Background and methods

See 2016 update

This publication is provided for historical reference only and the information may be out of date.

Background and methods

The first two editions of these guidelines were published in 2006 (2) and 2008 (3) as a collaborative effort of many partners, most of whom were members of the Green Light Committee (4). This 2011 update follows WHO requirements for developing guidelines as specified in the Handbook for Guideline Development (2010), which involve an initial scoping exercise, use of systematic reviews to summarize evidence and application of the GRADE approach to develop recommendations (5).

The updated guidelines focus on the detection and treatment of drug-resistant TB in settings where resources are limited. Priority topics identified by WHO in this field and by its external experts were:

case-finding (use of rapid molecular tests; investigation of contacts and other high-risk groups);
regimens for MDR-TB and their duration in HIV-positive and HIV-negative patients;
monitoring during treatment;
models of care.

The guidelines are limited to topics not covered by other WHO policy documents published recently, including treatment of drug-susceptible TB and use of antiretroviral agents, treatment of patients with isoniazid-resistant TB and TB infection control. The 2011 update was produced through a systematic process starting in early 2009. Priority areas to be included in the update had been identified from those listed as outstanding areas for future direction following publication of the emergency update (2008). The previous PMDT guidelines were evaluated via a user questionnaire (6). Various experts, including TB practitioners, public health professionals, national TB control programme staff, guideline methodologists, members of civil society and nongovernmental organizations providing technical support, and WHO staff, were invited to form a Guideline Development Group to inform the update process. A second group, comprising national TB control programme staff, WHO regional TB advisors, and clinical and public health experts, was appointed to serve as an External Review Group (the composition of both groups is listed in the Acknowledgements).

The Guideline Development Group provided input on the selection of questions to address outstanding topics of controversy or areas where changes in policy or practice were warranted. It also selected and scored outcomes to determine those that were critical or important for making decisions on recommendations and to identify the data which were to be sought during retrieval and synthesis of evidence. By September 2009, the scope of the guidelines had been agreed, the questions formulated, and the selection and scoring of the main outcomes had been completed. Between October 2009 and May 2010, teams from leading academic centres were commissioned to review and compile the evidence. The early results of the reviews were made available to members of the Guideline Development Group before and during a meeting to develop the recommendations held at WHO headquarters in Geneva, Switzerland, on 25–27 October 2010.

Questions and outcomes

Table 1 lists the seven priority questions identified by the Guideline Development Group, worded in the PICO (Population, Intervention, Comparator, Outcome) or similar format.

Table 1

PICO questions for the 2011 update of the guidelines.

Table 2 summarizes the scored outcomes that were selected by the Guideline Development Group. Fourteen members submitted scores for outcomes they considered to be the most critical when making decisions on choice of testing and treatment strategies. Members were asked to take a societal perspective in rating the outcomes. Relative importance was rated on an incremental scale:

Table

Table 2

Most important possible outcomes when making decisions on choice of testing and treatment strategies for drug-resistant-TB.

For the scope of question 1 (Table 1), the discussion leading to the recommendations the term rapid tests to those providing a diagnosis within two days of specimen testing, thereby including only tests using molecular techniques (line probe assay and Xpert MDR/RIF¹). The different groups of drugs referred to in the text are composed of the agents shown in Table 3. In the analyses of data for questions 3–5, streptomycin was found to be used but it is generally considered a first-line drug. Later-generation fluoroquinolones included levofloxacin (750mg/day or more), moxifloxacin, gatifloxacin and sparfloxacin. Ciprofloxacin, ofloxacin and levofloxacin (up to 600mg/day) were considered earlier-generation fluoroquinolones for this analysis.

Table 3

Groups of second-line anti-tuberculosis agents referred to in these guidelines.

Assessment of evidence and its grading

The evidence review teams assessed the evidence for the questions and their outcomes through a series of systematic literature reviews following an approved methodology that was documented (Annex 1). Titles, abstracts and full text of potentially relevant literature were screened using key subject words and text words. The search was not limited by study type or time period. Authors in the field and members of the Guideline Development Group were contacted to identify missing studies or studies in progress. Case-based data were collected from authors of published studies to analyse the effects relating to the questions dealing with bacteriology and treatment regimen (questions 2–6 in Table 1). Modelling work was done in the context of questions 1 and 2. The question on models of care (question 7) was addressed by a review of published and unpublished studies containing a full economic evaluation of patients on MDR-TB treatment.

Where possible, relative effects (hazard ratios, relative risks or odds ratios of an event) were calculated from pooled data of included studies. In two of the analyses, outcome was expressed as the cost per disability-adjusted life year (DALY) averted. The DALY is a summary indicator that expresses the burden of mortality and morbidity into a single value: perfect health is valued at 1 and death at 0 (a year with TB disease is valued at 0.729) (7). For the modelling of rapid drug-susceptibility testing (DST), estimated cost outcomes included total costs for each DST strategy, cost per MDR-TB case prevented, cost per TB-related death avoided and cost per DALY averted. Transmission of resistant strains and subsequent secondary cases were not estimated. For the analysis of models of care (question 7), costs considered for inclusion could be from any of the following perspectives: cost from the health service provider's perspective, cost from the patient's perspective (including direct medical costs as well as indirect costs related to transportation) and total societal cost. Whenever possible, the following outcomes were included in the outcome: proportion of treatment success, default or long-term deaths (including secondary, default and relapse cases) and case reproduction rate (transmission from primary cases).

GRADE evidence profiles based on the results of the systematic reviews were prepared for each question using a standard approach. These summaries present the effect of the intervention on each outcome (for example, the number of patients with MDR-TB), as well as the quality of the evidence for each outcome. The quality of evidence was assessed using the following criteria: study design, limitations in the studies (risk of bias), imprecision, inconsistency, indirectness, publication bias, magnitude of effect, dose–effect relations and residual confounding. Quality of evidence was categorized into four levels (Table 4).

Table 4

Quality of evidence and definitions (8).

The Guideline Development Group held teleconferences to discuss the available evidence, the presentation of the results and their impact on making recommendations. One discussant was chosen from among the group's members to assess the evidence for each of the questions and to complement the presentation of the evidence by the evidence review teams. A preparatory meeting was held in September 2010 to review the interim results of the work relating to the questions on treatment regimens and duration, and use of rapid DST. The group met at WHO headquarters in Geneva, Switzerland, between 25 and 27 October to develop the revised recommendations. A week before the meeting, members were able to review the evidence profiles for each question via a password-protected electronic website (EZ Collab site). During the meeting and in the following months, additional files and successive versions of the guidelines were shared with the group on the same site.

At the meeting, the GRADE evidence profiles were assessed by the members of the Guideline Development Group when preparing the recommendations. The group used standard decision tables to move from evidence to recommendations. One table was prepared for each recommendation to record decisions and ensure that the group uniformly considered the quality of the evidence, the certainty about the balance of benefits versus harms, the similarity in values and the costs of an intervention compared with the alternative. The profiles allowed members to base their judgments when making recommendations on evidence summarized in a concise and uniform manner. Agreement on the recommendations was reached following discussions. In their deliberations, members of the group assessed the level of evidence and judged the strength of the recommendations according to the criteria shown in Table 5 (see web Annex 2 for a glossary of GRADE terms).

Table 5

Assessment of the strength of a recommendation.

Apart from the quality of evidence, the strength of a recommendation was determined by the balance between desirable and undesirable effects, values and preferences, and costs or resource allocation (5). The higher the quality of evidence, the more likely that it leads to a strong recommendation. However, a strong recommendation may be made in the presence of very low quality evidence given variability in values and preferences between the experts, the balance between desirable and undesirable consequences of an intervention, and resource implications. For instance, evidence from observational studies without randomization is always of low quality, but if the studies are methodologically sound (not downgraded for concerns about the validity) and the estimates of effect are consistent, a strong recommendation may still be possible. It is important to note that when making a conditional recommendation, the group considered its application only to a specific group, population or setting, or that new evidence might change the balance of risk to benefit or that the benefits might not warrant the cost or resource requirements in all settings (see also Table 6).

Table 6

Implications of the strength of a recommendation for different users (5).

The recommendations in these guidelines are to be read along with the accompanying remarks on available evidence, which are relevant to their proper interpretation and implementation.

External review

The External Review Group commented on the questions during their formulation (in mid-2009) and on a draft text of the guidelines, including recommendations, following comments from the Guideline Development Group (in early 2011). For the initial discussion, eight of the peer reviewers submitted comments that were used for the revised set of priority questions submitted to the evidence review centres for the systematic reviews. Six reviewers made comments on the draft guidelines in early 2011.

Publication, implementation, evaluation and expiry

The guidelines will be published in English on the WHO web site as well as in a peer-reviewed publication. WHO's Stop TB Department will work closely with regional and country offices, the Stop TB Partnership and other implementing partners to ensure their wide dissemination through electronic and paper format.

A companion manual is planned for 2011 to provide practical information on implementing programmatic management of drug-resistant TB. The manual will update previous guidance on this subject.

An evaluation of how users have implemented the guidelines will be developed to measure different dimensions of uptake of the recommendations, including the time until adaptation (if any) and barriers to effective implementation.

It is expected that the Stop TB Department, in collaboration with its partners, will review and update these guidelines about four years after their publication or earlier if new evidence, regimens or diagnostic tests become available.

Footnotes

1: Xpert MTB/RIF refers to the currently available methodology that employs an automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance.

Publication Details

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Publisher

World Health Organization, Geneva

NLM Citation

Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis: 2011 Update. Geneva: World Health Organization; 2011. Background and methods.

Table 1PICO questions for the 2011 update of the guidelines

1.	At what prevalence of MDR-TB in any group of TB patients is rapid drug-susceptibility testing warranted to detect resistance to rifampicin and isoniazid or rifampicin alone on all patients in the group at the time of TB diagnosis, in order to prescribe appropriate treatment at the outset?
2.	Among patients with MDR-TB receiving appropriate treatment in settings with reliable direct microscopy is monitoring using sputum smear microscopy alone rather than sputum smear and culture, more or less likely to lead to the outcomes listed in Table 2 below?
3.	When designing regimens for patients with MDR-TB, is the inclusion of specific drugs (with or without documented susceptibility) more or less likely to lead to the outcomes listed in Table 2?
4.	When designing regimens for patients with MDR-TB, is the inclusion of fewer drugs in the regimen (depending on the drug used, the patient's history of its use and isolate susceptibility) more or less likely to lead to the outcomes listed in Table 2?
5.	In patients with MDR-TB, is shorter treatment, compared with the duration currently recommended by WHO, more or less likely to lead to the outcomes listed in Table 2?
6.	In patients with HIV infection and drug-resistant TB receiving antiretroviral therapy, is the use of drugs with overlapping and potentially additive toxicities, compared with their avoidance, more or less likely to lead to the outcomes listed in Table 2?
7.	Among patients with MDR-TB, is ambulatory therapy, compared with inpatient treatment, more or less likely to lead to the outcomes listed in Table 2?

Table 2Most important possible outcomes when making decisions on choice of testing and treatment strategies for drug-resistant-TB

Outcomes (text in parentheses shows the same outcome rephrased in the negative)		Average score	Relative importance
1.	Cure (treatment failure)	8.7	Critical
2.	Prompt initiation of appropriate treatment	8.3	Critical
3.	Avoiding the acquisition or amplification of drug resistance	8.1	Critical
4.	Survival (death from TB)	7.9	Critical
5.	Staying disease-free after treatment; sustaining a cure (relapse)	7.6	Critical
6.	Case holding so the TB patient remains adherent to treatment (default or treatment interruption due to non-adherence)	7.6	Critical
7.	Population coverage or access to appropriate treatment of drug-resistant TB	7.5	Critical
8.	Smear or culture conversion during treatment	7.4	Critical
9.	Accelerated detection of drug resistance	7.4	Critical
10.	Avoid unnecessary MDR-TB treatment	7.2	Critical
11.	Population coverage or access to diagnosis of drug-resistant TB	7.1	Critical
12.	Prevention or interruption of transmission of drug-resistant TB to other people, including other patients and health-care workers	6.9	Important but not critical
13.	Shortest possible duration of treatment	6.7	Important but not critical
14.	Avoiding toxicity and adverse reactions from anti-tuberculosis drugs	6.5	Important but not critical
15.	Cost to patient, including direct medical costs and other costs such as transportation and lost wages due to disability	6.4	Important but not critical
16.	Resolution of TB signs and symptoms; ability to resume usual life activities	6.3	Important but not critical
17.	Interaction of anti-tuberculosis drugs with non-TB medications	5.6	Important but not critical
18.	Cost to the TB control programme	5.4	Important but not critical

1–3 points	Not important for making recommendations on choice of testing and treatment strategies for drug-resistant TB^*
4–6 points	Important but not critical for making recommendations on choice of testing and treatment strategies
7–9 points	Critical for making recommendations on choice of testing and treatment strategies

*: None of the outcomes was scored in this category.

Table 3Groups of second-line anti-tuberculosis agents referred to in these guidelines

Group name	Anti-tuberculosis agent	Abbreviation
Second-line parenteral agent (injectable anti-tuberculosis drugs)	kanamycin	Km
	amikacin	Amk
	capreomycin	Cm

Fluoroquinolones	levofloxacin	Lfx
	moxifloxacin	Mfx
	gatifloxacin	Gfx
	ofloxacin	Ofx

Oral bacteriostatic second-line anti-tuberculosis drugs	ethionamide	Eto
	prothionamide	Pto
	cycloserine	Cs
	terizidone	Trd
	p-aminosalicylic acid	PAS

Group 5 drugs	clofazimine	Cfz
	linezolid	Lzd
	amoxicillin/clavulanate	Amx/Clv
	thioacetazone	Thz
	clarithromycin	Clr
	imipenem	Ipm

: NB. Other drugs not generally considered as second-line anti-tuberculosis agents were also used to treat drug-resistant TB in some of the cohorts included in this analysis. These included the parenteral agent viomycin, the fluoroquinolones ciprofloxacin and sparfloxacin, as well as azithromycin, roxithromycin, high-dose isoniazid and thioridazine, which were included under the Group 5.

Table 4Quality of evidence and definitions (8)

Quality of evidence	Definition
High (⊕⊕⊕⊕)	Further research is very unlikely to change our confidence in the estimate of effect.
Moderate (⊕⊕⊕○)	Further research is likely to have an important impact on our confidence in the effect and may change the estimate.
Low(⊕⊕○○)	Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low (⊕○○○)	Any estimate of effect is very uncertain.

Table 5Assessment of the strength of a recommendation

Strength	Definition
Strong	The Guideline Development Group is confident that the desirable effects of adherence to the recommendation outweigh the undesirable effects.
Conditional	The Guideline Development Group concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects.

Table 6Implications of the strength of a recommendation for different users (5)

Perspective	Strong recommendation	Conditional recommendation
For patients	Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.	The majority of individuals in this situation would want the suggested course of action, but many would not.
For clinicians	Most individuals should receive the intervention. Adherence to this recommendation according to the guidelines could be used as a quality criterion or performance indicator.	Recognize that different choices will be appropriate for individual patients, and that patients must be helped to arrive at a management decision consistent with their values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences.
For policy-makers	The recommendation can be adapted as policy in most situations.	Policy-making will require substantial debate and involvement of various stakeholders.