Managing Drug-Resistant Tuberculosis: Diagnosis and Treatment Strategies

1. Interim Draft Module 10 - September 2008 Chronic and Multi-drug Resistant (MDR) TB

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

3. Module Overview • Background • Identifying drug resistance • Management principles • Treatment principles • Second-line anti-TB drugs International Standard 15

4. Learning Objectives At the end of this presentation, participants will be able to: • Recognize the clinical errors and programmatic factors that can lead to the development of drug resistance • Recognize the signs of treatment failure that should trigger an evaluation for drug resistance and treatment adjustment • State several MDR-TB treatment and management principles

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

6. Drug-Resistant TB: Definitions • Multidrug-resistant (MDR): In-vitro resistance to at least isoniazid and rifampicin • Extensively drug-resistant (XDR): MDR plus resistance to fluoroquinolones and at least 1 of the 3 second-line injectable drugs (amikacin, kanamycin, capreomycin)

7. Estimated Global MDR Cases Estimated global incidence and proportion of MDR among TB cases, 2004 Zignol M, et al. JID 2006; 194: 479-85

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

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

10. 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

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

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

13. Strategies to Prevent MDR

14. Diagnosis of MDR-TB

15. 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)

16. Clinical Suspicion for MDR-TB Recognition of risk factors: • History of prior therapy (most powerful predictor) • History of nonadherence, 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)

17. Clinical Suspicion forMDR-TB (2) 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

18. 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

19. Drug-Susceptibility Test Limitations • Identification of MDR may take 4–8 weeks, and second-line drug sensitivity testing 6–12 weeks for results: • 2–4 weeks for initial culture to become positive • Additional 2–4 weeks to get 1st-line susceptibilities • Additional 2–4+ weeks (sent to CDC) to get 2nd-line susceptibilities 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

20. Drug-Susceptibility Test Limitations (2) • 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

21. Predicting Patterns of Resistance • Examine prior treatment regimen and 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 • 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

22. Summary: Diagnosing MDR-TB • 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 • Recognize when your patient is failing standard treatment • Obtain first- line drug susceptibility testing whenever possible for patients with suspected MDR

23. Treatment of Chronic & MDR-TB

24. Standard 15: Management of Drug-Resistant TB Patients with tuberculosis caused by drug-resistant (especially MDR) organisms should be treated with specialized regimens containing second-line anti-tuberculosis drugs At least 4 drugs to which the organisms are known or presumed to be susceptible should be used, and treatment should be given for at least 18 months Patient-centered measures are required to ensure adherence Consultation with a provider experienced in treatment of patients with MDR-tuberculosis should be obtained

25. Multidrug-Resistant TB “I have been treated several times over the past five years and I’m still coughing and can’t gain weight!”

26. Treatment Strategies Three approaches to treatment: Standardized regimens Empiric regimens Individualized treatment regimens (Ideal, but resources must be considered) WHO/HTM/TB/2006.361

27. Treatment Strategies (2) Standardized treatment: All patients in patient category/group receive same regimen Standardized treatment followed by individualized treatment: Initially all receive same treatment then adjust when individual DST results are available Empirical treatment followed by individualized treatment: Individually designed based on history of TB treatment and then adjusted when DST results available

28. Anti-tuberculosis Drug Groups Group 1 – First-line drugs: isoniazid, rifampicin, ethambutol, pyrazinamide Group 2 - Injectable agents: streptomycin, kanamycin, amikacin, capreomycin Group 3 - Fluoroquinolones: ofloxacin, levofloxacin, moxifloxacin Group 4 - Oral bacteriostatic agents: ethionamide, cycloserine, para-aminosalicylic acid (PAS), sodium PAS, (protionamide, terizidone, thioacetazone) Group 5 – Agents with unclear role in drug-resistant treatment: clarithromycin, clofazimine, high-dose INH, Amoxicillin/clavulanate, imipenem/cilastatin, linezolid

29. Designing the Treatment Regimen General Principles, WHO Use of at least four drugs highly likely to be effective Do not use drugs for which there is cross-resistance Eliminate drugs that are unsafe for the patient. Include drugs from groups 1-5 in a hierarchical order based on potency Be prepared to prevent, monitor and manage adverse effects from the drugs selected

30. Treatment Principles Use direct observation of treatment (DOT) Use daily, not intermittent, administration Treatment duration of a minimum of 18-24 months When possible, continue injectable for at least six months post-culture conversion Continue at least three oral drugs for full treatment duration

31. Potential Effectiveness: WHO • Effectiveness is supported by a number of factors: • Demonstrated susceptibility • No history of treatment failure with the drug • No contacts with resistance to the drug • Resistance rare in similar patients (surveys) • Drug is not commonly used in the area If at least 4 drugs are not certain to be effective, use 5 to 7 drugs, depending on specific drugs and degree of certainty

32. Cross-Resistance: WHO All rifamycins: high level cross-resistance Fluoroquinolones: variable, but probably should be assumed to be cross-resistant Amikacin and kanamycin: generally highly cross-resistant, but both should be tested Capreomycin and aminoglycosides: occasional cross-resistance, susceptibilities should be tested

33. Drug Contraindications: WHO Known severe drug allergy Unmanageable drug intolerance Risk of severe toxicity, with symptoms such as renal failure, hepatitis, hearing loss, depression, and psychosis Drugs of unknown quality (lack of quality assurance exposes patient to risks with unknown benefits)

34. Standardized Treatment Regimens Intensive Phase (minimum 6 months) Amikacin Ethionamide PZA Levofloxacin (Ethambutol) Continuation Phase (minimum 12 months) Ethionamide Levofloxacin PZA (Ethambutol) Use ethambutol in both phases of treatment if strains are still susceptible.

35. Empiric Regimens for MDR-TB

36. Ensure laboratory services for hematology, biochemistry and audiometry are available Establish a clinical and laboratory baseline before starting the regimen Initiate treatment gradually when using drugs that cause gastro-intestinal intolerance Ensure availability of ancillary drugs to manage adverse effects Use DOT for all doses Initiating Treatment: WHO

37. Management Principles Isolate until three consecutive sputum AFB smears are negative and there has been a good clinical response to treatment Initiate MDR-TB treatment in hospital if possible to provide patient education and monitoring and to treat drug toxicity Tailor toxicity monitoring to specific drugs employed Seek consultation with an expert as soon as drug resistance is known

38. Management Principles (2) Use daily patient-centered DOT throughout entire treatment course Record drugs given, bacteriological results, chest radiographic findings, and the occurrence of toxicities Optimize management of underlying medical conditions and nutritional status

39. More than watching patients swallow their pills… DOT is a support system that enables the completion of the long, difficult course of MDR-TB treatment A patient requires respect and dignity regardless of social class, educational level or unhealthy behaviors The whole patient, lifestyle and support system are assessed and routinely addressed in the delivery of care Goal: Inspire and empower patient via a relationship of trust and support Patient-centered DOT

40. Directly Observed Treatment Effect on Resistance and Relapse * P < 0.001 Weis SE, et al. NEJM 1994; 330(17): 1179-84

41. Monitoring Collect sputum specimens for smear and culture periodically during treatment once culture negative Obtain end-of-treatment sputum specimen for smear and culture Perform chest radiograph periodically during treatment and at end of treatment Resources permitting, monitor minimum of two years following treatment (quarterly during first year, every six months during second year)

42. As soon as isolate is known to be resistant to isoniazid and rifampicin, order second-line drug susceptibility testing Repeat susceptibility testing on cultures that remain positive after two–three months of treatment Laboratory Testing

43. Common Adverse Effects

44. Common Adverse Effects (2)

45. Common Adverse Effects (3)

46. Summary Treatment of MDR-TB is complex and costly. It is much easier to prevent than to treat Expert consultation should be obtained when MDR-TB is suspected Patients can be treated with a standardized or an empiric regimen Ideally the regimen should be guided by drug-susceptibilities

47. Summary (2) Considerable attention must be paid to treatment supervision and support A patient-centered approach to DOT is an important element of successful care Adverse effects of second-line drugs are common and may be severe. Monitoring for these effects is essential!

48. Summary: ISTC Standard Covered* Standard 15: Patients with MDR-TB should be treated with specialized regimens containing second-line anti-TB drugs. • At least 4 drugs to which isolate is known or presumed susceptible should be used • Treat > 18 months • Patient-centered measures are required to ensure adherence Consultation with a provider experienced in treatment of patients with MDR-TB should occur *[Abbreviated version]

49. 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.ucsf.edu The PIH guide to the Medical Management of Multidrug-Resistant Tuberculosis, International Edition. Partners in Health 2003 www.pih.org