Treatment of LTBI
Jean-Pierre Zellweger
Swiss Lung Association
Berne, Switzerland
Definitions of LTBI
• Latent TuBerculosis Infection
= mycobacteria are surviving in the organism, and may
start developing again if the immune defense
mechanisms fail (is probably true in some 10% of
infected contacts)
or
• Lasting TuBerculosis Immune response:
= mycobacteria were eliminated but the T-cells have
retained the memory of the contact and react to the
stimulation by specific antigens (TST or IGRAs) (may
be true in some infected contacts, who will never
develop the disease)
Mack U, Eur Respir J 2009;33:956-73
Definition of infected contacts
• TST
– 5 / 10 / 15 mm
– Cutoff depends on the prevalence of TB in the
population and the proportion of BCG vaccination
• IGRAs
– Manufacturer’s cutoff
– Higher cutoff
• Two-step testing
– TST, then confirmation of positive TST by IGRAs
Risk of tuberculosis in individuals with positive TST
Horsburgh CR, NEJM 2004;350(20):2060-67
Risk of tuberculosis in individuals with positive TST
and added risk factors
Horsburgh CR, NEJM 2004;350(20):2060-67
Risk of tuberculosis in individuals with positive TST
and added risk factors (updated list)
Erkens J ERJ 2010 (in press)
TB risk in contacts, by TST size and age
(180 cases among 26’542 contacts, rate 678/100’000)
180
160
140
120
household
close
casual
0-10 years
100
80
60
40
20
0
0-4
5-9
10-14
15+
Moran-Mendoza O, IJTLD 2007;11(9):1014-20
TB rate/100’000
by type of contact and TST size
12000
10000
8000
0-4 mm
5-9 mm
10-14 mm
+ 15 mm
6000
4000
2000
0
close
non close
casual
Moran-Mendoza O, IJTLD 2007;11(9):1014-20
TB reactivation in 4661 untreated close contacts
% 1.4
1.2
1
0.8
0.6
0.4
0.2
0
<3m
3-12 m
2nd y
3rd y
4th y
5th y
Lee MSN, IJTLD 2008;12(3):281-7
TB reactivation among contacts, by age group
Moran-Mendoza O, IJTLD 2007;11(9):1014-20
Risk of TB reactivation in men and women, by
size of TST
Radhakrishna S, IJTLD 2003; 7(11):1083-91
TB development within 2 years among 601
contacts, by test result (TST and IGRA)
601 contacts
S+ PTB
243 TST >5mm
(40%)
358 TST neg
1 TB*
(*IGRA +)
5 TB
(2.3%)
66 IGRA pos
(11%)
535 IGRA neg
0 TB
Diel R, AJRCCM 2008
25 prevent ttt
0 TB
41 no prevent ttt
6 TB
(14.6%)
How to reduce the risk of reactivation after
infection?
• First attempts of preventive treatment in the 50s,
publications from 1962
– Contacts of known TB cases
– Recent converters
– Populations with a high risk of infection (mental
institutions, Alaskan Eskimos, Greenland villagers)
– Inidividuals with positive TST and fibrotic lesions
(untreated TB)
• Usually treated with isoniazid for 3/4/6/8/12 mo
• Risk Reduction 21-96%
Morbidity from tuberculosis among contacts with a
positive TST, by size of the reaction, age and type of
treatment (isoniazid or placebo).
Ferebee SH, Adv Tuberc Res 1970;17:28-106
Efficacy of various durations of isoniazid therapy
(12, 24 and 52 weeks) compared to placebo in
tuberculin test reactors (IUATLD trial)
Comstock GW, ARRD 1979;119:827-30
Preventive treatment in special populations:
HIV+ contacts
Dooley KE, Clin Chest Med 2005;26:313-326
Risk of tuberculosis among HIV+ patients
(Swiss HIV cohort)
Elzi L, CID 2007;44:94-102
Toxicity of isoniazid preventive therapy in
HIV seronegative contacts
Toxicity of isoniazid preventive therapy in
HIV seropositive contacts
Isoniazid preventive therapy: how long?
Comstock GW, IJTLD 1999;3(10):847-50
Other therapeutic options: some evidences
• R
– 46% reduction of the risk among patients with silicosis and LTBI
treated with 3R
– 0 vs 8.6% reactivations in homeless contacts from H-resistant TB
treated by 6R
– Seems less toxic than 6 or 9H, with better adherence
• HR
– 41% reduction of the risk in patients with silicosis and LTBI treated
with 3HR
– 59% reduction of the risk in HIV+ patients with LTBI
• RZ
– studied only in HIV+ patients with LTBI: 3-49% reduction of the risk
but high rate of toxicity. No more recommended
Erkens C, ERJ in press 2010
Patients with LTBI and immunosuppressive
therapy (anti-TNF)
• Patients under anti-TNF have usually an underlying
disease which increases the risk of reactivation, if
infected
• Immunosuppressive therapy, like anti-TNF, further
incresase this risk
• Such patients must be screened for LTBI before
starting immunosuppressive therapy (history, chest
radiograph, TST, IGRA)
• Preventive therapy is indicated if there are signs of
LTBI
Contacts of drug-resistant TB
• R- resistant: H
• H-resistant: R
• HR-resistant: ???
– No controlled studies
– Empirical proposals:
• 6-12 ZE
• 6-12 Zquinolone
• 6-12 individualized therapy
Regimens used among children in contact with
MDR-TB
Schaaf HS, Pediatrics 2002;109:765-71
Outcome in children in contact with MDR-TB,
treated vs untreated
Schaaf HS, Pediatrics 2002;109:765-71
Does preventive therapy increase the risk of
drug resistance in case of reactivation?
• No evidence
• In LTBI due to sensitive strains, the
mycobacterial population is very limited (1001000 mycobacteria). The risk of inducing
resistance is close to zero
• In LTBI due to resistant strain, the preventive
treatment will not change anything
• If TB is already present, the preventive
treatment is NOT indicated!
Number needed to treat
to prevent one future case of TB
(assuming that all « positive » contacts receive a preventive treatment)
n 90
80
70
60
50
40
30
20
10
0
k
RA
ris
hi
gh
+
10
IG
IG
R
m
m
TS
T
TS
T
15
m
m
TS
T
10
m
m
5
TS
T
A
20 years
40 years
Diel R, Wrighton-Smith P and Zellweger JP, ERJ 2007;30:321-32
Indications for preventive therapy
• According to
– The probability of infection (size of TST, level of IGRA)
– The risk of reactivation (immune status, age)
– The potential severity of the disease
• Young age
• Contact with MDR-TB
Control before therapy
•
•
•
•
History (prior TB? Prior treatment?)
Complaints (incipient TB?)
Chest radiograph (ancient or incipient TB?)
Exclusion of active TB (complaints, suspect
signs on the chest radiograph)
Choice of the type of treatment
• Drug sensitivity of the index case (if known)
• Potential drug interactions (R with
anticoagulants, oral contraceptives and
methadone)
• Risk factors for adverse events (alcohol abuse,
active hepatitis)
• Hepatic tests (usually recommended)
• Social factors (stability or change of residency)
Surveillance during treatment
• Information about the duration of treatment
and possible adverse events
• Monthly clinical visit (tolerance, motivation,
adverse events)
• Biological tests if needed
• No prescription of the full therapy from the
beginning
Adherence with preventive treatment
• Highly variable (between 13 and 89%)
• Related to the duration of treatment (as the
drop-out rate over time is the same for both H
and R treatment, 3 months of HR or 4 months
with R may be preferable to 9 months with H)
• 85% of patients offered 4R completed the
treatment compared with 66% of those
offered 6H or 9H
LTBI treatment completion rates, by group
•
•
•
•
•
•
•
Contacts (6-12H): 35 to 89%
Prison and jail inmates (6-12H): 32 to 61%
Foreign-born (6-12H): 19 to 90%
Drug users (6-12H): 39 to 70%
Health care workers (6-12H): 27 to 82%
4R: 72 to 91%
3-6HR: 82%
Adherence with preventive therapy
Rennie TW, Eur Respir J 2007; 30:728-35
Possible interventions to increase the adherence
•
•
•
•
•
Education
Choice of a short regimen
Professional counseling
Peer education, peer support
Incentives (financial support, food)/enablers
(transportation facilities)
• DOPT
And if the patients does not receive/accept the
preventive treatment?
• Information about the signs and symptoms of
incipient tuberculosis
• Information about the risk in case of
immunosuppressive therapy (anti-TNF, highdose steroids, cancer chemotherapy,
transplantation) or immunodeficiency
• Follow-up and repeated screening: ???
Cost-effectiveness of preventive therapy
• Screening with IGRA and preventive therapy
with 9H is more cost-effective than other
screening and treatment options (Diel R,
Respir Med 2009)
• 4R is the most cost-effective option (Holland
DP, AJRCCM 2009)
Conclusions
• Preventive therapy decreases the risk of
reactivation among
–
–
–
–
Contacts of patients with active TB
Immunosuppressed patients with latent infection
Young children
Patients with signs of prior, untreated TB
• The definition of latent infection is indirect
• Even with stringent definitions, some infected
patients may be overtreated
• The adherence to preventive therapy is far from
ideal
We need:
• Better definition of infection
• Shorter treatment
• Less toxic treatment
• In theory, preventive treatment contributes to
the reduction of the reservoir of future cases of
tuberculosis
• If all individuals with latent tuberculosis were
treated before the reactivation, tuberculosis
could be eradicated…