Transcript TBpharmaceuticals

Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
TUBERCULOSIS
SAPRAA
23rd March 2007
Dr Joe Khoali
Medical Advisor
Gauteng TB Control Programme
TB CAN BE CURED!
TB anywhere is
TB everywhere!
Definition of terms
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
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• Mycobacterium species/Mycobacteria/Acid fast bacilli
– family of bacteria to which bacterium causing TB
belongs
– this big family includes other bacteria similar in
structure to TB bacteria but do not cause tuberculosis
disease
• Mycobacterium tuberculosis (MTB)/TB bacillus
– the mycobacterium that specifically causes tuberculosis
disease
• Pulmonary tuberculosis
– tuberculosis of the lungs
• Extra-pulmonary tuberculosis
– tuberculosis disease outside of the lung e.g. bone,
brain, blood etc
Def. cont.
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
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TB anywhere is
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• Smear microscopy
– examination of patient specimen under the microscope
• Culture
– cultivation of mycobacteria in the laboratory using
special media
• Drug susceptibility testing (DST)
– test for ability of anti-TB drugs to kill TB bacilli
• MDRTB
– multiple drug resistant TB (isoniazid & rifampicin),
• XDR – extensive drug resistant TB
– (MDR + fluoroquinolone+(kanamycin or amikacin or
capreomycin)
GAUTENG TB PROGRESS REPORT
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
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2004
2005
2006
Incidence per 100 000
373 per 100 000
376 per 100 000
444 per 100 000
Pulmonary TB
30 792
34 017
32 459
All TB cases
40 163
44 152
43 377
New Smear Positive cases
23 806
21 531
18972
Bacteriological coverage
93.3%
94.4%
89.9%
New smear Positive
Conversion Rate
75%
64.9%
New Smear Positive Cure
Rate
13 521 (62.4)
15 758 (66.7%)
Treatment Interruption Rate
1769 (8.2%)
6.9%
Treatment success rate
67.7%
71.4%
Deaths
1983 (9%)
2283 (9.5%)
Failure Rate
267 (1.2%)
371 (1.6%)
MDR TB
118 (0.2%)
129 (0.26%)
Background
Department of Health
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Department van Gesondheid
Umnyango wezeMpilo
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 4 combination drugs introduced in 2000
 Reasons for introduction:
fewer drugs
prevention of resistance
better ordering system
one expiry date
easier administration (DOT)
Back. cont.
Department of Health
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Department van Gesondheid
Umnyango wezeMpilo
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 Establishment of WHO-GDF since 2001
 Rationale
Reduction of TB drug costs
Donor funding for purchase of TB drugs
Standardised regimen world wide
Prevention of MDR-TB
 SA started using 4FDC before this process
Advantages of FDCs
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
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•
•
•
•
•
Fewer drugs improve compliance
Correct therapeutic levels
Fewer side effects – only 3 – 6% so far
Calculation of needs simpler
Drug ordering, stock control and storage is
easier
Reduced Tablets
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
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TB anywhere is
TB everywhere!
Body weight
Single drugs
FDCs
<35kg
7 – 12
2
<40kg
8 – 14
3
<50kg
9 – 17
3
<60kg
12 – 21
4
<70kg
13 – 25
5
Justification for dosage formulations
Department of Health
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Department van Gesondheid
Umnyango wezeMpilo
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• Different populations of TB bacilli
- metabolically active
- intermediately active
- semi-dormant bacilli (persisters)
- dormant bacilli
Action of TB drugs
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
Drug
Rif
X
X
X
INH
X
X
X
PZA
X
X
Eth
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Bacteriostatic Bacteriocidal Intracellular Extracellular
Strep
X
X
Regimen 1
Department of Health
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Department van Gesondheid
Umnyango wezeMpilo
Pre treament body
weight
Initial phase
2 months
5 x a week
Continuation phase
4 months
5 times a week
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3 times a week
RHZE
150/75/400/
275
RH 150/75
RH 300/150
RH 150/150
RH 300/150
30-37 kg
2 tablets
2 tablets
2 tablets
38-54 kg
3 tablets
3 tablets
3 tablets
55-70 kg
4 tablets
2 tablets
3 tablets
 71kg
5 tablets
2 tablets
3 tablets
Regimen 2
Pretreatm
ent body
weight
Initial phase
2 months
5 times a week
Initial phase
month 3
5 times a
week
Continuation Phase
5 times a week
RHZE
150/75/400/
275
Streptomycin
(g)
RHZE
150/75/400
/275
RH
150/75
E
400
30-37 kg
2 tabs
0.5
2tabs
2 tabs
2 tabs
38-54 kg
3 tabs
0.75
3 tabs
3 tabs
2 tabs
55-70 kg
4 tabs
1.0
 71 kg
5 tabs
1.0
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
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TB anywhere is
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RH
300/150
E
400
4 tabs
2 tabs
3 tabs
5 tabs
2 tabs
3 tabs
Fixed Dose Combination tablets for
children.
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
TB CAN BE CURED!
TB anywhere is
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• RHZ: 60/30/150
• RH: 60/30
• RH: 60/60 (for three times weekly
regimen)
Chemoprophylaxis.
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
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TB anywhere is
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• All children contacts less than 5 years of
infectious (smear positive) cases should
be examined.
– Healthy  prophylaxis - INH 5mg/kg
daily for 6 months
– If TB  treat - RHZ
Treatment of TB /HIV
Co-infection
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
• Guideline is clear on how to manage
concomitant TB/HIV disease – TB being
the commonest OI
• Principle is to screen for TB on entrance to
programme
• 2 scenarios
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– Develop TB while on ART’s
– TB before commencing ART
Approved ARVL RX Regimens
1a.
Department of Health
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2 NRTI’s + NNRTI
e.g. d4T+3TC+ Efavirenz
i.e. Stavudine+Lamivudine+ Stocrine
1b. 2 NRTI’s + NNRTI e.g. d4T+3TC+ Nevirapine
i.e. Stavudine+Lamivudine+ Viramune
2.
2NRTI’s + PI
e.g. AZT+ddi+ Kalitra
i.e. Zidovudine+ Didanosine+Lopinavir/Ritanovir
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TB anywhere is
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TB and ART’s
Interactions
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
• Rifampicin is a powerful inducer of Cytochrome P450
enzymes
• Avoid the use of PI’s with TB drugs
•
Substitute PI’s with NNRTI’s e.g. EFV or NVP
• AZT and DDI may interfere with absorption of Rifampicin
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(I.e. Treat TB first and HIV thereafter)
Treatment cont.
•
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
TB before commencing ART
– No history of stage IV and CD4>200 =
no ART. Assess after completion of TB
treatment
– If history of stage IV disease and/or
CD4<200, complete 2 months of TB
treatment before commencing ART
– If CD4<50 and patient tolerating TB
treatment, initiate ART after 2/52 of TB
treatment. Avoid nevirapine.
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TB anywhere is
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Treatment cont.
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
TB CAN BE CURED!
TB anywhere is
TB everywhere!
•
Develop TB on ART
– Regimen 1a = continue
– Regimen 1b = change NVP to Efivarenz
– Regimen 2 = increase the dose of the
kaletra combination until two weeks
after completion of TB treatment, then
restart the normal doses.
Common Adverse Reactions
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
Caused by
Adverse reaction
Signs and symptoms
Isoniazid
Peripheral neuropathy
Tingling sensation in hands
and feet
Itchy skin, rash
Allergy
Pyrazinami Gastrointestinal intolerance
de
Athralgia
Arthritis
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Upset stomach, vomiting
Joint aches
Gout (rare)
Common Adverse Reactions
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
Caused by
Adverse Reaction
Signs and Symptoms
Ethambutol
Eye damage
Blurred or changed vision
Altered color vision
Streptomycin
Ear damage
Balance problems
Hearing loss
Ringing in the ears
Itchy skin
Allergy
TB CAN BE CURED!
TB anywhere is
TB everywhere!
Common Adverse Reactions
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
TB CAN BE CURED!
TB anywhere is
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Caused by
Adverse reaction
Signs and symptoms
Rifampicin
Gastrointestinal
intolerance
Anorexia, nausea,
abdominal pain
Isoniazid, PZA, Rifampicin
Hepatitis
Abdominal pain,
anorexia, nausea,
vomiting, abnormal
LFTs
Management of Adverse Reactions
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
TB CAN BE CURED!
TB anywhere is
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•
Gastrointestinal
intolerance
•
•
•
Skin reactions
•
Take treatment at bedtime
Refer if severe intolerance eg nausea,
vomiting
Reassure, topical/oral anti-histamines
•
Hepatitis
•
Establish alcohol intake
•
All other
adverse/severe
reactions
•
Refer
Drug Interactions
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
TB CAN BE CURED!
TB anywhere is
TB everywhere!
• Relatively few drug interactions substantially change
concentrations of TB drugs
• TB drugs sometimes change concentrations of other
drugs
• Isoniazid increases phenytoin concentration to toxic
levels
• Rifampicin may reduce effect of oral diabetic drugs,
contraceptives, digoxin, oral anticoagulants,
phenobarbitones.
• Always refer patients for dosage adjustments
Multi-drug resistant TB
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
•
•
•
•
•
TB CAN BE CURED!
TB anywhere is
TB everywhere!
Increase in MDR-TB cases is an indication
of a poor performing TBCP.
MDR-TB is a man-made disease.
Laboratory diagnosis
Primary resistance (no history of TB Rx)
Acquired resistance (previous hx of TB Rx)
Risk factors for
development of MDR-TB
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
TB CAN BE CURED!
TB anywhere is
TB everywhere!
•
•
•
•
•
•
•
Previously unsuccessful TB treatment.
Interruption of TB treatment
Inappropriate TB treatment regimen.
Inappropriate TB treatment duration
Previous TB treatment in a hospital
High TB prevalence.
HIV+ is not an independent risk factor
MDR-TB PREVALENCE in South
Africa (2002)
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
• New cases: 1.7%
(range 1 – 2.4%)
• Re-treatment cases: 6.6%
(range 1.6–13.9%)
XDR-TB prevalence not known
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MDR-TB treatment concerns
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
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• Difficult and expensive to treat. [R28,000 vs
R400 patient]
• Intensive phase of 4 months, continuation
phase 12 months or more
• Second-line TB drugs cause more side
effects.
• Less effective: Only 50% cure rate.
• Some cases never convert to negative.
Second-line TB drugs
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
•
Classes
Category (6)
Drug(s)
1
Aminoglycosides
Kanamycin
Amikacin
Capreomycin
Polypeptides
2
Thioamides
Ethionamide
Prothionamide
3
Pyrazinamide
Pyrazinamide
4
Fluoroquinolones
Ofloxacin
Ciprofloxacin
5
Cycloserine / Terizidone
Cycloserine / Terizidone
6
Ethambutol
Ethambutol
7
PAS
PAS
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Classification of drugs available
for treatment of MDR-TB
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
•
Activity
Moderate
bactericidal
Low bactericidal
Bacteriostatic
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Drug/Category
Aminoglycosides
Thioamides
Pyrazinamide (acid pH)
Fluoroquinolones
Ethambutol
Cycloserine /
Terizidone
PAS
Designing MDR-TB Treatment
Regimens
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
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TB anywhere is
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• Minimum of four drugs necessary during
intensive phase (usually five drug
combination)
• At least three drugs not administered
previously for more than three months
• One drug option per category due to crossresistance
• Drugs selected from highest ranking
categories
• Aminoglycoside/Polypeptides must be
included during the intensive phase
• Fluoroquinolone must be included
throughout
General Treatment Principles
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
• Provide 18-24 months’ treatment, always
with intensive phase of at least 4 months
• PROVIDE DOT THROUGHOUT
• Warn patients about side-effects
• Manage side-effects appropriately
• Perform cultures monthly
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TB anywhere is
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Treatment Approaches
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
• Standardised
– All patients on the same regimen,
irrespective of drug susceptibility results
– NTCP policy in South Africa since 2000
• Individualised
– Regimen tailor-made according to drug
susceptibility pattern of strain
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TB anywhere is
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Standardised Regimen
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
• According to ethambutol resistance
– Intensive phase (4 months)
• kanamycin, ofloxacin, ethionamide,
pyrazinamide, ethambutol or
terizidone
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– Continuation phase (12 – 18 months)*
• ofloxacin, ethionamide, ethambutol or
terizidone
* (Shortened to 12 months following
culture conversion)
– Dose standardised according to three
weight bands (<50kg, 50-65kg, >65kg)
Treatment Monitoring
Department of Health
Lefapha la Maphelo
Department van Gesondheid
Umnyango wezeMpilo
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• Our fundamental responsibility
• Ensure adherence – DOT with patient
centered case management i.e education,
reassurance
• Sputum collection by end of 8 weeks to
assess response - SCR
• Check susceptibility if still positive at three
months
• Periodic evaluation (minimum monthly) to
assess adherence and identify adverse
reactions