Diagnosis, a weak link in global tuberculosis control – an interview with Madhukar Pai

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Tuberculosis (TB) kills more people today than HIV and malaria combined. In 2015, there were an estimated 10.4 million new TB cases worldwide and 1.8 million TB deaths. Case detection remains a huge stumbling block – of the 10.4 million new cases, the WHO estimate that only 6.1 million were detected and officially notified. This left a gap of 4.3 million cases that are considered ‘missing’ – either not diagnosed, or not notified to TB control programs.
In this interview, featured on Infectious Diseases Hub to mark World TB Day, Professor Madhukar Pai, Director of McGill Global Health Programs and Associate Director of McGill International Tuberculosis Centre (Montreal, Canada), provides insights into the case-detection problem and highlights potential solutions.
Could challenges in case detection prevent us meeting TB elimination goals? Discover more below.

First, could you introduce yourself and tell us a bit about your career to date?

I was born and raised in India. After completing my residency training in India, I did my PhD in epidemiology at University of California at Berkeley (CA, USA), and a postdoc fellowship at University of California San Francisco (CA USA). In 2006, I joined McGill University as an Assistant Professor, where I received early tenure in 2011. In 2013, I became the Associate Director of the McGill International TB Centre, and in 2014, I became the Director of McGill Global Health Programs. In 2015, I was promoted to full Professor, with a Canada Research Chair in Epidemiology and Global Health.

Could you describe the work currently being carried out by your research group at McGill University?

My research program is focused on improving the diagnosis and treatment of TB, especially in high-burden countries like India and South Africa. We do a lot of work in the area of TB diagnostics, including validation of new tools, synthesis of evidence on diagnostics, supporting the development of policies and work to improve access to good TB tests.

For example, in India, we partnered with the Clinton Foundation and the Bill & Melinda Gates Foundation to create the ‘Initiative for Promoting Affordable and Quality TB Tests’ (IPAQT). The Initiative aimed  to make WHO-approved TB tests 30–50% more affordable than market prices so they could reach more patients. Thanks to this unique initiative, over 142 private laboratories are engaged, and nearly 500,000 patients have received WHO-approved TB tests.

“We helped establish national and international standards for TB care and set benchmarks for quality TB care.”

We helped establish national and international standards for TB care and set benchmarks for quality TB care. Moreover, we developed a novel method for measuring TB care using simulated (mystery) patients. Insights from this work helped uncover that private providers in India underutilize TB tests, even when simulated patients present with typical TB symptoms; and highlighted a big gap between what doctors know about TB versus what they actually do in real practice. This approach is now being adopted by other countries.

Why is research on TB diagnostics an area of unmet need?

The global TB community has been fighting a protracted battle with antiquated, inefficient tools. For example, the most commonly used TB test, sputum smear microscopy, dates back to 1882 when Robert Koch first demonstrated the bacteria under a microscope.

Sadly, a vast majority of patients in high-TB burden countries are still diagnosed with this old technology, and a majority of TB patients are treated without any knowledge of the drug susceptibility results. This is in contrast with diseases like HIV and malaria, where there are excellent rapid tests that can be performed at the lowest levels of the healthcare system. Without better diagnostics, we cannot reach the missing 4.3 million patients who are either undiagnosed, or not notified.

“Without better diagnostics, we cannot reach the missing 4.3 million patients who are either undiagnosed, or not notified.”

Drug resistance is a major challenge in the control of TB – how can accurate diagnostics help us to tackle drug-resistant TB?

In many countries, only a quarter of patients with multidrug-resistant TB are detected, and not even half of all patients with drug-resistant TB are on second-line drug therapy. While highly accurate and rapid molecular tests such as Xpert MTB/RIF are now available to quickly detect TB as well as drug resistance, most high-burden countries are still reliant on sputum smear microscopy – a technology that is incapable of detecting drug resistance. This means patients are often managed with no information on drug-susceptibility test results.

The End TB Strategy, set out by the WHO, requires countries to routinely test all TB patients for drug-resistance. To reach this goal, we need better diagnostics to rapidly detect drug resistance, and available drug susceptibility tools like Xpert MTB/RIF, line probe assays and liquid cultures must be scaled-up to reach more patients.

There are diagnostics currently under development for TB – what is your assessment of new diagnostics currently in the pipeline? Are there any that you feel particularly optimistic about?

The development and roll-out of Xpert MTB/RIF by Cepheid (CA, USA) has been the biggest advance in TB detection. Cumulatively, since the launch of the Xpert MTB/RIF assay in 2010, over 6500 GeneXpert machines and 23 million Xpert MTB/RIF cartridges had been procured in the public sector in 130 of the 145 countries eligible for concessional pricing (as of 31 December 2016). Owing to this success, several companies are now engaged in TB diagnostics development.

“Among the tools in the pipeline, I am most optimistic about emerging rapid, robust, point-of-care molecular tests (e.g., GeneXpert Omni system by Cepheid; TrueNat by Molbio, India; EasyNAT by Ustar, China) that are designed for primary care settings. “

Among the tools in the pipeline, I am most optimistic about emerging rapid, robust, point-of-care molecular tests (e.g., GeneXpert Omni system by Cepheid; TrueNat by Molbio, India; EasyNAT by Ustar, China) that are designed for primary care settings. I would like to see them validated in the field for policy endorsement and roll-out.

I am concerned about the relative absence of non-sputum-based diagnostics in the pipeline. TB researchers are also searching for a biomarker-based test that can help identify latently infected individuals who are at the highest risk of developing active TB. Increased investments are necessary to support biomarker discovery, validation and translation into clinical tools.

Do you think the emergence of next-generation sequencing (NGS) is a promising tool for diagnosing and monitoring TB?

NGS is getting easier and cheaper, and the technological landscape is rapidly evolving. While it is exciting, I think NGS will find its value in rapid detection of drug resistance, rather than diagnosis or monitoring. To realize the clinical potential of NGS, several obstacles must first be overcome. These include direct application on clinical samples, reducing the turnaround time to results, accuracy of predicting phenotypic resistance, and resources requirements (cost, ability to be performed outside of reference laboratories, technical skill, ease of bioinformatics, etc.). I think these challenges are solvable, but need effort, partnerships and resources.

You helped create the Global Health Diagnostics Online platform – what do you hope this project will bring to the field of TB diagnostics?

“Despite recent investments in global health diagnostics, the potential for diagnostics to generate value for patients and health systems has not been met across all settings.”

Despite recent investments in global health diagnostics, the potential for diagnostics to generate value for patients and health systems has not been met across all settings. This is particularly true in low- and middle-income countries where disease burdens are high and diagnosis remains a big gap in care.

To address these challenges, Global Health Delivery online just launched a new Global Health Diagnostics community sponsored by FIND (Geneva, Switzerland), McGill Global Health Programs and McGill International TB Centre, with support from the Bill & Melinda Gates Foundation. In this community, we have over 700 professionals ranging from clinicians, policy-makers, researchers, implementers and advocates, sharing questions, successes and lessons learned to advance the field of global health diagnostics.

I am hoping the TB field will benefit from this platform. For example, one of the ongoing discussions in this community is the WHO’s proposal to create an Essential Diagnostics List. I am convinced TB will gain a lot if critical TB tests are included in the Essential Diagnostics List. This will help countries prioritize better, invest in diagnostics, streamline procurement and supply chain, and make good tests more affordable and accessible.

Looking forward, do you feel we’re on track to end the global TB epidemic by 2035, as per the End TB Strategy, and what do you think would help bring this about faster?

“Because case detection is such a big problem, I worry we will not meet the End TB Strategy goals, unless we dramatically improve diagnosis.”

Because case detection is such a big problem, I worry we will not meet the End TB Strategy goals, unless we dramatically improve diagnosis. While transformative tools are being developed, high-burden countries will need to improve the efficiency of their healthcare delivery systems, ensure better uptake of new technologies and achieve greater linkages across the TB care continuum. While we wait for next-generation technologies, national TB programs must scale-up the best diagnostics currently available, and use implementation science to get the maximum impact.

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Acknowledgments/Disclosures

Dr Pai does not have any financial or industry conflicts to disclose. He serves as a Consultant to the Bill & Melinda Gates Foundation. He serves on the Strategic and Technical Advisory Group for Tuberculosis (STAG-TB) committee of WHO, Geneva, Switzerland; Scientific Advisory Committee of FIND; and Access Advisory Committee of TB Alliance, New York (NY, USA).

Further reading (free access papers only)

  1. Pai M, Schito M. Tuberculosis diagnostics in 2015: landscape, priorities, needs, and prospects. J Infect Dis. 211(S2), S21–28 (2015)
  2. Pai M, Behr M, Dowdy D, et al. Tuberculosis. Rev. Dis. Primers. 2, 1–23 (2016).
  3. Pai M, Nicol MP, Boehme CC. Tuberculosis diagnostics: state of the art and future directions. Spectrum 4(5), TBTB2-0019-2016. (2016)
  4. Pai M, Weintraub R. Creating a community to advance global health diagnostics. Huffington Post Canada, 22 February, 2017.

Biography/Headshot

Prof Madhukar Pai, MD, PhD is a Canada Research Chair in Translational Epidemiology & Global Health at McGill University, Montreal. He is the Director of McGill Global Health Programs, and Associate Director of the McGill International TB Centre. Dr Pai did his medical training and community medicine residency in Vellore, India. He completed his PhD in epidemiology at University of California Berkeley, and a postdoctoral fellowship at the University of California San Francisco.

Dr Pai serves as a Consultant to the Bill & Melinda Gates Foundation. He serves on the STAG-TB committee of WHO, Geneva; Scientific Advisory Committee of FIND, Geneva; and Access Advisory Committee of TB Alliance, New York. He is on the editorial boards of Lancet Infectious Diseases, PLoS Medicine and eLife among others.

Dr Pai’s research is mainly focused on improving the diagnosis and treatment of tuberculosis, especially in high-burden countries like India and South Africa. His research is supported by grant funding from the Gates Foundation, Grand Challenges Canada, and Canadian Institutes of Health Research. He has more than 300 publications. He is recipient of the Union Scientific Prize, Chanchlani Global Health Research Award, and Haile T. Debas Prize. He is a member of the Royal Society of Canada.

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