Interventions for Tuberculosis Control and Elimination
description
Transcript of Interventions for Tuberculosis Control and Elimination
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