Treatment of LTBI

Jean-Pierre ZellwegerSwiss 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)

0

20

40

60

80

100

120

140

160

180

0-4 5-9 10-14 15+

household

close

casual

0-10 years

Moran-Mendoza O, IJTLD 2007;11(9):1014-20

TB rate/100’000 by type of contact and TST size

0

2000

4000

6000

8000

10000

12000

close non close casual

0-4 mm

5-9 mm

10-14 mm

+ 15 mm

Moran-Mendoza O, IJTLD 2007;11(9):1014-20

TB reactivation in 4661 untreated close contacts

0

0.2

0.4

0.6

0.8

1

1.2

1.4

< 3 m 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 contactsS+ PTB

358 TST neg 243 TST >5mm(40%)

535 IGRA neg 66 IGRA pos(11%)

25 prevent ttt 41 no prevent ttt

0 TB 6 TB(14.6%)

5 TB(2.3%)

1 TB*(*IGRA +)

Diel R, AJRCCM 2008

0 TB

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 inHIV 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 (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)

0102030405060708090

TST 5 m

m

TST 10

mm

TST 15

mm

TST 10

+ IG

RAIG

RA

high ri

sk

20 years40 years

Diel R, Wrighton-Smith P and Zellweger JP, ERJ 2007;30:321-32

n

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…