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2. MDR-TB management: what is new?
GB Migliori
WHO Collaborating Centre for TB and Lung Diseases,
Fondazione S. Maugeri, Tradate Italy

3. To describe and discuss:
Aims
To describe and discuss:
Existing guidelines and definitions
The epidemiology of TB and MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment
The principles of MDR-TB control, with prevention and public health aspects

4. To describe and discuss:
Aims
To describe and discuss:
Existing guidelines and definitions
The epidemiology of TB and MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment
The principles of MDR-TB control, with prevention and public health aspects

5. 2000

7. Guidelines for the programmatic management of drug-resistant tuberculosis (1)
1 Background information on DR-TB
2 Framework for effective control of DR-TB
3 Political commitment and coordination
4 Definitions: case registration, bacteriology and treatment outcomes
5 Case-finding strategies
6 Laboratory aspects
7 Treatment strategies for MDR-TB and XDR-TB
8 Mono- and poly-resistant strains
9 Treatment of DR-TB in special conditions and situations
10 DR-TB and HIV infection
11 Initial evaluation, monitoring of treatment and management of adverse effects

8. Guidelines for the programmatic management of drug-resistant tuberculosis (2)
12 Treatment delivery and community-based DR-TB support
13 Management of patients with MDR-TB treatment failure
14 Management of contacts of MDR-TB patients
15 Drug resistance and infection control
16 Human resources: training and staffing
17 Management of second-line antituberculosis drugs
18 Category IV recording and reporting system
19 Managing DR-TN through patient-centered care
ANNEX 1 Drug information sheets
ANNEX 2 Weight-based dosing of drugs for adults
ANNEX 3 Suggestions for further reading
ANNEX 4 Legislation, human rights, and patient’s right in TB care prevention and control
ANNEX 5 Use of experimental drugs outside of clinical trials
ANNEX 5 Methodology

9. Causes of DR

10. Causes of MDR
Patient mismanagement

11. +C, DST, SRL, QA, infection control
DOTS
MDR-TB
FUNDING: Government Commitment (10$/ case)
> money
Up to 20,000 $/ case
DIAGNOSIS: SS microscopy, QA and safety measures
+C, DST, SRL, QA, infection control
TREATMENT: SCC,DOT, 6-8 months, no hospitalization
24 months, mandatory DOT & hospitalization in reference facilities
TB drugs only, no AE
relevant toxicity, need special drugs + expertise
TREATMENT MONITORING: SS, standard outcome definitions
C, DST, special outcome definitons

12. Definitions Mono-R Poly-R MDR XDR SS+, C+ Cure, failure
Treatment monitoring
SS+, C+ to initiate Cat 4 regimen: at least 1 pre-treatment pre-treatment SS+ or C+ (colelction od sample: from 30 days before to 7 days after starting treatment);
SS and C conversion: at least 2 sets of SS/c negative (time to conversion calculated on the first set of SS and C)
Treatment monitoring: ad interim outcomes after 6 months based on SS and C results
Cure: case completing treatment according to the treatment protocol, consistently culture-negative (with at least 5 results) for the final 12 months of treatment
Failure: 2 or more of the 5 cultures are positive or one among the last 3. Failure is also there when the clinicians decides to terminate treatment early due to poor response or adverse events.

13. XDR= extensively drug-resistant TB Definition
Resistance to at least rifampicin and isoniazid, in addition to any fluoroquinolone, and to at least one of the three following injectable drugs used in anti-TB treatment: capreomycin, kanamycin and amikacin.

14. XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)
1st-line oral
Injectables
INH
RIF
PZA
EMB
(Rfb)
Fluoroquinolones SM KM
AMK CM
Oral bacteriostatic 2nd line
Cipro
Oflox
Levo
Moxi
(Gati)
Unclear efficacy
ETA/PTA
PASA
CYS
Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid

15. To describe and discuss:
Aims
To describe and discuss:
Existing guidelines and definitions
The epidemiology of TB and MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment
The principles of MDR-TB control, with prevention and public health aspects

16. Estimated absolute numbers of reported cases with MDR-TB*
Replace with updated map, change reds to darker shades of blue.
<100
100–999
1000–9999
>10,000
*among reported pulmonary TB patients

17. Distribution of MDR-TB among new TB cases, 1994-2010.

18. Distribution of MDR-TB among previously treated TB cases, 1994-2010.

19. Top 19 settings with MDR among new cases > 6% (1994-2007)
Indicates survey data reported
in an earlier phase of the project

20. The new MDR-TB world record
The highest proportions of MDR-TB ever reported in a survey have recently been found in Minsk, the capital city of Belarus:
35.3% (95%CI: ) in new pts
76.5% (95%CI: ) in previously treated pts

21. Notifications of MDR-TB increasing
BUT only ~ 1 in 6 (16%) of estimated cases of MDR-TB among reported TB patients diagnosed and treated in 2010
MDR-TB cases treated and estimated numbers not treated for MDR-TB, among notified TB patients, 2010
Notified cases of MDR-TB
Global Plan target ~270,000 in 2015
290,000
53,000
19,000

22. Proportion of TB patients tested for MDR-TB remains low
New cases
Previously treated
Global plan target for 2015 = 20%
Global plan target for 2015 = 100%

23. Scale-up of MDR-TB treatment vs. Global Plan targets
2007
2008
2009
2010
2011
2012
2013
2014
2015

24. Trend of MDR-TB among new cases, Estonia, Latvia and…Tomsk Oblast, RF
TB notification rate
% MDR among new

25. Countries that had reported at least one XDR-TB case by Oct 2011

26. To describe and discuss:
Aims
To describe and discuss:
Existing guidelines and definitions
The epidemiology of TB and MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment
The principles of MDR-TB control, with prevention and public health aspects

27. 20/36 HBCs* have insufficient capacity to diagnose MDR-TB≥1
Culture and DST laboratories per 5M, 2010
<1
*HBC= high-burden country
Countries = Afghanistan, Armenia, Azerbaijan, Bangladesh, Belarus, Brazil, Bulgaria, Cambodia, China, DR Congo, Estonia, Ethiopia, Georgia, India, Indonesia, Kazakhstan, Kenya, Kyrgyzstan, Latvia, Lithuania, Mozambique, Myanmar, Nigeria, Pakistan, Philippines, Republic of Moldova, Russian Federation, South Africa, Tajikistan, Tanzania, Thailand, Uganda, Ukraine, Uzbekistan, Viet Nam, Zimbabwe

28. Traditional view: who needs DST?
Cat I, II failures, chronics
Failure anti-TB TX in the private sector
Contacts of DR-/MDR-TB
HCW at risk, prisoners, homeless, etc.
No SS/C conversion Month 2,3
Residence in very high DR-prevalence settings
Exposure to poor quality drugs
Previous treatment by poor programmes
Co-morbidities favouring rapid transit/ malabsorbtion
HIV+

29. Who needs DST? Cat I, II failures, chronics
Failure anti-TB TX in the private sector
Contacts of DR-/MDR-TB
HCW at risk, prisoners, homeless, etc.
No SS/C conversion Month 2,3
Residence in very high DR-prevalence settings
Exposure to poor quality drugs
Previous treatment by poor programmes
Co-morbidities favouring rapid transit/ malabsorbtion
HIV+
ALL CASES??

30. The “magic” Gene Xpert

31. Roll-out of Xpert MTB/RIF
As of 30 September 2011
GeneXpert ordered – 40 countries
105 countries eligible for concessional prices, no order yet
Not eligible for concessional pricing
Source: FIND; more info at:

33. The message Any person at high risk of MDR-TB should
undergo rapid testing
to start an appropriate treatment immediately
while an additional sputum specimen undergoes conventional culture and DST

34. To describe and discuss:
Aims
To describe and discuss:
Existing guidelines and definitions
The epidemiology of TB and MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment
The principles of MDR-TB control, with prevention and public health aspects

35. The challenge of MDR

36. Expensive and toxic drugs are necessary

37. Grouping drugs 1st-line oral Injectables INH RIF PZA EMB (Rfb)
Fluoroquinolones
Group 4 SM KM
AMK CM
Oral bacteriostatic 2nd line
Cipro
Oflox
Levo
Moxi
(Gati)
Group 5
Unclear efficacy
ETA/PTA
PASA
CYS
Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid

38. How to design a MDR-TB regimen

40. Metanalysis of 9,153 cases from 32 Countries
Treatment success vs. to failure/relapse, was associated with use of:
later generation quinolones, ofloxacin, ethionamide or prothionamide
use of 4 or more likely effective drugs in the initial intensive phase, and 3 or more likely effective drugs in the continuation phase.
Maximum odds of success: initial intensive phase of months and total treatment duration of months

41. Changes to the recommendations on regimen composition between the 2008 and 2011 updates of WHO MDR-TB guidelines
2008 emergency update
2011 update
Include at least four anti-TB drugs with either certain, or almost certain, effectiveness during the intensive phase of Tx
Include at least 4 2nd -line anti-TB drugs likely to be effective as well as Z during the intensive phase of Tx
Consider adding more drugs in patients with extensive disease or uncertain effectiveness
No evidence found to support the use of > 4 2nd-line anti-TB drugs in patients with extensive disease. Increasing the number of 2nd - line drugs in a regimen is permissible if the effectiveness of some of the drugs is uncertain.
The regimen should include Z and/or E one FQ, one parenteral agent and 2nd -line oral bacteriostatic anti-TB drugs (no preference of oral bacteriostatic 2nd -line anti-TB drug was made).
The regimen should include Z a FQ, a parenteral agent, ethionamide (or prothionamide), and cycloserine, or else PAS if cycloserine cannot be used.
E may be considered effective and included in the regimen if DST shows susceptibility
E may be used but is not included among the drugs making up the standard regimen.
Tx with Group 5 drugs is recommended only if additional drugs are needed to bring the total to 4
Group 5 drugs may be used but are not included among the drugs making up the standard regimen

42. Treatment monitoring
Treatment failure was detected best with monthly culture in MDR-TB cases.
Thus the available evidence does not support replacing monthly culture (or quarterly culture) with monthly smear

46. GLC: advantages for projects
Access to quality-assured drugs
Access to low-cost drugs
Access to a continuous drug supply
Access to technical assistance
Access to an external monitoring mechanism
Increased rational use of drugs
Creation of wide evidence base for policy development

47. Estonia % of NTP budget spent on second line drugs 1998-2000

48. MDR treatment programme Decentralised case management
Registration
Establishment of treatment
Monitoring
Data management
Supervision
Decentralised case management
Case finding
Case management
in specialized MDR-TB hospitals
in district TB department, at home, at family physician
Ensure adherence
Record keeping
We established management system using consilium or physician’s consultation model, to access patient condition, to make accurate diagnosis, to decide treatment. Advantages of consilium is: possibility for patient to receive most effective treatment, possibility to supervise treatment, quick problem solving, and improvement of program management.
Consilium for MDR-TB case and programme management

49. Latvia, Side Effects - Cohort 2000
86% of patients experienced side effects
Median of 4 side effect reports per person
Most common side effects
Nausea %
Vomiting %
Abdominal pain %
Dizziness %
Hearing problems %
61% changed or discontinued drugs during treatment owing to side effects
2 patients stopped treatment due side effects

50. Results: Final Conversion Over Time
Among 204 patients 36 or 15% had negative culture at start of treatment. Of the 168 patients who started treatment culture positive 75% or 126 converted to culture negative in a median 61 days.
Excluding defaulters starting treatment culture negative versus culture positive was significantly related to successful outcome (96% versus 72%, P= 0,005)
N = 129 patients who converted, Latvia

53. What was not known on XDR?
Is the risk of death/ probability of success different from that of MDR?
Are their clinical characteristics different? in HIV-negative patients?
Is their infectiousness different?
Has the XDR definition a clinical relevance? Which is the role of susceptibility to first-line drugs different from HR?

56. XDR: a death sentence?

58. XDR compared with MDR, Italy-Germany
Death rate: 36.4 % vs 6.3% (RR 5.45)
Longer hospitalization (241.2±177.0 vs. 99.1±85.9 days) Cost?
Longer treatment duration (30.3±29.4 vs. 15.0±23.8 months) Cost?
Bacteriological conversion in 4/11 XDR- vs. 102/126 MDR-TB cases (median: smear: 110 vs. 41 days; culture: 97.5 vs. 58 days) Cost of new infections?
Emerging Infectious Diseases 2007

59. 4,853 C+, 361 MDR, 64 XDR
MDR-TB, susceptible at least one 1st drug
MDR-TB, resistant to all 1st line drugs
XDR-TB
Eur Respir J 2007

60. To describe and discuss:
Aims
To describe and discuss:
Existing guidelines and definitions
The epidemiology of TB and MDR-TB in Europe and globally derived from surveillance and M&E (Monitoring and Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment
The principles of MDR-TB control, with prevention and public health aspects

61. TB patients with inappropriate regimen have a 27-fold higher risk of developing MDR-TB
Multidrug resistance after inappropriate tuberculosis treatment: A meta-analysis
Marieke J. van der Werf, Miranda W. Langenda3, Emma Huitric, Davide Manissero
ERJ 2012 in press

62. Global Policy: MDR-TB and XDR-TB
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV prevalence settings
Mobilize urgently resources domestically and internationally
Promote research and development into new diagnostics, drugs and vaccines

63. Global Policy: MDR-TB and XDR-TB
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV prevalence settings
Mobilize urgently resources domestically and internationally
Promote research and development into new diagnostics, drugs and vaccines

64. Global Policy: MDR-TB and XDR-TB
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV prevalence settings
Mobilize urgently resources domestically and internationally
Promote research and development into new diagnostics, drugs and vaccines

65. Global Policy: MDR-TB and XDR-TB
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV prevalence settings
Mobilize urgently resources domestically and internationally
Promote research and development into new diagnostics, drugs and vaccines

66. Global Policy: MDR-TB and XDR-TB
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV prevalence settings
Mobilize urgently resources domestically and internationally
Promote research and development into new diagnostics, drugs and vaccines

67. “Nobody wants me around..”

69. Interventions over time: old weapons might be useful again to manage XDR
First sanatorium Germany, 1857
First Dispensary, Scotland, 1897
BCG vaccination
Pneumotorax, Italy, 1907
Drugs,
MMR,
Koch, Mtb,
1882
Fox:Ambulatory treatment, 1968
Styblo model, 1978
DOTS, 1991
sanatoria
Outbreak Management,
Risk Group Management
screening
drug therapy
Socio-economic improvement

70. XDR and TB control: which future ?