The burden of latent multidrug-resistant tuberculosis
Authors: Alberto L Garcia-Basteiro, Helen E Jenkins, Moleboleng Rangaka
Journal: The Lancet Infectious Diseases (2019)

In the past 10 years, there has been renewed interest in the early phases of the natural history of tuberculosis.1Kik SV Schumacher S Cirillo DM et al.An evaluation framework for new tests that predict progression from tuberculosis infection to clinical disease.Eur Resp J. 2018; 521800946Crossref PubMed Scopus (21) Google Scholar Estimates suggest that around 25% of the world's population could have latent tuberculosis infection,2Houben RMGJ Dodd PJ The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling.PLoS Med. 2016; 13e1002152Crossref PubMed Scopus (933) Google Scholar 5–10% of whom will develop active disease during their lifetime3Comstock GW Livesay VT Woolpert SF The prognosis of a positive tuberculin reaction in childhood and adolescence.Am J Epidemiol. 1974; 99: 131-138Crossref PubMed Scopus (509) Google Scholar (10% annually among people with HIV).4Small PM Fujiwara PI Management of tuberculosis in the United States.N Engl J Med. 2001; 345: 189-200Crossref PubMed Scopus (295) Google Scholar Failure to implement effective tuberculosis control measures to manage latent infection threatens elimination goals. Groups at high risk of active tuberculosis are the focus of programmatic management of latent tuberculosis infection.5WHOLatent TB infection: updated and consolidated guidelines for programmatic management.http://www.who.int/tb/publications/2018/latent-tuberculosis-infection/en/Date accessed: October 8, 2018Google Scholar Once active disease is ruled out, tuberculosis preventive therapy can be offered. However, such therapy is thought to be ineffective against multidrug-resistant (MDR) strains (ie, those resistant to isoniazid and rifampicin), and is thus rarely used to treat contacts of people with MDR tuberculosis. In The Lancet Infectious Diseases, Gwenan Knight and colleagues6Knight GM McQuaid CF Dodd PJ Houben RMGJ Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling.Lancet Infect Dis. 2019; (published online July 4.)http://dx.doi.org/10.1016/S1473-3099(19)30307-XSummary Full Text Full Text PDF PubMed Scopus (70) Google Scholar investigated the global burden of latent tuberculosis to provide the first estimates of the prevalence of latent MDR tuberculosis infection. They used surveillance and survey data, estimated annual risks of infection, and informative priors for patterns of increase to develop and validate a novel cohort method to calculate this burden. Knight and colleagues estimated that around 19 million people could be latently infected with MDR tuberculosis (10% of whom were infected in 2013 and 2014—ie, the most recent 2 years included in the model), representing around 1·2% of the total burden of latent infection. Children younger than 15 years, who progress to active disease more quickly than adults and therefore are a sentinel event suggesting recent local transmission, had more than double the risk of latent MDR tuberculosis infection that adults had. These data show that transmission of MDR strains of tuberculosis is worryingly high and probably increasing, and should be urgently addressed. Knight and colleagues also estimated that, even if all tuberculosis transmission was halted, reactivation of latent infections would mean that the future burden of MDR disease would still be substantial.6Knight GM McQuaid CF Dodd PJ Houben RMGJ Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling.Lancet Infect Dis. 2019; (published online July 4.)http://dx.doi.org/10.1016/S1473-3099(19)30307-XSummary Full Text Full Text PDF PubMed Scopus (70) Google Scholar Their work thus clearly emphasises the need for interventions to limit both transmission and reactivation of latent MDR tuberculosis infection. Knight and colleagues' findings have important implications at the individual and population level and for policy. Given that the prevalence of latent MDR tuberculosis infection will continue to rise if MDR tuberculosis transmission rates persist, an increasing proportion of people—and children especially—with latent infections7Huang C-C Becerra MC Calderon R et al.The impact of isoniazid preventive therapy on tuberculosis among household contacts of isoniazid-resistant patients.bioRxiv. 2019; (published online Nov 30.)DOI:10.1101/479865Google Scholar might not benefit from recommended tuberculosis preventive therapy regimens, and thus will be at increased risk of developing active MDR tuberculosis.8Jenkins HE Tolman AW Yuen CM et al.Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates.Lancet. 2014; 383: 1572-1579Summary Full Text Full Text PDF PubMed Scopus (214) Google Scholar At the population level, as the prevalence of latent tuberculosis infection decreases, the partial protective effect against reinfection or reactivation that latent infection with drug-susceptible tuberculosis provides9Cadena AM Hopkins FF Maiello P et al.Concurrent infection with Mycobacterium tuberculosis confers robust protection against secondary infection in macaques.PLoS Pathog. 2018; 14e1007305Crossref PubMed Scopus (47) Google Scholar against MDR strains will also diminish, thus increasing the risk of latent infection with MDR strains. In the meantime, Knight and colleagues' study emphasises the need to strengthen epidemiological surveillance of MDR tuberculosis and programmatic management of active and latent infections to reduce transmission of MDR tuberculosis (and thus the number of people with latent MDR tuberculosis). Only 25% of people with active MDR tuberculosis are detected (compared with 64% of people with all types of tuberculosis in 2017).10WHOGlobal tuberculosis report 2018. World Health Organization, Geneva2018Google Scholar Early identification of cases, prompt initation of highly effective treatment, and close treatment follow-up will help to shorten the infectious period, and MDR tuberculosis preventive therapies will clear infections or prevent disease progression. Further research priorities for diagnosis and treatment of latent MDR tuberculosis have been identified by Knight and colleagues. First, there is an urgent need to accelerate research into preventive therapy regimens for household contacts of people with confirmed MDR tuberculosis. Observational studies suggest that the contacts of people with MDR tuberculosis might benefit from tuberculosis preventive therapy, but no results from clinical trials have been published yet.11Fox GJ Schaaf HS Mandalakas A Chiappini E Zumla A Marais BJ Preventing the spread of multidrug-resistant tuberculosis and protecting contacts of infectious cases.Clin Microbiol Infect. 2017; 23: 147-153Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar Second, novel diagnostics or biosignatures that can identify the people in whom latent infection will progress to active tuberculosis—and thus who are likely to benefit from tuberculosis preventive therapy—are needed.12WHOConsensus meeting report: development of a target product profile (TPP) and a framework for evaluation for a test for predicting progression from tuberculosis infection to active disease. World Health Organization, Geneva2017Google Scholar Tools that can identify the resistance pattern of the infecting Mycobacterium tuberculosis strain are unlikely to be developed soon. However, given that contacts of cases with MDR tuberculosis might develop drug-susceptible or MDR tuberculosis,13Shah NS Yuen CM Heo M Tolman AW Becerra MC Yield of contact investigations in households of patients with drug-resistant tuberculosis: systematic review and meta-analysis.Clin Infect Dis. 2014; 58: 381Crossref PubMed Scopus (96) Google Scholar there is a clear need for universal tuberculosis preventive therapy (ie, treatment that is effective irrespective of the drug resistance pattern). Universal tuberculosis preventive therapy would be of great relevance in settings with a high prevalence of MDR tuberculosis, such as eastern Europe, where MDR strains account for more than 25% of tuberculosis transmission in several countries. Although Knight and colleagues' study advances approaches to and assumptions in modelling of latent tuberculosis infection, gaps remain. Most models of the latent tuberculosis burden assume lifelong infections2Houben RMGJ Dodd PJ The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling.PLoS Med. 2016; 13e1002152Crossref PubMed Scopus (933) Google Scholar, 6Knight GM McQuaid CF Dodd PJ Houben RMGJ Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modelling.Lancet Infect Dis. 2019; (published online July 4.)http://dx.doi.org/10.1016/S1473-3099(19)30307-XSummary Full Text Full Text PDF PubMed Scopus (70) Google Scholar—a contentious assumption given that some infections clear naturally or after treatment with sterilising tuberculosis preventive therapy. The definition of latent tuberculosis infection used did not account for mixed infections, and future models could examine the effect of mixed infections on susceptibility to reinfection or reactivation.9Cadena AM Hopkins FF Maiello P et al.Concurrent infection with Mycobacterium tuberculosis confers robust protection against secondary infection in macaques.PLoS Pathog. 2018; 14e1007305Crossref PubMed Scopus (47) Google Scholar Similarly, the reactivation rate could differ between recently infected and remotely infected individuals,14Behr MA Edelstein PH Ramakrishnan L Revisiting the timetable of tuberculosis.BMJ. 2018; 362k2738Crossref PubMed Scopus (194) Google Scholar and thus could affect the estimated burden of latent infection. It would be valuable to forecast the burden of latent MDR tuberculosis depending on different scenarios of progression and interventions towards the End TB targets at different timepoints, especially in children and young people. Additionally, sensitivity analysis with different MDR tuberculosis fitness cost rates and progression to active MDR disease would help to further clarify the magnitude and threat of the MDR tuberculosis epidemic. There is a need to strengthen surveillance systems for detection of MDR tuberculosis and adequate patient management for early initiation of second-line treatment and treatment follow-up. The tuberculosis epidemic will not be ended without tackling people who are latently infected, and thus an increasing focus on the left side of the curve of the natural history of tuberculosis should be considered in countries with the highest burden of infection, so that the criteria for recommending preventive therapies can be progressively expanded. This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on August 14, 2019 This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on August 14, 2019 We declare no competing interests. Global burden of latent multidrug-resistant tuberculosis: trends and estimates based on mathematical modellingWe estimate that three in every 1000 people globally carry latent MDR tuberculosis infection, and prevalence of MDR M tuberculosis in those with latent tuberculosis infection is more than double among those younger than 15 years. If current trends continue, the proportion of latent tuberculosis caused by MDR strains will increase, which will pose serious challenges for management of latent tuberculosis—a cornerstone of tuberculosis elimination strategies. Full-Text PDF Open AccessCorrection to Lancet Infect Dis 2019; 19: 802–03Garcia-Basteiro AL, Jenkins HE, Rangaka M. The burden of latent multidrug-resistant tuberculosis. Lancet Infect Dis 2019; 19: 802–03—In this Comment, the terms "MDR disease" and "latent disease" have been replaced with "MDR tuberculosis infection" and "latent infection", respectively, in several instances. The definition of multidrug resistance has also been updated to reflect that multidrug-resistant tuberculosis strains are resistant to both isoniazid and rifampicin. These changes have been made to the online version as of Aug 14, 2019. Full-Text PDF