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TB Epidemiology

Richard E. Chaisson, MDJohns Hopkins UniversityCenter for Tuberculosis Research

3

Richard E. Chaisson, MD

Professor of medicine, epidemiology, and international healthDirector of the Johns Hopkins University Center for Tuberculosis ResearchCo-founded the Johns Hopkins HIV Clinic cohortInterests focus on tuberculosis and HIV infection, including global epidemiology and control, prevention, clinical trials, and public health interventionsPrincipal investigator of the Consortium to Respond Effectively to the AIDS/TB Epidemic (CREATE)

Section A

General Epidemiology and Natural History

5

Statistics

“There are two kinds of statistics. The kind you look up and the kind you make up.”

— Archie Goodwin in Rex Stout’s Nero Wolfe

mystery Death of a Doxy, 1966

6

Highlights of 2006 Global TB Report

About 9 million new cases in 2004−

Sixteen million prevalent cases

−

Ninety-eight percent in developing countriesMore than 10% increase since 1997Increasing rates in Africa and Eastern Europe−

Decreasing elsewhere

1.9 million deaths−

Leading cause of death in people with HIV

Progress in case detection, but >50% still not diagnosed and treated!

7

Growth of TB in Africa and Eastern Europe

8

Estimated Number of TB Cases by Country, 2004

9

Estimated Incidence of TB by Country, 2004

10

Twenty-Two High-Burden Countries

11

Reported TB Cases, United States, 1982–2003

12

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

*Cases per 100,000

13Source: Comstock GW. Frost Revisited: The Modern Epidemiology of

Tuberculosis: The Third Wade Hamptom

Frost Lecture. Am. J. Epidemiol..1975; 101: 363-382. By permission of Oxford University Press. All Rights Reserved.

Cohort Analysis of Effect of Age on TB Incidence

14*Cases per 100,000

TB Case Rates* by Race/Ethnicity

15

U.S.-Born vs. Foreign-Born

16

Length of U.S. Residence Prior to TB Diagnosis, U.S.

17

Epidemiology of TB Fundamentals

Reservoir of infection humans (cattle)−

Virtually all transmission is person to person

Two-stage process−

Initial infection with M. tuberculosis

−

Progression from infection to disease

18

Epidemiology of TB Fundamentals

Risks for initial infection−

Source case factors

−

Environmental factors−

? Recipient factors

Risks for disease once infected−

Inoculum size

−

Cellular immunity−

Body habitus

−

Genetics

19

Exposure(close contact)

No infection70%

Infection~30%

Risk factors –

Close contact, BR>HH>Casual

–

Duration of contact –

Severity of disease, cough, cavities

Risk of Infection and Disease among Exposed Individuals

20

Number of Droplets Produced by Different Activities

21

TB Infection in Children by Type of Contact

22

TB Infection among Inflight Personnel

23

Risk of Infection and Disease among Exposed Individuals

24

HIV and Risk of TB Disease among Infected Individuals

25

Diagnostic Standards for Tuberculosis

Latent TBTuberculin skin test−PPD-S−Cutpoints

for positive−Nonspecific

Interferon-gamma assays

Active TBCXRSputum smear−Sensitivity 50%

Sputum cultureClinical criteria

26

TST Quantiferon

PPDQuantiferon

Gold

SensitivityCx+ TB pts

65.7%50/76 ≥5 mm

82.1%92/112+

89.0%105/118+

SpecificityBCG-vaccinated new nurses

35.4%40/113 <10 mm

56.0%108/192-

98.1%213/216-

Source: Mori et al. (2004, July 1). Am J Respir Crit Care Med, 170(1), 59–64.

Quantiferon for Latent and Active TB Diagnosis

27

ELISPOT and TST in School Contacts of Infectious TB

28

Response to ELISPOT or TST by BCG Vaccination Status

Vaccinated

(n = 467)Unvaccinated

(n = 68)

p for vaccinated

vs. unvaccinated

ELISPOTPositive

Negative131 (28.1%)

336 (71.9%)16 (23.5%)

52 (76.5%)0.44

Heaf

grade

4

3

2

1

0

52 (11.1%)

81 (17.6%)

110 (23.6%)

116 (24.8%)

108 (23.1%)

10 (14.7%)

2 (2.9%)

10 (14.7%)

13 (19.1%)

33 (48.5%)

0.002*

*χ2

test for trend across all five Heaf

gradesSource: Ewer et al. (2003, April 5). Lancet, 361(9364), 1168–1173.

Response to ELISPOT or TST by BCG vaccination status in a school TB outbreak

Section B

Epidemiologic Basis for TB Control

30

Strategies for Control of Tuberculosis

Detection and treatment of casesTreatment of latent infectionVaccination

31

Definitions of Tuberculosis Control

Diagnosis of 70% of all cases, with cure rates of 85%(WHO/IUATLD)

R0 <1−

Less than one secondary case for each new case

(Frost, 1937, Anderson and May, 1982)The incidence of tuberculosis goes down

32

Control Strategies for TB

33

Use Dots More Widely

34

DOT vs. DOTS

Directly Observed Therapy−

Supervision of all doses of TB medication by a health team member

Directly Observed Therapy, Short Course−

WHO policy for TB control, with programmatic imperatives to strengthen TB control efforts

35

What Is DOTS?

Governmental commitment to TB controlSystem for registration and follow-up of TB casesReliable supply of TB drugsMicrobiologic confirmation of TB diagnosisSupervision of at least the initial phase of TB therapy

36

TB Rates in U.S. Cities with High Incidence

37

Treatment Outcomes by WHO Region

38

DOTS Results in TB Incidence Decline

39

AFB Smears Performed by the TB Program, Peru

40

Full DOTS Implementation in Vietnam

41

What Can DOT(S) Do?

Increase treatment completion ratesReduce the emergence of drug-resistant TBImprove cost-effectiveness of TB controlIn conjunction with other interventions, reduce TB incidence

Section C

Challenges in TB Control

43

Challenges in the Control of Tuberculosis

HIV epidemicMDR tuberculosisHealth system weaknesses and lack of political will−

Poor infrastructure and lack of support

−

Weak organization of primary health services−

Private practitioners

−

Prisons

44

Tuberculosis and HIV

45

Tuberculosis and HIV

Estimated prevalence of HIV in adults (%)

Mea

sure

d pr

eval

ence

of H

IV in

TB

pat

ient

s (%

)

46

Uganda: Falling HIV Prevalence, Increasing TB Incidence

Rising TB incidence in setting of falling HIV prevalence in Uganda

47

TB in Botswana: Pre- and Post-DOTS, HIV

48

Reported TB Cases, U.S., 1979–1999

49

Major Challenges in HIV-Related TB

Case detection−

High prevalence of active TB in community

3% of HIV+ pregnant women8% of HIV VCT clients

−

Negative smears more commonTreatment of TB and HIV−

Drug interactions

−

Drug toxicity and adverse reactionsPrevention−

Use of preventive therapy

50Source: Espinal. (2001). N Engl J Med, 344, 1294–1303.

WHO/IAUTLD Survey of TB Drug Resistance, 1996–1999

Primary drug resistance—median 10.7%−

Primary MDR—median 1%

Acquired drug resistance—median 23%−

Acquired MDR—median 9.3%

MDR “hot spots” widespread

51Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin.

Primary MDR TB, United States, 1993–2002

52

MDR-TB and XDR-TB in HIV+ Patients, South Africa

41% of hospitalized patients in rural KwaZulu-Natal had MDR-TB25% of these had XDR-TB−

Resistant to first-

and second-line TB drugs

All HIV+52 of 53 diedMedian survival: 16 days

Source: Gandhi et al. (2006, August). International AIDS Conference, Toronto, Canada.

53

Global Approaches to MDR TB Control

Expansion and strengthening of DOTS−

Prevent creation of MDR cases through mismanagement

−

Assure access to drug supplyDOTS-Plus−

Second-line drugs for TB in setting of DOTS

−

Green Light Committee of WHOApproves proposals for national DOTS+ programs

New drug development−

Global Alliance for TB Drug Development

54

BCG* for Prevention of TB

Live attenuated vaccine derived from M. bovis early 1900s by Calmette and GuérinMost widely used vaccine in the worldEfficacy shown in clinical trials in 1930s–1950sRecent trials show lack of benefitGenetic evidence of attenuation of strain over years of laboratory passageNew vaccines in development, but will need to be compared with BCG

*Bacillus of Calmette

and Guérin (BCG)

55

Outcome/design Relative odds or risk 95% CI

TB preventionClinical trialsCase-control studies

0.490.50

0.34–0.700.39–0.64

Prevention of deathClinical trials 0.29 0.16–0.53

Meta-Analysis of BCG Effectiveness in 26 Studies

Source: Colditz

et al. (1994). JAMA, 271, 698–702.

56

Relationship to Lab Passage to BCG Efficacy

57

Strategies for Control of Tuberculosis: Limitations

Detection and treatment of cases−

Poor diagnostic capabilities

−

Poor compliance with treatment−

Emergence of drug resistance

−

HIV epidemicTreatment of latent infection−

Resources for screening and treatment

Vaccination−

Current vaccine doesn’t prevent disease or transmission

58

Imperatives for Controlling TB in the Coming Years

Expand DOTSIncrease case findingEvaluate and treat contacts of casesTreat high-risk patients with latent TBDecrease HIV prevalenceProvide effective treatment for HIVDevelop effective HIV and TB vaccines