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
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
5
2000
6
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
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
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
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
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
32
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
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
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
39
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
43
44
45
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
51
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?
54
55
56
XDR: a death sentence?
57
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
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
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
Global Policy: MDR-TB and XDR-TB
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 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
64
Global Policy: MDR-TB and XDR-TB
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 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
65
Global Policy: MDR-TB and XDR-TB
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-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
Global Policy: MDR-TB and XDR-TB
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-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 settings7. Mobilize urgently resources domestically and
internationally
8. Promote research and development into new diagnostics, drugs and vaccines
67
“Nobody wants me around..”
68
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 ?