Tuberculosis and Multidrug-resistant Tuberculosis: An overview

Tuberculosis (TB) is the world’s leading cause of death from an infectious agent. Today about 30,000 people will fall ill with tuberculosis, and 4,000 people will die from the disease. Tuberculosis usually affects the lungs, and is caused by the bacillus Mycobacterium tuberculosis which is spread through the air by coughing and speaking. Multidrug resistant TB (MDR-TB) is caused by an organism that is resistant to at least rifampicin and isoniazid, the two most common drugs used to treat TB.  These drug-resistant forms of TB are posing a significant public health crisis, being a major contributor to deaths from antimicrobial resistance globally and affecting approximately half a million people each year.

Improving the treatment for MDR-TB: The STREAM trial

STREAM is the world’s largest recruited, multi-country randomised clinical trial to examine shortened regimens for MDR-TB.

Prior to the STREAM 1 trial, WHO recommended the 9-11-month short regimen based on ‘very low quality’ evidence, so the shorter treatment had to be tested in a randomised trial setting. The health economic component led by LSTM showed that the short-regimen leads to economic benefits for health systems and patients.  These benefits are substantial, even when taking into account additional costs of safety monitoring (as high-dose moxifloxacin and clofazimine administered in the short regimen were known to increase the risk of prolongation of the QT interval- a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart, and thus increase the possibility of adverse events).

Squire, Langley, and Rosu participated in dissemination and discussion of the preliminary results of both the clinical and economic elements of the trial, including to the WHO Guideline Group in 2018 . These and the final published results, demonstrating non-inferiority of the 9-11-month regimen (compared to 20 month), contributed to the formulation of two updates to the WHO guidance on management of MDR-TB [3,4] and the WHO 2019 consolidated guidance endorsing shortened regimens with economic benefits for both patients and health systems [5]. The shortened MDR-TB regimen has already benefitted 200,000 people, with 82 countries having adopted it. The beneficiaries are predominantly poor people with TB in low- and middle-income countries (LMIC). Conservatively assuming a resultant health system cost saving of USD1,545 and direct patient cost saving of USD238 per patient (as calculated for Ethiopia), an overall societal cost saving of USD357 million was achieved in 2018.

The methodology developed in the STREAM trial is currently being used in further work:

• Phase 2  of the STREAM trial 
• The “Cost and cost-effectiveness analysis” section of the ShORRT operational research package developed by WHO/TDR to support rollout (currently in Benin, DRC, Pakistan and Nigeria) of all-oral shortened, primarily home-based MDR-TB regimens. These all-oral regimens will permit wide-scale shift to out-patient management of MDR-TB resulting in further savings for patients and health systems. 

Predictive Simulation Modelling for Rollout of Molecular Diagnosis for MDR-TB

There are multiple ways to diagnose tuberculosis, and each health setting is unique. Decision makers must choose between different testing technologies, and where to place them within health systems. With competing strategies providing different accuracies in their results, varying in their length of time and the demand they place on both health resources and patients, it is critical policy makers are able to predict the effect of rolling out a new strategy when allocating health budgets.

LSTM has pioneered the utilisation of operational models to represent health systems virtually. This approach has been used since 2014 to guide policy-making in the diagnosis of TB and MDR-TB in many countries, including Brazil, Russia, South Africa, Tanzania, Ethiopia, Philippines, Kenya, and Nepal. With the support of our collaborators Lanner, we use Witness predictive simulation software to represent health systems virtually, capturing and reflecting complex patient-pathways. Such modelling allows us to see how inputs such as equipment availability, diagnostic accuracies, patient heterogeneity and process times, affect the performance and costs of a strategy.

In our Tanzania modelling we used an integrated model to assess the effects of different algorithms of GeneXpert and LED fluorescence microscopy in Tanzania. We found that full scale-up of Xpert would have the greatest population-level effect, with the highest cost, though health economic analyses determined that this would be cost-effective.

Philippines TB-FIT Modelling

In the TB-FIT project we built a virtual health system model to compare impacts and cost-effectiveness of multiple diagnostic strategies for TB and MDR-TB diagnosis in Cavite Province, Philippines. Strategies were evaluated from a societal and health system perspective. We found that the optimum strategy for diagnostic yield was full rollout of GeneXpert Ultra for most sites, with the primary benefit coming from the additional identification of patients with MDR-TB, with this increase ranging considerably from 22% to 220% between sites.

Advocacy and method development

As a member of the Board of The International Union Against Tuberculosis and Lung Disease (2003-2016) including 3 years as President (2008-2011), and a member of the Strategic and Technical Advisory Group for TB (STAG-TB) of the WHO (2016-2018), Professor Squire has played a leading advocacy role for equity-focussed approaches to TB management.  He has played a pivotal role in ensuring that the impact on patient costs is incorporated into economic analysis of TB interventions and models of care, contributing to the inclusion of the target to end catastrophic costs for TB patients in the WHO End TB Strategy, launched in 2015.  As a member of the WHO Task Force on patient costs, he worked with Ewan Tomeny and international colleagues to develop a robust methodology for assessing TB patient costs . This methodology has become the gold standard for assessing patient costs, and Squire and team incorporated this into within-trial economic evaluations with the latest development being the inclusion of quality of life assessments. 

Research Outputs

Langley I,Lin H-H, Egwaga S, Doulla B, Ku C-C, Murray M, Cohen T, Squire SB (2014). Assessment of the patient, health system, and population effects of Xpert MTB/RIF and alternative diagnostics for tuberculosis in Tanzania: an integrated modelling approach. Lancet Global Health, Volume 2, Issue 10, Pages e581 - e591 doi:10.1016/S2214-109X(14)70291-8.

Langley I, Squire SB, Dacombe R, Madan J, E Silva JR, Barreira D, Galliez R, Oliveira MM, Fujiwara PI, Kritski A. (2015) Developments in Impact Assessment of New Diagnostic Algorithms for Tuberculosis Control. Clin Infect Dis. 2015 Oct 15;61Suppl 3:S126-34. doi: 10.1093/cid/civ580

Nunn AJ, Phillips PPJ, Meredith SK, Chiang CY, Conradie F, Dalai D, van Deun A, Dat PT, Lan N, Master I, Mebrahtu T, Meressa D, Moodliar R, Ngubane N, Sanders K, Squire SB, Torrea G, Tsogt B, Rusen ID; STREAM Study Collaborators.  (2019) A Trial of a Shorter Regimen for Rifampicin-resistant Tuberculosis. New England Journal of Medicine2019; 380(13):1201-1213 doi10.1056/NEJMoa1811867

Madan JJ, Rosu L, Girma M, van Rensburg C, Evans D, Langley I, Tomeny E, Nunn A, Rusen ID, Squire SB. (2020) STREAM: Economic evaluation of a short-standardised regimen for the treatment of rifampicin-resistant tuberculosis Bulletin of the WHO2020;98:297-372 doi.org/10.2471/BLT.20.000520

Abouyannis M,Dacombe R, Dambe I, Mpunga M, Faragher B, Gausi F, Ndhlovu H, Kachiza C, Suarez P, Mundy C, Banda HT, Nyasulu I, Squire SB (2014).  Drug resistance of Mycobacterium tuberculosis in Malawi. Bulletin of the WHO 2014; 92:798-806. doi: 10.2471/BLT.13.126532

Cohen DB, Mbendera K, Maheswaran H, Mukaka M, Mangochi H, Phiri L, Mpunga J, Madan J, Davies G, Corbett E, Squire SB (2019). Delivery of Long-Term Injectable Agents for Tuberculosis by Lay Carers: A Pragmatic Randomised Trial. 2019 Thorax http://dx.doi.org/10.1136/thoraxjnl-2018-212675