Unit 11: Drug Resistance and MDR-TB

1. Unit 11: Drug Resistance and MDR-TB Botswana National Tuberculosis Programme Manual Training for Medical Officers

2. Objectives At the end of this unit, participants will be able to: • Describe the development of drug resistance • Select and manage patients with mono-, multi- and poly-drug resistant TB • Identify when to perform sputum culture and sensitivity tests and whom to refer for subsequent categories of treatment

3. Drug Resistance Definitions Drug Resistance: isolates of M. tuberculosis resistant to 1 or more anti-TB drugs Primary Resistance Any patient with resistance and <1 month of ATT Often contacts of drug resistant patients infected with DR strain Acquired Resistance Development of in vitro resistance to anti-TB drugs during TB therapy

4. Types of Resistance • Confirmed mono-resistance: resistance to one first line drug • Confirmed poly-resistance: resistance to two or more first line drugs, but not both isoniazid and rifampicin • Confirmed multi-drug resistant TB (MDR-TB): resistance to at least both isoniazid and rifampicin

5. Multi-Drug Resistant (MDR) TB Resistance to both isoniazid and rifampicin Loss of 2 most powerful TB drugs Disastrous for patient and community Category IV regimens Less effective Longer duration More side-effects Much more expensive +++ Lower chances of cure

6. MDR in Botswana In 2005, MDR made up: 0.8% of new cases, 10.0% of retreatment cases In 1999, MDR made up: 0.5% of new cases and 9.0% of retreatment cases Sources: Talbot E, et al., 2003 (1999) Decosas J, et al., 2005 (2005)

7. XDR-TB:Extensively Drug Resistant TB Tuberculosis resistant to: INH & rifampicin + A fluoroquinolone (ciprofloxacin, ofloxacin) + One or more of the second line injectable ATT drugs: kanamycin OR amikacin OR capreomycin

8. XDR-TB in South Africa Study in 2006, Kwazulu-Natal: • 544 TB patients suspected to have resistance; 221 had MDR-TB • 53 of the 221 (24%) met criteria for XDR-TB • 44 of the 53 were tested for HIV • All were positive; 15 on ARVs • 52 of 53 patients died within 25 days of suspecting resistance– suggests high virulence Source: The Lancet, 2006.

9. Risk Factors for Resistance (1) Any patient with prior history of TB: • Failure of first-line regimen • Failure of re-treatment regimen and chronic TB cases • Patients who remain sputum smear-positive at two or three months of short course chemotherapy • Patients who revert from smear-negative to smear-positive at the end of the intensive phase

10. Risk Factors for Resistance (2) Exposure to a known MDR-TB case Poor adherence, malabsorption Cavitary disease (high burden of organisms) Inadequate treatment regimen Administering fewer than the recommended number of drugs (e.g., INH/RIF only during intensive phase)

11. Suspected Drug Resistance When treatment is unsuccessful Relapse Treatment failure Return after default If patient is a contact of a patient with known resistance Patient is a suspect while waiting for results

12. Confirmed Drug Resistance Confirmed by culture and drug sensitivity testing (C/DST) Culture takes approximately 28-42 days; DST an additional 28-42 Culture and DST are indicated for ALL patients with suspected drug resistance MDR-TB is a laboratory diagnosis All patients started on Category II regimen must have culture and DST obtained

13. Confirmed MDR-TB All patients with confirmed MDR should be referred for initiation and follow-up to: North: Nyangabgwe Referral Hospital, Francistown South: Princess Marina Hospital, Gaborone

14. Development of Drug Resistance (1) Two steps: Mutation and Selection • Mutation • Mutations conferring drug resistance occur in individual organisms at a very low rate • With high numbers of organisms (lung cavity) small populations resistant to each drug will exist

15. Development of Drug Resistance (2) • Selection • Organisms with resistant mutations to a particular drug will have an advantage over susceptible organisms when all are exposed to that drug • The resistant organisms can outgrow the susceptible organisms

16. Spontaneous Mutations to Anti-Tuberculosis Medications Ethambutol and pyrazinamide: 1 in every 100,000 cell divisions Isoniazid and streptomycin: 1 in every 1,000,000 cell divisions Rifampicin: 1 in every 100,000,000 cell divisions Spontaneous development of MDR-TB bacilli is extremely rare: 1 in every 100,000,000,000,000 (1014) cell divisions The product of the two probabilities of isoniazid and rifampicin mutation

17. Development of Drug Resistance (3) INH RIF Spontaneous drug-resistant mutations in bacterial population PZA Selection of INH-resistant bacterial population INH

18. Development of Drug Resistance (4) Additional spontaneous mutations INH INH RIF Selection and establishment of MDR

19. Pathogenesis of Secondary Drug Resistance Weeks of Rx: 0 16 24 INH RIF EMB Meanwhile, in the lab: Culture + + + INH R R R RIF S R R EMB S S R

20. Common Forms of Cross-Resistance • All rifamycins • Low-level INH resistance and ethionamide • Ethionamide and prothionamide • Amikacin and kanamycin • Fluoroquinolones (cipro and oflox– some next generation FQL, such as Lfx and Mfx, may retain activity) • Do not use drugs for which resistance crosses over

21. Prevention of Drug Resistance • Provide high enough concentrations of drugs to kill susceptible organisms • Use drug combinations that are able to kill the small numbers of organisms resistant to one or another of the drugs • Potent regimen (bactericidal, R and H) • Multi-drug therapy for drugs to protect each other from acquiring resistance • Correct prescription, standardised regimens • Adherence

22. Diagnosing MDR-TB Diagnosed through culture and DST of specimens, usually sputum, from TB patients Obtain drug susceptibility testing for TB patients that have risk factors for MDR-TB Chronic TB cases are especially at risk of having MDR-TB

23. Pre-treatment Evaluation and Care for MDR-TB Patients • Initial labs include: • HIV test, sputum smear microscopy, culture & DST, pregnancy test • Baseline renal, thyroid, and liver function tests • Care can be hospital-based, clinic-based, or community-based, but MUST have uninterrupted quality drug supply • Care should be given through multidisciplinary team of providers

24. Treating Mono- and Poly-resistant TB Needs to be managed by a specialist

25. Category IV Drug Groups (1) Group I: first-line oral drugs H,R,E,Z Group II: injectable agents strep, amikacin, kanamycin, capreomycin Group III: fluoroquinolones Cfx, Ofx, Lfx, Mfx

26. Category IV Drug Groups (2) Group IV: oral bacteriostatic second-line drugs ethionamide, prothionamide, cycloserine, terizidone, PAS, thiacetazone Group V: third-line agents with unclear efficacy clofazimine, amox/clav, linezolid

27. Basic Principles of Individualised (Category IV) Regimen Eliminate drugs that are not safe in the patient • Ethionamide in pregnancy • Cycloserine in someone with serious mental health problems • Injectable in pregnancy • Severe allergy

28. Designing a Treatment Strategy Treatment strategy dependant on several factors including: National drug resistance surveys Availability of drugs Prevalence of drug resistance Previous second-line drug exposure ALWAYS submit sputum for culture and sensitivity testing if drug resistance suspected!

29. Standardised MDR Treatment Regimens (1) • A standardised Category IV treatment regimen has been developed for Botswana • Uses 5 initial drugs to cover most patterns of resistance with at least 4 effective drugs • First-line (H,R,E,S) results should be available • An injectable agent and a fluoroquinolone (FQL) are the core of the regimen

30. Continuation Phase (min. 18 months) Ethionamide Ciprofloxacin PZA Ethambutol (if DST sensitive) Cycloserine (if resistant to ethambutol) Intensive Phase (min. 6 months) Amikacin Ethionamide PZA Ciprofloxacin Ethambutol (if DST show strain is sensitive) Cycloserine (if DST show strain is resistant to Ethambutol) Standardised MDRTreatment Regimens (2)

31. Building an MDR Treatment Regimen Include drugs from Groups 1-4 in a hierarchical order based on potency Step 1: use any first-line drug still susceptible Step 2: add an injectable agent Step 3: add a fluoroquinolone Step 4: use the remaining group IV drugs to make a regimen with at least 4 effective drugs “More is better than less”

32. Duration of Treatment Injectable agent: minimum of 6 months Total treatment: 18 months after culture conversion Some patients with extensive disease and extensive prior treatment may be treated for 24 months

33. Monitoring During Treatment (1)

34. Monitoring During Treatment (2)

35. Interim Outcome Measures (1) Culture conversion: defined as two consecutive negative cultures taken at least 30 days apart in patients with initially culture-positive TB Smear conversion: Two negative specimens at least 30 days apart With or without baseline culture

36. Interim Outcome Measures (2) Time to sputum conversion Interval between start of treatment and date of obtaining first negative specimen Record separately for smear and culture on MDR patient treatment card Average time to culture conversion = 2 months

37. Special Situations (1) Fertile women Avoid pregnancy: use injectable medroxy-progesterone (Depo-Provera) and/or condoms Pregnancy Postpone second line until delivery if it is safe Due to potential drug toxicity Cycloserine may be safer than ethionamide

38. Special Situations (2) • Breast-feeding • If possible, smear + mothers should avoid contact with their babies until they are smear negative • Treatment of mother outweighs risks of toxicity to baby • If safe and sustainable, artificial feeding would avoid risk of infant toxicity • Children • Can use needed second-line agents • Ciprofloxacin, ethionamide, cycloserine and amikacin successfully used • Monitor weight at each visit and adjust doses as needed

39. Common Side Effects (1) G.I. complaints Ethionamide Cycloserine PAS Quinolones Clofazimine Rifabutin Hepatotoxicity (early symptoms are anorexia and malaise, then abd pain, vomiting, jaundice) Isoniazid Rifampicin Ethionamide Pyrazinamide PAS Fluoroquinolones

40. Common Side Effects (2) • Behavioral changes • Cycloserine • Ethionamide • Isoniazid • Quinolones • Hearing loss, vestibular toxicity • Aminoglycoside • Capreomycin • Hypothyroidism • Ethionamide • PAS • Visual changes • Ethambutol • Rifabutin • Isoniazid • Linezolid • Hypokalemia, hypomagnesemia • Aminoglycosides • Capreomycin • Rash • All

41. Common Side Effects (3) • Bone Marrow Suppression • Rifampicin • Isoniazid • Linezolid • Peripheral neuropathy • Isoniazid • Ethionamide • Cycloserine • Linezolid • Seizures • Isoniazid • Cycloserine • Fluorquinolones • Headache • Fluroquinolones • Isoniazid • Cycloserine • Ethionamide • Ethambutol

42. Monitor for Efficacy Evidence of improvement Conversion of sputum smear and culture to negative Culture conversion approximately 2 months Culture conversion is not the same as a cure Patients may initially convert and later revert to culture positive status Chest X-ray may be unchanged or only show slight improvement

43. Outcome Measures • Cure • Treatment Completed • Death • Treatment default • Treatment failure • Transfer out

44. Extensively Drug Resistant (XDR) TB Also referred to as eXtremely Drug Resistant TB in the past Term coined in early 2006 following a joint survey by WHO and CDC Survey analysed data collected between 2000-2004; findings: XDR-TB in all regions of the world 4% of MDR-TB cases in US and 19% in Latvia met criteria for XDR-TB Source: WHO, 2008.

45. XDR-TB – Anti-TB Drugs XDR-TB virtually untreatable currently Global Alliance for Drug Development In clinical development: Moxifloxacin (INH sub.), Nitroimidazole PA-824 In Discovery phase: Nitroimidazole Analogs Mycobacterial Gyrase Inhibitors InhA Inhibitors Pleuromutlinis Linezolid Source: Global Alliance for TB Drug Development, 2007.

46. XDR-TB:What Can We Do Meanwhile? • Strengthen basic TB care, manage simple TB • Prompt diagnosis and treatment of drug resistant cases to prevent further transmission • Send sputums for DST for 2nd line medicines • Increase collaboration between HIV and TB control programmes • Retreatment cases • Prevent transmission in the health care settings

47. Global Response to MDR-TB & XDR-TB in 2007 Strengthen basic activities to control TB and HIV/AIDS Scale-up programmatic management Strengthen laboratory services Expand surveillance Foster infection control measures Strengthen ACSM Resource mobilization Promote research and development Source: WHO, 2007.

48. Key Points It is better to prevent than to treat drug resistance and MDR Standarised MDR treatment regimen should be used whenever possible Side effects of MDR treatment are frequent but manageable Important to monitor closely for treatment efficacy and toxicity