“International” TB treatment guidelines – The new WHO treatment recommendations

““International” TB International” TB treatment guidelines – treatment guidelines –

The new WHO treatment The new WHO treatment recommendationsrecommendations

Dr Dick MenziesDr Dick Menzies

Montreal Chest InstituteMontreal Chest Institute

McGill University, CanadaMcGill University, Canada

Overview of talkOverview of talk

Evidence based guidelines – why, and Evidence based guidelines – why, and how?how?

The recent WHO TB treatment The recent WHO TB treatment guidelines:guidelines:The questionsThe questionsThe evidence The evidence The recommendationsThe recommendations

Evidence-based guidelines – Evidence-based guidelines – why?why?

““Old” WHO way - “Expert panels”Old” WHO way - “Expert panels” Group of experts meet to ‘discuss’Group of experts meet to ‘discuss’ Opinions exchanged – not always politelyOpinions exchanged – not always politely Best/strongest/loudest/longest talker ‘wins’Best/strongest/loudest/longest talker ‘wins’

Lancet paper – VERY critical of processLancet paper – VERY critical of process ““New” WHO way – guidelines committeesNew” WHO way – guidelines committees

Evidence reviewed before hand – Evidence reviewed before hand – Evidence presented by non-committee membersEvidence presented by non-committee members Recommendations based on evidence presentedRecommendations based on evidence presented Best evidence wins (much less room for opinion)Best evidence wins (much less room for opinion)

Evidence-based guidelines – Evidence-based guidelines – How?How?

Step 1 – Ask the questions:Step 1 – Ask the questions:What is really wrong with current guidelines?What is really wrong with current guidelines?

Patients fail, or die, or relapse?Patients fail, or die, or relapse?What are the most important programmatic What are the most important programmatic

problemsproblemsTreatment is too long, or patients defaultTreatment is too long, or patients default

Step 2 – Involve the “evidence – gatherers”Step 2 – Involve the “evidence – gatherers”These are different people. Not necessarily TB These are different people. Not necessarily TB

experts. Objective. Fair. Disciplined. Thorough. experts. Objective. Fair. Disciplined. Thorough. (good looking, smart….)(good looking, smart….)

Evidence-based guidelines – Evidence-based guidelines – How?How?

Step 3 – Conduct a systematic reviewStep 3 – Conduct a systematic reviewDevelop selection criteria – FIRST Develop selection criteria – FIRST

These are based on study methodsThese are based on study methodsSearch the published literatureSearch the published literature

All possibly relevant papersAll possibly relevant papersRead MANY papers – select those that meet Read MANY papers – select those that meet

criteria – the right patients, the right methodscriteria – the right patients, the right methodsStep 4 – Meta-analysisStep 4 – Meta-analysis

Produce an estimate of effect – how well does Produce an estimate of effect – how well does the drug/regimen work overall?the drug/regimen work overall?

WHO treatment recommendations for new, WHO treatment recommendations for new, and previously treated cases -The Questionsand previously treated cases -The Questions

1. In new cases:1. In new cases: How long should Rifampin be given?How long should Rifampin be given?What is the optimal schedule – ie what What is the optimal schedule – ie what

intermittency is optimal?intermittency is optimal? 2. Should treatment be modified for HIV-2. Should treatment be modified for HIV-

TB?TB? 3. What is the evidence for the current 3. What is the evidence for the current

retreatment regimen?retreatment regimen?How to treat INH resistance?How to treat INH resistance?

Systematic review and meta-analysis.Systematic review and meta-analysis.Q1: Q1: Treatment of new casesTreatment of new cases

Estimate failure, relapse, or acquired Estimate failure, relapse, or acquired drug resistance in previously untreated drug resistance in previously untreated patients.patients.Duration of RifampinDuration of RifampinIntermittent therapyIntermittent therapy

MethodsMethods

Search strategySearch strategyMedline (1950-April 2008), EMBASE Medline (1950-April 2008), EMBASE

(1988-2008), Cochrane Central (1988-2008), Cochrane Central Register of Controlled Trials (through Register of Controlled Trials (through first quarter 2008)first quarter 2008)

Selection of studies by 2 reviewersSelection of studies by 2 reviewers1 - titles and abstracts1 - titles and abstracts

2 - full-text articles – if disagreement 2 - full-text articles – if disagreement then reviewed with 3rd reviewerthen reviewed with 3rd reviewer

Criteria for Study selection Criteria for Study selection

Published in English, French or SpanishPublished in English, French or Spanish Randomized Trials onlyRandomized Trials only

Rifampin containing regimensRifampin containing regimens Standardized treatment (s)Standardized treatment (s)

New cases – no previous treatmentNew cases – no previous treatment Bacteriologically confirmed Bacteriologically confirmed

Initial diagnosis – culture positiveInitial diagnosis – culture positive Failure and/or Relapse – culture positiveFailure and/or Relapse – culture positive

Drug Sensitivity testing: Drug Sensitivity testing: PRE – in allPRE – in all POST – in failures / relapsesPOST – in failures / relapses

Methods - Statistical AnalysisMethods - Statistical Analysis

Pooled results across all studiesPooled results across all studiesEach arm within each study = Each arm within each study =

independent cohortindependent cohort Random effects meta-analysisRandom effects meta-analysis I-squared statistic calculated to I-squared statistic calculated to

assess heterogeneityassess heterogeneity meta-regression was used to adjust meta-regression was used to adjust

for other potentially confounding for other potentially confounding patient and treatment covariates:patient and treatment covariates:Age, initial drug-resistance, DOT, Age, initial drug-resistance, DOT,

completion of follow-upcompletion of follow-up

Treatment of New cases Treatment of New cases Summary of study review and selectionSummary of study review and selection

Identified from PubMed, EMBASE, Cochrane Database literature search: (after eliminating duplicates)

2215 titles1978 titles excluded

Titles retained for review of abstracts: 237 78 abstracts excluded after review 9 Reviews

25 Not RCT/Cohort (case control, prevalence, cross sectional design, program report) 1 Regimen not reported 8 Outcomes not by Regimen 17 No outcomes 4 Individualized treatment 4 Latent TB/Non M.TB Non pulmonary TB 3 MDR TB 2 Not drug therapy

Full text reviewed: 301

135 additional full texts identified from references and

reviews

75 Reports included

(57 Trials)

109 were excluded after review 4 Reviews 4 Not RCT/Cohort (case control, prevalence, cross sectional design, program report) 8 Regimen not reported 16 Outcomes not by Regimen 30 No Outcomes 12 Individualized treatment 4 Latent TB/Non M.TB/Non pulmonary TB 1 MDR TB, 9 Not drug therapy 2 Mono-therapy 19 other

Rates of treatment failure or Rates of treatment failure or recurrence - randomized trial of recurrence - randomized trial of

rifampin throughout (2HRZE / 4HR) rifampin throughout (2HRZE / 4HR) vs. rifampin for the first 2 months vs. rifampin for the first 2 months

(2HRZE / 6HE)(2HRZE / 6HE)

Lancet 2004; 364: 1244-51

HIV negative New cases HIV negative New cases Duration of Rifampin and Duration of Rifampin and FailureFailure

(17,000+ patients in 57 trials)

Rifampin Rifampin durationduration

Arms Arms (N)(N)

Events/Events/

SubjectSubjectss

EvenEvent t

raterate

(95% CI)(95% CI)

1-2 months1-2 months 7272 94/413394/4133 1.8%1.8% (0.2, (0.2, 3.3)3.3)

3-5 months3-5 months 4242 16/250816/2508 0.3%0.3% (0.0, (0.0, 0.6)0.6)

6-7 months6-7 months 178178 150/1006150/100600

0.4%0.4% (0.1, (0.1, 0.7)0.7)

8+ months8+ months 2020 12/160712/1607 0.3%0.3% (0, 0.6)(0, 0.6)

HIV negative New casesHIV negative New casesDuration of Rifampin and Duration of Rifampin and RelapseRelapse

(17,000+ patients in 57 trials)

Rifampin Rifampin durationduration

Arms Arms (N)(N)

Events/Events/

SubjectSubjectss

EvenEvent t

raterate

(95% CI)(95% CI)

1-2 months1-2 months 6767 373/354373/35455

10.810.8%%

(6.4, (6.4, 15.2)15.2)

3-5 months3-5 months 3737 182/256182/25611

6.1%6.1% (3.0, (3.0, 9.1)9.1)

6-7 months6-7 months 174174 384/923384/92300

3.4%3.4% (2.5, (2.5, 4.3)4.3)

8+ months8+ months 2525 19/215119/2151 0.9%0.9% (0.3, 1.5)(0.3, 1.5)

Duration of Rifampin and treatment Duration of Rifampin and treatment outcomes in new cases (non-HIV)outcomes in new cases (non-HIV)((17,000+ patients in 57 trials - Results of Meta-Results of Meta-

regression)regression)

RifampiRifampin n duratiodurationn

Failure Failure

IRR (95% IRR (95% CI)CI)

Relapse Relapse


ADRADR


1-2 1-2 monthsmonths

2.2 (1.8, 2.2 (1.8, 2.9)2.9)

2.5 (3.4, 2.5 (3.4, 7.1)7.1)

3.3 (2.1, 3.3 (2.1, 5.0)5.0)


0.8 (0.5, 0.8 (0.5, 1.2)1.2)

2.1 (1.7, 2.1 (1.7, 2.5)2.5)

1.9 (1.2, 1.9 (1.2, 3.0)3.0)


1.0 1.0 (reference)(reference)


1.0(referenc1.0(reference)e)

8+ 8+ monthsmonths

1.2 (0.8, 1.2 (0.8, 1.8)1.8)

0.5 (0.4, 0.5 (0.4, 0.8)0.8)

1.5 (0.8, 1.5 (0.8, 2.9)2.9)

Duration of Rifampin – WHO Duration of Rifampin – WHO recommendationsrecommendations

2HRZE/4HR – the 6-month RIF regimen –2HRZE/4HR – the 6-month RIF regimen –

“ “The regimen of first choice for all new The regimen of first choice for all new casescases””

2HRZE/6HE – the 2-month RIF regimen –2HRZE/6HE – the 2-month RIF regimen –

“ “Should be phased out as rapidly as Should be phased out as rapidly as possible”possible”

1717

Intermittent therapyIntermittent therapy

Possible because of long half life of Possible because of long half life of drugsdrugs

And slow growth of M TBAnd slow growth of M TB Intermittent therapy does workIntermittent therapy does work

In-vitro (cultures only)In-vitro (cultures only)In animal studiesIn animal studiesIn humans – randomized trialsIn humans – randomized trials

What is the lowest frequency?What is the lowest frequency?How early can it start?How early can it start?

Systematic review and meta-analysis.Systematic review and meta-analysis.Q1: Intermittent Treatment of new Q1: Intermittent Treatment of new

casescases Methods - Same search and Methods - Same search and

selection as for duration of RIFselection as for duration of RIF

1919

Intermittent regimens and Intermittent regimens and FailureFailure

Administration of drugs

Arms (N)

Pooled event rate

95% Conf Interval

All Daily 173 2.6% 1.8 – 3.4

Daily initially – then intermittent

76 2.0% 0.4 – 3.7

All Intermittent

– thrice weekly

53 2.7% 0.1 - 4.4

All Intermittent

– twice weekly

17 8.8% 1.5 – 16

2020

Intermittent regimens and Intermittent regimens and RelapseRelapse

Administration of drugs

Arms (N)

Pooled event rate

95% Conf Interval

All Daily 149 6.7% 5.4 – 8.0

Daily initially – then intermittent

65 7.0% 5.1 – 8.9

All Intermittent

– thrice weekly

52 6.8% 5.6 – 8.1

All Intermittent

– twice weekly

17 10.7% 7.2 – 14.3

Effect of Intermittent regimensEffect of Intermittent regimens(New cases – HIV negative)(New cases – HIV negative)(Twice weekly dropped from analysis)(Twice weekly dropped from analysis)

DosingDosing

schedulschedulee

Failure Failure


Relapse Relapse


ADRADR


Daily Daily throughout throughout




Daily then Daily then thrice weekly thrice weekly

0.8 (0.5, 1.3)0.8 (0.5, 1.3) 1.0 (0.7, 1.3)1.0 (0.7, 1.3) 0.9 (0.4, 1.8)0.9 (0.4, 1.8)

Daily then Daily then twice weekly twice weekly

1.3 (0.9, 1.8)1.3 (0.9, 1.8) 0.8 (0.7, 1.1)0.8 (0.7, 1.1) 0.7 (0.4, 1.1)0.7 (0.4, 1.1)

Thrice weekly Thrice weekly throughoutthroughout

1.3 (0.97, 1.3 (0.97, 1.7)1.7)

1.1 (0.9, 1.3)1.1 (0.9, 1.3) 4.9 (3.3, 4.9 (3.3, 7.4)7.4)

2222

Intermittency and relapse: a meta-Intermittency and relapse: a meta-analysis. analysis.

(Chang et al, Am J Resp Crit Care Med. 2006; 174: (Chang et al, Am J Resp Crit Care Med. 2006; 174: 1153-58)1153-58)

Systematic review of 17 studies with 5,208 patients, Systematic review of 17 studies with 5,208 patients, and 200 relapse events.and 200 relapse events.

Higher risk Higher risk if cavitation or 2 month culture positive if cavitation or 2 month culture positive

Daily through-out Daily through-out – Lowest: – Lowest: RR= 1.0RR= 1.0

Daily then 3X weeklyDaily then 3X weekly: : RR = 1.6RR = 1.6

Daily then 2X weeklyDaily then 2X weekly: : RR = 2.8RR = 2.8

3x weekly through-out3x weekly through-out: : RR = 5.0RR = 5.0

- greatest increase if cavitation or 2 month culture - greatest increase if cavitation or 2 month culture positivepositive

- Also greater if followed by 1X weekly Rifapentine- Also greater if followed by 1X weekly Rifapentine

2323

Intermittent therapy for TB in Intermittent therapy for TB in children – meta-analysischildren – meta-analysis. . (Ramesh Menon (Ramesh Menon

et al, Indian Pediatrics. 2009; May 20)et al, Indian Pediatrics. 2009; May 20)

Systematic review and meta-analysis – children Systematic review and meta-analysis – children less than 16. Four trials with 466 childrenless than 16. Four trials with 466 children

Daily therapy had higher cure ratesDaily therapy had higher cure rates

Twice weekly intermittent had Odds of cure: Twice weekly intermittent had Odds of cure: Per protocol: Per protocol: 0.27 (0.15, 0.51)0.27 (0.15, 0.51)

Intention to treat: Intention to treat: 0.66 (0.23, 1.84)0.66 (0.23, 1.84)

2424

Summary - Intermittent Summary - Intermittent therapytherapy

Intermittent regimens facilitates DOTIntermittent regimens facilitates DOTOnce weekly = totally unacceptable Once weekly = totally unacceptable Twice weekly = worse resultsTwice weekly = worse resultsThrice weekly = slightly worseThrice weekly = slightly worse

OK under ideal conditionsOK under ideal conditionsBUT – worse if HIV infected or drug resistant BUT – worse if HIV infected or drug resistant

Best is daily therapy in first two monthsBest is daily therapy in first two monthsThen can switch to intermittentThen can switch to intermittent

If self-administered – give dailyIf self-administered – give daily

Intermittent regimens – WHO Intermittent regimens – WHO recommendationsrecommendations

Daily through-out – considered the Daily through-out – considered the standard of care standard of care

Daily then intermittent 3X/week Daily then intermittent 3X/week acceptable alternative acceptable alternative

Thrice weekly ‘can be used – Thrice weekly ‘can be used – conditional’conditional’

Twice weekly – should not be usedTwice weekly – should not be used

Q2: Treatment of HIV co-Q2: Treatment of HIV co-infected TB cases:infected TB cases:

Assess the impact on Assess the impact on failurefailure, , relapserelapse and and death during death during treatmenttreatment of active TB in of active TB in HIV-infected patients of:HIV-infected patients of:

i)i) Duration of rifampin or Duration of rifampin or rifabutinrifabutin

ii)ii) Dosing schedule (daily vs. Dosing schedule (daily vs. intermittent) in the initial intermittent) in the initial intensive phase of therapyintensive phase of therapy

Q2: HIV-TB treatment - Q2: HIV-TB treatment - methodsmethods

Same search strategy and methods Same search strategy and methods of reviewof review

Except, studies included if:Except, studies included if:RCT or Cohort studiesRCT or Cohort studies

Included:Included:6 Randomized trials6 Randomized trials21 Cohort studies21 Cohort studies

Adjusted incidence rate ratios (aIRR) of Adjusted incidence rate ratios (aIRR) of failure and relapse in HIVTB cases for failure and relapse in HIVTB cases for

DurationDuration of Rifamycin of Rifamycin

Duration of Rifampin

Failure:aIRR* (95% CI)

Relapse:aIRR* (95% CI)

2 Months 1.3 (0.4, 4.1)

3.6 (1.1, 11.7)

6 Months 1.0 (0.4, 2.8)

2.4 (0.8, 7.4)

≥8 Months 1.0 (reference)

1.0 (reference)

Adjusted incidence rate ratios (aIRR) of Adjusted incidence rate ratios (aIRR) of failure and relapse in HIVTB cases by failure and relapse in HIVTB cases by

IntermittencyIntermittency (dosing schedule) (dosing schedule)

Dosing schedule

Failure:IRR (95% CI)

Relapse:IRR (95% CI)

Initial phase daily

1.0 (reference)

1.0 (reference)

Initial phase thrice weekly

4.0 (1.5, 10.4)

4.8 (1.8, 12.8)

Overall p value

(.02) (.002)

3030

Other studies: Efficacy of a 6-month Other studies: Efficacy of a 6-month vs 9-month intermittent regimen in vs 9-month intermittent regimen in HIV infected patients with TB – an HIV infected patients with TB – an RCTRCT. . (Swaminanthan et al, Am J Resp Crit Care Med; (Swaminanthan et al, Am J Resp Crit Care Med;

2010; 181: 743-51)2010; 181: 743-51)

327 HIV-TB adults randomized to 6 vs 9 months 327 HIV-TB adults randomized to 6 vs 9 months therapytherapy

Bacteriologically confirmed relapseBacteriologically confirmed relapse::

Relapse with 9 monthsRelapse with 9 months: 7% RR: 1.0 (reference): 7% RR: 1.0 (reference)

Relapse with 6 months: Relapse with 6 months: 15% RR: 2.0 (1.3, 3.2)15% RR: 2.0 (1.3, 3.2)

FailureFailure: 19 P: 19 Patients failed - 15 developed acquired atients failed - 15 developed acquired MDR, and 4 developed RIF Mono-ResistanceMDR, and 4 developed RIF Mono-Resistance

If INH resistance 30% vs 5% if DSIf INH resistance 30% vs 5% if DS

Failure with MDR if H resistant: 8.4 times Failure with MDR if H resistant: 8.4 times more likely (2.2, 32)more likely (2.2, 32)

WHO recommendationsWHO recommendations

No difference in duration – 6 monthsNo difference in duration – 6 months9 months if other risk factors for relapse9 months if other risk factors for relapse

Avoid intermittent therapy initiallyAvoid intermittent therapy initially

Interestingly in India……..Interestingly in India……..Will move to 9 months for all HIV-TBWill move to 9 months for all HIV-TBBut initially 3 times weeklyBut initially 3 times weekly

Q3. RetreatmentQ3. RetreatmentPreviously treated patients are more likely to Previously treated patients are more likely to

have DR-TB. Treatment is more complexhave DR-TB. Treatment is more complexMost likely – Mono-resistance (INH, or Strep)Most likely – Mono-resistance (INH, or Strep)Also poly-resistance (INH & EMB or INH & Strep)Also poly-resistance (INH & EMB or INH & Strep)And MDR-TBAnd MDR-TB

Can one regimen treat all this?Can one regimen treat all this?WHO “Cat 2”. The standard retreatment regimenWHO “Cat 2”. The standard retreatment regimen2SHRZE/1HRZE/5HRE2SHRZE/1HRZE/5HRE

Q3. Questions for DR-TB Q3. Questions for DR-TB treatment/ retreatmenttreatment/ retreatment

Does standard therapy work – if Does standard therapy work – if mono- or poly-drug resistant? mono- or poly-drug resistant? (Dogma (Dogma “INH Mono-R is of no “INH Mono-R is of no significance clinically”)significance clinically”)

What is the evidence for the current What is the evidence for the current retreatment regimen (Cat 2)retreatment regimen (Cat 2)

What is the treatment for INH mono-What is the treatment for INH mono-resistance?resistance?

Does standard initial therapy work Does standard initial therapy work – if drug resistance? – if drug resistance? FailureFailure

Systematic review of 57 studies with 20,000 Systematic review of 57 studies with 20,000

patientspatients.. Initial Initial Drug Drug

ResistancResistancee

Arms Arms (N)(N)

Events/Events/

SubjectsSubjectsEvenEven

t t raterate

(95% CI)(95% CI)

Pan-Sensitive 127127 121/1511121/151177

0.3%0.3% (0.1, 0.4)(0.1, 0.4)

INH resistant 6868 26/48326/483 3.0%3.0% (0.7, (0.7, 5.3)5.3)

Streptomycin Resistant

5454 6/3166/316 1.3%1.3% (0, 2.8(0, 2.8

Poly-drug resistance

4242 41/28741/287 8.4%8.4% (2.1, (2.1, 14.7)14.7)

Does standard initial therapy work – Does standard initial therapy work – if drug resistance? if drug resistance? RelapseRelapse

Systematic review of 57 studies with 20,000 patients.Systematic review of 57 studies with 20,000 patients.

Initial Initial Drug Drug

ResistancResistancee

Arms Arms (N)(N)

Events/Events/

SubjectsSubjectsEvenEven

t t raterate

(95% CI)(95% CI)

Pan-Sensitive 124124 685/135685/1350808

3.4%3.4% (2.5, 4.3)(2.5, 4.3)

INH resistant 6666 60/40860/408 10.610.6%%

(5.8, 15)(5.8, 15)


5454 36/29936/299 9.3%9.3% (4.1, (4.1, 14.5)14.5)


4242 26/21726/217 9.8%9.8% (3.8, 16)(3.8, 16)

Does standard initial therapy work – if Does standard initial therapy work – if drug resistance? drug resistance? (Meta-regression)(Meta-regression)

Initial Initial Drug Drug

resistancresistancee

Failure Failure IRR (95% IRR (95%

CI)CI)

RelapseRelapse IRR (95% IRR (95%

CI)CI)

Acquired Acquired drugdrug

resistanceresistance


Pan-Sensitive




INH resistant

9.8 (7.2, 9.8 (7.2, 13.7)13.7)

2.2 (1.7, 30)2.2 (1.7, 30) 6.3 (4.1, 6.3 (4.1, 9.5)9.5)


6.4 (3.9, 6.4 (3.9, 10.2)10.2)

2.0 (1.4, 2.0 (1.4, 2.8)2.8)

7.0 (4.3, 7.0 (4.3, 11.6)11.6)


28 (19, 40)28 (19, 40) 2.2 (1.5, 2.2 (1.5, 3.2)3.2)

12.9 (8.3, 12.9 (8.3, 20)20)

What is the evidence for What is the evidence for the current the current WHO standard retreatment WHO standard retreatment

(2SHRZE/1HRZE/5HRE)(2SHRZE/1HRZE/5HRE)

Systematic review – all yearsSystematic review – all yearsRCT or cohort studiesRCT or cohort studies

What is the evidence for What is the evidence for the current the current WHO standard retreatment WHO standard retreatment

(2SHRZE/1HRZE/5HRE)(2SHRZE/1HRZE/5HRE)

NO randomized trials foundNO randomized trials found7 cohorts only – some quite small7 cohorts only – some quite small

Results of the WHO retreatment Results of the WHO retreatment regimen in regimen in Mono-resistance to INHMono-resistance to INH

((2HRZES/1HRZE/5HRE2HRZES/1HRZE/5HRE))

Total Number Total Number TreatedTreated

Number (%) Number (%) who Failedwho Failed

39 7 (7 (18%18%))

31 6 (6 (19%19%))

18 8 (8 (44%44%))

Results of the WHO retreatment Results of the WHO retreatment regimen in mixed drug resistant regimen in mixed drug resistant

strains strains (No MDR)(No MDR)((2HRZES/1HRZE/5HRE2HRZES/1HRZE/5HRE))

Treatment Scheme Treated (N)

Failure & Relapse

2[HRZES]3/1[HRZE]3/5[HRE]3 46 8.7%

2[HRZES]3/1[HRZE]3/5[HRE]3 389 13.4%

2HRZES/1HRZE/5HRE 183 25.7%

2[HRZES]3/2[HRZE]3/5[HRE]3 11 45.5%

What is the evidence for What is the evidence for treatment of INH resistant TBtreatment of INH resistant TB

Systematic review – all patients with INH Systematic review – all patients with INH mono-resistance, or other DR-TB, or mono-resistance, or other DR-TB, or retreatmentretreatment

All Randomized trials over past 50 yearsAll Randomized trials over past 50 yearsDouble blind, Controlled, Double blind, Controlled, Standard regimens to each armStandard regimens to each armMicrobiologically confirmed outcomes Microbiologically confirmed outcomes

Failure and RelapseFailure and RelapseAcquired drug resistanceAcquired drug resistance

The evidence for treatment of drug resistant The evidence for treatment of drug resistant TB TB

RCT in Drug resistance / Re-RCT in Drug resistance / Re-treatmenttreatment

Number by decade when they started enrolmentNumber by decade when they started enrolment

0

10

20

30

40

Nu

mb

er

of

stu

die

s

1950's 1960's 1970's 1980's 1990's 2000

Year study started

Note: To date NO phase 3 trial in MDR-TB

Intermittent therapy and Intermittent therapy and Treatment outcomes - INH Treatment outcomes - INH

resistance resistance (from multivariate meta-regression)(from multivariate meta-regression)

FailureFailureIRR IRR

(95% CI)(95% CI)

RelapseRelapseIRR IRR

(95% CI)(95% CI)

Acquired Acquired drug drug

resistanceresistanceIRR (95% CI)IRR (95% CI)

Daily InitiallyDaily Initially 1.0 1.0 (reference)(reference)

1.0(reference)1.0(reference) 1.0(referenc1.0(reference)e)

3X weekly thru-3X weekly thru-outout

3.0 (2.0, 3.0 (2.0, 4.5)4.5)

1.5 (0.9, 2.5)1.5 (0.9, 2.5) 2.4 (1.4, 2.4 (1.4, 4.2)4.2)


2.4 (1.6, 2.4 (1.6, 3.5)3.5)

4.5 (1.9, 4.5 (1.9, 10.7)10.7)

1.5 (0.9, 2.5)1.5 (0.9, 2.5)

Number of drugs in initial phase to Number of drugs in initial phase to which strains sensitive - INH which strains sensitive - INH

resistanceresistance (from multivariate meta-regression)(from multivariate meta-regression)

Number of Number of DrugsDrugs

FailureFailureIRR (95% CI)IRR (95% CI)

RelapseRelapseIRR (95% CI)IRR (95% CI)

Acquired drug Acquired drug resistanceresistance

IRR (95% CI)IRR (95% CI)

11 10.0 (3.9, 28)10.0 (3.9, 28) 6.8 (1.3, 36)6.8 (1.3, 36) No obs.No obs.

2 2 5.0 (2.4, 11.0)5.0 (2.4, 11.0) 4.6 (1.7, 4.6 (1.7, 12.2)12.2)

60 (4.0, 60 (4.0, 99)99)

3 3 3.1 (1.5, 6.7)3.1 (1.5, 6.7) 3.8 (1.5, 3.8 (1.5, 10.0)10.0)

27 (1.7, 27 (1.7, 99)99)

4 4 1.0 (reference)1.0 (reference) 1.0 1.0 (reference)(reference)


Q3. Retreatment – WHO Q3. Retreatment – WHO recommendationsrecommendations

In the absence of any clear evidence:In the absence of any clear evidence:Retreatment regimen retained for:Retreatment regimen retained for:

RelapseRelapseRetrun after defaultRetrun after default

But, strong recommendation for Drug But, strong recommendation for Drug Sensitivity Testing for all previously Sensitivity Testing for all previously treated patientstreated patients

Evidence neededEvidence needed

Summary -Summary -The evidence based The evidence based

approach for Current approach for Current WHO WHO treatment guidelinestreatment guidelines

Well defined step-wise processWell defined step-wise process Lengthy evidence gatheringLengthy evidence gathering

Which is rigorous and objectiveWhich is rigorous and objective Committee recommendation based on evidenceCommittee recommendation based on evidence

Reduces reliance on expert opinion Reduces reliance on expert opinion The major weakness of the process:The major weakness of the process:

IfIf the evidence is weak the evidence is weak

Treatment of Drug resistant TB Treatment of Drug resistant TB (retreatment) EVIDENCE IS NEEDED(retreatment) EVIDENCE IS NEEDED

Recent WHO treatment guidelines Recent WHO treatment guidelines – Most important points:– Most important points:

Duration of RIF – 6 months minimumDuration of RIF – 6 months minimum8-9 months if risk for relapse8-9 months if risk for relapse

Initial phase (2 months) – Daily preferredInitial phase (2 months) – Daily preferredEspecially if HIV, or DR-TBEspecially if HIV, or DR-TBContinuation can be 3 times weeklyContinuation can be 3 times weeklyAvoid twice weeklyAvoid twice weekly

HIV-TB – preference for longer duration, daily HIV-TB – preference for longer duration, daily therapytherapy

Treatment of Drug resistant TB (retreatment) Treatment of Drug resistant TB (retreatment) EVIDENCE IS NEEDEDEVIDENCE IS NEEDED

Thank you!Thank you!TeşekkürlerTeşekkürler!!

Merci!Merci!

Intermittent therapy and Treatment Intermittent therapy and Treatment outcomes – with initial INH outcomes – with initial INH

resistance resistance (from multivariate meta-regression)(from multivariate meta-regression)

FailureFailureIRR IRR

(95% CI)(95% CI)

RelapseRelapseIRR IRR

(95% CI)(95% CI)

Acquired Acquired drug drug

resistanceresistanceIRR (95% CI)IRR (95% CI)

Daily InitiallyDaily Initially 1.0 1.0 (reference)(reference)

1.0(reference)1.0(reference) 1.0(referenc1.0(reference)e)


3.0 (2.0, 3.0 (2.0, 4.5)4.5)

1.5 (0.9, 2.5)1.5 (0.9, 2.5) 2.4 (1.4, 2.4 (1.4, 4.2)4.2)


2.4 (1.6, 2.4 (1.6, 3.5)3.5)

4.5 (1.9, 4.5 (1.9, 10.7)10.7)

1.5 (0.9, 2.5)1.5 (0.9, 2.5)

Effect of Intermittent regimens on Failure, Relapse, and Effect of Intermittent regimens on Failure, Relapse, and ADRADR

AcknowledgementsAcknowledgements Initial design and planning:Initial design and planning:

Woojin Lew, Madhu Pai, Olivia OxladeWoojin Lew, Madhu Pai, Olivia Oxlade Study review:Study review:

Woojin Lew, Dan Martin, Anita Paydar, Ian Woojin Lew, Dan Martin, Anita Paydar, Ian MartinMartin

Data analysis:Data analysis:Andrea Benedetti, Madhu PaiAndrea Benedetti, Madhu Pai

Secretarial (tables, tables and more tables)Secretarial (tables, tables and more tables)Anita Paydar and Ria ChoeAnita Paydar and Ria Choe

Effect of rifampin on plasma concentrations of Protease Inhibitors (% of normal AUC)

Effect of rifampin on plasma concentrations of Protease Inhibitors (% of normal AUC)

0102030405060708090

100

SQV RTV IDV NLV AMP LPV ATV

Perc

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f nor

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*

Clin Infect Dis 1999; 28: 419-30

*

With 100 mg RTV

12th CROI, abstract 657

Effect of rifabutin on plasma Effect of rifabutin on plasma concentrations of Protease concentrations of Protease

Inhibitors Inhibitors (% of normal AUC)(% of normal AUC)

0102030405060708090

100


Clin Infect Dis 1999; 28: 419-30

What is the right approach for What is the right approach for Retreatment? Since there is no clear Retreatment? Since there is no clear

best regimenbest regimen……

Based on likelihood of drug resistance – NATIONAL Based on likelihood of drug resistance – NATIONAL approachapproach

Predict - based on Initial drug resistancePredict - based on Initial drug resistance Know – from surveillance in 3 types of Know – from surveillance in 3 types of

Retreatment casesRetreatment cases Based on reason for retreatment – at least 2 Based on reason for retreatment – at least 2 regimensregimens

Failures – Failures – PredictionPrediction - highly likely MDR - highly likely MDR Relapse – Relapse – PredictionPrediction - less MDR – but variable - less MDR – but variable Return after default – Insufficient published Return after default – Insufficient published

evidence evidence Consider previous treatmentConsider previous treatment

2RIF vs 6RIF2RIF vs 6RIF

Documents

“International” TB treatment guidelines – The new WHO treatment recommendations