Drug-resistant TB in the world : Achievements & opportunities for treatment Dennis FALZON – WHO/HQ СЪЕЗД ФТИЗИАТРОВ РОССИИ (Г. ВОРОНЕЖ) 27 мая 2015

Drug-resistant TB in the world : Achievements & opportunities

for treatment

Dennis FALZON – WHO/HQ

СЪЕЗД ФТИЗИАТРОВ РОССИИ (Г. ВОРОНЕЖ)27 мая 2015 г.

The global TB situation (1)Global trends in estimated rates of TB incidence,

prevalence and mortality

Global trends in estimated incidence rate including HIV-positive TB (green) and estimated incidence rate of HIV-positive TB (red). The dashed lines represent the Stop TB Partnership targets of a 50% reduction in prevalence and mortality rates by 2015 compared with 1990. Shaded areas represent uncertainty bands. Mortality excludes TB deaths among HIV-positive people.

Rate

per

100

,000

per

yea

r

Rate

per

100

,000

per

yea

r

Rate

per

100

,000

pop

ulati

on

Estimated incidence, 2013

Estimated number of

deaths, 2013

1.1 million*(1.0–1.3 million)

9.0 million(8.6–9.4 million)

480,000(350,000–610,000)

All forms of TB

Multidrug-resistant TB

HIV-associated TB 1.1 million (1.0–1.2 million)

360,000(310,000–410,000)

Source: WHO Global Tuberculosis Report 2014 * Excluding deaths attributed to HIV/TB

210,000(130,000–290,000)

The global TB situation (2)

Percentage of new TB cases with MDR-TB

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 2014. All rights reserved

Percentage of previously treated TB cases with MDR-TB

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 2014. All rights reserved

Percentage of new and previously treated TB cases with MDR-TB globally and in the top 10 countries, 2014

Percentage of new and previously treated TB cases with MDR-TB globally and in the top 10 countries, 2014

MDR-TB cases estimated to occur among notified pulmonary TB cases, 2013

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 2014. All rights reserved

Countries that notified at least one case of XDR-TB

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 2014. All rights reserved

DR-TB surveillance and treatment

1st ed. DRS guidelines

Global Project launched

SRL network launched

2nd ed. DRS guidelines

1st global DRS report

2nd global DRS report

3rd ed. DRS guidelines

3rd global DRS report

4th global DRS report

4th ed. DRS guidelines

M/XDR-TB report

1994 1997 2000 2003 2004 2008 2009 2010 2015

2014 TB report

5th ed. DRS guidelines

beingfinalized

The Global Project on Anti-TB Drug Resistance Surveillance, 1994-2015

Progress in global coverage of surveillance data on drug resistance, 1994-2014

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 2014. All rights reserved

Diagnostic DST (1)For rifampicin +/- isoniazid in new bacteriologically-confirmed

TB cases, 2009-2013 (& projections 2011-15 as per Global Plan)

Diagnostic DST (3)For fluoroquinolones and second-line injectable drugs

among MDR-TB cases, 2013

RR-/MDR-TB notification and enrolmentMDR-TB cases and additional rifampicin-resistant TB cases detected (orange)

compared with TB cases enrolled on MDR-TB treatment (turquoise), global trend and trend in 27 high MDR-TB burden countries, 2009–2013

Outcomes of MDR-TB treatmentMDR-TB cohorts 2009-2011, top 10 MDR-TB burden countries*

*number of cases observed shown over the bars

Outcomes of XDR-TB treatmentXDR-TB cohorts 2011, by WHO Region*

*number of cases observed shown over the bars

Resistance to fluoroquinolones and second-line injectable drugs: impact on MDR-TB outcomes. Eur Respir J. 2012 Oct 25; doi: 10.1183/09031936.00134712

Treatment in MDR-TB+ (1)(circles=point estimates; lines=95% confidence limits)

Number of patients with laboratory-confirmed XDR-TB started on treatment in 2013

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 2014. All rights reserved

Countries that had used bedaquiline for the treatment of M/XDR−TB as part of expanded access, compassionate use or under normal

programmatic conditions by the end of 2013

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 2014. All rights reserved

WHO policy on programmatic management

of DR-TB

WHO guidance on the management of drug-resistant TB since 1996

Methods for WHO guidelines Evidence-based Systematic reviews Data from randomised controlled trials vs. observational studies Expert groups from broad constituencies GRADE method to:

assess the quality of evidence translate evidence into recommendations

Transparency; minimize bias; communicate uncertainties

The quality of evidenceDefinition QualityFurther research is very unlikely to change our confidence in the estimate of effect.

High

Further research is likely to have an important impact on our confidence in the effect and may change the estimate.

Moderate

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Low

Any estimate of effect is very uncertain. Very low

Guyatt GH et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924-6

Implications of the strength of a recommendation for different users

Adapted from Guyatt GH et al. GRADE Working Group. Going from evidence to recommendations. BMJ 2008; 336(7652):1049–1051

WHO Policy Development Framework• Partners (industry, researchers, consortia,

…)• Body of evidence available (publications,

SRA approval)

• Collection of data on pre-clinical and clinical development phases

• cost-effectiveness analysis

• Experts, methodologists, end-users • Guidelines Review Committee• GRADE process for evidence synthesis

• Peer-review by ERC• Strategic and Technical Advisory Group • Endorsement/revision/addition• Advise to WHO to proceed/not with policy

• Guidelines Review Committee • Dissemination to Member States• Promotion with stakeholders & funders• Phased implementation & scale-up plan

Development of new TBdrugs or new regimens

Reviewing the evidence

Convening an Expert Group

Developing policy proposaland recommendations

Formulating anddisseminating policy

4 Repurposed Drugs6 New Drugs

3 New Classes Drugs currently in the regulatory review process for MDR-TB

Bedaquiline & delamanid: timeline to WHO policy

December 2012 : conditional approval of Bdq by US FDA

January 2013 :WHO expert group meeting on Bdq

June 2013 : Release of WHO guidance on Bdq

April 2014 : conditional approval of Dlm by EMA

April 2014 : WHO expert group meeting on Dlm

October 2014 : Release of WHO guidance on Dlm

WHO guidance on bedaquiline : milestones (1)

• Data available from FDA public website• Request for additional specific data to Janssen • WHO commissions

• summary report of the publicly available evidence

• an assessment of the validity of sputum culture conversion at 6 months and time to culture conversion as surrogate markers of MDR-TB treatment outcomes

• a cost-effectiveness analysis based on modeling

WHO guidance on bedaquiline : milestones (2)Review of evidence by WHO

• Overall objective: • To evaluate the added benefit of bedaquiline for the treatment of MDR-TB

and, if appropriate, to provide recommendations to WHO for interim guidance on its use in conjunction with other second-line drugs used in MDR-TB treatment.

• Specific objectives: • To evaluate the efficacy and safety of bedaquiline in addition to currently

WHO recommended MDR-TB treatment;• To evaluate the balance between harms and benefits of the drug, its

potential cost-effectiveness, patient- and provider preferences and concerns, and the feasibility of introducing the drug in MDR-TB programmes;

• To provide, as appropriate, recommendations on the use of the drug as part of WHO-recommended MDR-TB treatment regimens, including attention to concerns/constraints relevant to the potential use of a new drug for which Phase III clinical trial data are not yet available.

WHO guidance on bedaquiline : milestones (3)WHO Guidelines Development Group

WHO guidance on bedaquiline : milestones (4)WHO Guidelines Development Group Meeting

• Review of data using GRADE method

• PICO question:• “In MDR-TB patients, does the addition of bedaquiline to a

background regimen based on WHO-recommendations safely improve patient outcomes?”

• Selected outcomes 1. Cure by 120 weeks 2. Serious adverse events during investigational 24 weeks treatment phase3. Mortality 4. Time to culture conversion over 24 weeks5. Culture conversion at 24 weeks6. Acquired resistance to second-line drugs (fluoroquinolones, amino-

glycosides and capreomycin) at 72 weeks

WHO guidance on bedaquiline : milestones (5)Phase 2b trial data

WHO guidance on bedaquiline : milestones (6)Study design (1)

Patients with MDR-TB were assigned in a 1:1 ratio to receive either bedaquiline (400 mg once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks) or placebo, plus a preferred five-drug, second-line anti-TB background regimen. Total treatment period was 18-24 months, during which bedaquiline was administered for 6 months. The total trial duration was 120 weeks (30 months), which included an anticipated 6-month period after the completion of treatment.

WHO guidance on bedaquiline : milestones (8)

WHO guidance on bedaquiline : milestones (9)

WHO guidance on bedaquiline : milestones (10)Trial C208 : QTcF changes from reference (ITT population)

WHO guidance on bedaquiline : milestones (11)Mortality

Study Type of study Bedaquiline PlaceboPhase 1 Deaths 0 0Phase 2Study C202* Deaths

Randomised, open-label, dose ranging, EBA study

N=452 (4.4%)

N=30 0

Trial C208 Stage 1 Deaths

Randomised, placebo-controlled, 8 week exposure

N=232 (8.7%)

N=242 (8.3%)

Trial C208 Stage 2 Deaths**

Randomised, placebo-controlled, 24 week exposure

N=7910 (12.7%)

N=812 (2.5%)

Trial C209 Deaths

Open label, uncontrolled, 24 week exposure

N=23316 (6.9%)

n/a

* Reference drugs: INH+RMP, not placebo** Relative Risk 5.1 (p=0.017)

“Bedaquiline may be added to a WHO-

recommended regimen in adult patients with

pulmonary MDR-TB” (conditional recommendation,

very low confidence in estimates of effect)Subject to the following 5 conditions:1. Treatment under close monitoring 2. Proper patient selection 3. Patient informed consent4. Treatment as per WHO recommendations5. Active pharmacovigilance in place

WHO guidance on bedaquiline : milestones (12)WHO interim policy guidance (June 2013)

MDR + resistance or severe intolerance to …

1st line

2nd LI FQN Group 4 Group 5

FQ, but not 2nd LI E, Z Yes ? Higher generation

Add all 3* Bdq + 0-3*

2nd LI (both classes), but not FQ

E, Z Usually not

Yes; if possible higher generation

Add all 3* Bdq + 0-3*

2 or 3 Group 4 drugs, but not FQ or 2nd LI

E, Z Yes Yes Add 1* Bdq + 1-2*

FQ & 2nd LI (includes XDR-TB)

E, Z ? Amgly. or polyp.

? Higher generation

Add all 3* Bdq + 0-3*

* Depending on confidence in the effectiveness of Group 4 drugs

Source: Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. (2014)

WHO guidance on bedaquiline : milestones (13)Indications for use (2014)

WHO guidance on bedaquiline : milestones (14)

pyrazinamide possible?

Source: Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. (2014)

In particular …I Vasilyeva, T Kasayeva & Russian Society of TB specialistsWHO Russian FederationNational programme managers (providing data)Ernesto JaramilloChristian LienhardtMatteo ZignolKarin WeyerMany others at WHO, partners, technical agencies

Acknowledgements