Transcript Development of extensive drug resistance in Multi

Development of extensive drug
resistance in Multi-Drug resistant
tuberculosis patients
MSF anti-TB programmes in
Abkhazia and Uzbekistan
Authors: Cathy Hewison, Vinciane Sizaire, Helen Cox,
Stobdan Kalon, Stefan Nieman and Jonathan Polonsky
Some definitions
Multi-Drug Resistant (MDR) TB:
Tuberculosis resistant to at least Isoniazid
and Rifampicin
 Extensive Drug Resistant (XDR) TB:
MDR TB resistant as well to a
fluoroquinolone (Oflo- or moxifloxacin)
and a 2nd line injectable (Kanamycin or
Capreomycin)
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Settings
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Abkhazia:
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TB treatment as per WHO recommendation since 1998
DST survey (Sept 2000 – March 2002):
 MDR TB rate in new cases = 4%
 MDR TB rate in re-treatment cases = 18.7%
Nov 2004: Green Light Committee approval
Aug 2001: 1st patient enrolled on MDR treatment
March 2003 – Sept 2005: Genotyping for the Long drug
study
Settings
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Nukus (Uzbekistan)
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TB treatment as per WHO recommendation since 1998
with total coverage of Karakalpakstan achieved end of
2002
DST survey in 2001:
 MDR TB rate in new cases = 13%
 MDR TB rate in re-treatment cases = 40%
Early 2003: Green Light Committee approval
Sept 2003: 1st patient enrolled on MDR treatment
Since May 2007: Genotyping study
Objectives
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Primary objectives
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To evaluate the XDR rate among MDR TB patients at
diagnosis
To evaluate the rate of MDR TB cases who become
XDR while on an adapted treatment
Secondary objectives
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Amongst patients who become XDR during MDR
treatment:
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Identify the potential risk factors for developing XDR
Evaluate treatment outcomes
Define needs in further research from the current findings and
eventual operational implications
Method
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Retrospective cohort analysis of:
 All MDR TB patients diagnosed at the 1st DST
from the beginning of the project till end of
December 2006, in order to evaluate the
baseline XDR rate
 All MDR TB patients enrolled on MDR
treatment from the beginning of the project till
end of December 2006, excluding those XDR
at diagnosis, in order to evaluate the rate of
MDR patients who become XDR while on
treatment.
MDR TB diagnosis and follow-up
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Diagnosis:
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DST to all 1st line TB drugs, except Z, performed
systematically in all M+, by MGIT in Abkhazia and by
L-J in Nukus (MGIT will be available in June 2007)
DST to 2nd Line by L-J in all MDR patients identified
Follow-up:
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Abkhazia: Culture/DST 1x/month during the IP and
1x/2 months during the CP
Nukus:Culture from M2, 1x/month till culture
conversion then 1x/2 months. DST 1x/3 months
MDR TB patients management
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Individual Treatment regimen:
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IP: Minimum of 4 in Abkhazia, 5 in Nukus, 2nd Line TB
drugs to which patient is susceptible, including an
injectable for 4 to 6 months after culture conversion
CP: Same regimen but the injectable for 18 months
DOT
Comprehensive management of side-effects
Infection control measures in the hospital:
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UV lights
Ventilation (difficult in the winter time)
High filtration masks for staff and visitors
Separation of the patients
MDR treatment outcomes
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Treatment outcomes are reported according
to WHO and international definitions:
Cure
 Treatment completed
 Death
 Failure
 Default
 Still on treatment
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Results: Baseline XDR rate
among MDR TB patients
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Abkahzia:
Sept 2000 – Dec 2006:147 MDR patients
diagnosed
 6 (4.1%) were XDR at the time of diagnosis
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Nukus:
Sept 2003 – Dec 2006: 428 MDR patients
diagnosed
 7 (1.6%) were XDR at diagnosis
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Results: Development of XDR TB
during MDR treatment and outcomes
# MDR patients enrolled
on treatment
Abkhazia
Nukus
102
334
# patients who developed 13
XDR TB
(12.7%)
27
(8.1%)
Outcomes amongst XDR 0 success
5 success
11 failures
0 defaulter
5 died
6 still on TT
6 failures
3 defaulters
3 died
1 still on TT
Results: Potential factors contributing to
the development of XDR
Variable
Abkhazia
Nukus
OR
p
OR
2.3
0.44 1.25
0.58
Age group Linear variable
0.99
0.61 0.99
0.70
TB TT
history
New vs previously treated
Prev treated w/ 2nd L vs rest
0.21
1.48
0.14 0.42
0.52 1.26
0.41
0.58
Baseline
resistance
to 2nd L
Prior resistance to any 2nd L
vs none
1.80
0.32 4.82
< 0.001
Sex
Level
M vs F
p
Results: Discussion
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4.1% in Abkhazia and 1.6% in Nukus of MDR
patients are XDR at the time of diagnosis
13% in Abkhazia and 8% in Nukus of the MDR
patients become XDR, while on a comprehensive
MDR treatment
The only RF strongly associated with XDR
development is the baseline resistance to 2nd Line
drugs, confirmed by the multivariate analysis in
Nukus (OR=6.02, p < 0.001)
We need also to look at the level of adherence to
treatment as a RF
Conclusions
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The apparition of XDR TB from a best practice
MDR TB management is concerning
What are the mechanisms behind the XDR
apparition?
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True amplification
Re-infection
Multiple infections
Laboratory contamination
Conclusions
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MDR strains genotyping through the treatment
and molecular epidemiology are needed to:
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Estimate the relative contribution of double infection,
super-infection or true resistance amplification
Better define the RF that contribute to the development
of XDR
Identify clusters, within families or within the hospital
Operational implications
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If super-infection between patients during the stay
in the hospital:
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If family clusters
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Urgent needs to improve infection control within the
hospital
Consider ambulatory treatment from the beginning?
Aggressive active screening in all family members?
If true amplification
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Use more aggressive treatment regimen, including 3rd
Line TB drugs
Call for research on new drugs