1. William Burman Denver Public Health Tuberculosis Trials Consortium
Great needs, great opportunities: a critical time in tuberculosis research
William Burman
Denver Public Health
Tuberculosis Trials Consortium

2. Abdominal pain, fevers in a Sudanese refugee
34 year old man
7 weeks of non-bloody diarrhea, fevers, and diffuse abdominal pain
Weight loss of 12 kg, severe fatigue
Past history
Malaria X 5; meds - none
Travel – born in Sudan, to Egypt in 4/01
No prior TB or TB treatment

3. Initial evaluation Severely ill HIV-positive, CD4 – 6 (advanced AIDS)
Chest X-ray – minimal abnormalities
CT scan of the abdomen – enlarged lymph nodes, fluid (ascites)

4. Diagnosis / treatment TB from sputum, peritoneal fluid
Resistant to INH, rifampin, streptomycin
Diagnosis – disseminated MDR-TB
TB treatment for MDR-TB
8 weeks later – antiretroviral therapy
Completed TB treatment, working full-time

5. Diagnosis / treatment TB from sputum, peritoneal fluid
Resistant to INH, rifampin, streptomycin
Diagnosis – disseminated MDR-TB
TB treatment for MDR-TB
8 weeks later – antiretroviral therapy
Completed TB treatment, working full-time

6. Trajectories of TB incidence in nine
regions of the world
Lancet 2006;367:938-40

7. Prevalence of MDR-TB among previously untreated patients, 2009
Lancet 2009;373:

8. Drug resistance in Donetsk Oblast, Ukraine (2005-6), by prior treatment
Int J Tuberc Lung Dis 2008;12:756-62

9. Prevalence of primary MDR-TB in Tomsk Oblast, Russia
WHO: Antituberculosis drug resistance in the world: report #4 (2008)

10. Prevalence of MDR-TB in Africa over time – 2004, 2008, and current estimate
Orange: > 2% MDR among all TB cases
Emerg Infect Dis 2008; 14:

11. Survival of 654 patients with drug-resistant TB (Tugela Ferry, South Africa)
Most patients died before initial results of the culture were available
Am J Respir Crit Care Med 2010; 181: 80-86

12. Challenges to global TB control
HIV co-infection
Dramatically increases the risk of TB
Overwhelms TB control programs
May facilitate acquired and transmitted drug resistance
Multidrug resistance
Dramatically decreases response to therapy and use of treatment as prevention

13. Tools needed to regain TB control
Diagnostics
Rapid and sensitive diagnosis of active TB
Rapid detection of drug resistance
Treatment
Effective treatment for MDR-TB
Shorter treatment for drug-susceptible TB
Prevention
Better vaccine
Better infection control in high-burden settings

14. Rapid genotypic detection of drug resistance among smear positive sputum specimens
97% interpretable results
Am J Respir Crit Care Med 2008;177:787-92

15. Novel TB drugs in clinical development
TMC207
OPC67683
PA824
SQ109
PNU100480
Activity in
mouse model
Potent
Moderate
Stage of clinical
development
2B/3 2B 2A 1

16. Activity of TMC207 vs. placebo (both with optimized background therapy) for MDR-TB
N Engl J Med 2009;360:

17. Bottlenecks in TB clinical research
Better tools to guide early-stage development (analogous to viral load)
Insufficient funding for TB clinical research
Inadequate support for implementation research on how to get new tools into the field and assure appropriate research

18. The cycle of transient improvements in TB control
Intervention
Success
Complacency
Resurgence
Recognition

19. Summary – prospects for regaining momentum in global TB control
On the cusp of dramatic improvements in diagnosis and treatment of TB
Funding needed for clinical trials and implementation evaluations
Need to avoid the complacency of temporary success in the U.S.
“TB anywhere is TB everywhere”