Thank you for viewing this presentation. We would like to remind you that this material is the...

Thank you for viewing this presentation.

We would like to remind you that this material is the property of the author.

It is provided to you by the ERS for your personal use only, as submitted by the

author.

2012 by the author

MDR-TB management: what is new?

GB Migliori

WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Tradate Italy

3

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

Aims





5

2000

7

Guidelines for the programmatic management of drug-resistant tuberculosis (1)

1 Background information on DR-TB2 Framework for effective control of DR-TB3 Political commitment and coordination 4 Definitions: case registration, bacteriology and treatment

outcomes5 Case-finding strategies 6 Laboratory aspects 7 Treatment strategies for MDR-TB and XDR-TB 8 Mono- and poly-resistant strains9 Treatment of DR-TB in special conditions and situations10 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 failure14 Management of contacts of MDR-TB patients15 Drug resistance and infection control 16 Human resources: training and staffing17 Management of second-line antituberculosis drugs 18 Category IV recording and reporting system19 Managing DR-TN through patient-centered careANNEX 1 Drug information sheetsANNEX 2 Weight-based dosing of drugs for adultsANNEX 3 Suggestions for further readingANNEX 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

DOTS MDR-TB

FUNDING: Government Commitment (10$/ case)

> money

Up to 20,000 $/ caseDIAGNOSIS: 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

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

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 (KM or AMK or CM)

15

Aims





Estimated absolute numbers of reported cases with MDR-TB*

*among reported pulmonary TB patients

<100100–999

1000–9999>10,000

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

17

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

18

19

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

Indicates survey data reported in an earlier phase of the project

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: 27.7-42.8) in new pts

• 76.5% (95%CI: 66.1-86.8) in previously treated pts

20

The new MDR-TB world record

Notifications of MDR-TB increasingBUT only ~ 1 in 6 (16%) of estimated cases of MDR-TB among reported TB patients diagnosed and treated in 2010

Notified cases of MDR-TB

19,000

53,000

Global Plan target ~270,000 in 2015

MDR-TB cases treated and estimated numbers not treated for MDR-TB, among notified TB patients, 2010

290,000

Proportion of TB patients tested for MDR-TB remains low

Global plan target for 2015 = 100%

Previously treatedNew cases

Global plan target for 2015 = 20%

Scale-up of MDR-TB treatment vs. Global Plan targets

20112010200920082007 2012 2013 2014 2015

24

Trend of MDR-TB among new cases, Estonia, Latvia and…Tomsk Oblast, RF

% MDR among new

Estonia

Latvia

TB notification rate

Tomsk oblast, RF

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

26

Aims





20/36 HBCs* have insufficient capacity to diagnose MDR-TB

*HBC= high-burden countryCountries = 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

≥1<1

Culture and DST laboratories per 5M, 2010

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??

The “magic” Gene Xpert

Roll-out of Xpert MTB/RIFAs 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/laboratory/mtbrifrollout

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

Aims





35

The challenge of MDR

36

Expensive and toxic drugs are necessary

37

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

Group 1

Group 2

Group 3

Group 4

Group 5

Grouping drugs

38

How to design a MDR-TB regimen

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

41

Changes to the recommendations on regimen composition between the 2008 and 2011 updates of WHO MDR-TB guidelines

2008 emergency update 2011 updateInclude 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

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

73%

15%

0%

20%

40%

60%

80%

100%

Open MarketPrices

GLC Prices

48

MDR treatment programmeDecentralised case management

Centralised Registration Establishment of treatment Monitoring Data management SupervisionDecentralised 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 Consilium for MDR-TB case and programme managementprogramme management

49

Latvia, Side Effects - Cohort 2000

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

50

Results: Final Conversion Over Time

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

XDR-TB

MDR-TB, resistant to all 1st line drugs

MDR-TB, susceptible at least one 1st drug

Eur Respir J 2007

4,853 C+, 361 MDR, 64 XDR

60

Aims





TB patients with inappropriate regimen have a 27-fold higher risk of developing MDR-TB

61

Multidrug resistance after inappropriate tuberculosis treatment: A meta-analysisMarieke J. van der Werf, Miranda W. Langenda3, Emma Huitric, Davide ManisseroERJ 2012 in press

62

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 settings7. Mobilize urgently resources domestically and

internationally8. Promote research and development into new

diagnostics, drugs and vaccines

63


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






64



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

timely diagnosis of MDR-TB and XDR-TB






65




timely 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

66




timely 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

67

“Nobody wants me around..”

69

Interventions over time: Interventions over time: old weapons might

be useful again to manage XDR

First sanatorium First sanatorium Germany, 1857Germany, 1857 First Dispensary, First Dispensary,

Scotland, 1897Scotland, 1897

Koch, Mtb,Koch, Mtb,18821882

Drugs, 1945-1962Drugs, 1945-1962

MMR,1950-1980MMR,1950-1980

Fox:Ambulatory treatment, 1968Fox:Ambulatory treatment, 1968

Styblo model, 1978Styblo model, 1978

DOTS, 1991DOTS, 1991

sanatoriasanatoria Outbreak Management,Outbreak Management,

Risk Group ManagementRisk Group Management

screeningscreening

BCG vaccinationBCG vaccination

drug therapydrug therapy

Socio-economic improvementSocio-economic improvement

Pneumotorax, Italy, 1907Pneumotorax, Italy, 1907

70

XDR and TB control: which future ?

Thank you for viewing this presentation. We would like to remind you that this material is the...

Documents

Transcript of Thank you for viewing this presentation. We would like to remind you that this material is the...