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MDR-TB management: what is new?
GB Migliori
WHO Collaborating Centre for TB and Lung Diseases,
Fondazione S. Maugeri, Tradate Italy
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
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
200
0
5
6
Guidelines for the programmatic management of
drug-resistant tuberculosis (1)
1 Background information on DR-TB
2 Framework for effective control of DR-TB
3 Political commitment and coordination
4 Definitions: case registration, bacteriology and treatment
outcomes
5 Case-finding strategies
6 Laboratory aspects
7 Treatment strategies for MDR-TB and XDR-TB
8 Mono- and poly-resistant strains
9 Treatment of DR-TB in special conditions and situations
10 DR-TB and HIV infection
11 Initial evaluation, monitoring of treatment and management of
adverse effects
7
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 failure
14 Management of contacts of MDR-TB patients
15 Drug resistance and infection control
16 Human resources: training and staffing
17 Management of second-line antituberculosis drugs
18 Category IV recording and reporting system
19 Managing DR-TN through patient-centered care
ANNEX 1
Drug information sheets
ANNEX 2
Weight-based dosing of drugs for adults
ANNEX 3
Suggestions for further reading
ANNEX 4
Legislation, human rights, and patient’s right in TB
care prevention and control
ANNEX 5
Use of experimental drugs outside of clinical trials
8
ANNEX 5
Methodology
Causes of DR
9
Causes of MDR
Patient mismanagement
10
DOTS
FUNDING: Government
Commitment (10$/ case)
DIAGNOSIS: SS microscopy,
QA and safety measures
MDR-TB
> money
Up to 20,000 $/ case
+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
11
Definitions
•
•
•
•
Mono-R
Poly-R
MDR
XDR
• SS+, C+
• Cure, failure
• Treatment monitoring
12
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.
13
XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)
1st-line
oral
•INH
Injectables
•RIF
•SM
Fluoroquinolones
•PZA
•KM
•Cipro
•EMB
•AMK •Oflox
•Levo
•CM
•(Rfb)
•Moxi
•(Gati)
Oral bacteriostatic 2nd line
•ETA/PTA
•PASA
•CYS
Unclear efficacy
Not routinely recommended,
efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
clarithromycin, clofazamine,
linezolid, inmipenem/cilastatin,
14
high dose isonizid
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
15
Estimated absolute numbers of
reported cases with MDR-TB*
<100
100–999
1000–9999
>10,000
*among reported pulmonary TB patients
Distribution of MDR-TB among new TB
cases, 1994-2010.
17
Distribution of MDR-TB among
previously treated TB cases, 1994-2010.
18
Top 19 settings with MDR among new cases >
6% (1994-2007)
Indicates survey data reported
in an earlier phase of the project
19
The new MDR-TB world record
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
Notifications of MDR-TB increasing
BUT 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
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
53,000
19,000
Proportion of TB patients tested
for MDR-TB remains low
New cases
Global plan target
for 2015 = 20%
Previously treated
Global plan target
for 2015 = 100%
Scale-up of MDR-TB treatment
vs. Global Plan targets
2007
2008
2009
2010
2011
2012
2013
2014
2015
Trend of MDR-TB among new cases,
Estonia, Latvia and…Tomsk Oblast, RF
Estonia
Latvia
Tomsk oblast, RF
TB notification rate
% MDR among new
24
Countries that had reported at least one XDR-TB
case by Oct 2011
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
26
20/36 HBCs* have insufficient
capacity to diagnose MDR-TB
≥1 Culture and DST
<1 laboratories per 5M, 2010
*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
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+
28
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??
29
The “magic” Gene Xpert
Roll-out of Xpert MTB/RIF
As 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
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
33
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
34
The challenge of MDR
35
Expensive and
toxic drugs are
necessary
36
Grouping drugs
Group 1
1st-line
oral
•INH
Injectables
•RIF
•SM
Fluoroquinolones
•PZA
•KM
•Cipro
•EMB
•AMK •Oflox
•Levo
•CM
•(Rfb)
Group 2
Group 3
•Moxi
•(Gati)
Group 4
Oral bacteriostatic 2nd line
•ETA/PTA
•PASA
•CYS
Group 5
Unclear efficacy
Not routinely recommended,
efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
clarithromycin, clofazamine,
linezolid, inmipenem/cilastatin,
37
high dose isonizid
How to design a MDR-TB regimen
38
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
Changes to the recommendations on regimen composition between the
2008 and 2011 updates of WHO MDR-TB guidelines
2008 emergency update
2011 update
Include 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).
E may be considered effective and included in
the regimen if DST shows susceptibility
Tx with Group 5 drugs is recommended only if
additional drugs are needed to bring the total to
4
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 used but is not included among the
drugs making up the standard regimen.
Group 5 drugs may be used but are not included
among the drugs making up the standard 41
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
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
46
Estonia % of NTP budget spent on
second line drugs 1998-2000
100%
73%
80%
60%
15%
40%
20%
0%
Open Market
Prices
GLC Prices
47
MDR treatment programme
Decentralised case management
Centralised
 Registration
 Establishment of treatment
 Monitoring
 Data management
 Supervision
Decentralised 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
programme management
48
Latvia, Side Effects - Cohort 2000
 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
49
Results: Final Conversion Over Time
N = 129 patients who converted, Latvia
50
51
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?
53
54
55
XDR: a death
sentence?
56
57
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 XDRvs. 102/126 MDR-TB cases (median:
smear: 110 vs. 41 days; culture: 97.5 vs.
58 days)
Cost of new infections?
58
Emerging Infectious Diseases 2007
4,853 C+, 361 MDR, 64 XDR
MDR-TB, susceptible at least one 1st drug
MDR-TB, resistant to all 1st line drugs
XDR-TB
59
Eur Respir J 2007
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
60
TB patients with inappropriate regimen have a 27fold higher risk of developing MDR-TB
Multidrug resistance after inappropriate tuberculosis treatment: A
meta-analysis
Marieke J. van der Werf, Miranda W. Langenda3, Emma Huitric, Davide
Manissero
ERJ 2012 in press
61
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
62
Global Policy: MDR-TB and XDR-TB
1.
2.
Strengthen basic TB control, to prevent M/XDR-TB
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
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
5.
6.
7.
8.
63
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
64
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
65
Global Policy: MDR-TB and XDR-TB
1.
2.
3.
4.
5.
6.
7.
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
8. Promote research and development
into new diagnostics, drugs and
vaccines
66
“Nobody wants me
around..”
67
68
Interventions over time: old weapons might
be useful again to manage XDR
First sanatorium
Germany, 1857 First Dispensary,
Scotland, 1897
BCG vaccination
Pneumotorax, Italy, 1907
Drugs, 1945-1962
Koch, Mtb,
1882
MMR,1950-1980
Fox:Ambulatory treatment, 1968
Styblo model, 1978
DOTS, 1991
Outbreak Management,
sanatoria
Risk Group Management
screening
drug therapy
Socio-economic improvement
69
XDR and TB control: which future ?
70