Research Article: Reimagining the Research Approach to Tuberculosis†

Date Published: March 22, 2018

Publisher: The American Society of Tropical Medicine and Hygiene

Author(s): Anthony S. Fauci, Robert W. Eisinger.


Controlling and ultimately ending tuberculosis (TB) as a public health scourge will require a multifaceted and comprehensive approach involving the intensification of public health efforts, including scaling-up the delivery of current diagnostic, preventive, and therapeutic tools. However, a critically important element in the effort to end TB is an accelerated biomedical research effort to address the many unanswered questions about the disease process itself and to develop improved and innovative countermeasures. An intensive effort toward these research goals will facilitate the achievement of the aspirational goal of ending TB.

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More than 130 years after the discovery of Mtb as the etiologic agent of TB, we still know surprisingly little about the precise mechanisms of TB disease pathogenesis. Generations of research advances and technologies applied to other diseases have bypassed the field of TB research. Key questions remain unanswered, particularly regarding the complex interactions between the pathogen and the host. This gap in our knowledge will benefit greatly from interdisciplinary, systems biology approaches to TB pathogenesis that include computational and mathematical modeling of the complex biological interactions between pathogen and host. Such efforts will contribute greatly to enlightening the still opaque areas of maintenance of latency, escape from latency, disease activation, and correlates of immunity.15 In addition, key research challenges in pathogenesis must be addressed with regard to TB/HIV co-infection, including the factors associated with higher rates of progression to active TB and the accelerated course of HIV in coinfected individuals; different clinical/radiographic manifestations of pulmonary TB; and reduced immune control and a greater degree of extrapulmonary TB dissemination.16 Limitations of animal models of dual infection are also an impediment that must be addressed.

The GeneXpert MTB/rifampicin resistant diagnostic (Cepheid, Sunnyvale, CA) has been a welcome addition to the TB diagnostic armamentarium.2 However, there is still a need for improved and transformative TB diagnostics to overcome the severe limitations of antiquated, nonstandardized, and imprecise techniques which are used presently in most settings. In addition, the application of twenty first century diagnostic technologies that can detect Mtb in a variety of clinical specimens from multiple body sites in addition to sputum, as well as advanced approaches for monitoring and predicting treatment outcomes are a priority. If we can detect a single copy of HIV RNA in the blood of an HIV-infected individual and track disease progression with viral load testing, we should be able to develop a comparable diagnostic and disease monitoring capability for TB, as far-fetched as this might seem at present.

World Health Organization’s recent report Antibacterial Agents in Clinical Development: An Analysis of the Antibacterial Clinical Development Pipeline, including Tuberculosis noted the critical need for additional support for basic science on Mtb, drug discovery, and clinical development of better TB treatment strategies.20 Current treatment regimens recommended by WHO include up to four drugs for 6 months, but result in an insufficient ∼83% cure rate globally in newly diagnosed individuals. World Health Organization also has cited the desperate need for newer, non-toxic drugs and shorter regimens for treatment of MDR-TB because the current regimens include four to seven drugs for 9–20 months, with only a ∼54% cure rate globally.2

A safe and effective TB vaccine is urgently needed to protect against all forms of TB in adults and adolescents.25,26 Recent modeling exercises underscore that a new TB-preventive vaccine that is 60% efficacious and provided to 20% of adults and adolescents globally could avert ∼60–70 million cases in its first 25 years of use, and an infant vaccine could potentially avert 6–7 million new TB cases.26




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