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MULTI DRUG RESISTANT
TUBERCULOSIS: CHALLENGES
AND SOLUTIONSAND SOLUTIONS
A/Prof. Nguyen Viet Nhung, MD., PhDVice director, National Lung Hospital, Hanoi, Viet Nam
Deputy Manager, National Tuberculosis control ProgramVice President, Viet Nam Association against TB and Lung Diseases
Regional Green Light Committee - WHO / WPR
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 3. Why the scale up of PMDT is so slow ? Challeneges / Solutions
– Diagnosis
– Treatment
– Prevention
– Resources
4. Conclusion
Definitions
• MDR (Multi-Drug Resistance) = Resistance to at least INH and RIF
• XDR (eXtensively Drug Resistant) = MDR plus resistance to fluoroquinolones, and one 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
Estimating MDR-TB cases
Estimated TB incidence
- Incident TB (new and relapse)
Primary MDR-TB
- Incidence of retreatment (exc
relapse)Acquired MDR-TB
Incidence – based
estimate MDR
TB case notification
Apply %MDR among new
MDR-TB among new
Apply %MDR among retreatment
MDR-TB among retreatment
Above is simplified illustration.
Full details available M/XDR-TB 2010 Global Report, WHO
Notification-based
estimate of MDR
Estimated MDR-TB incidence
vs
Estimates based on notifications
Estimated MDR incidence
• Based on all TB incidence
Notification based estimate
• Notified NSP x %MDR (new)
• Notified Ret x %MDR (ret)
• Issues in assumptions for %MDR
among sm-ve, EP and detected
cases
• MDR-TB among undetected TB –
too ambitious as target
• Notified Ret x %MDR (ret)
• Theoretically ‘detectable TB’
• MDR-TB among undetected TB
not included
Estimated number
of cases
Estimated number
of deaths
1.4 million*
(1.3–1.6 million)
8.7 million
(8.3–9.0 million)
All forms of TB
The Global Burden of TB - 2011
630,000
(460,000-790,000)out of ~12 million
prevalent TB cases
Multidrug-resistant TB
HIV-associated TB 1.1 million (13%)
(1.0–1.2 million)
430,000(400,000–460,000)
Source: WHO Global Tuberculosis Report 2012 * Including deaths attributed to HIV/TB
Unknown, but
probably > 150,000
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
Distribution of proportion of MDR
among treated TB cases, 1994-2011
Number of MDR TB cases estimated among
notified pulmonary TB cases in 2011 (Detectable)
Estimated number of MDR-TB Cases, 2011
>60% of all cases are in 5 countriesRussian Federation
44,000 (14% of global MDR burden)
China
61,000
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
India
66,000(21% of global MDR
burden)
61,000(20% of global MDR
burden)
Philippines
11,000(4% of global
MDR burden)
Pakistan
10,000(3% of global MDR
burden)
South Africa
8,100Based on old
survey data
MDR-TB 3.7% (2.1–5.2%)
of new cases and 20%
(13–26%) of previously
treated cases.
310 000 (220 000– 400
000) MDR-TB cases
among notified PTB in
2011. (detectable)
Notified cases of MDR-TB as a percentage of MDR-TB cases estimated
to occur among notified pulmonary TB cases, 2011
(DST coverage)
To date, 84 countries have reported
at least one XDR-TB case
In 84 countries , About 9% of MDR-TB cases are XDR
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)
In WPR: Estimated MDR-TB burden
S-E Asian
29%
China, 77% Philippines, W Pacific
African
14%
American
2%
East Med.
5%
European
24%
China, 77% Philippines,
14%
Viet Nam,
5%
Others, 5%
W Pacific
25%
79,000
China 61,000 + Philippines 11,000 + Vietnam 3700 >96%
WPR: distribution of new / reTx MDR-TB
burden
Estimated
among reTx,
18554,
23%Estimated
among new,
60699,
77%
23%
Total burden: 79,000
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%)
WHO Guidelines for Programmatic WHO Guidelines for Programmatic WHO Guidelines for Programmatic WHO Guidelines for Programmatic Management of DrugManagement of DrugManagement of DrugManagement of Drug----resistant TB resistant TB resistant TB resistant TB
+
2011 UpdateWHO/HTM.TB/2011.6
2008 Emergency UpdateWHO/HTM.TB/2008.402
+
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 • 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
1. Sustained political commitment
3. Appropriate treatment strategies that
2. Rationale casefinding: accurate, timely
diagnosis through quality-assured culture,
DST, Molecular test (LPA, Expert)
DOTS MDR-TB Management
Framework
Political commitment
Quality microscopy service
D.O.T /supervised
$
5. R and R system designed for MDR-TB
Manag. – integrated in TB control
4. Uninterrupted supply of quality assured
SLDs
3. Appropriate treatment strategies that
utilize SLDs under proper management
conditions / DOT
D.O.T /supervised
treatment
Regular availability of 1st line drugs
Standardized records & reports TB Register
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 &
Framework Component 1:
international partners
• Addressing factors leading to emergence of MDR-TB
• Procurement of quality-assured drugs and legislation to assure
rational use
• Strategy: DST/Molecular test for all patients <> only
MDR risk groups (e.g. failures, chronics)
Accurate case finding strategy including accurate and
timely diagnosis through quality assured culture &
DST or/and molecular test
Framework Component 2:
Among new cases Among retreatment cases
WPR% of the
total burden
Number to be
tested
% of the total
burden
Number to be
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
WPR
Cat II failure
+ Other Ret
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
Framework Component 3:
– 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
• Management of adverse drug reactions and co-morbidities
• Tracing defaulter• Health education and counseling• Provision of enablers
What is DOT ?
You just have to take the pills and that’s it!
E. Jaramillo, 2006
X
XDR - TB treatment
• The management of XDRTB is introduced:
– Individual regimen
– Basic principles
– Consider extended duration of the injectable– 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)
• 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)
Uninterrupted supply of quality assured second-line anti-TB drugs
Framework Component 4:
– 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
Recording and reporting system designed for Drug-resistant TB management
• Recording and reporting enables:
– Patient registration
– Monitoring of program
Framework Component 5:
TB RegisterTB RegisterTB RegisterTB Register
– Monitoring of program
performance (incl. culture, DST,
laboratory tests, etc.)
• Interim indicators
• Final outcome analysis
– Comparison of different cohorts
PMDT should be implemented in phase maner:
pilot, expansion, scale up
Different stages- different issues- different needs
Scale up
Issues: Financial
Pilot
Issues: Technical
Needs: Technical support
Expansion
Issues:Managerial
Needs:
Experience sharing, regional platform, global platform, advocacy
Issues: Financial
Needs: Fund security, supervision, monitoring
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)
(Reg 7)
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
Current situation of PMDT
SLOW scale up SLOW scale up
Very few patients are treated
No treatment reported. Some
MDR-TB treatment levels
compared to estimated
burden in 2010
387
13
40
440,000
estimated
cases
Treated in WHO/ Green Light
Committee programmes
Countries report treatment, standard
unknown
No treatment reported. Some
treatment probably obtained, quality
unknown
Why the scale up of PMDT is so slow ?
Challenges / Solutions Challenges / Solutions
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
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 levelstarget levels
Actual Country plans
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• 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)
Short Standardized Treatment of MDR TB
Intensive phase: GEZC KHP
4 months, extended till sputum
conversion
Continuation phase: GEZC
5 months
Kanamycin (K)
Prothionamide (P)Prothionamide (P)
Isoniazid (H)*
Gatifloxacin (G)* Gatifloxacin (G)*
Clofazimine, C Clofazimine, C
Ethambutol, E Ethambutol, E
Pyrazinamide, P Pyrazinamide, P
40
*high dose
Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684–692
Groups of second-line anti-TB drugs
“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. 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
Lead OptimizationPreclinical
DevelopmentGLP Tox.
Phase I Phase II Phase III
Delamanid (OPC-67683)
Gatifloxacin
Moxifloxacin
Rifapentine
AZD5847
Bedaquiline (TMC-207)
Linezolid
Novel Regimens2
PA-824
CPZEN-45
DC-159a
Q201
SQ609
SQ641
Preclinical DevelopmentDiscovery1 Clinical Development
Diarylquinoline
DprE Inhibitors
GyrB inhibitors
InhA Inhibitors
LeuRS Inhibitors
Global TB Drug Pipeline
BTZ043
TBA-354
PA-824
Rifapentine
SQ-109
Sutezolid (PNU-100480)
SQ641LeuRS Inhibitors
MGyrX1 inhibitors
Mycobacterial Gyrase
Inhibitors
Pyrazinamide Analogs
Riminophenazines
Ruthenium (II) complexes
Spectinamides
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
clofazimine in combinations and is scheduled to begin September 2012.
Updated: June 18, 2012
www.newtbdrugs.org
4 Repurposed Drugs
6 New Drugs
3 New Classes
Drugs currently in the regulatory
review process
MDR TB TREATMENT
3. Adverse effect management
4. Programatic Management:
o DOT – provider : Community based vs hospitalization
approach
o Drugs supply matched rapid diagnosiso 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
2008n = 309
38%31%
1%
Cured26%
2009n = 416
Treatment Outcome
Source : Dr. Vivian
25%
15%7%
8%
31%Completed
Failed
Died
Lost to follow up
Ongoing
48%
15%
10%
1%
Phillipines - the role of private sector ?
Common Reasons of Treatment
Interruption Philippines Source: Year 2010, 9 TCs; Year 2011, 18 TCs
Year 2010 Year 2011
Financial problem: …
Personal problem/socio-…
ADRs
Co-morbidity
16%
17%
20%
20%
Busy with …
ADRs
Personal problem/socio-…
Financial problem: …
11%
17%
19%
20%
0% 5% 10% 15% 20%
Conflict with Health …
Errand/meeting
Was in province (or …
Financial problem …
Busy with …
Marriage problem / …
Financial problem: …
1%
4%
5%
7%
9%
10%
0% 5% 10% 15% 20% 25%
Typhoon, bad weather, …
Was in province (or …
Errand/meeting
Marriage problem / …
Financial problem …
Co-morbidity
Busy with …
1%
2%
5%
8%
9%
9%
11%
Source : Dr. Vivian
IMPLEMENTATION RESULTS VietnamTreatment outcome (patient lot 101)
Successful cases
Failed cases
Complete treatment Death
No assessmentReturn by default
First cohort 101 pts First cohort 101 pts
(2009)
73% succesful
Conversion rate after 6 months of treatment
(2012 Vietnam)
No Provinces
Total of
patients
evaluated
Total of
conversions
Conversion
rate
1 HCMC 417 314 75%
2 Hanoi 30 21 70%
3 Nam Dinh 22 19 86%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%
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 • 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.
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 – Advicacy global / regional / national / subnational
• Management capacity of NTP
– NTP infrastructure
– TB control network
– Stop TB partnership
• Strategy – resource driven target
– Diagnosis
– Treatment
Targets driven by Financial resources – Viet Nam
Sample Financial Analysis combined
with Desired Outcomes
Source: Courtesy of C Fitzpatrick, STB/HQ
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, – 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
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 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.
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 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.
