Tuberculosis in the United States, 2004

Thomas R. Navin, MD

CDC

March 2005

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

Tuberculosis Case Rates and Death RatesUnited States, 1953 2003

TB Case Rates

TB Death Rates

Year

Rat

e p

er 1

00,0

00 P

op

ula

tio

n60

50

40

30

20

10

053 58 63 68 73 78 83 88 93 98 03

< 1.7

1.8 - 2.8

2.9 - 4.4

4.5 - 5.5 (national case rate = 4.9)

> 5.6

FIGURE 1. TB Case Rates* by State, United States, 2004

D.C.

*Rate: per 100,000 population Data are provisional

0

100

200

300

1994

1996

1998

2000

2002

2004

Year

Cas

es

Missouri

TB Case Reports, Missouri, 1994-2004

0

2

4

6

8

10

12

1994

1996

1998

2000

2002

2004

Year

Rat

e Missouri

Rest of U.S.

Region

TB Case Rates*, Missouri and United States, 1994-2004

* Rate per 100,000

1

10

1994

1996

1998

2000

2002

2004

Year

Rat

e Missouri

Rest of U.S.

Region

TB Case Rates*, Log Scale

* Rate per 100,000

FIGURE 2. TB Cases by Origin of Birth, Case Count, and Rate, United States, 1993-2004*

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Year of Reporting

TBC

ase

Cou

nt

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

Rat

epe

r10

0,00

0

No. foreign-born TB casesNo. US-born TB casesForeign-born case rateUS-born case rate

*Data are provisional.

Percent Foreign-born TB Cases, United States, 2004*

D.C.

*Percent foreign-born cases over total cases

57% – 66%

≥ 67%

41% - 56% (%foreign-born for U.S.= 53.7%)

26% - 40%

≤ 25%

0

10

20

30

40

50

1993 1995 1997 1999 2001 2003

TB Case Rates* by Race/Ethnicity** United States, 1993-2003

Ca

ses

per

10

0,00

0

WhiteBlackHispanic

American Indian/Alaska NativeAsian/Pacific Islander

*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.

Primary MDR TBUnited States, 1993-2003

0

100

200

300

400

500

93 94 95 96 97 98 99

0

1

2

3

No. of Cases Percentage

Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin.

No. of Cases Percentage

00 01 02 03

Primary MDR TB inU.S.-born vs. Foreign-born

Persons, United States, 1993-2003

0

1

2

3

1993 1995 1997 1999 2001 2003

U.S.-born Foreign-born

% R

esis

tan

t

Note: Based on initial isolates from persons with no prior history of TB.MDR TB defined as resistance to at least isoniazid and rifampin.

Estimated HIV Coinfection in Persons Reported with TB, United States,

1993-2002

0

10

20

30

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

All Ages Aged 25 - 44

% C

oin

fect

ion

Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group.

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%

Program Indicators: Completion of therapy, 2002

Percentage completing treatment within 1 year

Missouri 84.4%

Region 68.8%

Rest of U.S. 69.7%

Program Indicators: DOT*, 2002

Percentage Receiving DOT

Missouri 87.6%

Region 71.0%

Rest of U.S. 70.9%

* DOT or DOT+SA

Preventable TB Case Analysis

• Nearly half of Missouri’s TB cases are preventable.

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

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

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.

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

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

Spoligotyping

• PCR probes at 43 different sites

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

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

Spoligotyping

= 111-111-111-111-111-111-100-111-111-111-110-000-111-111-1

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 7 7 7 7 7 7 7 7 7 7

000 0

100 4

110 6

Always 1 or 0 for last probe

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)

MIRU

0

25000

50000

75000

100000

125000

150000

0 50 100 150 200 250 300 350 400 450 500 550 600Size (nt)

Dye

Sig

nal

60

68.64

7080

90

100 120

137.51

140 160 180

190

200

217.80

219.08

220

231.54

232.63

233.70

238.82

240

259.06

260 280 300 320 340 360

362.75

363.99

365.38

380 400 420 440 460480 500

520 540 560 580 600 620

Locus 4 3 repeats

Locus 63 repeats

Locus 71 repeat

CEQ 8000

Automated Sequencer

Sample Printout

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

Reading Lab Report

• Look at spoligotype and MIRU pattern (i.e., the PCR tests) is the first step

• If don’t match any other isolate, then not part of a cluster, no further testing needed

• If match another isolate’s PCR results, may indicate recent transmission

When To Ask For RFLP?

• To decide if isolates with matching spoligo and MIRU are truly clustered—when 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

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

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

Presence of Any Epidemiologic Links Discovered during Contact/Cluster Investigations of 555 Cases in Intrasite

Genotyping Clusters (NTGSN)

283; 51%272; 49%

No epi linksfound

Epi links found

Interferon-gamma Assays

• QuantiFERON Gold

• T Spot TB assay

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

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)

Treatment regimens for tuberculosis:New drug candidates

Andrew Vernon, MD, MHS

Chief, Clinical and Health Systems Research Branch

Division of TB Elimination

March 2005

…with thanks to Rick O’Brien

28 clinical sites worldwide

CDC Administrative, Statistical, and Data Management Center

Rio de Janeiro

Barcelona

Kampala

Durban

New drugs

• Moxifloxacin

• Ethambutol congeners (SQ-109)

• Diarylquinolines

• Nitroimidazole (PA-824)

Fluoroquinolones

• No cross-resistance with other TB drugs

• Commonly used for MDR TB

• Role in therapy of drug susceptible TB uncertain

Relative TB activity of Fluoroquinolones

HIGHEST: Gatifloxacin, Moxifloxacin, Sparfloxacin

NEXT: Levofloxacin

LOWER: Ciprofloxacin , Ofloxacin

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

0

1

2

3

4

5

6

7

8

9

10

0 1 2 3 4 5 6

Duration of treatment (mos.)

Log

CF

U in

ent

ire lu

ng

Untreated

2RHZ+4RH

2RHZM+4RHM

2RMZ+4RM

Activity of Moxi in Combination Therapy

2.5 logs

2/5 mice had 1 cfu each

6/6 mice culture pos.

3/6 mice culture pos.

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 (<6 months)

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.)

Diarylquinolines (DARQ)(lead compound = R207910)

Diarylquinolines (DARQ)(lead compound = R207910)

NitroimidazolesNitroimidazoles

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

PA-824 developmentPA-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

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

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

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

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%)

TB MorbidityUnited States, 1999-2003

Year Cases Rate*2000 16,377 5.82001 15,989 5.62002 15,075 5.22003 14,874 5.12004 14,511 4.9

*Cases per 100,000

TB Case Rates* by Age Group and Sex, United States, 2003

0

5

10

15

<15 yrs 15-24 yrs 25-44 yrs 45-64 yrs 65+ yrs

Male Female

Ca

ses

per

10

0,00

0

*Cases per 100,000.

Cohort Effect and TB Mortality Rates, Massachusetts*

0

200

400

600

800

1000

0 5 15 25 35 45 55 65

Age (yrs)

De

ath

Ra

te

pe

r 1

00

,00

0

1880 data

Cohort of 1880

* Frost, Amer J Hyg, 1939

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 > 1 1.0  

Poverty Income ratio < 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

TBI Risk Factors – Foreign-born populationFactor 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 > 1 1.0  

Poverty Income ratio < 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

Relative Risk of TB Each Year After Initial Infection1

0

0.2

0.4

0.6

0.8

1

1 2 3 4 5

Year Since Infection

Re

lati

ve

Ris

k

1. Sutherland I. KNCV 1968

TB Outbreaks Grow Slowly

0

1

2

3

4

5

6

7

8

1996 1997 1998 1999 2000 2001 2002 2003 2004

Years

Nu

mb

er o

f ca

ses

Case-Patients by Date of Diagnosis; Oklahoma, 2001-2002 (N=35)

0

2

4

6

8

Jun

Jul

Au

gS

ep Oct

No

vD

ecJa

nF

eb Mar

Ap

rM

ayJu

n

Jul

Au

gS

ep Oct

No

v

Ca

se

Culture confirmed Clinical Case

Index

2001 2002