Treatment of Tuberculosis: New Cases

1. Interim Draft Module 6A - July 2008 Treatment of Tuberculosis: New Cases

2. Project Partners • Collaborative project Funded by the United States Agency for International Development (USAID)

3. Module Overview • Essential anti-TB drugs • Standard Category I regimens (new cases) • Management of smear-negative suspect case • Treatment of TB in special populations • Pregnancy • Liver disorders • Renal disease International Standards 7, 8 & 10

4. Learning Objectives At the end of this presentation, participants will be able to: • Describe the drug regimens used in the initial treatment phase of both new pulmonary and extrapulmonary tuberculosis (EPTB) • Describe next step if sputum remains smear- positive at the end of 2nd month of Category I treatment • Identify treatment and management approaches in TB patients with co-morbid conditions

5. Lines and Regimens Defined • First-Line Therapy • Category I regimen for new patients • Category II regimen for re-treatment patients • Suspicion of resistance to one anti-TB drug • Second-Line Therapy • For patients with resistant TB to more than one drug • Poly-drug and multi-drug resistance

6. First Line Anti-Tuberculosis Drugs • Isoniazid (INH, H) • Rifampicin (RIF, R) • Pyrazinamide (PZA, Z) • Ethambutol (EMB, E) • Streptomycin (SM, S) Plus Pyridoxine

7. Standards for Treatment

8. Standard 7: Public Health Effects of Treatment Any practitioner treating a patient for tuberculosis is assuming an important public health responsibility. To fulfill this responsibility, the practitioner must not only prescribe an appropriate regimen, but also be capable of assessing the adherence of the patient to the regimen and addressing poor adherence when it occurs. By so doing, the provider will be able to ensure adherence to the regimen until treatment is completed.

9. Effect of Treatment on Public Health Why is TB Treatment a Public Health Measure? • Providing the patient with an effective treatment that kills the organisms will rapidly reduce and ultimately eliminate 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.

10. Effect of Treatment on Public Health (2) 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

11. Standard 8: Initial Phase of Treatment All patients (including those with HIV infection) who have not been treated previouslyshould receive an internationally accepted first-line treatment regimen using drugs of known bioavailability. The initial phase should consist of two months of isoniazid, rifampicin, pyrazinamide and ethambutol.

12. Modern TB Chemotherapy • INH – kills rapidly growing organisms and dormant organisms • PZA – kills TB bacilli inside the macrophage and cavities • RIF and PZA kill slowly growing organisms • sterilizing activity • INH, RIF and EMB protect each other from development of resistance Coombs D et al. Ann Intern Med 1990;112:397-406

13. Standard 8: Initial Phase of Treatment • Ethambutol may be omitted in the initial phase of treatment for adults and children who: • have negative sputum smears • do not have extensive PTB or severe forms of EPTB disease, and • are known to be HIV negative.

14. Adequate TB treatment requires: • An appropriate combination of anti-TB medications to prevent resistance • Correctly prescribed dosage • Taken regularly by the patient • Treatment for a sufficient period of time to prevent relapse • All doses directly observed (DOT)  Never add a single drug to a failing regimen

15. 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

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

17. Initial Phase of Treatment 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)

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

19. Standard 8: Continuation Phase of Treatment • The preferred continuation phase consists of isoniazid and rifampicin given for four months. • Isoniazid and ethambutol given for six months is an acceptable continuation phase regimen that may be used when adherence cannot be assured, but is associated with a higher rate of failure and relapse, especially in patients with HIVinfection.

20. Treatment Recommendations 1. Streptomycin may be substituted for EMB. 2. Ethambutol may be omitted for adults and children who have negative sputum smears, do not have extensive pulmonary tuberculosis or severe forms of extra-pulmonary disease and who are HIV negative 3. Associated with higher rate of treatment failure and relapse; should generally not be used in patients with HIV infection.

21. Standard 8: Drug Formulations and Doses • The doses of antituberculosis drugs used should conform to international recommendations. • Fixed-dose combinations (FDC) of two (INH and RIF), three (INH, RIF and PZA), and four (INH, RIF, PZA, and EMB) drugs are highly recommended, especially when medication ingestion cannot be observed.

22. Adult Daily Dose of FDC Tabs

23. 12-15 Pills Per Day to Only 4-5 FDCs Image source: Jad Davenport Image source: Pierre Virot

24. Dose Recommendations mg/kg (range) *The recommended daily dose of ethambutol is higher in children (20 mg/kg) than in adults (15mg/kg), because the pharmacokinetics are different (peak serum ethambutol concentrations are lower in children than in adults receiving the same mg/kg dose)

25. 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

26. Standard 10 All patients should be monitored for response to therapy, best judged in patients with pulmonary TB by follow-up sputum microscopy (2 specimens): • at completion of the initial phase of treatment (2 months) • 5 months, and • at the end of treatment Patients who have positive smears during the 5th month of treatment should be considered as treatment failures and have therapy modified appropriately.

27. Required Monitoring – Category I • New sputum smear-positive patients should have sputum smear exam: • At the end of initial phase (month 2) • During continuation phase (month 5) • At the end of treatment  If sputum smear remains positive at the end of month 2: • Extend initial phase for additional month after which continuation phase may be initiated • Consider collection of sputum after end of 3rd month to evaluate for smear conversion

28. Case study 1

29. Case 1 • 29-year-old man • Presents with 2-3 years of cough, 2-3 months of night sweats, and 15 lb weight loss • HIV negative • Past Medical History: • TST + in 1991 Question: What would you do now?

30. TB Diagnostic Algorithm:HIV Negative or Low Prevalence Area All Pulmonary TB Suspects Sputum AFB Microscopy; Assess for HIV

31. Case 1 (2) • Three spontaneous sputum specimens were smear negative for AFB • Question:How would you manage this patient?

32. TB Diagnostic Algorithm:HIV Negative or Low Prevalence Area All Pulmonary TB Suspects Sputum AFB Microscopy Assess for HIV 2 or 3 smears + 2 or 3 smears - Only 1 smear + Rx: Non-anti TB antibiotics Repeat AFB • No improvement after 1 week Question:What would you do now? Yes TB

33. Case 1 (3) • A repeat sputum specimen was sent using sputum induction • Chest X-ray was also obtained • The sputum specimen was smear-positive • Question:What now?

34. Case 1 (4) • The patient is started on INH, rifampicin, ethambutol, and pyrazinamide • The sputum culture result returns positive for M. tuberculosis complex • A sputum specimen is obtained after 2 months of treatment and is smear-positive Question:What do we do now?

35. Case 1 (5) • Continue initial phase for 1 more month • Collect sputum prior to completion of month 3 then switch to continuation phase

36. Treatment of Extrapulmonary TB (EPTB)

37. Treatment of EPTB • In general, EPTB is treated the same as pulmonary tuberculosis • Streptomycin replaces EMB when treating CNS TB • Some experts recommend extending the duration of therapy in patients with: • Meningeal tuberculosis • Bone/joint tuberculosis • Corticosteroids may be useful in some forms of extrapulmonary tuberculosis

38. Treatment of EPTB (2) Treatment Duration and Use of Steroids

39. Treatment Special Situations

40. Treatment During Pregnancy • Risk to mother and fetus is far greater from untreated TB than from the drugs used to treat TB • Increased risk of spontaneous abortion • Increase in perinatal mortality • Small for gestational age births • Increased maternal morbidity • Congenital TB • Increased risk of perinatal and early post-natal transmission

41. Treatment During Pregnancy (2) • Isoniazid (INH), rifampicin and ethambutol are known to be safe for administration during pregnancy • There is insufficient data on the teratogenic effect of PZA • Supplement with pyridoxine 25mg/day • Streptomycin should be avoided • Monitor for signs of hepatotoxicity during pregnancy and immediate post-partem

42. Breastfeeding • Most of the TB medications are secreted into breast milk but not in significant concentrations (usually < 1-12% of levels measured in the serum) • Levels are not likely to lead to toxicity in the infant • Levels will not be sufficient to protect the infant – infant should receive IPT • Supplement mom with B6 while breastfeeding

43. TB Treatment and Liver Disease • Use standard short-course regimen for patients without clinical evidence of chronic liver disease but history of: • Hepatitis virus carriage • Acute hepatitis • Excessive alcohol consumption • Use a liver-sparing regimen for patients with established chronic liver disease • 2SHRE/6HR or 2SHE/10 HE

44. Hepatitis • Hepatitis (asymptomatic elevation AST/ALT occurs in 20% patients on 4 drugs) • Drug induced hepatitis =  AST or ALT 3 times upper limits of normal in the presence of symptoms OR  >5 times if asymptomatic • INH, PZA and RIF can all cause hepatotoxicity • Hepatitis from INH is age related, from PZA is dose related, and RIF is unpredictable and less common

45. TB Treatment and Hepatitis • If  3x normal with symptoms or >5x normal without symptoms: • stop all anti-TB medications and evaluate patient • refer patient to doctor for clinical evaluation • try to rule out other causes of acute liver disease • if severely ill, may start 3 non-hepatotoxic drugs • after AST <2 times upper limit of normal — rechallenge drugs one-by-one starting with drugs that are not hepatotoxic

46. The Renal Impaired TB Patient • Patients with end stage renal disease (ESRD) have increased risk for progression to active TB disease • Risk is 10 – 25 times greater for persons with ESRD than in the general population

47. The Renal Impaired TB Patient (2) • If CrCl <30ml/min., including hemodialysis patients, administer anti-TB treatment thrice weekly after dialysis at the following doses: • Isoniazid and rifampicin 10mg/kg • PZA 25-35mg/kg • EMB 15-25mg/kg • Include supplemental pyridoxine 25-50mg with the thrice weekly regimen to prevent peripheral neuropathy

48. Case study 2

49. Case 2, Part 1 • A 32-year-old man diagnosed with sputum smear-positive PTB is ready to begin TB treatment under your care. He has never been diagnosed or treated for TB before • He reports 4 weeks of a productive cough with fever, sweats and weight loss. He currently weighs 53 kg • Two sputum smears are positive on direct microscopy Q1:How do you classify this patient?

50. Case 2, Part 1 (2) Q2:What medications do you start with for the initial phase? Q3:How many pills per day does he take with FDCs according to his weight? Q4: Approximately how many pills per day does he take with traditional individual tablets?