Dr. Hermawan Chrisdiono, Sp.

P
RSUD Kabupaten Kediri
 Infection Disease

Exposed
Infection
to
DR-TB
with
drug resistant
strain
Drug-resistant
Risk factors Risk factors
tuberculosis
Risk
factors

Drug-susceptible
Tuberculosis
Exposed Infection with
to drug-susceptible
DS-TB strain
 DOTS acceleration
ISTC 2006/2009
TB/HIV Collaboration
DOTS-plus
DOTS

TB CASES
HIV Epidemic Patient-centered care
& MDR-TB approach
 DEFINITION
Primary resistance
drug resistance among new cases
never received TB drugs or received them for < 1
month
new terminology adopted by WHO : Resistance
among new cases

Secondary (Acquired) resistance

drug resistance in a patient who previous received at
least 1 month of TB therapy
new terminology adopted by WHO : Resistance among
previously treated cases
WHO/IUATLD Global Project Drug-Resistance Surveillance Report No. 3
 Definitions
Mono Drug Resistance
against only one drug
Poly Drug Resistance
against two or more drugs, but not against both H and R, e.g. against
S and H
(These are less serious because they can be effectively treated with the cat I and II
regimen, using first-line TB drugs)
Multi Drug Resistance
against at least H and R
Extensive Drug Resistance (XDR-TB)
MDR
AND against a fluoroquinolone
AND against one or more of the injectable drugs: kanamycin,
amikacin, capreomycin
Complete (Totally) Drug Resistance
How Does Drug-Resistant TB Develop?

Wild M. tuberculosis strain

Spontaneous mutation

Drug-resistant strain

Selection by poor regimen,

drug supply or adherence

Acquired drug resistance

Transmission due to diagnostic

delays, overcrowding and
inadequate infection control

Primary drug resistance

 The March of Resistance

Drug MDR- XDR- Total

suscepti TB TB DR TB
ble TB* 1990 2006 ?

*or limited Resistance to H&R Resistance to HR and Resistance to

resistance 2nd line drugs all available
manageable Arises from
drugs
with 4 drug mismanagement of Arises from
regimen - DOTS TB mismanagement of No treatment
MDR Treatment options
Treatable with 2nd
line drugs Treatment options
seriously restricted
 MDR-TB causes
(from program perspective)
Regimen prescription (providers!)
Wrong drugs or combination of drugs
Wrong duration
Drug management
Quality
Loose drugs instead of FDCs
Penetration in local marketplace
Case management (providers!)
No observation (DOT)
 Risk factors MDR-TB
(from patient history)
Previous treatment
Relapses
Failures
Chronics
Contacts with drug resistant TB
Residence/birth in high prevalence setting
Failure to convert at 2 months
HIV infection
Inadequate infection control measures
Causes of Inadequate antituberculosis treatment
 Magnitude of the MDR-TB problem
WHO estimates incident cases in 2003
458.000 (95% conf limits, 321.000-
689.000)
Most MDR TB cases are not diagnosed !!
Prevalent cases estimates to be two or
three times higher than incident cases
 Estimated Global MDR Cases
Estimated global incidence and proportion
of MDR among TB cases, 2004

2004 TB cases MDR cases %

New Cases 8,897,743 272,906 2.7

Previously 982,639 181,408 18.5

treated cases

Total cases 9,880,382 424,203 4.3

Zignol M, et al. JID 2006; 194: 479-85

Distribution of MDR: No Prior Treatment

Distribution of MDR rates among new cases (previously untreated)

Zignol M, et al. JID 2006; 194: 479-85

Distribution of MDR: Prior Treatment

Distribution of MDR rates among previously treated cases

Zignol M, et al. JID 2006; 194: 479-85

Problem analysis MDR in Indonesia
Only 20% of hospitals & < 5% of private providers are
currently involved in DOTS
No data on TB drug resistance, except for few small
studies (West Java MDR: 5% !!!).
Some second line drugs are free available on the market
and currently used in first line regimens!
Neglect to take treatment history causes miss-
classification and under-treatment..
 Risk factors for increase of MDR
in Indonesia (1)
l Therapeutic chaos : prescription of inadequate doses /
combinations of drugs
Many TB patients are treated by private providers, not following
DOTS
l unsupervised treatment, no monitoring
l no registration, no reporting
l high costs to the patients (fees)
l Un-controlled use of second-line drugs in hospitals and private
sector (quinolones, kanamycin etc)
l Poor treatment performance in most hospitals:
low conversion rate & low cure rate because many patients drop-out from treatment.
l inadequate drug supplies and distribution
 Risk factors for increased MDR
in Indonesia (2)
Currently the chronic TB cases cannot be
treated (no DOTS plus available)
These chronic cases continue to transmit
drug resistant TB

TB- HIV is looming

The real MDR-
TB/ XDR-TB in
Indonesia

?
 MDR-TB: A Challenge to Health
System
Case identification of MDR-TB requires culture,
species identification, and drug susceptibility
testing

How many quality assured laboratory to be

established to ensure accessibility, taking into
account the size of population, geographic
characteristics and the epidemic of tuberculosis?
 MDR is More Costly to Cure (Peru)

$20-40 $50 - 400 $1,000 - 10,000

100
Treatment success (%)

80

60

40

20

0
All TB Re-treatment MDR TB
 MDR-TB is harder to cure

100
all TB MDR-TB

80
Treatment success (%)

60

40

20

0
Russia Dominican Korea Peru Hong Kong
Rep. Espinal MA et al. JAMA 2000; 283:2537-2545
 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
 History
1994 Global drug resistance surveillance project launched
1999 Stop TB Working Group on DOTS-Plus for MDR-TB
1999 Negotiations with pharmaceutical industries
2000 Green Light Committee Initiative launched
2000 First DOTS-Plus project launched
2002 The Global Fund decides that all MDR-TB drugs
should go through the GLC mechanism
2005 MDR-TB control proven feasible and cost-effective
2006 WHO MDR-TB guidelines, Global Plan to Stop TB,
New Stop TB Strategy (DR-TB component 2)
2006 New funding Initiatives UNITAID
2009 WHA recommended tool for scaling up MDR-TB
management
 DOTS-Plus scale up of through the GLC

40

35 September 2005 35 projects

Number of projects

30

25

20

15

10

0
2000 2001 2002 2003 2004 2005
 GLC approved projects through June 2009

1. Azerbaijan
2. Armenia
3. Belarus
4. Bulgaria
5. Estonia
6. Georgia
7. Kazakhstan
8. Kyrgyzstan
9. Latvia
Uncertain 10.
11.
Lithuania
Moldova
12. Romania
demand 13. Russia
14. Serbia
15. Tajikistan
16. Ukraine
17. Uzbekistan

1. Belize
1. Bangladesh
2. Bolivia
2. Bhutan
3. Costa Rica
3. India
4. Dominican Republic
1. Egypt 4. Indonesia
5. Ecuador
1. Burkina Faso 2. Jordan 5. Myanmar
6. El Salvador
2. Cameroon 3. Lebanon 6. Nepal
7. Guatemala
8. Haiti 3.
4.
Higher
DR Congo
Ethiopia
4.
5.
Pakistan
Syria
7.
8.
Sri Lanka
Timor-Leste
9. Honduras
10. Mexico 5.
6.
price
Guinea
Kenya
6. Tunisia
1. Cambodia
11. Nicaragua
7. Lesotho 2. China
12. Paraguay
8. Liberia 3. Micronesia
13. Peru
9. Mozambique 4. Mongolia
14. Uruguay
10. Rwanda 5. Philippines
11. Senegal 6. Samoa
12. Swaziland 7. Vietnam
13. Uganda
14. Tanzania

GLC-approved projects in 66 countries

~ 54'550 patients approved for enrolment
 Parameters to consider when
designing a DOTS-Plus strategy
Government and NTP commitment
Well performing basic DOTS
Program is able to implement the 5 components of
DOTS-Plus
Rational case-finding strategy using quality assured
smear, culture and DST ( concordance with a SRL)
Representative DRS data for rational country/area-
specific treatment design and planning of procurement
Reliable DOT throughout treatment
Free effective side-effect management
Regular supply of ALL drugs involved!
 Assessment of sites: Issues that need to
be addressed in all sites
Lack of EQA assured lab capacity
Inadequate use of available second line drugs
(inadequate regimens, financial barriers, no
SL-DST)
No experience with 4 types of SLD
Alternative for family member DOT
Funding of hospitalization, lab tests, human
resources, incentives.
Why should Indonesia consider to use the
GLC mechanism ?

Access to a complex market of quality

assured second line drugs
Preferential prices (pooled procurement)
Technical assistance ; benefiting from
GLC experiences worldwide
Requirement of the GFATM grant /
International quality label (donors)
 Preparation
Programmatic management of DR-TB (DOTS-Plus)

Assesment / Situation Analysis

DOTS progress & capacity (case management, Lab capacity)
Magnitude of MDR-TB (DRS, Treatment Failure Rate etc)
Resistance pattern (DRS)
Drug distribution (Cat-1 and cat-2)
Analysis on relevancy
Feasibility
Lab preparation (improvement & EQA)
Pilotting (Area & Institution)
Scale-up step-wise
How to detect
MDR-TB
 M(X)DR-TB Suspects (1)
High probability of resistance

Failures Cat II and

Chronics (>80%),
Failure Cat I
I am
a suspect
MDR-TB

Exposure to known MDR-TB

case (80%)
 M(X)DR-TB Suspects (2)
Middle probability of resistance
Failures from private sector
Cat I remaining AFB+ at months 2-3
Relapses
Return after default
I am
a suspect Exposure in institutions with high
MDR-TB
MDR-TB
Residence in high MDR-TB
prevalence area
History!! of poor (or unknown)
quality TB drugs, poor
M(X)DR-TB Suspects (3)
Low probability of resistance
Diarrhoea:
malabsorption of
drugs
HIV in some areas
associated with
MDR-TB
 MDR-TB suspects in Indonesia
Chronic cases
Proven with previous patients card and from history
Patients failing re-treatment (category 2)
Proven with information from the TB register
Patients reporting previous TB treatment
Including second line drugs such as quinolones and kanamycin (in
hospital, private sector)
Patients failing first line (category 1) treatment
Patient still smear positive at month 3 of first line (category 1)
treatment
Relapse cases
Patients who return after default
After category 1 and/or category 2 treatment
Symptomatic TB suspects reporting close contact with
confirmed MDR-TB patients
Including health care workers in the MDR-TB ward
How to Designing
MDR-TB Regimen
 Principles of MDR treatment
At least 4 drugs with (almost) certain effectiveness
No drugs from failing regimen.
Initial phase 6 months, at least 6 days per week
Smears and culture monthly till culture conversion
Continuation (after conversion) for at least 18
months
DOT throughout
DST guiding treatment
Contacts closely monitored
 Grouping of anti TB drugs
Grouping Drugs
Group 1 : first-line oral anti TB INH (H), Rif (R), Ethambutol (E),
drugs Pyrazinamide (Z)
Group 2 : injectable anti TB agents Streptomycin (S), Kanamycin (Km),
Amikacin (Am), Capreomycin (Cm),
Viomycin (Vi)
Group 3 : fluoroquinolone Cypro (cfx), oflo (ofx), levo (lfx),
moxifloxacin (mfx), gatifloxacin (gfx)
Group 4 : oral bacteriostatic Ethionamid (Eto), Protheonamide (Pto),
second-line anti TB agents cycloserin (Cs), Terizidone (Trd), p-
aminocaliclic acid (PAS), Theocetazon
(Th)
Group 5 : anti TB agents with Clofazimine (Cfx),
unclear efficacy (not Amoxicillin/Clavulanat (Amx/Clv),
recommended by WHO for Linezolid (Lzo)
routine use in MDR-TB patients

WHO, 2006
 Second-Line Drug Classes for MDR TB Treatment

Aminoglycosides Amikacin, Kanamycin

Polypeptides Capreomycin

First Fluoroquinolones Ciprofloxacin, Ofloxacin

line +
drugs
Thioamides Ethionamide, Prothionamide

Serine analogues Cycloserine

PAS

WHO. Guidelines for the programmatic management of drug-resistant tuberculosis. 2006.

You Cannot Cure MDR-TB As
Fast As You Can Create It

Lalloo UG et al
Recent Advances in the Medical & Surgical Treatment of MDR-TB
Curr Opin Pulm Med (2004)
 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
 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
 Framework Component 3:
Appropriate treatment strategies that utilize SLDs under proper
management conditions

Management of
adverse
drug reactions and
co-morbidities
Health education and
counseling
Provision of enablers

You just have to take the

pills and thats it!
X E. Jaramillo, 2006
 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)
 How do we respond to the
MDR-TB/XDR-TB problem?
We need to address the known factors
contributing to drug-resistance

1. No supervised treatment
2. Bad adherence / supervision
To implement
3. No standard treatments
a good DOTS
4. Frequent drug stock-outs Programme,
5. Anti-TB drugs of poor quality with quality
6. Non-programmatic management
7. No hospital infection control

Prior to starting an MDR-TB project, it is mandatory to address

adequately all these factors
J P Caminero
Summary
Treatment of MDR TB: not cost effective
Technically difficult and yields
low cure rates
Expensive, drawing resources
away from the treatment of
pan-susceptible disease
Treatment of drug-resistant
strains, when improperly
monitored, give rise to even
more resistant organisms
Decreased virulence and
transmissibility of MDR TB
strains
Summary (2)

DOTS! and nothing else!

TB is being defeated by
model DOTS program.

DOTS is our best hope of

preventing the emergence
of resistance to anti-TB
drugs
TOP MANAGEMENT

PREVENTION

DOTS STRATEGY
ISTC
2006/2009

MDR-TB