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

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?

8 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.

9 1 st -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 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 All rights reserved

Prevalence of MDR-TB among new TB cases,

Prevalence of MDR-TB, retreatment cases,

15 Top 19 settings with MDR among new cases > 6% ( ) 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 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

19 Causes of MDR

20 Causes of MDR Patient mismanagement

21

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

23 Step 2: Single resistance, Danger ahead!

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

MDR-/XDR-TB: a manmade product!

27

Results of ECDC/TBNET survey Environmental measures Contact investigation HIV regimen Tx durationIC committee Cough etiquette Staff training on IC

Results of ECDC/TBNET survey Environmental measures Contact investigation HIV regimen Tx durationIC committee Cough etiquette Staff training on IC

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. (%) 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 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

≥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

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

SiteTPFPFNTNSENS in C+(95% CI) SPE in C- (95% CI) Lima, Peru (93-98)100(96-100) Baku, Azerbaijan (77-89)99(92-100) Cape Town, SA (88-96)99(97-100) Durban, SA (70-92)99(96-99) Mumbai, India (92-98)100(90-100) Total (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 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?

54 Latvia, Adverse Events 86% of patients experienced side effects Median of 4 side effect reports per person Most common side effects Nausea73.0% Vomiting38.7% Abdominal pain38.2% Dizziness35.8% Hearing problems 28.4% 61% changed or discontinued drugs during treatment owing to side effects 2 patients stopped treatment due side effects

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

56 Consilium for MDR-TB case and programme management

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58

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60 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

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

62 How to design a MDR-TB regimen

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MDR-TB treatment expanding BUT 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 ,000 19,000 Especially low in two regions with largest number of cases

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?

69 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 use 5.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

70 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 use 5.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

71 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 use 5.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

72 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 use 5.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

73 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 use 5.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

The STOP TB Strategy – Pursue high-quality DOTS expansion and enhancement a.Secure political commitment, with adequate and sustained financing b.Ensure early case detection, and diagnosis through quality-assured bacteriology c.Provide standardised treatment with supervision, and patient support d.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 populations a.Scale–up collaborative TB/HIV activities b.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 information b.Strengthen infection control in health services, other congregate settings and households c.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 providers a.Involve all public, voluntary, corporate and private providers through Public-Private Mix (PPM) approaches b.Promote use of the International Standards for Tuberculosis Care (ISTC) 5.Empower people with TB, and communities through partnership a.Pursue advocacy, communication and social mobilization b.Foster community participation in TB care, prevention and health promotion c.Promote use of the Patients' Charter for Tuberculosis Care 6.Enable and promote research a.Conduct programme-based operational research, and introduce new tools into practice b.Advocate for and participate in research to develop new diagnostics, drugs and vaccines

The STOP TB Strategy – Pursue high-quality DOTS expansion and enhancement a.Secure political commitment, with adequate and sustained financing b.Ensure early case detection, and diagnosis through quality-assured bacteriology c.Provide standardised treatment with supervision, and patient support d.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 populations a.Scale–up collaborative TB/HIV activities b.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 information b.Strengthen infection control in health services, other congregate settings and households c.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 providers a.Involve all public, voluntary, corporate and private providers through Public-Private Mix (PPM) approaches b.Promote use of the International Standards for Tuberculosis Care (ISTC) 5.Empower people with TB, and communities through partnership a.Pursue advocacy, communication and social mobilization b.Foster community participation in TB care, prevention and health promotion c.Promote use of the Patients' Charter for Tuberculosis Care 6.Enable and promote research a.Conduct programme-based operational research, and introduce new tools into practice b.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