country by 2006. Yet, India has the world’s largest number of TB cases at 23% of the global total. Although lakhs of lives are saved, both the annual mortality (due to TB) and incidence rate remain very high at over 200,000 and 167 cases per 100,000 population, respectively3. It is now evident more than ever before that the battle against TB is to be fought on several fronts and extends beyond implementation of biomedical strategies. A multi-pronged and accelerated approach with enhanced resources is necessary to meet the targets of the End TB Strategy, namely to reduce TB deaths by 95% and bring down new cases by 90% till 2035.
Knowing the enemy: the TB conundrum
Our current appreciation of the complex challenges in TB control stems from a rich legacy of public health experiences and research that commenced with Robert Koch’s discovery of the TB bug in 1882. It became evident that a cocktail of eminently suitable for rapid spread of the bug. Subsequent to acquiring an infection, two alternative outcomes are possible, namely frank disease or latent infection, reflecting the remarkable plasticity of interaction between human host and TB pathogen. A robust immunity is associated with bacterial adaptation to a dormant quiescent state, often leading to a lifelong latent infection. However, when a lowering of immunity occurs, reactivation of the disease takes place.
According to WHO estimates, one-third of the world’s population and 40% of India’s population play host to the TB bacillus as a latent TB infection, highlighting the magnitude of the problem in high burden countries. Thus, it stands to reason that eradication of latent infection holds the key to TB elimination. Also, despite the availability of anti-TB drugs, the long duration of treatment is often associated with poor compliance resulting in incomplete cures and the development and spread of drug resistance. This emphases the need to shorten treatment duration. Moreover, persistent organisms are poorly cleared by standard therapy, underscoring the requirement for new drugs that target persistent/dormant bacteria.
Other factors also fuel the TB epidemic and lead to the progression of a latent TB infection to active disease. These include malnutrition, lowered immunity (e.g. as in HIV infection, ageing, diabetes, smoking and silicosis), environmental factors (e.g. indoor air pollution, inadequate ventilation), and socio-economic conditions like poverty, urbanisation and overcrowding. Thus, while diagnosis and treatment are undoubtedly the cornerstones of TB control by the medical approach, social, sanitation and public health interventions, along with improved standards of diet and living can contribute significantly to the decline of TB, as documented in records from the pre-chemotherapy era4.
In recognition of the enormous scale and complexity of this public health problem and towards ending the global TB epidemic by 2035 (less than 10 cases per 100,000 persons per year), the End TB Strategy of WHO proposes a three-pillared integrated approach. It includes providing patient-centred care and prevention, combining universal health coverage policy and social protection, and intensified research for discovery of new tools, interventions and strategies and their rapid implementation. In this context, it is heartening that many leads generated by TB researchers in India have the potential to be translated into useful tools towards fulfilling the mandate of the End TB Strategy.
Biomedical tools, interventions and strategies for TB control
Pillar 3 of the WHO End TB Strategy recognises the need for intensified research to achieve the goal of ending the global TB epidemic. Priority R&D areas include understanding pathogenesis and immunity, developing PoC diagnostic tests including triage test and one for latent TB, vaccines that protect people of all ages against TB, new therapeutics and novel regimens to combat the challenges of drug resistance, to shorten treatment and to cure LTBI, and importantly, implementing research to facilitate the adoption of new tools by the control programmes. Significant progress has been made, and several useful tools are in the pipeline and in various stages of testing5. A boost in research funds by closing funding gaps and clear pathways for translation are immediate needs for development and rapid uptake of new tools.
Early contributions to TB control from India
Landmark studies from India have made lasting contributions to the development of TB control strategies worldwide. Indian studies demonstrated for the first time the efficacy of chemotherapy in a domiciliary setting in lieu of sanatoria-based treatment. This finding revolutionised the outlook towards TB treatment and enabled the formulation of the DOTS programme used worldwide. The utility of microscopy for case finding and the efficacy of Short Course Chemotherapy, with drugs administered on an intermittent basis were also first demonstrated in India.
Another notable contribution was in the area of vaccine efficacy analysis. The efficacy of the mass BCG campaign started from 1951 was questioned when the results of a meticulously designed BCG vaccine clinical trial in Chingleput district, Tamil Nadu were decoded in 1980, revealing that the vaccine did not offer protection against pulmonary TB. Following extensive review, the mass BCG campaign was dropped but continued in children to afford protection against serious childhood forms of TB. The three national TB institutes play a pivotal role in various aspects of TB control such as programme development, training and capacity building, developing laboratory tools, providing quality assurance, assessing disease burden, monitoring of the programme and influencing TB control policies2, 6.
Research in the post-genomic era
Research contributions from a large number of Indian groups over recent years, particularly since the TB genome was decoded, have greatly enhanced our understanding of biochemical, physiological and metabolic processes in the tubercle bacillus.
Noteworthy contributions have been made in many areas including DNA replication, transcription, translation and recombination processes and mechanisms, deciphering of gene regulatory, redox and metabolic control strategies, lipid and polyphosphate metabolism, bacterial adaptation to stresses and signalling mechanisms, molecular basis of host-pathogen interactions and the strategies used by both to subvert each other, dormancy and biofilm models to study bacterial adaptation, immune signalling mechanisms, systems biology and molecular genetic approaches to identify novel drug targets and mechanisms of drug resistance, and also identification of host factors as novel intervention targets against TB.
Structures have been elucidated for a large number of TB proteins. These span almost all the pathway categories and offer ample opportunities for rational drug design to fight the TB bug. These efforts are summarised in comprehensive publications7, 8, 9.
Lasting contributions made by Indian biomedical scientists in formulating control strategies in previous years were possible due to concerted efforts by all stakeholders in an environment of commitment and urgency to mitigate the TB public health problem. Several decades later and despite programmatic efforts, TB remains a public health challenge, and not surprisingly, the End TB Strategy calls for an integrated approach that encompasses biomedical, public health and social measures. Original leads have been generated in laboratories through funding support of various agencies. Many of these have the potential for progressing to novel tools for TB control.
Sustained effort on the part of researchers, combined with the assured commitment of funding agencies including biosafety laboratory support, will be needed to fulfil the target. In addition, a clear pathway is needed to guide tool-specific translation of laboratory findings, including interactions with the RNTCP and national TB laboratories. Several Indian institutions and Industries are actively engaged in developing these tools. More efforts are required to make an impact. And it is urgent because the development and adoption of new tools and interventions constitute an essential pillar of the End TB Strategy, without which the goal of ending the TB epidemic is likely to remain a mission impossible.
* The author is from the Department of Biotechnology, All India Institute of Medical Sciences, New Delhi-110029, India.