Treatment of Tuberculosis, 2017

Charles L. Daley, MDNational Jewish Health

University of Colorado Health Sciences CenterProp

erty o

f Pres

enter

Not for

Rep

roduc

tion

Treatment of TuberculosisDisclosures

• Advisory Board – Horizon, Johnson and Johnson, Otsuka and Spero

• Investigator – Insmed

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Objectives

After participating in this lecture, you should be able to:1. Describe the objectives of anti‐tuberculosis therapy2. Describe the recommended treatment regimens for drug susceptible pulmonary TB3. Describe the recommended approach to treatment monitoring

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Outline

• Approach  to treatment decisions in patients with suspected TB?

• Objectives of Anti‐tuberculosis Therapy• Organization and Supervision of Therapy• Recommended Treatment Regimens

– Treatment of Paucibacillary Disease

• Monitoring for Treatment Response and Adverse Drug Reactions

• Can we shorten the duration of therapy?Prop

erty o

f Pres

enter

Not for

Rep

roduc

tion

Asian‐Born Student in her 20’s, 

PPD+ at college clinic• Asymptomatic• Erythromycin for mild pneumonia 6 mo. ago in Asia

• Chest X‐ray: nodular infiltrate

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Audience Response Question

Which of the following would be the most appropriate next step?A. Collect sputum for culture and wait for resultsB. Collect sputum for culture and start 4‐drug regimenC. Begin isoniazid and rifampin preventive therapyD. Begin treatment for community acquired pneumoniaE. Do nothing, her TST result is likely a false positiveProp

erty o

f Pres

enter

Not for

Rep

roduc

tion

Factors Affecting Decision to Initiate Treatment

Patient

Laboratory/Radiologic

Clinical status/suspicious

Favors Treatment Initiation Favors Delayed or no Treatment

Public Health

Risk for progressionYoung age (< 2 yo)TB exposure

Risk for AENo TB exposure

Radiograph cw TBSmear positive, NAAT positiveSmear negative, NAAT positive

Radiograph not cw TBSmear positive, NAAT negativeSmear negative, NAAT negative

Life threatening diseaseSymptoms cw TBAlternative diagnosis unlikely

Stable diseaseSymptoms not cw TBAlternative diagnosis likely

High transmission riskConcern for lost to f/u Low transmission risk

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Objectives Of Anti-tuberculosis Therapy

Never treat active TB with a single drug

Rapid killing of multiplying bacilli (bactericidal effect)

Achievement of relapse-free cure (sterilizing effect)

Protection against acquisition of drug resistance

INH

RIF, PZA

INH, RIF, EMBPropert

y of P

resen

ter

Not for

Rep

roduc

tion

Organization and Supervision of Therapy (2)

1.  Do case management interventions improve outcomes compared to curative therapy alone among patients with TB?

We suggest using case management interventions(conditional recommendation, low quality of evidence)

Studies Patient Educationand Counseling

Standard Approach

Relative Risk

Adherence 1 53.6% 29.3% 1.83 (1.14‐2.92)Treatment Completion

1 72.9% 42.0% 1.71 (1.32‐2.22)Prop

erty o

f Pres

enter

Not for

Rep

roduc

tion

Organization and Supervision of Therapy (2)

We suggest using DOT rather than SAT (conditional recommendation, low quality of evidence)

2.  Does self‐administered therapy (SAT) have similar outcomes compared to directly observed therapy (DOT) in patients with various forms of TB?

Studies DOT SAT Relative RiskTreatment Success 1 74.6% 73.0% 0.94 (0.89‐0.98)Culture conversion 1 88.4% 81.8% 0.92 (0.87‐0.98)

No difference in mortality, treatment completion or relapseProp

erty o

f Pres

enter

Not for

Rep

roduc

tion

Organization and Supervision of Therapy (2)

We suggest using DOT rather than SAT (conditional recommendation, low quality of evidence)

2.  Does self‐administered therapy (SAT) have similar outcomes compared to directly observed therapy (DOT) in patients with various forms of TB?

Studies DOT SAT Relative Risk

Treatment Success 1 74.6% 73.0% 0.94 (0.89‐0.98)

Culture conversion 1 88.4% 81.8% 0.92 (0.87‐0.98)

No difference in mortality, treatment completion or relapsePopulation-based studies:

reduction in acquisition and transmission of drug-resistant TB (Texas), increased treatment success in HIV infected patients (NYC)reduction in mortality and lost to follow-up (Brazil)

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Priority Situations for the Use of Directly Observed Therapy

• Positive sputum smear • Treatment failure/relapse• Drug resistance• HIV infection• Previous treatment• Intermittent dosing

• Current or prior substance abuse

• Previous nonadherence • Children/adolescents• Mental/emotional/

physical disability• Resident at correctional

or long-term care facility• HomelessnessProp

erty o

f Pres

enter

Not for

Rep

roduc

tion

Treatment of TuberculosisStandard Regimen

Isoniazid

Rifampin

Pyrazinamide

Ethambutol

0 1 2 3 4 5 6months

Initial Phase Continuation Phase

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Duration of Treatment

Regimen Duration, mos

Treatment Success

SM, PAS 18‐24 75%INH, SM, PAS 18‐24 95%INH, SM (or EMB), PZA  9 95%2 INH, RIF, SM/ 7 INH, RIF 9 95%2 INH, RIF, EMB/ 7 INH, RIF 9 95%2 INH, RIF, EMB, PZA/ 4 INH, RIF 6 95%

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Recommended Treatment RegimensDaily vs. Intermittent Dosing?

3.  Does intermittent dosing in the intensive phase have similar outcomes compared to daily dosing in the intensive phase for treatment of drug‐susceptible pulmonary TB?

Daily rather than intermittent dosing (strong recommendation, moderate quality of evidence)

Three times weekly therapy may be considered in patients who are not HIV-infected and at low risk for relapse (non-cavitary and/or smear negative (conditional recommendation, low quality of evidence)

Twice weekly therapy after an initial two weeks of daily therapy may be considered for patients who are not HIV-infected and are also at low risk risk of relapse (conditional recommendation/very low quality of evidence)

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Recommended Treatment RegimensDaily vs. Intermittent Dosing?

4.   Does intermittent dosing in the continuation phase have similar outcomes compared to daily dosing in the intensive phase for treatment of drug‐susceptible pulmonary TB?

Daily or three times weekly continuation phase (strong recommendation, moderate quality of evidence)

Three times weekly instead of twice weekly therapy if intermittent therapy is used(conditional recommendation, low quality of evidence)

Recommend against use of once weekly therapy with rifapentine600 mg (strong recommendation, high quality of evidence)

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Relapse Rates By Cavitation and 2‐Month Culture Status

6‐month regimen Cav+C2m+

Cav+C2m‐

Cav‐C2m+

Cav‐C2m‐

Daily 6.0 2.2 1.8 0.6Daily IP + thrice weekly CP 6.1 3.3 2.2 1.2Daily IP + twice weekly CP 15.6 5.7 5.4 1.9Thrice weekly 14.5 5.3 4.6 1.7Daily IP with Rp in CP 25.3 9.0 8.4 3.0Thrice weekly IP with Rp in CP 36.1 12.9 12.0 4.3

IP – intensive phase, CP continuation phase, Rp – rifapentineCav – cavitary, C2m – 2 month culture status

Chang et al, AJRCCM 2006; 174;1153‐1158

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Initial ContinuationReg Drugs Interval/Dose Drugs Interval/Dose

1 INHRIFEMBPZA

7 days/wk (56) or 5 days/wk (40)

INH/RIF 7 days/wk (126) or 5 days/wk (90)

2 INHRIFEMBPZA

7 days/wk (56) or 5 days/wk (40)

INH/RIF 3 days/wk (54)

ATS/CDC/IDSA. AJRCCM 2016 167:735

Preferred Regimens for Newly Diagnosed Pulmonary TB

Effectiveness

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Alternative Regimens

Initial ContinuationReg Drugs Interval/Dose Drugs Interval/Dose3* INH

RIFEMBPZA

3X wkly (24) INH/RIF 3X wkly (54)

4** INHRIFEMBPZA

7 days/wk (14) then twice wkly (12)

INH/RIF 2X wkly (36)

ATS/CDC/IDSA. AJRCCM 2016 167:735

Effectiveness

*Use with caution in patients with HIV or cavitary disease**Do not use in patients with HIV or smear positive and/or cavitary disease

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Treatment of TuberculosisCompletion of Therapy

• Completion of therapy is defined as the number of doses taken

• Initial phase - All of the specified doses should be delivered within 3 months

• Continuation phase - All of the specified doses should be administered within 6 months

• Thus, a 6-month regimen should be completed within 9 months

ATS/CDC/IDSA AJRCCM 2016 Prop

erty o

f Pres

enter

Not for

Rep

roduc

tion

Interruptions in Treatment

Time point of interruption

Details of interruption Approach

Intensive Phase Lapse is < 14 days Continue treatment

Lapse is ≥ 14 days Restart treatment

Continuation Phase Received ≥ 80% of doses and was sm (‐) at diagnosis

Further treatment may not be necessary

Received ≥ 80% of doses and was sm (+) at diagnosis

Continue treatment unless 2 consecutive mos missed then restart

Received < 80% of doses and lapse < 3 mos

Continue treatment

Received < 80% of doses and lapse ≥ 3 mos

Restart treatment

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Treatment of TuberculosisExtending Therapy in High Risk

Isoniazid

Rifampin

Pyrazinamide

Ethambutol

0 1 2 3 4 5 6 7 8 9months

Initial Continuation Phase*

*Extend continuation phase from 4 to 7 months if:1) cavitary disease and 2) culture positive at 2 mos

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Relapse Rates By Cavitation and 2‐Month Culture Status

6‐month regimen Cav+C2m+

Cav+C2m‐

Cav‐C2m+

Cav‐C2m‐

Daily 6.0 2.2 1.8 0.6Daily IP + thrice weekly CP 6.1 3.3 2.2 1.2Daily IP + twice weekly CP 15.6 5.7 5.4 1.9Thrice weekly 14.5 5.3 4.6 1.7Daily IP with Rp in CP 25.3 9.0 8.4 3.0Thrice weekly IP with Rp in CP 36.1 12.9 12.0 4.3

IP – intensive phase, CP continuation phase, Rp – rifapentineCav – cavitary, C2m – 2 month culture status

Chang et al, AJRCCM 2006; 174;1153‐1158

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Extending the Duration of Therapy

• Either cavitation or positive sputum culture at 2 months of therapy plus:– >10 % below ideal body weight– Smoker– Diabetes mellitus– HIV infection– Other immunosuppressive conditions– Extensive disease on chest radiograph

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Case 1• 29 year old HIV negative

Chinese man with chronic cough, night sweats, and weight loss

• Sputum is AFB smear and culture positive

• After two months of treatment his smears are positive

• Culture results after two months of therapy return as negative

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Audience Response Question

• This patient should be treated for 9 months.

A. TrueB. False

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

2 month culture

positive?

Algorithm to Guide Duration of Continuation-Phase Treatment

Cavitypresent?

HIV-infected

?

Yes Yes

Yes

Give continuation-phase treatment

for 7 monthsNo

Give continuation-phase treatment

for 4 months

No

No

On anti-TB Rx

CDCProp

erty o

f Pres

enter

Not for

Rep

roduc

tion

Treatment in Special SituationsPaucibacillary Disease (Sm‐, Cx‐)

9. Does a shorter duration of treatment have similar outcomes compared to a standard 6‐month treatment duration among HIV‐negative patients with paucibacillary TB?

Suggest a 4-month treatment regimen for treatment of HIV-negative adult patients with AFB smear- and culture-negative pulmonary TB(Conditional recommendation / Very low quality of evidence)

Study N Regimen RelapseHong Kong 325 INH‐RIF‐PZA‐SM X 4 mos 4.0%Arkansas 414 INH‐RIF X 4 mos 1.2%Singapore 196 2INH‐RIF‐PZA / 2INH‐RIF

2INH‐RIF‐PZA / 2INH3‐RIF3<1.0%

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Initial culture

negative?

Four-Month Regimen for Paucibacillary Disease

Clinical or x-ray

improved

YesYes

Give continuation-phase treatment for

2 months

No

On anti-TB Rx

Stop treatment

2 mos 4 mos

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Nahid P, et al. Clin Infect Dis. 2016;63(7):e147-e195.

Monitoring for Treatment Response and Adverse Reactions

Shaded - optionalProp

erty o

f Pres

enter

Not for

Rep

roduc

tion

Management of Treatment Failure

• 90-95% of patients treated for pulmonary TB with regimens containing INH and RIF will have negative sputum cultures by 3 mos

• Treatment failure is defined as continuously or recurrently positive cultures after 4 mos

• If still culture positive after 3 months of therapy:– Recheck drug susceptibility tests– Assess adherence– Consider malabsorption of drugs

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Management of Treatment Failure

• Treatment failure - Culture positive after 4 months of therapy:– If the patient is seriously ill or sputum AFB

smear +, an empirical regimen should be started with at least 2-3 new drugs

– If the patient is not seriously ill consider waiting for the results of drug susceptibility testing

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Randomized Trials of Short Course Flouroquinolone Regimens

Study Location N RegimensUnfavorable Outcomes

P (in miTTanalysis)

ReMOX 9 countries in Africa, Asia, Central Am.

1931 2 HRZE/4HR2 HRZM/2HRM2 MRZE/2MR

16%23%24%

‐‐‐NSNS

South Indian Trial

2 sites in India 429 2 HRZE/4HR2 HRZM/2HRM2 HRZG/2HRG

9%11%20%

‐‐‐.38.02

OFLOTUB 5 countries in Africa

1836 2 HRZE/4HR2 HRZG/2HRG

17%21%

‐‐‐NS

RIFAQUIN 4 countries in Africa

827 2 HRZE/4HR2 RZEM/4M1Rp12 RZEM/2M2Rp2

14%14%27%

‐‐‐NSS

Gillespie SH, et al. NEJM 2014;371:1577 Jindani A et al. NEJM 2014;371:1599Merle CS, et al NEJM 2014;371:1588 Jawahar MS, et al. PLoS One 2013;8

Lanoix JP, et al. Clin Infect Dis 2015

Propert

y of P

resen

ter

Not for

Rep

roduc

tion

Summary

• Treatment and its completion is the single most important factor in controlling TB in a population

• Treatment involves initiation of 4‐drugs in the initial phase followed by two drugs during the continuation phase

• Duration of therapy is 6 months– Treatment should be extended to 9 months when cavitation is present 

on the x‐ray AND the culture is still positive after 2 month of therapy.

• Duration of therapy can be 4 months for smear and culture negative pulmonary TB

• Patients should be monitored for response to therapy (culture conversion) and for evidence of adverse drug reactions

Propert

y of P

resen

ter

Not for

Rep

roduc

tion