WHO Guidelines on guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update
Nathan Geffen, TBonline
The World Health Organisation (WHO) has updated its guidelines for drug-resistant TB. 
The guidelines were last published in 2008. 
The guidelines make eleven recommendations. All of them were supported by very low quality evidence.
1. Rapid drug susceptibility testing of isoniazid and rifampicin or rifampicin alone is recommended if there are resources to do it and if rifampicin resistance is not rare in the patient group. Currently the line probe assay and the GeneXpert are the only diagnostic tools to meet the WHO criteria for rapid diagnosis (two days or less).
2. Sputum smear microscopy and sputum smear culture, rather than sputum smear microscopy alone is recommended for the monitoring of patients with MDR TB during treatment.
This is a change from the 2008 guidelines that recommended monthly sputum smear microscopy and culture examination prior to culture conversion to negative and quarterly culture, with monthly smear examination after conversion.
Data pooled from 10 observational studies indicated that monthly sputum smear microscopy and culture performed best at identifying treatment failures early. This is conditional recommendation because of the resources required to implement it.
3. MDR TB patients should be treated with a flouroquinoline. This is a strong recommendation.
4. MDR TB patients should be treated with a late-generation flouroquinolone (levofloxacin, moxifloxacin, gatifloxacin and sparfloxacin) rather than an earlier-generation one. This is a conditional recommendation.
5. MDR TB patients should be treated with ethionamide or prothionamide. This is a strong recommendation.
6. In the treatment of MDR TB patients, four second-line drugs likely to be effective (including an injectable, kanamycin, amikacin or capreomycin) as well as pyrazinamide should be included in the intensive treatment phase. This is a conditional recommendation.
7. MDR TB patients should be treated with at least pyrazinamide, a fluoroquinolone, an injectable, ethionamide (or prothionamide) and cycloserine (or PAS if cycloserine cannot be used). This is a conditional recommendation.
Recommendations 3 to 7 were based on the results of three systematic reviews of observational data. Bias was likely substantial because some drugs may have been used for sicker patients. Nevertheless, this is the best available evidence.
Analysis showed that in the intensive phase a regimen with at least four drugs was likely to be effective. The analysis did not show any injectable to be superior to any other, so kanamycin is recommended because of its lower cost.
Fluoroquinolones were significantly associated with cure and this association was greater with later-generation ones. The recommendations gave higher weight to interventions that increased the risk of cure and reduced the risk of failure, relapse and death. Consequently fluoroquinolines were strongly recommended despite potential long-term serious adverse events. The recommendation for later-generation fluoroquinolines was conditional because of the unknown long-term side effects of these drugs. Ciprofloxacin may have some anti-TB activity but it should not be used.
For oral bacteriostatic drugs the association with cure was higher for ethionamide than cycloserine which was higher than PAS. PAS is only recommended if there is no other effective drug available to make up the four-drug regimen. No significant association between cure and any of the following was found: amoxicillin/clavulanate, azithromycin, clarithromycin, clofazimine, roxithromycin and thiocetazone.
There were too little data on linezolid and high-dose isoniazid. Pyrazinamide showed slight benefit in one analysis.
Patients with XDR TB were excluded from this analysis so these recommendations do not necessarily apply to them. Nevertheless, the WHO recommends that the same principles used to design MDR TB regimens should be used for XDR TB regimens.
The regimen composition recommendations differ only in small nuances from the 2008 guidelines. Ethambutol has been removed as an alternative to pyrazinamide in the new guidelines, albeit that the new guidelines acknowledge that the decrease in efficacy associated with ethambutol in their analysis could be due to confounding.
8. The intensive phase of treatment for MDR TB patients should be at least eight months. This is a conditional recommendation.
9. A total treatment duration of at least 20 months is recommended.
The evidence base for recommendations 9 and 10 is the same as recommendations 3 to 7 and subject to confounding and bias. There was an association between treatment success and the length of treatment and the length of the intensive phase.
The 2008 guidelines recommended at least six months intensive phase treatment and at least 18 months of total treatment.
10. ART is recommended for all HIV-positive patients with MDR TB irrespective of CD4 count, starting within eight weeks after TB treatment. This was a strong recommendation.
Ten studies, none of them randomised controlled trials, informed this recommendation. The quality of evidence varied from low to very low quality. The recommendation is based in part on evidence from studies for any patients with TB and HIV (ie majority non DR patients).
11. Patients with MDR TB should be treated using mainly ambulatory care rather than models of care based on hospitalisation. This is a conditional recommendation. The data for this recommendation came from published and unpublished studies in Estonia, Peru, Philippines and Russia, but none of these were randomised controlled trials. Nor did these studies allow direct comparisons of effects between models of care. The key considerations informing this recommendation was that the cost per disability adjusted life-year was generally lower in outpatient models and that these models appear to reduce exposure to infectious drug-resistant patients. However, the guidelines warn that ambulatory care can shift the burden of cost from the service provider to the patient (eg increased travel and food costs). Therefore implementation of ambulatory care models must be accompanied by provision of what the document calls “appropriate enablers”.
The guidelines state that important gaps in knowledge should be addressed in future research, particularly in the context of large-scale expansion of treatment for patients with drug-resistant TB. The document further calls for randomised controlled trials to determine the best combination of drugs and optimal treatment duration. Further research on (1) paediatric MDR TB treatment, (2) best regimens for patients with isoniazid resistance, (3) prophylaxis for contacts of MDR TB and (4) therapy for relief from adverse reactions due to second-line drugs is needed.
A common theme throughout these guidelines is the lack of evidence to support the recommendations.
The development of new TB drugs like TMC207 and OPC-67683 needs to be completed. The phase IIB trial results of TMC207 suggest that it is already better tested than many second-line TB drugs and therefore should be available to patients.
MSF has pioneered outpatient MDR TB care in South Africa. It would strengthen recommendation 11 if they published more data on this.
- WHO. Guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.
- WHO. Guidelines for the programmatic management of drug-resistant tuberculosis, Emergency update 2008, WHO, Geneva, 2008.