TREATMENT of TB in ADULTS by Dr. Irfhan Ali Hyder Ali

LEARNING OBJECTIVES To update on treatment regimes & modalities for PTB & EPTB To present evidence-based updates to best suit TB management in Malaysia To emphasise on the importance of proper treatment

INTRODUCTION Important to provide a standardised TB regimen for all TB cases This section will cover all aspects of treatment: Pulmonary TB (PTB) New cases Relapse cases Extrapulmonary TB (EPTB) Standard regimes & duration

AIM OF TREATMENT Cure & reduce transmission Risk of developing TB is determined: infectiousness of index case smear positive PTB; PTB with cavities; laryngeal TB nature & duration of contact immune status of contact

EDUCATION Nature of disease Necessity of strict adherence with prolonged treatment Risks of defaulting treatment Side effects of medication Risks of transmission & need for respiratory hygiene as well as cough/sneeze etiquette

PULMONARY TUBERCULOSIS (PTB) IN ADULTS

NEW CASES 6-month regimen consisting of 2 months of EHRZ (2EHRZ) followed by 4 months of HR (4HR) is recommended for newly-diagnosed PTB.

RECOMMENDED ANTITB DRUGS RECOMMENDED DOSES Daily 3X a week Dose (range) in mg/kg body weight Maximum in mg Isoniazid (H) 5 (4 - 6) 300 10 (8 - 12) 900 Rifampicin (R) 600 Pyrazinamide (Z) 25 (20 - 30) 2000 35 (30 – 40)* 3000* Ethambutol (E) 15 (15 - 20) 1600 30 (25 – 35)* 2400* Streptomycin (S) 15 (12 - 18) 1000 15 (12 – 18)* 1500*

NEW CASES (cont.) Pyridoxine 10 - 50 mg daily needs to be added if isoniazid is prescribed. *Daily treatment is the preferred regimen. Adopted from WHO. Treatment of Tuberculosis Guidelines (4th Ed.), 2010

IMPORTANT POINTS Rifampicin should be used for the whole duration of treatment. NS difference in effectiveness & safety between rifampicin & other antibiotics in the rifamycin group. whenever possible, rifampicin dosage should not be lower than recommended dosage (10 - 12 mg/kg). Pyrazinamide beyond 2 months during the intensive phase does not confer further advantage if the organism is fully susceptible. Recurrence rate is low for both ethambutol-based regimen & for streptomycin-based regimen.

TREATMENT OF NEW CASES

PREVIOUSLY TREATED TB New cases who have taken treatment for more than one month & are currently smear or culture positive again (i.e. failure, relapse or return after default)

DEFINITION Previously treated Patient previously treated for TB including relapse, failure & default cases . Relapse A patient whose most recent treatment outcome was “cured” or “treatment completed”, & who is subsequently diagnosed with bacteriologically positive TB by sputum smear microscopy or culture. Treatment after failure A patient who has received Category I treatment for TB & in whom treatment has failed. Treatment after default A patient who returns to treatment, bacteriologically positive by sputum smear microscopy or culture, following interruption of treatment for 2 or more consecutive months.

PREVIOUSLY TREATED TB Recommend: retreatment regimen containing first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR-TB in these patients or if such data is not available. Drug sensitivity test (DST) must be done for patients. When results become available, drug regimen should be adjusted appropriately. *This is WHO statement, no retrievable evidence available.

TO START OR NOT? Interruption in intensive phase: If ≥14 days, to restart from beginning i.e. Day 1. If <14 days, to continue form last dose.

TO START OR NOT? Interruption in maintenance phase: If interruption occurs after patient receives 80% of total planned doses, treatment may be stopped if sputum AFB smear was negative at initial presentation. If sputum AFB smear was positive, treatment should be continued to achieve total number of doses. If total doses <80% & interruption lapse is ≥2 months, restart treatment from beginning. If total doses is <80% & interruption lapse is <2 months, continue treatment from date it stops to complete full course.

TREATMENT OF PREVIOUSLY TREATED TB

OPTIMAL DURATION Patients with sputum positive PTB should receive antiTB drugs for a minimum duration of 6 months. Regimens with shorter duration of rifampicin are associated with higher risk of failure, relapse & acquired drug resistance. Even in patients with non-cavitary disease & confirmed sputum culture, conversion at 2 months fares poorer with a 4-month regimen compared to 6-month regimen.

OPTIMAL DURATION

MAINTENANCE PHASE In new patients with PTB, WHO recommends daily dosing throughout the course of antiTB treatment. However, a daily intensive phase followed by thrice weekly maintenance phase is an option provided that each dose is directly observed & patient has improved clinically. A maintenance phase with twice weekly dosing is not recommended.

MAINTENANCE PHASE There is no difference in treatment failure, relapse & acquired drug resistance rates between daily & different intermittent dosing regimens in the maintenance phase.1, 2, 3 1Menzies D et al., PLoS Med, 2009 2Mwandumba HC et al., Cochrane, 2001 3Chang KC et al., Thorax, 2011

MAINTENANCE PHASE

FIXED-DOSE COMBINATION (FDC) IN MALAYSIA Forecox-Trac Film Coated Tab: isoniazid, rifampicin, ethambutol & pyrazinamide Rimactazid 300 Sugar Coated Tab: isoniazid, & rifampicin Rimcure 3-FDC Film Coated Tab: isoniazid, rifampicin & pyrazinamide Akurit-Z Tab: isoniazid, rifampin (rifampicin) & pyrazinamide Akurit Tab: isoniazid & rifampin (rifampicin) Akurit-Z Kid Dispersible Tab: isoniazid, rifampin (rifampicin) & pyrazinamide Akurit-4: ethambutol, isoniazid, rifampin (rifampicin) & pyrazinamide

FDC IN MOH 4-Drug combination: isoniazid 75 mg, rifampicin 150 mg, pyrazinamide 400 mg & ethambutol 275 mg tablet 3-Drug combination: isoniazid 75 mg, rifampicin 150 mg & pyrazinamide 400 mg tablet

RECOMMENDED DOSES 30 - 37 kg body weight: 2 tablets daily More than 70 kg body weight: 5 tablets daily

EFFECTIVENESS FDCs compared to separate-drug regimens significantly reduce risk of non-compliance by 17% & consequently improve effectiveness of therapy.1 In term of bioavailability, FDCs are proven to be bioequivalent to separate-drugs formulations at the same dose levels.2 1Bangalore S et al., Am J Med, 2007 2Agrawal S et al., Int J Pharm, 2002

OTHER ADVANTAGES Smaller number of tablets to be ingested may also encourage patient adherence. Prescription errors are likely to be less frequent for FDCs due to easy adjustment of dosage according to patient weight.

FDC

DIRECTLY OBSERVED THERAPY (DOT) Direct observation of drug ingestion of the DOTS component should not be the sole emphasis in TB control programmes. It should not be a blanket approach; instead it should be a process of negotiation & support, incorporating patients’ characteristics & choices.

DIRECTLY OBSERVED THERAPY (DOT) Enhanced DOTS involving intensive contact tracing & treating the contacts with TB can reduce incidence of TB within a community (p=0.04).1 1Cavalcante SC et al., Int J Tuberc & Lung Dis. 2010

DOT

EXTRAPULMONARY TUBERCULOSIS (EPTB) IN ADULTS

DURATION OF EPTB TREATMENT - NICE RECOMMENDATION1 • Meningeal TB – 2 months S/EHRZ+10HR* • Peripheral lymph node TB – should normally be stopped after 6 months • Bone & joint TB – 6 months • Pericardial TB – 6 months 1National Collaborating Centre for Chronic Conditions and the Centre for Clinical Practice. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. 2011

DURATION OF EPTB TREATMENT - WHO RECOMMENDATION1 Regimen should contain 6 months of rifampicin: 2HRZE/4HR* Duration of treatment for TB meningitis is 9 - 12 months &, bone & joint TB is 9 months 1World Health Organization. Treatment of tuberculosis Guidelines. Fourth ed. 2010

MILIARY & DISSEMINATED TB There is no retrievable evidence on optimal duration of treatment for disseminated TB & miliary TB. There should be low threshold to suspect TB meningitis in these groups of patients & treatment duration should be prolonged between 9 to 12 months.

OPTIMAL DURATION OF EPTB TREATMENT

CORTICOSTEROIDS IN EPTB Corticosteroid therapy may benefit patients with some forms of EPTB. However literature on corticosteroids in various form of EPTB is scant.

CORTICOSTEROIDS IN EPTB TREATMENT

TB MENINGITIS Severity Regime Grade I disease Week 1: IV dexamethasone sodium phosphate 0.3 mg/kg/day Week 2: 0.2 mg/kg/day Week 3: Oral dexamethasone 0.1 mg/kg/day Week 4: Oral dexamethasone a total of 3 mg/day, decreasing by 1 mg each week Grade II & III disease Week 1: IV dexamethasone sodium phosphate 0.4 mg/kg/day Week 2: 0.3 mg/kg/day Week 3: 0.2 mg/kg/day Week 4: 0.1 mg/kg/day, then oral dexamethasone for 4 weeks, decreasing by 1 mg each week Prasad K et al., Cochrane, 2008

TB PERICARDITIS

SURGERY IN PTB Diagnosis & obtaining tissue for culture & drug sensitivity Management of TB complications Treatment of the disease itself where drug therapy alone may be deemed insufficient to achieve cure

SURGERY IN PTB While the advancement in surgical techniques including video-assisted thoracoscopy surgery/thoracotomy has reduced the surgical mortality & morbidity, surgery for PTB is still associated with significant complications due to the presence of adhesions & scarring.

MAIN CHANGES IN CPG TB 2012 Evidence-based Treatment after interruption explained in more detail Treatment regimes (maintenance) changed to daily or 3X a week FDCs mentioned DOTS covered in more detail & done to suit Malaysian context Duration of treatment for EPTB more concise Use of steroids recommended for TB meningitis & pericarditis

TAKE HOME MESSAGES Adhere to standard regime Use correct doses & adequate duration Ensure compliance Treatment needs to be individualised Consult a doctor/physician with experience in TB management when in doubt

THANK YOU irf7399@yahoo.com