Effect of the short-course regimen on the global epidemic of multidrug-resistant tuberculosis
Authors: Giovanni Sotgiu, Giovanni Battista Migliori
Journal: The Lancet Respiratory Medicine (2016)

In May, 2016, WHO launched new guidelines for the management of multidrug-resistant tuberculosis,1WHO treatment guidelines for drug-resistant tuberculosis. 2016 update. World Health Organization, Geneva2016http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/enGoogle Scholar including a conditional recommendation of the so-called shorter regimen. Originally known as the Bangladesh regimen,2Van Deun A Maug AK Salim MA et al.Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis.Am J Respir Crit Care Med. 2010; 182: 684-692Crossref PubMed Scopus (534) Google Scholar this 9 month course of treatment is much cheaper (less than US$1000) than the normally used longer regimen (up to 24 months; US$20 000 or more)3Diel R Vandeputte J de Vries G Stillo J Wanlin M Nienhaus A Costs of tuberculosis disease in the European Union: a systematic analysis and cost calculation.Eur Respir J. 2014; 43: 554-565Crossref PubMed Scopus (134) Google Scholar and potentially more effective. If successful, introduction of the short-course regimen will make a substantial difference to the treatment of multidrug-resistant tuberculosis, which is at present lengthy, difficult (because of common adverse events), and expensive. Only roughly 50–60% of patients will have successful outcomes.4WHOGlobal tuberculosis report 2016. World Health Organization, Geneva2016http://www.who.int/tb/publications/global_report/en/Google Scholar, 5Falzon D Gandhi N Migliori GB et al.for the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TBResistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes.Eur Respir J. 2013; 42: 156-168Crossref PubMed Scopus (320) Google Scholar, 6Migliori GB Sotgiu G Gandhi NR et al.for the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TBDrug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis.Eur Respir J. 2013; 42: 169-179Crossref PubMed Scopus (215) Google Scholar By contrast, in early observational studies,1WHO treatment guidelines for drug-resistant tuberculosis. 2016 update. World Health Organization, Geneva2016http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/enGoogle Scholar, 2Van Deun A Maug AK Salim MA et al.Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis.Am J Respir Crit Care Med. 2010; 182: 684-692Crossref PubMed Scopus (534) Google Scholar the new short-course regimen achieved a success rate of more than 90% across a range of settings, such as in Bangladesh, Niger, and Cameroon.4WHOGlobal tuberculosis report 2016. World Health Organization, Geneva2016http://www.who.int/tb/publications/global_report/en/Google Scholar The newly recommended regimen includes kanamycin, moxifloxacin (gatifloxacin in the original Bangladesh regimen), protionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol for 4–6 months, followed by moxifloxacin, clofazimine, pyrazinamide, and ethambutol for the remaining 5 months. The advantages of an effective and safe regimen that is standardised (therefore easy to administer), costs 20 times less, and lasts less than half the duration of the longer regimen are obvious. However, enthusiasm needs to be balanced with careful assessment of the likely effect of introducing the short-course regimen, taking into account the varying proportions of eligible patients (ie, those who have not been previously treated with second-line drugs and are unlikely to be resistant to them). At present, no evidence exists on the effects of implementing the short-course regimen in the medium and long term.5Falzon D Gandhi N Migliori GB et al.for the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TBResistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes.Eur Respir J. 2013; 42: 156-168Crossref PubMed Scopus (320) Google Scholar In The Lancet Respiratory Medicine, Emily A Kendall and colleagues7Kendall EA Fojo AT Dowdy DW Expected effects of adopting a 9 month regimen for multidrug-resistant tuberculosis: a population modelling analysis.Lancet Respir Med. 2016; (published online Dec 15.)http://dx.doi.org/10.1016/S2213-2600(16)30423-4PubMed Google Scholar describe a sophisticated dynamic transmission model to project the reduction in incidence of multidrug-resistant tuberculosis by 2024. The primary analysis was tailored to a southeast Asian setting and showed a median decline in incidence of 14% (95% uncertainty range [UR] −36 to 39)—from 4·9 [4·2–5·9] per 100 000 population in 2014 to 4·3 [2·9–7·6] per 100 000 population in 2024—if current practices continue. The investigators also attempted to capture, in different scenarios, factors driving future effects of introducing the short-course regimen. These factors included long-term efficacy of the short-course regimen, degree of treatment scale-up, and the likely transmission of drug-resistant Mycobacterium tuberculosis strains in the community. At present, information is missing on the regimen's efficacy under programmatic conditions, the durability of its effectiveness (eg, no additional drug resistance generated), and its potential to increase numbers of patients who are ineligible for treatment because of additional resistance. Kendall and colleagues7Kendall EA Fojo AT Dowdy DW Expected effects of adopting a 9 month regimen for multidrug-resistant tuberculosis: a population modelling analysis.Lancet Respir Med. 2016; (published online Dec 15.)http://dx.doi.org/10.1016/S2213-2600(16)30423-4PubMed Google Scholar modelled several scenarios based on different combinations of the factors mentioned above. In the most optimistic scenario in which the short-course regimen would double treatment access and achieve long-term efficacy, the incidence of multidrug-resistant tuberculosis in 2024 (3·3 [95% UR 2·2–5·6] per 100 000 population) would be 23% (10–38) lower compared with the continued use of longer therapy (4·3 [2·9–7·6] per 100 000 population). If treatment access does not expand (ie, only efficacy is improved with the new regimen), the relative decline in incidence would be 14% (4–28), whereas if the new regimen improves only treatment access but not efficacy the relative decline would be 11% (3–24). However, if 30% of patients are ineligible for the short-course regimen because of second-line drug resistance, the relative change in incidence would be −2% (−20 to 28). Kendall and colleagues7Kendall EA Fojo AT Dowdy DW Expected effects of adopting a 9 month regimen for multidrug-resistant tuberculosis: a population modelling analysis.Lancet Respir Med. 2016; (published online Dec 15.)http://dx.doi.org/10.1016/S2213-2600(16)30423-4PubMed Google Scholar provided examples of many possible scenarios, of which two are particularly useful. Assuming a reasonable success rate of the short-course regimen (85%) in programmatic conditions, in a problematic setting with 50% durable cure in patients receiving the longer regimen and 50% of patients who are ineligible for the short-course regimen, the relative change in incidence of multidrug-resistant tuberculosis would be −2% (95% UR −15 to 13). In a less pessimistic scenario in which the longer therapy has a success rate of 77% and 30% of patients would be ineligible for the short-course treatment, the relative reduction in incidence would 18% (8–32).7Kendall EA Fojo AT Dowdy DW Expected effects of adopting a 9 month regimen for multidrug-resistant tuberculosis: a population modelling analysis.Lancet Respir Med. 2016; (published online Dec 15.)http://dx.doi.org/10.1016/S2213-2600(16)30423-4PubMed Google Scholar These two scenarios are likely to represent the extremes, so the real decline will probably lie between the values in these two examples.8Javaid A, Ahmad N, Shaheen Z, Khan AH. Applicability of World Health Organization's recommended new shorter regimen in an MDR-TB high burden country. Eur Respir J (in press).Google Scholar, 9van der Werf M, Hollo V, Kodmon C, Dara M, Catchpole M. Eligibility for shorter treatment of multidrug-resistant tuberculosis in the European Union. Eur Respir J (in press).Google Scholar We hope the excellent results achieved by the short-course regimen will be consistent when scaled up across a range of settings. It will be crucial to correctly apply the WHO guidance1WHO treatment guidelines for drug-resistant tuberculosis. 2016 update. World Health Organization, Geneva2016http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/enGoogle Scholar, 10Sotgiu G Tiberi S D'Ambrosio L Centis R Zumla A Migliori GB WHO recommendations on shorter treatment of multidrug-resistant tuberculosis.Lancet. 2016; 387: 2486-2487Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar and ensure rapid molecular testing (complemented by drug susceptibility testing when necessary) to prevent prescription of the short-course regimen to patients who are resistant to one or more drugs in the regimen and thus the development of super-resistance. Although some evidence shows that the pessimistic scenario (in which 50% of patients are ineligible for short-course regimen) can be real in certain settings (such as Pakistan and Europe8Javaid A, Ahmad N, Shaheen Z, Khan AH. Applicability of World Health Organization's recommended new shorter regimen in an MDR-TB high burden country. Eur Respir J (in press).Google Scholar, 9van der Werf M, Hollo V, Kodmon C, Dara M, Catchpole M. Eligibility for shorter treatment of multidrug-resistant tuberculosis in the European Union. Eur Respir J (in press).Google Scholar), we need to focus on the potential of the short-course regimen to benefit individual patients and reduce the burden of multidrug-resistant tuberculosis worldwide.10Sotgiu G Tiberi S D'Ambrosio L Centis R Zumla A Migliori GB WHO recommendations on shorter treatment of multidrug-resistant tuberculosis.Lancet. 2016; 387: 2486-2487Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 11Sotgiu G Tiberi S D'Ambrosio L et al.for the International Carbapenem Study GroupFaster for less, the new ‘shorter’ regimen for multidrug-resistant tuberculosis.Eur Respir J. 2016; 48: 1503-1507Crossref PubMed Scopus (59) Google Scholar More information is also needed on the potential effect of other concomitant epidemics, such as HIV and diabetes. For example, in Latin America, particularly Mexico, up to 40% of patients with multidrug-resistant tuberculosis also have diabetes.12Muñoz-Torrico M, Caminero JA, Migliori GB, et al. Diabetes is associated with severe adverse events in multidrug-resistant tuberculosis. Arch Bronconeumol (in press).Google Scholar As clinicians and public health experts, we welcome the important opportunity offered by the short-course regimen to treat eligible patients. The careful and detailed modelling described by Kendall and colleagues is particularly helpful in predicting the likely effects on the overall epidemic in different scenarios worldwide. We declare no competing interests. Expected effects of adopting a 9 month regimen for multidrug-resistant tuberculosis: a population modelling analysisThe short-course regimen has potential to substantially lessen the multidrug-resistant tuberculosis epidemic, but this effect depends on its long-term efficacy, its ability to expand treatment access, and the role of second-line drug resistance. Full-Text PDF Open Access