Transcript Van Deun A, et al. Am J Resprir Crit Care Med 2010

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 by
Liisa 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;358:340
Photo: 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
Transmission
Chemotherapy
Doctor’s delay
Prophylactic
treatment
Preventive
therapy
Patient’s delay
Infectious
tuberculosis
Exposure
Sub-clinical
infection
Death
Non-infectious
tuberculosis
BCG
vaccination
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
Transmission
Chemotherapy
Doctor’s delay
Prophylactic
treatment
Preventive
therapy
Patient’s delay
Infectious
tuberculosis
Exposure
Sub-clinical
infection
Death
Non-infectious
tuberculosis
BCG
vaccination
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
Concentration (mg / L)
(log scale)
Maximum Serum Concentration and Range of Minimum
Inhibitory Concentration of Anti-Tuberculosis Drugs
40
10
2
0.5
0.1
0.02
0.005
INH
RMP
PZA
EMB
SM
TH
Peloquin CA, et al. Int J Tuberc Lung Dis 1999;3:703-10
Acocella G. Clin Pharmacokinetics 1978;3:108-27
Pählka R, et al. J Clin Pharm Ther 1999;24:219-25
Davidson PT, et al. Clin Chest Med 1986;7:425-38
Grosset J, et al. Adv Tuberc Res 1970;17:107-53
Zierski M. Pneumologie 1981;35:1075-1105
Chemical Structure of Isoniazid
O
NH-NH2
C
N
Meyer H, Mally J. Monatshefte Chemie 1912;33:393-414
O
Model of Isoniazid Action
NH-NH2
C
Isoniazid
N
Passive diffusion
KatG
activation
Antagonists
Reactive oxygen/
organic radicals
Efflux
NAT?
AhpC?
Multiple targets
DNA damage?
NAD metabolism?
Mycolic acid synthesis
InhA, KasA
Zhang Y, et al. In: Hatfull GF, et al.
Molecular Genetics of Mycobacteria, 2000
Pharmacokinetics of Isoniazid, Fasting vs High-Fat Meal
Concentration (mg/L)
5
Fasting
4
3
2
High-fat
meal
1
0
0
5
10
15
20
25
Time (hours)
Peloquin CA, et al. Int J Tuberc Lung Dis 1999;3:703-10
Clearance of Isoniazid from Serum, by Acetylator
Type and Age Among Tuberculosis Patients
Clearance (mL/min/kg)
8
7
Rapid
acetylators
6
5
4
3
Slow
acetylators
2
1
0
0
15
25
35
45
55
65
75
75+
Age group (years)
Kergueris MF, et al. Eur J Clin Pharmacol 1986;30:335-40
Appropriateness of Union-Recommended Weight
Brackets for the Dosage of Isoniazid (75 mg / tablet)
25-39 kg
2 tablets
6.5
40-55 kg
3 tablets
> 55 kg
4 tablets
upper
range
Dosage (mg/kg)
6.0
5.5
5.0
4.5
lower
range
4.0
3.5
20
30
40
50
60
Body weight (kg)
70
80
Isoniazid Adverse Drug Events
Frequent
(≥ 5 per 100)
Liver enzyme
elevations
Common
(≥1 per 100 and < 5
per 100)
Infrequent
(≥ 1 per 1,000 and <
1 per 100)
Hepatitis
Peripheral
neuropathy
Drug fever
Rare
(≤ 1 per 1,000)
Seizures
Hallucinosis
Psychosis
Memory loss
Optic neuropathy
Pellagra
Pyridoxine
responsive anemia
Metabolic acidosis
Pyridoxine nonresponsive psychosis
Lupus erythematosus
Hemolytic anemia
Agranulocytosis
Pure red cell aplasia
Alopecia
Asthma
Dermatitis
Hepatitis Risk on Isoniazid Preventive
Chemotherapy Trial of the IUAT, by Age
INH, total
allocated
8
Cases per 1,000
7
6
5
4
3
2
INH, no previous
liver damage
1
Placebo group
0
20
35
45
55
75
Age group (years)
Riska N. Bull Int Union Tuberc 1976;51:203-8
Hepatitis Risk in Isoniazid Preventive
Chemotherapy Trial of IUAT, by Time of Onset
Isoniazid
Cases per 1,000
2
1
Placebo
0
0
10
20
30
40
50
Time of onset of hepatitis (week)
Riska N. Bull Int Union Tuberc 1976;51:203-8
Isoniazid Interactions
Effects of isoniazid
potentiated
PAS
Insulin
Carbamazepine
Theophylline
Effects of isoniazid
opposed
Prednisolone
Ketoconazole
Effect of drug
potentiated by
isoniazid
Anti-coagulants
Anti-epileptics
Benzodiazepines
Haloperidol
Tricylcic antidepressants
Theophylline
Effect of drug
opposed by isoniazid
Enflurane
Chemical Structure of Rifampicin
CH3
CH3
OH
OH
OOCCH3
O
H3C
OH
OH
H3C
H3CO
CH3
NH
CH3
CH=N N
O
N-CH3
OH
O
CH3
O
Maggi N, Pasqualuci C, Ballotta R, Sensi P.
Chemotherapy 1966;11:285-92
Bioavailability of 600mg Rifampicin by Excipient
and Manufacturing Process in Healthy Volunteers
Mean serum level (mg/L)
15
Reference
10
5
Change of excipient and
manufacturing process
0
0
1
2
3
6
9
Hours after administration
Cavenaghi R. Bull Int Union Tuberc Lung Dis 1989;64(1):36-7
Plasma Pharmacokinetics of Rifampicin Following
Administration of 600 mg to Healthy Volunteers
Serum concentration (mg/L)
14
12
10
8
6
4
2
0
0
2
4
6
9
12
18
24
30
Time (hr)
Peloquin CA, et al. Antimicrob Agents Chemother 1997;2670-9
Mean serum level (mg/L)
Pharmacokinetics of Rifampicin Following Meals
Empty stomach
100 g glucose
2 egg whites
50 g butter
8
6
4
2
0
0
2
4
6
8
Hours after ingestion
Purohit SD, et al. Tubercle 1987;68:151-2
Rifampicin tissue penetration
1.4
Tissue-to-serum ratio
1.2
Cavity lining
Lung parenchyma
Kidney
1.0
0.8
Bone (pyogenic)
Pleura
0.6
0.4
0.2
Caseum
CSF (meningitis)
0.0
Kenny MT, et al. Drug Metabolism Rev 1981;12:159-218
Appropriateness of Union-Recommended Weight
Brackets for the Dosage of Rifampicin (150 mg / tablet)
25-39 kg
2 tablets
13
40-55 kg
3 tablets
> 55 kg
4 tablets
upper
range
Dosage (mg/kg)
12
11
10
9
lower
range
8
7
20
30
40
50
60
Body weight (kg)
70
80
Total Serum Bilirubin Levels in Adults with Normal Liver Function After Ingestion of Rifampicin
Total serum bilirubin (mg / dL)
Day 1
1.5
Day 11
1.5
Upper normal limit
1.0
Upper normal limit
1.0
12 mg / kg
0.5
0.5
12 mg / kg
8 mg / kg
8 mg / kg
0.0
0.0
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Time after rifampicin ingestion (hours)
Curci G, et al. Arch Monaldi 1970;25:427
Results of a Meta-Analysis of Hepatitis Frequency
Associated with Isoniazid and Rifampicin
Per cent with hepatitis
3.0
2.5
2.0
1.5
1.0
0.5
0.0
INH
alone
INH +
other
RMP +
other
INH +
RMP
Steele MA, et al. Chest 1991;99:465-71
Rifampicin Adverse Drug Events
Frequent
(≥ 5 per 100)
Bilirubin elevations in
the beginning of
treatment
Orange discoloration
of urine and tears
Liver enzyme
elevations
Common
(≥1 per 100 and < 5
per 100)
Infrequent
(≥ 1 per 1,000 and <
1 per 100)
Hepatitis
Pruritus
Flu syndrome
Drug fever
Rare
(≤ 1 per 1,000)
Interstitial nephritis
Glomerulonephritis
Renal failure
Toxic epidermal
necrolysis
Oligomenorrhea
Amenorrhea
Anaphylactic shock
Thrombocytopenia
Neutropenia
Leukopenia
Hemolytic anemia
Pseudomembranous
colitis
Eosinophilic colitis
Lupus erythematosus
Myopathy
Rifampicin Interactions
Effects of rifampicin
potentiated
Co-trimoxazole
Effects of rifampicin
opposed
Effect of drug
potentiated by
rifampicin
Acetominophen
Effect of drug opposed
by rifampicin
Anti-arrhythmics
Anti-asthmatics
Anti-coagulants
Anti-fungals
Anti-malarials
Anti-retroviral protease
inhibitors
Barbiturates
Benzodiapezins
Beta blockers
Hormones
Immunosuppressants
Cardiac glycosides
Opioids
Vitamin K and D
Trimethoprim
Chemical Structure of Pyrazinamide
N
O
C NH2
N
Kushner S, et al. Am J Chem Soc 1952;74:3617
Plasma Pharmacokinetics of Pyrazinamide Following
Administration of 1,500 mg to Healthy Volunteers
Serum concentration (mg/L)
30
25
20
15
10
5
0
0
2
4
6
9
12
18
24
30
36
Time (hr)
Peloquin CA, et al. Antimicrob Agents Chemother 1997;2670-9
Appropriateness of IUATLD-Recommended Weight
Brackets for the Dosage of Pyrazinamide (400 mg / tablet)
25-39 kg
2 tablets
32
40-55 kg
3 tablets
> 55 kg
4 tablets
upper
range
Dosage (mg/kg)
30
28
26
24
22
lower
range
20
18
20
30
40
50
60
Body weight (kg)
70
80
Pyrazinamide Adverse Drug Events
Frequent
(≥ 5 per 100)
Arthralgias
Common
(≥1 per 100 and < 5
per 100)
Nausea
Infrequent
(≥ 1 per 1,000 and <
1 per 100)
Hepatitis
Rash
Nausea
Rare
(≤ 1 per 1,000)
Sideroblastic anemia
Lupus erythematosus
Convulsions
Photodermatitis
Pyrazinamide Interactions
Effects of
pyrazinamide
potentiated
Allopurinol
Effects of
pyrazinamide
opposed
Zidovudin (?)
Effect of drug
potentiated by
pyrazinamide
Effect of drug
opposed by
pyrazinamide
Uricosuric drugs
Chemical Structure of Ethambutol
H 3C
C
H2
C
H
CH2OH
NH
(CH2)2
.
2HCl
NH
H 3C
C
H2
C
H
CH2OH
Thomas JP, et al. Am Rev Respir Dis 1961;83:891-3
Plasma Pharmacokinetics of Ethambutol Following
Administration of 25 mg/kg Body Weight, Healthy Volunteers
Serum concentration (mg/L)
5
4
3
2
1
0
0 1 2
4
8
24
Time (hr)
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)
Retrobulbar neuritis
Periaxial ocular
toxicity
Rare
(≤ 1 per 1,000)
Aplastic anemia
Eosinophilic
pneumonia
Thrompocytopenia
Hyperuricemia
Ethambutol Interactions
Effects of ethambutol
potentiated
Effects of ethambutol
opposed
Effect of drug
potentiated by
ethambutol
Effect of drug
opposed by
ethambutol
None
Aluminummagnesium antacids
None
None
Schatz A, Bugie E, Waksman SA. Proc Soc Experiment Biol Med 1944;55:66-9
Chemical Structure of Streptomycin
NH
H
NCNH2
O
NH
H
NCNH2
OH
CHO
O
OH
H2C
OH
HO
HO
O
O
HO H2C
H3CNH
OH
Schatz A, Bugie E, Waksman SA.
Proc Sco Exper Biol Med 1944;55:66-9
Plasma Pharmacokinetics of Streptomycin Following
Administration of 1 g to Tuberculosis Patients
Serum concentration (mg/L)
35
30
25
20
15
10
5
0
0
1
2
3
4
8
12
Time (hr)
Acocella G, et al. Am Rev Respir Dis 1985;132:510-5
Streptomycin Adverse Drug Events
Frequent
(≥ 5 per 100)
Vestibular toxicity
Common
(≥1 per 100 and < 5
per 100)
Cochlear toxicity
Hypersensitivity
reactions
Infrequent
(≥ 1 per 1,000 and <
1 per 100)
Renal damage
Rare
(≤ 1 per 1,000)
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
Chemical Structure of Thioacetazone
O
H3C
C
N
H
H
C
N
N
H
C
S
Domagk G. Naturwissenschaften 1946;33:315
NH2
Thioacetazone Adverse Drug Events
Frequent
(≥ 5 per 100)
Weight loss
Nausea
Vomiting
Itching
Mental disturbances
Headache
Blurred vision
Perioral numbness
Common
(≥1 per 100 and < 5
per 100)
Toxic epidermal
necrolysis (in HIV
infected patients)
Infrequent
(≥ 1 per 1,000 and <
1 per 100)
Toxic epidermal
necrolysis (in non
HIV infected patients)
Rare
(≤ 1 per 1,000)
Agranulocytosis
Tuberculosis Patient in Malawi with Thioazetazone-Associated
Toxic Epidermal Necrolysis
Photo courtesy: Tone Ringdal
Frequency of Adverse Reactions to Major Antituberculosis
Drugs During Routine Treatment Services
Thrombocytopenia
RMP (fatal)
INH
Neuropathy
Vertigo
SM
INH
Hepatitis
Rash
EMB
0.1
0.3
RMP
PZA
RMP
PZA
1
3
10
Events per 1,000 person-months (log scale)
Ormerod LP, et al. Tuber Lung Dis 1996;77:37-42
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 AntiTuberculosis Drug Resistance
o Crude probability of selection
o Differential bactericidal activity
o Sub-inhibitory concentrations
o Differential lag phases of drugs
Cumulative percentage resistant
Cumulative Percentage of Strains Resistant to
Streptomycin, BMRC Streptomycin Trial, 1947
100
80
60
Median
40
20
7 weeks
0
0
20
40
60
80
100
120
140
Days after initiation of treatment
British Medical Research Council. Br Med J 1948;2:769-82
Number of organisms
Replications of a susceptible organism and emergence of
a spontaneously resistant mutant, linear scale
1000*106
Susceptible
500*106
100*106
0
Resistant
0
5
10
15
20
Time / number of replications
25
30
Replications of a susceptible organism and emergence of
a spontaneously resistant mutant, logarithmic scale
1010
Susceptible
Number of organisms
109
108
107
106
105
104
103
102
101
10
Resistant
0
0
5
10
15
20
Time / number of replications
25
30
Number of bacilli in a cavity
107
106
Selection under pressure:
chemotherapy gives opportuinity
Susceptible strain as a
whole killed by drugs
105
104
Resistant mutants become
dominant strain under pressure
103
102
10
1
Spontaneoulsy resistant mutants:
approximately 1 in 1 million
Time of chemotherapy
Rifampicin
kills isoniazid-resistant
mutants
Rifampicin
kills susceptible organisms
Isoniazid
kills rifampicin-resistant
mutants
Isoniazid
kills susceptible organisms
Frequency of Spontaneous Mutations to
Anti-Tuberculosis Medications
Frequency of mutation
10-6
10-7
10-8
10-9
10-10
EMB
SM
INH
RMP
David HL. Appl Microbiol 1970;20:810-4
Creating Drug Resistance in a 49-Year-Old Patient
KM
PZA
SM
EMB
INH
RMP
++
Culture
+
----
Smear
0
12
24
Month of chemotherapy
36
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 Initial
Two-Day Phases of Treatment with INH and RMP
Number of viable bacilli
Susceptible
bacilli
Regrowth
INH-resistant mutants
0
2
4
Treatment taken
6
8
10
Treatment taken
Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15
Number of viable bacilli
Subinhibitory Drug Concentrations During Regrowth
Regrowth in
sub-inhibitory
concentration
of drug A
Mutants
resistant
to A
Killing phase
Regrowth
Mitchison DA. In J Tuberc Lung Dis 1998;2:10-15
Post-Antibiotic Effects with M. tuberculosis - Lag Periods Before
Commencement of Growth After Exposure in 7H10 Medium
Streptomycin
Isoniazid
Ethambutol
Rifampicin
0
1
2
3
4
5
6
7
8
9
10
Lag after 24 hr exposure to drug (days)
Mitchison DA, et al. Postgr Med J 1971;47:737-41
Number of viable bacilli
Bacteriopausal Effects During Regrowth
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
Per cent of resistance
emerging to isoniazid
Ability of Drugs to Prevent as Companion Drug
the Emergence of Isoniazid Resistance
15
10
5
0
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
o
Settings with a high prevalence of HIV
infection among tuberculosis patients
o
Settings with self-administered fixed-dose
combinations
Log reduction in colony-forming units
Early, Two-Day Bactericidal Activity of Antituberculosis Drugs,
Measured as the Reduction in Colony-Forming Units in Sputum
-0.2
Nil
PZA
TH
SM
RMP EMB INH
SHRZE
0
0.2
0.4
0.6
0.8
Jindani A, et al. Am Rev Respir Dis 1980;121:939-49
Bactericidal Activity of Isoniazid Alone
Compared to a HRZS Regimen
106
Drug-free control
Log CFU
105
104
H
HRZS
3
10
0
2
4
6
8
10
12
14
Day of treatment
Jindani A. Thesis. University of London, 1979
Two Populations of Tubercle Bacilli and
Their Evolution During Chemotherapy
Number of
organisms
Extr
acel
lular
Failure
baci
lli
Relapse
Intracellular b
acilli
Duration of chemotherapy
Grosset J. Excerpta Medica 1977:1-11
Comparative Activity of Isoniazid and Rifampicin in
Experiments Mimicking High and Low Metabolism
Control 37o C
Change from starting count
(log10 cfu / mL)
2
1-hr control
1
0
1-hr INH
-1
INH 37o C
-2
1-hr RMP
RMP 37o C
-3
0
5
10
15
20
25
30
Days
Dickinson JM, et al. Am Rev Respir Dis 1981;123:367-71
The Action of Anti-Tuberculosis Drugs
Extent of
activity
High
Prevention of
resistance
Isoniazid
Early bactericidal
activity
Isoniazid
Rifampicin
Sterilizing activity
Rifampicin
Pyrazinamide
Ethambutol
Ethambutol
Rifampicin
Isoniazid
Streptomycin
Streptomycin
Pyrazinamide
Pyrazinamide
Thioacetazone
Thioacetazone
Thioacetazone
Ethambutol
Streptomycin
Low
Mitchison DA. Tubercle 1985;66:219-25
Sputum Conversion Among Patients Receiving
Streptomycin vs Placebo, USPHS Trial
100
Per cent positive
80
60
Placebo
Streptomycin
40
20
0
0
3
6
9
12
Month of treatment
Long ER, et al. Publ Health Rep 1950;65:1421-51
Per cent with resistant strains
Emergence of Resistance on Streptomycin and / or
Para-Aminosalicylic Acid Alone or in Combination
80
Streptomycin
alone
60
PAS
alone
40
20
Streptomycin
and PAS
0
0
28
42
60
75
90
120
Day of treatment
Tempel CW, et al. Am Rev Tuberc 1951;63:295-311
Culture Conversion of Pulmonary Tuberculosis in Patients
with Susceptible Organisms, Receiving SM-INH-PAS
Per cent positive
100
80
60
1954
40
20
2004
0
0
2
4
6
8
10
12
Months of chemotherapy
Crofton J. Am Rev Tuberc 1958;77:869-71
Effect of an Initial Streptomycin Supplement on the
Efficacy of 12 Months Isoniazid plus Thioacetazone
Per cent culture positive
100
12 TH
80
2 STH / 10 TH
60
40
20
0
0
2
4
6
8
10
12
Month after start of treatment
East African / British Medical Research Councils. Tubercle 1966;47:1-32
Basic Chemotherapy Regimens
Tested in Clinical Trials
Duration Intensive
(mo)
6
2 SHRZ
6
2 EHRZ
Continuation
4 RH
4 RH
8
8
2 SHRZ
2 EHRZ
6 TH
6 EH
12
2 STH
10 TH
Jindani A, et al
Lancet 2004;364:1244-51
Jindani A, et al
Lancet 2004;364:1244-51
Introduction of Directly Observed Therapy and Program Indicators
of Tuberculosis Control, Tarrant County, Texas 1980-92
DOT
Number of cases per 100,000 population
1.2
Multidrug-resistant relapse
0.8
0.4
0.0
1.2
Primary resistance
0.8
0.4
0.0
1.2
Acquired resistance
0.8
0.4
0.0
1980
1982
1984
1986
1988
1990
1992
Year of notification
Weis SE, et al. N Engl J Med 1994;330:1179-84
Considerations for Treatment Regimens in
Patients with Initial Isoniazid Resistance
Possibly at point of failure:
2 S{RH}Z / 6 {TH}
Placed on retreatment:
2 SE{RH}Z / 1 E{RH}Z / 5 E{RH}
Considerations for Treatment Regimens in
Patients with Initial Isoniazid Resistance
Possibly at point of failure:
2 S{RH}Z / 6 {EH}
Placed on retreatment:
2 SE{RH}Z / 1 E{RH}Z / 5 E{RH}
Considerations for Treatment Regimens in
Patients with Initial Isoniazid Resistance
Possibly at point of failure:
2 S{RH}Z / 6 {EH}
Placed on retreatment:
2 SE{RH}Z / 6 E{RH}Z
Considerations for Treatment Regimens in
Patients with Initial Isoniazid Resistance
Possibly at point of failure:
2 S{RH}Z / 4 {RH}
Placed on retreatment:
2 SE{RH}Z / 1 E{RH}Z / 5 E{RH}
Plasma Pharmacokinetics of Following Administration of
600 mg Rifampicin or Rifapentine to Healthy Volunteers
Serum concentration (mg/L)
14
12
10
8
6
4
Rifapentine
2
0
Rifampicin
0 2 4 6 9 12
18
24
30
36
48
72
Time (hr)
Peloquin CA, et al. Antimicrob Agents Chemother 1997;2670-9
Keung ACF, et al. Antimicrob Agents Chemother 1999;43:1230-33
USPHS Study 22: Acquired Rifamycin MonoResistance 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-Positive
Tuberculosis Cases without Prior Treatment, Benin and Ivory Coast
After 12 Years of Rifampicin Usage in the National Program
333
320
Number of cases
300
200
8-mo regimen:
6-mo regimen:
2 S{HR}Z / 6 {TH}
2 {HRZ} / 4 RH
100
MDR:
1 (0.3%)
MDR:
17 (5.3%)
0
Benin
Ivory Coast
Trébucq 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
Frequent Case: Initial INH Resistance
One perspective
Another perspective
2 EHRZ / 6 EH
2 EHRZ / 4 RH
Failure / relapse:
relatively frequent
Failure / relapse:
relatively infrequent
2 SEHRZ / 6 ERHZ
2 SEHRZ / 1 ERHZ / 5 ERH
Failure = MDR
Relatively infrequent
Failure = MDR
Relatively frequent
Failures of failures: appropriate numerator
Cascade of regimens
No
Hr
2 SPH / 16 PH
90% effective
Yes
Standardization
advantageous
{HR}r
No
2 EHRZ / 4 RH
90% effective
Yes
{HR+}r
No
Bangladesh-type
regimen
90% effective
Yes
Standardization
options limited
and unclear
{HRIF}r
XDR
{HRF}r
{HRI}r
“MDR-plus”
Subsets of MDR
HrRr
HrRrFr
Simple to cure
?
70%-90%
HrRrIr HrRrFrIr
Difficult to cure
?
?
1 Centers
Almost impossible
to cure
1%-15% 1
for Disease Control and Prevention
Morb Mortal Wkly Rep 2006;55:301-5
Cross-resistance among second-line injectable drugs, Georgia
Per cent with pattern
100
80
Resistant to at least:
Kanamycin
Amikacin
Capreomycin
KsAs
KrCs
AsCs
ArCs
60
ArCr
KrCr
KrAr
78
69
66
40
20
0
Number of strains in each group
Jugheli L, et al. Antimicrob Agents Chemother 2009;53:5064-8
Treatment of MDR tuberculosis in Damien Foundation
Projects, Bangladesh, 1997-2007
Van Deun A, et al. Am J Resprir Crit Care Med 2010:182;684-92
Treatment of MDR tuberculosis in Damien Foundation
Projects, Bangladesh, 1997-2007
Van Deun A, et al. Am J Resprir Crit Care Med 2010:182;684-92
Treatment of MDR tuberculosis in Damien Foundation
Projects, 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
Probability remaining free
of adverse outcome (%)
100
95
Gatifloxacin-based regimen
90
85
80
Failure
Default
Death
Relapse
75
70
65
Ofloxacin-based regimens
Hazard ratio: 0.39 (95% CI 0.26-0.59)
0
180
360
540
720
Time in 30-day intervals
Ofloxacin
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
Gatifloxaxin
206
198
193
190
182
176
172
165
163
128
192
187
179
175
168
165
139
195
191
186
177
175
166
164
131
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
Cumulative per cent
100
Ofloxacin
regimens
80
Reason for premature stop
Gatifloxacin
regimen
60
O
22
29
16
G
11
12
1
40
Death
Default
Failure
20
Patients 221 206
0
0
3
6
9
12
15
18
21
24
Month from start to ending treatment
Van Deun A, et al. Am J Resprir Crit Care Med 2010:182;684-92
Deaths among patients after treatment start, on and
after treatment, by regimen and time of death
Cumulative percent dead
100
80
60
40
On
treatment
20
After
treatment
26 Ofloxacin deaths
19 Gatifloxacin deaths
0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42
Months since treatment start
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 €)
Kanamycin
Prothionamide
4-month intensive phase prolonged
if still smear-positive after 4 months
Isoniazid
Fixed 5-month continuation phase
Gatifloxacin
Ethambutol
Pyrazinamide
Clofazimine
Van Deun A, et al. Am J Resprir Crit Care Med 2010:182;684-92
Smear-to-Culture Ratio During Chemotherapy
by Treatment Regimen, USPHS Trials
Smear-to-culture ratio
INH + RMP
2.5
2.0
1.5
INH + SM
1.0
INH
0.5
0 2 4 6 8 10 12 14 16 18 20
24
28
32
36
40
Week of treatment
Mount FW, et al. Am Rev Tuberc 1953;68;264-9
Mount FW, et al. Am Rev Tuberc 1954;70:521-6
Newman R, et al. Am Rev Respir Dis 1974:109:216-32
The Union’s proposed cascade of regimens
2 EHRZ / 4 RH
2 EHRZS / 6 RH
RrHrIrFs
RrHrIsFr
RrHrIrFr
4+ KPGHZEC / 6 HZEC GLC?
GLC?
???
RrHrIsFs
Prophylactic Treatment
(Or perhaps better: primary prophylaxis)
Transmission
Chemotherapy
Doctor’s delay
Prophylactic
treatment
Preventive
therapy
Patient’s delay
Infectious
tuberculosis
Exposure
Sub-clinical
infection
Death
Non-infectious
tuberculosis
BCG
vaccination
Protection Against Acquisition of Tuberculous Infection,
USPHS Trials with Isoniazid Prophylactic Treatment
Schools
Contacts of
new cases
Contacts of
known cases
Mental patients
- 50
0
20
40
50
Protection (%) (log scale)
Ferebee SH. Adv Tuberc Res 1969;17:28-106
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
Transmission
Chemotherapy
Doctor’s delay
Prophylactic
treatment
Preventive
therapy
Patient’s delay
Infectious
tuberculosis
Exposure
Sub-clinical
infection
Death
Non-infectious
tuberculosis
BCG
vaccination
Albert Calmette
Konrad Birkhaug
Normal Reaction Course to Vaccination with
BCG French Strain in Korean Newborn
At vaccination
Approximately
3 wk post-vacc
Approximately
1 yr post-vacc
Approximately
6 wk post-vacc
Picture courtesy: Kim SJ, April 7, 2001
Korean Institute of Tuberculosis
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
Yes
A
B
Person-yrs of
observation
N1
No
C
D
N2
A+C
B+D
N1 + N2
Total
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
a+c
b+d
n1 + n 2
Total
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 Studies
Tuberculosis Death, Meningitis and Disseminated Tuberculosis
N. Am. Indians
Death
Chicago
Death
Philadelphia
Death
Saskatchewan
Death
New York City
Death
-400
-100
0 30 50
80
90
Per cent protection
95
Protection from BCG Vaccination - Retrospective Studies
Protection Against Death, Disseminated, and Meningeal Tuberculosis
Meningitis
Hospital controls
Miliary, meningitis
Sao Paolo
Buenos Aires
Miliary, meningitis
Meningitis
Neighborhood controls
Extrapulmonary
Papua New Guinea
Sao Paolo
Nagpur
Disseminated
Bangkok
Delhi
Meningitis
Meningitis
Control diarrhea
Meningitis
Meningitis
Control pneumonia
Meningitis, miliary
Bela Horizonte
Bela Horizonte
Bela Horizonte
Rangoon
-400
-100
0 30 50
80
90
Per cent protection
95
Effectiveness of BCG Against Meningeal Tuberculosis,
Meta-Analysis of Case-Control Studies, 1947-1993
Buenos Aires, 1988
São Paulo, 1990/93
Bahia, 1991
São Paulo, 1990/93
Nagpur, 1996
Delhi, 1989
Bela Horizonte, 1988
Chennai, 1996
Summary measure
Bela Horizonte, 1965
Delhi, 1964
Papua New Guinea, 1958
Delhi, 1956
Yangon, 1952
Lucknow, 1947
-40 0 20
50
80
90
Per cent protection (log scale)
Bourdin Trunz B, et al. Lancet 2006;367:1173-80
Protection from BCG Vaccination - Prospective Studies
Protection in Infants
Saskatchewan
Infants, any form
Saskatchewan
Infants, morbidity
Chicago
Infants, any form
Chicago
Infants, any form
Chicago
Infants, morbidity
-400
-100
0 30 50
80
90
Per cent protection
95
Protection from BCG Vaccination - Retrospective Studies
Protection Infants
Laboratory
confirmed
All forms
Bangkok
Bangkok
Saudi Arabia
All forms
Bangui
All forms
Buenos Aires
All forms
Birmingham
All forms
Canadian Indians
All forms
Lusaka
HIV negative
Asians, UK
All forms
Papua New Guinea
All forms
Rangoon
All forms
Sri Lanka
All forms
Lusaka
-400
HIV positive
-100
0 30 50
80
90
Per cent protection
95
Protection from BCG Vaccination - Prospective Studies
Protection in Children
Children, any form
Puerto Rico
Children, pulmonary
culture confirmed
Chingleput
Children, any form
Madanapelle
-400
-100
0 30 50
80
90
Per cent protection
95
Protection from BCG Vaccination - Retrospective Studies
Protection in Children
Bangkok
Children, any form
Case-control
Edinburgh
Children, any form
Case-control
Children, pulmonary
Contact study
Cali
-400
-100
0 30 50
80
90
Per cent protection
95
Protection from BCG Vaccination - Prospective Studies
Protection in Adults
Nurses
Ulleval
Adolescents
England
South Africa
Mine workers
Madanapelle
Adults
Adults, Pulmonary
Culture confirmed
Chingleput
Adults, first or
second vaccination
Karonga District
-400
-100
0 30 50
80
90
Per cent protection
95
Protection from BCG Vaccination - Prospective Studies
Protection all Ages
Haiti
All forms
N. Am. Indians
All forms
Madanapelle
All forms
Muscogee / Russell
All forms
All forms, 5-28 yr,
10-yr follow-up
Pulmonary,
Culture confirmed
Muscogee
Chingleput
Illinois
Mental institutions
Muscogee
All forms, 5-28 yr,
20-yr follow-up
-400
-100
0 30 50
80
90
Per cent protection
95
Protection from BCG Vaccination - Retrospective Studies
Protection in Adults and Persons of Any Age
Canadian Indians
Any age
Case-control
Chile
Adults
Case-control
-400
-100
0 30 50
80
Per cent protection
90
95
Protection / Harm from BCG Compared to Placebo
During Follow-up, by Age, Chingleput Trial, South India
Harm / protection (%)
20
Protection
0
Harm
-20
0
5
15
25
35
45
Age group (years)
Tuberculosis Research Centre Chennai. Indian J Med Res 1999;110:56-69
Protection / Harm from BCG Compared to Placebo
During Follow-up, Chingleput Trial, South India
Harm / protection (%)
20
Protection
0
Harm
-20
-40
-60
-80
-100
-120
-140
0.0
2.5
5.0
7.5
10.0
12.5
15.0
Year of follow-up
Tuberculosis Research Centre Chennai. Indian J Med Res 1999;110:56-69
Protection Afforded by BCG Vaccination
in British School Children During Follow-up
100
Protection (%)
80
60
40
20
0
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Year of follow-up
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
Moreau, 1924
Tokyo, 1925
Gothenburg, 1926
Pasteur, 1927
Danish, 1931
Tice, 1934
Montreal, 1937
Glaxo, 1954
Connaught, 1948
Pasteur, 1961
Pasteur Merieux, 1989
Oettinger T, et al. Tuber Lung Dis 1999;79:243-50
Brosch R, et al. Proc Natl Acad Sci 2007;104:5596-5601
Cases per 10,000 vaccinees
A well kept secret?
Tuberculosis case incidence by BCG strain, Hong Kong
6
5
4
3
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 to
Mycobacterium avium Complex, Sweden, 1969-93
Number of reported cases
80
60
Discontinuation of mass
BCG vaccination
40
20
0
70
75
80
85
90
Year of report
Data courtesy: Romanus V. Written communication, Feb 18, 2000
Risk of Tuberculosis During Follow-up, by Initial
Tuberculin Reaction Size, BCG Trial, Great Britain
Incidence per 10,000
70
Tuberculin
negative
60
50
40
30
20
Reacting to
100 TU only
10
0
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Year of follow-up
D'Arcy Hart P, et al. Br Med J 1977;2:293-5
Protection from BCG and from Small Tuberculin Skin
Test Reactions During Follow-up, BCG Trial, Great Britain
BCG vaccinated
Per cent protection
80
70
50
Reacting to
100 TU only
0
-100
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Year of follow-up
D'Arcy Hart P, et al. Br Med J 1977;2:293-5
Risk of Tuberculosis During Follow-up by Initial
Tuberculin Skin Test Induration Size, Karonga, Malawi
Relative risk (log scale)
10
3
Ref
1
0.5
0.2
0
1-5
6 - 10
11 - 15
16 - 20
20 +
Induration (mm)
Fine PEM, et al. Lancet 1994;344:1245-9
Effect of Environmental Mycobacteria:
Blocking and Masking Hypothesis
Andersen P, et al. Nature Rev 2005;3:656-62
BCG Osteitis and Childhood Tuberculosis in
Swedish-Born Children, Sweden 1949-1993
Number of cases
Gothenburg strain produced in:
Sweden
Denmark
Cessation of mass
BCG vaccination
30
BCG osteitis
Childhood
tuberculosis
20
10
0
1950 1955 1960 1965 1970 1975 1980 1985 1990
Year of report
Romanus V. Smittskyddsinstitutet, Stockholm: 1995
Incident cases per 100,000 population
Incidence of dissemination BCG disease in infants
infected with HIV, Cape Town, South Africa, 2004-2006
1600
1400
1200
Note:
1000
No comparison group, but
generally estimated at
1 per million
800
600
400
Hesseling AC, et al. Bull World Health Organ 2009;87:505-511
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)
Transmission
Chemotherapy
Doctor’s delay
Prophylactic
treatment
Preventive
therapy
Patient’s delay
Infectious
tuberculosis
Exposure
Sub-clinical
infection
Death
Non-infectious
tuberculosis
BCG
vaccination
Protection Against Tuberculosis Among Tuberculin
Reactors, with Isoniazid During Treatment Year
Mental patients
Contacts of
known cases
Alaskan villagers
Greenland villagers
0
50
70
90
Protection (%) (log scale)
Ferebee SH, et al. Am Rev Respir Dis 1963;88:161-75
Mount FW, et al. Am Rev Respir Dis 1962;85:821-7
Comstock 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 Contacts
of New Cases with Isoniazid Preventive Therapy
Netherlands Navy
Kenya
USA
Japan
- 50
0
50
70
90
95
Protection (%) (log scale)
Veening GJJ. Bull Int Union Tuberc 1968;41:169-71
Egsmose T, et al. Bull World Health Organ 1965;33:419-33
Ferebee SH, et al. Am Rev Respir Dis 1962;85:490-521
Bush OB, et al. Am Rev Respir Dis 1965;92:732-40
Protection Against Tuberculosis Among Persons with
Various Risk Factors with Isoniazid Preventive Therapy
Fibrotic lesions (IUAT)
Fibrotic lesions (USPHS)
Fibrotic lesions (New York)
Hemodialyis
Silicosis
0
50
70
90
Protection (%) (log scale)
International Union Against Tuberculosis Committee on Prophylaxis
Bull World Health Organ 1982;60:555-64
Ferebee SH. Adv Tuberc Res 1969;17:28-106
Katz J. Am Rev Respir Dis 1962;86:8-15
John GT, et al. Transplantation 1994;57:1683-4
Hong Kong Chest Service / Tuberculosis Research Centre, Madras /
British Medical Research Council. Am Rev Respir Dis 1992;145:36-41
Preventive
therapy
Infection
with M. tbc
Tuberculosis
TNF-α
HIV replication
Increased
immunosuppression
AIDS
Granuloma
formation
Protection Against Tuberculosis with Isoniazid Preventive Therapy - HIV Infection
Risk
Regimen
Control
Study place
HIV
12 mo H
P
Port-au-Prince
HIV
6 mo H2
P
Lusaka
HIV
6 mo H
P
Kampala
HIV
6 mo H
P
New York City
HIV
6 mo H
P
Nairobi
- 50
0
50
70
90
Protection (%) (log scale)
Pape JW, et al. Lancet 1993;342:268-72
Mwinga A, et al. AIDS 1998;12:2447-57
Whalen CC, et al. N Engl J Med 1997;337:801-8
Gordin FM, et al. N Engl J Med 1997;337:315-20
Hawken MP, et al. AIDS 1997;11:875-82
Protection Against Tuberculosis Among Persons with Fibrotic
Lesions, by Length of Isoniazid Preventive Therapy
12 months
6 months
All study participants
3 months
12 months
6 months
Completers - compliers
3 months
- 50
0
30
50
70
90
Protection (%) (log scale)
International Union Against Tuberculosis Committee on Prophylaxis
Bull World Health Organ 1982;60:555-64
Effect of Various Durations of Preventive Therapy
on Risk of Tuberculosis in Bethel Isoniazid Studies
5
Cases per 100
4
3
2
1
0
0
3
6
9
12
15
18
21
Months of treatment
Comstock GW. Int J Tuberc Lung Dis 1999;3:847-50
Long-Term Efficacy of Isoniazid Preventive Therapy
Fibrotic lesions
Per cent protection
100
80
Alaska villagers
60
40
20
Greenland villagers
0
0
1
2
3
4
5
6
7
Year of follow-up
International Union Against Tuberculosis Committee
on Prophylaxis. Bull World Health Organ 1982;60:555-64
Ferebee SH. Adv Tuberc Res 1969;17:28-106
Horwitz O, et al. Bull World Health Organ 1966;35:509-26
Efficacy of Six Months Isoniazid Preventive Therapy Among
HIV Infected Patients During Follow-Up, Uganda
Johnson JL, et al. AIDS 2001;15:2137-47
Protection Against Tuberculosis with Rifampicin Preventive Therapy
Risk
Regimen
Control
Study place
HIV
3 mo RH
Placebo
Kampala
HIV
3 mo RHZ
Placebo
Kampala
Silicosis
12 wk R
Placebo
Hong Kong
Silicosis
12 wk RH
Placebo
Hong Kong
HIV
3 mo R2Z2
Placebo
Lusaka
- 50
0
50
70
80
Protection (%) (log scale)
Whalen CC, et al. N Engl J Med 1997;337:801-8
Hong Kong Chest Service, et al. Am Rev Respir Dis 1992;145:36-41
Mwinga A, et al. AIDS 1998;12:2447-57
Protection Against Tuberculosis with Rifampicin vs Isoniazid Preventive Therapy
Risk
Regimen
Control
Study place
Silicosis 12 wk R
24 wk H
Hong Kong
12 mo H
US / collab
Silicosis 12 wk RH 24 wk H
Hong Kong
HIV
2 mo RZ
HIV
24 wk R2Z2 24 wk H2
Haiti
HIV
3 mo R2Z2 6 mo H2
Lusaka
- 100
- 50
0
30
50
70
Protection (%) (log scale)
Hong Kong Chest Service, et al. Am Rev Respir Dis 1992;145:36-41
Gordin F, et al. JAMA 2000;1445-50
Halsey NA, et al. Lancet 1998;786-92
Mwinga A, et al. AIDS 1998;12:2447-57
American Thoracic Society / Centers for Disease Control
Preventive Therapy Recommendations
ATS / CDC. Morb Mortal Wkly Rep 2003;52:735-9
Joint Tuberculosis Committee of the British Thoracic Society
Preventive 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 Police
Officers in Dar es Salaam, Tanzania, 1998
Number of persons
400
HIV Pos: 14.1%
of 2,782 tested
8 of 37 had asymptomatic
smear-positive tuberculosis
300
200
100
Got
result
Accept
PT
Started Adherent
Evaluated INH
for 6 mo
0
Bakari M, et al. East Afr Med J 2000;77:494-7
Preventive Therapy Use at a ProTEST Site
South Africa, 2000 - 2002
Number of persons
200
Past
TB
150
To 6 mo INH
TB
sympt
100
50
Eligible
Analyzed
Adherent
nonadherent
1 dose
only
Eligible
Started
Non-adherent
0
HIV +
Rowe KA, et al. Int J Tuberc Lung Dis 2005;9:263-9
Tuberculosis Incidence in an HIV-Infected Cohort of
Patients on Anti-Retroviral Therapy, Switzerland, 1996-2005
Number of Patients
6000
5000
4000
3000
2000
1000
0
Cohort HIV pos
Subjects
6,018
Missed
Averted
30
0
<5mm
>=5mm
Prev ther
4,168
390
144
10
0.1
16
0.2
0
9.4
Total
56
9.7
Elzi L, et al. Clin Infect Dis 2007;44:94-102
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
Kristian Andvord’s break-through observation
Andvord K F. Norsk Magasin for Lægevidenskapen 1930;91:642-60
Tuberculosis Notification Rates Among Males,
by Birth Cohort, Finland 1954 -1994
1902
1954
196
100
1
4
1912
974
198
4
19
52
194
2
32
19
50
10
1892
1922
1994
62
19
Notifications per 100,000
(log scale)
500
5
1
1972
0.5
0
20
40
60
80
Age (years)
Härö AS. Tuberc Respir Dis Yearbook 1998;24:1-151
Andvord’s conclusion
Childhood experience with
Mycobacterium tuberculosis
predicts adult experience
Fate of M tuberculosis in calcified lesions
Pulmonary
Author
Lymphatic
Lesions
Sterile
Lesions
Sterile
10
9
16
10
Rabinowitch
-
-
30
19
Koenigsfeld
21
17
18
13
Schroeder
40
40
61
60
Opie
92
77
91
70
-
-
17
17
27
16
-
-
Anders
-
-
58
50
Saenz
44
33
-
-
Total
234
192
291
239
Schmitz
Griffith
Rubinstein
Percentage sterile
82.1
82.1
Canetti G. Paris: Vigot Frères, 1939, 305 pp
Primary Infection and Reinfection at Autopsy
Among Persons not Dying from Tuberculosis
Number of cases
100
80
Primary
98
Reinfection
61
60
4+ lesions
40
20
3 lesions
2 lesions
1 lesion
0
Canetti G. Tubercle 1950;31:224-33
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
The “Koch Phenomenon”
A primary infection leads to a delayed response and often takes a mild and
self-limited course
A reinfection commonly results in a rapid response with tissue necrosis
Drawings: Koch R. Mittheilungen aus dem Kaiserlichen Gesundheitsamte 1884;2:1-88.
Phenomenon: Koch R. Dtsch Med Wochenschr 1891;17:101-2.
Protection Afforded by BCG Vaccination
in British School Children During Follow-up
100
Protection (%)
80
60
40
20
0
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Year of follow-up
D'Arcy Hart P, et al. Br Med J 1977;2:293-5
Remaining live bacilli
Morbidity / mortality
Re-infection
Primary
infection
Andvord
Canetti
Age
Time / age
Re-infection
Abortive
Primary
infection
Koch
Time
BCG protection
Tissue destruction
Progressive
BMRC
Time
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
Miliary
After 2 months chemotherapy
Tuberculosis
After 6 months chemotherapy