Treatment of Tuberculosis, PDF Free Download

Treatment of Tuberculosis, 2017 Charles L. Daley, MD National Jewish Health University of Colorado Health Sciences Center

Treatment of Tuberculosis Disclosures Advisory Board Horizon, Johnson and Johnson, Otsuka and Spero Investigator Insmed

Objectives After participating in this lecture, you should be able to: 1. Describe the objectives of anti tuberculosis therapy 2. Describe the recommended treatment regimens for drug susceptible pulmonary TB 3. Describe the recommended approach to treatment monitoring

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?

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

Audience Response Question Which of the following would be the most appropriate next step? A. Collect sputum for culture and wait for results B. Collect sputum for culture and start 4 drug regimen C. Begin isoniazid and rifampin preventive therapy D. Begin treatment for community acquired pneumonia E. Do nothing, her TST result is likely a false positive

Factors Affecting Decision to Initiate Treatment Patient Laboratory/ Radiologic Clinical status/ suspicious Public Health Risk for progression Young age (< 2 yo) TB exposure Radiograph cw TB Smear positive, NAAT positive Smear negative, NAAT positive Life threatening disease Symptoms cw TB Alternative diagnosis unlikely High transmission risk Concern for lost to f/u Risk for AE No TB exposure Radiograph not cw TB Smear positive, NAAT negative Smear negative, NAAT negative Stable disease Symptoms not cw TB Alternative diagnosis likely Low transmission risk Favors Treatment Initiation Favors Delayed or no Treatment

Objectives Of Anti-tuberculosis Therapy 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, EMB Never treat active TB with a single drug

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 Education and 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)

Organization and Supervision of Therapy (2) 2. Does self administered therapy (SAT) have similar outcomes compared to directly observed therapy (DOT) in patients with various forms of TB? We suggest using DOT rather than SAT (conditional recommendation, low quality of evidence) 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 relapse Population-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)

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 Homelessness

Treatment of Tuberculosis Standard Regimen Isoniazid Rifampin Pyrazinamide Ethambutol Initial Phase Continuation Phase 0 1 2 3 4 5 6 months

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%

Recommended Treatment Regimens Daily 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)

Recommended Treatment Regimens Daily 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 rifapentine 600 mg (strong recommendation, high quality of evidence)

Relapse Rates By Cavitation and 6 month regimen 2 Month Culture Status Cav+ C2m+ Cav+ C2m Cav C2m+ Cav C2m Daily 6.0 2.2 1.8 0.6 Daily IP + thrice weekly CP 6.1 3.3 2.2 1.2 Daily IP + twice weekly CP 15.6 5.7 5.4 1.9 Thrice weekly 14.5 5.3 4.6 1.7 Daily IP with Rp in CP 25.3 9.0 8.4 3.0 Thrice weekly IP with Rp in CP 36.1 12.9 12.0 4.3 IP intensive phase, CP continuation phase, Rp rifapentine Cav cavitary, C2m 2 month culture status Chang et al, AJRCCM 2006; 174;1153 1158

Preferred Regimens for Newly Initial Continuation Reg Drugs Interval/Dose Drugs Interval/Dose 1 INH RIF EMB PZA 2 INH RIF EMB PZA Diagnosed Pulmonary TB 7 days/wk (56) or 5 days/wk (40) 7 days/wk (56) or 5 days/wk (40) INH/RIF 7 days/wk (126) or 5 days/wk (90) INH/RIF 3 days/wk (54) Effectiveness ATS/CDC/IDSA. AJRCCM 2016 167:735

Alternative Regimens Initial Continuation Reg Drugs Interval/Dose Drugs Interval/Dose 3* INH RIF EMB PZA 4** INH RIF EMB PZA 3X wkly (24) INH/RIF 3X wkly (54) 7 days/wk (14) then twice wkly (12) INH/RIF 2X wkly (36) 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 ATS/CDC/IDSA. AJRCCM 2016 167:735

Treatment of Tuberculosis Completion 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

Interruptions in Treatment Time point of interruption Details of interruption Approach Intensive Phase Lapse is < 14 days Continue treatment Continuation Phase Lapse is 14 days Received 80% of doses and was sm ( ) at diagnosis Received 80% of doses and was sm (+) at diagnosis Received < 80% of doses and lapse < 3 mos Restart treatment Received < 80% of doses and lapse 3 mos Further treatment may not be necessary Continue treatment unless 2 consecutive mos missed then restart Continue treatment Restart treatment

Treatment of Tuberculosis Extending Therapy in High Risk Isoniazid Rifampin Pyrazinamide Ethambutol Initial Continuation Phase* 0 1 2 3 4 5 6 7 8 9 months *Extend continuation phase from 4 to 7 months if: 1) cavitary disease and 2) culture positive at 2 mos

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

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

Audience Response Question This patient should be treated for 9 months. A. True B. False

Algorithm to Guide Duration of Continuation-Phase Treatment On anti-tb Rx No 2 month culture positive? Give continuationphase treatment for 4 months Yes Cavity present? No No HIVinfected? Yes Give continuationphase treatment for 7 months Yes CDC

Treatment in Special Situations Paucibacillary 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 Relapse Hong 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 / 2INH 3 RIF 3 <1.0%

Four-Month Regimen for Paucibacillary Disease On anti-tb Rx Initial culture negative? Yes 2 mos 4 mos Clinical or x-ray improved Yes No Give continuationphase treatment for 2 months Stop treatment

Monitoring for Treatment Response and Adverse Reactions Shaded - optional Nahid P, et al. Clin Infect Dis. 2016;63(7):e147-e195.

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

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

Randomized Trials of Short Course Flouroquinolone Regimens Study Location N Regimens ReMOX South Indian Trial OFLOTUB RIFAQUIN 9 countries in Africa, Asia, Central Am. 1931 2 HRZE/4HR 2 HRZM/2HRM 2 MRZE/2MR 2 sites in India 429 2 HRZE/4HR 2 HRZM/2HRM 2 HRZG/2HRG 5 countries in Africa 4 countries in Africa 1836 2 HRZE/4HR 2 HRZG/2HRG 827 2 HRZE/4HR 2 RZEM/4M 1 Rp 1 2 RZEM/2M 2 Rp 2 Unfavorable Outcomes 16% 23% 24% 9% 11% 20% 17% 21% 14% 14% 27% P (in mitt analysis) NS NS.38.02 NS NS S Gillespie SH, et al. NEJM 2014;371:1577 Jindani A et al. NEJM 2014;371:1599 Merle CS, et al NEJM 2014;371:1588 Jawahar MS, et al. PLoS One 2013;8 Lanoix JP, et al. Clin Infect Dis 2015

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