0. СЪЕЗД ФТИЗИАТРОВ РОССИИ (Г. ВОРОНЕЖ)
Dennis FALZON – WHO/HQ
СЪЕЗД ФТИЗИАТРОВ РОССИИ (Г. ВОРОНЕЖ)
27 мая 2015 г.

1. The global TB situation (1)
Global trends in estimated rates of TB incidence, prevalence and mortality
Rate per 100,000 per year
Rate per 100,000 population
TB incidence rates have been falling worldwide for about a decade, thus achieving the MDG global target. They are falling in all six WHO regions, but the overall decline (1.5% per year since 2000) remains slow. At this rate, the global levels of TB will not reach the elimination threshold by Trends in TB prevalence and mortality rates are also on the decline and appear likely to approach the STP targets of reaching 50% their 1990 value by 2015
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 Shaded areas represent uncertainty bands. Mortality excludes TB deaths among HIV-positive people.

2. Estimated number of deaths, 2013
The global TB situation (2)
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
In 2013, it was estimated that the global incidence of TB was 126 cases per 100,000 population, with most cases occurring in Asia (56%) and Africa (29%). About 480,000 new MDR-TB cases were estimated to emerge, while some 210,000 MDR-TB patients died in the same year.
210,000 (130,000–290,000)
* Excluding deaths attributed to HIV/TB

3. Percentage of new TB cases with MDR-TB
A new analysis of trends focusing on the years 2008−2013 shows that, at the global level, the proportion of new cases with MDR-TB remains unchanged. However, serious MDR-TB epidemics in some countries jeopardise progress.
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 All rights reserved
Workshop for 18 high-priority countries of the WHO European Region on recording and reporting of drug resistant tuberculosis

4. 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 All rights reserved
Workshop for 18 high-priority countries of the WHO European Region on recording and reporting of drug resistant tuberculosis

5. Percentage of new and previously treated TB cases with MDR-TB globally and in the top 10 countries, 2014
Workshop for 18 high-priority countries of the WHO European Region on recording and reporting of drug resistant tuberculosis

6. Percentage of new and previously treated TB cases with MDR-TB globally and in the top 10 countries, 2014
Workshop for 18 high-priority countries of the WHO European Region on recording and reporting of drug resistant tuberculosis

7. MDR-TB cases estimated to occur among
notified pulmonary TB cases, 2013
This slide shows the absolute number of MDR-TB cases by country among the new and retreated pulmonary TB cases notified by countries to WHO in No adjustment for under-notification of TB cases was performed but, in countries without a measured estimate of MDR among TB cases, a modeled value was used. About 60% of cases occur in Brazil, China, India, the Russian Federation and South Africa alone (“BRICS” countries).
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 All rights reserved
Workshop for 18 high-priority countries of the WHO European Region on recording and reporting of drug resistant tuberculosis

8. Countries that notified at least one case of XDR-TB
About 9.0% ( %) of MDR-TB cases in countries with representative surveillance data have XDR-TB. To date, 100 countries had reported one or more XDR-TB cases.
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 All rights reserved
Workshop for 18 high-priority countries of the WHO European Region on recording and reporting of drug resistant tuberculosis

9. DR-TB surveillance
and treatment

10. The Global Project on
Anti-TB Drug Resistance Surveillance,
Global Project launched
SRL network launched
1st global DRS report
2nd global DRS report
3rd global DRS report
4th global DRS report
M/XDR-TB report
2014 TB report
1994
1997
2000
2003
2004
2008
2009
2010
2015
1st ed. DRS guidelines
2nd ed. DRS guidelines
3rd ed. DRS guidelines
4th ed. DRS guidelines
5th ed. DRS guidelines
being
finalized
Workshop for 18 high-priority countries of the WHO European Region on recording and reporting of drug resistant tuberculosis

11. Progress in global coverage of surveillance data on
drug resistance,
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 All rights reserved
Workshop for 18 high-priority countries of the WHO European Region on recording and reporting of drug resistant tuberculosis

12. Diagnostic DST (1)
For rifampicin +/- isoniazid in new bacteriologically-confirmed
TB cases,
(& projections as per Global Plan)
Globally, 8.5% of new bacteriologically positive and 17% of retreatment TB cases were reported with drug-susceptibility test (DST) results for rifampicin in 2013, short of, respectively, the 20% and 100% Global Plan targets set for The low score is partly due to a lack of sufficient access of TB patients to DST. Another reason in some countries is the low capture of results from laboratories owing to inadequate TB information systems.

13. For fluoroquinolones and second-line injectable drugs
Diagnostic DST (3)
For fluoroquinolones and second-line injectable drugs
among MDR-TB cases, 2013
In MDR-TB patients, the detection of resistance to fluoroquinolones and second-line injectable drugs has important implications for their treatment. In 2013, only 23% of MDR-TB patients had DST results reported for these two classes of drugs. Poor recovery of laboratory test results accounts to a large degree for the low coverage observed in certain regions. The high coverage in the African Region is dominated by the data from South Africa. About one third of MDR-TB patients have resistance to one of these drug classes, or to both (extensive drug resistance; XDR-TB). Many of these patients would be eligible for treatment with bedaquiline and delamanid, new drugs approved by WHO since 2013 for inclusion in MDR-TB regimens.

14. RR-/MDR-TB notification and enrolment
MDR-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
RR-/MDR-TB detection and enrolment on MDR-TB treatment increased between 2009 and In 2013, the number of RR-/MDR-TB cases totalled >136,000 compared to 111,000 in In contrast, only about 97,000 TB cases were reported to have started MDR-TB treatment in 2013, or about 45% of the Global Plan target for that year. A number of countries are not able to place MDR-TB patients on appropriate treatment at the same pace at which they are diagnosed, as a consequence of limited capacity in the curative services. The ratio of enrolled to diagnosed cases was lower than 60% in 10 high MDR-TB burden countries in 2013 and lowest in Myanmar (34%), South Africa (41%), and Tajikistan (30%).

15. Outcomes of MDR-TB treatment
MDR-TB cohorts , top 10 MDR-TB burden countries*
In the 2011 cohort, the proportion of MDR-TB patients with a successful outcome varied substantially between countries and averaged to about 48% globally. This has remained static in recent years, although the number of cases monitored for outcomes has increased in all WHO Regions. Of the 126 countries reporting outcomes for 2011 cohorts, 29 achieved or exceeded the Global Plan target of 75% success.
*number of cases observed shown over the bars

16. Outcomes of XDR-TB treatment
XDR-TB cohorts 2011, by WHO Region*
Among XDR-TB patients in 40 countries for whom outcomes were reported in the 2011 cohort, overall 22% completed treatment successfully and 35% died; while in 10% treatment failed and 33% were lost to follow up or their treatment outcome was not evaluated. In South Africa, which accounted for 59% of XDR-TB patients with outcomes reported, treatment success was only 15% and 40% of patients died; 36% of patients were lost to follow up or not evaluated. New drugs and more effective regimens are urgently needed to improve the outcomes for patients with XDR-TB.
*number of cases observed shown over the bars

17. Treatment in MDR-TB+ (1)
(circles=point estimates; lines=95% confidence limits)
Resistance to fluoroquinolones and second-line injectable drugs: impact on MDR-TB outcomes. Eur Respir J Oct 25; doi: /

18. Number of patients with laboratory-confirmed
XDR-TB started on treatment in 2013
In 2013, 54 countries and territories reported treating XDR−TB cases. Globally, 3,232 XDR-TB cases were enrolled on treatment, up from 1,852 cases in 2012 and reflecting increases in enrolments in 17 high MDR-TB burden countries. Most of the cases in 2013 were notified from Ukraine (1,006), South Africa (612), India (364) and Kazakhstan (305).
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 All rights reserved

19. 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
By the end of 2013, at least 24 countries reported having used bedaquiline to treat a total of 186 patients (5 countries did not specify the number of cases treated) as part of efforts to expand access to treatment for MDR-TB, either for compassionate use or under normal programmatic conditions in the public or private sectors. Three quarters of these patients were reported by three countries: Armenia, South Africa and Swaziland.
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 All rights reserved

22. WHO policy on programmatic management
of DR-TB

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

24. 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
Import the drug and use under specific conditions
Enforced drug use politics
Policy and law in place
How to get the drug into the country
Drug management to avoid misuse
Responsibility from e authority . Use under specific conditions.
Allow use immediately based on existing data and recommendations from WHO
All tb drug must be protected and used appropriately
Example of Brazil; keeping resistance very low as only provided through physicians

25. The quality of evidence
Definition
Quality
Further 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

26. 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

27. WHO Policy Development Framework
Development of new TB
drugs or new regimens
Reviewing the evidence
Convening an Expert Group
Developing policy proposal
and recommendations
Formulating and
disseminating policy
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
Development of a "Policy Development Framework” for the introduction of new TB drugs/regimens in countries:
. describes the process for development of policies for treatment of TB including the new drugs/regimens
- used to guide the development or update of policy recommendations (guidelines) as data on specific drugs/regimens become available
Guidelines Review Committee
Dissemination to Member States
Promotion with stakeholders & funders
Phased implementation & scale-up plan

28. Drugs currently in the regulatory review process for MDR-TB
4 Repurposed Drugs
6 New Drugs
3 New Classes
Drugs currently in the regulatory review process for MDR-TB

29. 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
WHO expert group meeting on Dlm
October 2014 :
Release of WHO guidance on Dlm

30. WHO guidance on bedaquiline : milestones (1)

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

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

33. 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
Cure by 120 weeks
Serious adverse events during investigational 24 weeks treatment phase
Mortality
Time to culture conversion over 24 weeks
Culture conversion at 24 weeks
Acquired resistance to second-line drugs (fluoroquinolones, amino-glycosides and capreomycin) at 72 weeks

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

35. 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 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.
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 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.

36. WHO guidance on bedaquiline : milestones (8)

37. WHO guidance on bedaquiline : milestones (9)

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

39. WHO guidance on bedaquiline : milestones (11)
Mortality
Study
Type of study
Bedaquiline
Placebo
Phase 1 Deaths
Phase 2
Study C202*
Deaths
Randomised, open-label, dose ranging, EBA study
N=45
2 (4.4%)
N=30
Trial C208 Stage 1
Randomised, placebo-controlled, 8 week exposure
N=23
2 (8.7%)
N=24
2 (8.3%)
Trial C208 Stage 2
Deaths**
Randomised, placebo-controlled, 24 week exposure
N=79
10 (12.7%)
N=81
2 (2.5%)
Trial C209
Open label, uncontrolled, 24 week exposure
N=233
16 (6.9%)
n/a
* Reference drugs: INH+RMP, not placebo
** Relative Risk 5.1 (p=0.017)

40. WHO guidance on bedaquiline : milestones (12)
WHO interim policy guidance (June 2013)
“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 consent
4. Treatment as per WHO recommendations
5. Active pharmacovigilance in place

41. WHO guidance on bedaquiline : milestones (13)
Indications for use (2014)
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
Usually not
Yes; if possible higher generation
2 or 3 Group 4 drugs, but not FQ or 2nd LI
Add 1*
Bdq + 1-2*
FQ & 2nd LI (includes XDR-TB)
? Amgly. or polyp.
* 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)

42. WHO guidance on bedaquiline : milestones (14)
pyrazinamide possible?
Source: Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. (2014)

43. Acknowledgements
In particular … I Vasilyeva, T Kasayeva & Russian Society of TB specialists WHO Russian Federation National programme managers (providing data) Ernesto Jaramillo Christian Lienhardt Matteo Zignol Karin Weyer Many others at WHO, partners, technical agencies