TREATMENT of TB in ADULTS

Jamalul Azizi Bin Abdul Rahaman

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INTRODUCTION
Tuberculosis (TB) remains an important disease both globally & in Malaysia

Number of TB cases in the country continues to increase unabated

High rates of morbidity & mortality due to:

Delayed presentation Advanced HIV
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RATIONALE FOR CPG

TB issues in Malaysia
A common disease Affects many organs in the body Managed by doctors at all levels
Primary care General medicine Subspecialty

Lack of standardisation in TB management

Inaccurate diagnosis Inappropriate empirical treatment
There is a need to standardise TB management to minimise the risk of multidrug-resistant (MDR) TB

OBJECTIVES OF CPG
To assist clinicians & other healthcare providers in making evidence-based decisions about appropriate management of TB specifically on:
screening diagnosis treatment follow-up prevention referral
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SCOPE OF CPG
Epidemiology & High Risk Groups Investigations Treatment of TB in Adults LTBI in Adults TB in Children TB in Pregnancy, Lactation & Use of Oral Contraceptive Pills Liver & Renal Impairment HIV Infection Follow-up & Adverse Drug Events MDR-TB Prevention Referral Criteria Implementing the Guidelines
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TARGET POPULATION
Patients with TB
Adults Paediatrics

Types of TB
Pulmonary (PTB) Extrapulmonary (EPTB)

Co-morbidity e.g. HIV

Confirmed, suspected & latent TB

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TARGET USERS
Healthcare professionals & relevant stakeholders in all healthcare settings including
Doctors Pharmacists Allied health professionals Medical students & trainees Tuberculosis programme managers Patients & carers/non-governmental organisations
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3rd Edition CPG vs 2nd Edition CPG

(2012)

(2002)

Evidence-based Systematic review approach Expansion of chapters e.g.:- Lab. investigations EPTB TB in Children HIV MDR-TB Appendices (inc. Drug Table) New chapters e.g.:- LTBI Referral criteria Peer review (external reviewers) Quick Reference

Consensus-based

43 RECOMMENDATIONS

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TB LABORATORY INVESTIGATIONS

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INTRODUCTION Diagnosis of TB is based on the detection of acid fast bacilli (AFB) on smears & culture of Mycobacterium tuberculosis from clinical specimens.

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MICROSCOPY
Microscopy
Presumptive diagnosis Sputum Ziehl-Neelsen staining for AFB Conventional microscope
low sensitivity (20 - 60%)1

Light emitting diode-based fluorescence microscopy (LED FM)2

10% more sensitive shorter time spent quicker turnaround time

1 2

Steingart KR et al., Lancet Infect Dis, 2006

Shenai S et al., Int J Tuberc Lung Dis, 2011

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CONVENTIONAL LIGHT MICROSCOPY

Acid fast bacilli

IMMUNOFLUORESCENCE MICROSCOPY

AFB bacilli IF stain (low mycobacterial load)

IMMUNOFLUORESCENCE MICROSCOPY

iMAGING IN TB

INTRODUCTION
iMAGING may assist in: identifying the lesion characterising the lesion assessing the extent/severity assisting in intervention There are NO imaging features that are pathognomonic for TB & the findings may mimic those of many other diseases.

CHEST RADIOGRAPH
Normal chest radiography may be seen in up to 15% of patients with proven TB.1 CXR is sensitive but not specific; any abnormality may suggest TB in an immunosuppressed person. Abnormalities on chest radiographs may be suggestive of, but never diagnostic of TB. Activity of TB cannot be made accurately on a single radiograph alone, sputum smears/culture must be obtained.
1Burrill

J et al. Radiographics, 2007

iMAGING MODALITIES IN EPTB

US can be used in intestinal TB (to assess ascites & lymphadenopathy), renal TB & also in soft tissue involvement.

CT is the preferred imaging modality in assessing abdominal TB & may also be used in musculoskeletal involvement of TB.

MRI is the preferred modality in cranial and musculoskeletal TB.

CXR is indicated in all cases of EPTB

iMAGING

TREATMENT of TB in ADULTS

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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

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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
a. Nature of disease b. Necessity of strict adherence with prolonged treatment c. Risks of defaulting treatment d. Side effects of medication e. Risks of transmission & need for respiratory hygiene as well as cough/ sneeze etiquette
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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 newlydiagnosed PTB.

RECOMMENDED ANTITB DRUGS

DRUG RECOMMENDED DOSES Daily 3X a week

Dose (range) Maximum in Dose (range) Maximum in in mg/kg mg in mg/kg mg body weight body weight Isoniazid (H) 5 (4 - 6) 300 10 (8 - 12) 900 Rifampicin (R) 10 (8 - 12) 600 10 (8 - 12) 600 Pyrazinamide 25 (20 - 30) 2000 35 (30 40)* 3000* (Z) Ethambutol 15 (15 - 20) 1600 30 (25 35)* 2400* (E) Streptomycin 15 (12 - 18) 1000 15 (12 18)* 1500* (S)
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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.
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TREATMENT OF NEW CASES

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FLOW CHART FOR 6 MONTHS TREATMENT OF PTB

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FOLLOW-UP AFTER COMPLETION OF ANTITB TREATMENT

Follow-up clinic visits should not be conducted routinely after treatment completion.

Patients should be told to watch for symptoms of relapse & how to contact the TB service rapidly through primary care or a TB clinic.
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FOLLOW-UP

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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)

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DEFINITION
Patient previously treated for TB including relapse, failure & default cases . 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. A patient who has received Category I treatment for TB & in whom treatment has failed. A patient who returns to treatment, bacteriologically positive by sputum smear microscopy or culture, following interruption of treatment for 2 or more consecutive 13 months.

Previously treated

Relapse

Treatment failure

Treatment after default

PREVIOUSLY TREATED TB
Recommend: retreatment regimen containing firstline drugs 2HRZES/1HRZE/5HRE if countryspecific data show low or medium levels of MDRTB 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.

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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.

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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.
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TREATMENT OF PREVIOUSLY TREATED TB

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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.
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OPTIMAL DURATION

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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.

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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 2Mwandumba

D et al., PLoS Med, 2009 HC et al., Cochrane, 2001 3Chang KC et al., Thorax, 2011

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MAINTENANCE PHASE

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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
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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

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RECOMMENDED DOSES
30 - 37 kg body weight: 2 tablets daily

38 - 54 kg body weight: 3 tablets daily

55 - 70 kg body weight: 4 tablets daily

More than 70 kg body weight: 5 tablets daily

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EFFECTIVENESS
FDCs compared to separate-drug regimens significantly reduce risk of noncompliance 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 26

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.

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FDC

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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.

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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

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DOT

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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

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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

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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.

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OPTIMAL DURATION OF EPTB TREATMENT

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CORTICOSTEROIDS IN EPTB

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

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CORTICOSTEROIDS IN EPTB TREATMENT

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TB MENINGITIS
Severity Grade I disease Regime 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 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 39

Grade II & III disease

TB PERICARDITIS

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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
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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.

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WHEN TO REFER

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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
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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

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THANK YOU

jamalulazizi@gmail.com

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