Tuberculosis in the United States, 2004

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Tuberculosis in the United States, 2004

• Thomas R. Navin, MD
• CDC
• March 2005

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TB Presentation Overview

• How we count TB cases in the U.S.
• Descriptive epi
• Analytic epi
• New items on the horizon
• Genotyping
• New diagnostic tests
• New drugs

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TB Case Reports, Missouri, 1994-2004
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TB Case Rates, Missouri and United States,
1994-2004
Rate per 100,000
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TB Case Rates, Log Scale
Rate per 100,000
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Percent Foreign-born TB Cases, United States,
2004
D.C.
57 66
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26 - 40
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Percent foreign-born cases over total cases
41 - 56 (foreign-born for U.S. 53.7)
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TB Case Rates by Race/Ethnicity United States,
1993-2003
Cases per 100,000
Cases per 100,000.All races are non-Hispanic.
In 2003, Asian/Pacific Islander category includes
persons who reported race as Asian only and/or
Native Hawaiian or Other Pacific Islander only.
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Primary MDR TBUnited States, 1993-2003
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Primary MDR TB inU.S.-born vs. Foreign-born
Persons, United States, 1993-2003
Resistant
Note Based on initial isolates from persons with
no prior history of TB. MDR TB defined as
resistance to at least isoniazid and rifampin.
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Estimated HIV Coinfection in Persons Reported
with TB, United States,1993-2002
Coinfection
Note Minimum estimates based on reported
HIV-positive status among all TB cases in the
age group.
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Characteristics of TB Cases, 2004
Missouri U.S. U.S.
Total cases 131 100.0 100.0
U.S.-born 91 69.5 45.7
Foreign-born 35 26.7 53.1
Marginalized 21 16.0 18.3
Black 48 36.6 27.6
Hispanic 13 9.9 28.7
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Program Indicators Completion of therapy, 2002
Percentage completing treatment within 1 year
Missouri 84.4
Region 68.8
Rest of U.S. 69.7
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Program Indicators DOT, 2002
Percentage Receiving DOT
Missouri 87.6
Region 71.0
Rest of U.S. 70.9
DOT or DOTSA
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Preventable TB Case Analysis

• Nearly half of Missouris TB cases are
  preventable.
• The majority of preventable cases (85) involved
  a missed opportunity to screen patients with risk
  factors for TB.

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Recommendations

• Physicians in Missouri must remain aware of risk
  factors for TB and test at-risk asymptomatic
  persons
• - contacts of infectious TB patients
• - persons with medical risk-factors for TB

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Universal Genotyping of M. tuberculosis

• In 2004 CDC established the capacity to conduct
  universal TB genotyping. One isolate from every
  patient with TB can now be genotyped in real
  time.

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Value of Genotyping

• Identify and prevent recent transmission
• Enhance contact investigations
• Identify nontraditional settings of transmission
• Facilitate identification of outbreaks
• Improve clinical management
• More readily identify false-positive cultures
• Help distinguish between relapse and reinfection

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CDC Genotyping Program Laboratory Algorithm

• Two tiered testing to maximize discriminatory
  power
• PCR
• MIRU Variable number tandem
  repeats of
  
• 
  mycobacterial interspersed repetitive units
• Spoligotyping Spacer oligonucleotide
• IS6110-based RFLP
• Done only for isolates that match by both PCR
  tests
• When TB programs request it

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Spoligotyping

• PCR probes at 43 different sites

1 2 3 4 5 6 7 8 9 10 . . . . . . . . . . . . .
20 . . . . . . . . . . . . 30 . . . . . . . . . .
. . 40 . . . . 43
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Spoligotyping

• Does the probe recombine (hybridize) with
  genetic material at that site?
• Assign 1 or 0 to each of the 43 probes

No 0
Yes 1
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Spoligotyping

• 111-111-111-111-111-111-100-111-111-111-110-000-
  111-111-1

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Spoligotyping

• Each triplet gets assigned an octal code
• Spoligotype then reported as 15 digits
• 777777477760771

1 2 3 4 5 6 7 8 9 10 . . . . . . . . . . . . .
20 . . . . . . . . . . . . 30 . . . . . . . . . .
. . 40 . . . . 43
111 7
000 0
100 4
110 6
7 7 7 7 7 7 7 7
7 7
Always 1 or 0 for last probe
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MIRU Mycobacterial
Interspersed Repetitive Units

• Also uses PCR technologybut on a different part
  of the DNA
• Looks at 12 different loci and counts Variable
  Number Tandem Repeats (VNTR)

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MIRU
Sample Printout
Locus 6 3 repeats
Locus 4 3 repeats
CEQ 8000 Automated Sequencer
Locus 7 1 repeat
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MIRU

• Looks at 12 different loci and counts VNTR
• MIRU-VNTR pattern is then reported as a 12-digit
  number
• Example 123323153323
• means there are
• 3 repeats at Locus 6

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Reading Lab Report

• Look at spoligotype and MIRU pattern (i.e., the
  PCR tests) is the first step
• If dont match any other isolate, then not part
  of a cluster, no further testing needed
• If match another isolates PCR results, may
  indicate recent transmission

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When To Ask For RFLP?

• To decide if isolates with matching spoligo and
  MIRU are truly clusteredwhen you need additional
  evidence for or against match
• Not necessarily needed
• An unusual PCR cluster is likely a true
  cluster
• If it is obvious that the persons with matching
  isolates transmitted TB among each other

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RFLP

• Third method
• Less automated, requires more lab resources
• Experienced laboratorian must eyeball
• Each genotyping lab will assign unique number to
  each distinct RFLP in its database
• The PCR tests use standardized coding
• But the RFLP label in itself has no meaning
  outside the lab which assigned it

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RFLP

• Lab assigns unique number or label to each RFLP
  in its database
• RFLP designation arbitrary and does not
  correspond to genetic make-up

Ex 051 052 051
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Presence of Any Epidemiologic Links Discovered
during Contact/Cluster Investigations of 555
Cases in Intrasite Genotyping Clusters (NTGSN)
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Interferon-gamma Assays

• QuantiFERON Gold
• T Spot TB assay

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Interferon-gamma Assays

• QuantiFERON Gold now FDA approved
• Measures IFN release from T cells
• Based on M. tuberculosis specific antigens
• ESAT6 and CFP10
• Should not give false-positive result due to
• BCG vaccination
• Nontuberculous mycobacteria
• CDC working on publishing guidelines for use

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Interferon-gamma Assays

• T Spot TB assay
• Enzyme-linked immunospot assay
• Counts number of T cells producing IFN
• Based on ESAT6 and CFP10
• Not yet FDA approved (available in Europe)

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Treatment regimens for tuberculosisNew drug
candidates

• Andrew Vernon, MD, MHS
• Chief, Clinical and Health Systems Research
  Branch
• Division of TB Elimination
• March 2005

with thanks to Rick OBrien
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2004 Distribution of TB Trials Consortium
Clinical Sites
Barcelona
Kampala
28 clinical sites worldwide CDC
Administrative, Statistical, and Data Management
Center
Rio de Janeiro
Durban
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New drugs

• Moxifloxacin
• Ethambutol congeners (SQ-109)
• Diarylquinolines
• Nitroimidazole (PA-824)

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Fluoroquinolones

• No cross-resistance with other TB drugs
• Commonly used for MDR TB
• Role in therapy of drug susceptible TB uncertain

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Relative TB activity of Fluoroquinolones
HIGHEST Gatifloxacin, Moxifloxacin,
Sparfloxacin NEXT Levofloxacin LOWER
Ciprofloxacin , Ofloxacin
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Features of Quinolones and TB Therapy
Drug Serum Peak Half life TB
MIC Ciprofloxacin 750 2.3 4 2.0 Ofloxacin
400 4.6 7 2.0 Levofloxacin 500 6.0
7 1.0 Sparfloxacin 400 1.3
20 0.5 Gatifloxacin 400 4.4
7 0.5 Moxifloxacin 400 4.5 12 0.5
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Activity of Moxi in Combination Therapy
2/5 mice had 1 cfu each
2.5 logs
6/6 mice culture pos.
3/6 mice culture pos.
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Clinical Trails of Moxifloxacin

• Multiple studies substituting moxi for ethambutol
• CDC plans phase II trial substituted moxi for INH
  (MRZE) vs. the standard control regimen (HRZE)
• Will measure sputum-culture conversion
• If successful, future plan to move clinical
  trials of Moxi in very short regimens (lt6 months)

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Congeners of Ethambutol

• Targeting the enzymes involved in long chain
  fatty acid metabolism unique to mycobacteria
• Based on computerized screening of possible
  compounds for predicted activity based on organic
  structure (Dr. Cliff Barry and colleagues
  NIAID)
• Current lead compound SQ-109 moving into animal
  and human trials soon (Sequella Inc.)

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Diarylquinolines (DARQ)(lead compound R207910)
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Nitroimidazoles

• Potent bactericidal antitubercular compound
  series
• Narrow spectrum of activity (TB specific)
• Promising efficacy comparable to INH in animal
  models
• Active on non-replicating (latent?) TB
• Leading candidate PA-824

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PA-824 development

• Acquired by Global Alliance for TB Drug
  Development
• Currently being developed in partnership with
  Chiron
• Animal efficacy studies promising
• Animal and human toxicology studies to begin soon

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What are the prospects for more new drugs soon?

• Moxifloxacin in multiple clinical trials
• Ethambutol congeners (SQ-109) moving to
  clinical phase
• Diarylquinolines (DARQ) moving to clinical
  phase
• Nitroimidazole (PA-824) in pre-clinical phase

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Case of the Week An 18-year-old man with no
clinically significant medical history presented
with a 6-month history of an increasing mass on
the left side of his back
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Overview of National TB Surveillance System

• Data reported from 59 reporting areas
• 50 states
• D.C. and New York City
• Puerto Rico
• 6 jurisdictions in Pacific and Caribbean

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U.S. TB Case Definition

• Incident cases, active disease
• Three alternatives
• 1. Bacteriological confirmation (81)
• 80 culture confirmed
• 2. Clinical evidence (12)
• 3. provider diagnosis ( 7)

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TB MorbidityUnited States, 1999-2003
Year Cases Rate
2000 16,377 5.8 2001 15,989
5.6 2002 15,075 5.2 2003 14,874
5.1 2004 14,511 4.9
Cases per 100,000
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TB Case Rates by Age Group and Sex, United
States, 2003
Cases per 100,000

Cases per 100,000.
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Cohort Effect and TB Mortality Rates,
Massachusetts
1880 data
Cohort of 1880
Frost, Amer J Hyg, 1939
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TBI Risk Factors - US-born population
Factor Adjusted Odds Ratio 95 CI
Race-Ethnicity    
White Non-Hispanic 1.0  
Black Non-Hispanic 7.5 3.6- 15.3
Mexican-American 5.2 2.5- 10.5
Other 2.6 0.2- 30.3
Socio-Economic Status    
Poverty Income Ratio gt 1 1.0  
Poverty Income ratio lt 1 1.9 1.0-  3.8
Sex    
Female 1.0  
Male 1.9 1.1- 3.1
Age Group    
1-14 years 1.0  
15-24 years 2.2 0.2- 30.9
25-44 years 6.0 1.2- 29.2
45-64 years 21.4 4.7- 97.0
65 years 34.3 6.0- 196.2
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TBI Risk Factors Foreign-born population
Factor Adjusted Odds Ratio 95 CI
Race-Ethnicity    
White Non-Hispanic 1.0  
Black Non-Hispanic 1.0 0.4- 2.3
Mexican-American 0.9 0.4- 2.1
Other 1.0 0.4-2.5
Socio-Economic Status    
Poverty Income Ratio gt 1 1.0  
Poverty Income ratio lt 1 1.7 0.7-4.0
Sex    
Female 1.0  
Male 2.0 1.3-3.0
Age Group    
1-14 years 1.0  
15-24 years 1.0 0.3- 4.9
25-44 years 2.0 0.9- 4.7
45-64 years 3.0 1.2- 7.6
65 years 1.0 0.3-3.0
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Relative Risk of TB Each Year After Initial
Infection1
1. Sutherland I. KNCV 1968
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TB Outbreaks Grow Slowly
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Case-Patients by Date of Diagnosis Oklahoma,
2001-2002 (N35)
Culture confirmed
Clinical Case
Index
2001
2002