The Challenge of MDR

Meeting with Journalists Organizer: National Press Foundation

Lille, October 27, 2011
Presenter: Hans L Rieder
The Union, Paris, France University of Zurich, Switzerland

Cumulative Percentage of Strains Resistant to Streptomycin, BMRC Streptomycin Trial, 1947

Cumulative percentage resistant
100 80

60
Median

40

20 0 0 20
7 weeks

40

60

80

100

120

140

Days after initiation of treatment

British Medical Research Council. Br Med J 1948;2:769-82

Frequency of Spontaneous Mutations to Anti-Tuberculosis Medications

10-6

Frequency of mutation

10-7 10-8 10-9 10-10

EMB

SM

INH

RMP

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

Number of bacilli in a cavity

107 106 105 104 103 102 10

1

Selection under pressure: chemotherapy gives opportuinity Susceptible strain as a whole killed by drugs

Resistant mutants become dominant strain under pressure

Spontaneoulsy resistant mutants: approximately 1 in 1 million

Time of chemotherapy

Drug A kills Drug B-resistant mutants

Drug B kills Drug Aresistant mutants

Drug A kills susceptible organisms

Drug B kills susceptible organisms

Bactericidal Effects During Two Successive Initial Two-Day Phases of Treatment with INH and RMP
Susceptible bacilli

Regrowth

Number of viable bacilli

0

INH-resistant mutants

10

Treatment taken

Treatment taken

Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15

Subinhibitory Drug Concentrations During Regrowth

Regrowth in sub-inhibitory concentration of drug A

Number of viable bacilli

Mutants resistant to A

Killing phase

Regrowth

Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15

Bacteriopausal Effects During Regrowth

Number of viable bacilli

Regrowth starting

Lag due to drug A

Mutants resistant to A

Lag due to drug B

Killing phase

Regrowth

Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15

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 Drug the Emergence of Isoniazid Resistance

Per cent of resistance emerging to isoniazid
15

10

RMP

SM

EMB

TH

Mitchison DA. J Roy Coll Phys London 1980;14:91-9

Potential Risks for Acquisition of MDR

o Settings with a high prevalence of initial isoniazid resistance Settings with a high prevalence of HIV infection among tuberculosis patients Settings with self-administered fixed-dose combinations

Two Populations of Tubercle Bacilli and Their Evolution During Chemotherapy

Failure Number of organisms
Extr ace llular b
(Requires bactericidal activity)

Relapse
acill i
(Requires sterilizing activity)

Intracellular ba cilli

Duration of chemotherapy
Grosset J. Excerpta Medica 1977:1-11

Culture Conversion of Pulmonary Tuberculosis in Patients with Susceptible Organisms, Receiving SM-INH-PAS
100 80 60 40 20
2004 1954

Per cent positive

0 0 2 4 6 8 10 12

Months of chemotherapy
Crofton J. Am Rev Tuberc 1958;77:869-71

Drug resistance is a man-made problem

From poor policy.

i.e., 2 SH / 10H or 2 PH / 10H is acceptable practice or is thats why we now have a mess 40 years later?

World Health Organization. WHO Expert Committee on Tuberculosis. Eighth Report. Tech Rep Ser 1964;290:1-24

Drug resistance is a man-made problem

to bad practice

National Tuberculosis Institute Bangalore. Bull World Health Organ 1974;51:473-89 Responsible for conduct and report include: A Geser (WHO Epidemiologist) and T Olakowsi, WHO Medical Officer

Monoresistance: 1 drug

Polyresistance: 2 or more drugs

MDR plus: MDR simple: RMP-INH-FQ RMP-INH or only RMP-INH-Inj

Schematic: not a real quantitative distribution!

INH-RMP = MDR

XDR: RMP-INH-FQ-Injectable

Other polyresistance

Other drugs

Isoniazid

Principle of the cascade of regimens

Provide a clinical trial-established first-line regimen with high likelihood of success to all new patients

Provide a second-line regimen with high likelihood of success to all patients with a non-successful prior treatment outcome requiring re-treatment (failure, return after default, recurrent tuberculosis)

Prevalence of Multidrug-Resistance Among Incident Smear-Positive Tuberculosis Cases without Prior Treatment, Benin and Ivory Coast After 12 Years of Rifampicin Usage in the National Program
333
300

320

Number of cases

200

8-mo regimen:
2 S{HR}Z / 6 {TH} 100

6-mo regimen:
2 {HRZ} / 4 RH

MDR: 1 (0.3%)
0

MDR: 17 (5.3%) Ivory Coast

Benin

Trbucq A, et al. Int J Tuberc Lung Dis 1999;3:466-70 Dosso M, et al. Int J Tuberc Lung Dis 1999;3:805-9

The Regimen Cascade

8- or 18-mo INH-throughout regimen: 2 S-H-PAS / 16 H-PAS 2 S-H-R-Z / 6 H 2 E-H-R-Z / 8 E-H 90% effective 6- or 8-mo RMP-throughout regimen:

H res ?
yes

no

H monoresistance

R res ?
yes MDR

no

2 S-E-H-R-Z / 6 E-H-R-Z 2 E-H-R-Z / 4 H-R 90% effective

9- to 12-mo FQ-throughout regimen:

FQ-K res ?
yes XDR

no

4(+) K-G-T-C-H-E-Z / 5 G-C-E-Z 90% effective

Complex! Toxic! 21-mo regimen poor effectiveness (50%)

Anti-Tuberculosis Drugs
Essential drugs:
Isoniazid

Other drugs / classes:

Other aminoglycosides

Rifampicin
Pyrazinamide Ethambutol Streptomycin Thioacetazone

Polypeptides
Thioamides Cycloserine Para-aminosalicylic acid Fluoroquinolones

Oxazolidinones
Diarylquinolines

Treatment of MDR tuberculosis in Damien Foundation Projects, 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

100 95 90 85 80 75 70 65
Failure Default Death Relapse

Probability remaining free of adverse outcome (%)

Gatifloxacin-based regimen

Ofloxacin-based regimens

Hazard ratio: 0.39 (95% CI 0.26-0.59)

0 180 360 540 720

Time in 30-day intervals

Ofloxacin Gatifloxaxin
221 208 200 188 177 171 160 156 151 149 195 184 175 167 158 156 151 203 191 177 172 164 157 152 149 193 190 182 176 172 165 163 128 192 187 179 175 168 165 139 195 191 186 177 175 166 164 131

206 198

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 ) Kanamycin Prothionamide Isoniazid 4-month intensive phase prolonged if still smear-positive after 4 months Fixed 5-month continuation phase

Gatifloxacin
Ethambutol Pyrazinamide Clofazimine

Van Deun A, et al. Am J Respir Crit Care Med 2010;182:684-92

Conclusions
o A well-tolerated, effective treatment regimen for MDR tuberculosis has been developed over an 11-year period in Bangladesh among patients without HIV infection, nave 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 o o o Sufficiently powered clinical trials to confirm or refute findings (funding?) Observational studies in other countries with and without HIV infection among their tuberculosis patients (in progress) Development of sequentially adaptive regimens in settings which have lost fluoroquinolone or injectable drug activity Any new regimen must retain drug affordability for the owners of the national programs

Cascade of regimens Yes

Established with available generic drugs

Hr

No

2 EHRZ / 6 EH 90% effective

{HR}r Yes {HR+}r Yes

No

2 EHRZ / 4 RH 90% effective

Bangladesh-type regimen

No

90% effective

Requires new drug classes

{HRIF}r XDR

{HRF}r

{HRI}r

MDR-plus

Establish the frequency of MDR subsets

HrRr
Simple to cure

HrRrFr

HrRrIr HrRrFrIr
Almost impossible to cure

Difficult to cure

? 70%-90%

1%-15% 1

1 Centers

for Disease Control and Prevention. Morb Mortal Wkly Rep 2006;55:301-5

Semiquantitative presentation of emergence of drug resistance

Regimen preferred by majority
S SH PH SP SPH ERH ERHZ

Streptomycin

Isoniazid

Rifampicin

Fluoroquinolones

Time axis of introduction of drug

S: Streptomycin P: Para-aminosalicylic acid H: Isoniazid E: Ethambutol Z: Pyrazinamide

Fully susceptible

H-res MDR XDR

The Unions proposed revised cascade of regimens Identical with WHO (also 2 EHRZ / 4 EHR) Different from WHO SEHRZ / 1 EHRZ / 5 EHR) HrRrIsFs 4+ KPGHZEC / 5 GZEC 2 EHRZ / 4 HR

2 SEHRZ / 6 HR

HrRrIrFs ?

HrRrIsFr ?

HrRrIrFr
???

Diarylquinolines?
At-Khaled N, Alarcn 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, Trbucq 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. 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 o Two months initial phase of all new smear-positive cases; Four months continuation phase of rifampicincontaining 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 Indicators of Tuberculosis Control, Tarrant County, Texas 1980-92
1.2 DOT Multidrug-resistant relapse

Number of cases per 100,000 population

0.8 0.4 0.0 1.2 0.8 0.4 0.0 1.2 0.8 0.4 0.0 1980 1982 1984 1986

Primary resistance

Acquired resistance

1988

1990

1992

Year of notification
Weis SE, et al. N Engl J Med 1994;330:1179-84

Just three core drugs * have emerged in almost 70 years of chemotherapy

o
o

Isoniazid
Rifampicin

4th generation fluoroquinolones (gatifloxacin, moxifloxacin)

* Note: the notion of a core drug is a hypothetical research concept

Core drug-based * principles of chemotherapy

o o Achieve failure- and relapse-free cure through use of a core drug 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