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

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

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)

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

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

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

Prevalence of MDR-TB among previously untreated patients, 2009 Lancet 2009;373:1861-73

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

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

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: 1345-52

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

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

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

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

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

Activity of TMC207 vs. placebo (both with optimized background therapy) for MDR-TB N Engl J Med 2009;360:2397-2405

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

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

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”