Welcome to the TB Working
Group of CORE Group
March 22, 2010
We will start at 10:30 am, eastern time
Sarah Royce, MD
2
WHO
Treatment of Tuberculosis
Guidelines, 2009
What’s new?
TB working group, CORE Group
March 22, 2010
Sarah Royce, MD, MPH
University of California, San Francisco
SarahRoyceMD@gmail.com
http://www.who.int/tb/publications/2
010/2010/en/index.html
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Outline
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•
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Why a fourth edition
New recommendations
Integrating MDR prevention, diagnosis, and
treatment into the National TB Program
(NTP)
Implementation: what will it take?
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Universal access to quality TB care
for all TB patients
• No longer assign lower priority to patients
•
with smear negative or MDR disease (formerly
Category 3, 4)
Detection and treatment of MDR-TB should
be an integral part of NTP activities
6
Critique of prior WHO guidelines
• Not evidence-based
• Too much dependence on expert opinion
• Decisions not transparent
Oxman, Lancet 2007; 369
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New WHO requirements for
guidelines: formulate questions
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Duration of rifampin in new patients
Dosing frequency in new patients
TB treatment in people living with HIV
Sputum monitoring and treatment
extension
Regimen for new TB patients in countries
with high levels of isoniazid resistance
Use of the 8 month retreatment regimen
with first line drugs (“Cat 2”)
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New WHO requirements
• Retrieve and synthesize all available
evidence, assess quality using GRADE
• External experts develop recommendations
based on:
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–
–
–
Quality of the evidence
Balance between potential benefits and harms
Patient values and preferences
Resource use
• Explain reasons (transparency)
http://www.gradeworkinggroup.org/
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Strength of recommendations
• Strong (“should”): desirable effects clearly
outweigh undesirable
– High quality evidence, large certain benefit
• Conditional (“may”): trade offs are uncertain
– Evidence is lacking or low quality
– Benefits small or difficult to quantify, may not justify
cost
• Weak: insufficient evidence (based on field
application and expert opinion)
• Not rated: quality of evidence not assessed
using GRADE methodology
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Duration of rifampin in new
pulmonary TB patients
Recommendation #1. (Strong)
• New pulmonary TB patients should receive
a regimen with 6 months of rifampin:
2HRZE / 4HR*
• Phase out 2HRZE / 6HE regimen
*Key: H Isoniazid, Rifampin, Z Pyrazinamide,
Ethambutol, Streptomycin
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Basis for 6 month R regimen
• High quality of evidence showing that changing
to a 6 month R regimen would avert:
– 112 relapses per 1000 new TB patients, and
– 3-12 deaths per 1000 new TB patients
• Benefits outweigh risks (possible increase in
acquired MDR, which could be mitigated by
strengthening patient support)
• Cost to supervise R in continuation phase may
be offset by savings from avoiding retreatments
• Patients will value disease-free survival
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Dosing frequency in new pulmonary
TB patients receiving 6R
Intensive Continuatio
n
Recommendation #2. (Strength)
Daily
Daily
Optimal (Strong)
Daily
3 times per
week
Acceptable alternative for any new TB
patient receiving DOT (Conditional)
3 times
3 times per
per week week
Acceptable alternative (Conditional)
provided the patient is:
• receiving DOT, and
• not living with HIV or in an HIV
prevalent setting
Note: Daily intensive-phase dosing may help prevent acquired
drug resistance in TB patients starting treatment with isoniazid
resistance
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Dosing frequency of TB treatment for
people living with HIV*
Intensive Continuatio
n
Daily
Daily
Recommendation #4.1-3 (Strength)
Daily
Acceptable alternative (Conditional)
3 times per
week
3 times
3 times per
per week week
(Strong)
No longer an option
*also for TB patients living in HIV prevalent settings, defined as
countries, subnational administrative units or selected facilities
where the HIV prevalence among adult pregnant women is > 1%
or > 5% among TB patients
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TB treatment for people living with HIV
Recommendation #4.4 (Strong): receive at
least the same duration of TB treatment as
HIV negative patients
Includes new WHO recommendations* to
• Start antiretroviral treatment in all HIVinfected individuals with active TB,
irrespective of CD4 cell count
• Start TB treatment first, followed by ART as
soon as possible after starting TB treatment
*WHO. Rapid advice: antiretroviral therapy for HIV infection in adults and
adolescents. 2009. http://www.who.int/hiv/pub/arv/advice/en/
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Sputum monitoring during treatment
of smear + pulmonary TB
Recommendation #5.1 (Conditional): sputum
smear microscopy may be performed at the
completion of the intensive phase of first line
drug regimens
Basis: smear status at the end of the intensive
phase is a poor predictor of relapse, failure
and pretreatment isoniazid resistance.
Still recommended because:
•
•
Useful indicator of TB program performance
Positive smear should trigger assessment of the
patient, as well as additional sputum monitoring
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Sputum monitoring, new patients
Recommendations #5.2-3 (Strong): if specimen
obtained at end of intensive phase is smear +, repeat
at end of third month. If still positive, obtain culture
and DST
Failure: + bacteriology
at 5th month or later, or
MDR detected any time
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Treatment extension in new
pulmonary TB patients receiving 6R
Recommendation #6 (Strong): extension of the
intensive phase is not recommended if a
positive sputum smear is found at completion
of the intensive phase
Basis:
• preliminary results from one moderate quality
study show modest reduction in relapse
• insufficient evidence to determine which patients
most likely to benefit
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Sputum monitoring, previously
treated patients on first line drugs
Recommendation #5.4 (Strong): if specimen obtained
at end of intensive phase is sm +, obtain culture, DST
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Drug resistance
• In new patients
– In countries with high levels of isoniazid
resistance in new patients, how prevent
MDR?
• In previously treated patients
– Which (if any) groups of patients should
receive a retreatment regimen with first line
drugs?
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Why concern about isoniazid
resistance in new patients?
• Outcomes are significantly worse than for
patients with isoniazid susceptible disease
– Risk of failure 11x higher, and relapse 2x higher
• It’s a stepping stone to MDR
– 5x higher risk of acquired drug resistance
• It’s common: Globally, 7% of new patients
resistant to at least isoniazid (but not yet to
rifampin).
Menzies D. PLoS Med, 2009; WHO/Union. Anti-TB drug resistance, 4th report, 2008.
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Regimen for new patients where level
of isoniazid resistance is high*
• Recommendation #3 (Weak): New patients
may receive isoniazid, rifampin, and
ethambutol (HRE) for continuation phase
treatment, as an alternative to isoniazid and
rifampin (HR)
• Based on expert opinion (insufficient
evidence)
*Where H susceptibility testing is not done or results not
available before the continuation phase
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Urgent need for research
To determine the:
• Most effective treatment for isoniazid
resistant TB
• Level of isoniazid resistance that would
warrant the additional of ethambutol or other
drugs to continuation phase of all new
patients
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Why concern about previously
treated patients?
• Comprise 13% of global TB notifications
• Have MDR levels 5x higher than new patients
• Low treatment success with first line drug
retreatment regimen (2HRZES/HRZE/5HRE)
- For patients who have relapsed 74%
- Returning after default
64%
- Whose prior treatment failed
58%
WHO, Global TB Report, 2009;
WHO/Union Anti-TB drug resistance 4th report, 2008
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MDR in retreatment TB cases,
10 countries, 1997-2007
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Previously treated patients
Recommendation #7. (Not rated)
• Obtain specimens for culture and DST at or
before the start of retreatment
• Perform DST for at least isoniazid, rifampin
The approach to initiating retreatment depends
on when/if DST results are available (country’s
laboratory capacity)
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Type of
DST
Rapid
Results
available
Hours to
days
Approach to
retreatment
Use DST results to
decide if MDR regimen
needed
Conventional Days to
weeks
Start empiric regimen
while awaiting DST
results. Once DST
results available, may
change regimen.
None
(Interim)
Use empiric regimen for
full course of treatment.
Not
available
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MDR likelihood
(patient registration group)
Type of
High
Medium
DST
(after failure)
(relapse, default)
Rapid
DST results guide choice of regimen
from the start
While awaiting DST results (empiric):
MDR regimen 2HRZES/HRZE/5HR
Conventiona
E
l
Modify on basis of DST results once
available
None
Interim: See section 3.7.3
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Country-specific drug resistance data
NTPs should obtain and use their countryspecific drug resistance data on failure,
relapse and default patient groups to
determine the levels of MDR (rec #7.5)
Need to verify or modify the assignment of:
• Failure patients to high likelihood of MDR
• Relapse and default patients to moderate
likelihood of MDR
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1st line drug retreatment regimen for
patients in groups with medium levels
of MDR, pending DST results (rec #7)
Example: 30% of relapse patients have MDR
Benefit: retreatment regimen with first line
drugs is not supported by evidence from
clinical trials
Harm: 30% with MDR will be inadequately
treated while awaiting DST results
Menzies, PLoS 2009
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How high a level of MDR in a group
warrants starting an empiric MDR
regimen while awaiting DST results?*
Policy decision for each NTP based on factors
such as:
• Number of MDR-TB patients the country has
the capacity to enroll in MDR treatment
• Short term risk of death from MDR-TB due to
concomitant conditions (especially HIV)
*If rapid molecular based testing not available
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Universal access to quality TB care
for all TB patients
• Detection and treatment of MDR-TB should
be an integral part of NTP activities
Will the new recommendations help?
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Integrating MDR detection into NTP
Obtain specimens for culture and DST:
• At start of treatment for
–
–
–
–
all previously treated patients (rec #7)
TB patients with known contact to MDR-TB
HIV positive TB patients
New patients if level MDR in new patients >3%
• During treatment
– If new patients are sm+ at months 2, 3 (rec #5)
– If previously treated patients are sm+ at month 3 (rec
#5)
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Integrating MDR treatment into NTP
NTPs need 3 standard regimens:
• “New patient regimen” with 6 months of R
• “Retreatment regimen with first line drugs”
(Rapid molecular-based DST makes this
regimen obsolete)
• “MDR regimen”
Begin empiric MDR treatment if high likelihood
of MDR (and rapid DST not available) (rec #7)
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Prevention of MDR
Prevent transmission of MDR:
• Early detection, MDR treatment
Avoid acquiring MDR during treatment:
• Adequate patient support and supervision
• Fixed dose combinations (FDC), patient kits
• Daily intensive phase dosing (rec #2,4)
• Intermittent dosing no longer an option for
retreatment with first line drugs
• May use HRE continuation phase if high levels
H resistance in new patients (rec #3)
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Implementation—What will it take?
• Expanding treatment supervision and patient
support so countries:
– can safely use R throughout therapy (rec #1)
– provide daily dosing at least during intensive
phase (rec #2, 4)
• Expansion of DST capacity (espec. rapid tests)
– Global Lab Initiative
http://www.who.int/tb/dots/laboratory/gli/en/index.html
• Scale up of MDR treatment
– Green Light Committee Initiative
http://www.who.int/tb/challenges/mdr/greenlightcommittee/en
/index.html
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Better drug resistance data
• Routine DST of all previously treated TB cases,
reason for retreatment (ongoing surveillance)
• Periodic drug resistance surveys of new cases
(until routine DST available for all new cases)
For choice of regimens and program planning
To evaluate these recommendations
– Ensure TB programs are saving lives without
generating drug resistance
See also WHO. Guidelines for the surveillance of drug resistance in TB. 2009.
http://www.who.int/tb/publications/2009/en/index.html
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External expert group members
S. Cavalcante
J. Chakaya (Chair)
S. Egwaga
R. Gie
P. Gondrie
T. Harries
P. Hopewell
B. Kumar
K. Lambregts
S. Mase
R. Menzies
A. Nakanwagi
M. Nasehi
A. Nunn
H. Schunemann
Z. Udwadia
A. Vernon
R. Vianzon
G. Williams
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More acknowledgements:
WHO and others
M. Aziz
L. Blanc
M. Espinal
G. Gargioni
H. Getahun
R. Granich
M. Grzemska (Lead)
S. Hill
S. Keshavjee
E. Jaramillo
F. Mirzayev
S. Ottmani
O. Oxlade
P. Phillips
K. Weyer
D. Ortega
M. Raviglione
A. Reid
K. Steingart
M. Zignol
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Additional references
1. Menzies D et al. Effect of duration and intermittency of rifampin on
TB treatment outcomes – A systematic review and meta-analysis.
PLoS Med. 2009; 6(9): e1000146.
doi:10.1371/journal.pmed.1000146.
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjour
nal.pmed.1000146
2. Menzies D et al. Standardized treatment patients with previous
treatment and/or with mono-resistance to isoniazid – a systematic
review and meta-analysis. PLoS Med. 2009; 6(9): e1000150.
doi:10.1371/journal.pmed.1000150
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjour
nal.pmed.1000150
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