Jean-Pierre Zellweger Swiss Lung Association Berne, Switzerland 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) Moran-Mendoza O, IJTLD 2007;11(9):1014-20

TB rate/100’000 by type of contact and TST size Moran-Mendoza O, IJTLD 2007;11(9):1014-20

TB reactivation in 4661 untreated close contacts % 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) 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

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 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 (100-1000 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 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, high-dose 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…