Dr. Richard Chaisson, Professor of Medicine, Epidemiology and International Health and Director of the Center for Tuberculosis Research at the Johns Hopkins University in Baltimore was the keynote Jan. 19 as part of the Washington Global Health Discovery Series. His talk was on ""What Will It Take To Control TB?"

1. What Can Be Done to
Control Tuberculosis?
Richard E. Chaisson, MD
Center for Tuberculosis Research
Johns Hopkins University

2. A History of TB Control:
Mission Accomplished?
• 1882 – Koch discovers the tubercle bacillus*
• 1907 – von Pirquet adapts Koch’s tuberculin
• 1919 – Calmette and Guerin produce BCG vaccine
• 1943 – Schatz and Waksman discover streptomycin*
• 1948 – BMRC trial of streptomycin vs bed rest
• 1952 – Development of INH
• 1966 – Development of rifampin
• 1978 – Short-course TB therapy  6 months
*Awarded Nobel Prize

3. Federal Funding for Tuberculosis Research
and Control, 1962 - 1990
BR Bloom and CJL Murray, Science 1992;257:1055-64

4. Reported Tuberculosis Cases in the United States, 1953 - 1999
80000
Number of cases (log scale)
40000
20000
1950 1960 1970 1980 1990 2000
Year of notification
Centers for Disease Control and Prevention
Reported Tuberculosis in the United States, 1999

5. Estimated Global Incidence of Tuberculosis,
1990 - 2005
140
Cases per 135
100,000
130
125
120
1990 1995 2000 2005
WHO 2007

6. WHO Estimates of Global Burden
of Tuberculosis as of December 31, 2008
Estimated Estimated
number of number of
cases deaths
All forms of TB 9.4 million 1.3 million*
MDR-TB 511,000 ~150,000
XDR-TB 50,000 30,000
*excludes 500,000 HIV-TB deaths

7. TB Incidence in Africa, 1990 and 2005
Chaisson and Martinson, N Engl J Med 2008;358:1089

8. XDR TB outbreak in
Tugela Ferry, South Africa
Survival of XDR TB Patients at the
Church of Scotland Hospital (N=53)
1.1
1.0
.9
.8
Proportion Surviving
.7
.6
.5
.4
.3
.2
.1
0.0
-.1
0 30 60 90 120 150 180 210 240
Days since Sputum Collected
Gandhi et al., Lancet 2006; 368:1575-80

9. TB in HIV+ Patients at Chris Hani
Baragwanath Hospital, Soweto, South Africa
– TB admissions 2005-2008:
• 6500-6800 per year
• 18-20 new cases per day
– 85% HIV+
– >90% fully drug susceptible
– Inpatient mortality = 18%
• ~1200 deaths per year from
drug-susceptible TB
Edgington et al., Int J Tuberc Lung Dis 2006;10:1018; ML Wong, pers. comm.; Martinson et al., AIDS. 2007;21:2043 Shah et al., JAIDS
2009, epub

10. Tools to Control of Tuberculosis
What went wrong?
• Failure to apply tools broadly
– Weaknesses in health systems
• Inadequacies of existing tools
– Smear detection of cases ~50%
– Adherence to regimens is very poor
– BCG vaccine does not prevent adult TB
• Changing epidemiological situation
– HIV epidemic and other co-morbidities
– MDR
• Lack of understanding of best
epidemiologic approaches

11. An Epidemiological Model of Tuberculosis in the United States
INFECTED
Step 1
CASES
Infected
Step 4 Cases
Step 2
Step 3
UNINFECTED
Ferebee, SH. Natl Tuberc Assoc Bull 1967;53:4

12. An Epidemiological Model of Tuberculosis in the United States
INFECTED
Interventions to control TB
Step 1 Find and treat cases: Steps 2 and 4
Treat latent TB: Steps 1 and 3
Vaccinate susceptible: Step 2
CASES
Step 4
Step 2
Step 3
UNINFECTED
Ferebee, SH. Natl Tuberc Assoc Bull 1967;53:4

13. The Kolin Study of Tuberculosis Control with
Mass Case Finding and Treatment
Mass case finding
Type 1960 1961 1962 1963 1964
New Cases 46 132 61 88 47
Relapses 29 25 18 13 16
Chronic 29 40 17 11 8
Other 26 26 42 14 20
Total 150 233 138 126 91
Rates per 100,000 Population
“It is concluded from the study that in developed countries priority should be given to
adequate treatment of all persons with active tuberculosis, and to early diagnosis in
persons consulting physicians and in the high-risk populations.”
Styblo et al., Bull WHO 1967;37:819-74

14. World Health Organization Strategies for
Tuberculosis Control, 1974 – present
• Passive case detection and treatment
– DOTS targets added in 1991
• 70% case detection, 85% cure rate
• BCG vaccination of all children at birth
• Isoniazid preventive therapy for young
children exposed to smear-positive cases
(PPD+)

15. Epidemiologic Basis for TB Control
Key Considerations for Strategies
• Where are the seedbeds of tuberculosis?
– Who has latent TB infection?
– Who amongst these is most likely to develop disease?
• Who has active TB and how can they be reached?
– What proportion of cases are detected, and when?
– Is treatment effective in controlling spread?
• Where is TB transmission occurring, and how can
it be curtailed?
– Who are the contacts of cases who become infected?
– What measures can be taken to reduce transmission?
• What can be done to reduce susceptibility?
– Vaccination
– Antiretrovirals
– Control of co-morbidities, e.g., diabetes

16. The Origin of TB Cases:
Prevalence of Risk Factors in Patients with Culture-Confirmed
Pulmonary TB in Baltimore
Characteristic No. (Total = 139) %
Foreign born 12 9%
HIV Infection 31 24%
IDU 28 20%
Diabetes 18 14%
Renal Failure 12 9%
Recent Cancer 8 6%
Steroid Use 7 6%
Oursler et al., CID 2002;34:729-9

17. TB Incidence and Prevalence of Diabetes, 2010 and 2030
Dooley and Chaisson, Lancet Infect Dis, 2009; 9: 737–46

18. Smoking and incident TB in HIV-infected adults
in Soweto, South Africa
Pack Pack
years Incidence IRR years Incidence IRR
6.5 6.7
<1 REF Never REF
(5.9-7.4) (6.0-7.6)
9.0 1.36 7.8 1.15
1-5 Past
(6.8-11.7) (1.01-1.82) (5.8-1.2) (0.9-1.55)
12.8 1.95 10.7 1.59
>5 Current
(9.7-16.7) (1.44-2.60) (8.4-13.4) (1.21-2.05)
Martinson et al CROI 2008

19. Biomedical Tools and Public Health
Control of infectious diseases requires:
- effective biomedical tools (diagnostics,
drugs and vaccines) and
- effective public health strategies for
applying and utilizing the tools at the
population level to reduce disease burden

20. Current Tools for Controlling TB
Target Available tools
Diagnostics Sputum smear, culture, x-rays, (molecular assays)
Drugs Isoniazid, rifampin, PZA, ethambutol, 2nd line
drugs
Vaccine BCG (>10 strains)

21. Current Strategies for Controlling TB
• Passive case finding (DOTS)
– Relying on sputum smear (~50% sensitivity)
– No drug susceptibility testing
– Most cases not diagnosed or effectively treated
• INH preventive therapy
– Rarely used outside US and Europe
• BCG Vaccination
– Most widely used vaccine, but not effective
• Infection control
– Little attention has been paid to controlling
transmission

22. A Platform for Controlling Global Tuberculosis
• FIND the TB that is there
– Passive case detection is not sufficient
• TREAT the TB that is found
– Treatment success is unacceptably low
– Treatment for M/XDR is abysmal
– New drugs and treatment strategies urgently needed
• Prevent the TB that hasn’t occurred yet
– Preventive therapy essential for high risk populations
– Infection (transmission) control critical
– Control susceptibility (antiretrovirals, diabetes control)
– New vaccine essential

23. FIND TB
• Identify TB suspects
– Symptomatic screening in health facilities
– Campaigns to identify prevalent cases
• Community-based active case finding
• Evaluate TB suspects
– Better use of existing technologies
– New technologies

24. Estimated TB case detection rates
in 2008, by WHO region
90
78 78
Case detection rate (%)
80 70
70 65
57
60
47
50
40
30
20
10
0
a
a
R
pe
fic
as
ic
si
EM
ic
ro
ci
fr
A
er
Pa
A
Eu
st
m
Ea
rn
A
te
th
es
u
So
W
WHO 2009 EMR = Eastern Mediterranean Region

25. Routine detection of TB in HIV-infected
patients in Vietnam and Thailand
Diagnosis N detected/N Percent
Any TB 147//1060 14%
Pulmonary only 61/147 42%
Extrapulmonary only 21/147 14%
Both 65/147 44%
Pulmonary Cases
Smear + 47/126 37%
Liquid culture + 124/126 98%
Lymph node aspirates
Smear + 16/52 31%
Culture + 34/82 42%
Monkongdee et al., AJRCCM 2009, epub

26. Outside the HIV Clinic:
Prevalence of Active TB with Case Finding in HIV-Infected
Populations
Setting Time Prevalence of Active TB
Population Studied Period in Population
HIV+ Women in HIV MTCT Soweto 2001 13% OF TST+
Program South 3% overall
(N=438) Africa
Patients in HIV Home Care Phnom 2001 9% of patients
Program (N=441) Penh
Adults in HIV VCT Program Cape 2000-1 8% of HIV+
(N=5000) Town
Adult residents of an urban Cite Soleil 1991-2 6% of HIV+
shantytown Haiti 2% of HIV–
(N=10,900)
Nachega 2003; Kimerling 2002; Coetzee 2005; Desourmeaux 1996

27. Should we consider campaigns to detect
prevalent, untreated TB cases?

28. Impact of mass radiography on TB case
detection, incidence and survival
• 1945-1948 – USPHS screened 6 million people in
21 communities with CXR
– 85-90% of cases unknown to local health depts.
– TB mortality decreased significantly
• 1950’s – USPHS used mass x-ray on ships, trains,
airplanes and dog sleds to screen Alaskan natives
– Tuberculosis mortality declined
• 665/100,000 in 1950
• 116/100,000 in 1957
Golub et al., Active case finding of tuberculosis: historical perspective and future prospects. IJTLD
2005;9:1183

29. Rocinha favela, Rio de Janeiro

30. A cluster-randomized trial of door-to-door active
case finding for TB in Rio de Janeiro
(14 clusters, 58,587 residents)
Analysis Time Household Pamphlet Rate ratio
Case Finding Only (95% CI)
TB incidence TB incidence
Intervention only 9.34/1000 py 6.04/1000 py 1.55 (1.10, 1.99)
Intervention plus 5.16/1000 py 4.93/1000 py 1.05 (0.56, 1.54)
60 days
Post-intervention Pre-intervention Rate ratio
TB incidence TB incidence (95% CI)
Entire Study 4.5/1000 py 3.4/1000 py 1.3 (0.97, 1.77)
Miller et al., IJTLD in press

31. Availability of culture and drug susceptibility
testing in TB/HIV high-burden countries
Country Culture Drug Susceptibility Testing
N of Labs N per 5 million N of Labs N per 10 million
South Africa 15 1.5 10 2.1
Nigeria 2 0.1 1 0.1
Ethiopia 1 0.1 1 0.1
DR Congo 1 0.1 1 0.2
Kenya 5 0.7 1 0.3
Tanzania 3 0.4 1 0.2
Uganda 3 0.5 2 0.6
Zimbabwe 1 0.4 1 0.7
Mozambique 1 0.2 1 0.5
Cambodia 3 1.0 1 0.7
WHO Global TB Report, 2009

32. New TB Diagnostic Tools
• LED fluorescent microscopy
• Liquid culture (e.g. MGIT)
• Capilia TB
– Rapid strip test that detects a TB-specific antigen from
culture
• Molecular assays (e.g. Cepheid GeneXpert,
Hain GenoType MTBDRplus)
– Rapid detection
of TB and drug-resistance

33. Impact of Improving Case Finding and Treatment on
Tuberculosis Control: A Mathematical Model
1000
TB Incidence, per 100,000
900
800
700
600
0.0%
500 -1.0%
-0.3%
400 -2.1%
-1.5%
300 -0.3%
-2.8% -1.8%
200 -0.7%
-3.4% -2.5% -1.0%
100 -11.2% -2.9% -1.4%
-0.8% -0.7% -4.2%
0 -0.6% -4.6% -3.3%
0 20 40 60 80 100
Year/Case Detection Rate (%)
Increase CDR to 70% immediately, then hold
Hold CDR constant constant
Increase CDR by 1%/year 22 High burden countries
Increase CDR by 2%/year
Dowdy and Chaisson, Bull WHO 2009: 87:296–304

34. TREAT TB
• Assure treatment completion for all patients
• Prevent the emergence of drug resistance
• Manage co-morbidities
– HIV, diabetes, ESRD, IDU
• New drugs to improve therapy
– M/XDR TB treatment
– Treatment-shortening regimens

36. Rocinha Family Health Program
Community Health Worker Team

37. Results of DOTS: Health Center-Based versus
Community-Based using CHWs
DOTS at Health Center DOTS CHWs
N= 565 N=331
Non-slum Patients Slum Patients Slum Patients
Cure, all cases 272/355 (77%) 165/210 (78%) 288/331 (87%)
Cure, new cases 236/289 (82%) 138/164 (84%) 230/261 (88%)
Cure, new smear +
106/134 (79%) 82/98 (84%) 135/153 (88%)
cases
Cure, retreatment
36/66 (55%) 27/46 (59%) 58/70 (83%)
cases
Abandoned 39/355 (11%) 27/210 (13%) 16/331 (5%)
Cavalcante et al., Int J TB Lung Dis 2007;11:544-9

38. New Drugs for TB
• Fluoroquinolones
– Moxifloxacin
• Rifapentine
• TMC 207 (ATP synthase inhibitor)
– In Phase 2 trials for MDR TB in Africa
• Nitroimidazopyrans
– PA-824
– OPC-67683
• Phase 2 trial for MDR TB beginning in January 2008
• Diamines (SQ-109)
– Phase 1 studies complete, awaiting Phase 2
• Oxazolidinones
• >12 other new compounds in development

39. Moxifloxacin vs. Ethambutol as 4th Drug in Initial
Phase of TB Therapy:
Culture Conversion by Week
MOX EMB
100
0.02
0.14
80 0.30
0.01 0.01
% Culture 60 0.0001
Negative 40 0.001
0.04
20
0
0 1 2 3 4 5 6 7 8
Week of Treatment
Conde et al., Lancet 2009; 373:1183-9

40. Bactericidal activity of daily regimens in
mice
8
R10H25Z150
RIF10 INH PZA
7
Log10 CFU per lung
R10M100Z150
RIF10 MOX PZA
6
2 logs P10M100Z150
RPT10 MOX PZA
5
4
3 4
2 logs
1
0
0 2 4 6 8 10 12 14 16
Weeks
Rosenthal et al., PLoS Medicine 2007;4(12):e344

41. TMC 207 for MDR TB
Culture conversion at 2 months
8.7%
culture
negative
47.5%
culture
p = 0.003 negative
Diacon et al., N Engl J Med 2009;360:2397

42. PREVENT TB
• TB preventive therapy for high-risk
individuals without active TB
• Contact evaluation and treatment
• Prevention of nosocomial transmission

43. Isoniazid Preventive Therapy:
The (George) Comstock Lode

44. TB Rates in the 6 Years After 1-year of Treatment
with INH or Placebo in the Bethel Trial
16
14
TB per 1,000 PY
12
10
Placebo
8
INH
6
4
2
0
1 2 3 4 5 6
Year After Randomization
Cumulative reduction 5.1%  2.1% = 60%
GW Comstock, Ferebee SH, Hammes LM.. Am Rev Respir Dis 1967;95:935-43.

45. Efficacy of IPT in HIV+ Adults: Risk
of TB
• 11 randomised trials with 8,130 HIV+ participants 
overall reduction in TB = 36%, reduction PPD+ = 62%
Relative Risk (Fixed)
95% CI
1.0
Reference
0.64
TB incidence
0.95
Death
Woldehanna and Volmink, Cochrane Review 2006

46. TB screening, treatment and IPT 2002-2008
By 2008, 1 out of 4 estimated HIV positive TB
patients were identified and put on TB treatment
1200.0
59
2002
1000.0 2003
2004
Thousands of patients
2005
800.0 2006
71 2007
600.0 2008
400.0 44
14 77 63
200.0
84 58
17 28
59 7 63 3 72 28 3 26 10 25 42
0.0
Screened for TB Diagnosed with TB IPT
Data for 2008 is preliminary and does not include data from European region

47. Infection Control?

49. New paradigms
• What can be done now to control TB in
communities with high burdens of TB?
• How can multiple interventions be
combined to yield maximal effects?

50. CREA E
Mission
To organize, implement and evaluate novel
public health strategies to reduce tuberculosis
incidence in populations with high rates of HIV
and TB co-infection.
Funded by the Bill and Melinda Gates Foundation

51. The CREATE Portfolio of
Population-Level Studies
Study Intervention Design (N)
Mass TB preventive Cluster randomized
therapy for S.A. gold trial
miners (~60,000)
Intensified TB case Community
finding, contact randomized trial
evaluations in Zambia (~1.2 million)
and S.A.
Preventive therapy and Phased
ARVs for HIV patients implementation trial
in Rio de Janeiro (15,000)

53. Prevalence of INH resistance after
receiving IPT vs. controls without IPT
7/58 (12.1%) First
episodes
12/200 (6.0%)
32/270 (11.8%)
1/13 (7.7%) Retreatment
episodes
14/75 (18.7%)
van Halsema, IAS 2009

54. ZAMSTAR
• 24 communities in South Africa and
Zambia
• Designed to reduce TB prevalence through
– improved TB case finding by increased access
to TB diagnostics for symptomatic persons
– Household interventions for families of TB
patients, which include HIV testing and
treatment, TB screening, and IPT for contacts
of TB cases
PIs: P. Godfrey-Faussett, H. Ayles,
N. Beyers

56. ZAMSTAR
Preliminary Results
• Baseline population surveys
– TB prevalence 900/100,000 in Zambia and
2,200/100,000 in South Africa!
• Enhanced Case Finding
– 15-26% of all TB cases in intervention
communities detected by ECF
• Household evaluations
– >2-5% of households have secondary TB case
– ~50% contacts HIV tested
• HIV prevalence high - ~50%
• >50% HIV+ started on ART

57. The THRio Study:
A Clinic - Randomized Trial of INH
Preventive Therapy in HIV+ Patients
• 29 HIV clinics randomized to time that IPT
program initiated
• TB rates compared pre- and post- intervention
29
4 Control
Clinic 3 Follow-up
2 Intervention
1
1 2 3 4 5 30 36 42
Month

58. TB Rates by ART and INH
Treatment Status, 2003-2005
Exposure Person- TB Incidence Rate Percent
category Years Cases (per 100 PYs) Reduction
No Rx 3,865 155 4.01 (3.40-4.69) -
ART only 11,627 221 1.90 (1.66-2.17) 52%
IPT only 395 5 1.27 (0.41-2.95) 68%
Both 1,253 10 0.80 (0.38-1.47) 80%
Total 17,140 391 2.28 (2.06-2.52)
Golub et al., AIDS 2007;21:1441-8

59. Tools and Strategies for Reducing the
Global Burden of TB
• Improved diagnostics ( case finding)
– Better tests
– Campaigns to find prevalent cases
• Improved therapy ( treatment completion)
– Shorter duration regimens to assure adherence
– New drugs for MDR/XDR TB
• Prevention
– INH preventive therapy
– Reduction of susceptibility (ART, diabetes, smoking)
– Effective vaccine
• Combination of approaches essential

60. Lessons from Tuberculosis Control for
Communicable Disease Control
• Good biomedical tools are essential but not
sufficient for disease control
• Understanding the epidemiology and
dynamics of the disease is essential for
targeting interventions
• Trials of control that measure population
level impacts are important
• It ain’t over till it’s over!

61. With thanks to…
Jonathan Golub Neil Martinson
Ann Miller Peter Godfrey-Faussett
Solange Cavalcante Gavin Churchyard
Betina Durovni Liz Corbett
Jacques Grosset Eric Nuermberger
Larry Moulton The CREATE Team
Marcus Conde Generous funders - BMGF
David Dowdy NIH, CDC, FDA

62. Thank you