Transcript New tools and technologies: the way forward

New tools and technologies:
the way forward
William Burman MD
Denver Public Health
Tuberculosis Trials Consortium
Presenter disclosures
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Chair - Data Safety and Monitoring
Board for TMC207 studies
Tibotec pays my employer for my time
What does it take to control
TB?
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Timely diagnosis – prevent morbidity,
mortality, and ongoing transmission
Infection control – hospitals, clinics
Drug-resistance testing – ensure correct
treatment
Adherence to multidrug therapy and caseholding – complete the treatment
Contact-tracing and treatment of contacts –
identify secondary cases, prevent active
disease
Current tools for TB control: United
States
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Diagnosis: sputum smear and culture
Infection control: negative pressure rooms
Drug-resistance testing: culture-based
methods
Treatment regimens:
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6 months for susceptible cases, 24 months for
MDR
Directly-observed therapy
Contact tracing: tuberculin skin test, chest Xray
Current tools for TB control: highburden, low-resource settings
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Diagnosis: sputum smear
Infection control: none
Drug-resistance testing: none
Treatment regimens:
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8 months for susceptible cases
MDR treatment usually not available
Increasing use of DOT
Contact tracing: not done
Sputum smear by HIV status
60
Percentage (%)
50
40
HIV positive
HIV negative
30
20
10
0
Negative
1+
2+
3+
Smear Status
Tubercle Lung Dis 1993;75:191-4
Diagnosis and management of children
with TB: high-burden settings
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Priority: low (“not the source of ongoing
transmission, do OK anyway”)
Diagnosis: smear positive in < 10%
Drug-susceptibility testing: not available
Treatment
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Inappropriate doses
Lack of child-friendly formulations – inexact
dosing (cut pills), extemporaneous
formulations with unproven PK
TB diagnosis and treatment – the
patient’s perspective (Zambia)
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Average of 6.7 health encounters prior
to diagnosis of TB
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63 days from first visit to diagnosis
Costs of “free TB care”
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Time off work (46%) for an average of 48
days
Travel to appointments – 16% of monthly
income
Needham DM, et al. Health Policy 2004; 67: 93-106
Rural KwaZuluNatal-Tugela Ferry
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KwaZuluNatal: Msinga, Tugela
Ferry
• 2,000 sq km rural district
• High rate of poverty,
unemployment
High incidence/prevalence TB
• TB incidence >1,054/100,000
• 70-90% % of TB cases HIV+
• High case fatality rate among
HIV+ (40% before ARVs)
High prevalence of HIV
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25-40% in antenatal attendees
G Friedland 2007
1539 Patients
with Isolates sent
544 patients
Culture-Positive for M.tb
323 (59%)
Not Resistant
to both Isoniazid & Rifampicin
221 (41%)
Resistant to INH & Rifampin
(MDR TB)
128 cases of MDR TB
In US in 2004
53
(10% Culture-Positive)
Resistant to all tested drugs
(XDR TB)
Lancet 2006 Nov 4;368:1575-80
Survival of 654 patients with drug-resistant
TB, from the time of sputum collection
Most patients died before initial results of
the culture were available
Am J Respir Crit Care Med 2010; 181: 80-86
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
How did this happen?
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Highly-susceptible population – HIV
Late diagnosis
Little, if any infection control measures
Lack of drug-susceptibility testing (“not a
problem in Africa”)
Overwhelmed treatment programs – hard to
assure DOT, treatment completion
No contact tracing
How did this happen?
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Highly-susceptible population – HIV
Late diagnosis
Little, if any infection control measures
Lack of drug-susceptibility testing (“not a
problem in Africa”)
Overwhelmed treatment programs – hard to
assure DOT, treatment completion
No contact tracing
Predictable that MDR-TB emerged in sub-Saharan Africa;
sobering how long it took to be recognized
What do we need to restore the
momentum in TB control?
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Diagnosis: point-of-care test that is highly
sensitive (HIV, children) and specific
Drug susceptibility testing: 1-day test suitable
for district hospitals
Treatment
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1-2 month regimens for susceptible TB
6 month, well-tolerated regimens for MDR
Validated pediatric dosing, child-friendly
formulations
What do we need to restore the
momentum in TB control? II
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Infection control in high-burden settings
Better vaccine
Political will and funding to make new
tools available where needed
Prospects for new tools for TB control
PCR-based detection and drugresistance testing (GeneXpert)
Sensitivity and specificity of
GeneXpert system (n = 1730)
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Detection of M. tuberculosis (1 specimen)
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Sensitivity
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Smear-positive: 98%
Smear-negative: 73% (3 specimens: 90%)
Specificity – 99%
Detection of RIF-resistance
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Sensitivity: 98%
Specificity: 98%
Boehme C, et al. N Engl J Med 2010; 363:1005-15
New diagnostic tests for TB
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Latent TB
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Interferon gamma release assays: more
sensitive and more specific
Active TB
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More sensitive microscopy systems
Rapid culture systems (7-14 days)
Nucleic acid amplification-based tests
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More sensitive (approaching culture) and more
specific than sputum smear
Challenges in the application of new
diagnostic tests
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U.S.
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Shrinking TB control budgets
Familiarity with old, “inexpensive” tests
High-burden settings
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Technical demands of culture, current
nucleic acid amplification systems
Algorithms for targeting use of tests
Funding to support roll-out
Laboratory personnel
Tuberculosis drug development –
the Rip van Winkle disease
PZA
INH
Strep
Ethambutol
Rifampin
RPT
2010
1998
1968
1965
1956
1952
1944
Current options for improving TB
treatment
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Fluoroquinolones
Enhanced dose rifamycins
Novel drugs – new mechanisms of action,
active against MDR / XDR (as well as drugsusceptible strains)
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TMC207
OPC-67683 / PA824
SQ109
PNU100480
4 possible new drug classes
Effect of TMC207 vs. placebo (both with an
optomized background regimen) on sputum
culture conversion in patient with MDR-TB
9%
48%
P = 0.003
48%
(N = 44)
N Engl J Med 2009;33:1389-95
Prospects for improvements in TB
treatment – next decade
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MDR-TB:
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Drug susceptible TB
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Reliable regimen of 12 months or less
duration (from 24 months)
Marked improvement in tolerability of
therapy
3-month regimen (from 6-9 months)
Latent TB
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1-2 month regimen (from 9 months)
Challenges in improving TB
treatment
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Clinical trials capacity – esp. pediatrics
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U.S.
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NIH is expanding involvement in TB trials
TB control program funding cuts
High-burden settings
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Funding for Global Fund
Assuring appropriate use of new drugs –
prevent MDR 2.0
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Combined formulations
TB vaccine development
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BCG – most widely used vaccine in the
world
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Marked variability in strains
Limited efficacy – esp. in high-burden
settings
Can cause disease in persons with HIV
New vaccines – in early clinical trials
Will this momentum in new tools for
TB control be sustained?
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Incentives for developing products for
neglected diseases
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Problems of using patent exclusivity
Monetary prize for major advance
Markets in emerging economies
Continued involvement by governments,
foundations, Public-Private Partnerships
Great needs – great opportunities
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Major improvements in TB diagnosis
and treatment on the horizon
Major challenges to ensure that these
improvements are made available to TB
patients – in the U.S. and high-burden
settings
With recognition and political will, these
challenges can be met