Transcript Risk of acquired drug resistance during DOTS tuberculosis

Risk of acquired drug resistance
during DOTS tuberculosis
treatment in a setting of high
drug resistance
Helen S. Cox1,3, Stefan Niemann2, Gabit Ismailov3, Daribay
Doshetov4, Juan Daniel Orozco3, Lucie Blok5,6, Sabine RüschGerdes2, Yared Kebede5
1Australian
International Health Institute, Melbourne, Australia,
Borstel, National Reference Center for Mycobacterium,
Borstel, Germany,
3Médecins Sans Frontières, Karakalpakstan, Uzbekistan,
4Ministry of Health, Nukus, Karakalpakstan, Uzbekistan,
5Médecins Sans Frontières, Amsterdam, Holland.
6Royal Tropical Institute, Holland (current
2Forchungszentrum
Background
2 regions:Karakalpakstan (Uzbekistan)
& Dashoguz (Turkmenistan).
Combined population of 2.8 million.
DOTS implemented from 1998-2003
Case notification in 2002 (462/100,000
& 213/100,000 in Karak. and Dash.
respectively)
(Background)
DOTS outcomes for all SS (+) cases
Karakalpakstan, 1998-2003
Death rate
11%
Failure rate
16%
Cure rate
42%
Default rate
11%
Treatment
completed
20%
Success Rate 62%
(Background)
DST survey : July 2001-Jan 2002
Karakalpakstan
Type of
Resistance
Mono-resist.
PDR
MDR
Re-treatment TOTAL
New
(N= 213)
cases (%) cases (%)
(N=106)
14.1
18.8
13.2
Any resistance 48.1
(N=107)
17.7
22.4
40.2
80.4
15.9
21.6
26.8
64.3
Dashoguz: MDR rates 4% in new and 18% in
re-treatment cases
(Background)
Drug resistance and treatment outcome
in 6 former Soviet Union countries
TOT
n
Success
%
Failure
%
MDR
%
65
7.1%
18.7%
77
17%
16%
Kemerovo prison
112
30
304
52
31.6%
40%
Kazakhstan
115
56
19%
37%
Karakalpakstan
645
55.3
15%
40%
Doshoguz
505
69
12.4%
18%
Abkhasia
Karabagh
*M. Bonnet, V. Sizaire, Y. Kebede et al; Does one size fit all? Drug resistance and
standard treatments: results of six tuberculosis programs in former Soviet
countries. Int J Tuberc Lung Dis 2005 9(10):1147-1154.
Study Objective
Quantify the extent of acquired drug
resistance during standardized
chemotherapy among a cross-sectional
sample of patients enrolled in a DOTS
TB program in a high resistance setting
in Uzbekistan and Turkmenistan
Study Design
• Samples taken from four districts in each
region between July 2001 and March 2002.
• Sputum smear +ve patients were enrolled.
• Repeat samples for smear positives at end of
intensive phase and 2 months into cont.
phase obtained
• Written informed consent was obtained.
• Patients were started on Cat I (intermittent
cont.) & Cat II regimen.
• Hospitalized during intensive phase
• DOT by health worker in cont. phase.
Laboratory testing and
statistical analysis
• Sputum samples sent to SRL, Borstel,
Germany for analysis.
• DST for H,R,E,S,Z by LJ proportion method
and BACTEC 460TB
• Fingerprinting done using IS6110
• All isolates were analyzed by spoligotyping
technique.
• Molecular typing data analyzed with bionumeric software
• Epi-info used for data entry and analysis
Results
• Both DNA fingerprinting and DST results
were available from 382 patients.
• Repeat samples obtained from 82
patients.
– 20 excluded (10 different strain, 5 double
infection, 5 lab contamination)
• 62 infected with same strain as at
diagnosis
Results
• Of the 382 patients at diagnosis > 50%
of were infected with strains with some
resistance
• A third were infected with strains
resistant to 2 or more first line drugs.
• Overall, 19 of the 62 identical strains
(31%) developed new drug resistance
during treatment.
(Results)
Amplification of drug resistance
First-line drug
resistance
profile
Diagnosis, Repeat
number of testing,
strains
number of
identical
strains (%)
Amplification detected
among identical strains
(%, 95% confidence
interval)
Pansusceptible
Monoresistant
Polyresistant
MDR
177
12 (7%)
2 (1.1%, 0.1-4.0)
72
10 (14%) 1 (1.4%, 0.0-7.5)
65
16 (25%) 11 (17%, 9-28)
68
24 (35%) 5 (7%, 2-16)
Amplification of drug resistance during treatment and treatment
outcomes for 19 patients in which amplification was detected.
New cases : Category I DOTS treatment 2HREZ(S)/ 4H3R3
Patient
Drug R at
diagnosis
Resistance
at end of
intensive
phase
Resistance 2 Treatment
months into
outcome
the
continuation
phase
Amplified
drug
resistance
during
treatment.
1
SUSC
S
S
Failure
S
2
HS
HRS
Failure
R
3
HS
HRS
Failure
R
4
HS
HRS
HRS
Failure
R
5
HS
HRS
Default
R
6
HES
HRES
Failure
R
7
HSZ
HESZ
Comp
E
8
HRS
HRESZ
Failure
EZ
9
HRS
HRSZ
Died
Z
10
HRES
HRESZ
Cured
Z
HRS
Amplification of drug resistance during treatment and treatment
outcomes for 19 patients in which amplification was detected.
Previously treated: Category II DOTS treatment 2HRZES/ 1HREZ/ 5H3R3E3
Patient
Drug R at
diagnosis
Resistance
at end of
intensive
phase
Resistance 2 Treatment
months into
outcome
the
continuation
phase
Amplified
drug
resistance
during
treatment.
11
SUSC
SUSC
HRS
Failure
HRS
12
S
HS
Failure
H
13
HS
HRES
Failure
RE
14
HSZ
HRESZ
Died
RE
15
HES
HRES
Failure
R
16
HES
HRESZ
Failure
RZ
17
HESZ
HESZ
HRSZ
Failure
R
18
HR
HRES
Failure
ES
19
HRES
HRZS
Died
Z
HRESZ
HRES
Reversion of drug resistance
• Some strains became susceptible to
drugs that were initially resistant.
• 5 strains lost resistance to E
• 3 strains lost resistance to S
Discussion
• 19 out of 62 patients with identical strains
developed additional drug resistance.
• 17% patients with PDR-TBamplified
resistance further MDR
• 7% MDR-TB developed further 1st line
resistance.
• Overall 11/314 (3.5%) not initially infected
with MDRdeveloped MDR after SCC.
• Majority with amplificationpoor outcome.
Discussion
• Limited study on drug amplification in SCC
• Large scale study done in Tomsk (Russia)*
– 42% not initially infected with MDR-TB and have
failed treatment, acquired MDR-TB.
– H or R resistance highest rate of resistance
amplification (71% developed MDR-TB)
• Tomsk study didn’t include molecular typing
(DNA finger printing)
*Seung KJ et al. The effect of Initial Drug resistance on treatment Response
and Acquired Drug Resistance during Standardized Short-Course
Chemotherapy for Tuberculosis. CID 2004;39:1321-1328.
Discussion
• Present study included mol. Genotyping
• Highest rate of resistance amplification
among H and S resistant isolates.
• Beijing genotype* highly prevalent in
FSU regions more susceptible to
amplify resistance
*Cox HS, Kubica T, Male R, Doshetov D, Kebede Y, Rüsch-Gerdes S, Niemann
S. The Beijing genotype and drug resistant tuberculosis in the Aral Sea region of
Central Asia. Resp Res 2005, 6:134.
Discussion
• Amplification level under estimated  only
smear +ve cases were re-tested.
• If all samples cultured  additional
amplification might have been detected
• Reversion of resistance to susceptible
– Less accurate DST for E and S
– DST for E is often problematic
– Different resistance profile within same bacillary
population
Summary
• Demonstrated high level of drug resistance
amplification after DOTS SCC in settings with
underlying resistance to first line drugs.
• Need for projects to weigh additional cost for DST
against management of newly created MDR-TB
systematic DST vital.
• Standard regimen using 2nd line drugs for patients at
risk of MDR amplification required.
• Further determine, what level of drug resistance
prevalence would require routine DST to avoid
creation of unnecessary and costly drug resistance.
• Strategy to reduce risk of amplification through
integration of DR-TB management
Acknowledgements
We would like to thank MSF national
and expatriate staff, MOH staff of
Karakalpakstan and Doshoguz; and the
SRL in Borstel, Germany.