Treatment of Tuberculosis: Retreatment

1. Interim Draft Module 6B - July 2008 Treatment of Tuberculosis:Retreatment

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

3. Module Overview • Identifying drug resistance • Selecting Category II regimen • Monitoring required for patients on a Category II regimen International Standard 14

4. Learning Objectives At the end of this presentation, participants will be able to: • Describe the development of drug resistance • Determine candidates for and manage patients on a Category II regimen • Identify when to perform sputum culture and sensitivity tests and whom to refer for second-line treatment

5. Standard 14: Drug-Resistant TB • An assessment of the likelihood of drug resistance should be obtained for all patients and is based on: • history of prior treatment, • exposure to a possible source case having drug-resistant organisms, and • the community prevalence of drug resistance • Patients who fail treatment and chronic cases should always be assessed for possible drug resistance • For patients in whom drug resistance is considered to be likely, culture and drug-susceptibility testing for isoniazid, rifampicin, and ethambutol should be performed promptly

6. Drug-Resistant TB: Definitions • Mono-resistant:In-vitro resistance to a single first-line anti-tuberculosis drug • Poly-resistant:In-vitro resistance to more than one drug, but not the combination of isoniazid and rifampicin

7. Drug-Resistant TB: Definitions (2) • Primary drug-resistance: “New Cases” Drug resistance in a patient who has never been treated for tuberculosis or received less than one month of therapy • Secondary (acquired) drug-resistance: “Previously Treated Cases” Drug resistance in a patient who has received at least one month of anti-TB therapy

8. Impact of Resistance on Outcome % of cases with failure or death, standard 4-drug regimen Espinal MA, et al. JAMA. 2000;283(19):2537-45

9. Pathogenesis of Drug Resistance

10. INH = 1 in 106 RIF = 1 in 108 EMB = 1 in 106 Strep = 1 in 106 INH + RIF = 1 in 1014 Frequency of Resistance Mutations

11. Development of Drug Resistance Multiple Drugs vs. Monotherapy 1 2 3 I = INH resistant, R = RIF resistant, P = PZA resistant

12. Development of Drug Resistance (2) Further acquired resistance after single drug added I = INH resistant, R = RIF resistant, P = PZA resistant

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

14. Factors that Lead to Drug Resistance Causes of inadequate treatment: • Patient-related factors • Healthcare provider-related factors • Healthcare system-related factors

15. Factors that Lead to Drug Resistance Patient-related factors: • Non-adherence, default • Malabsorption of drugs • Adverse drug reactions • Lack of information, transportation, money • Social barriers to treatment adherence • Substance dependency disorders

16. Factors that Lead to Drug Resistance Healthcare provider-related factors: • Inadequate initial treatment regimen: Wrong combination or doses, guideline noncompliance • Treatment “in the dark” for retreatment cases: no drug susceptibility testing available, or results delayed • Clinical errors: Adding a single drug to a failing regimen • Lack of proper monitoring • Lack of proper provider awareness

17. Factors that Lead to Drug Resistance Healthcare programme-related factors: • Unavailability of drugs (stock-outs or delivery disruptions) • Poor drug quality, poor storage conditions • Poorly organized or under-funded TB-control programmes • Inappropriate or no guidelines • Lack of appropriate or timely laboratory testing

18. Overcoming Drug Resistance • Mono-resistance is the most common • Isoniazid alone • Streptomycin alone • Category I regimen will cure S resistant TB and may cure INH resistant TB • For extra assurance, we use Category II when INH resistance is possible or suspected

19. Introduction to Category II Regimen • For persons who may have infection with a tuberculosis strain resistant to one drug • Adds a fifth drug, streptomycin, to the other first-line medications • Prolongs treatment to 8 months total • Requires two months of injections (given 5 days/week), impacting on choices of DOT

20. Category II Regimen Eligibility • Previously treated sputum smear-positive • Return after default (category I or II regimen) • Relapse after completion of category I or II regimen • Recurrent tuberculosis (smear-negative) • Treatment failure on category I regimen (caution – treatment failures are at increased risk for MDR-TB)

21. Recurrent TB Treatment • A patient who clinically seems to have relapsed but has negative smear or culture • If patient did not complete prior Category I treatment: • Restart Category I treatment • If recurrent TB diagnosed after completion of Category I regimen:  Start Category II regimen

22. Treatment Failure - Category I • Treatment failure on category I regimen (smear-positive) • Sputum specimen that is smear-positive after 5 months treatment should also be sent for culture and repeat drug susceptibility testing • Caution must be taken when initiating category II regimen for treatment failure of category I case (adds a single drug, streptomycin, to the failing regimen)

23. Category II Regimen • 2 months initial phase: 5 drugs daily • HRZES (streptomycin injection given 5 days/week) • 1 month initial phase: 4 drugs daily (all oral) • HRZE • 5 months continuation phase: 3 drugs daily • HRE

24. Adult Daily Dose of Streptomycin

25. Child’s Daily Dose of Streptomycin WHO. Treatment of Tuberculosis: Guidelines for National Programmes, 2003.

26. Monitoring: Initial Phase • Send 2 sputum samples for AFB smear and culture plus DST prior to treatment start • Month 1&2: 4 oral drugs (HRZE) daily plus streptomycin IM 5 days/week • Send 2 sputum smears at week 10* • If smears are negative, can move into continuation phase after completion of third month • Month 3: HRZE daily; optional = HRZE 3 x weekly *If initially smear negative, not necessary to perform routine follow-up sputum smears

27. Monitoring: Initial Phase (2)  If sputum smear remains positive at the end of month 3: • Extend initial phase with 4 drugs for an additional month, and • Collect and send sputum specimens for smear exam again at end of 4th month • Move to continuation phase after completion of month 4

28. Monitoring: Continuation Phase • Sputum smear and culture exam: • At the end of month 5 • At the end of treatment (month 8) • Total treatment duration for Category II patient is 8 months

29. Treatment Outcome: Category II • Cured • Adhered with 8 months of treatment • Clinically improved • Sputum smears negative at 5 and 7 months

30. Treatment Outcome: Category II (2) • Treatment completed • Adhered with 8 months of treatment • Clinically improved • Cannot fulfill criteria for cure because • Initially smear negative pulmonary TB • Cannot produce sputum so does not have negative smears on follow-up • Extra-pulmonary TB

31. Treatment Outcome: Category II (3) • Treatment failure • Smear positive at months 5 or 7  Obtain culture and drug susceptibilities • Treatment interrupter • Missed <2 months • Treatment defaulter • Missed ≥2 months

32. Culture and Sensitivity Tests • Performed for category II regimen patients: • All patients at the beginning of therapy • If smear positive during month 3 • If smear positive at 5 or 7 months • Take appropriate action for • Negative culture • MTB culture, drug susceptible: category I regimen • MTB culture, single drug resistant: category II regimen • MTB culture, resistant HR, HE, RE: go to 2nd line • MOTT: treat as appropriate

33. Case Study Activity

34. Summary Category II regimen is effective for patients with single drug resistance Category II regimen: Has specific indications Requires more intensive sputum monitoring Category II regimen poses more challenges to adherence: 2 months daily injections Longer initial phase 8 month total therapy DOT throughout treatment course is recommended

35. Summary: ISTC Standard Covered* Standard 14: Assessment for drug resistance should be obtained based on a history of: • Prior treatment • Exposure to a possible drug-resistant source • High community prevalence • Treatment failure or chronic disease If suspicion for drug-resistance, obtain culture and drug-susceptibility testing promptly. *[Abbreviated version]