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Welcome to the TB Working Group of CORE Group

March 22, 2010 We will start at 10:30 am, eastern time

Sarah Royce, MD

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

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http://www.who.int/tb/publications/2 010/2010/en/index.html
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Outline
Why a fourth edition New recommendations Integrating MDR prevention, diagnosis, and treatment into the National TB Program (NTP) Implementation: what will it take?

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
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Critique of prior WHO guidelines

Not evidence-based Too much dependence on expert opinion Decisions not transparent

Oxman, Lancet 2007; 369

New WHO requirements for guidelines: formulate questions

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:
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 Daily Daily Daily 3 times per week 3 times per week Recommendation #2. (Strength) Optimal (Strong)

Acceptable alternative for any new TB patient receiving DOT (Conditional) 3 times Acceptable alternative (Conditional) per week 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 3 times per week Daily 3 times per week 3 times per week Recommendation #4.1-3 (Strength) (Strong) Acceptable alternative (Conditional) 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 Days to weeks

Approach to retreatment Use DST results to decide if MDR regimen needed Start empiric regimen while awaiting DST results. Once DST results available, may change regimen. Use empiric regimen for full course of treatment.
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Conventional

None (Interim)

Not available

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MDR likelihood (patient registration group) Type of High Medium (after failure) (relapse, default) DST 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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