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TREATMENT OF TUBERCULOSIS, 2003

TREATMENT OF TUBERCULOSIS, 2003. American Thoracic Society Centers for Disease Control and Prevention Infectious Diseases Society of America. Division of Tuberculosis Elimination Centers for Disease Control and Prevention. Why a New TB Treatment Statement?.

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TREATMENT OF TUBERCULOSIS, 2003

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  1. TREATMENT OF TUBERCULOSIS, 2003 American Thoracic Society Centers for Disease Control and Prevention Infectious Diseases Society of America Division of Tuberculosis Elimination Centers for Disease Control and Prevention

  2. Why a New TB Treatment Statement? • Last TB treatment statement published in 1994 • Several new drugs available e.g., rifapentine, newer fluoroquinolones • New research information on treatment regimens

  3. What’s New? (1) • Provider/program responsibility for successful treatment, not the patient • Patient-centered case management with emphasis on directly observed therapy (DOT) • Evidence-based ratings of treatment options • Role of two-month sputum cultures to identify patients at increased relapse risk

  4. What’s New? (2) • Extend treatment for patients with drug-susceptible pulmonary TB at increased risk for relapse • Role of new drugs (rifabutin, rifapentine, and fluoroquinolones) • Practical aspects of therapy: drug administration, fixed-dose combinations, adverse effects monitoring and management, and drug interactions

  5. What’s New? (3) • Treatment completion defined primarily by number of doses ingested within specified time • Description of special treatment situations: • HIV/AIDS • Children • Extrapulmonary TB • Culture-negative TB • Pregnancy and breast feeding • Hepatic and renal disease

  6. What’s New? (4) • Updated guidelines for management of drug-resistant TB • Recommendations compared with those of the World Health Organization (WHO) and the International Union Against TB and Lung Disease (IUATLD); WHO DOTS strategy described • Current research status to improve treatment

  7. Fundamental Responsibility and Approach in TB Treatment • Provider (or program) responsible for prescribing appropriate regimen AND ensuring successful completion of therapy • Directly observed therapy (DOT) with patient-centered case management is preferred approach

  8. Isoniazid Rifampin Pyrazinamide Ethambutol Rifabutin* Rifapentine Streptomycin Cycloserine p-Aminosalicylic acid Ethionamide Amikacin or kanamycin* Capreomycin Levofloxacin* Moxifloxacin* Gatifloxacin* Antituberculosis Drugs First-Line Drugs Second-LineDrugs * Not approved by the U.S. Food and Drug Administration for use in the treatment of TB

  9. Ethambutol EMB Isoniazid INH Pyrazinamide PZA Rifampin RIF Rifapentine RPT Streptomycin SM Drug Abbreviations

  10. Role of New Drugs (1) • Rifabutin: For patients receiving medications having unacceptable interactions with rifampin (e.g., persons with HIV/AIDS) • Rifapentine: Used in once-weekly continuation phase for HIV-negative adults with drug-susceptible noncavitary TB and negative AFB smears at completion of initial phase of treatment

  11. Role of New Drugs (2) • Fluoroquinolones (Levofloxacin, Moxifloxacin, Gatifloxacin): Used when -first-line drugs not tolerated; -strains resistant to RIF, INH, or EMB; or -evidence of other resistance patterns with fluoroquinolone susceptibility

  12. Epidemiologic information Clinical, pathological, chest x-ray findings Microscopic examination of acid-fast bacilli (AFB) in sputum smears Nucleic acid amplification test (when performed) Factors Guiding Treatment Initiation

  13. When to Consider Treatment Initiation • Positive AFB smear • Treatment should not be delayed because of negative AFB smears if high clinical suspicion: • History of cough and weight loss • Characteristic findings on chest x-ray • Emmigration from a high-incidence country

  14. Baseline Diagnostic Examinations for TB • Chest x-ray • Sputum specimens (= 3 obtained 8-24 hours apart) for AFB microscopy and mycobacterial cultures • Routine drug-susceptibility testing for INH, RIF, and EMB on initial positive culture

  15. Other Examinations to Conduct When TB Treatment Is Initiated (1) • Counseling and testing for HIV infection • CD4+ T-lymphocyte count for HIV-positive persons • Hepatitis B and C serologic tests, if risks present

  16. Other Examinations to Conduct When TB Treatment Is Initiated (2) • Measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, serum creatinine, and platelet count • Visual acuity and color vision tests (when EMB used)

  17. A. Preferred; should generally be offered B. Alternative; acceptable to offer C. Offer when preferred/alternative regimens cannot be given D. Should generally not be offered E. Should never be offered I.At least one properly randomized trial with clinical endpoints II.Clinical trials that either are not randomized or were conducted in other populations III.Expert opinion IDSA/USPHS* Rating System for Treatment Recommendations Strength of the Recommendation Quality of Supporting Evidence *IDSA-Infectious Diseases Society of America; USPHS-U.S. Public Health Service

  18. Treatment Regimens • Four regimens recommended for treatment of culture-positive TB, with different options for dosing intervals in continuation phase • Initial phase: standard four drug regimens (INH, RIF, PZA, EMB), for 2 months, (except one regimen that excludes PZA) • Continuation phase: additional 4 months or (7 months for some patients)

  19. Why Extend Continuation-Phase Treatment for 3 Months? • Cavitary disease and positive sputum culture at 2 months associated with increased relapse in clinical trials • Extended continuation phase decreased relapses in silicotuberculosis (from 20% to 3%)

  20. When to Extend Continuation-Phase Treatment for 3 Months? • Cavitary pulmonary disease and positive sputum cultures at completion of initial phase • Initial phase excluded PZA • Once-weekly INH and rifapentine started in continuation phase and sputum specimen collected at the end of initial phase is culture positive • HIV-infected with positive 2-month sputum culture

  21. High clinical suspicion for active TB Algorithm to Guide Duration of Continuation-Phase Treatment for Culture-Positive TB Patients Place patient on initial-phase regimen: INH, RIF, EMB, PZA for 2 months Isspecimen collected at end of initial phase (2 months) culture positive? NO YES Give continuation-phase treatment of INH/RIF daily or twice weekly for 4 months

  22. Algorithm to Guide Duration of Continuation-Phase Treatment for Culture-Positive TB Patients (Continued) Wasthere cavitation on initial CXR? YES NO Is thepatient HIV positive? Give continuation-phase treatment of INH/RIF daily or twice weekly for 7 months NO YES Give continuation- phase treatment of INH/RIF daily or twice weekly for 4 months Give continuation- phase treatment of INH/RIF daily for 7 months

  23. Treatment of Culture-Positive TB (1) (Rated: AI in HIV-negative, AII in HIV-positive patients) Initial Phase 2 months - INH, RIF, PZA, EMB daily (56 doses, within 8 weeks) Continuation Phase • Options: • 4 months - INH, RIF daily (126 doses, within 18 weeks) • 4 months - INH, RIF twice / week (36 doses, within 18 weeks) • 7 months - INH, RIF daily (217 doses, within 31 weeks)* • 7 months - INH, RIF twice / week (62 doses, within 31 weeks)* * Continuation phase increased to 7 months if initial chest x-ray shows cavitation and specimen collected at end of initial phase (2 months) is culture positive

  24. Treatment of Culture-Positive TB (2) Twice-Weekly Options(Rated: AII for HIV-negative, BII for HIV-positive patients*) Initial Phase 0.5 months - INH, RIF, PZA, EMB daily (10-14 doses, within 2 weeks) THEN 1.5 months - INH, RIF, PZA, EMB twice / week (12 doses, within 6 weeks) Continuation Phase • Options: • 4 months - INH, RIF twice / week (36 doses, within 18 weeks) • 7 months - INH, RIF twice / week (62 doses, within 31 weeks) * Regimen rated BII for HIV-positive patients with CD4+ T-lymphocytes cell count >100/µl. Not recommended for those with CD4+ T-lymphocytes cell count < 100/µl

  25. Treatment of Culture-Positive TB (3) Thrice-Weekly Options(Rated: BI for HIV-negative, BII for HIV-positive patients) Initial Phase 2 months - INH, RIF, PZA, EMB 3 times / week (24 doses, within 8 weeks) Continuation Phase • Options: • 4 months - INH, RIF 3 times / week (54 doses, within 18 weeks) • 2) 7 months - INH, RIF 3 times / week (93 doses, within 31 weeks)

  26. Treatment of Culture-Positive TB (4) Regimens without Pyrazinamide(Rated: CI for HIV-negative, CII for HIV-positive patients) Initial Phase 2 months - INH, RIF, EMB daily (56 doses, within 8 weeks) Continuation Phase • Options: • 7 months - INH, RIF daily (217 doses, within 31 weeks) • 2) 7 months - INH, RIF twice / week (62 doses, within 31 weeks)* * Twice weekly dosing is not recommended for persons with CD4+ T-lymphocytes cell count < 100/µl

  27. Algorithm to Guide Rifapentine (RPT) Usein Continuation Phase Is the patient HIV positive? NO YES Not eligible for RPT Wasthere cavitation on initial CXR? NO YES Not eligible for RPT Wasthe sputum AFB smear positive at 2 months? NO YES Not eligible for RPT

  28. Give treatment of INH/RIF daily or twice weekly for 4 months Continue treatment until 4 months of INH/RPT completed Extend treatment with INH/RPT for total of 7 months Begin treatment with once-weekly INH/RPT Algorithm to Guide Rifapentine (RPT) Usein Continuation Phase (Continued) IsRPT considered for treatment? YES NO Isspecimen collected at endof initial phase (2 months) culture positive? YES NO

  29. Treatment of Culture-Positive TB Rifapentine in Continuation Phase (Rated: BI for HIV-negative*, EI for HIV-positive patients) Initial Phase • Options: • 2 months - INH, RIF, PZA, EMB daily (56 doses, within 8 weeks) • 0.5 months - INH, RIF, PZA, EMB daily (10-14 doses, within 2 weeks) • THEN1.5 months - INH, RIF, PZA, EMB twice / week (12 doses, within 6 weeks) Continuation Phase Options: 1) 4 months - INH, RPT once weekly (18 doses, within 18 weeks) 2) 7 months - INH, RPT once weekly (31 doses, within 31 weeks) * Regimen is limited to noncavitary disease in HIV-negative patients. Sputum must be smear negative at completion of 2 months of treatment

  30. Algorithm to Guide Treatment of Culture-Negative TB High clinical suspicion for active TB despite negative smears based on: • Abnormal chest x-ray • Clinical symptoms • No other diagnosis • Positive tuberculin skin test Patient placed on initial phase regimen: INH, RIF, EMB, PZA for 2 months

  31. Algorithm to Guide Treatment of Culture-Negative TB (Continued) Isinitial culture positive? NO YES Wastheresymptomaticor chest x-ray improvement after 2 months of treatment? Continue treatment for culture-positive TB NO YES • Discontinue treatment • Patient presumed to have LTBI • Treatment completed Give continuation- phase treatment of INH/RIF dailyor twice weekly for2 months

  32. Treatment of Culture-Negative TB* Initial Phase 2 months - INH, RIF, EMB, PZA daily (56 doses, within 8 weeks) Continuation Phase • Options: • 2 months - INH, RIF daily (56 doses, within 8 weeks) • 2) 2 months - INH, RIF twice / week (16 doses, within 8 weeks) * All cultures are negative, but evaluation at 2 months reveals clinical and chest x-ray response to antituberculosis drug therapy

  33. Treatment Monitoring (1) • Monthly sputum for AFB smear and culture (until 2 consecutive cultures negative) • Serial sputum smears every 2 weeks to assess early response • Additional drug-susceptibility tests if culture-positive after 3 months of treatment

  34. Treatment Monitoring (2) • Periodic (minimum monthly) evaluation to assess adherence and identify adverse reactions • Repeat chest x-ray: -At completion of initial treatment phase for patients with initial negative cultures -At end of treatment for patients with culture-negative TB -Generally not necessary for patients with culture positive TB

  35. Treatment Monitoring (3) • Renal function, AST, ALT, bilirubin, and platelet count if abnormalities at baseline • Visual acuity and color vision monthly if EMB used > 2 months or doses > 15-20 mg/kg

  36. Completion primarily defined by number of ingested doses within specified time frame Examples 1) 6-month daily regimen (7 days/wk) = at least 182 doses of INH and RIF, and 56 doses of PZA 2) 6-month daily regimen (5 days/wk) = at least 130 doses Determining Drug Completion (1)

  37. Determining Drug Completion (2) • Specified doses must be administered 1) Within 3 months for initial phase 2) Within 6 months for 4-month continuation phase $ Consider therapy interrupted if target doses not met within specified time period

  38. Management of Initial Phase Treatment Interruptions If lapse > 14 days, start from beginning If lapse < 14 days, continue treatment to complete total doses warranted (if can be completed within 3 months)

  39. Start over from the beginning Algorithm for Management of Treatment Interruptionsin the Initial Phase How long is the interruption? Is it < 14 days? NO YES Start over from the beginning Is the treatment completed within 3 months? NO YES Continue treatment to complete total doses warranted

  40. If received > 80% continuation-phase doses and: 1) sputum AFB smear negative on initial presentation, further therapy not necessary 2) sputum AFB smear positive on initial presentation, continue to complete full course Management of Continuation Phase Treatment Interruptions

  41. If received < 80% continuation-phase doses and: 1) lapse < 3 months duration, continue to complete full course (as long as all doses can be completed within 6 months) 2) lapse was 3 months or greater, then start initial phase 4-drug regimen from the beginning Management of Continuation Phase Treatment Interruptions

  42. Algorithm for Management of Continuation Phase Treatment Interruptions What is the total percentage of doses completed? Is it <80%? NO YES -Additional treatment may not be necessary if sputum was AFB smear negative at baseline -If sputum smear was positive, continue treatment to complete planned total number of doses warranted Is theduration of interruption <3 months? YES NO Continue treatment; if not completed in6 months, start initial phase 4-drug regimen from beginning Start initial phase 4-drug regimen from beginning

  43. Common Adverse Reactions to Drug Treatment (1)

  44. Common Adverse Reactions to Drug Treatment (2)

  45. Common Adverse Reactions to Drug Treatment (3)

  46. Drug Interactions • Relatively few drug interactions substantially change concentrations of antituberculosis drugs • Antituberculosis drugs sometimes change concentrations of other drugs -Rifamycins can decrease serum concentrations of many drugs, (e.g., most of the HIV-1 protease inhibitors), to subtherapeutic levels -Isoniazid increases concentrations of some drugs (e.g., phenytoin) to toxic levels

  47. Relapse (1) • A patient’s cultures become and remain negative while receiving antituberculosis drugs, but at some point after completion of therapy: • patient develops culture-positive TB disease again, or 2) patient experiences clinical or radiographic deterioration consistent with active TB disease • Most relapses occur within the first 12 months after completion of therapy

  48. Relapse (2) • Patients with cavitation on initial chest radiograph and a positive culture at completion of 2 months of therapy are at increased risk of relapse with standard 6-month regimens • Patients with relapse are at increased risk for acquired drug resistance, especially if the therapy was not directly observed

  49. Treatment Failure • Defined as positive cultures after 4 months of treatment in patients for whom medication ingestion was ensured • Single new drug should never be added to a failing regimen; it may lead to acquired resistance to the added drug • Add at least three new drugs (e.g., fluoroquinolone, ethionamide, and an injectable drug: SM, amikacin, kanamycin, or capreomycin) to the existing regimen being cognizant of the possibility of drug resistance

  50. Drug Resistance (1) • Established only by drug-susceptibility testing • Treatment of TB caused by drug-resistant organisms should be done in close consultation with an expert • Patients not on DOT in the past or who had irregular treatment are at risk of drug resistance

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