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

G. B. MiglioriWHO Collaborating Centre for TB and Lung Disease,Fondazione S. Maugeri, Care and Research InstituteTradate, Italy

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

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?

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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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1st-line oral

•INH

•RIF

•PZA

•EMB

•(Rfb)

Injectables

•SM

•KM

•AMK

•CM

Fluoroquinolones

•Cipro

•Oflox

•Levo

•Moxi

•(Gati)

Oral bacteriostatic 2nd line

Unclear efficacy•ETA/PTA

•PASA

•CYS

Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid

XDR= HR + 1 FQ + 1 Injectable (AMK, CM or KM)

Outline

• Definitions

• Epidemiology





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 oneXDR-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

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Top 19 settings with MDR among new cases > 6% (1994-2007)

Indicates survey data reported in an earlier phase of the project

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

Outline

• Definitions

• Epidemiology





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

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Causes of MDR

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Causes of MDR

Patient mismanagement

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Step 1:Everything OKbut don’t miss the cure

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Step 2:Single resistance,Danger ahead!

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

MDR-/XDR-TB: a manmade product!

Results of ECDC/TBNET survey

Environmental measures

Contactinvestigation

HIV regimen

Tx duration ICcommittee

Coughetiquette

Staff training on IC

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

TB Treatment: loopholes identified

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

20/201 (10)

Inadequate dosage, no. (%) 13/201 (6.5)

Inadequate duration, no. (%) 34/201 (17)

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

1/201 (0.5)

Outline

• Definitions

• Epidemiology





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

1) Drugs

2) Vaccines

3) Diagnostics

4) Funding opportunities

Diagnosis by smear microscopyEastern Europe

Diagnosis, smear conversion, failure, cure

Solid and Liquid cultures

≥1

<1

18/36 HBCs* have insufficient capacity to diagnose MDR-TB

*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

Culture laboratories per 5M and DST laboratories per 10M population, 2009

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DL Ling, M Pai, ERJ 08

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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

Site TP FP FN TN SENS in C+(95% CI)

SPE in C- (95% CI)

Lima, Peru 201 0 8 101 96(93-98) 100(96-100)

Baku, Azerbaijan

123 1 24 68 84(77-89) 99(92-100)

Cape Town, SA

136 1 10 185 93(88-96) 99(97-100)

Durban, SA 36 3 7 215 84(70-92) 99(96-99)

Mumbai, India

179 0 8 35 96(92-98) 100(90-100)

Total 675 5 57 604 92(90-94) 99(98-100)

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

Proportion of TB patients tested for MDR-TB remains low

New

Global plan target for 2015 =20%

Previously treated

Global plan target for 2015 =100%

Outline

• Definitions

• Epidemiology





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Latvia, Adverse Events

86% of patients experienced side effectsMedian of 4 side effect reports per personMost 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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Consilium for MDR-TB case and programme management

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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±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

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XDR-TB

MDR-TB, resistant to all 1st line drugs

MDR-TB, susceptible at least one 1st drug

Eur Respir J 2007

Cohort: 4,853 C+, 361 MDR, 64 XDR

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How to design a MDR-TB regimen

MDR-TB treatment expandingBUT only reaching ~12% of TB patients with MDR-TB

Numbers treated for MDR-TB Numbers treated as % total estimated cases of MDR-TB among all notified cases of TB

GLC = Green Light Committee

Global Plan target ~270,000 in 2015

30,000

19,000

Especially low in two regions with largest number of cases

Outline

• Definitions

• Epidemiology





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Global Policy: MDR-TB and XDR-TB

1. Strengthen basic TB control, to prevent M/XDR-TB

2. Scale-up programmatic management and care of MDR-TB and XDR-TB

3. Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB

4. Ensure availability of quality drugs and their rational use5. Expand MDR-TB and XDR-TB surveillance 6. Introduce infection control, especially in high HIV

prevalence settings7. Mobilize urgently resources domestically and

internationally8. Promote research and development into new diagnostics,

drugs and vaccines

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1. Strengthen basic TB control, to prevent M/XDR-TB2. Scale-up programmatic management and care of MDR-TB

and XDR-TB

3. Strengthen laboratory services for adequate and timely diagnosis of MDR-TB and XDR-TB

4. Ensure availability of quality drugs and their rational use5. Expand MDR-TB and XDR-TB surveillance 6. Introduce infection control, especially in high HIV



drugs and vaccines

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and XDR-TB 3. Strengthen laboratory services for adequate and timely

diagnosis of MDR-TB and XDR-TB

4. Ensure availability of quality drugs and their rational use

5. Expand MDR-TB and XDR-TB surveillance 6. Introduce infection control, especially in high HIV



drugs and vaccines

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diagnosis of MDR-TB and XDR-TB4. Ensure availability of quality drugs and their rational use5. Expand MDR-TB and XDR-TB surveillance

6. Introduce infection control, especially in high HIV prevalence settings

7. Mobilize urgently resources domestically and internationally

8. Promote research and development into new diagnostics, drugs and vaccines

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diagnosis of MDR-TB and XDR-TB4. Ensure availability of quality drugs and their rational use5. Expand MDR-TB and XDR-TB surveillance 6. Introduce infection control, especially in high HIV


internationally

8. Promote research and development into new diagnostics, drugs and vaccines

The STOP TB Strategy – 2010

1. Pursue high-quality DOTS expansion and enhancementa. Secure political commitment, with adequate and sustained financing b. Ensure early case detection, and diagnosis through quality-assured bacteriologyc. Provide standardised treatment with supervision, and patient supportd. Ensure effective drug supply and management e. Monitor and evaluate performance and impact

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

3. Contribute to health system strengthening based on primary health care a. Help improve health policies, human resources development, financing, supplies, service delivery and informationb. Strengthen infection control in health services, other congregate settings and householdsc. Upgrade laboratory networks, and implement the Practical Approach to Lung Health (PAL) d. Adapt approaches from other fields and sectors, and foster action on the social determinants of health

4. Engage all care providersa. Involve all public, voluntary, corporate and private providers through Public-Private Mix (PPM) approachesb. Promote use of the International Standards for Tuberculosis Care (ISTC)

5. Empower people with TB, and communities through partnershipa. Pursue advocacy, communication and social mobilizationb. Foster community participation in TB care, prevention and health promotionc. Promote use of the Patients' Charter for Tuberculosis Care

6. Enable and promote researcha. Conduct programme-based operational research, and introduce new tools into practiceb. 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

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

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