Unit 7: Treatment of TB

1. Unit 7: Treatment of TB Botswana National Tuberculosis Programme Manual Training for Medical Officers

2. Objectives At the end of this unit, participants will be able to: Explain the principles of TB treatment Use the category regimens appropriately Properly monitor treatment, follow-up, and end of treatment Discuss side effects of drugs and their management

3. Admission Policy Admit patients who present with the following: TB meningitis and miliary TB, until ambulatory Danger signs (e.g., respiratory distress, temperature of 39º C or more, inability to walk unaided) Spinal TB Severe adverse events (e.g. hepatitis) Observe strict infection control and isolation procedures

4. Aims of TB Treatment Cure the patient of TB Prevent death from active TB or its latent effects Prevent relapse of TB Prevent the development of acquired resistance Prevent transmission of TB to others

5. Importance of Follow-up Retrospective analysis in 1997 in Gaborone with 127 patients: 11.8% had treatment delay 10.2% had incomplete workup (one smear performed) & were not registered 4.5% had 2 or more positive smears and were not registered for treatment Source: Creek T, et al., Int J Tuberc Lung Dis, 2000.

6. Treatment Regimens Category I regimen for new patients Category II regimen for re-treatment patients Category III regimen for children with less severe cases of TB Category IV for chronic and MDR-TB cases

7. First-Line Anti-TB Drugs (1)

8. First-Line Anti-TB Drugs (2)

9. Mode of Action: Special Population Hypothesis High Continuous Growth INH (RMP, SM) PZA RMP Speed of bacterial growth In Acid environment Spurts Of Metabolism Dormant Low Source: Mitchison DA, Tubercle, 1985.

10. The Action of Anti-tuberculosis Drugs

11. Modern TB Chemotherapy (1) INH – kills rapidly growing organisms (early bactericidal activity) INH and RMP protect each other from development of resistance Rifampicin and pyrazinamide kill slowly growing organisms Sterilising activity Source: Combs D et al., Ann Intern Med., 1990.

12. History of TB Treatment TB Drug Development Milestones 1944 | Streptomycin 1949 | P-Aminosalicylic Acid 1952 | Isoniazid 1954 | Pyrazinamide 1955 | Cycloserine 1962 | Ethambutol 1963 | Rifampicin Courtesy of: Global Alliance for TB Drug Development, 2007.

13. History of TB Treatment in Botswana • S= streptomycin • T= thiacetazone • H= isoniazid • R= rifampicin • Z= pyrazinamide • E=ethambutol • 1975-1986: 2STH/16TH • 1986-1993: 2SHRZ/4HR • 1993-present: 2HRZE/4HR

14. Modern TB Chemotherapy (2) British Thoracic Society No. 2; 1982 Initial 2 months HRZE Continuation 4 months HR 97% cure rate US Public Health Service No. 21; 1990 Initial 2 months HRZ+/-E Continuation 4 months HR 97% cure rate Source: Iseman, MD. A Clinician’s Guide to Tuberculosis. 2000. British Thoracic Society, 1982.

15. Category I Regimen Initial Phase Normally two months 4 drugs: 2HRZE Isoniazid (H) Rifampicin (R) Pyrazinamide (Z) Ethambutol (E) Daily and observed Continuation Phase Normally four months 2 drugs: 4HR Isoniazid (H) Rifampicin (R) Daily and observed

16. Category I Regimen Eligibility New Patients Sputum smear + PTB Sputum smear – PTB Extra-pulmonary TB TB Meningitis: streptomycin substitutes for ethambutol Streptomycin should not be used if pregnant

17. Category I:Adult Daily Dose of Single Drugs Source: BNTP, 2007.

18. FDC: Fixed DoseCombination Tabs (1) Courtesy of: STOP TB Partnership

19. FDC: Fixed Dose Combination Tabs (2) • Fixed Dose Combination pills include two, three or even four drugs in one pill • Advantages of FDCs • Reduces the number of pills patients must take • Minimises errors in dosing • Simplifies distribution of pills to patients • Simplifies monitoring adherence

20. Category I:Adult Daily Dose FDCs

21. Treatment Follow-up • Patients should be assessed monthly during treatment (more frequently, if needed) • Symptoms: cough, weight loss, fever, adverse effects • Adherence: review the treatment card • Adverse events: enquire about any side effects • Weight measurement: adjust dosages to account for any weight change • Sputum smear: obtain at 2 and at 5-6 months

22. The Role of CXR in Follow-Up • There is no need for routine CXR in follow-up of PTB patients • CXR can be useful for the follow-up of some EPTB patients (e.g., pleural effusion) • Treatment decisions in PTB (switching to continuation phase, ending treatment) should generally be based upon sputum smear exams at stated intervals and clinical monitoring

23. Monitoring Treatment Response Important to tuberculosis control Allows assessment of Infectivity of a patient Response to treatment Outcome of treatment Assessed through clinical, laboratory and radiological methods Relies primarily on sputum conversion X-rays are not part of routine follow-up of TB cases in Botswana

24. Category I: End of 2 Months of Treatment

25. Category I: 5-6 Months of Treatment

26. Introduction to Category II Regimen Adds a fifth drug, streptomycin, to the other first-line medications Prolongs treatment to 8 months in total Initiated and managed by the same clinicians and nurses as category I Requires two months of injections (given daily)

27. Category II Regimen Children • Intensive phase • 2 months SHRZ • 1 month HRZ • Continuation phase • 5 months HR Adults • Intensive phase • 2 months SHRZE • 1 month HRZE • Continuation phase • 5 months HRE Courtesy of: WHO, 2008.

28. Category II Regimen Eligibility For smear-positive or culture-positive retreatment cases after Relapse Default Treatment failure

29. Category II:Adult Daily Dose of Single Drugs Source: BNTP, 2007.

30. Category II:Adult Daily Dose FDCs Source: BNTP, 2007.

31. Category II Regimen: Pregnancy Streptomycin should be avoided in pregnancy if possible Due to possible foetal ear damage and nephrotoxicity Women of childbearing age should have a pregnancy test prior to starting category II If not pregnant, advise contraception

32. Category II: End of 3 Months of Retreatment AFB positive AFB negative Repeat sputum for culture and drug sensitivity testing Continue with remaining four drugs for one month Repeat smear at the end of four months Proceed with continuation phase as planned Positive result at the end of four months Start patient on continuation phase Repeat smear at five months Positive results indicate failure of treatment Conduct sputum smear microscopy at the end of three months of retreatment

33. Category II: End of 8 months of Treatment

34. Treating Mono- and Poly-resistant TB

35. Category III Regimen This is the recommended regimen for most children with TB in Botswana Intensive phase 2 months HRZ Continuation phase 4 months HR

36. Category IV Regimen and Eligibility Specially-designed standardised or individualised regimens are recommended For all patients who remain or become smear positive after completing a fully supervised retreatment regimen For chronic and MDR-TB cases Second line TB drugs include amikacin, ethionamide, ciprofloxacin and first line drugs with continued activity against M. tuberculosis

37. Treatment of Severe Forms of TB Prolong the continuation phase to 6 months for the following sites of disease: Tuberculous meningitis* TB percardiditis Disseminated TB Spinal disease with neurologic complications *For tuberculous meningitis: substitute streptomycin for ethambutol during the initial phase of treatment Source: Basquoz N, 2007.

38. Treatment of Severe TB: Adjuvant Corticosteroid Indications: TB meningitis, TB pericarditis, Massive lymphadenopathy with airway obstruction Recommended dose: usually prednisolone TB meningitis: 2mg/kg/day up to 60mg/day for 4 weeks, then taper over several weeks TB pericarditis: 2mg/kg/day up to 60mg/day for 4 weeks, then 30mg/day for 4 weeks, then taper over several weeks In patients that cannot tolerate oral medication, IV dexamethasone is recommended

39. Side Effects Each TB medication has potential side effects and drug interactions Patients should be educated on particulars of potential side effects Courtesy of: Virot P, Lung Health Image Library, 2004.

40. Clinical Monitoring for Toxicity Symptoms Nausea Vomiting Right upper quadrant pain Burning in feet Change in vision Joint pain Dizziness Signs Fever Rash Jaundice Pallor Other signs of anaemia Confusion, psychosis Seizures

41. Paradoxical Reactions Apparent clinical worsening of TB on appropriate therapy Caused by an immunologic reaction to TB as patient improves Common with TB adenitis Also occurs with brain tuberculomas and other manifestations Monitor for bacteriologic relapse/failure Continue TB treatment Steroid therapy may be helpful for severe paradoxical reaction, after excluding TB treatment failure and other etiologies of apparent clinical worsening

42. Common Adverse Drug Reactions (1)

43. Common Adverse Drug Reactions (2)

44. Common Adverse Drug Reactions (3)

45. Shared Side Effects of TB and ARV Therapy

46. Managing Minor Side Effects Loss of appetite, nausea, abdominal pain Provide anti-emetics such as promethazine or metoclopromide Check liver function tests or ALT, especially if symptoms persist Joint pains Aspirin or Non-Steroidal Anti-Inflammatory Drugs (NSAID) Peripheral Neuropathy Give pyridoxine 100-200 mg daily until symptoms disappear and then decrease to preventive dose Orange/red urine Reassurance Source: WHO, 2004.

47. Managing Major Side Effects Severe rash Stop all drugs; see Unit 8 Jaundice, vomiting and abdominal pain, confusion Stop all drugs; see Unit 8 Visual changes Stop ethambutol and revise treatment Generalised reaction, shock, purpura Stop all drugs until stable

48. Serial Drug Challenge When symptoms of a major side effect have subsided, wait two weeks Reintroduce TB medicines as described in Table 6.7 in the Botswana National Tuberculosis Programme Manual

49. Schedule for Reintroduction of Anti-TB Drugs

50. Drug Interactions • With many patients on ARVs also taking ATT, quite common for drug levels to be altered to some degree • Antituberculosis drugs sometimes change concentrations of other drugs • Rifampicin 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