MDR-/XDR-TB: is the white plague spectrum back?

G. B. Migliori WHO Collaborating Centre for TB and Lung Disease, Fondazione S. Maugeri, Care and Research Institute Tradate, Italy

Q1: the 2 previous slides show that

1) M/XDR-TB is dangerous like a wild animal 2) M/XDR-TB is a clinical nightmare 3) M/XDR-TB is a death sentence 4) M/XDR-TB is a problem in Africa

Aims

• Demonstrate that M/XDR-TB is a real (global) threat to TB control, and urgent action is needed • Call for more research on key priorities • Advocate for the collaboration of European Chest Physicians

Outline

• Definitions • Epidemiology • How does M/XDR-TB develop?

• How is M/XDR-TB diagnosed?

• Can M/XDR-TB be cured?

• What can we do to prevent M/XDR-TB?

Outline

• Definitions • Epidemiology • How does M/XDR-TB develop?

• How is M/XDR-TB diagnosed?

• Can M/XDR-TB be cured?

• What can we do to prevent M/XDR-TB?

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. 8

XDR= HR + 1 FQ + 1 Injectable (AMK, CM or KM) 1 st -line oral

•

INH

•

RIF

•

PZA

•

EMB

•

(Rfb)

• • • •

Injectables SM KM AMK CM Fluoroquinolones

•

Cipro

•

Oflox

•

Levo

•

Moxi

•

(Gati)

• • •

Oral bacteriostatic 2nd line ETA/PTA PASA CYS Unclear efficacy Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, high dose isonizid

Outline

• Definitions • Epidemiology • How does M/XDR-TB develop?

• How is M/XDR-TB diagnosed?

• Can M/XDR-TB be cured?

• What can we do to prevent M/XDR-TB?

Q2: M/XDR is

1) Highly prevalent in specific settings 2) Highly prevalent outside Europe 3) Not affecting Africa 4) Identified whenever somebody looked for it

Countries that had reported at least one XDR-TB case by end 2010

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 2010. All rights reserved

Prevalence of MDR-TB among new TB cases, 1994-2009

Prevalence of MDR-TB, retreatment cases, 1994-2009

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

15

M/XDR-TB is becoming, in selected settings, a time bomb

Outline

• Definitions • Epidemiology • How does M/XDR-TB develop?

• How is M/XDR-TB diagnosed?

• Can M/XDR-TB be cured?

• What can we do to prevent M/XDR-TB?

Q3: MDR is

1) Difficult to select 2) Is mainly due to patient’s mistakes 3) Is mainly due to sub-standard drugs 4) Is a multi-factorial man-made phenomenon

Causes of MDR

19

Causes of MDR

Patient mismanagement

20

21

Step 1: Everything OK but don’t miss the cure

22

Step 2: Single resistance, Danger ahead!

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Step 3: MDR-TB, Open door to XDR-TB

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MDR-/XDR-TB: a manmade product!

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Results of ECDC/TBNET survey

Contact investigation Tx duration HIV regimen IC committee Cough etiquette Staff training on IC Environmental measures

Results of ECDC/TBNET survey

Contact investigation Tx duration HIV regimen IC committee Cough etiquette Staff training on IC Environmental measures

Surgical masks (yes for patients)

Surgical masks (yes for patients)

Q4: is the behaviour of the actors correct in this slide?

Fit test

Respiratory Fit Testing

WHO Policy on Infection control

1) Managerial activities 2) Administrative controls 3) Environmental controls 4) Personal protection

WHO Policy on Infection control

1) Managerial activities 2) Administrative controls 3) Environmental controls 4) Personal protection

TB Treatment: loopholes identified

Inadequate TB regimen choice (4 active drugs ensured), no. (%) Inadequate dosage, no. (%)

20/201 (10) 13/201 (6.5)

Inadequate duration, no. (%) Ineffective management adverse events TB treatment, no. (%)

34/201 (17)

1/201 (0.5)

Outline

• Definitions • Epidemiology • How does M/XDR-TB develop?

• How is M/XDR-TB diagnosed?

• Can M/XDR-TB be cured?

• What can we do to prevent M/XDR-TB?

Q5: the main recent advances on TB management were related to

1) Drugs 2) Vaccines 3) Diagnostics 4) Funding opportunities

Diagnosis by smear microscopy Eastern Europe

Diagnosis, smear conversion, failure, cure

Solid and Liquid cultures

18/36 HBCs* have insufficient capacity to diagnose MDR-TB ≥1 <1 Culture laboratories per 5M and DST laboratories per 10M population, 2009 * 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

43

DL Ling, M Pai, ERJ 08

44

DL Ling, M Pai, ERJ 08

Examples of implications of introduction of Genotype MTBDRplus

Uzbekistan: 17% MDR among new cases, 45% among PT cases, 23% PT among all SS+ cases • Before Hain: culture, 1st line DST for all SS+patients n= 6600 , then 2nd line DST for R resistant cases n=1700 • After Hain: Hain test for all 6600 patients, followed by culture+ 1st+2nd line DST for H and/or R res cases n= 3400 • Advantages : – Early diagnosis and MDR treatment for R resistant cases ( 1700 ) – Early diagnosis and adequate treatment for H resistant cases ( 1700 ) – 50 % reduction of laboratory workload for culture/DST – Reduction in time to diagnosis of XDR TB

Gene Xpert

Sensitivity and Specificity of a single, direct GeneXpert vs culture (2 solid and 2 liquid cultures) Site TP

Lima, Peru 201

FP

0

FN

8

TN

101

SENS in C+(95% CI)

96(93-98)

SPE in C- (95% CI)

100(96-100) Baku, Azerbaijan Cape Town, SA Durban, SA 123 136 36 Mumbai, India Total 179 675 1 1 3 0 5 24 10 7 8 57 68 84(77-89) 99(92-100) 185 93(88-96) 99(97-100) 215 35 84(70-92) 96(92-98) 99(96-99) 100(90-100) 604 92(90-94) 99(98-100)

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

Outline

• Definitions • Epidemiology • How does M/XDR-TB develop?

• How is M/XDR-TB diagnosed?

• Can M/XDR-TB be cured?

• What can we do to prevent M/XDR-TB?

Latvia, Adverse Events



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 73.0% 38.7% 38.2% 35.8% 28.4%



61% changed or discontinued drugs during treatment owing to side effects



2 patients stopped treatment due side effects

54

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

55

Consilium for MDR-TB case and programme management

56

57

58

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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

15.0

±85.9 days) ±23.8 months) Cost?

• Longer treatment duration (30.3±29.4 vs. 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

60

Cohort: 4,853 C+, 361 MDR, 64 XDR MDR-TB, susceptible at least one 1 st drug MDR-TB, resistant to all 1 st line drugs XDR-TB

61

Eur Respir J 2007

How to design a MDR-TB regimen

62

63

64

65

66

MDR-TB treatment expanding BUT only reaching ~12% of TB patients with MDR-TB Numbers treated for MDR-TB Global Plan target ~270,000 in 2015 Numbers treated as % total estimated cases of MDR-TB among all notified cases of TB 30,000 19,000 Especially low in two regions with largest number of cases GLC = Green Light Committee

Outline

• Definitions • Epidemiology • How does M/XDR-TB develop?

• How is M/XDR-TB diagnosed?

• Can M/XDR-TB be cured?

• What can we do to prevent M/XDR-TB?

Global Policy: MDR-TB and XDR-TB 7.

8.

3.

4.

5.

6.

1.

2.

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

69

Global Policy: MDR-TB and XDR-TB 4.

5.

6.

7.

8.

1.

2.

3.

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

70

Global Policy: MDR-TB and XDR-TB 1.

2.

3.

7.

8.

4.

5.

6.

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

71

Global Policy: MDR-TB and XDR-TB 1.

2.

3.

4.

5.

6.

7.

8.

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

72

Global Policy: MDR-TB and XDR-TB 4.

5.

6.

1.

2.

3.

7.

8.

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

73

The STOP TB Strategy – 2010 1.

2.

3.

4.

5.

6.

a.

b.

c.

d.

e.

a.

b.

c.

d.

a.

b.

c.

a.

b.

a.

b.

c.

a.

b.

Pursue high-quality DOTS expansion and enhancement

Secure political commitment, with adequate and sustained financing Ensure early case detection, and diagnosis through quality-assured bacteriology Provide standardised treatment with supervision, and patient support Ensure effective drug supply and management Monitor and evaluate performance and impact

Address TB-HIV, MDR-TB, and the needs of poor and vulnerable populations

Scale–up collaborative TB/HIV activities Scale-up prevention and management of multidrug-resistant TB (MDR-TB) Address the needs of TB contacts, and poor and vulnerable populations

Contribute to health system strengthening based on primary health care

Help improve health policies, human resources development, financing, supplies, service delivery and information Strengthen infection control in health services, other congregate settings and households Upgrade laboratory networks, and implement the Practical Approach to Lung Health (PAL) Adapt approaches from other fields and sectors, and foster action on the social determinants of health

Engage all care providers

Involve all public, voluntary, corporate and private providers through Public-Private Mix (PPM) approaches Promote use of the International Standards for Tuberculosis Care (ISTC)

Empower people with TB, and communities through partnership

Pursue advocacy, communication and social mobilization Foster community participation in TB care, prevention and health promotion Promote use of the Patients' Charter for Tuberculosis Care

Enable and promote research

Conduct programme-based operational research, and introduce new tools into practice Advocate for and participate in research to develop new diagnostics, drugs and vaccines

The STOP TB Strategy – 2010 1.

2.

3.

4.

5.

6.

a.

b.

c.

d.

e.

a.

b.

c.

d.

a.

b.

c.

a.

b.

a.

b.

c.

a.

b.

Pursue high-quality DOTS expansion and enhancement

Secure political commitment, with adequate and sustained financing Ensure early case detection, and diagnosis through quality-assured bacteriology Provide standardised treatment with supervision, and patient support Ensure effective drug supply and management Monitor and evaluate performance and impact

Address TB-HIV, MDR-TB, and the needs of poor and vulnerable populations

Scale–up collaborative TB/HIV activities Scale-up prevention and management of multidrug-resistant TB (MDR-TB) Address the needs of TB contacts, and poor and vulnerable populations

Contribute to health system strengthening based on primary health care

Help improve health policies, human resources development, financing, supplies, service delivery and information Strengthen infection control in health services, other congregate settings and households Upgrade laboratory networks, and implement the Practical Approach to Lung Health (PAL) Adapt approaches from other fields and sectors, and foster action on the social determinants of health

Engage all care providers

Involve all public, voluntary, corporate and private providers through Public-Private Mix (PPM) approaches Promote use of the International Standards for Tuberculosis Care (ISTC)

Empower people with TB, and communities through partnership

Pursue advocacy, communication and social mobilization Foster community participation in TB care, prevention and health promotion Promote use of the Patients' Charter for Tuberculosis Care

Enable and promote research

Conduct programme-based operational research, and introduce new tools into practice Advocate for and participate in research to develop new diagnostics, drugs and vaccines

Conclusions

• •

M/XDR-TB is ubiquitous In some settings its prevalence is high enough to compromise TB control in absence

•

of prompt action Recent advances in new diagnostics needs to be complemented by parallel development

•

of new drugs and vaccines Chest physicians have a key role in ensuring prevention of development of further MDR-TB by ensuring early diagnosis and effective treatment of newly diagnosed, pan-susceptible, TB cases