royce who treat guide 22 mar 10

7/28/2019 Royce WHO Treat Guide 22 Mar 10

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Welcome to the TBWorking Group of CORE

Group

March 22, 2010

We will start at 10:30 am, eastern


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Sarah Royce, MD

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WHOTreatment of

TuberculosisGuidelines, 2009

Whats new?TB working group, CORE GroupMarch 22, 2010

Sarah Royce, MD, MPHUniversity of California, SanFrancisco

[email protected]


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http://www.who.int/tb/publications/2010/2010/en/index.html

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Outline

Why a fourth edition

New recommendations

Integrating MDR prevention,diagnosis, and treatment into theNational TB Program (NTP)

Implementation: what will it take?


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Universal access to quality TBcare

for allTB patients

No longer assign lower priority topatients with smear negative or MDRdisease (formerly Category 3, 4)

Detection and treatment of MDR-TBshould be an integral part of NTP 6


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Critique of prior WHO

guidelines Not evidence-based

Too much dependence on expertopinion

Decisions not transparent

Oxman, Lancet 2007; 369


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for guidelines: formulate

questions

Duration of rifampin in newpatients

Dosing frequency in new patients

TB treatment in people living withHIV

Sputum monitoring and treatmentextension

Regimen for new TB patients incountries with high levels ofisoniazid resistance

Use of the 8 month retreatmentre imen with first line dru s (Cat


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New WHO requirements

Retrieve and synthesize allavailable evidence, assess qualityusing GRADE

External experts developrecommendations based on: Quality of the evidence

Balance between potential benefits and

harms Patient values and preferences

Resource use

Explain reasons (transparency)

http://www.gradeworkinggroup.o


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Strength ofrecommendations

Strong (should): desirable effectsclearly outweigh undesirable High quality evidence, large certain benefit

Conditional (may): trade offs areuncertain Evidence is lacking or low quality

Benefits small or difficult to quantify, may notjustify cost

Weak: insufficient evidence (based onfield application and expert opinion)

Not rated: quality of evidence not

assessed using GRADE methodology 10


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Duration of rifampin in newpulmonary TB patients

Recommendation #1. (Strong)

New pulmonary TB patients should

receive a regimen with 6 months ofrifampin: 2HRZE / 4HR*

Phase out 2HRZE / 6HE regimen

*Key: H Isoniazid, Rifampin, Z Pyrazinamide,Ethambutol, Streptomycin


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Basis for 6 month Rregimen

High quality of evidence showing thatchanging to a 6 month R regimenwould 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, whichcould be mitigated by strengtheningpatient support)

Cost to supervise R in continuation

phase may be offset by savings from 12


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pulmonary TB patientsreceiving 6R

Intensive

Continuation

Recommendation #2.(Strength)

Daily Daily Optimal (Strong)

Daily 3 times

per week

Acceptable alternative for any

new TB patient receiving DOT(Conditional)

3 timesper

week

3 timesper week

Acceptable alternative(Conditional) provided the

patient is: receiving DOT, and not living with HIV or in anHIV prevalent setting

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Note: Daily intensive-phase dosing may helpprevent acquired drug resistance in TB patients

starting treatment with isoniazid resistance


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treatment for

people living with HIV*

Intensive

Continuation

Recommendation #4.1-3(Strength)

Daily Daily (Strong)

Daily 3 timesper week

Acceptable alternative(Conditional)

3 timesper

week

3 timesper week

No longer an option

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*also for TB patients living in HIV prevalent settings,defined as countries, subnational administrativeunits or selected facilities where the HIV prevalenceamong adult pregnant women is > 1% or > 5%

among TB patients


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TB treatment for peopleliving with HIV

Recommendation #4.4 (Strong):receive at least the same durationof TB treatment as HIV negativepatients

Includes new WHOrecommendations* to

Start antiretroviral treatment in all

HIV-infected individuals with activeTB, irrespective of CD4 cell count Start TB treatment first, followed

by ART as soon as possible afterstarting TB treatment 15

*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 duringtreatment of smear +

pulmonary TBRecommendation #5.1 (Conditional):sputum smear microscopy may beperformed at the completion of theintensive phase of first line drugregimens

Basis: smear status at the end of theintensive phase is a poor predictor of

relapse, failure and pretreatmentisoniazid resistance.Still recommended because: Useful indicator of TB program

performance16

S i i


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Sputum monitoring, newpatients

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Recommendations #5.2-3 (Strong): ifspecimen obtained at end of intensivephase is smear +, repeat at end of thirdmonth. If still positive, obtain culture and

DST

Failure: + bacteriologyat 5th month or later, orMDR detected any time

T t t t i i


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Treatment extension innew pulmonary TB patients

receiving 6R

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Recommendation #6 (Strong):extension of the intensive phase isnot recommended if a positive

sputum smear is found at completionof the intensive phase

Basis:

preliminary results from one moderatequality study show modest reduction inrelapse

insufficient evidence to determine

Sp t m monitoring


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Sputum monitoring,previously treated patients

on first line drugs

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Recommendation #5.4 (Strong): if specimenobtained at end of intensive phase is sm +,obtain culture, DST


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Drug resistance

In new patients

In countries with high levels ofisoniazid resistance in newpatients, how prevent MDR?

In previously treated patients

Which (if any) groups of patientsshould receive a retreatmentregimen with first line drugs?

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Why concern about


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Why concern aboutisoniazid resistance in new

patients? Outcomes are significantly worsethan for patients with isoniazidsusceptible disease

Risk of failure 11x higher, and relapse2x higher

Its a stepping stone to MDR

5x higher risk of acquired drugresistance

Its common: Globally, 7% of new

patients resistant to at least isoniazid21Menzies D. PLoS Med, 2009; WHO/Union. Anti-TB drug resistance, 4th


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Regimen for new patientswhere level of isoniazid

resistance is high* Recommendation #3 (Weak): Newpatients may receive isoniazid,rifampin, and ethambutol (HRE) forcontinuation phase treatment, as analternative to isoniazid and rifampin(HR)

Based on expert opinion (insufficientevidence)

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*Where H susceptibility testing is not done orresults not available before the continuation

phase


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Urgent need for research

To determine the:

Most effective treatment for isoniazidresistant TB

Level of isoniazid resistance thatwould warrant the additional ofethambutol or other drugs tocontinuation phase of all newpatients

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Why concern about


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Why concern aboutpreviously treated

patients?

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Comprise 13% of global TBnotifications

Have MDR levels 5x higher than newpatients

Low treatment success with first linedrug retreatment regimen(2HRZES/HRZE/5HRE)

- For patients who have relapsed 74%

- Returning after default 64%

- Whose prior treatment failed 58%

HO, Global TB Report, 2009;

HO/Union Anti-TB drug resistance 4th report, 2008

MDR in retreatment TB


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MDR in retreatment TBcases,

10 countries, 1997-2007

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Previously treated patients

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Recommendation #7. (Not rated)

Obtain specimens for culture and DSTat or before the start of retreatment

Perform DST for at least isoniazid,rifampin

The approach to initiating retreatmentdepends on when/if DST results areavailable (countrys laboratorycapacity)


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Type ofDST

Resultsavailable

Approach toretreatment

Rapid Hours todays

Use DST results todecide if MDR regimenneeded

Conventional Days toweeks

Start empiric regimenwhile awaiting DSTresults. Once DSTresults available, maychange regimen.

None(Interim)

Notavailable

Use empiric regimen forfull course of treatment.

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MDR likelihood(patient registration group)

Type ofDST

High(after failure)

Medium(relapse, default)

Rapid DST results guide choice of regimenfrom the start

Conventional

While awaiting DST results (empiric):

MDR regimen 2HRZES/HRZE/5HRE

Modify on basis of DST results onceavailable

None Interim: See section 3.7.3

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Country-specific drugresistance data

NTPs should obtain and use theircountry-specific drug resistance dataon failure, relapse and default

patient groups to determine thelevels 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 29

regimen for patients in


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regimen for patients ingroups with medium levels

of MDR, pending DSTresults (rec #7)

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Example: 30% of relapse patients

have MDRBenefit: retreatment regimen with

first line drugs is not supported by

evidence from clinical trialsHarm: 30% with MDR will be

inadequately treated while awaiting

DST resultsMenzies, PLoS 2009


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a group warrants startingan empiric MDR regimen

while awaiting DST results?*

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Policy decision for each NTP based on

factors such as: Number of MDR-TB patients the

country has the capacity to enroll inMDR treatment

Short term risk of death from MDR-TBdue to concomitant conditions(especially HIV)

*If rapid molecular based testing not available


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Universal access to quality TBcarefor allTB patients

Detection and treatment of MDR-TBshould be an integral part of NTPactivities

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Integrating MDR detectioninto 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) 33

I t ti MDR t t t


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Integrating MDR treatmentinto NTP

NTPs need 3 standard regimens: New patient regimen with 6

months of R

Retreatment regimen with firstline drugs

(Rapid molecular-based DST makes

this regimen obsolete) MDR regimen

Begin empiric MDR treatment if high

likelihood of MDR (and rapid DST 34


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Prevention of MDRPrevent transmission of MDR:

Early detection, MDR treatment

Avoid acquiring MDR during treatment:

Adequate patient support andsupervision

Fixed dose combinations (FDC),patient kits

Daily intensive phase dosing (rec#2,4)

Intermittent dosing no longer an 35

I l t ti Wh t ill


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ImplementationWhat willit take?

Expanding treatment supervisionand patient support so countries:

can safely use R throughout therapy(rec #1)

provide daily dosing at least duringintensive phase (rec #2, 4)

Expansion of DST capacity (espec.rapid tests)

Global Lab Initiativehttp://www.who.int/tb/dots/laboratory/gli/en/index.html

Scale up of MDR treatment

Green Light Committee Initiativehttp://www.who.int/tb/challenges/mdr/greenlightcom36

B tt d i t d t


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Better drug resistance data

Routine DST of all previously treatedTB cases, reason for retreatment(ongoing surveillance)

Periodic drug resistance surveys ofnew cases (until routine DSTavailable for all new cases)

For choice of regimens and programplanning

To evaluate these recommendations

Ensure TB programs are saving37

See also WHO. Guidelines for the surveillance of drug resistance in TB.2009.

External expert group


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External expert groupmembers

S. Cavalcante

J. Chakaya (Chair)

S. Egwaga

R. Gie

P. GondrieT. Harries

P. Hopewell

B. KumarK. Lambregts

S. Mase

R. Menzies

A. Nakanwagi

M. Nasehi

A. Nunn

H. SchunemannZ. Udwadia

A. Vernon

R. VianzonG. Williams

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More acknowledgements:WHO and others

M. AzizL. Blanc

M. Espinal

G. Gargioni

H. GetahunR. Granich

M. Grzemska (Lead)

S. Hill

S. Keshavjee

E. Jaramillo

F. MirzayevS. Ottmani

O. Oxlade

P. Phillips

K. Weyer

D. Ortega

M. Raviglione

A. ReidK. Steingart

M. Zignol

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Additional references

1. Menzies D et al. Effect of duration and intermittencyof rifampin on TB treatment outcomes A systematicreview and meta-analysis. PLoS Med. 2009; 6(9):e1000146. doi:10.1371/journal.pmed.1000146.

http://www.plosmedicine.org/article/info%3Adoi

%2F10.1371%2Fjournal.pmed.1000146

2. Menzies D et al. Standardized treatment patientswith previous treatment and/or with mono-resistanceto isoniazid a systematic review and meta-analysis.PLoS Med. 2009; 6(9): e1000150.

doi:10.1371/journal.pmed.1000150http://www.plosmedicine.org/article/info%3Adoi

%2F10.1371%2Fjournal.pmed.1000150

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royce who treat guide 22 mar 10

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