Interventions for Tuberculosis Control and Elimination

Slides from the web site http://www.tbrieder.org

Compiled by:

Hans L Rieder

Brick kindly provided by Reuben Granich

Pot kindly provided byLiisa Parkkali

The Area of the “Magic Mountain”

Children with Tuberculosis at the Springfield House Open-Air School, Clapham Common, London, November 1932

Jacobson C. Lancet 2001;358:340Photo: Hutton Getty

Efficacy, effectiveness, efficiency…

Efficacy What can the drug do? (ideal conditions)

Effectiveness What does the drug do? (usual conditions)

Efficiency What does it take / cost to make it work?

With the input from Enarson DA, October 6,2006

Preventivetherapy

Prophylactictreatment

Exposure

BCGvaccination

Patient’s delay

Sub-clinicalinfection

Non-infectioustuberculosis

Infectioustuberculosis

Doctor’s delay

ChemotherapyTransmission

Death

An Epidemiologic Approach to Tuberculosis Interventions

Reduction of the incidence of tuberculous infection

Essence of the tuberculosis control strategy: identification and curative chemotherapy for cases transmitting M. tuberculosis

Reduction of the prevalence of tuberculous infection

Component of the tuberculosis elimination strategy: identification and preventive chemotherapy for persons already infected

Chemotherapy

Preventivetherapy

Prophylactictreatment

Exposure

BCGvaccination

Patient’s delay

Sub-clinicalinfection

Non-infectioustuberculosis

Infectioustuberculosis

Doctor’s delay

ChemotherapyTransmission

Death

Anti-Tuberculosis Drugs

Essential drugs: Other drugs / classes:

Isoniazid Other aminoglycosides

Rifampicin Polypeptides

Pyrazinamide Thioamides

Ethambutol Cycloserine

Streptomycin Para-amino salicylic acid

Thioacetazone Fluoroquinolones

Oxazolidinones

Diarylquinolines

Maximum Serum Concentration and Range of MinimumInhibitory Concentration of Anti-Tuberculosis Drugs

Con

cent

ratio

n (m

g / L

)(lo

g sc

ale)

0.005

0.02

0.1

0.5

2

10

40

Peloquin CA, et al. Int J Tuberc Lung Dis 1999;3:703-10Acocella G. Clin Pharmacokinetics 1978;3:108-27

Pählka R, et al. J Clin Pharm Ther 1999;24:219-25Davidson PT, et al. Clin Chest Med 1986;7:425-38

Grosset J, et al. Adv Tuberc Res 1970;17:107-53Zierski M. Pneumologie 1981;35:1075-1105

INH RMP PZA EMB SM TH

N

CNH-NH2

O

Chemical Structure of Isoniazid

Meyer H, Mally J. Monatshefte Chemie 1912;33:393-414

N

CNH-NH2

O

KatGactivation

Reactive oxygen/organic radicals

Multiple targets

Mycolic acid synthesisInhA, KasA

DNA damage? NAD metabolism?

Antagonists

NAT?AhpC?

Efflux

Isoniazid

Passive diffusion

Zhang Y, et al. In: Hatfull GF, et al.Molecular Genetics of Mycobacteria, 2000

Model of Isoniazid Action

Pharmacokinetics of Isoniazid, Fasting vs High-Fat Meal

Time (hours)

0 5 10 15 20 25

Con

cent

ratio

n (m

g/L)

0

1

2

3

4

5

Peloquin CA, et al. Int J Tuberc Lung Dis 1999;3:703-10

Fasting

High-fatmeal

Clearance of Isoniazid from Serum, by AcetylatorType and Age Among Tuberculosis Patients

Age group (years)

0 15 25 35 45 55 65 75

Cle

aran

ce (

mL/

min

/kg)

0

1

2

3

4

5

6

7

8

Kergueris MF, et al. Eur J Clin Pharmacol 1986;30:335-40

75+

Rapidacetylators

Slowacetylators

Appropriateness of Union-Recommended WeightBrackets for the Dosage of Isoniazid (75 mg / tablet)

Body weight (kg)

20 30 40 50 60 70 80

Dos

age

(mg/

kg)

3.5

4.0

4.5

5.0

5.5

6.0

6.5 25-39 kg2 tablets

40-55 kg3 tablets

> 55 kg4 tablets

upperrange

lowerrange

Isoniazid Adverse Drug Events

Frequent(≥ 5 per 100)

Common(≥1 per 100 and < 5

per 100)

Infrequent(≥ 1 per 1,000 and <

1 per 100)

Rare(≤ 1 per 1,000)

Liver enzyme elevations

HepatitisPeripheral neuropathyDrug fever

SeizuresHallucinosisPsychosisMemory lossOptic neuropathyPellagraPyridoxine responsive anemiaMetabolic acidosisPyridoxine non-responsive psychosisLupus erythematosusHemolytic anemiaAgranulocytosisPure red cell aplasiaAlopeciaAsthmaDermatitis

Hepatitis Risk on Isoniazid PreventiveChemotherapy Trial of the IUAT, by Age

Age group (years)

20 35 45 55 75

Cas

es

per

1,00

0

0

1

2

3

4

5

6

7

8

Riska N. Bull Int Union Tuberc 1976;51:203-8

INH, totalallocated

INH, no previousliver damage

Placebo group

Hepatitis Risk in Isoniazid PreventiveChemotherapy Trial of IUAT, by Time of Onset

Time of onset of hepatitis (week)

0 10 20 30 40 50

Cas

es

per

1,00

0

0

1

2Isoniazid

Placebo

Riska N. Bull Int Union Tuberc 1976;51:203-8

Isoniazid Interactions

Effects of isoniazid potentiated

Effects of isoniazid opposed

Effect of drug potentiated by

isoniazid

Effect of drug opposed by isoniazid

PASInsulinCarbamazepineTheophylline

Prednisolone

Ketoconazole

Anti-coagulantsAnti-epilepticsBenzodiazepinesHaloperidolTricylcic anti-depressantsTheophylline

Enflurane

O

CH3CH3

OH

OOCCH3 H3C

CH3

H3CO

CH3

NH

OHOH

H3C

OH

CH=N N N-CH3O

OCH3

Maggi N, Pasqualuci C, Ballotta R, Sensi P.Chemotherapy 1966;11:285-92

OH

Chemical Structure of Rifampicin

O

15

10

5

00 1 2 3 6 9

Hours after administration

Cavenaghi R. Bull Int Union Tuberc Lung Dis 1989;64(1):36-7

Bioavailability of 600mg Rifampicin by Excipientand Manufacturing Process in Healthy Volunteers

Me

an

se

rum

leve

l (m

g/L

)

Reference

Change of excipient andmanufacturing process

Plasma Pharmacokinetics of Rifampicin FollowingAdministration of 600 mg to Healthy Volunteers

Time (hr)

0 2 4 6 9 12 18 24 30

Se

rum

co

nce

ntra

tion

(m

g/L

)

0

2

4

6

8

10

12

14

Peloquin CA, et al. Antimicrob Agents Chemother 1997;2670-9

Pharmacokinetics of Rifampicin Following Meals

Hours after ingestion

0 2 4 6 8

Mea

n se

rum

leve

l (m

g/L)

0

2

4

6

8Empty stomach100 g glucose2 egg whites50 g butter

Purohit SD, et al. Tubercle 1987;68:151-2

Kenny MT, et al. Drug Metabolism Rev 1981;12:159-218

Rifampicin tissue penetrationT

issu

e-to

-ser

um r

atio

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4Cavity liningLung parenchymaKidney

Bone (pyogenic)

Pleura

Caseum

CSF (meningitis)

Appropriateness of Union-Recommended WeightBrackets for the Dosage of Rifampicin (150 mg / tablet)

Body weight (kg)

20 30 40 50 60 70 80

Dos

age

(mg/

kg)

7

8

9

10

11

12

13 25-39 kg2 tablets

40-55 kg3 tablets

> 55 kg4 tablets

upperrange

lowerrange

Total Serum Bilirubin Levels in Adults with Normal Liver Function After Ingestion of Rifampicin

0 4 8 12 16 20 24

Tot

al s

erum

bili

rubi

n (m

g / d

L)

0.0

0.5

1.0

1.5

Upper normal limit

Day 1

Time after rifampicin ingestion (hours)

0 4 8 12 16 20 240.0

0.5

1.0

1.5

Upper normal limit

Day 11

Curci G, et al. Arch Monaldi 1970;25:427

12 mg / kg

8 mg / kg

12 mg / kg

8 mg / kg

Results of a Meta-Analysis of Hepatitis FrequencyAssociated with Isoniazid and Rifampicin

Per

cen

t with

hep

atiti

s

0.0

0.5

1.0

1.5

2.0

2.5

3.0

INHalone

INH +other

RMP +other

INH +RMP

Steele MA, et al. Chest 1991;99:465-71

Rifampicin Adverse Drug Events

Frequent(≥ 5 per 100)

Common(≥1 per 100 and < 5

per 100)

Infrequent(≥ 1 per 1,000 and <

1 per 100)

Rare(≤ 1 per 1,000)

Bilirubin elevations in the beginning of treatment

Orange discoloration of urine and tears

Liver enzyme elevations

HepatitisPruritusFlu syndromeDrug fever

Interstitial nephritisGlomerulonephritisRenal failureToxic epidermal necrolysisOligomenorrheaAmenorrheaAnaphylactic shockThrombocytopeniaNeutropeniaLeukopeniaHemolytic anemiaPseudomembranous colitisEosinophilic colitisLupus erythematosusMyopathy

Rifampicin Interactions

Effects of rifampicin potentiated

Effects of rifampicin opposed

Effect of drug potentiated by

rifampicin

Effect of drug opposed by rifampicin

Co-trimoxazole Acetominophen Anti-arrhythmicsAnti-asthmaticsAnti-coagulantsAnti-fungalsAnti-malarialsAnti-retroviral protease inhibitorsBarbituratesBenzodiapezinsBeta blockersHormonesImmunosuppressantsCardiac glycosidesOpioidsVitamin K and DTrimethoprim

N

NCO

NH2

Chemical Structure of Pyrazinamide

Kushner S, et al. Am J Chem Soc 1952;74:3617

Plasma Pharmacokinetics of Pyrazinamide FollowingAdministration of 1,500 mg to Healthy Volunteers

Time (hr)

0 2 4 6 9 12 18 24 30 36

Se

rum

co

nce

ntra

tion

(m

g/L

)

0

5

10

15

20

25

30

Peloquin CA, et al. Antimicrob Agents Chemother 1997;2670-9

Appropriateness of IUATLD-Recommended WeightBrackets for the Dosage of Pyrazinamide (400 mg / tablet)

Body weight (kg)

20 30 40 50 60 70 80

Dos

age

(mg/

kg)

18

20

22

24

26

28

30

3225-39 kg2 tablets

40-55 kg3 tablets

> 55 kg4 tablets

upperrange

lowerrange

Pyrazinamide Adverse Drug Events

Frequent(≥ 5 per 100)

Common(≥1 per 100 and < 5

per 100)

Infrequent(≥ 1 per 1,000 and <

1 per 100)

Rare(≤ 1 per 1,000)

Arthralgias Nausea HepatitisRashNausea

Sideroblastic anemiaLupus erythematosusConvulsionsPhotodermatitis

Pyrazinamide Interactions

Effects of pyrazinamide potentiated

Effects of pyrazinamide

opposed

Effect of drug potentiated by pyrazinamide

Effect of drug opposed by

pyrazinamide

Allopurinol Zidovudin (?) Uricosuric drugs

H3C CH2

CH

CH2OH

NH

(CH2)2 . 2HCl

NH

CH

CH2OHCH2

H3C

Chemical Structure of Ethambutol

Thomas JP, et al. Am Rev Respir Dis 1961;83:891-3

Plasma Pharmacokinetics of Ethambutol FollowingAdministration of 25 mg/kg Body Weight, Healthy Volunteers

Time (hr)

0 1 2 4 8 24

Ser

um c

once

ntra

tion

(mg/

L)

0

1

2

3

4

5

Place VA, et al. Am Rev Respir Dis 1963;87:901-4

Ethambutol Adverse Drug Events

Frequent(≥ 5 per 100)

Common(≥1 per 100 and < 5

per 100)

Infrequent(≥ 1 per 1,000 and <

1 per 100)

Rare(≤ 1 per 1,000)

Retrobulbar neuritis

Periaxial ocular toxicity

Aplastic anemiaEosinophilic pneumoniaThrompocytopeniaHyperuricemia

Ethambutol Interactions

Effects of ethambutol potentiated

Effects of ethambutol opposed

Effect of drug potentiated by

ethambutol

Effect of drug opposed by ethambutol

None Aluminum-magnesium antacids

None None

Schatz A, Bugie E, Waksman SA. Proc Soc Experiment Biol Med 1944;55:66-9

O

H3CNH

OH

HOH2C

O

H2C

HO

CHO

O

OH

OH

NCNH2

OH

Chemical Structure of Streptomycin

NCNH2

HO

HNH

HNH

Schatz A, Bugie E, Waksman SA.Proc Sco Exper Biol Med 1944;55:66-

9

O

Plasma Pharmacokinetics of Streptomycin FollowingAdministration of 1 g to Tuberculosis Patients

Time (hr)

0 1 2 3 4 8 12

Ser

um c

once

ntra

tion

(mg/

L)

0

5

10

15

20

25

30

35

Acocella G, et al. Am Rev Respir Dis 1985;132:510-5

Streptomycin Adverse Drug Events

Frequent(≥ 5 per 100)

Common(≥1 per 100 and < 5

per 100)

Infrequent(≥ 1 per 1,000 and <

1 per 100)

Rare(≤ 1 per 1,000)

Vestibular toxicity Cochlear toxicity

Hypersensitivity reactions

Renal damage Neuromuscular blockade

Streptomycin Interactions

Effects of streptomycin potentiated

Effects of streptomycin

opposed

Effect of drug potentiated by streptomycin

Effect of drug opposed by streptomycin

Diuretics None Curare-like drugs None

HC

N NH

CS

NH2NH

C

O

H3C

Chemical Structure of Thioacetazone

Domagk G. Naturwissenschaften 1946;33:315

Thioacetazone Adverse Drug Events

Frequent(≥ 5 per 100)

Common(≥1 per 100 and < 5

per 100)

Infrequent(≥ 1 per 1,000 and <

1 per 100)

Rare(≤ 1 per 1,000)

Weight lossNauseaVomitingItchingMental disturbancesHeadacheBlurred visionPerioral numbness

Toxic epidermal necrolysis (in HIV infected patients)

Toxic epidermal necrolysis (in non HIV infected patients)

Agranulocytosis

Tuberculosis Patient in Malawi with Thioazetazone-AssociatedToxic Epidermal Necrolysis

Photo courtesy: Tone Ringdal

Frequency of Adverse Reactions to Major AntituberculosisDrugs During Routine Treatment Services

Events per 1,000 person-months (log scale)

0.1 0.3 1 3 10

RMP (fatal)

INH

SM

INH RMP PZA

EMB RMP PZA

Ormerod LP, et al. Tuber Lung Dis 1996;77:37-42

Thrombocytopenia

Neuropathy

Vertigo

Hepatitis

Rash

Adverse Drug Events in Patients with HIV Infection

Implicated drug

Reaction INH RMP PZA EMB SM TH

Hepatic ? ? ? ?

Dermatologic ? ?

Other ? ? ? ? ?

Requirements from an Anti-Tuberculosis Drug

o Ability to prevent emergence of resistance in the companion drug

o Early bactericidal activity

o Sterilizing activity

Mitchison DA. Tubercle 1985;66:219-25

Hypotheses About Emergence of Anti-Tuberculosis Drug Resistance

o Crude probability of selection

o Differential bactericidal activity

o Sub-inhibitory concentrations

o Differential lag phases of drugs

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

Days after initiation of treatment

0 20 40 60 80 100 120 140

Cu

mu

lativ

e p

erc

en

tag

e r

esi

sta

nt

0

20

40

60

80

100

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

Median

7 weeks

Replications of a susceptible organism and emergence ofa spontaneously resistant mutant, linear scale

Time / number of replications

0 5 10 15 20 25 30

Num

ber

of o

rgan

ism

s

100*106

500*106

1000*106

0

Susceptible

Resistant

Replications of a susceptible organism and emergence ofa spontaneously resistant mutant, logarithmic scale

Time / number of replications

0 5 10 15 20 25 30

Nu

mb

er

of o

rga

nis

ms

101

100

Susceptible

Resistant

102

103

104

105

106

107

108

109

1010

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

Rifampicinkills susceptible organisms

Rifampicinkills isoniazid-resistantmutants

Isoniazidkills rifampicin-resistantmutants

Isoniazidkills susceptible organisms

Frequency of Spontaneous Mutations toAnti-Tuberculosis Medications

Fre

quen

cy o

f 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

Smear

Culture + + + ----

0 12 24 36

Month of chemotherapy

KMPZASMEMBINHRMP

Creating Drug Resistance in a 49-Year-Old Patient

Errors in Management Leading to MDR in the USA

Findings Among 28 of 35 Patients with MDR

o Adding a single drug to a failing regimen

o Inadequate primary regimen

o Failure to recognize primary or acquired resistance

o Failure to recognize and deal with non-adherence

o Inappropriate preventive therapy

Mahmoudi A, et al. JAMA 1993;270:65-8

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

Post-Antibiotic Effects with M. tuberculosis - Lag Periods BeforeCommencement of Growth After Exposure in 7H10 Medium

Lag after 24 hr exposure to drug (days)

0 1 2 3 4 5 6 7 8 9 10

Streptomycin

Isoniazid

Ethambutol

Rifampicin

Mitchison DA, et al. Postgr Med J 1971;47:737-41

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

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

Early, Two-Day Bactericidal Activity of Antituberculosis Drugs,Measured as the Reduction in Colony-Forming Units in Sputum

Lo

g r

ed

uct

ion

in c

olo

ny-

form

ing

un

its

Nil PZA TH SM RMP EMB INH SHRZE

Jindani A, et al. Am Rev Respir Dis 1980;121:939-49

-0.2

0

0.2

0.4

0.6

0.8

Bactericidal Activity of Isoniazid AloneCompared to a HRZS Regimen

Day of treatment

0 2 4 6 8 10 12 14

Log

CF

U

106

103

104

105 Drug-free control

HHRZS

Jindani A. Thesis. University of London, 1979

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

Relapse

Comparative Activity of Isoniazid and Rifampicin inExperiments Mimicking High and Low Metabolism

Days

0 5 10 15 20 25 30

Ch

an

ge

fro

m s

tart

ing

co

unt

(lo

g 10 c

fu /

mL

)

-3

-2

-1

0

1

2 Control 37o C

RMP 37o C

INH 37o C

1-hr control

1-hr INH

1-hr RMP

Dickinson JM, et al. Am Rev Respir Dis 1981;123:367-71

The Action of Anti-Tuberculosis Drugs

Extent of activity

Prevention of resistance

Early bactericidal activity

Sterilizing activity

High Isoniazid Isoniazid Rifampicin

Rifampicin Pyrazinamide

Ethambutol

Ethambutol Rifampicin Isoniazid

Streptomycin

Streptomycin Streptomycin

Pyrazinamide Pyrazinamide Thioacetazone

Low Thioacetazone Thioacetazone Ethambutol

Mitchison DA. Tubercle 1985;66:219-25

Sputum Conversion Among Patients ReceivingStreptomycin vs Placebo, USPHS Trial

Month of treatment

0 3 6 9 12

Per

cen

t pos

itive

0

20

40

60

80

100

Streptomycin

Placebo

Long ER, et al. Publ Health Rep 1950;65:1421-51

Emergence of Resistance on Streptomycin and / orPara-Aminosalicylic Acid Alone or in Combination

Day of treatment

0 28 42 60 75 90 120

Per

cen

t with

res

ista

nt s

trai

ns

0

20

40

60

80

PASalone

Streptomycinalone

Streptomycinand PAS

Tempel CW, et al. Am Rev Tuberc 1951;63:295-311

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

Effect of an Initial Streptomycin Supplement on theEfficacy of 12 Months Isoniazid plus Thioacetazone

Month after start of treatment

0 2 4 6 8 10 12

Per

cen

t cul

ture

pos

itive

0

20

40

60

80

100

12 TH

2 STH / 10 TH

East African / British Medical Research Councils. Tubercle 1966;47:1-32

Basic Chemotherapy Regimens Tested in Clinical Trials

Duration (mo)

Intensive Continuation

6 2 SHRZ 4 RH

6 2 EHRZ 4 RH

8 2 SHRZ 6 TH

8 2 EHRZ 6 EH

12 2 STH 10 TH

Jindani A, et alLancet 2004;364:1244-51

Jindani A, et alLancet 2004;364:1244-51

Introduction of Directly Observed Therapy and Program Indicatorsof Tuberculosis Control, Tarrant County, Texas 1980-92

0.0

0.4

0.8

1.2N

um

be

r o

f ca

ses

pe

r 1

00

,00

0 p

op

ula

tion

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

Considerations for Treatment Regimens in Patients with Initial Isoniazid Resistance

Possibly at point of failure:

2 S{RHH}Z / 6 {THTH}

Placed on retreatment:

2 SE{RHH}Z / 1 E{RHH}Z / 5 E{RHH}

Considerations for Treatment Regimens in Patients with Initial Isoniazid Resistance

Possibly at point of failure:

2 S{RHH}Z / 6 {EHEH}

Placed on retreatment:

2 SEE{RHH}Z / 1 EE{RHH}Z / 5 EE{RHH}

Considerations for Treatment Regimens in Patients with Initial Isoniazid Resistance

Possibly at point of failure:

2 S{RHH}Z / 6 {EHEH}

Placed on retreatment:

2 SEE{RHH}Z / 6 EE{RHH}Z

Considerations for Treatment Regimens in Patients with Initial Isoniazid Resistance

Possibly at point of failure:

2 S{RHH}Z / 4 {RHRH}

Placed on retreatment:

2 SE{RHRH}Z / 1 E{RHRH}Z / 5 E{RHRH}

Plasma Pharmacokinetics of Following Administration of600 mg Rifampicin or Rifapentine to Healthy Volunteers

Time (hr)

0 2 4 6 9 12 18 24 30 36 48 72

Ser

um c

once

ntra

tion

(mg/

L)

0

2

4

6

8

10

12

14

Peloquin CA, et al. Antimicrob Agents Chemother 1997;2670-9

Rifampicin

Rifapentine

Keung ACF, et al. Antimicrob Agents Chemother 1999;43:1230-33

USPHS Study 22: Acquired Rifamycin Mono-Resistance with HIV-Associated Tuberculosis Treated

with Once-Weekly Rifapentine and Isoniazid

No Regimen Failures Relapses Rifamycin Resistance

31 2 EHRZ / 4 H2R2 0 3 0

30 2 EHRZ / 4 H1Rp1 0 5 4

NB: some patients received twice- or thrice-weekly intensive phase treatment; 80 to 90% of doses directly observed

Vernon A, et al. Lancet 1999;353:1843-7

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

Frequent Case: Initial INH Resistance

One perspective Another perspective

2 EHRZ / 6 EHH 2 EHRZ / 4 RHRH

Failure / relapse:

relatively frequent

Failure / relapse:

relatively infrequent

2 SEHHRZ / 6 ERHHZ 2 SEHRHRZ / 1 ERHRHZ / 5 ERHRH

Failure = MDR

Relatively infrequent

Failure = MDR

Relatively frequent

Failures of failures: appropriate numerator

Hr

{HR}r

{HR+}r

{HRF}r {HRI}r{HRIF}r

No

No

No

2 SPH / 16 PH

Yes

Yes

Yes

2 EHRZ / 4 RH

Bangladesh-typeregimen

Cascade of regimens

Standardizationadvantageous

Standardizationoptions limited

and unclear

XDR “MDR-plus”

90% effective

90% effective

90% effective

Subsets of MDR

HrRr HrRrFr HrRrIr HrRrFrIr

Simple to cure Difficult to cureAlmost impossible

to cure

?70%-90% ? ? 1%-15% 1

1 Centers for Disease Control and PreventionMorb Mortal Wkly Rep 2006;55:301-5

Cross-resistance among second-line injectable drugs, GeorgiaP

er c

ent w

ith p

atte

rn

0

20

40

60

80

100

Resistant to at least:Kanamycin Amikacin Capreomycin

ArCr KrCr KrAr

ArCs

KrCsAsCsKsAs

Number of strains in each group

78 6669

Jugheli L, et al. Antimicrob Agents Chemother 2009;53:5064-8

Treatment of MDR tuberculosis in Damien FoundationProjects, Bangladesh, 1997-2007

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

Treatment of MDR tuberculosis in Damien FoundationProjects, Bangladesh, 1997-2007

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

Treatment of MDR tuberculosis in Damien FoundationProjects, Bangladesh, 1997-2007

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

Time from treatment start to treatment stop of MDR treatment

Month from start to ending treatment

Cum

ulat

ive

per

cent

0

20

40

60

80

100

0 3 6 12 18 21 249 15

Gatifloxacinregimen

Ofloxacinregimens

Reason for premature stop

DeathDefault

Failure

O G

16

2229

1112

1

Patients 221 206

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

Deaths among patients after treatment start, on andafter treatment, by regimen and time of death

Months since treatment start

Cum

ulat

ive

perc

ent d

ead

0

20

40

60

80

100

26 Ofloxacin deaths

19 Gatifloxacin deaths

Ontreatment

Aftertreatment

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

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

Smear-to-Culture Ratio During Chemotherapyby Treatment Regimen, USPHS Trials

Week of treatment0 4 8 12 16 20 24 28 322 4 6 8 10 12 14 16 18 200 4 8 12 16 20 24 28 32 36 40

Sm

ear-to-culture ratio

0.5

1.0

1.5

2.0

2.5

Mount FW, et al. Am Rev Tuberc 1953;68;264-9Mount FW, et al. Am Rev Tuberc 1954;70:521-6

Newman R, et al. Am Rev Respir Dis 1974:109:216-32

INH + RMP

INH + SM

INH

2 EHRZ / 4 RH

2 EHRZS / 6 RH

4+ KPGHZEC / 6 HZEC

RrHrIsFsRrHrIrFs RrHrIsFr RrHrIrFr

The Union’s proposed cascade of regimens

GLC? GLC? ???

Prophylactic Treatment(Or perhaps better: primary prophylaxis)

Preventivetherapy

Prophylactictreatment

Exposure

BCGvaccination

Patient’s delay

Sub-clinicalinfection

Non-infectioustuberculosis

Infectioustuberculosis

Doctor’s delay

ChemotherapyTransmission

Death

Protection Against Acquisition of Tuberculous Infection,USPHS Trials with Isoniazid Prophylactic Treatment

Protection (%) (log scale)

- 50 0 20 40 50

Ferebee SH. Adv Tuberc Res 1969;17:28-106

Schools

Contacts ofnew cases

Contacts ofknown cases

Mental patients

Indications for Prophylactic Treatment(Prevention of Infection)

In industrialized countries:

o Uncontrollable exposure to an infectious case

In low-income countries:

o Children born into a household with an infectious case

Vaccination

Preventivetherapy

Prophylactictreatment

Exposure

BCGvaccination

Patient’s delay

Sub-clinicalinfection

Non-infectioustuberculosis

Infectioustuberculosis

Doctor’s delay

ChemotherapyTransmission

Death

Albert Calmette

Konrad Birkhaug

Picture courtesy: Kim SJ, April 7, 2001Korean Institute of Tuberculosis

At vaccinationApproximately3 wk post-vacc

Approximately6 wk post-vacc

Approximately1 yr post-vacc

Normal Reaction Course to Vaccination withBCG French Strain in Korean Newborn

Protection from BCG Vaccination

o Protection against dissemination, meningitis, and death

o Protection of infants against any form

o Protection of children other than infants

o Protection of adults

Design of a Prospective Study

Outcome

Exposure Ill Healthy Person-yrs of observation

Yes A B N1

No C D N2

Total A+C B+D N1 + N2

Incidence rate among the exposed: A / N1

Incidence rate among the non-exposed: C / N2

Incidence rate ratio (“relative risk”): (A/N1) /(C/N2)

Design of a Retrospective Study

Outcome

Exposure Case Control Total

Yes a b n1

No c d n2

Total a+c b+d n1 + n2

Odds of exposure among cases: a / c

Odds of exposure among controls: b / d

Relative odds (odds ratio): (a * d) / (b * c)

Protection from BCG Vaccination - Prospective StudiesTuberculosis Death, Meningitis and Disseminated Tuberculosis

Per cent protection

-400 -100 0 30 50 80 90 95

N. Am. Indians

Chicago

Philadelphia

Saskatchewan

New York City

Death

Death

Death

Death

Death

Protection from BCG Vaccination - Retrospective StudiesProtection Against Death, Disseminated, and Meningeal Tuberculosis

Per cent protection

Meningitis Hospital controlsSao Paolo

Buenos Aires

Papua New Guinea

Sao Paolo

Miliary, meningitisMeningitis Neighborhood controls

Delhi

Bela Horizonte

Bela Horizonte

Bela Horizonte

Nagpur

Rangoon

Bangkok

Meningitis Control pneumonia

Extrapulmonary

Meningitis, miliary

Meningitis Control diarrhea

Meningitis

Meningitis

Disseminated

Miliary, meningitis

-400 -100 0 30 50 80 90 95

Effectiveness of BCG Against Meningeal Tuberculosis,Meta-Analysis of Case-Control Studies, 1947-1993

Per cent protection (log scale)

0-40 50 80 9020

Buenos Aires, 1988

São Paulo, 1990/93

Delhi, 1989Bela Horizonte, 1988

Chennai, 1996Summary measure

São Paulo, 1990/93Bahia, 1991

Nagpur, 1996

Papua New Guinea, 1958

Lucknow, 1947Yangon, 1952

Bela Horizonte, 1965Delhi, 1964

Delhi, 1956

Bourdin Trunz B, et al. Lancet 2006;367:1173-80

Protection from BCG Vaccination - Prospective StudiesProtection in Infants

Per cent protection

-400 -100 0 30 50 80 90 95

Infants, any form

Infants, morbidity

Infants, any form

Infants, any form

Infants, morbidity

Saskatchewan

Saskatchewan

Chicago

Chicago

Chicago

Protection from BCG Vaccination - Retrospective StudiesProtection Infants

Per cent protection

Laboratoryconfirmed

All forms

All forms

All forms

HIV positive

All forms

All forms

All forms

All forms

All forms

HIV negative

All forms

All forms

Bangkok

Bangkok

Saudi Arabia

Bangui

Lusaka

Birmingham

Canadian Indians

Lusaka

Asians, UK

Papua New Guinea

Rangoon

Sri Lanka

Buenos Aires

-400 -100 0 30 50 80 90 95

Protection from BCG Vaccination - Prospective StudiesProtection in Children

Per cent protection

Puerto Rico

Chingleput

Madanapelle

-400 -100 0 30 50 80 90 95

Children, any form

Children, pulmonaryculture confirmed

Children, any form

Protection from BCG Vaccination - Retrospective StudiesProtection in Children

Per cent protection

Bangkok

Edinburgh

Cali

Children, any formCase-control

Children, any formCase-control

Children, pulmonaryContact study

-400 -100 0 30 50 80 90 95

Protection from BCG Vaccination - Prospective StudiesProtection in Adults

Per cent protection

Nurses

Adolescents

Mine workers

Adults

Adults, PulmonaryCulture confirmed

Adults, first orsecond vaccination

-400 -100 0 30 50 80 90 95

Ulleval

England

South Africa

Madanapelle

Chingleput

Karonga District

Protection from BCG Vaccination - Prospective StudiesProtection all Ages

Per cent protection

-400 -100 0 30 50 80 90 95

All forms

All forms

All forms

All forms

Pulmonary,Culture confirmed

Mental institutions

Haiti

N. Am. Indians

Madanapelle

Muscogee / Russell

Muscogee

Chingleput

Illinois

MuscogeeAll forms, 5-28 yr,20-yr follow-up

All forms, 5-28 yr,10-yr follow-up

Protection from BCG Vaccination - Retrospective StudiesProtection in Adults and Persons of Any Age

Per cent protection

Canadian Indians

Chile

Any ageCase-control

AdultsCase-control

-400 -100 0 30 50 80 90 95

Protection / Harm from BCG Compared to PlaceboDuring Follow-up, by Age, Chingleput Trial, South India

Age group (years)

Har

m /

prot

ectio

n (%

)

-20

0

20

Protection

Harm

Tuberculosis Research Centre Chennai. Indian J Med Res 1999;110:56-69

0 5 15 25 35 45

Protection / Harm from BCG Compared to PlaceboDuring Follow-up, Chingleput Trial, South India

Year of follow-up

0.0 2.5 5.0 7.5 10.0 12.5 15.0

Har

m /

prot

ectio

n (%

)

-140

-120

-100

-80

-60

-40

-20

0

20 Protection

Harm

Tuberculosis Research Centre Chennai. Indian J Med Res 1999;110:56-69

Protection Afforded by BCG Vaccinationin British School Children During Follow-up

Year of follow-up

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Pro

tect

ion

(%)

0

20

40

60

80

100

D'Arcy Hart P, et al. Br Med J 1977;2:293-5

Hypotheses to Explain Differences in BCG Protection

o Methodologic biases

o Differences in vaccine strains

o Differences in vaccine dose

o Differences in M. tuberculosis strains

o Disease due to exogenous reinfection

o Infection with environmental mycobacteria

o Genetic differences in vaccinees

o Nutritional differences in vaccinees

Smith PG, Fine PEM. In: Davies PDO, Clinical Tuberculosis, Chapman & Hall, London 1998

A Genealogical Tree of BCG Vaccine Substrains

Pasteur, 1921

Pasteur, 1927

Danish, 1931

Glaxo, 1954

Pasteur Merieux, 1989

Moreau, 1924Tokyo, 1925

Gothenburg, 1926

Tice, 1934

Montreal, 1937

Pasteur, 1961

Connaught, 1948

Oettinger T, et al. Tuber Lung Dis 1999;79:243-50

Brosch R, et al. Proc Natl Acad Sci 2007;104:5596-5601

A well kept secret?Tuberculosis case incidence by BCG strain, Hong Kong

Cas

es p

er 1

0,00

0 va

ccin

ees

3

4

5

6

Paris strain Glaxo strain

ten Dam HG. In: Tuberculosis (Reichman LB, Hershfield ES, eds)Marcel Dekker Inc, New York: 1993:251-74

Reported Cases of Mycobacteriosis due toMycobacterium avium Complex, Sweden, 1969-93

Year of report

70 75 80 85 90

Nu

mb

er

of r

ep

ort

ed

ca

ses

0

20

40

60

80

Data courtesy: Romanus V. Written communication, Feb 18, 2000

Discontinuation of massBCG vaccination

Risk of Tuberculosis During Follow-up, by InitialTuberculin Reaction Size, BCG Trial, Great Britain

Year of follow-up

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Inci

denc

e pe

r 10

,000

0

10

20

30

40

50

60

70

Reacting to100 TU only

Tuberculinnegative

D'Arcy Hart P, et al. Br Med J 1977;2:293-5

Protection from BCG and from Small Tuberculin SkinTest Reactions During Follow-up, BCG Trial, Great Britain

Year of follow-up

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Pe

r ce

nt p

rote

ctio

n

Reacting to100 TU only

BCG vaccinated

D'Arcy Hart P, et al. Br Med J 1977;2:293-5

80

70

50

0

-100

Risk of Tuberculosis During Follow-up by InitialTuberculin Skin Test Induration Size, Karonga, Malawi

Induration (mm)

Rel

ativ

e ris

k (lo

g sc

ale)

0.2

0.5

1

3

10

0 1 - 5 6 - 10 11 - 15 16 - 20 20 +

Fine PEM, et al. Lancet 1994;344:1245-9

Ref

Effect of Environmental Mycobacteria:Blocking and Masking Hypothesis

Andersen P, et al. Nature Rev 2005;3:656-62

BCG Osteitis and Childhood Tuberculosis inSwedish-Born Children, Sweden 1949-1993

Year of report

1950 1955 1960 1965 1970 1975 1980 1985 1990

Num

ber

of c

ases

0

10

20

30

Romanus V. Smittskyddsinstitutet, Stockholm: 1995

SwedenGothenburg strain produced in: Cessation of mass

BCG vaccination

BCG osteitis

Childhoodtuberculosis

Denmark

Indications for BCG Vaccination

In industrialized countries:

o Uncontrollable exposure to an infectious case

o High risk of exposure to MDR tuberculosis ?

In low-income countries:

o Vaccination as early as possible in life

o No revaccination at school entrance

Preventive Therapy(Or perhaps better: secondary prophylaxis)

Preventivetherapy

Prophylactictreatment

Exposure

BCGvaccination

Patient’s delay

Sub-clinicalinfection

Non-infectioustuberculosis

Infectioustuberculosis

Doctor’s delay

ChemotherapyTransmission

Death

Protection Against Tuberculosis Among TuberculinReactors, with Isoniazid During Treatment Year

Protection (%) (log scale)

0 50 70 90

Mental patients

Contacts ofknown cases

Alaskan villagers

Greenland villagers

Ferebee SH, et al. Am Rev Respir Dis 1963;88:161-75Mount FW, et al. Am Rev Respir Dis 1962;85:821-7Comstock GW. Am Rev Respir Dis 1962;86:810-22

Horwitz O, et al. Bull World Health Organ 1966;35:509-26

Protection Against Tuberculosis Among Contactsof New Cases with Isoniazid Preventive Therapy

Protection (%) (log scale)

Netherlands Navy

USA

Japan

Kenya

Veening GJJ. Bull Int Union Tuberc 1968;41:169-71Egsmose T, et al. Bull World Health Organ 1965;33:419-33

Ferebee SH, et al. Am Rev Respir Dis 1962;85:490-521Bush OB, et al. Am Rev Respir Dis 1965;92:732-40

0 50 70 90- 50 95

Protection Against Tuberculosis Among Persons withVarious Risk Factors with Isoniazid Preventive Therapy

Protection (%) (log scale)

0 50 70 90

International Union Against Tuberculosis Committee on ProphylaxisBull World Health Organ 1982;60:555-64

Ferebee SH. Adv Tuberc Res 1969;17:28-106Katz J. Am Rev Respir Dis 1962;86:8-15

John GT, et al. Transplantation 1994;57:1683-4Hong Kong Chest Service / Tuberculosis Research Centre, Madras /

British Medical Research Council. Am Rev Respir Dis 1992;145:36-41

Fibrotic lesions (IUAT)

Fibrotic lesions (USPHS)

Hemodialyis

Silicosis

Fibrotic lesions (New York)

Preventivetherapy

Infectionwith M. tbc Tuberculosis TNF-α

HIV replication

Granulomaformation

Increasedimmunosuppression

AIDS

Protection Against Tuberculosis with Isoniazid Preventive Therapy - HIV Infection

Protection (%) (log scale)

Pape JW, et al. Lancet 1993;342:268-72Mwinga A, et al. AIDS 1998;12:2447-57

Whalen CC, et al. N Engl J Med 1997;337:801-8Gordin FM, et al. N Engl J Med 1997;337:315-20

Hawken MP, et al. AIDS 1997;11:875-82

Lusaka

Nairobi

Kampala

Regimen Study place

Port-au-Prince12 mo H

6 mo H2

6 mo H

6 mo H

6 mo H

New York City

HIV

Risk

HIV

HIV

HIV

HIV

P

Control

P

P

P

P

0 50 70 90- 50

Protection Against Tuberculosis Among Persons with FibroticLesions, by Length of Isoniazid Preventive Therapy

Protection (%) (log scale)

0 50 70- 50

3 months

International Union Against Tuberculosis Committee on ProphylaxisBull World Health Organ 1982;60:555-64

30 90

6 months

12 months

12 months

6 months

3 months

All study participants

Completers - compliers

Effect of Various Durations of Preventive Therapyon Risk of Tuberculosis in Bethel Isoniazid Studies

Months of treatment

0 3 6 9 12 15 18 21

Cas

es p

er 1

00

0

1

2

3

4

5

Comstock GW. Int J Tuberc Lung Dis 1999;3:847-50

Long-Term Efficacy of Isoniazid Preventive Therapy

Year of follow-up

0 1 2 3 4 5 6 7

Per

cen

t pro

tect

ion

0

20

40

60

80

100 Fibrotic lesions

Alaska villagers

Greenland villagers

International Union Against Tuberculosis Committeeon Prophylaxis. Bull World Health Organ 1982;60:555-64

Ferebee SH. Adv Tuberc Res 1969;17:28-106Horwitz O, et al. Bull World Health Organ 1966;35:509-26

Efficacy of Six Months Isoniazid Preventive Therapy AmongHIV Infected Patients During Follow-Up, Uganda

Johnson JL, et al. AIDS 2001;15:2137-47

Protection Against Tuberculosis with Rifampicin Preventive Therapy

Protection (%) (log scale)

Whalen CC, et al. N Engl J Med 1997;337:801-8Hong Kong Chest Service, et al. Am Rev Respir Dis 1992;145:36-41

Mwinga A, et al. AIDS 1998;12:2447-57

Placebo

Placebo

Control

Placebo

Placebo

Placebo

Kampala

Study place

Kampala

Hong Kong

Hong Kong

Lusaka

12 wk RH

3 mo R2Z2

Regimen

3 mo RH

3 mo RHZ

12 wk R

Risk

HIV

HIV

Silicosis

Silicosis

HIV

0 50 70 80- 50

Protection Against Tuberculosis with Rifampicin vs Isoniazid Preventive Therapy

Protection (%) (log scale)

Hong Kong Chest Service, et al. Am Rev Respir Dis 1992;145:36-41Gordin F, et al. JAMA 2000;1445-50

Halsey NA, et al. Lancet 1998;786-92Mwinga A, et al. AIDS 1998;12:2447-57

0 50 7030- 50- 100

Risk Regimen Control Study place

LusakaHIV 3 mo R2Z2 6 mo H2

US / collabHIV 2 mo RZ 12 mo H

Hong KongSilicosis 12 wk RH 24 wk H

HaitiHIV 24 wk R2Z2 24 wk H2

Hong KongSilicosis 12 wk R 24 wk H

American Thoracic Society / Centers for Disease ControlPreventive Therapy Recommendations

ATS / CDC. Morb Mortal Wkly Rep 2003;52:735-9

Joint Tuberculosis Committee of the British Thoracic SocietyPreventive Therapy Recommendations

Joint Tuberculosis Committee of the British Thoracic Society Thorax 2000:55:887-901

Factors Determining Effectiveness of Preventive Chemotherapy

o Probability of tuberculous infection

o Risk of tuberculosis given infection

o Efficacy of regimen

o Adherence to treatment

Effectiveness of Preventive Chemotherapy

Probability of infection

Risk of tuberculosis

Efficacy of regimen

Adherence to treatment

Overall effectiveness

Number to treat to prevent

1 case

0.80 0.05 0.60 0.30 0.007 139

0.80 0.10 0.60 0.30 0.014 69

0.80 0.30 0.60 0.30 0.043 23

0.80 0.30 0.90 0.30 0.065 15

0.80 0.30 0.90 0.50 0.108 9

0.90 0.30 0.90 0.80 0.194 5

Preventive Therapy for HIV Infected PoliceOfficers in Dar es Salaam, Tanzania, 1998N

um

be

r o

f pe

rson

s

0

100

200

300

400

HIV Pos: 14.1%of 2,782 tested

Gotresult

AcceptPT

EvaluatedStarted

INHAdherentfor 6 mo

Bakari M, et al. East Afr Med J 2000;77:494-7

8 of 37 had asymptomaticsmear-positive tuberculosis

Preventive Therapy Use at a ProTEST SiteSouth Africa, 2000 - 2002

Num

ber

of p

erso

ns

0

50

100

150

200

HIV + Eligible Started Non-adherent

TBsympt

PastTB

Eligible Ana-lyzed

Adhe-rentnon-adhe-rent

1 doseonly

Rowe KA, et al. Int J Tuberc Lung Dis 2005;9:263-9

To 6 mo INH

Tuberculosis Incidence in an HIV-Infected Cohort ofPatients on Anti-Retroviral Therapy, Switzerland, 1996-2005

Num

ber

of P

atie

nts

0

1000

2000

3000

4000

5000

6000

Missed 30 10 16 0Averted 9.4

Subjects 6,018 4,168 390 144

Cohort HIV pos <5mm >=5mm Prev ther

Elzi L, et al. Clin Infect Dis 2007;44:94-102

0.20.10

Total

569.7

Problems with Preventive Chemotherapy

o Difficulties in ensuring adherence

o Efficacious but inefficient

o Rare adverse drug events

o Ensuring certainty to exclude active tuberculosis

Considerations in the Use of Preventive Therapy

Logistic and material feasibility and ease:

o Household contacts > persons with risk factors > risk groups > general population

o Drug costs: isoniazid << rifampicin, pyrazinamide

o Risk perception adherence

Indications for Preventive Therapy

In industrialized countries:

o Young persons with tuberculous infection

o Persons with risk factors

In low-income countries:

o Children < 5-yr-old, free of disease living with a sputum smear-positive case

To conclude:

Some food for thought

All too cherished working hypotheses

Once infected with Mycobacterium tuberculosis, infection persists for the remaining life time and may reactivate at any time.

The immunologic response we measure informs us about persisters

Andvord K F. Norsk Magasin for Lægevidenskapen 1930;91:642-60

Kristian Andvord’s break-through observation

Tuberculosis Notification Rates Among Males,by Birth Cohort, Finland 1954 -1994

Age (years)

0 20 40 60 80

Not

ifica

tions

pe

r 10

0,0

00(lo

g sc

ale)

0.5

1

5

10

50

100

500

Härö AS. Tuberc Respir Dis Yearbook 1998;24:1-151

1954

1994

1972

1962

1952

19421932

1922

1912

18921902

1984

1974

1964

Andvord’s conclusion

Childhood experience with Mycobacterium tuberculosis predicts adult experience

Fate of M tuberculosis in calcified lesions

Pulmonary Lymphatic

Author Lesions Sterile Lesions Sterile

Schmitz 10 9 16 10

Rabinowitch - - 30 19

Koenigsfeld 21 17 18 13

Schroeder 40 40 61 60

Opie 92 77 91 70

Griffith - - 17 17

Rubinstein 27 16 - -

Anders - - 58 50

Saenz 44 33 - -

Total 234 192 291 239

Percentage sterile 82.1 82.1

Canetti G. Paris: Vigot Frères, 1939, 305 pp

Primary Infection and Reinfection at AutopsyAmong Persons not Dying from Tuberculosis

Num

ber

of c

ases

0

20

40

60

80

100

1 lesion

2 lesions

3 lesions

4+ lesions

Canetti G. Tubercle 1950;31:224-33

98 61

Primary Reinfection

Observation and dilemma

Observation Bacilli are killed in the majority of cases following primary infection

A large proportion of disease in adults is the result of reinfection

Dilemma Reconciling Andvord and Canetti

Drawings: Koch R. Mittheilungen aus dem Kaiserlichen Gesundheitsamte 1884;2:1-88.Phenomenon: Koch R. Dtsch Med Wochenschr 1891;17:101-2.

The “Koch Phenomenon”

A primary infection leads to a delayed response and often takes a mild andself-limited course

A reinfection commonly results in a rapid response with tissue necrosis

Protection Afforded by BCG Vaccinationin British School Children During Follow-up

Year of follow-up

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

Pro

tect

ion

(%

)

0

20

40

60

80

100

D'Arcy Hart P, et al. Br Med J 1977;2:293-5

Cross-sectional

Birth cohort

Age

Mor

bidi

ty /

mor

talit

y

Time / age

Rem

ain

ing

live

baci

lli

Primaryinfection

Re-infection

Andvord

Time

Tis

sue

de

stru

ctio

n

Primaryinfection

Re-infection

Progressive

Abortive

Koch

Canetti

Time

BC

G p

rote

ctio

n

BMRC

Rieder HL. Int J Epidemiol 2008;37:932-4

Reconciliation?

Observation Childhood experience predicts adult mortality (Andvord)

Observation Tubercle bacilli from the primary infection are commonly eliminated (Canetti)

Observation Reinfection results in tissue destruction (Koch)

Reconciliation Primary infection primes the child’s immune system, re-infection in the previously infected adult results in an immunologic response with tissue-destroying (cavitary) tuberculosis

Trying to fit observations ….

o A first infection is commonly overcome and frequently ends in the elimination of bacilli but primes the immune system for a decade or more

o A primed immune system may protect against subsequent re-infection or, alternatively, results in a severe tissue damaging response

o A positive tuberculin skin test is neither expression of live bacilli nor of protective immunity, it only reflects the immune response following prior infection

Conclusions

o Chemotherapy of infectious tuberculosis has both individual and epidemiologic impact

o BCG vaccination impacts on individual health, but little on the epidemiologic situation

o Treatment of other than infectious cases benefits individuals but impacts little on the epidemiologic situation

o Preventive therapy may benefit the individual but is unlikely to impact importantly on the epidemiologic situation

After 2 months chemotherapy After 6 months chemotherapy

Miliary Tuberculosis