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MULTI DRUG RESISTANT  TUBERCULOSIS: CHALLENGES       AND SOLUTIONS         A/Prof. Nguyen Viet Nhung, MD., PhD      Vice d...
Contents1. MDR TB epidemiological figures2. Programatic management of drug resistant tuberculosis - PMDT    – Frame work (...
Definitions• MDR (Multi-Drug Resistance) = Resistance to  at least INH and RIF• XDR (eXtensively Drug Resistant) = MDR  pl...
Estimating MDR-TB cases                                                - Incident TB (new                                 ...
Estimated MDR-TB incidence                            vs              Estimates based on notificationsEstimated MDR incide...
The Global Burden of TB - 2011                                Estimated number           Estimated number                 ...
Distribution of proportion of MDRamong new TB cases, 1994-2011The boundaries and names shown and the designations used on ...
Distribution of proportion of MDRamong treated TB cases, 1994-2011
Number of MDR TB cases estimated amongnotified pulmonary TB cases in 2011 (Detectable)
Estimated number of MDR-TB Cases, 2011 >60% of all cases are in 5 countries                                               ...
Notified cases of MDR-TB as a percentage of MDR-TB cases estimatedto occur among notified pulmonary TB cases, 2011(DST cov...
To date, 84 countries have reportedat 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                     ...
In WPR: Estimated MDR-TB burden             S-E Asian               29%                                   W Pacific       ...
WPR: distribution of new / reTx MDR-TB                burden   Estimated  among reTx,    18554,      23%                  ...
WPR target by 2015              as per global plan   100% of reTx,    18554, 24%20% of new,12140, 15%                   To...
WHO Guidelines for Programmatic              Drug-Management of Drug-resistant TB                         + 2008 Emergency...
MDR-TB control framework• Framework for MDR-TB management: a flexible  scheme consisting of core principles that can be  a...
DOTS                        MDR-TB Management                                       FrameworkPolitical commitment         ...
Framework Component 1:        Sustained political commitment• In the context of a well-functioning DOTS programme• Long-te...
Framework Component 2:     Accurate case finding strategy including accurate and      timely diagnosis through quality ass...
+ Other RetCat II failure
Framework Component 3:   Appropriate treatment strategies that utilize SLDs       under proper management conditions• Appr...
• Management of adverse drugWhat is DOT ?     reactions and co-morbidities                • Tracing defaulter             ...
XDR - TB treatment• The management of XDRTB is introduced:   – Individual regimen   – Basic principles   – Consider extend...
Framework Component 4:     Uninterrupted supply of quality assured           second-line anti-TB drugs• Many challenges of...
Framework Component 5:      Recording and reporting system designed for            Drug-resistant TB management• Recording...
PMDT should be implemented in phase maner:            pilot, expansion, scale upDifferent stages- different issues- differ...
Phases of Implementation                                                        1st Public                                ...
PMDT in Vietnam• 2007: GLC’s approval• 2009: pilot in Ho Chi Minh city• 2011: 6 treatment sites + 14 satellite provinces w...
Current situation of PMDT     SLOW scale up
Very few patients are treated                     MDR-TB treatment levels                     compared to estimated       ...
Why the scale up of PMDT is so slow ?       Challenges / Solutions
DIAGNOSIS OF MDR TB• Access to MDR TB diagnosis is still a challenge               Conventional culture and DST Solid – li...
Response to MDR-TB: % DST,detected and treatedOnly 4% of new and 6% of already treated TB patients undergo DST Enrolments ...
MDR TB TREATMENT1. SLDs, ancillary drugs – available and   affordable  • A course of SLDs is still very expensive  • Becau...
Short Standardized Treatment of MDR TB    Intensive phase: GEZC KHP      Continuation phase: GEZC    4 months, extended ti...
Groups of second-line anti-TB drugs
“Totally drug-resistant TB” anddevelopments in India in 2012In December 2011, Mumbai, India : reported term “total drugres...
Global TB Drug Pipeline  Discovery1                    Preclinical Development                                            ...
MDR TB TREATMENT3. Adverse effect management4. Programatic Management:  o   DOT – provider : Community based vs hospitaliz...
Treatment Outcome              2008                             2009               n = 309                         n = 416...
Common Reasons of Treatment    Interruption Philippines                                                       Source: Year...
IMPLEMENTATION RESULTS Vietnam                          Treatment outcome (patient lot 101)       Successful cases        ...
Conversion rate after 6 months of treatment             (2012 Vietnam)                      Total of                      ...
MDR TB PREVENTIONSome country with increase M/XDR TB – a manmade phenomenon, we need:   • Maintain the High Quality of DOT...
Insufficient Resource• Human resource   – Decentralization: Community involvement / PPM – PMDT / integration• Financial ga...
Targets driven by Financial resources – Viet Nam
Sample Financial Analysis combined     with Desired Outcomes                 Source: Courtesy of C Fitzpatrick, STB/HQ
Country Preapration, Viet NamEfficiency gain: The NTP need to strengthen networks to find out the    most cost-effective P...
Conclusion• M/XDR TB is really threaten the world and need to  be addressed globally.• PMDT is only way to control MDR TB ...
Acknowledgements•   WHO/Stop TB Department: Mario Raviglione, Philippe      Glaziou, Christian Lienhardt, Enesto Jaramillo...
THANKS YOU    FOR YOUR ATTENTION     vietnhung@yahoo.com       Togetherfor a World free of TB !
Lecture mdr tb nhung
Lecture mdr tb nhung
Lecture mdr tb nhung
Lecture mdr tb nhung
Lecture mdr tb nhung
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  1. 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 ProgramVice President, Viet Nam Association against TB and Lung Diseases Regional Green Light Committee - WHO / WPR
  2. 2. Contents1. MDR TB epidemiological figures2. Programatic management of drug resistant tuberculosis - PMDT – Frame work (guideline) – Implementation in phase maner: pilot, expansion, scale up – Current situation3. Why the scale up of PMDT is so slow ? Challeneges / Solutions – Diagnosis – Treatment – Prevention – Resources4. Conclusion
  3. 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. 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 newNotification-based TB case notificationestimate 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. 5. Estimated MDR-TB incidence vs Estimates based on notificationsEstimated 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. 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 casesSource: WHO Global Tuberculosis Report 2012 * Including deaths attributed to HIV/TB
  7. 7. Distribution of proportion of MDRamong new TB cases, 1994-2011The 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 concerningthe 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 borderlines for which there may not yet be full agreement. WHO 2012. All rights reserved
  8. 8. Distribution of proportion of MDRamong treated TB cases, 1994-2011
  9. 9. Number of MDR TB cases estimated amongnotified pulmonary TB cases in 2011 (Detectable)
  10. 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 MDRMDR-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 datatreated cases.310 000 (220 000– 400 Pakistan000) MDR-TB cases 10,000 India Philippinesamong notified PTB in (3% of global MDR burden) 66,000 11,0002011. (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 HealthOrganization 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. 11. Notified cases of MDR-TB as a percentage of MDR-TB cases estimatedto occur among notified pulmonary TB cases, 2011(DST coverage)
  12. 12. To date, 84 countries have reportedat least one XDR-TB case In 84 countries , About 9% of MDR-TB cases are XDR
  13. 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. 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. 15. WPR: distribution of new / reTx MDR-TB burden Estimated among reTx, 18554, 23% Estimated among new, 60699, 77% Total burden: 79,000
  16. 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. 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. 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. 19. DOTS MDR-TB Management FrameworkPolitical commitment 1. Sustained political commitment $Quality microscopy 2. Rationale casefinding: accurate, timelyservice diagnosis through quality-assured culture, DST, Molecular test (LPA, Expert)D.O.T /supervised 3. Appropriate treatment strategies thattreatment utilize SLDs under proper management conditions / DOTRegular availabilityof 1st line drugs 4. Uninterrupted supply of quality assured SLDsStandardized records 5. R and R system designed for MDR-TB& reports TB Register Manag. – integrated in TB control
  20. 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. 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. 22. + Other RetCat II failure
  23. 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. 24. • Management of adverse drugWhat 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. 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. 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. 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. 28. PMDT should be implemented in phase maner: pilot, expansion, scale upDifferent 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. 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. 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. 31. Current situation of PMDT SLOW scale up
  32. 32. Very few patients are treated MDR-TB treatment levels compared to estimated burden in 2010 No treatment reported. Some440,000 treatment probably obtained, qualityestimated 387 unknowncases Countries report treatment, standard unknown 40 13 Treated in WHO/ Green Light Committee programmes
  33. 33. Why the scale up of PMDT is so slow ? Challenges / Solutions
  34. 34. 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
  35. 35. Response to MDR-TB: % DST,detected and treatedOnly 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
  36. 36. MDR TB TREATMENT1. 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 treatment2. Treatment regimens: Long and tocixity / short course (WHO recommended with OR)
  37. 37. 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 40Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684–692
  38. 38. Groups of second-line anti-TB drugs
  39. 39. “Totally drug-resistant TB” anddevelopments in India in 2012In December 2011, Mumbai, India : reported term “total drugresistance”. March 2012 WHO convened 40 experts to discuss itsimplications: no reliable definition beyond XDR-TB, no changes tothe current guidelines. In addition, DST to certain drugs and therelease 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
  40. 40. 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 InhibitorsChemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone1 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 secondclinical trial (NC002) of this regimen was launched in March 2012 and will test the efficacy of the regimen in drug-sensitiveand multidrug-resistant patients. The third clinical trial (NC003) will evaluate PA-824, TMC-207, pyrazinamide and www.newtbdrugs.orgclofazimine in combinations and is scheduled to begin September 2012. Updated: June 18, 2012
  41. 41. MDR TB TREATMENT3. Adverse effect management4. Programatic Management: o DOT – provider : Community based vs hospitalization approach o Drugs supply matched rapid diagnosis5. Good clinical practice in Prvate sector : PPM Partnership (consider: Not just threaten but also opportunity for NTP)6. Treatment capacity: SLD, management and resource
  42. 42. Treatment Outcome 2008 2009 n = 309 n = 416 1% 26% 38% Cured 31% Completed 48% Failed1% Died 25% Lost to follow up 10% Ongoing 8% 15% 7% 15% Phillipines - the role of private sector ? Source : Dr. Vivian
  43. 43. 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
  44. 44. IMPLEMENTATION RESULTS Vietnam Treatment outcome (patient lot 101) Successful cases Complete treatment Death Failed cases Return by default No assessmentFirst cohort 101 pts(2009)73% succesful
  45. 45. 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%
  46. 46. MDR TB PREVENTIONSome country with increase M/XDR TB – a manmade 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.
  47. 47. 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
  48. 48. Targets driven by Financial resources – Viet Nam
  49. 49. Sample Financial Analysis combined with Desired Outcomes Source: Courtesy of C Fitzpatrick, STB/HQ
  50. 50. Country Preapration, Viet NamEfficiency gain: The NTP need to strengthen networks to find out the most cost-effective PMDT model, including novel regimensAdvocate for increase: • Domestic: – Investment of the Government, – Local authority at provinces, – Health assurance and – So-called socialization of PMDT • External supports: optimal use all opportunitiesAdvocacy: • VSTP – partners • Evidence based advocacy • Role of WHO
  51. 51. 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.
  52. 52. 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.
  53. 53. THANKS YOU FOR YOUR ATTENTION vietnhung@yahoo.com Togetherfor a World free of TB !
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