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

ent

age

resi

stan

t

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

Fre

qu

enc

y o

f mu

tatio

n

10-6

10-7

10-8

10-9

10-10

David HL. Appl Microbiol 1970;20:810-4

EMB SM INH RMP

Nu

mb

er

of b

aci

lli in

a c

avi

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

of v

iabl

e ba

cilli

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

um

be

r o

f via

ble

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

via

ble

baci

lli

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

Pe

r ce

nt p

osi

tive

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

iazi

d

Oth

er d

rugs

Oth

er p

olyr

esis

tanc

e

INH-RMP = “MDR”

MDR “simple”:RMP-INH

only

XDR:

RM

P-IN

H-F

Q-In

ject

able

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

of c

ases

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

Anti-Tuberculosis Drugs

Essential drugs: Other drugs / classes:

Isoniazid Other aminoglycosides

Rifampicin Polypeptides

Pyrazinamide Thioamides

Ethambutol Cycloserine

Streptomycin Para-aminosalicylic acid

Thioacetazone Fluoroquinolones

Oxazolidinones

Diarylquinolines

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

ba

bili

ty r

em

ain

ing

fre

eo

f ad

vers

e o

utc

om

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

cas

es p

er 1

00,0

00 p

opul

atio

n

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