THE TRIALS RELATED TO TREATMENT OF LTB

INFECTION

Dr. SERİR AKTOĞU ÖZKANDr. SERİR AKTOĞU ÖZKAN

IIzmir Göğüs Hastalıkları ve Cerrahisizmir Göğüs Hastalıkları ve Cerrahisi Eğitim ve Eğitim ve Araştırma HastanesiAraştırma Hastanesi

aktogu@yahoo.comaktogu@yahoo.com

THE CONTROLTHE CONTROL OF OF TTUBERCULOSISUBERCULOSIS

to detect of patients with active tuberculosisto detect of patients with active tuberculosis to cure the patients with active TBto cure the patients with active TB to detect and treatment of persons with LTBI at to detect and treatment of persons with LTBI at

high risk for developing to active TBhigh risk for developing to active TB

TREATMENT OF LATENT TB INFECTIONTREATMENT OF LATENT TB INFECTION

to detect LTBI with high risk for to detect LTBI with high risk for

developing developing TBTB

to start sto start standart tandart treatment of treatment of LTBI LTBI

to complete of sto complete of standart tandart treatment of treatment of LTBI LTBI

Persons with increased risk for developing Persons with increased risk for developing TBTB

Recent infection with Recent infection with M. tuberculosisM. tuberculosis

Clinical conditions that are associated with Clinical conditions that are associated with an increased risk for progression of LTBI to an increased risk for progression of LTBI to active TBactive TB ( (several factors that are several factors that are associated with decreased cell-based associated with decreased cell-based immunity).immunity).

Several factors associated with impaired Several factors associated with impaired cell-based immunitycell-based immunity

Younger thanYounger than 5 5 yr of age, adolescents and yr of age, adolescents and

young adultsyoung adults HIV HIV infectioninfection, , who are receiving who are receiving

immimmuunnoosupsuppressive theapy pressive theapy (anti-(anti-TNF-TNF- αα drugsdrugs, , systemic corticosteroids, solid systemic corticosteroids, solid organ organ transplantatransplantation), tion),

chronic renal failurechronic renal failure, leukemias, lymphomas, , leukemias, lymphomas, carcinoma of the head or neck and lung v.scarcinoma of the head or neck and lung v.s

TREATMENT OF TREATMENT OF LTBLTBII

Isoniazid has been the mainstay of LTBI treatment Isoniazid has been the mainstay of LTBI treatment

for >40 years.for >40 years.

The preferred treatment for LTBI is 9 months of The preferred treatment for LTBI is 9 months of

daily H daily H

Effectiveness of the drug 25- 93 % Effectiveness of the drug 25- 93 %

Disadvantages: hepatotoxicity, poor completion Disadvantages: hepatotoxicity, poor completion

rate, high H resistance rate, high H resistance

RANDOMIZED TREATMENT TRIALS IN HIV INFECTED SUBJECTS

2 months of R (600mg) and Z (15-20mg/kg) in2 months of R (600mg) and Z (15-20mg/kg) incombination (RZ) proved to be as effective as 6combination (RZ) proved to be as effective as 6months of (H) treatment for prevention of TB months of (H) treatment for prevention of TB Disease and was well tolerated. Disease and was well tolerated.

Halsey NA, Coberly JS, Desormeaux J et al. Randomized trials of isoniazid Halsey NA, Coberly JS, Desormeaux J et al. Randomized trials of isoniazid

Versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 Versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1

İnfection. İnfection. Lancet Lancet 1998; 351: 786-92. 1998; 351: 786-92.

LTBI TREATMENT IN HIV INFECTED SUBJECTS

2-3 months of RZ for LTBI treatment in HIV2-3 months of RZ for LTBI treatment in HIV infected patients was recommended by Theinfected patients was recommended by The Centers for Disease Control and Prevention (CDC)Centers for Disease Control and Prevention (CDC) in 1998.in 1998.

The person with positive tuberculin reaction whoThe person with positive tuberculin reaction whoare considerd to be at high risk for developing for are considerd to be at high risk for developing for active TB should be offered treatment of LTBI active TB should be offered treatment of LTBI

TREATMENT REGIMENS FOR LTBITREATMENT REGIMENS FOR LTBI

ATS, CDC, AM J Respir Crit Care Med 2000;161: S221-S247

Severe or fatal hepatotoxicity in patients taking RZ Severe or fatal hepatotoxicity in patients taking RZ

for LTBI for LTBI

21 hepatotoxicity between 12 Feb- 24 Ağust 200121 hepatotoxicity between 12 Feb- 24 Ağust 2001 5 of whom died5 of whom died The preferred treatment is 9 months of daily HThe preferred treatment is 9 months of daily H The regimen of 2RZ should generally not beThe regimen of 2RZ should generally not be

offered for treatment of LTBI and intensiveoffered for treatment of LTBI and intensivemonitoring is requiredmonitoring is required

MMWR 2001; 50: 733-735MMWR 2001; 50: 733-735 JAMA; 2001: 286: 1445-1446.JAMA; 2001: 286: 1445-1446.

High risk of hepatotoxicityHigh risk of hepatotoxicity Intensive monitoring is required Intensive monitoring is required 2RZ is not cost-effective for tuberculosis control 2RZ is not cost-effective for tuberculosis control

programsprograms Standart therapy for LTBI is 9 months HStandart therapy for LTBI is 9 months H

A Meta-analysis : R plus Z versus H for treating A Meta-analysis : R plus Z versus H for treating LTBI LTBI

6 6 trialstrials: Haiti, Me: Haiti, Mexicoxico, USA, Br, USA, Brazilazil, , SSpapainin, Zambia, , Zambia, Hong-KongHong-Kong

2-3 2-3 monthsmonths RZ ve RZ versusrsus standart 6-12 ay H re standart 6-12 ay H regimens gimens randomizerandomizedd ccontrollontrolleded trialstrials..

Incidence of TBIncidence of TB: : 00%% 2RZ 2RZ0.40.4%% 6H 6H

SevereSevere hepatoto hepatotoxicityxicity8.28.2% 2RZ% 2RZ1.71.7% 6H% 6H

SevereSevere advers advers eventsevents11.411.4% 2RZ% 2RZ2.92.9% 6H % 6H Gao et al. Int. J Tuberc Lung Dis 2006; 10: 1-11Gao et al. Int. J Tuberc Lung Dis 2006; 10: 1-11

Recommendations and Reports

July 7, 2006 / 55(RR09);1-44

Prevention and Control of Tuberculosis in Correctional and

Detention Facilities: Recommendations from CDC

Endorsed by the Advisory Council for the Elimination of Tuberculosis, the National Commission on Correctional Health Care, and the American Correctional Association

The material in this report originated in the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (proposed), Kevin Fenton, MD, PhD, Director, and the Division of Tuberculosis Elimination, Kenneth G. Castro, MD, Director.

Corresponding address: Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (proposed), CDC, 1600 Clifton Road, NE, MS E-10, Atlanta, GA 30333. Telephone: 404-639-8120; Fax: 404-639-8604.

Summary

L

A(II) A(II)B(II) B(II)B(I) C(I)B(II) C(I)B(II) B(III)

2707818052120

DailyTwice wklyDailyTwice wklyDaily

9

6

4

H

H

R

Rating EvidenceHIV- HIV+

No of doses

IntervalDuration

Drugs

www.cdc.gov/mmvr/preview/mmwrhtml/ 2006

TREATMENT REGIMENS FOR LTBITREATMENT REGIMENS FOR LTBI

Retrospective designRetrospective design

Treatment completion 9H (62 %), 4R (86 %)Treatment completion 9H (62 %), 4R (86 %) Hepatotoxicity 9H (1.4 %), 4R (0 %)Hepatotoxicity 9H (1.4 %), 4R (0 %) Side effects and drug reactions 9H (6.1 %), Side effects and drug reactions 9H (6.1 %),

4R (3.1%)4R (3.1%) Conclusions: Patients receiving 4R were Conclusions: Patients receiving 4R were

significantly more likely to complete therapy than significantly more likely to complete therapy than those receiving 9Hthose receiving 9H

Efitorial CommentEfitorial CommentConsider Rifampin BUT be cautiousConsider Rifampin BUT be cautious

Rifampin must be used with cautionRifampin must be used with caution

Rifampin monotherapy can relaese Rifampin monotherapy can relaese

Rifampin resistanceRifampin resistance

Randomized controlled trials is required for Randomized controlled trials is required for

medical and public health recommendations. medical and public health recommendations.

Chest 2006; 130: 1638-1639Chest 2006; 130: 1638-1639

Treatment for LTBI in people who exposed to MDR-TB

• Z plus E or Z ve Quinolone 6-12 months ,if M. Tuberculosis strain isolated from the index case is susceptible to these drugs )

Preventing TB in people at risk of MDRPreventing TB in people at risk of MDR

No randomized controlled trials No randomized controlled trials The balance of benefits and harms The balance of benefits and harms

associated with treatment for LTBI in associated with treatment for LTBI in people exposed to MDR-TB is far from people exposed to MDR-TB is far from clear.clear.

Anti TNF- alfa Treatment and TBAnti TNF- alfa Treatment and TB

(infliximab, etanercept, adalimumab)(infliximab, etanercept, adalimumab)

RA patients is at incresed risk of TB versus theRA patients is at incresed risk of TB versus the

general populationgeneral population RA patients treated with TNF antagonists has a RA patients treated with TNF antagonists has a

4-20-fold incresed risk of TB versus RA patients not 4-20-fold incresed risk of TB versus RA patients not treated withTNF antagonists treated withTNF antagonists

Arthritis and Rheumatism 2005; 52: 1986-1992Arthritis and Rheumatism 2005; 52: 1986-1992

Arthritis and Rheumatism 2003; 48: 2122-2127 Arthritis and Rheumatism 2003; 48: 2122-2127

The increase in TB is associated with Anti-TNF-alfa.The increase in TB is associated with Anti-TNF-alfa. Prior of commencing of anti-TNF-alfa, all patients Prior of commencing of anti-TNF-alfa, all patients

should have their risk of TB assessed: history of TB should have their risk of TB assessed: history of TB infection and treatment, a clinical examination, a infection and treatment, a clinical examination, a chest x-ray, Tuberculin testing chest x-ray, Tuberculin testing

It is important to exclude of active TBIt is important to exclude of active TB If the patient has active TB, full course of standart If the patient has active TB, full course of standart

chemotherapy is required.chemotherapy is required.

For patients with an normal chest x-ray and noFor patients with an normal chest x-ray and no

immunosuppressant therapy,Tuberculin testing is immunosuppressant therapy,Tuberculin testing is usefuluseful

The accuracy and reliability of Tuberculin testing is The accuracy and reliability of Tuberculin testing is

affected by immunsupressant therapy. affected by immunsupressant therapy.

For patients with normal chest x-ray and BCG, no For patients with normal chest x-ray and BCG, no

history of TB, no immunosuppressant thrapy, history of TB, no immunosuppressant thrapy, Tuberculin testing of 0-14, no further action is Tuberculin testing of 0-14, no further action is

needed and anti-TNF-alfa theray can beneeded and anti-TNF-alfa theray can becommenced.commenced.

No BCG, and tuberculin testing of 0-5, no further No BCG, and tuberculin testing of 0-5, no further

action is needed and anti-TNF-alfa therapy can beaction is needed and anti-TNF-alfa therapy can becommenced. commenced.

II. RAED The Statement of ConsensusII. RAED The Statement of Consensus Meeting 7 May 2005 / İzmirMeeting 7 May 2005 / İzmir

Anti TB therapy must be completed prior to Anti TB therapy must be completed prior to

commencing anti TNF-alfa therapy.commencing anti TNF-alfa therapy. Prior of commencing of anti-TNF-alfa, all patients Prior of commencing of anti-TNF-alfa, all patients

should have their risk of TB assessed: history of should have their risk of TB assessed: history of TB infection and treatment, chest x-ray and, TB infection and treatment, chest x-ray and, tuberculin skin testing. tuberculin skin testing.

II. RAED The Statement of ConsensusII. RAED The Statement of Consensus Meeting 7 May 2005 / İzmirMeeting 7 May 2005 / İzmir

If the patient with tuberculin testing of 1-4 mmIf the patient with tuberculin testing of 1-4 mm

(negative), no fibrocalcific lesions in chest x ray,(negative), no fibrocalcific lesions in chest x ray,and no contact with TB within last year, it is and no contact with TB within last year, it is recommended to repeat tuberculin testingrecommended to repeat tuberculin testingIf the second tuberculin testinf is 1-4 mm, there is If the second tuberculin testinf is 1-4 mm, there is no need for LTBI treatmentno need for LTBI treatment

However, the risk of TB outweighs the risk of However, the risk of TB outweighs the risk of chemoprophylaxis, therapy for LTBI may be chemoprophylaxis, therapy for LTBI may be started. started.

II. RAED The Statement of ConsensusII. RAED The Statement of Consensus Meeting 7 May 2005 / İzmirMeeting 7 May 2005 / İzmir

Following conditions are required standart Following conditions are required standart treatment with H 9 month: treatment with H 9 month:

The patients with normal chest x-ray but The patients with normal chest x-ray but

tuberculin test of ≥ 5 mmtuberculin test of ≥ 5 mm The patient with abnormal chest x-ray The patient with abnormal chest x-ray

(fibrocalcific lesions and/or tuberculin (fibrocalcific lesions and/or tuberculin testing ≥ 5 mm and excluding active TB testing ≥ 5 mm and excluding active TB

The patient who contact with active TB patients The patient who contact with active TB patients

within last yearwithin last year Health care workers with high risk ofTB Health care workers with high risk ofTB

Turkish Thoracic Society 10 th Annual CongressTurkish Thoracic Society 10 th Annual CongressMini Symposia 2007 Mini Symposia 2007

Tuberculosis and anti-TNF-Tuberculosis and anti-TNF-αα Therapy Therapy

Most of patients (72%) had BCG markMost of patients (72%) had BCG mark Most of patients (69%) were currently taking ≥1Most of patients (69%) were currently taking ≥1

immunosuppressive drug other than anti TNF-immunosuppressive drug other than anti TNF-ααat the initiation of treatment.at the initiation of treatment.

%9 had taken none of them%9 had taken none of them

CONCLUSIONSCONCLUSIONS

It is important It is important to detect of persons with LTBI at to detect of persons with LTBI at

high risk for developing to active TBhigh risk for developing to active TB Standart treatment for LTBI is 9 months of H dailyStandart treatment for LTBI is 9 months of H daily Treatment completion is of paramount importance Treatment completion is of paramount importance

to the success of LTBI therapyto the success of LTBI therapy No standart treatment for close contacts of No standart treatment for close contacts of

MDR-TB casesMDR-TB cases