2. Jean-Pierre Zellweger Swiss Lung Association Berne, Switzerland
Treatment of LTBI
Jean-Pierre Zellweger
Swiss Lung Association
Berne, Switzerland

3. 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

4. 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

5. Risk of tuberculosis in individuals with positive TST
Horsburgh CR, NEJM 2004;350(20):

6. Risk of tuberculosis in individuals with positive TST and added risk factors
Horsburgh CR, NEJM 2004;350(20):

7. Risk of tuberculosis in individuals with positive TST and added risk factors (updated list)
Erkens J ERJ 2010 (in press)

8. TB risk in contacts, by TST size and age (180 cases among 26’542 contacts, rate 678/100’000)
Moran-Mendoza O, IJTLD 2007;11(9):

9. TB rate/100’000 by type of contact and TST size
Moran-Mendoza O, IJTLD 2007;11(9):

10. TB reactivation in 4661 untreated close contacts%
Lee MSN, IJTLD 2008;12(3):281-7

11. TB reactivation among contacts, by age group
Moran-Mendoza O, IJTLD 2007;11(9):

12. Risk of TB reactivation in men and women, by size of TST
Radhakrishna S, IJTLD 2003; 7(11):

13. TB development within 2 years among 601 contacts, by test result (TST and IGRA)
S+ PTB
358 TST neg
243 TST >5mm
(40%)
1 TB*
(*IGRA +)
5 TB
(2.3%)
535 IGRA neg
66 IGRA pos
(11%)
0 TB
25 prevent ttt
41 no prevent ttt
0 TB
6 TB
(14.6%)
Diel R, AJRCCM 2008

14. 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%

15. 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

16. 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

17. Preventive treatment in special populations: HIV+ contacts
Dooley KE, Clin Chest Med 2005;26:

18. Risk of tuberculosis among HIV+ patients (Swiss HIV cohort)
Elzi L, CID 2007;44:94-102

19. Toxicity of isoniazid preventive therapy in HIV seronegative contacts

20. Toxicity of isoniazid preventive therapy in HIV seropositive contacts

21. Isoniazid preventive therapy: how long?
Comstock GW, IJTLD 1999;3(10):847-50

22. Other therapeutic options: some evidences
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

23. Erkens C, ERJ in press 2010

24. 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

25. 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

26. Regimens used among children in contact with MDR-TB
Schaaf HS, Pediatrics 2002;109:765-71

27. Outcome in children in contact with MDR-TB, treated vs untreated
Schaaf HS, Pediatrics 2002;109:765-71

28. 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 ( 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!

29. Number needed to treat to prevent one future case of TB (assuming that all « positive » contacts receive a preventive treatment) n
Diel R, Wrighton-Smith P and Zellweger JP, ERJ 2007;30:321-32

30. 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

31. 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)

32. 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)

33. 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

34. 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

35. 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%

36. Adherence with preventive therapy
Rennie TW, Eur Respir J 2007; 30:728-35

37. 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

38. 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, high-dose steroids, cancer chemotherapy, transplantation) or immunodeficiency
Follow-up and repeated screening: ???

39. 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)

40. 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

41. We need: Better definition of infection Shorter treatment
Less toxic treatment

42. 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…