Initial Treatment of Tuberculosis

1. Initial Treatment of Tuberculosis Your name Institution/organization Meeting Date International Standards 7, 8, 10, 13, 17, 21

2. Initial Treatment of Tuberculosis Objectives: At the end of this presentation, participants will have an understanding of: • Drug regimens used in the initial treatment of both pulmonary and extrapulmonary tuberculosis • The basis for the public health benefits of treating tuberculosis • The clinical and microbiological effects of treatment • The rationale for patient monitoring and reporting • The main adverse effects of antituberculosis drugs

3. Initial Treatment of Tuberculosis Overview: • Effect of appropriate treatment on public health • First-line treatment recommendations • Treatment of extrapulmonary tuberculosis • Monitoring of treatment • Adverse reactions • Recording and reporting International Standards 7, 8, 10, 13, 17, and 21

4. Standards for Treatment

5. Initial Treatment of Tuberculosis Standards 7 & 8

6. Standard 7: Public Health Responsibility Any practitioner treating a patient for tuberculosis is assuming an important public health responsibility to prevent ongoing transmission of the infection and the development of drug resistance. To fulfill this responsibility the practitioner must not only prescribe an appropriate regimen, but also utilize local public health services and other agencies, when necessary, to assess the adherence of the patient and to address poor adherence when it occurs.

7. Effect of Treatment on Public Health Why is TB Treatment a Public Health Measure? • Effective treatment rapidly kills organisms, reducing the bacillary population in respiratory secretions, thus reducing the potential for transmission. • Effective multiple-drug treatment greatly reduces the risk of resistant organisms emerging. • Effective treatment decreases the duration and severity of illness and reduces the risk of death.

8. Effect of Treatment on Public Health Effects of Treatment on the Incidence of Tuberculosis in Peru 220 DOTS 1990 200 case finding 180 Pulmonary TB cases/100,000 160 140 PTB falling at 6%/yr 120 100 2000 1980 1985 1990 1995

9. Standard 8: Initiation of Treatment (1 of 2) All patients (including those with HIV infection) who have not been treated previously should receive an internationally accepted first-line treatment regimen using drugs of known bioavailability. The initial phase should consist of two months of isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB).

10. Effect of Treatment on Bacillary Population Mixed population (susceptible and resistant) INH resistant bacilli Emergence of INH resistant strain because of ineffective treatment (INH monotherapy) Log cfu Effective multi-drug therapy 0 2 4 6 8 10 12 14 16 18 20 22 24 Weeks

11. Unintended Monotherapy and Resistance * Results not known to clinician

12. Treatment Goals Microbiological Goals of Antituberculosis Chemotherapy • Kill tubercle bacilli rapidly (early bactericidal effect) • Prevent the emergence of drug resistance • Eliminate persistent bacilli to prevent relapse (sterilizing effect)

13. Activities of Antituberculosis Drugs Highest ++++ High +++ Intermediate ++ Low +

14. Standard 8: Continuation of Treatment The continuation phase should consist of isoniazid and rifampicin given for four months The doses of antituberculosis drugs used should conform to international recommendations (2 of 2) • Fixed-dose combinations (FDCs) of two (INH and RIF), three (INH, RIF, and PZA), and four (INH, RIF, PZA, and EMB) drugs are highly recommended

15. Treatment Recommendations 1. Associated with higher rate of acquired drug resistance and must be given using directly-observed therapy. Where feasible, daily dosing is preferred. May consider daily initiation phase, then 3x week continuation phase. 3x weekly dosing not recommended if living with HIV or living in an HIV-prevalent setting.

16. Dose Recommendations Adults: mg/kg (range)

17. Standard 17: Treat Co-morbid Disease (1 of 2) • All providers should conduct a thorough assessment for co-morbid conditions that could affect tuberculosis treatment response or outcome • At the time the treatment plan is developed, the provider should identify additional services that would support an optimal outcome for each patient and incorporate these services into an individualized plan of care

18. Standard 17: Treat Co-morbid Disease (2 of 2) This plan should include assessment of and referrals for treatment of other illnesses with particular attention to those known to affect treatment outcome, for instance care for diabetes mellitus, drug and alcoholtreatment programs, tobacco smoking cessation programs, and other psychosocial support services, or to such services as antenatal or well baby care

19. Treatment of Extrapulmonary TB

20. Treatment of Extrapulmonary TB • In general, extrapulmonary tuberculosis is treated the same as pulmonary tuberculosis • Some experts recommend extending the duration of therapy in patients with: • Meningeal tuberculosis • Bone/joint tuberculosis • Corticosteroids may be useful adjunctive treatment in some forms of extrapulmonary tuberculosis

21. Treatment of Extrapulmonary TB Treatment Duration and Use of Steroids

22. Monitoring Treatment for TB and Public Health Reporting Standards 10, 13, & 21

23. Standard 10: Monitoring Treatment (1 of 2) Response to therapy in patients with pulmonary tuberculosis should be monitored by follow-up sputum smear microscopy (2 specimens) at the time of completion of the initial phase of treatment (2 months). If the sputum smear is positive at completion of the initial phase, sputum smears should be examined again at 3 months and, if possible, culture and drug susceptibility testing should be performed. 1 of 2

24. Standard 10: Monitoring Treatment (2 of 2) In patients with extrapulmonary TB and in children, the response to treatment is best assessed clinically. 2 of 2

25. Monitoring: Timing of Sputum Specimens Initial Phase Continuation Phase Isoniazid Rifampicin Pyrazinamide Ethambutol Months 0 1 2 3 4 5 6 Assessment for failure Diagnostic End of intensive phase Completion [*Obtain if smear-positive at month 2]

26. Treatment Outcomes for Pulmonary TB 1.2% 50% 10% 98% 64% Dead Sputum negative 32% Sputum positive 20% 18% 0.8% No Chemotherapy Poor Chemotherapy Good Chemotherapy Grzybowski S et al, Bull Int Union Tuberc1978; (53)2: 70-5

27. Monitoring: Adverse Reactions • Drugs are listed in order of relative likelihood of causing adverse reaction. • INH/RIF and RIF/PZA appear to have synergistic effects in causing hepatitis

28. Adverse Reactions: Rash Classic drug-related rash Severe skin rash from thioacetazone

29. Drug-induced Hepatotoxicity Hepatotoxic reactions: • Transaminase elevation age-dependent with INH • Transaminase elevation dose-dependent with PZA • Cholestasis (increase in bilirubin and alkaline phosphatase) with RIF • Symptoms imply significant hepatotoxicity • (Mild transaminase elevation may not be clinically significant)

30. Managing Hepatotoxicity Management • Hold all medications and follow liver enzymes for significant hepatotoxicity • Re-challenge depends on circumstances and severity of liver dysfunction • In general, patients should be restarted with EMB (the least hepatotoxic drug) and RIF, usually followed in several days by INH if there is no worsening of liver function

31. Standard 13: Monitoring Record A written record of all medications given, bacteriologic response, and adverse reactions should be maintained for all patients

32. Standard 21: Reporting Cases All providers must report both new and retreatment tuberculosis cases and their treatment outcomes to local public health authorities, in conformance with applicable legal requirements and policies. ISTC Training Modules 2008

33. Initial Treatment of Tuberculosis Summary: • Appropriate treatment and assessment of adherence to treatment is an important public health issue. • The use of internationally accepted first-line treatment regimens is associated with a high cure rate and a low risk of acquired drug resistance.

34. Initial Treatment of Tuberculosis Summary (cont.): • Pulmonary and extrapulmonary TB are generally treated with the same regimens. (Exception: extended duration in meningeal and bone/joint disease.) • Treatment includes assessment and services for co-morbid conditions that may effect tuberculosis treatment outcomes • Monitoring for both response to treatment and for potential adverse events is essential.

35. Summary: ISTC Standards Covered* Standard 7: Practitioners assume an important public health responsibility in ensuring both appropriate treatment regimens and assessment of treatment adherence for their patients. * Abbreviated versions

36. Summary: ISTC Standards Covered* Standard 8: All patients (including those with HIV infection) who have not been previously treated should receive an internationally accepted treatment regimen of known bioavailability: • Initial phase: 2 months INH, RIF, PZA, and EMB • Continuation phase: 4 months INH and RIF The doses of anti-TB drugs used should conform to international recommendations. Fixed-dose combinations are highly recommended. * Abbreviated versions

37. Summary: ISTC Standards Covered* Standard 10: Response to therapy in patients with pulmonary TB should be monitored by follow-up 2 sputum smears at the end of the initial phase, and if positive, repeated at the end of 3 months (if positive at 3 months, obtain culture and DST). In extrapulmonary TB and in children, the response to treatment is best assessed clinically. * Abbreviated versions

38. Summary: ISTC Standards Covered* Standard 13: A written record of all medications given, bacteriologic responses, and adverse reactions should be maintained for all patients. Standard 17: All providers should conduct a thorough assessment and provide services or referrals for co-morbid conditions with particular attention to those known to effect treatment outcome * Abbreviated versions

39. Summary: ISTC Standards Covered* Standard 21: All providers must report both new and retreatment TB cases and their treatment outcomes to local public health authorities * Abbreviated versions

40. Alternate Slides

41. Purpose of ISTC

42. ISTC: Key Points • 21 Standards (revised/renumbered in 2009) • Differ from existing guidelines:standards present what should be done, whereas, guidelines describe how the action is to be accomplished • Evidence-based, living document • Developed in tandem with Patients’ Charter for Tuberculosis Care • Handbook for using the International Standards for Tuberculosis Care

43. ISTC: Key Points • Audience: all health care practitioners, public and private • Scope:diagnosis, treatment, and public health responsibilities; intended to complement local and national guidelines • Rationale:sound tuberculosis control requires the effective engagement of all providers in providing high quality care and in collaborating with TB control programs

44. Questions

45. Initial Treatment of Tuberculosis 1.A 28 year-old woman taking standard four-drug treatment for TB for five weeks now complains of nausea, vomiting, and right upper-quadrant discomfort. When seen in clinic she is noted to have scleral icterus and right upper-quadrant tenderness. Her urine is dark colored. What is the appropriate action to take at this time? Stop all drugs Stop isoniazid Give pyridoxine (vitamin B6) Replace pyrazinamide with streptomycin

46. Initial Treatment of Tuberculosis 2.A 68 year-old woman with smear-positive TB needs to start treatment. She lives too far to be given directly-observed treatment (DOT) by your office. Which treatment regimen is preferred for this patient? Isoniazid and ethambutol for twelve months Isoniazid/rifampicin/ethambutol for the first two months, followed by isoniazid/rifampicin for an additional four months Fixed-dose combination of isoniazid/rifampicin/pyrazinamide for nine months Fixed-dose combinations of isoniazid/rifampicin/ethambutol/pyrazinamide for the first two months, followed by isoniazid/rifampicin for an additional four months

47. Initial Treatment of Tuberculosis 3.In considering treatment for extrapulmonary disease, all of the following statements are correct except: Extrapulmonary disease is a sign of disseminated disease, and therefore always requires a longer duration of treatment Most presentations of extrapulmonary TB can be treated with the same standard six month regimens used for pulmonary TB Extending the duration of therapy is recommended by many experts for central nervous system (CNS) and bone/joint extrapulmonary TB Corticosteroids are sometimes recommended for pericardial and central nervous system (CNS) extrapulmonary TB