Transcript Tuberculosis in Foreign-born Persons, United States 1993-1997

Preserving Effective TB Treatment Study
(PETTS)
San Antonio, Texas
25 September 2012
Peter Cegielski, MD, MPH
International Research and Programs Branch
Division of Tuberculosis Elimination
Preview
• Background and rationale
• Objectives
• Subjects, Methods
• Results
•
– Baseline
– Follow up
Conclusions and next steps
XDR TB as % of MDR TB
Predicting the Growth of XDR TB
Inadequate treatment of MDR TB results in
growth of XDR TB
% of MDR TB cases detected and treated
Blower S, Supervie V. Lancet Infectious Diseases 2007;7:443.
Can we preserve the effectiveness of
second-line drug treatment of MDR TB?
Increasing
treatment
of MDR TB
Increasing
resistance
to SLDs
Acquired resistance to second-line
drugs: Can it be prevented?
• How often does it occur?
• How soon does it occur after starting treatment?
• Does it differ for different drugs?
• How does it affect patient outcomes?
PETTS Study Objectives
• To determine the frequency, timing, and risk
•
factors for acquired resistance to SLD
– Program characteristics (GLC)
– Patient characteristics
– Mycobacterial characteristics
– Treatment
To determine the effect of acquired SLD
resistance on patient outcomes
PETTS Overview
•
Prospective cohort study in 9 countries
– 5 GLC-approved: Estonia, Latvia, Russia, Peru,
Philippines (11 sites)
– 4 non-GLC: S. Africa, S. Korea, Thailand, Taiwan (15
sites)
•
•
•
Consecutive consenting adults with locally confirmed
pulmonary MDR TB enrolled at start of MDR TB treatment,
2005-2008
Sputum culture at start of treatment and monthly sputum
cultures shipped to CDC for testing
Patients followed for 2 years, until treatment completed or
end of study (30 June 2010)
PETTS Overview 2
•
First and last isolate from each patient tested at
CDC for susceptibility to 12 drugs
– indirect proportion method on Middlebrook 7H10
agar plates
•
If drug susceptibility test (DST) results differ 
genotyping (spoligo, MIRU-24)
– Same genotype: ACQUIRED RESISTANCE
– Different genotypes: different strains
PETTS Study Design
Pretreatment  Treatment  Acquired resistance
Patient outcome
Incidence of
acquired
resistance
GLC-approved
MDR TB
treatment
programs
Non-GLC
MDR TB
treatment
programs
Incidence of
acquired
resistance
= patient with acquired resistance
Baseline PETTS isolates
Country
N Baselines
Tested
N Usable
Baselines
N included: MDR
confirmed
Clinical data
Estonia
50
46
46 (92%)
Latvia
106
103
100 (94%)
Peru
213
202
177 (83%)
Philippines
456
414
397 (87%)
South Africa
425
348
293 (69%)
South Korea
119
105
99 (91%)
Russia
132
119
115 (87%)
Thailand
63
60
51 (81%)
1564
1397 (89%)
1278 (82%)
Total
Prevalence of drug resistance in MDR baseline
isolates, 8 countries, 2005-2008 (n=1278)
% RESISTANT
Range across sites (%
RES)
RBT
68.5
56.0-82.6
EMB
64.6
47.1-89.1
SM
69.0
46.5-100
KM
18.5
1.8-42.0
AMK
16.0
1.8-35.0
CAP*
12.0
0.3-27.7
1 SL-INJ
20.0
2.0-47.0
3 SL-INJ*
10.5
0.3-25.6
FQ
12.9
7.1-32.3
THA
19.5
7.3-30.5
PAS
10.7
2.0-34.3
XDR
6.7
0.8-15.2
DRUG
* n=1270
Follow Up Data
• Clinical data
•
– Patient follow up ended - June 2010
– Data checking and cleaning ongoing
– Interim database through November 2011
Microbiology
– Final shipments of cultures - September 2010
– Final culture DST completed - October 2011
– Genotyping to be completed – March 2012
Duration of Follow Up
• Duration of follow up on treatment (days)
• Mean: 579 (std. dev. 228)
• Median: 616 (1st-99th percentiles 48 – 1132)
• Mode: 728
• Total: 2,623 person-years
• Duration of microbiological follow up
• Mean number cultures per patient: 14.7
• Mean number positive cultures per patient:
3.5
Adherence to Treatment
(% of days treatment received on schedule)
• 87.8% of patients were ≥ 90% adherent
• 12.2% of patients were < 90% adherent
• 7.2% of patients were < 80% adherent
• 1.9% of patients were < 50% adherent
Treatment Outcomes - Overall
• 961 (58.1%) Cured / treatment completed /
continuing treatment
• 102 (6.2%) Treatment failure
• 227 (13.7%) Death
• 323 (19.5%) Default
• 1613 Sum of Above
• 41 (2.5%) Unknown
Treatment Outcome by Country (%)
Cure/Comp
Failure
Death
Default
A
50.0
10.4
6.3
33.3
B
62.9
12.4
5.7
19.1
C
D
E
F
G
H
I
58.6
71.1
60.2
47.6
46.7
92.0
76.5
0.5
3.2
11.9
6.6
17.1
2.0
5.9
12.6
7.5
13.6
26.9
1.0
6.0
11.8
28.3
18.3
14.4
18.9
35.2
0.0
5.9
Green Light Committee vs.
Treatment Outcome [n (%)]
Cure/Comp. Failure
Death
Default
Total
82 (9.1)
GLC
588 (65.0)
47 (5.2)
188 (20.8)
905
Non-GLC
373 (52.7)
55 (7.8) 145 (20.5) 135 (19.1)
708
Total
*missing=41
961
102
227
323
1613*
P-value
<0.0001
Green Light Committee vs.
Treatment Outcome [n (%)]
Cure/Comp. Failure
Death
Default
Total
82 (9.1)
GLC
588 (65.0)
47 (5.2)
188 (20.8)
905
Non-GLC
373 (52.7)
55 (7.8) 145 (20.5) 135 (19.1)
708
Total
*missing=41
961
102
227
323
1613*
P-value
<0.0001
Green Light Committee x Treatment
Outcome, excluding HIV-infected patients
Cure/Comp.
Failure
Death
Default
Total
GLC
579 (65.1)
46 (5.2)
81 (9.1)
184 (20.7)
890
Non-GLC
241 (56.2)
41 (9.6)
58 (13.5)
89 (20.7)
429
820
87
139
273
1319
Total
P-value = 0.0006
Use of Directly Observed Therapy
x Treatment Outcome
Cure/Comp.
Failure
Death
Default
Full DOT
(n=1039)
647 (62.3)
56 (5.4)
139 (13.4)
197 (18.9)
Partial DOT
(n=464)
264 (56.9)
28 (6.0)
83 (17.9)
89 (19.2)
No DOT
(n=107)
48 (44.9)
18 (16.8)
4 (3.7)
37 (34.6)
P < 0.0001
Baseline Resistance to ≥ 1 Second-line
Injectable Drug x Treatment Outcome
Cure/Comp
Failure
Death
Default
Sus. (n=1060)
684 (64.5)
50 (4.7)
114 (10.7)
212 (20.0)
Res. (n=237)
91 (38.4)
40 (16.9)
62 (26.2)
44 (18.6)
P-value
<0.0001
Baseline Resistance to Fluoroquinolones
x Treatment Outcome
Cure/Comp
Failure
Death
Default
Sus. (n=1138)
713 (62.6)
59 (5.2)
136 (12.0)
230 (20.2)
Res. (n=159)
62 (39.0)
31 (19.5)
40 (25.2)
26 (16.3)
P-value
< 0.0001
Baseline Extensive Drug Resistance
(XDR) x Treatment Outcome
Cure/Comp
Failure
Death
Default
Sus (n=1219)
754 (61.9)
70 (5.7)
151 (12.4)
244 (20.0)
Res (n=78)
21 (26.9)
20 (25.6)
25 (32.1)
12 (15.4)
P-value
< 0.0001
Emergence of Drug Resistance: Isolates Analyzed
893 pairs of
isolates with
DST results
825 pairs of
MDR
isolates
GLC:
442 pairs of
isolates
Non-GLC:
383 pairs of
isolates
Does the GLC achieve it’s objective of
preventing acquired drug resistance?
Comparison of DST results in
first vs. last paired isolates*
GLC
Non-GLC
% Acquired FQ res.
10.1%
20.8%
% Acquired SL-INJ res.
12.5%
12.2%
% Acquired XDR (≥1 drug)
21.0%
51.1%
% Acquired XDR (2 classes)
3.0%
5.6%
* Mean 5 mos. between first and last isolate
Considerations for Acquired Drug Resistance
Analysis




There are many country specific factors other than whether
sites applied for GLC or not that need to be considered for
association with acquired drug resistance
Genotyping results are necessary to confirm that BL and
Final isolates are the same strain
For matching genotypes, repeat DSTs are required for
confirmation
We do occasionally see a loss of resistance between BL
and final isolates. Again, genotyping and repeat DSTs are
essential
Acquired Resistance to ≥1 Second-line
Injectable Drug x Treatment Outcome
Cure/Comp
Failure
No (n=761)
408 (53.6)
68 (8.9)
124 (16.3) 161 (21.2)
Yes (n=79)
28 (35.4)
12 (15.2)
22 (27.9)
17 (21.5)
436
80
146
178
P-value
= 0.005
Total
Death
Default
Acquired Resistance to
Fluoroquinolones x Treatment Outcome
Cure/Comp
Failure
Death
Default
(n=736)
410 (55.7)
57 (7.7)
112 (15.2)
157 (21.3)
Yes (n=104)
26 (25.0)
23 (22.1)
34 (32.7)
21 (20.2)
P-value
< 0.0001
No
Acquired Extensive Drug Resistance
(XDR) x Treatment Outcome
Cure/Comp
Failure
Death
Default
No (n=754)
418 (55.4)
62 (8.2)
116 (15.4)
158 (21.0)
Yes (n=86)
18 (20.9)
18 (20.9)
30 (34.9)
20 (23.3)
P-value
< 0.0001
Summary
• Treatment data complex, results preliminary
• Several risk factors have very strong
•
associations with outcome
– Country, GLC, previous treatment, severity of
disease, baseline drug resistance, DOT,
persistence of positive cultures
Acquired drug resistance has a severe impact
on outcomes
Next Steps
• Completion of data checking and cleaning
• Extend analyses to identify salient risk
•
•
factors controlling for differences between
samples from different countries
Compare genotypes of baseline and final
isolates
Test isolates between first and last to
determine timing and specific mutations
leading to acquired drug resistance
Acknowledgements
CDC, Atlanta, Georgia, USA
Ken Castro
Eugene McCray
Charles Wells
Tracy Dalton*
Ekaterina Kurbatova*
Julia Ershova*
Allison Taylor*
Bryan Kim*
Gail Starks*
Andrey Borisov*
Michael Chen*
Lauren Cowan
Lois Diem*
Denise Hartline*
Jamila Franklin*
Dorothy Kaminski*
Heather Alexander
Beverly Metchock
Tom Shinnick
David Sikes
Kathrine Tan*
Andy Vernon
Emory University, Atlanta, Georgia, USA
Charlotte Kvasnovsky*
Melanie Wolfgang*
Tropical Disease Foundation, Manila, Philippines
Janice Campos Caoili*
Grace Egos
Maricelle Gler
Ruffy Guilatco
Nellie Mangubat
Imelda Quelapio
Thelma Tupasi
Tartu University, No. Estonia Regional Hospital
& National TB Registry,,Tallinn, Estonia
Kai Kliiman
Piret Viiklepp
Manfred Danilovitz
Tiina Kummik
Klavdia Levina
State Centre of TB and Lung Disease, Riga, Latvia
Girts Skenders
Ingrida Sture
Liga Kuksa
Gunta Dravniece
Vaira Leimane
Medical Research Council, Pretoria, S. Africa
Martie van der Walt
Jeannette Brand
Joey Lancaster
Ronel Odendaal
Karin Weyer
Office of Disease Prevention and Control 7th
Muang District, Ubon Ratchatani, Thailand:
Rattanawadee Akksilp
Somsak Akksilp
Wanlaya Sitti
Wanpen Wattanaamornkiet
Korean Institute of TB, Seoul, and National
Masan TB Hospital, Masan, South Korea
Hee Jin Kim
Hee Jung Lee
Chang-ki Kim
Woojin Lew
Ray Cho
Sungkyu Park
Nackmoon Sung
Russian Federation: Central TB Research Institute,
Moscow; Orel Oblast TB Dispensary; Vladimir Oblast TB
Dispensary; Northern State Medical University and
Arkhangelsk Reg. TB Dispensary;
Vladislav Erokhin & CTRI Team, Moscow
Andrey Maryandyshev, Nina Nizovtseva, Director Perkhin,
and team from Arkhangelsk
Boris Kazenniy and team from Orel
Grigory Volchenkov and team from Vladimir
Ministry of Health / National TB Strategy, National Institute of
Health, Socios en Salud Sucursal, Lima City & Lima East Health
Districts, LIma, Peru
Oswaldo Jave
Jaime Bayona
Luis Asencios
Carmen Contreras
Cesar Bonilla
Martin Yagui
Gloria Yale
National Institute of Allergy & Infectious Disease,
Bethesda, Maryland, USA
Clifton Barry III
Laura Via
USAID Washington & Moscow
Christy Hansen
Amy Bloom
Cheri Vincent
Nikita Afanasiev
WHO Geneva, Copenhagen, Moscow, Lima
Mario Raviglione
Paul Nunn
Melina Abrahan
Richard Zaleskis
Wieslaw Jakubowiak
Mario Valcarcel
* Global Coordinating Team
Smoking x Treatment Outcome
No
(n=1211)
Yes
(n=377)
Cure/Comp.
Failure
Death
Default
749 (61.8)
52 (4.3)
174 (14.4)
236 (19.5)
204 (54.1)
50 (13.3)
40 (10.6)
83 (22.0)
P-value
< 0.0001
Alcohol Abuse x Treatment Outcome
No
(n=1287)
Yes
(n=250)
Cure/Comp.
Failure
Death
Default
807 (62.7)
70 (5.4)
163 (12.7)
247 (19.2)
128 (51.2)
30 (12.0)
31 (12.4)
61 (24.4)
P-value
< 0.0001
Previous Treatment History x
Treatment Outcome
Cure/Comp
Failure
Death
Default
None
(n=217)
141 (65.0)
13 (6.0)
17 (7.8)
46 (21.2)
1st-line drugs
(n=1150)
690 (60.0)
56 (4.9)
184 (16.0)
220 (19.1)
2nd-line drugs
(n=222)
114 (51.3)
32 (14.4)
25 (11.3)
51 (23.0)
P value
< 0.0001
Radiographic Extent of Disease x
Treatment Outcome
Cure/Comp.
Failure
Death
Default
Unilateral
(n=308)
212 (68.8)
9 (2.9)
25 (8.1)
62 (20.1)
Bilateral
(n=1276)
732 (57.4)
92 (7.2)
201 (15.7)
251 (19.7)
P-value
< 0.0001
Cavitary Lung Disease x
Treatment Outcome
Cure/Comp.
Failure
Death
Default
None
(n=593)
384 (64.8)
25 (4.2)
78 (13.1)
106 (17.9)
Unilateral
(n=615)
377 (61.3)
36 (5.8)
79 (12.9)
123 (20.0)
Bilateral
(n=377)
182 (48.3)
40 (10.6)
69 (18.3)
86 (22.8)
P value
< 0.0001
Number of positive cultures
Cure/Comp
Failure
Death
Default
1
(n=554)
392 (70.8)
1 (0.2)
55 (9.9)
106 (19.1)
2
(n=467)
322 (69.0)
15 (3.2)
46 (9.8)
84 (18.0)
3
(n=220)
125 (56.8)
8 (3.6)
33 (15.0)
54 (24.6)
4-5
(n=170)
81 (47.6)
9 (5.3)
35 (20.6)
45 (26.5)
6-8
(n= 89)
26 (29.2)
17 (19.1)
25 (28.1)
21 (23.6)
9-24 (n=110)
13 (11.8)
52 (47.3)
33 (30.0)
12 (10.9)
P-value
< 0.0001
Baseline Resistance to All 4 First-line
Drugs x Treatment Outcome
Cure/Comp
Failure
Death
Default
No (n=699)
432 (61.8)
41 (5.9)
77 (11.0)
149 (21.3)
Yes (n=597)
343 (57.5)
49 (8.2)
98 (16.4)
107 (17.9)
775
90
175
256
P-value
= 0.006
Total
Emergence of Resistance to Fluoroquinolones:
Preliminary Data
GLC
Non-GLC
# Pairs of isolates
442
383
# Baselines susceptible
to FQ
376
318
Of baseline susceptible,
# final isolates resistant
to FQ
38
66
10.1%
20.8%
% Emergent FQ
resistance
Emergence of Resistance to SL-INJ: Preliminary Data
GLC
Non-GLC
# Pairs of isolates
442
383
# baselines susceptible to
all SL-INJ
335
279
Of baseline susceptible, #
final isolates resistant to
≥1SL-INJ
42
34
12.5%
12.2%
% Emergent resistance to
≥1 SL-INJ
Emergence of XDR TB: Preliminary Data
MDR (no FQ or SL-INJ resistance)
XDR
GLC
Non-GLC
# Pairs of isolates
442
383
# baselines susceptible to FQ
and all SL-INJ
296
250
Of baseline susceptible, # final
isolates resistant to FQ and ≥1
SL-INJ (XDR)
9
14
% Emergent resistance to FQ
and ≥1 SL-INJ (XDR)
3.0%
5.6%
Emergence of XDR TB: Preliminary Data
pre-XDR
XDR
GLC
Non-GLC
# Pairs of isolates
442
383
# baselines resistant to either
FQ or all SL-INJ (pre-XDR)
119
92
Of baseline susceptible, # final
isolates resistant to FQ and ≥1
SL-INJ (XDR)
25
47
% Emergent resistance to FQ
or ≥1 SL-INJ (XDR)
21.0%
51.1%
*Pre-XDR refers to BL MDR isolates that also have resistance to either a FQ or ≥1 SL-INJ
Study sample for analysis of acquired
resistance vs. treatment outcomes
Core Clinical Database
n=1654
Baseline DST results
n=1426 patients
No follow up isolate n=486
Follow up isolate no
growth/contam. n=46
Only baseline
culture positive
n=566
Baseline and ≥1 follow
up cultures positive
n=1088
Baseline and final isolate
pairs with DST results
n=894
Analysis of acquired resistance
n=860 confirmed MDR