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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
WHO guidelines for the
programmatic management of
drug-resistant TB : 2011 update
D Falzon,1 E Jaramillo,1 H Schünemann2:
The PMDT Guideline Development Group
(1) Stop TB Dept, WHO, Switzerland.
(2) McMaster University, Canada.
European Respiratory Society
Annual Congress 2011
Amsterdam, The Netherlands
WHO/HTM/TB/2011.6
Previous versions of the Guidelines
2006
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2008
Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
2011 update of PMDT Guidelines
Early 2009 : Evaluation of old guidelines
Mid-2009 : Scoping
Late 2009 - Early 2010 : Evidence reviews
October 2010 : Guideline Development Group Meeting
December 2010 : first draft of Guideline
February 2011 : WHO Guideline Review Committee approval
June 2011 : release of 2011 update of Guidelines
August 2011 : online publication in European Respiratory Journal
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Priority questions (1)
A Guideline Development Group of experts on various aspects of MDR-TB
identified 7 priority questions to be tacked by the future update :
1) At what prevalence of MDR-TB in any group of TB patients is rapid drugsusceptibility 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
treatment success (and other outcomes) ?
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 treatment success (and other outcomes) ?
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Priority questions (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 treatment success (and other outcomes) ?
5) In patients with MDR-TB, is shorter treatment, compared with the
duration currently recommended by WHO, more or less likely to lead
to treatment success (and other outcomes) ?
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 treatment success (and other outcomes) ?
7) Among patients with MDR-TB, is ambulatory therapy, compared
with inpatient treatment, more or less likely to lead to treatment
success (and other outcomes) ?
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Evidence Reviews
Teams based in leading academic centres
assessed existent evidence for the questions
using :
- Systematic reviews of literature (as per
Cochrane Handbook)
- Meta-analysis of individual patient data
- Simulations using modelling
- Cost-effectiveness analysis
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
The quality of evidence
Quality
High
Moderate
Low
Very low
Definition
Further research is very unlikely to change our
confidence in the estimate of effect.
Further research is likely to have an important impact
on our confidence in the effect and may change the
estimate.
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.
Any estimate of effect is very uncertain.
Guyatt GH et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
BMJ. 2008 Apr 26;336(7650):924-6
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Implications of the strength of a
recommendation for different users
Adapted from Guyatt GH et al. GRADE Working Group. Going from evidence to recommendations.
BMJ, 2008, 336(7652):1049–1051
Guidelines for the programmatic management of drug-resistant TB 2011 Update
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ERS Congress, Amsterdam, Sep 2011
Recommendation 1
Rapid drug susceptibility testing (DST) of isoniazid
and rifampicin or of rifampicin alone is
recommended over conventional testing or no
testing at the time of diagnosis of TB, subject to
available resources (conditional recommendation /
very low quality evidence)
Evidence : simulations from modelling work
Rapid DST of INH & RIF at the time of diagnosis was the most cost
effective testing strategy for any patient group or setting, even at very
low levels of resistance among TB patients (MDR-TB in >1% and
isoniazid resistance (other than MDR-TB) in >2%).
Rifampicin resistance detected by Xpert MTB/RIF in patient groups in
whom MDR is rare has low predictive value and results need to be
confirmed by phenotypic DST or line probe assay.
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Recommendation 2
The use of sputum smear microscopy and culture
rather than sputum smear microscopy alone is
recommended for the monitoring of patients with
MDR-TB during treatment (conditional
recommendation / very low quality evidence)
Evidence : individual patient data and simulations from modelling
Monthly sputum smear microscopy and culture was the best strategy in
identifying failures earlier. Sputum smear microscopy alone resulted in
delayed detection of failure.
Sputum smear microscopy results are of use to clinicians in identifying
patients likely to fail their treatment and instituting infection control
measures in a timely manner. Resource implications are important.
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Recommendations 3 to 5
In the treatment of patients with MDR-TB, a
fluoroquinolone should be used (strong
recommendation / very low quality evidence).
In the treatment of patients with MDR-TB, a latergeneration fluoroquinolone rather than an earliergeneration fluoroquinolone should be used (conditional
recommendation / very low quality evidence).
In the treatment of patients with MDR-TB, ethionamide
(or prothionamide) should be used (strong
recommendation / very low quality evidence).
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Recommendations 6 and 7
In the treatment of patients with MDR-TB, four secondline anti-tuberculosis drugs likely to be effective
(including a parenteral agent), as well as pyrazinamide,
should be included in the intensive phase (conditional
recommendation / very low quality evidence).
In the treatment of patients with MDR-TB, regimens
should include at least pyrazinamide, a fluoroquinolone,
a parenteral agent, ethionamide (or prothionamide), and
either cycloserine or PAS (p-aminosalicylic acid) if
cycloserine cannot be used (conditional recommendation
/ very low quality evidence).
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Groups of second-line drugs
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
About recommendations 3 to 7
Evidence: meta-analysis of >9000 individual MDR-TB patient data from 32
published observational studies, none being randomised controlled trials (RCTs)
Bias may be due to use of certain drugs for sicker patients, incomplete
ascertainment of relapse, the under-representation of certain geographical
regions, and missing data for some of the variables examined. Adjustments
were made to try to counter these limitations but findings from this analysis
may not necessarily be generalizeable to all MDR-TB cases. XDR-TB patients
were excluded.
Clear benefit of fluoroquinolones, particularly later-generation drugs. Among
the oral bacteriostatic drugs, the association with cure was higher with
ethionamide than with cycloserine, which was higher than with PAS. No
particular parenteral agent was considered superior. No effect for Group 5
drugs or ethambutol.
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Changes in recommendations on regimen composition
between the 2008 and 2011 updates of the guidelines
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Recommendations 8 and 9
In the treatment of patients with MDR-TB, an intensive
phase of at least 8 months’ duration is recommended
(conditional recommendation / very low quality
evidence).
In the treatment of patients with MDR-TB, a total
treatment duration of at least 20 months is
recommended in patients without any previous MDRTB treatment (conditional recommendation / very low
quality evidence).
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
About recommendations 8 and 9
Evidence: same individual patient data meta-analysis as was used
for treatment regimen composition questions (recommendations
3 to 7)
Recommendation is not “pegged” to sputum conversion. Previous
recommendations (2008) were to use a parenteral agent for a
minimum of 6 months and at least 4 months past culture
conversion, and a minimum total length of treatment of 18
months after culture conversion. Most patients may be expected
to receive this length of treatment but in some it may have to be
modified depending on their bacteriological status and other
indicators of treatment progress
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Odds of success by duration of treatment
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Recommendation 10
Antiretroviral therapy is recommended for all patients with HIV
and drug-resistant TB requiring second-line anti-tuberculosis
drugs, irrespective of CD4 cell-count, as early as possible (within
the first 8 weeks) following initiation of anti-tuberculosis
treatment (strong recommendation / very low quality evidence).
Evidence: from 10 observational studies of treatment outcomes when antiretroviral
therapy (ART) and second-line anti-tuberculosis drugs were used together.
Available data did not allow assessment for a number of outcomes of interest, namely
avoiding the additional acquisition of drug resistance, preventing TB transmission,
sustaining relapse-free cure, establishing the optimal duration of MDR-TB treatment,
avoiding unnecessary MDR-TB treatment, and reducing cost and improving population
access to appropriate care.
The strength of the recommendation is based in part on indirect evidence from its use
in any patient with active TB, which shows large beneficial effects and a very high
mortality when ART is not employed, particularly in very immunocompromised patients
(CD4 cell-count <50 cells/mm3)
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Recommendation 11
Patients with MDR-TB should be treated using mainly
ambulatory care rather than models of care based
principally on hospitalization (conditional
recommendation / very low quality evidence
Evidence : cost-effectiveness modelled for all possible countries using a
probabilistic analysis of real data from four countries (Estonia, Peru, Philippines,
Russian Fed [Tomsk]). None were from RCTs.
The benefit of reduced transmission can only be expected if proper infection
control measures are in place in both the home and the clinic. Admission to
hospitals for patients who do not warrant it may also have important social and
psychological consequences which need to be taken into account. There may be
important barriers to accessing clinic-based ambulatory care, including distance
to travel and other costs to individual patients. Shifting costs from the service
provider to the patient has to be avoided, and implementation may need to be
accompanied by appropriate enablers.
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Research Gaps
This update revealed important gaps in knowledge, including:
- A lack of moderate or high quality evidence from randomized
controlled trials for optimizing treatment regimens in patients with
MDR-TB, including the best combination of drugs and treatment
duration;
- Lack of evidence for optimal drug regimens for treating patients
with isoniazid resistance, with XDR-TB and with non-MDR-TB
polydrug-resistance;
- Very limited information about treatment of paediatric MDR-TB;
- Identification of the most effective chemoprophylaxis for contacts
of MDR-TB cases;
- The therapy for symptomatic relief from adverse reactions linked
to second-line anti-tuberculosis drugs.
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011
Acknowledgements
WHO/HQ
Léopold Blanc, Chris Duncombe, Dennis Falzon, Christopher Fitzpatrick, Katherine Floyd, Haileyesus Getahun
Malgorzata Grzemska, Christian Gunneberg, Ernesto Jaramillo, Christian Lienhardt, Fuad Mirzayev, Paul Nunn,
Mario C. Raviglione, Delphine Sculier, Marco Antonio de Avila Vitoria, Fraser Wares, Karin Weyer, Matteo Zignol
Guideline Development Group
Jaime Bayona, José A. Caminero, Charles L. Daley, Agnes Gebhard, Myriam Henkens, Timothy H. Holtz, Joël
Keravec, Salmaan Keshavjee, Aamir J. Khan, Vaira Leimane, Andrey Mariandyshev, Carole D. Mitnick, Gloria
Nwagboniwe, Domingo Palmero, Ma. Imelda Quelapio, Michael L. Rich, Sarah Royce, Sabine Rüsch-Gerdes,
Archil Salakaia, Rohit Sarin, Holger Schünemann, Elena Skachkova, Francis Varaine
External Review Group
Samiha Baghdadi, Mercedes Becerra, Vineet Bhatia, Masoud Dara, Mirtha del Granado, Reuben Granich,
Lindiwe Mvusi, Nani Nair, Norbert Ndjeka, Wilfred A.C Nkhoma, Katsunori Osuga, Hendrik Simon Schaaf,
Catharina van Weezenbeek, Irina Vasilyeva, Wang Xie Xiu, Richard Zaleskis
Evidence review teams
Harvard University, US - Chunling Lu, Carole D. Mitnick, Richard A. White
McGill University, Canada - Melissa Bauer, Richard (Dick) Menzies, Olivia Oxlade
University of California (San Francisco), US - Gail Kennedy, George Rutherford, Karen Steingart
University of Washington, US - Matthew Arentz, David Horne, Patricia Pavlinac, Judd L. Walson
Consultant
Patricia Whyte
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Guidelines for the programmatic management of drug-resistant TB 2011 Update
ERS Congress, Amsterdam, Sep 2011