DOTS strategy

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• 2012 by the author

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

• To describe and discuss
• Existing guidelines and definitions
• The epidemiology of TB and MDR-TB in Europe and
  globally derived from surveillance and ME
  (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

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Aims

• To describe and discuss
• Existing guidelines and definitions
• The epidemiology of TB and MDR-TB in Europe and
  globally derived from surveillance and ME
  (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

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2000
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• 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

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• 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 patients
  right in TB care prevention and control
• ANNEX 5 Use of experimental drugs outside of
  clinical trials
• ANNEX 5 Methodology

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Causes of DR
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Causes of MDR
Patient mismanagement
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DOTS MDR-TB
FUNDING Government Commitment (10/ case) gt 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
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Definitions

• Mono-R
• Poly-R
• MDR
• XDR
• SS, C
• Cure, failure
• Treatment monitoring

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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.

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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
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Aims

• To describe and discuss
• Existing guidelines and definitions
• The epidemiology of TB and MDR-TB in Europe and
  globally derived from surveillance and ME
  (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

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Estimated absolute numbers of reported cases with
MDR-TB
lt100
100999
10009999
gt10,000
among reported pulmonary TB patients
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Distribution of MDR-TB among new TB cases,
1994-2010.
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Distribution of MDR-TB among previously treated
TB cases, 1994-2010.
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Top 19 settings with MDR among new cases gt 6
(1994-2007)
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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 (95CI 27.7-42.8) in new pts
• 76.5 (95CI 66.1-86.8) in previously treated
  pts

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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
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Proportion of TB patients tested for MDR-TB
remains low
Previously treated
New cases
Global plan target for 2015 100
Global plan target for 2015 20
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Scale-up of MDR-TB treatment vs. Global Plan
targets
2011
2010
2009
2008
2007
2012
2013
2014
2015
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Trend of MDR-TB among new cases, Estonia, Latvia
andTomsk Oblast, RF
Estonia
Latvia
Tomsk oblast, RF
TB notification rate
MDR among new
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Countries that had reported at least one XDR-TB
case by Oct 2011
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Aims

• To describe and discuss
• Existing guidelines and definitions
• The epidemiology of TB and MDR-TB in Europe and
  globally derived from surveillance and ME
  (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

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20/36 HBCs have insufficient capacity to
diagnose MDR-TB
Culture and DST laboratories per 5M, 2010
1
lt1
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
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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

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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??

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The magic Gene Xpert
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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 www.who.int/tb/laborat
ory/mtbrifrollout
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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

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Aims

• To describe and discuss
• Existing guidelines and definitions
• The epidemiology of TB and MDR-TB in Europe and
  globally derived from surveillance and ME
  (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

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The challenge of MDR
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Expensive and toxic drugs are necessary
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Grouping drugs
Group 1
1st-line oral
Group 2
Injectables

• INH
• RIF
• PZA
• EMB
• (Rfb)

Group 3
Fluoroquinolones
Group 4

• SM
• KM
• AMK
• CM

Oral bacteriostatic 2nd line
Group 5

• 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
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How to design a MDR-TB regimen
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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 7.1-8.5 months and total treatment duration of
  18.6-21.5 months

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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 gt 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
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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

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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

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Estonia of NTP budget spent on second line
drugs 1998-2000
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MDR treatment programmeDecentralised case
management

• Centralised
• 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

Consilium for MDR-TB case and programme management
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Latvia, Side Effects - Cohort 2000

• 86 of patients experienced side effects
• Median of 4 side effect reports per person
• Most common side effects
• Nausea 73.0
• Vomiting 38.7
• Abdominal pain 38.2
• Dizziness 35.8
• Hearing problems 28.4
• 61 changed or discontinued drugs during
  treatment owing to side effects
• 2 patients stopped treatment due side effects

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Results Final Conversion Over Time
N 129 patients who converted, Latvia
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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?

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XDR a death sentence?
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XDR compared with MDR, Italy-Germany

• Death rate 36.4 vs 6.3 (RR 5.45)
• Longer hospitalization (241.2177.0 vs. 99.185.9
  days) Cost?
• Longer treatment duration (30.329.4 vs.
  15.023.8 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
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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
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Aims

• To describe and discuss
• Existing guidelines and definitions
• The epidemiology of TB and MDR-TB in Europe and
  globally derived from surveillance and ME
  (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

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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
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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

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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

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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

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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

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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

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Nobody wants me around..
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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, 1945-1962
MMR,1950-1980
Koch, Mtb, 1882
FoxAmbulatory treatment, 1968
Styblo model, 1978
DOTS, 1991
sanatoria
Outbreak Management, Risk Group Management
screening
drug therapy
Socio-economic improvement
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XDR and TB control which future ?