Monday, October 01, 2012

EID Journal: Challenges To Defining TDR-TB



(From the 2011 TB Progress Report)


# 6600


In January of this year reports began to emerge out of India regarding what was being called Totally Drug Resistant (TDR) tuberculosis (see Crof’s report India: New TB strain is "totally drug-resistant" (updated)).


While not an officially recognized term, TDR-TB was portrayed by the media as a frightening escalation of the existing classifications of Multi-drug resistant (MDR-TB) and Extensively-drug resistant (XDR-TB).


Resistant forms of Tuberculosis have come about primarily as the result of incomplete, irregular, or inappropriate treatment and management of infected patients.


A few days later (January 14th), the World Health Organization updated their Drug-resistant tuberculosis FAQ where they take exception to the term TDR-TB.


Why are these terms not yet recognised by WHO?

Terms such as “totally drug resistant” have 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 and limitations on the use of results remain: conventional DST for the drugs that define MDR and XDR-TB has been thoroughly studied and consensus reached on appropriate methods, critical drug concentrations that define resistance, and reliability and reproducibility of testing

Around the same time we saw an ECDC Comment On Drug Resistant TB In India. One of the points being made in the comments section (excerpted below) is that the term TDR-TB is as yet not well defined, and may be misleading.



Total drug resistant TB is a relative notion and depends on the local drugs available and tested on. This term/expression should either be avoided or should be defined worldwide. The World Health Organization (WHO) has internationally-endorsed treatment recommendations for the treatment of drug-susceptible, MDR-TB and XDR-TB.


In March, as part of my World TB Day Roundup, the World Health Organization released this statement on the supposed TDR-TB, cautioning:


More evidence and better diagnostics needed before redefining severe forms of drug-resistant TB says WHO

Note for the media

23 March 2012 | Geneva - Reports of tuberculosis (TB) cases with severe patterns of drug resistance are increasing, said experts who attended a WHO meeting in Geneva on 21-22 March. Participants stressed that the emergence of drug resistance should be a wake-up call for Ministries of Health. The group urged the global TB community to make greater efforts to prevent drug resistance and scale up provision of appropriate care and management to avoid a scenario where TB becomes incurable.

Insufficient evidence

The meeting concluded that there is currently insufficient evidence to adopt new case definitions for drug-resistant TB. Drug susceptibility testing (DST), which is key to defining new levels of drug resistance, lacks accuracy for several of the drugs that are used to treat multi drug-resistant (MDR) and extensively drug resistant (XDR)-TB. Secondly, there is insufficient correlation of DST results with clinical response to treatment for several drugs currently used to treat XDR-TB. Thirdly, new drugs are currently undergoing clinical trials, and could prove effective against drug resistant strains. The meeting urged diagnostics companies and TB laboratories to develop better diagnostic tests and also agreed that WHO and technical partners should develop more detailed guidance on XDR-TB treatment.

(Continue . . . )



All of which brings us to a new article appearing ahead of print in the CDC’s EID Journal that looks at the:


Challenges and Controversies in Defining Totally Drug-Resistant Tuberculosis

Peter Cegielski , Paul Nunn, Ekaterina V. Kurbatova, Karin Weyer, Tracy L. Dalton, Douglas F. Wares, Michael F. Iademarco, Kenneth G. Castro, and Mario Raviglione

In March 2012, in response to reports of tuberculosis (TB) resistant to all anti-TB drugs, the World Health Organization convened an expert consultation that identified issues to be resolved before defining a new category of highly drug-resistant TB.


Proposed definitions are ambiguous, and extensive drug resistance is encompassed by the already defined extensively drug-resistant (XDR) TB. There is no evidence that proposed totally resistant TB differs from strains encompassed by XDR TB.


Susceptibility tests for several drugs are poorly reproducible. Few laboratories can test all drugs, and there is no consensus list of all anti-TB drugs. Many drugs are used off-label for highly drug resistant TB, and new drugs formulated to combat resistant strains would render the proposed category obsolete. Labeling TB strains as totally drug resistant might lead providers to think infected patients are untreatable. These challenges must be addressed before defining a new category for highly drug-resistant TB.

(Continue . . . )


Given the complexities of evaluating for total drug resistance, attaching the label TDR-TB to these strains may well be both premature and inaccurate.


But the sobering fact remains, if you are infected with one of these XDR-TB strains - and no drug is available to you that can treat it – for you, it may as well be totally resistant.


Of course, this disparity of available medical treatment exists for a great many diseases around the world, and is not just limited to TB.



The authors of the EID study conclude with this warning:


As countries increase treatment of MDR and XDR TB, it is inevitable that resistance to second-line drugs will increase. New drugs and better diagnostic tools are needed urgently for patients with highly drug-resistant TB.


For more on the global spread of TB, you may wish to revisit:


WHO-ECDC: Joint Report On Tuberculosis In Europe
Resistant TB: The Limits Of Surveillance & Reporting
WHO: Blood Tests To Detect Active TB Unreliable

1 comment:

Anonymous said...

hello michael
your paper is OK, as usual,
just a question: I canno't find the link to EID : the ressource cannot be found.
I ve a bad connexion and not the possibility to search.
could you please give the likn ( or the month of the publication in EID )
thank you very much