The document discusses multi-drug resistant tuberculosis (MDR-TB), including its global epidemiology, challenges in diagnosis and treatment, and solutions through programmatic management. It notes that MDR-TB cases are estimated to affect over 600,000 people globally each year, with over 80% of cases located in 22 countries. Successful scale-up of MDR-TB treatment programs has been slow due to challenges with accurate and timely diagnosis, long and toxic treatment regimens, and limited availability of quality second-line drugs. Strengthening laboratory capacity, improving treatment strategies, and sustaining political and financial commitment are keys to addressing these challenges.

1. MULTI DRUG RESISTANT
TUBERCULOSIS: CHALLENGES
AND SOLUTIONS
A/Prof. Nguyen Viet Nhung, MD., PhD
Vice director, National Lung Hospital, Hanoi, Viet Nam
Deputy Manager, National Tuberculosis control Program
Vice President, Viet Nam Association against TB and Lung Diseases
Regional Green Light Committee - WHO / WPR

2. Contents
1. MDR TB epidemiological figures
2. Programatic management of drug resistant tuberculosis - PMDT
– Frame work (guideline)
– Implementation in phase maner: pilot, expansion, scale up
– Current situation
3. Why the scale up of PMDT is so slow ? Challeneges / Solutions
– Diagnosis
– Treatment
– Prevention
– Resources
4. Conclusion

3. Definitions
• MDR (Multi-Drug Resistance) = Resistance to
at least INH and RIF
• XDR (eXtensively Drug Resistant) = MDR
plus resistance to fluoroquinolones, and one
of the second-line injectable drugs (amikacin,
kanamycin, or capreomycin)
• Drug resitant TB among newly detected cases
/ retreated cases

4. Estimating MDR-TB cases
- Incident TB (new
Primary MDR-TB
and relapse)
Estimated TB
Incidence – based incidence
estimate MDR - Incidence of
retreatment (exc Acquired MDR-TB
relapse)
Apply %MDR among MDR-TB among
new new
Notification-based TB case notification
estimate of MDR
Apply %MDR among MDR-TB among
retreatment retreatment
Above is simplified illustration.
Full details available M/XDR-TB 2010 Global Report, WHO

5. Estimated MDR-TB incidence
vs
Estimates based on notifications
Estimated MDR incidence Notification based estimate
• Based on all TB incidence • Notified NSP x %MDR (new)
• Notified Ret x %MDR (ret)
• Issues in assumptions for %MDR • Theoretically ‘detectable TB’
among sm-ve, EP and detected
cases • MDR-TB among undetected TB
• MDR-TB among undetected TB – not included
too ambitious as target

6. The Global Burden of TB - 2011
Estimated number Estimated number
of cases of deaths
All forms of TB 8.7 million 1.4 million*
(8.3–9.0 million) (1.3–1.6 million)
HIV-associated TB 1.1 million (13%) 430,000
(1.0–1.2 million) (400,000–460,000)
Multidrug-resistant TB 630,000 Unknown, but
(460,000-790,000) probably > 150,000
out of ~12 million
prevalent TB cases
Source: WHO Global Tuberculosis Report 2012 * Including deaths attributed to HIV/TB

7. Distribution of proportion of MDR
among new TB cases, 1994-2011
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 2012. All rights reserved

8. Distribution of proportion of MDR
among treated TB cases, 1994-2011

9. Number of MDR TB cases estimated among
notified pulmonary TB cases in 2011 (Detectable)

10. Estimated number of MDR-TB Cases, 2011
>60% of all cases are in 5 countries
Russian Federation
44,000
(14% of global MDR burden)
China
61,000
(20% of global MDR
MDR-TB 3.7% (2.1–5.2%) South Africa burden)
of new cases and 20% 8,100
Based on old
(13–26%) of previously survey data
treated cases.
310 000 (220 000– 400 Pakistan
000) MDR-TB cases 10,000 India Philippines
among notified PTB in (3% of global MDR
burden) 66,000 11,000
2011. (detectable) (21% of global MDR (4% of global
burden) MDR burden)
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 2012. All rights reserved

11. Notified cases of MDR-TB as a percentage of MDR-TB cases estimated
to occur among notified pulmonary TB cases, 2011
(DST coverage)

12. To date, 84 countries have reported
at least one XDR-TB case
In 84 countries , About 9% of MDR-TB cases are XDR

13. MDR-TB burden
in the WPR
Estimate number of MDR-TB in
selected countries
Global
estimate
Retreatment
New Sm+
Source: Global TB Control 2009
update (WHO), MDR-TB estimate
from M/XDR-TB 2010 Global
Report on Surveillance and
Response (WHO)

14. In WPR: Estimated MDR-TB burden
S-E Asian
29%
W Pacific Philippines,
25% China, 77%
14%
European 79,000
24% Viet Nam,
5%
Others, 5%
African
14%
East Med.
5% American
2%
China 61,000 + Philippines 11,000 + Vietnam 3700 >96%

15. WPR: distribution of new / reTx MDR-TB
burden
Estimated
among reTx,
18554,
23%
Estimated
among new,
60699,
77%
Total burden: 79,000

16. WPR target by 2015
as per global plan
100% of reTx,
18554, 24%
20% of new,
12140, 15%
Total target by 2015 : 30,694 (39%)

17. WHO Guidelines for Programmatic
Drug-
Management of Drug-resistant TB
+
2008 Emergency Update 2011 Update
WHO/HTM.TB/2008.402 WHO/HTM.TB/2011.6

18. MDR-TB control framework
• Framework for MDR-TB management: a flexible
scheme consisting of core principles that can be
adapted according to local settings
• Requires a comprehensive approach integrated in
National TB Programs rather than in individual
clinical medical practice
• Built upon the five elements of the DOTS strategy
Guidelines for Programmatic management of Drug-resistant TB,
WHO, 2008

19. DOTS MDR-TB Management
Framework
Political commitment 1. Sustained political commitment
$
Quality microscopy 2. Rationale casefinding: accurate, timely
service diagnosis through quality-assured culture,
DST, Molecular test (LPA, Expert)
D.O.T /supervised
3. Appropriate treatment strategies that
treatment
utilize SLDs under proper management
conditions / DOT
Regular availability
of 1st line drugs 4. Uninterrupted supply of quality assured
SLDs
Standardized records
5. R and R system designed for MDR-TB
& reports TB Register
Manag. – integrated in TB control

20. Framework Component 1:
Sustained political commitment
• In the context of a well-functioning DOTS programme
• Long-term investment of resources (human and financial)
• Coordination efforts between community, local governments &
international partners
• Addressing factors leading to emergence of MDR-TB
• Procurement of quality-assured drugs and legislation to assure
rational use

21. Framework Component 2:
Accurate case finding strategy including accurate and
timely diagnosis through quality assured culture &
DST or/and molecular test
• Strategy: DST/Molecular test for all patients <> only
MDR risk groups (e.g. failures, chronics)
Among new cases Among retreatment cases
WPR
% of the Number to be % of the total Number to be
total burden tested burden tested
CAM 67% 71 33% 10
CHN 80% 18 20% 4
LAO 81% 20 19% 4
MOG 16% 71 84% 4
PHL 73% 25 27% 5
VTN 54% 37 46% 5

22. + Other Ret
Cat II failure

23. Framework Component 3:
Appropriate treatment strategies that utilize SLDs
under proper management conditions
• Appropriate regimens (for at least 18 months)
• Directly observed therapy (DOT) / supervised treatment during
the entire course of treatment
– Incentives: housing; food, transport
– Patient education; Social and emotional support
– Tracing defaulters
• Recommended regimen:
– PZA, 2nd line injectable, later generation FQ,
Ethionamide/Protionamide and Cycloserine/PAS
• Model of care: mainly ambulatory
• Management of adverse drug reactions
• Trained manpower

24. • Management of adverse drug
What is DOT ? reactions and co-morbidities
• Tracing defaulter
• Health education and counseling
• Provision of enablers
X
You just have to take
the pills and that’s it!
E. Jaramillo, 2006

25. XDR - TB treatment
• The management of XDRTB is introduced:
– Individual regimen
– Basic principles
– Consider extended duration of the injectable
– Use of newer generation fluoroquinolone
– Use of Group 5 agents
– Consider surgery, if indicated
– Treat HIV, if applicable
– Consider NEW TB DRUG ? (Compasionate use)

26. Framework Component 4:
Uninterrupted supply of quality assured
second-line anti-TB drugs
• Many challenges of drug procurement
– Global production of quality-assured drugs is limited
(due to small market ?)
– Long lead time (as long as 8 months)
– Short shelf-life (as short as 12 months)
– Regimens are frequently adjusted (due to side-
effects, DST results, and lack of treatment response)
– Drug registration may be lengthy and costly

27. Framework Component 5:
Recording and reporting system designed for
Drug-resistant TB management
• Recording and reporting enables:
– Patient registration
TB Register
– Monitoring of program
performance (incl. culture, DST,
laboratory tests, etc.)
• Interim indicators
• Final outcome analysis
– Comparison of different cohorts

28. PMDT should be implemented in phase maner:
pilot, expansion, scale up
Different stages- different issues- different needs
Scale up
Issues: Financial
Expansion Needs: Fund
security,
Issues:
supervision,
Managerial
monitoring
Needs:
Pilot Experience
Issues: Technical sharing, regional
platform, global
Needs: Technical
platform,
support
advocacy

29. Phases of Implementation
1st Public
facility (LCP) Scaling-up
PMDT started
(Reg 7)
•An additional 6,750 MDR TB cases is targeted to be treated under Category IV treatment from 2013 to 2014
•A total of about 15,000 MDR – TB cases is targeted to be treated by 2016 (PhilPACT)

30. PMDT in Vietnam
• 2007: GLC’s approval
• 2009: pilot in Ho Chi Minh city
• 2011: 6 treatment sites + 14 satellite provinces were trained (20
PMDT sites in total)
• 2012: Upgraded 4 satellites into treatment sites, and trained 15 more
satellite provinces = 35 PMDT provinces (including 10 treatment
sites)
• Until Feb/2013: Total 1580 patients were enrolled, 1379 patients
currently on treatment
• 2013 - 2015: 4000 patients are expected to be enrolled

31. Current situation of PMDT
SLOW scale up

32. Very few patients are treated
MDR-TB treatment levels
compared to estimated
burden in 2010
No treatment reported. Some
440,000 treatment probably obtained, quality
estimated 387 unknown
cases
Countries report treatment, standard
unknown
40
13 Treated in WHO/ Green Light
Committee programmes

34. Why the scale up of PMDT is so slow ?
Challenges / Solutions

35. DIAGNOSIS OF MDR TB
• Access to MDR TB diagnosis is still a challenge
Conventional culture and DST Solid – liquid : Long time
Rapid diagnostics - LPA – Xpert MTB/Rif : expensive and
rolling out slow
Sample collection and transportation
Role of non-public health care provider
• Need to
– Strengthen Lab capacity
• Culture and DST
• Morlecular techniques LPA
– Speciment collection & transportation
– Strengthen Avocacy, communication and health educcation

36. Response to MDR-TB: % DST,
detected and treated
Only 4% of new and 6% of already treated TB patients undergo DST
Enrolments on treatment Only ~ 1 in 5 MDR-TB cases among
notified TB patients detected and
treated globally in 2011
Global Plan
target levels
Actual Country plans

38. MDR TB TREATMENT
1. SLDs, ancillary drugs – available and
affordable
• A course of SLDs is still very expensive
• Because the market for SLDs is tiny
$20 for a course of first line treatment
$4000 for a course of 2nd line treatment
2. Treatment regimens: Long and tocixity / short
course (WHO recommended with OR)

40. Short Standardized Treatment of MDR TB
Intensive phase: GEZC KHP Continuation phase: GEZC
4 months, extended till sputum 5 months
conversion
Kanamycin (K)
Prothionamide (P)
Isoniazid (H)*
Gatifloxacin (G)* Gatifloxacin (G)*
Clofazimine, C Clofazimine, C
Ethambutol, E Ethambutol, E
Pyrazinamide, P Pyrazinamide, P
*high dose
40
Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684–692

41. Groups of second-line anti-TB drugs

42. “Totally drug-resistant TB” and
developments in India in 2012
In December 2011, Mumbai, India : reported term “total drug
resistance”. March 2012 WHO convened 40 experts to discuss its
implications: no reliable definition beyond XDR-TB, no changes to
the current guidelines. In addition, DST to certain drugs and the
release of new drugs will change this position in future.
But, … Positive impact to Indian government :
laboratory and hospital facilities were improved,
contact-tracing stepped up and infection control.
Medical staff and funding were increased substantially.
Access to second-line drugs was provided to eligible patients.
National regulations governing private sales of anti-TB medication
By 2012, all 35 states in the country are expected to provide PMDT
In May 2012, a web based surveillance system was initiated

43. Global TB Drug Pipeline
Discovery1 Preclinical Development Clinical Development
Preclinical GLP
Lead Optimization Phase I Phase II Phase III
Development Tox.
Diarylquinoline CPZEN-45 BTZ043 AZD5847 Delamanid (OPC-67683)
DprE Inhibitors DC-159a TBA-354 Bedaquiline (TMC-207) Gatifloxacin
GyrB inhibitors Q201 Linezolid Moxifloxacin
InhA Inhibitors SQ609 Novel Regimens2 Rifapentine
LeuRS Inhibitors SQ641 PA-824
MGyrX1 inhibitors 4 Repurposed Drugs Rifapentine
Mycobacterial Gyrase SQ-109
Inhibitors
6 New Drugs Sutezolid (PNU-100480)
Pyrazinamide Analogs 3 New Classes
Riminophenazines
Ruthenium (II) complexes Drugs currently in the regulatory
Spectinamides review process
Translocase-1 Inhibitors
Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone
1 Ongoing projects without a lead compound series can be viewed at http://www.newtbdrugs.org/pipeline-discovery.php.
2 Combination regimens: first clinical trial (NC001) of a novel TB drug regimen testing the three drug combination of PA-824,
moxifloxacin, and pyrazinamide was initiated November 2010 and completed in 2011 with promising results. The second
clinical trial (NC002) of this regimen was launched in March 2012 and will test the efficacy of the regimen in drug-sensitive
and multidrug-resistant patients. The third clinical trial (NC003) will evaluate PA-824, TMC-207, pyrazinamide and www.newtbdrugs.org
clofazimine in combinations and is scheduled to begin September 2012.
Updated: June 18, 2012

44. MDR TB TREATMENT
3. Adverse effect management
4. Programatic Management:
o DOT – provider : Community based vs hospitalization
approach
o Drugs supply matched rapid diagnosis
5. Good clinical practice in Prvate sector : PPM
Partnership
(consider: Not just threaten but also opportunity for NTP)
6. Treatment capacity: SLD, management and resource

46. Treatment Outcome
2008 2009
n = 309 n = 416
1%
26% 38% Cured
31%
Completed
48% Failed
1% Died
25% Lost to follow up
10% Ongoing
8%
15%
7%
15%
Phillipines - the role of private sector ?
Source : Dr. Vivian

47. Common Reasons of Treatment
Interruption Philippines Source: Year 2010, 9 TCs; Year 2011, 18 TCs
Year 2010 Year 2011
Co-morbidity 20% 20%
Financial problem:…
ADRs 20% 19%
Personal problem/socio-…
Personal problem/socio-… 17% 17%
ADRs
Financial problem:… 16% 11%
Busy with…
Marriage problem /… 10% 9%
Co-morbidity
Busy with… 9% 9%
Financial problem…
Financial problem… 7% 8%
Marriage problem /…
Was in province (or… 5% 5%
Errand/meeting
Errand/meeting 4% Was in province (or… 2%
Conflict with Health… 1% Typhoon, bad weather,… 1%
0% 5% 10% 15% 20% 0% 5% 10% 15% 20% 25%
Source : Dr. Vivian

48. IMPLEMENTATION RESULTS Vietnam
Treatment outcome (patient lot 101)
Successful cases Complete treatment Death
Failed cases Return by default No assessment
First cohort 101 pts
(2009)
73% succesful

49. Conversion rate after 6 months of treatment
(2012 Vietnam)
Total of
Total of Conversion
No Provinces patients
conversions rate
evaluated
1 HCMC 417 314 75%
2 Hanoi 30 21 70%
3 Nam Dinh 22 19 86%
4 Hai Duong 8 8 100%
5 Da Nang 29 25 86%
6 Quang Nam 13 13 100%
7 K74 69 53 77%
8 Binh Dinh 7 5 71%
9 Can Tho 26 15 58%
Total 621 473 76%

50. MDR TB PREVENTION
Some country with increase M/XDR TB – a man
made phenomenon, we need:
• Maintain the High Quality of DOTS prevent MDR TB
• Quality of PMDT prevents XDR TB
• Improve TB drugs management, strictly use in private
sector
• Good Clinical practice should be applied for TB care in
every where.

51. Insufficient Resource
• Human resource
– Decentralization: Community involvement / PPM – PMDT / integration
• Financial gap
– Political commitment at all level (central and local)
– Health insurrance
– International partnership
– Advicacy global / regional / national / subnational
• Management capacity of NTP
– NTP infrastructure
– TB control network
– Stop TB partnership
• Strategy – resource driven target
– Diagnosis
– Treatment

52. Targets driven by Financial resources – Viet Nam

53. Sample Financial Analysis combined
with Desired Outcomes
Source: Courtesy of C Fitzpatrick, STB/HQ

55. Country Preapration, Viet Nam
Efficiency gain: The NTP need to strengthen networks to find out the
most cost-effective PMDT model, including novel regimens
Advocate for increase:
• Domestic:
– Investment of the Government,
– Local authority at provinces,
– Health assurance and
– So-called socialization of PMDT
• External supports: optimal use all opportunities
Advocacy:
• VSTP – partners
• Evidence based advocacy
• Role of WHO

56. Conclusion
• M/XDR TB is really threaten the world and need to
be addressed globally.
• PMDT is only way to control MDR TB but has many
challenges, therefore scale up PMDT is still very slow.
• Research on areas such as new diagnostic tests, new
drugs, new regimens, new approaches and also
resource suistainability is very important and urgent
need to scale up PMDT world wide
• Advocacy for MDR TB control is an urgent need to
policy makers nationally and globally to make
adequate resources for PMDT and TB control as the
whole.

57. Acknowledgements
• WHO/Stop TB Department: Mario Raviglione, Philippe
Glaziou, Christian Lienhardt, Enesto Jaramillo
• WHO/WPRO: Catharina Van Weezenbeek, Nobu Nishikiori
(former), Tauhid Islam. Ma. Imelda D. Quelapio (former)
rGLC : Chen-Yuan Chiang, Richard Lumb, Ben Marais,
Nona Rachel Mira, Lee Reichman, Jacques van den
Broek, Yew Wing Wai, Takashi Yoshiyama
• WHO Viet Nam: Cornelia Hennig
• NTP Viet Nam: Prof. Dinh Ngoc Sy, PMDT group: Hoang
Thanh Thuy, Nguyen Van Thieu et al.

58. THANKS YOU
FOR YOUR ATTENTION
vietnhung@yahoo.com
Together
for a World free of TB !