Transcript Revision of WHO Tx Guidelines DEWG Oct09 Dr M.Grzemska []

Revising the WHO
TB Treatment Guidelines
Process and new recommendations
Malgosia Grzemska
Matteo Zignol
Stop TB Department
World Health Organization
DEWG meeting, 13-14 October 2009
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Outline
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Rationale for revision
New WHO methods for guidelines development
Overview of the 7 questions
New recommendations and supporting evidence
Focus on: Previously treated patients
Research needs
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Need for revision of Treatment Guidelines
to implement Stop TB Strategy
• Universal access to quality TB care
• Current treatment categories assign lower priority to
smear negative patients, and MDR
• Programmatic management of MDR (within NTPs)
• 7 of 22 high TB burden countries have > 1 lab
performing culture per 5 million population
• < 5% of the world’s 500,000 MDR cases notified
• Green Light Committee covers <5% of world’s MDR
• Treatment of HIV associated TB
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WHO guidelines are insufficiently
transparent and not evidence based
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Lack of use of systematic reviews
Lack of transparency about judgements
Too much dependence on expert opinion
Insufficient resources
Oxman, Lavis & Fretheim, Lancet. 2007; 369
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New WHO requirements
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Define scope and target audience
Formulate precise questions and critical outcomes
Retrieve and synthesize all available evidence
Summarize evidence using standard template
Assess of quality of evidence (GRADE)
Consider resource use, patient values and
preferences
• Link evidence to recommendations, explaining
reasons for judgements
Source: WHO Handbook for guideline development, March 2008
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Questions for revision
Question 1. Duration of rifampicin for treatment of new
patients?
• 2HRZE/6HE vs. 2HRZE/4RH
Question 2. Dosing frequency?
• Daily throughout
• Daily intensive/3x weekly
• 3 times weekly throughout
Question 3. High levels of isoniazid resistance
• Adding a drug in continuation phase to "protect
rifampicin"
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Questions for revision (2)
Question 4. TB treatment in presence of HIV?
• Length of treatment and dosing frequency
Question 5. Sputum monitoring (at 2 months and later)?
• Sputum monitoring for predicting relapse, failure and
pre-treatment isoniazid resistance?
Question 6. TB treatment extension?
• Extension of the intensive phase or the continuation
phase for reducing failure or relapse
Question 7. Previously treated cases
• Which groups of patients should receive a retreatment
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regimen with first line drugs?
Overview of methods
• Systematic literature review for each question
• Evidence synthesized and presented to the
Guideline Group
• GRADE methodology used for evaluating
quality of evidence
• Recommendations based on:
– quality of the evidence,
– values, and costs,
– feasibility of implementation at country level
– judgments about trade offs between benefits
and harms.
Guideline Group – meeting on recommendations, Paris October 2008
Question 1.
Should new pulmonary TB patients be treated with
the 6 months or the 2 months rifampicin regimen?
Recommendations
• New patients should receive a regimen containing 6
months of RIF: 2HRZE / 4HR.
• The treatment regimen with 2 months RIF: 2HRZE/6HE
should be phased out.
Supporting evidence
• Shorter RIF significantly associated with higher Relapse
• 2RIF somewhat associated with higher Failure
• If Drug resistance – absolute difference between 2RIF and
6RIF even greater
Question 2. When a country selects 2HRZE/4HR,
should patients be treated with a daily or 3 times
weekly intensive phase?
Recommendations
• Where feasible, the optimal dosing frequency for new
patients is TB is daily throughout the course of therapy
• New patients may receive a daily intensive phase
followed by three times weekly continuation phase
• Three times weekly dosing throughout therapy
[2(HRZE)3 / 4(HR)3] is another alternative as long as:
– patient is receiving directly observed therapy of every
dose, and
– patient NOT living with HIV or living in an HIVprevalent setting.
• New patients with TB should not receive twice weekly
dosing for the full course of treatment
Question 2. When a country selects 2HRZE/4HR,
should patients be treated with a daily or 3 times
weekly intensive phase?
• Supporting evidence
– No significant increase in failure, relapse, or acquired drug
resistance in pan-susceptible patients - when comparing daily
dosing throughout therapy with the intermittent regimens
– Patients receiving three times weekly dosing throughout therapy
had 3.3 times higher rates of acquired drug resistance than patients
who received daily treatment
– For patients with INH resistance, three times weekly intensive
phase - significantly higher risk of failure and acquired drug
resistance
– Insufficient data to support the use of regimens that are given two
times weekly throughout therapy. On operational grounds, missing
one dose means the patient receives only half the regimen
Question 3. What should be the continuation
phase in countries with high levels of
isoniazid resistance
Recommendations
• In populations with known (or suspected) high
levels of INH resistance, new TB patients may
receive HRE - in the continuation phase
• Supporting evidence
– Inadequate evidence to quantify the ability of
ethambutol to “protect rifampicin”
– Expert opinion based
Question 4. Should intermittent regimens be
used for persons living with HIV? What should
be the duration of TB treatment in people living
with HIV?
Recommendations
• TB patients living with HIV and TB patients living in HIV
prevalent settings should receive daily TB treatment (at
least during the intensive phase)
• For the continuation phase, the optimal dosing frequency
is also daily for these patients
• If a daily continuation phase not possible, three times
weekly dosing during the continuation phase acceptable
• TB patients living with HIV receive the same duration of
TB treatment as HIV-negative TB patients
Question 4. Should intermittent regimens be
used for persons living with HIV? What should
be the duration of TB treatment in people living
with HIV?
Supporting evidence
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Double rate of failure and relapse if intermittent
regimen administered throughout
No change in failure, relapse and death if regimen
prolonged to 9 months
Use of ARV significantly reduces failure, relapse
and death
Question 5. How effective is sputum monitoring
for predicting relapse, failure and pre-treatment
INH resistance?
Recommendations
• For smear positive pulmonary TB patients,
sputum smear microscopy may be performed at
completion of the intensive phase (end 2 months)
• If at end of 2 months smear positive – repeat
smear microscopy at the end of 3 months
• If at end of 3 months smear positive – send for
culture and DST
Question 5. How effective is sputum monitoring
for predicting relapse, failure and pre-treatment
INH resistance?
Supporting evidence
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Sputum smear at month 2 or 3 of treatment has
limited utility in predicting relapse
Quality of evidence in most studies that assessed
failure - very low
Main rationale for recommending the addition of a
3 month sputum smear - detect poor response to
therapy (due to DR or MDR) earlier than 5 month
Question 6.
In new patients, how effective is treatment
extension for preventing failure or relapse?
Recommendations
• In patients treated with the regimen containing
Rifampicin for 6 months, if a positive sputum
smear is found at completion of the intensive
phase, the extension of the intensive phase is not
recommended
Question 6.
In new patients, how effective is treatment
extension for preventing failure or relapse?
Supporting evidence
• Preliminary results from 1 moderate quality study
shows only modest benefit in decreasing risk of
relapse
• Historically, when the new patient regimen
included only 2 months of RIF, the extension of the
intensive phase meant an extra month of RIF. This
extra month is less important now, when the
recommended regimen is 6 month of rifampicin.
Question 7.
Previously treated cases
• Which (if any) groups of patients should
receive a retreatment regimen with first line
drugs?
– What is the best regimen for previously
treated patients, so that if they have MDR,
they receive effective treatment?
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Question 7.
Previously treated cases
Recommendations
• All previously treated TB patients should have
culture and DST done before or at the start of
treatment.
• In settings where rapid DST is available, the
results should guide the choice of regimen
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Question 7. Previously treated cases
Recommendations
• In settings where rapid DST results are not routinely
available, empiric treatment should be started as follows:
– TB patients whose treatment has failed or other patient
groups with high likelihood of MDR-TB should be started on
an empiric MDR regimen.
– TB patients returning after defaulting or relapsing from their
first treatment may receive the retreatment regimen
containing first line drugs 2HRZES / 1HRZE / 5HRE
– As soon as DST results known – regimens should be
adjusted
– NTPs should obtain and use their country-specific drug
resistance data of failure, relapse and default patient groups
to determine the levels of MDR.
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Question 7. Previously treated cases
Supporting evidence
• Studies using WHO standard retreatment
(2SHRZE/1HRZE/5HRE)
– RCT in Retreatment – None
– RCT in New cases – None
– Cohorts in Retreatment – 12 arms with 1,410
patients
D. Menzies, TDG meeting, Paris 21-23 October 2008
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Question 7. Previously treated cases
Supporting evidence
• A few Cohort studies have been reported:
– Largest groups were pan-sensitive
– In INH resistant – Varying, but poor results
– In Mixed (most like programme conditions)
• Highly variable results, but mostly POOR
• Perhaps reflecting underlying drug resistance
– No data in Strep resistant, or Poly-drug
resistance (other than MDR)
D. Menzies, TDG meeting, Paris 21-23 October 2008
MDR-TB among previously treated TB
cases, 1994-2007 (IV Global DRS Report)
< 6%
6 - 20%
20 - 40 %
>40 %
No data
* Sub-national coverage in India, China,
Russia, Indonesia.
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health
Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on
maps represent approximate border lines for which there may not yet be full agreement.
 WHO 2006. All rights reserved
MDR in retreatment TB cases from drug
resistance surveys and surveillance in 10
countries, 1997-2007
100%
80%
32%
32%
49%
60%
40%
20%
0%
Relapses
Failures
Defaulters
1,283 cases*
206 cases*
208 cases*
Not MDR
*data from 12 settings in 10 countries
MDR
“Retreatment”
Treatment success (cure + complete) for patients:
• Who have relapsed
74% (54% - 87%)
• Returning from default
65% (36% - 74%)
• Smear + after 5th month (fail) 58% (27% - 69%)
Source: WHO, Global TB Control, 2009 Report
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Research needs (proposed by Guideline Group)
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In new smear-positive pulmonary TB patients
who have failed first line TB treatment, does an
empirical MDR-TB regimen compared with the
standard WHO retreatment regimen with first
line drugs increase treatment success rate and
reduce failure at the end of this second course
of TB treatment?
What is the level of MDR in subgroups of
previously treated patients: failed first vs.
subsequent course of therapy, returned after
defaulting, relapsed?