MDRTB

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MDR-TB

• Carole Mitnick
• World TB Day 2000
• Boston University School of Public Health

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Overview

• What is MDR-TB?
• Where is it prevalent and in what dimensions?
• What has been the global policy response to
  MDR-TB?
• What strategies exist to minimize the impact of
  MDR-TB?

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What is MDR-TB?

• M. tuberculosis resistant to INH and RIF
• Naturally occurring mutants, 1 in 106 organisms
• Further selection precipitated by inadequate
  therapy (acquired resistance)
• Primary resistance occurs through transmission
• Requires longer, more expensive treatment with
  less effective and more toxic drugs
• Requires access to culture and DST

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Prevalence Estimates Vary

• 50 million infected with drug-resistant strains
• 1997 estimate 100,000 cases of MDR-TB
• 1997 WHO/IUATLD antituberculosis resistance
  report (35 sites)
• prevalence believed to be an underestimate
• median, any resistance 7.5 (0.9-35.1)
• median, MDR-TB 2.2 (0-22.1)
• hot spots Dominican Republic, Argentina,
  Ivanovo, Latvia, Estonia, Ivory Coast

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Prevalence Estimates Vary

• 2000 antituberculosis resistance report, released
  today (72 sites)
• median, any resistance 11.1 (0-52)
• median, MDR-TB 1.7 (0-22.1)
• gt3 prevalence MDR Estonia, Henan Zhejiang
  provinces, Latvia, Ivanovo Tomsk oblasts, Iran,
  Mozambique, Tamil Nadu, Peru

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Policy Response to MDR-TB

• DOTS
• Government commitment
• Bacteriologically confirmed diagnosis
• Standardized, short-course, directly observed
  multidrug regimen for treatment of TB (SSCC)
• Regular, uninterrupted supply of drugs and
  diagnostic materials
• Systematic monitoring and evaluation of program
  activities

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MDR-TB Myth 1

• DOTS will eliminate MDR-TB.

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DOTS can prevent MDR-TB

• SCC can cure and prevent acquisition of
  resistance in individuals with pan-susceptible
  disease
• Cant expect SCC to cure or prevent transmission
  of MDR or poly-resistant disease
• polyresistancemore than one drug, not INH and
  RIF
• Caution about use of Category II SCC in failures
• Category I 2HREZ4HR
• Category II 2SHREZ1HREZ6HR

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K Th H R E Z
S H R E Z
Th H R E Z
H R E Z
H R E Z
S H R E
H R
H R
H R
INCREASING RESISTANCE
H R E Z S

• H
• R
• E
• Z

H R E Z S K
H R E
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Drug-susceptibility results at treatment
initiation (n164) Mariinsk prison, Kemerovo,
Russia, 1997-98
Kimerling, et al. Inadequacy of the current WHO
re-treatment regimen in a central Siberian
prison treatment failure and MDR-TB. IJTLD 1999
3(5)451-3.
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Treatment outcomes for 210 DOTS (SHREZ) patients
Mariinsk prison, Kemerovo, Russia, June
1996-March 1997
Kimerling, et al. Inadequacy of the current WHO
re-treatment regimen in a central Siberian
prison treatment failure and MDR-TB. IJATLD
1999 3(5)451-3.
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Resistance patterns at treatment initiation
Colony 3, Baku, Azerbaijan, Cohorts 6-14
(October 1996-October 1998)
with resistant strains
treatment history
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Results on DOTS (n467)Central Penitentiary
Hospital, Baku, Azerbaijan, 1995-1997
Coninx, Mathieu, Debacker, et al, 1999.
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MDR-TB in Ivanovo Oblast, Russia

• WHO/CDC implemented DOTS in civilian population
  in 1995
• 30 of 514 new patients treated between 1996 and
  1998 had poor treatment outcomes
• 5 (26) had primary MDR-TB
• Primary MDR-TB more than doubled AFTER DOTS
  implementation
• 1996 3.8 (7 of 186) primary MDR-TB
• 1998 9.4 (11 of 117) primary MDR-TB

Source MMWR 1999 48(30)661-663
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DOTS in Peru a model program

• Implemented in 1991
• NTP covers gt90 of country
• 90 of detected patients treated successfully
• PCF strategy may detect up to 80 of
  smear-positive TB patients
• MDR-TB as proportion of TB ranges in Peru from
  0.6 to 12.0

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TB incidence in Peru, 1987-1998(all cases and
smear-positive cases)
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Response DOTS-Plus for MDR-TB

• Political will of relevant government bodies
• Access to laboratory facilities for microscopy,
  culture, and DST
• Directly observed therapy
• Uninterrupted supply of first- and second-line
  drugs
• Reliable monitoring system allowing cohort
  analysis of treatment outcomes
• Relevant operational research to identify
  constraints in project implementation

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Descriptive characteristics of 96 MDR-TB patients
Mean age 28.4 10.6 yrs (range 11-66)
Number Percent Sex Male
49 51 Female 47 49 Previous TB
Treatments 1-2 39 41 3 or
more 57 59 Comorbid disease Yes 31 32 No
65 68
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Distribution of combined multidrug-resistance to
5 first-line drugs (n96)
number of MDR-TB patients
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High Grade Drug ResistanceA Grim Reality in Peru
LV 11 yo male dx with TB in 1998 Received
and failed 2 treatments R to H, R, E, Z, S,
KM, CM,THA, CPX S to CS (AMK, RFB, CLR
pending)
CC 23 yo male dx with TB in 1996 Received
and failed 3 treatments R to H, R, E, Z, S,
KM, CM, THA, CPX, AMK, RFB, CLR S to CS
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MDR-TB Myth 2

• MDR-TB is less infectious than drug-susceptible
  TB.

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MDR-TB Myth 3

• Patient noncompliance is the chief cause of
  MDR-TB.

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• TB/MDR-TB Household Contact History
• in 53 patients
• 79 (43) have any known TB contact
• 42 (22) have known contact with
• lab-documented MDR-TB
• 57 (30) have known contact who
• died with TB
• 42 (22) have known contact who
• died during DOT-SCC or DOT-retx

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Proportion of 53 MDR-TB patients with primary vs.
acquired resistance by 1997 WHO definition
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ITR in 84 MDR-TB patientsCarabayllo, Peru,
August 1996 to June 1999
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Cumulative proportion of patients with 2nd
consecutive negative monthly culture results,
among those completing 2, 3, 4, or 5 months of
therapy
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Preliminary outcomes in 74 MDR-TB patients
receiving at least 4 months of therapyAll
patients initiated therapy between August 1996
and May 1999
cured, or in treatment and culture negative 85
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MDR-TB Myth 4

• MDR-TB is too expensive to treat in poor
  countries it detracts attention and resources
  from treating drug-susceptible disease.

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Cost of 18-month regimen for the treatment of
two-, four-, and five-drug resistant TB (1997
prices) (six months for injectable)
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Drug-cost comparison Second-line antituberculous
drugs
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Reduced Prices of 2nd Line TB Drugs
Drug Formulation 1997 1999
Decline Price Price
Amikacin 1 gm vial 9.00 0.90
90 Cycloserine 250 mg tab 3.99 0.50
87 Ethionimide 250 mg tab 0.90 0.14
84 Kanamycin 1 gm vial 2.50 0.39
84 Capreomycin 1 gm vial 29.90 0.90
97 Ofloxacin 200 mg tab 2.00 0.05 98
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