The Challenge of MDR/TB (Dr. Hans Rieder)
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Transcript of The Challenge of MDR/TB (Dr. Hans Rieder)
The Challenge of MDRMeeting with Journalists
Organizer: National Press Foundation
Lille, October 27, 2011
Presenter: Hans L Rieder
The Union, Paris, FranceUniversity of Zurich, Switzerland
Cumulative Percentage of Strains Resistant toStreptomycin, BMRC Streptomycin Trial, 1947
Days after initiation of treatment
0 20 40 60 80 100 120 140
Cum
ulat
ive
perc
enta
ge re
sist
ant
0
20
40
60
80
100
British Medical Research Council. Br Med J 1948;2:769-82
Median
7 weeks
Frequency of Spontaneous Mutations toAnti-Tuberculosis Medications
Freq
uenc
y of
mut
atio
n
10-6
10-7
10-8
10-9
10-10
David HL. Appl Microbiol 1970;20:810-4
EMB SM INH RMP
Num
ber o
f bac
illi i
n a
cavi
ty
101
102
103
104
106
105
107
Spontaneoulsy resistant mutants:approximately 1 in 1 million
Selection under pressure:chemotherapy gives opportuinity
Time of chemotherapy
Susceptible strain as awhole killed by drugs
Resistant mutants becomedominant strain under pressure
Drug Akills susceptible organisms
Drug Akills Drug B-resistantmutants
Drug Bkills Drug A-resistant mutants
Drug Bkills susceptible organisms
Bactericidal Effects During Two Successive InitialTwo-Day Phases of Treatment with INH and RMP
0 2 4 6 8 10
Num
ber o
f via
ble
baci
lli
Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15
Treatment taken Treatment taken
Susceptiblebacilli
INH-resistant mutants
Regrowth
Subinhibitory Drug Concentrations During RegrowthN
umbe
r of v
iabl
e ba
cilli
Mutantsresistantto A
Regrowth insub-inhibitoryconcentrationof drug A
Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15
Killing phase Regrowth
Bacteriopausal Effects During RegrowthN
umbe
r of v
iabl
e ba
cilli
Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15
Mutantsresistantto A Lag due to
drug B
Lag due to drug A
Regrowth starting
Killing phase Regrowth
Probability of resistant mutant:
1 in 106 for drug A
1 in 106 for drug B
(1 in 106) x (1 in 106 )= 1 in 1012 for both drug A and drug B
2 drugs to which the organism is susceptible should suffice
Ability of Drugs to Prevent as Companion Drugthe Emergence of Isoniazid Resistance
Per
cen
t of r
esis
tanc
eem
ergi
ng to
ison
iazi
d
0
5
10
15
Mitchison DA. J Roy Coll Phys London 1980;14:91-9
RMP SM EMB TH
Potential Risks for Acquisition of MDR
o Settings with a high prevalence of initial isoniazid resistance
o Settings with a high prevalence of HIV infection among tuberculosis patients
o Settings with self-administered fixed-dose combinations
Two Populations of Tubercle Bacilli andTheir Evolution During Chemotherapy
Number oforganisms
Extracellular bacilli
Intracellular bacilli
Duration of chemotherapy
Grosset J. Excerpta Medica 1977:1-11
Failure(Requires bactericidal activity)
Relapse(Requires sterilizing activity)
Culture Conversion of Pulmonary Tuberculosis in Patientswith Susceptible Organisms, Receiving SM-INH-PAS
Months of chemotherapy
0 2 4 6 8 10 12
Per
cen
t pos
itive
0
20
40
60
80
100
Crofton J. Am Rev Tuberc 1958;77:869-71
1954
2004
World Health Organization. WHO Expert Committee on Tuberculosis.Eighth Report. Tech Rep Ser 1964;290:1-24
“Drug resistance is a man-made problem…”
From poor policy….
i.e., 2 SH / 10H or 2 PH / 10H is “acceptable practice”
…or is that’s why we now have a mess 40 years later?
National Tuberculosis Institute Bangalore. Bull World Health Organ 1974;51:473-89Responsible for conduct and report include:
A Geser (WHO Epidemiologist) and T Olakowsi, WHO Medical Officer
“Drug resistance is a man-made problem…”…to bad practice
Monoresistance:1 drug
Polyresistance:2 or more drugs
Ison
iazid
Oth
er d
rugs
Oth
er p
olyr
esist
ance
INH-RMP = “MDR”
MDR “simple”:RMP-INH
only
XDR:
RM
P-IN
H-FQ
-Inje
ctab
le
MDR “plus”:RMP-INH-FQ
orRMP-INH-Inj
Schematic: not a real quantitative distribution!
Principle of the cascade of regimens
Provide a clinical trial-established first-lineregimen with high likelihood of success
to all new patients
Provide a second-line regimen with high likelihood of success to all patients with anon-successful prior treatment outcome
requiring re-treatment (failure, returnafter default, recurrent tuberculosis)
Prevalence of Multidrug-Resistance Among Incident Smear-PositiveTuberculosis Cases without Prior Treatment, Benin and Ivory Coast
After 12 Years of Rifampicin Usage in the National Program
Num
ber o
f cas
es
0
100
200
300
Trébucq A, et al. Int J Tuberc Lung Dis 1999;3:466-70Dosso M, et al. Int J Tuberc Lung Dis 1999;3:805-9
Benin Ivory Coast
333 320
MDR:1 (0.3%)
MDR:17 (5.3%)
8-mo regimen:
2 S{HR}Z / 6 {TH}
6-mo regimen:
2 {HRZ} / 4 RH
Hres ?
Rres ?
FQ-Kres ?
H monoresistance
XDR
MDR
yes
yes
yes
no
no
no
8- or 18-mo INH-throughout regimen:2 S-H-PAS / 16 H-PAS2 S-H-R-Z / 6 H 2 E-H-R-Z / 8 E-H
≥ 90% effective
9- to 12-mo FQ-throughout regimen:
4(+) K-G-T-C-H-E-Z / 5 G-C-E-Z
≥ 90% effective
6- or 8-mo RMP-throughout regimen:
2 S-E-H-R-Z / 6 E-H-R-Z2 E-H-R-Z / 4 H-R
≥ 90% effective
Complex! Toxic! 21-mo regimen – poor effectiveness (50%)
The Regimen Cascade
Treatment of MDR tuberculosis in Damien FoundationProjects, Bangladesh, 1997-2007
Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684-92
Kaplan-Meier analysis of primary adverse endpoint
Time in 30-day intervals
Pro
babi
lity
rem
aini
ng fr
eeof
adv
erse
out
com
e (%
)
0 180 360
Ofloxacin221
540 720
75
70
85
80
95
90
100
Ofloxacin-based regimens
Gatifloxacin-based regimen
Hazard ratio: 0.39 (95% CI 0.26-0.59)65
Gatifloxaxin
208203
200195
191
188184
149177
177175
172
171167
164
160158
157
156156
152
151151
149
206198
195
193192
191
190187
131186
182179
177
176175
175
172168
166
165165
164
163139
128
FailureDefaultDeathRelapse
Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684-92
The (minimum) 9-month regimen for MDR in Bangladesh (220 €)
Gatifloxacin
Ethambutol
Pyrazinamide
Clofazimine
Kanamycin
Prothionamide
Isoniazid
4-month intensive phase prolongedif still smear-positive after 4 months
Fixed 5-month continuation phase
Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684-92
Conclusionso A well-tolerated, effective treatment regimen for MDR
tuberculosis has been developed over an 11-year period in Bangladesh among patients without HIV infection, naïve to prior use of second-line drugs
o The regimen is affordable (220 €) for low-income countries
o The regimen is simple enough to be prescribed, observed, and managed at regional or even peripheral level
Where to go from here?1) Apply the regimen in multiple settings in which success is likely, to
alleviate quickly the sorry state of affairs that only 2% of patients with MDR are estimated to currently obtaining treatment
2) Implement the appropriate research agenda:o Sufficiently powered clinical trials to confirm or refute findings
(funding?)o Observational studies in other countries with and without HIV
infection among their tuberculosis patients (in progress)
o Development of sequentially adaptive regimens in settings which have lost fluoroquinolone or injectable drug activity
o Any new regimen must retain drug affordability for the owners of the national programs
Hr
{HR}r
{HR+}r
{HRF}r {HRI}r{HRIF}r
No
No
No
2 EHRZ / 6 EH
Yes
Yes
Yes
2 EHRZ / 4 RH
Bangladesh-typeregimen
Cascade of regimens
XDR “MDR-plus”
90% effective
90% effective
90% effectiveEstablishedwith availablegeneric drugs
Requiresnew drug
classes
Establish the frequency of MDR subsets
HrRr HrRrFr HrRrIr HrRrFrIr
Simple to cure Difficult to cureAlmost impossible
to cure
?70%-90% ? ? 1%-15% 1
1 Centers for Disease Control and Prevention. Morb Mortal Wkly Rep 2006;55:301-5
SSHPHSP
SPH ERH ERHZ
Streptomycin Isoniazid Rifampicin Fluoroquinolones
Time axis of introduction of drug
Regimen preferred by majority
S: StreptomycinP: Para-aminosalicylic acidH: IsoniazidE: EthambutolZ: Pyrazinamide
Semiquantitative presentation of emergence of drug resistance
H-res
Fully susceptible
MDRXDR
2 EHRZ / 4 HR
2 SEHRZ / 6 HR
4+ KPGHZEC / 5 GZEC
HrRrIsFsHrRrIrFs HrRrIsFr HrRrIrFr
The Union’s proposed revised cascade of regimens
? ? ???
Identical with WHO(also 2 EHRZ / 4 EHR)
Different from WHO(2 SEHRZ / 1 EHRZ / 5 EHR)
Aït-Khaled N, Alarcón E, Armengol R, Bissell K, Boillot F, Caminero J A, Chiang C Y, Clevenbergh P, Dlodlo R,Enarson D A, Enarson P, Fujiwara P I, Harries A D, Heldal E, Hinderaker S G, Monedero I, Rieder H L, Rusen I D,
Trébucq A, Van Deun A, Wilson N.Management of tuberculosis. A guide to the essentials of good practice. (Sixth edition).
Paris: International Union Against Tuberculosis and Lung Disease, 2010.
Diarylquinolines?
World Health Organization. Word Health Organization Document 2010;WHO/HTM/TB/2009.420:1-147
When is direct observation of treatment necessary?
Direct observation of treatment is always recommended in the following cases:
o Two months initial phase of all new smear-positive cases;
o Four months continuation phase of rifampicin-containing regimens, for all new smear-positive cases;
Quoted from:World Health Organization 1997; WHO/TB/97.220:44
Introduction of Directly Observed Therapy and Program Indicatorsof Tuberculosis Control, Tarrant County, Texas 1980-92
0.0
0.4
0.8
1.2N
umbe
r of c
ases
per
100
,000
pop
ulat
ion
0.0
0.4
0.8
1.2
Year of notification
1980 1982 1984 1986 1988 1990 19920.0
0.4
0.8
1.2
Weis SE, et al. N Engl J Med 1994;330:1179-84
Multidrug-resistant relapse
Primary resistance
Acquired resistance
DOT
Just three core drugs * have emerged in almost 70 years of chemotherapy
o Isoniazid
o Rifampicin
o 4th generation fluoroquinolones (gatifloxacin, moxifloxacin)
* Note: the notion of a “core drug” is a hypothetical research concept
Core drug-based * principles of chemotherapy
o Achieve failure- and relapse-free cure through use of a core drug
o Ensure that the core drug is safely protected by well-tolerated companion drugs against emergence of resistance against it
* Note: the notion of a “core drug” is a hypothetical research concept