Innovations in Tuberculosis Diagnostics: Progress and Translational Challenges

Abstract

Despite the long and hard battle against tuberculosis (TB), WHO estimated that 9 million people developed the disease in 2013, and nearly 1.5 million people died of TB (World Health Organization, 2014). To make matters worse, drug-resistance is a growing threat, and 3 out of 9 million TB cases are either not diagnosed, or not notified to TB control programs. But there is some good news from the perspective of new tool introduction. Slowly but surely, the landscape of TB technologies is changing (Pai and Schito, 2015). We now have a variety of new TB diagnostics, including rapid molecular tests (e.g. Xpert MTB/RIF, Cepheid Inc., USA) for detection as well as drug susceptibility testing (DST) (UNITAID, 2014). We also have new TB drugs (e.g. bedaquiline and delamanid) on the market, and new TB drug regimens are expected within the next 2–3 years. These are major, exciting developments in the fight against a very ancient scourge. This article reviews the current best diagnostic tools available for TB diagnosis and monitoring, and describes the most important gaps, and translational challenges for developing innovative products that can meet the needs (Table 1). Table 1 Unmet needs in TB diagnosis and monitoring. As shown in the Table, there are critical unmet needs that range from a simple, triage test for use in the community, to DST tools that can detect a range of mutations for several important drugs that will make up future drug regimens (Denkinger et al., 2015a, Denkinger et al., 2015b). For the next-generation DST tools, a big translational challenge is the paucity of good data on the correlation of mutations with phenotypic DST results and clinical outcomes and the association with cross-resistance (Solomon et al., 2015). This is particularly important to make sure that we have companion diagnostics for emerging TB drug regimens (Denkinger et al., 2015b). The translational challenges associated with DST are reviewed elsewhere (Solomon et al., 2015). For the development of rapid triage tests, non-sputum based tests for active TB, highly predictive LTBI tests, and an accurate test for cure, we need validated biomarkers. Although considerable efforts are being made to identify biomarkers that can meet some of these needs, progress has been slow, and the translational challenges have been reviewed elsewhere (Wallis et al., 2010). Increased investments are necessary to support biomarker discovery, validation, and translation into clinical tools. Unfortunately, a recent analysis of the TB R&D funding landscape by Treatment Action Group showed a big gap between investment needed and actual expenditure on R&D. Donors, governments, and members of the Stop TB Partnership will need to device creative strategies to plug this gap. While the TB diagnostics R&D space has managed to attract over 50 companies and product developers, they will require technical and funding support to overcome the translational challenges shown in Table 1. Organizations such as Foundation for Innovative New Diagnostics (FIND), Geneva, Bill and Melinda Gates Foundation, World Health Organization, UNITAID, Global Laboratory Initiative, Stop TB Partnership's New Diagnostics Working Group, Critical Path Institute, PATH, McGill International TB Centre, and several academic partners have worked together to produce several reports that are of great relevance, including a technology and market landscape report, a needs assessment study, a consensus report on target product profiles of highest priority, a series of market analyses, and a series of articles which outline the characteristics of the next-generation assays, and translational challenges for product development. All of these are available on a website (www.tbfaqs.org) created to provide answers to the most frequently asked questions by TB product developers. Hopefully, these collective efforts will result in a more robust pipeline of tools that can overcome the translational challenges, and push the agenda towards the goal of TB elimination.