Tuberculosis (TB)

“Totally Drug-Resistant” tuberculosis: a WHO consultation on the diagnostic definition and treatment options

21-22 March 2012

Background

Within a year of the first reports of extensively resistant TB (XDR-TB) in 2006, isolated cases were reported in Italy that had resistance to all first-line anti-TB drugs (FLD) and second-line anti-TB drugs (SLD) that were tested. In 2009, a cohort of 15 patients in Iran was reported which were resistant to all anti-TB drugs tested. The terms ‘extremely drug resistant’ (‘XXDR-TB’) and ‘totally drug-resistant TB’ (‘TDR-TB’) were given by the respective authors reporting this group of patients. Recently, a further 4 patients from India with ‘totally drug resistant tuberculosis (‘TDR-TB’) were described, with subsequent media reports of a further 8 cases.

The term ‘totally drug resistant’ has not been clearly defined for tuberculosis. While the concept of ‘total drug resistance’ is easily understood in general terms, in practice, in vitro drug susceptibility testing (DST) is technically challenging. XDR-TB severely reduces the options for treatment although they have not been studied in large cohorts. Treatment options for XDR-TB patients who have resistance to additional second-line anti-TB drugs are even more limited.

In order to facilitate discussion and to make surveillance consistent, an initial step was for WHO and partners to develop consensus on whether a new definition for ‘totally drug-resistant TB’ was needed or not, and if so, what the definition might be. The treatment options of XDR-TB patients who have resistance to additional second-line anti-TB drug as well as the steps required to make such treatment available, also required discussion. The Stop TB Department of WHO therefore convened a technical consultation in Geneva on 21-22 March 2012, back-to-back with an Expert Group meeting evaluating existing DST methods for first- and second-line anti-TB drugs.

Meeting objectives

  • To provide an overview of current information on XDR-TB and XDR-TB with additional drug resistance;
  • To review the feasibility and implications of a definition to cover the most severe patterns of resistance;
  • To review treatment options for patients with XDR-TB and XDR-TB cases with additional drug resistance.

Main conclusions

  • Reports of tuberculosis (TB) patients with severe patterns of drug resistance are increasing and present clinicians with a formidable challenge. However, a new definition of resistance beyond extensively drug-resistant TB (XDR-TB ) is not recommended, given technical difficulties with drug susceptibility testing (DST) of many anti-TB medicines, insufficient evidence to link such DST results to treatment outcomes of patients, and the lack of standardised DST methods for several anti-TB drugs (including new investigational compounds);
  • DST for drugs used to define multidrug-resistant (MDR) and XDR-TB are accurate and reproducible. The methods and critical concentrations for determining resistance are standardised. As a new recommendation, all injectables and all fluoroquinolones should routinely be tested in specimens from confirmed MDR-TB patients to screen for XDR-TB. Moxifloxacin should be tested at two concentrations to guide use of the drug in ofloxacin-resistant patients;
  • DST for all other drugs remains problematic for technical reasons (eg. drug instability in solution, drug binding to proteins in the media, low pH requirements, etc). Some drugs can only be tested in specific media and with specific laboratory supplies, requiring specialist training. For some drugs (particularly Group 5 and new investigational drugs) no methods exist. Countries are therefore not advised to invest resources in developing new or additional laboratory capacity for DST of these drugs. Increased investment into research is needed to develop standardised DST methods;
  • Molecular DST offers promise for DST and may be superior to current reference standards (phenotypic methods). However, mutations conferring resistance are not all known (and very limited for most second-line drugs) and testing is technically demanding and expensive. As a result molecular DST cannot replace phenotypic methods yet, with the exception of those molecular tests endorsed by WHO for rapid rifampicin resistance detection. Research to identify mutations conferring resistance should be accelerated and increased investment is needed to develop new tests;
  • WHO will promote initiatives for early collaboration among pharmaceutical companies producing investigational new TB drugs to use these drugs in novel combination regimens and to facilitate their introduction into clinical settings;
  • The compassionate use of new TB drugs in patients with advanced forms of drug-resistant TB, and for whom other treatment options are limited, will require collaboration between national TB control programmes, Ministries of Health and pharmaceutical companies to ensure that the necessary regulatory frameworks are in place to facilitate access while preventing the development of resistance to the new drugs as a result of misuse;
  • There is a pressing need for properly conducted studies evaluating head-to-head comparisons of available DST methods, in different epidemiological settings, and linked to patient management and clinical outcomes. WHO will take the lead in providing guidance on the evidence which national TB control programmes and other implementing partners need to collect on patients being treated for drug-resistant TB and ensure that these data provide a more robust knowledge base to inform future policy decisions.
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