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Think TBPlano, TexasMay 6 2010May 6, 2010

Treatment of TB DiseaseLisa Y Armitige, MD, PhDg , ,

May 6, 2010

Treatment of T b l iTuberculosis

Lisa Y Armitige, MD, PhD

Medical ConsultantMedical ConsultantHeartland National TB Center

Associate Professor of Medicine and PediatricsDivision of Adult Infectious Diseases

University of Texas HSC at Tyler

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Purpose 1 5. Recommended Treatment Regimens 36

What’s New In this Document 1 CONTENTS OF 6. Practical Aspects of Treatment 42

Summary 1 THE 80-Page 7. Drug Interactions 45

1 Introduction and Background 13 Document 8 Treatment in Special Situations 501. Introduction and Background 13 Document 8. Treatment in Special Situations 50

2. Organization and Supervision of Treatment 15 9. Management of Relapse, Treatment Failure, and Drug Resistance

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3. Drugs in Current Use 19 10. Treatment of Tuberculosis in Low-Income Countries: Recommendations and Guidelines of the WHO and the IUATLD

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4. Principles of Antituberculosis Chemotherapy 32 11. Research Agenda for Tuberculosis Treatment 74

USPHS/IDSAEvidenced-based Rating Scale

• Strength of the Recommendation– A = Preferred– B = Acceptable alternative– C = Offer when unable to give A or B– D = Should generally NOT be offered– E = Should NEVER be offered

• Quality of Supporting Evidence– I = Randomized clinical trial– II = Clinical trial, not randomized– III = Expert opinion

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Updates and Changes in TB Therapy

• To identify patients at increased risk of relapse y p p– Obtain sputum smear and culture at end of initial phase of

treatment (2months)

• Recommended Extended therapy for patients with drug-susceptible pulmonary TB– Who have cavitation on initial CXR and

Wh h iti t lt t ti 2 th f – Who have a positive sputum culture at time 2 months of completion of therapy

• Counting Doses – Define treatment completion by number of doses taken as

well as duration of treatment

Other Updates and Changes:Dosing Schedules

• HIV + individuals with low CD4 counts should NOT be given twice weekly therapy

• Daily therapy can be 7 days per week ORDaily therapy can be 7 days per week ORcan be 5 days per week IF given by DOT and the organism is drug susceptible

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Role of New Agents

• RIFABUTIN (RBT): May be used as a primary drug for patients (especially HIV+) receiving medications having unacceptable interactions with rifampin (e.g. Protease Inhibitors, methadone)

• Fluoroquinolones (Levofloxacin-agent of choice) may be used when first line drugs are not tolerated or the organism is resistant– Moxifloxacin rapidly becoming agent of choice

Treatment of Culture-Positive Drug Susceptible Pulmonary TB

• General conclusions from the literature– 6 mo (26 wk) is the MINIMUM duration of RX– 6 mo regimens require rifampin and INH

throughout and PZA for the first 2 months 6 mo regimens are effective without INH if PZA – 6 mo regimens are effective without INH if PZA given throughout

– Intermittent regimens (2-3x/wk): DOT ONLY!• Drug susceptible isolate• Regimen contains INH and rifampin

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Treatment of Culture-Positive Drug Susceptible Pulmonary TB

• General conclusions from the literature:– Without PZA - minimum duration is 9 months– Without rifampin - minimum duration is 12 months

(up to 18 months)Streptomycin and ethambutol (EMB) are – Streptomycin and ethambutol (EMB) are approximately equivalent in effect (BUT concern about increasing Streptomycin resistance among foreign born leads to preference of EMB for initial therapy)

Drugs Currently in Use

First line Second line

Isoniazid (H) Ethionamide Levofloxacin

Rifampin (Rif) Amikacin Moxifloxacin

Rifabutin (RBT) Capreomycin Gatifloxacin

Rifapentine Streptomycin ClofazamineRifapentine Streptomycin Clofazamine

Ethambutol (EMB) Cycloserine ?Linezolid

Pyrazinamide (Z) PAS ?Imipenem

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Treatment of Patients with TB Disease

• Initiation phase of therapy– 8 weeks– INH, Rifampin and PZA +/-EMB

C ti ti h f th• Continuation phase of therapy– 16 weeks– INH and Rifampin

Treatment of Culture Positive Pulmonary Disease

Regimens Rated A-1 (HIV Uninfected)INITIAL PHASE2 mo I,R,Z,E daily (56 doses, 8wks) or2 mo I,R,Z,E 5x/wk (40 doses, 8wks) then

CONTINUATION PHASE4 mo - I,R daily (126 doses, 18 wks) or4 mo – I,R 5x/wk (90 doses, 18 wks) or4 mo – I,R, 2x/wk (36 doses, 18 wks)

Continuation phase increased to 7 mo if initial CXR shows cavities and Sputum culture is positive at 2 mo

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Treatment of Culture Positive Pulmonary Tuberculosis

Initial h

– Regimens Rated A-II (HIV Uninfected)

• 2weeks – I,R,Z,E daily (14 doses) then• 6 weeks – I,R,Z,E twice weekly (12 doses)

continuation

phase

• PLUS (DOT only) • 4mo – I,R Twice weekly (36 doses, 18 weeks)

phase

BJS1

Treatment of Culture Positive Pulmonary Tuberculosis

Initial h

– Regimens Rated A-III (HIV Uninfected)• 2 weeks – I,R,Z,E 5x/week (10 doses) then• 6 weeks – I,R,Z,E twice weekly (12 doses)

continuation

phase

– PLUS (DOT only) • 4mo – I,R Twice weekly (36 doses, 18 weeks)

continuation phase

BJS2

Slide 13

BJS1 Barbara Seaworth, 11/14/2002

Slide 14

BJS2 Barbara Seaworth, 11/14/2002

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Treatment of Culture Positive Pulmonary TB

– THRICE WEEKLY – “HONG KONG” REGIMENRegimen Rated BI (HIV uninfected)

– Initial phase• 2mo – I,R,Z,E 3x/week (24 doses, 8weeks)

PLUS

– Continuation phase• 4mo – I,R 3x/wk (54 doses, 18 weeks)

Drug Susceptibility Tests

• INH Rifampin Ethambutol and PZA are • INH, Rifampin, Ethambutol, and PZA are recommended for each initial isolate

• Expect results by day 28

• If the private lab does not do susceptibilities, f l may lead to unnecessary delaysreferral may lead to unnecessary delays

– Positive culture should be sent for DST within 24 hrs, lab should not wait for culture to grow on solid media

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Baseline and Follow-up Evaluation

• For pulmonary TB – Monthly sputum until two consecutive cultures are negative– a negative 2 month sputum is crucial– 80% should convert by 2 mo, 95% by 3 mo

What About Ethambutol?

• A four drug regimen is recommended until susceptibility tests are reported

• If treatment is being initiated after drug susceptibility tests are known and the organisms are susceptible, ethambutol is not necessaryare susceptible, ethambutol is not necessary

• EMB can be stopped as soon as the lab reports an isolate susceptible to INH & rifampin.

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TBTC STUDY 22: RATE OF FAILURE/RELAPSE, BY REGIMEN,

SPUTUM CULTURE, AND CHEST RADIOGRAPH

20%

culture at 2 mo Chest radiograph at study entry

Lancet 2002; 360:528.

Prolongation of Continuation Phase

• Rational for Extending Therapy– Continuation of PZA for an additional 2

months was not helpful in drug susceptible disease

– Prolongation of continuation phase by 2 months decreased relapses in silico-tuberculosis from 20% to 2%

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Effect of Prolonging Therapy on Treatment Failure or Relapse

Treatment of Silico-tuberculosis

Outcome SHRZ - 6mo* SHRZ – 8mo*(n=49) (n=50)

____________________________________Relapse 20% 2%

* Three times weekly therapy Am Rev Respir Dis 1991;143:262-267

End of Therapy Cavity:A Risk Factor for Relapse

Hamilton; Int J Tuber Lung Dis 2008

* Independent of culture results

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New Treatment Guidelines Tailoring Treatment Regimens

P l ti f ti ti h• Prolongation of continuation phase– Positive 2 month culture with cavitary disease

– Extrapulmonary disease• Meningitis• Disseminated disease in children• Disseminated disease in children

– HIV TB in children and adolescents

ATS, CDC, IDSA: Treatment of Tuberculosis 2003

Additional New Treatment Guidelines Tailoring Treatment Regimens

• Consider Prolongation of continuation phase when patient:– Slow to clinically or radiographically respond

– Positive 2 month culture OR cavitary disease? y

– End of therapy (EOT) cavity present

– <10% ideal body weight?

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Relapse

• Circumstance in which a patient becomes and remains culture-negative while receiving antituberculosis drugs but at some point after completion of therapy, either becomes culture-positive again or experiences clinical and radiographic deterioration consistent with active tuberculosis

Treatment Guidelines 2003

• “Microbiological Confirmation of Relapse Should be Pursued Vigorously”– Confirm true relapse

– Use DNA fingerprinting to identify new infection causing the disease versus relapse

– Identify drug susceptibility pattern of isolate

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Relapsed Tuberculosis

M t ela e cc ithi the fi t 6 12 th • Most relapses occur within the first 6 – 12 months after stopping therapy but some occur 5 or more years later

• Nearly all drug susceptible patients who were treated with a rifamycin and received DOT will

l ith d tibl irelapse with drug susceptible organisms

– Treat with standard RIPE regimen

Treatment Related Risk Factors for Early Relapse of TB

• Evaluation of 113 cases of relapsed TB when matched with case Evaluation of 113 cases of relapsed TB when matched with case controls

– Non-cavitary TB, relapse rate: 1.1%

– Cavitary TB relapse rates:• Thrice weekly Rx: 7.8%• Daily Rx: 3.3%• Extended thrice weekly: 0 5%• Extended thrice weekly: 0.5%• Extended daily 0.4%

– Extending either intensive phase or both was beneficial

Chang, Am J Respir Crit Care Med. 2004; 170: 1124-30

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Dose-Response RelationshipDaily versus Intermittent Therapy

• Review of several trials 200 cases of relapse 6 mo Rx• Review of several trials, 200 cases of relapse, 6 mo Rx

• Relapse rates higher when intermittent therapy used especially in initiation phase – Daily IP, 3 x/wk CP: 1.6%– Daily IP 2x/wk CP: 2.8%– 3/wk IP and CP: 5.0%

• Relapse higher especially with cavitary disease and positive 2 month cultures– Only 6 month daily or 6 mo daily IP and 3/wk CP had

relapse rates <5%

Chang Am J Respir Crit Care Med 2006; Vol 174 p 1153

Medical Factors Associated With Relapse of Tuberculosis

• Cavitary TB• Cavitary TB• Extensive disease on CXR; bilateral infiltrates• Positive 2 month culture• Associated medical conditions

– Diabetes– HIV– Malabsorption of TB drugs

• Tuberculous lymphadenitis• Underweight at diagnosis and failure to gain• Drug resistant disease• Prior treatment for tuberculosis

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Treatment Factors Associated with Relapse of Tuberculosis

• Dosing intensity (Dose itself)• DOT• Adherence• Duration of therapy

– Intensive phasep– Continuation phase– Both

• Rifampin containing regimen

In the Treatment of TB, You Get What You Pay For…

• “ A consistent theme has begun to appear: more extensive A consistent theme has begun to appear: more extensive disease requires more treatment, and the fewer total doses, the higher the risk that treatment will prove inadequate”

– What should we conclude? • First: More is more and less is less

– More treatment means more cures

• Second: Programs need to consider some individualization of therapytherapy

• Third: Should not deter us from intermittent therapy but should remind us of need for sophisticated management based on case-specific circumstances

– Should not be surprised that individuals differ in their response.

Vernon & Iademarco (CDC) Am J Resp Crit Care Med 2004: 170, pp 1040-41

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Case Study

• 47 yr old male, recurrence of TB– Weight at Dx 117 pounds (<10% IBW)– Two months, 114 pounds– Three months, 114 pounds– Four months, 115 pounds

• Extensive cavitary disease on CXR

• Sputum smear + 5 ½ months

• Sputum culture + 3 ½ months

Example

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Importance of Nutrition in TB Treatment Response

• Patients 10% below ideal body weight at diagnosis have a 20% chance of relapse if they don’t regain at least 5% by end of two months of Rx

Impact of Poor Nutrition on TB Relapse

Reference: Lack of Weight Gain and Relapse Risk in a Large Tuberculosis Treatment Trial: Awal Khan, Timothy R. Sterling, Randall Reves, Andrew Vernon, C. Robert Horsburgh and and the Tuberculosis Trials Consortium; American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 344-348, (2006)

“Weight gain of 5% or less during the first 2 months of therapy is associated with an increased risk of relapse, even after controlling for other factors ”

– If CXR cavitary & 2 mo sputum culture +, 50% chance of relapse

Khan Am J Resp Crit Care Med 2006

Produced by Heartland National TB Center. Consultation to healthcare providers at 1-800-TEX-LUNG

2303 SE Military Drive, San Antonio, TX 78223

WWW.HeartlandNTBC.org

This product produced with funds awarded by the Centers for Disease Control & Prevention (CDC)

Created 3-08

even after controlling for other factors.

Lack of Weight Gain and Relapse Risk, TBTC Study 22

• Relapse risk high in those underweight at diagnosis 19.1% versus 4.8%

• Among pts underweight at Dx, weight gain ≤ 5% after 2 mo tx:– Relapse risk 18.4% vs. 10.3%p– If also cavitary disease: 18.9%– If cavitary and + 2 month culture: 50.5%

Khan. 2006 Am J Resp & Crit Care Med;174:344-48

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Nutrition Risk Score: Relation to Respiratory Failure & Death

• Miliary TB (MTB) develops in 1 – 2% of patients and is associated with acute respiratory failure (ARF) and death

• NRS ≥3 independent risk ARF and deathp– Lower BMI, fewer lymphocytes, lower cholesterol, &

albumin in those who died– 14/56 pts with MTB developed ARF

Kim, Europ Resp Society 2008

Relapse Risk With Four Month Rx

Johnson; AJRCCM June 09

HIV Neg, 2 mo culture Neg, Non-Cavitary TB in Uganda.

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Active TB During Pregnancy

• Treatment:• Treatment:– INH, Rifampin, Ethambutol x 9 months

• Stop ethambutol if susceptible to INH and rifampin– PZA only if drug resistance is present

• PZA regarded as safe by most countries in world (only US and Australia don’t)

• Follow carefully for hepatotoxicity– During pregnancy– Three months postpartum

TB in Patients treated with TNF-αAntagonists

• TNF-α: key role in control of latent TB y– Animal models– Clinical disease in recipients

• Current agents • Infliximab (Remicade)• Etanercept (Enbrel)• Adalimumab (Humira)( )• Certolizumab (Cimzia)

• Treatment with these agents is associated with the development of active TB, often disseminated with aggressive progression

• TB reported more frequently than other OI

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Warning: Risk of Infections: Infliximab

• Tuberculosis (frequently disseminated or Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation), …and other opportunistic infections have been observed in patients receiving Remicade some of these infections have been fatal

• Patients should be evaluated for LTBI with a TST

• Treatment of LTBI should be initiated prior to therapy with Remicade

• SEE WARNINGS

PDR 2004

TB in Patients treated with TNF-αMonoclonal Antibodies

• 70 cases of active TB reported in patients treated with infliximab (up to 5/29/01)– TB developed after median of 12 weeks

• 48 developed disease after 3 or less infusions– 48/70 (69%) had extra pulmonary disease

• 17 disseminated• 11 lymphatic, 4 peritoneal, 2 pleural

1 h i l t i t b l b • 1 each meningeal, enteric, paravertebral, bone, genital and bladder

• Confirmed by biopsy in 33 patients– 12 patients died despite stopping TNF-α antagonist

Keane N Engl J Med 2001; 345: 1098-104

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TB in Rheumatoid Arthritis and Effect of TNF-α Antagonists

• TB incidence in 6,460 infliximab treated patients followed prospectively in Spanish data base– 61.9/100,000– No cases with other agents

• TB incidence in 10,782 patients 1998-1999 prior to widespread use of infliximab

– 6.2/100,000

• Marked decrease in TB with use of screening– No cases in patients who had had TST or prophylaxis

Gomez-Reino Arthritis Rheum 2003; 48:2122-2127

Management of Patients with Suspected Infection Receiving TNF-α Antagonist

• Stop TNF- antagonist if fever and other signs/symptoms consistent with an infectious process occur in a patient at possible risk for tuberculosis

• Aggressive evaluation

• Start empiric therapy for suspected pathogens while waiting ltcultures

• Dual infections have been reported

• Disagreement about when or whether TNF- antagonist can be restarted

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Paradoxical Upgrading in TNF Alpha Blocker Recipients

• Reactions similar in intensity to those noted in HIV infected individuals

• Anti-inflammatory treatment important therapeutic interventionintervention– Steroids reported beneficial by Garcia et al in CID,

2005 – Steroid use controversial by others

Delayed ResponseCulture Positive at 3 Months

• Definitely Concerningy g

• Ask TB lab to repeat susceptibility studies on last positive culture

• Assess compliance

• Consider serum therapeutic drug levels

• Evaluate response to therapy– Clinically and radiographically

By the time you know this it is 4 months into therapy!

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“Treatment Failure”Culture Positive at 4 Months

Repeat susceptibility studiesRepeat susceptibility studies• On last positive culture• And request on the “new sputum culture” now

– Serum drug levels if not previously done– Clinical evaluation

Augment therapy• Add at least two and preferably three new drugs to

which the isolate is likely to be susceptible• Even if no clinical or radiographic evidence of failure

MMWR Treatment of Tuberculosis 2003; 52

Tuberculosis Drug Serum Level Monitoring Recommended

• Delayed response to therapy• Advanced AIDS with evidence of malabsorption• Seriously ill patient to maximize therapy• Toxicity evaluation• Use of second line drugs• Acquired drug resistanceAcquired drug resistance• Relapse• Potential for drug-drug interactions• Renal and hepatic insufficiency

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Rifampin Dose - High is Better

• Killing of MTB, suppression of resistance and post antibiotic effect were all linked to higher peak serum concentrations

• Rifampin is active against M Tb in exponential growth phase and non replicating organismsgrowth phase and non replicating organisms

• Short half life not important but peak concentration was

Gumbo; Antimicrob Agents Chemother, 2007

Rifampin Dose - High is Better

• Mouse studies with rifapentine (10-, 15-, & 20-,mg/kg twice a week) versus rifampin (10mg daily) with INH twice a week) versus rifampin (10mg daily) with INH and PZA– Superior bactericidal and sterilizing activity with higher dose

rifapentine

• Mouse studies in 1960’s showed microbiological and survival superiority of once weekly rifampin vs same cumulative dose given q day x 6 weeksg q y

• Total suppression of resistance at Cmax/MIC=175– MIC~0.125, Cmax 8 – 24 at 600mg daily– If Cmax =24 (usually is closer to 8) ratio would be 192– If Cmax = 8 ratio would be 64

Gumbo; Antimicrob Agents Chemother, 2007

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TBTC Study 27Moxifloxin Substituted for Ethambutol

Burman; Am J Resp Crit Care Med 2006

TB Trial Consortium Study 29

• Part I compare standard therapy (rifampin 10mg/kg) to:– 3 x/wk rifapentine 15mg/kg + Moxi/PZA/EMB– Daily rifampin 15mg/kg + Moxi/PZA/EMB– Daily rifapentine 7.5mg/kg + Moxi/PZA/EMB

P t II• Part II– Increase to rifapentine 20mg/kg 3x/wk, and daily rifampin

20mg/kg & rifapentine 10mg/kg

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Prolonged Positive Smears

• 51 year old male

• Slow clinical and CXR improvement

• Prolonged conversion of cultures (10 weeks)

W.C. 12-18-01

• Prolonged conversion of smears (7½ months)

Significance of Persistent + AFB Smears

• Review of lab data of 428 patients, 30 with smear persistently positive >20weeks– 23/30 had a negative culture– 7/30 positive culture “ treatment failure”

• Of those with negative cultures - none relapsed

• Most received standard therapy for 12 months– PZA was continued for 2-3 months

Al-Moamary Chest 1999; 116:726-731

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Prolonged Positive Smears

12 months of RX• 12 months of RX

• Culture and smear – 20 months after stopping TB meds

W. C. 12-11-2002

• CXR still extensive cavitary infiltrates

M. bovis & Genotyping - Texas

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Management of Treatment Interruptions

• Initial phase of therapy– <14 days –complete standard # of doses– >14 days – restart from the beginning

• Continuation phase– >80% doses by DOT – if initial smear negative, may stop– Repeat culturep

• >3 month interruption restart from beginning• <3 month interruption, culture positive, restart• <3 month interruption, culture negative, give an

additional 4 months

Where to Get More Information

• HEARTLAND NATIONAL TB CENTER– 1-800-TEX LUNG: Medical Consultation and

Technical Assistance Line– Future training courses

• CDC

• TB Educate

• TBresources.com

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Thanks!!Questions?