Great needs, great opportunities: a critical time in tuberculosis research

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Great needs, great opportunities a critical time
in tuberculosis research

• William Burman
• Denver Public Health
• Tuberculosis Trials Consortium

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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

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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)

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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

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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

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Trajectories of TB incidence in nine regions of
the world
Lancet 2006367938-40
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Prevalence of MDR-TB among previously untreated
patients, 2009
Lancet 20093731861-73
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Drug resistance in Donetsk Oblast, Ukraine
(2005-6), by prior treatment
Int J Tuberc Lung Dis 200812756-62
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Prevalence of primary MDR-TB in Tomsk Oblast,
Russia
WHO Antituberculosis drug resistance in the
world report 4 (2008)
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Prevalence of MDR-TB in Africa over time 2004,
2008, and current estimate
Orange gt 2 MDR among all TB cases
Emerg Infect Dis 2008 14 1345-52
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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
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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

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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

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Rapid genotypic detection of drug resistance
among smear positive sputum specimens
N 536 97 interpretable results
Am J Respir Crit Care Med 2008177787-92
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Novel TB drugs in clinical development
Drug TMC207 OPC67683 PA824 SQ109 PNU100480
Activity in mouse model Potent Potent Potent Mod
erate Potent
Stage of clinical development 2B/3 2B 2A 2A 1
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Activity of TMC207 vs. placebo (both with
optimized background therapy) for MDR-TB
N Engl J Med 20093602397-2405
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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

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The cycle of transient improvements in TB control
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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