Drug-Resistant Tuberculosis

1. Drug-Resistant Tuberculosis Your name Institution/organization Meeting Date International Standard 14

2. Drug-Resistant Tuberculosis Objectives: At the end of this presentation, participants will be able to: • Define the areas with the highest global burden of MDR. • Understand the microbiological basis for the development of drug resistance. • Recognize the clinical errors and programmatic factors that can lead to the development of drug resistance. • Recognize the risk factors for MDR and the signs of treatment failure that should trigger an evaluation for drug resistance and treatment adjustment.

3. Drug-Resistant Tuberculosis Overview: • Definitions • Global burden and individual impact • Pathogenesis and clinical/programmatic contributors to development • Early identification and risk factors • Recommendations for diagnosis International Standard 14

4. Drug-Resistant Tuberculosis MDR-TB is a manmade problem…It is costly, deadly, debilitating and is a major threat to our current control strategies.

5. Standard 14: Drug-Resistant TB • An assessment of the likelihood of drug resistance, based on • history of prior treatment, • exposure to a possible source case having drug-resistant organisms, • and the community prevalence of drug resistance, should be obtained for all patients. • 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: Resistance to a single drug • Poly-resistant: Resistance to more than one drug, but not the combination of isoniazid and rifampicin • Multidrug-resistant (MDR): Resistance to at least isoniazid and rifampicin • Extensively drug-resistant (XDR): MDR plus resistance to fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin)

7. Drug-Resistant TB: Definitions • 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. Estimated Global MDR Cases Estimated global incidence and proportion of MDR among TB cases, 2006 *175 countries reporting; **185 countries reporting WHO Anti-tuberculosis drug resistance in the world, Fourth global report, 2008

9. Estimated Global MDR Cases • Estimated global prevalence of MDR (based on 2-3 year duration as an active case): 1,000,000 –1,500,000 cases • Estimated 42% of global MDR cases have had prior treatment • China and India carry 50% of the global MDR burden, with the Russian Federation carrying a further 7% WHO Anti-tuberculosis drug resistance in the world, Fourth global report, 2008

10. Distribution of MDR: No prior treatment Distribution of MDR rates among new cases (previously untreated) Zignol M, et al. JID 2006; 194: 479-85

11. Distribution of MDR: Prior Treatment Distribution of MDR rates among previously treated cases Zignol M, et al. JID 2006; 194: 479-85

12. Individual Impact of MDR • Average direct medical costs per case in the US: $27,752 [Burgos, et al. CID 2005; 40: 968-75] • Long treatment duration (18-24 mos.), often difficult and toxic • Long periods of isolation may be necessary • Depression is common • Disease may be incurable (chronic) • Higher rate of death

13. 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

14. Pathogenesis of Drug Resistance

15. 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

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

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

18. Development of Drug Resistance Mixed population (susceptible and resistant) INH-resistant bacilli Emergence of INH-resistant strain because of ineffective treatment (INH monotherapy) Effective multi-drug therapy 0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 0 2 2 2 4 Weeks

19. Resistance: Unintended Monotherapy * Results not known to clinician

20. Resistance: Unintended Acquired * Results not known to clinician

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

22. 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

23. 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

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

25. Strategies to Prevent MDR

26. Diagnosis of MDR-TB

27. Diagnosis of MDR-TB Appropriate diagnosis and timely treatment intervention for MDR-TB is facilitated by: • Recognition of risk factors for MDR-TB • Early recognition of treatment failure • Drug-susceptibility testing (if available)

28. Clinical Suspicion for MDR-TB Recognition of risk factors: • History of prior therapy (most powerful predictor) • History of non-adherence, default • Residence in an MDR-endemic area • Exposure to known or suspected MDR-TB case (“incurable” TB or TB requiring multiple treatment courses) • HIV infection (in some settings)

29. Clinical Suspicion forMDR-TB Early recognition of treatment failure: • Cough should improve within the first two weeks of effective treatment • Signs of failure: lack of sputum conversion, persistent or recurrent cough, continued fever, night sweats and failure to gain weight

30. Laboratory Diagnosis of MDR Drug-susceptibility testing, if available, should be ordered when: • Risk factors for MDR are present • There is evidence of treatment failure Results can both: • Confirm diagnosis of drug resistance • Guide treatment choices

31. Drug-Susceptibility Results: Problems Identification of MDR may take 4 – 8 weeks, and second-line drug testing 6 – 12 weeks for results: • 2 – 4 weeks for initial culture to become positive • Additional 2 – 4 weeks to get 1st-line DST • Additional 2 – 4 weeks to get 2nd-line DST  In view of this inherent delay, don’t wait to treat with an augmented regimen if MDR suspicion is high and resistance pattern can be predicted.

32. Drug-Susceptibility Results: Problems • Drug-susceptibility testing requires training and experience • Quality assurance is difficult • Testing is unreliable for some drugs, especially ethambutol and pyrazinamide • Results will sometimes differ in different laboratories

33. Predicting Patterns of Resistance • Examine prior treatment regimen: Consider all drugs used previously as potentially ineffective Example: A symptomatic patient with 2 prior treatment courses using red capsules, white pills and shots Predict: Resistance to INH, RIF, and streptomycin

34. Predicting Patterns of Resistance • If there has been contact to a known MDR case, use pattern of drug resistance in index case • Use epidemiologic information determined from surveys to identify patterns and rates of resistance • Presence of RIF resistance predicts MDR

35. Drug-Resistant Tuberculosis Summary: • Early suspicion, diagnosis and appropriate treatment is critical in preventing further progression and transmission of drug-resistant disease • Prior treatment is the most significant predictor for drug resistance, but learn to recognize all risk factors

36. Drug-Resistant Tuberculosis Summary (cont.): • Recognize when your patient is failing standard treatment • Obtain first- line drug susceptibility testing whenever possible for patients with suspected MDR

37. 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]

38. Alternate Slides

39. Resources • WHO: Guidelines for the programmatic management of drug-resistant tuberculosis www.who.int/tb • Drug-Resistant Tuberculosis, A Survival Guide for Clinicians www.nationaltbcenter.edu • The PIH guide to the Medical Management of Multidrug-Resistant Tuberculosis, International Edition. Partners in Health 2003. www.pih.org

40. Purpose of ISTC

41. ISTC: Key Points • 17 Standards • 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

42. 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

43. Questions

44. Drug-resistant Tuberculosis 1.A 68 year-old man presents with cough and weight loss for 2 months. He recalls treatment for TB eight years ago, but believes it only lasted a few months. A chest film reveals a cavitary infiltrate in the right apex of the lung. Factors that predict or are associated with a risk for the development of drug-resistance would include all of the following except: Prior inadequate TB treatment Development of chronic diarrhea with possible malabsorption of drugs New diagnosis of diabetes Persistent cough and weight loss after two months of standard therapy

45. Drug-resistant Tuberculosis 2.Extensively-drug resistant (XDR) TB is defined as TB that is resistant to: At least six anti-tuberculosis drugs At least isoniazid and rifampicin Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, and a fluoroquinolone Isoniazid, rifampicin, a fluoroquinolone, and at least one of these three injectable agents (amikacin, kanamycin, capreomycin)

46. Drug-resistant Tuberculosis 3.Which of the following statements regarding the microbiologic pathogenesis of drug-resistant tuberculosis is most correct? Patients with cavitary tuberculosis have a low bacillary load and therefore are unlikely to harbor any naturally occurring drug-resistant organisms Mono-therapy with a single anti-tuberculosis drug can lead to selective proliferation of naturally occurring drug-resistant organisms Acquired resistance to anti-tuberculosis drugs only occurs for isoniazid and rifampicin In a patient on a standard initial four-drug treatment regimen with evidence for clinical failure in whom there is a high suspicion for drug resistance, the addition of a fluoroquinolone alone will reduce the risk for further development of drug resistance