Transcript TB and HIV - Treatment Action Campaign

Accelerating
the development of faster acting and
affordable drug combinations
to fight tuberculosis.
Community Advocacy for New Tools
and Strategies to Address TB/HIV:
TB Treatment
Christo van Niekerk
Tuberculosis (TB)
• Tuberculosis, an ancient and relentless
pandemic, continues to ravage continents,
societies and families.
• Yet today the world still depends on
outdated drugs delivered in a complex
multi-drug regimen for six or more months.
• No new drugs have been introduces in 30
years
Global Epidemic
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2 billion people are infected with M. tb
9 million new active TB cases a year
2 million people die/year; 1/15 sec
~ 400,000 new cases of MDR-TB a year
12 million persons are TB/HIV co-infected
Biggest killer of women of childbearing age
Economic toll: $12 billion a year
Current TB therapy, though efficacious, is
inadequate to control the global TB
epidemic - too long and too complex
Factors Contributing to Current
TB Epidemic
• HIV epidemic
• failing public health infrastructures
• increasing poverty and homelessness
• IV drug use (living conditions)
Tuberculosis (TB)
• A disease caused by a bacterium (bug):
Mycobacterium tuberculosis (M. tb; MTB)
• 50 years after introduction of an effective
drug, TB remains 2nd only to AIDS as the
leading infectious cause of death in the
world
Natural History of TB
(in the absence of HIV infection)
50%
50%
10%
90%
Clinical Presentations
• Latent TB Infection
• Pulmonary TB
– Smear positive (cavitating)
– Smear negative
• Extra Pulmonary TB
• TB in children
– Miliary TB
– TB meningitis
– Pulmonary TB
– Other
State of the
Field
• Lengthy - 6-8 months of 4 drugs taken in
combination
• Outdated – drugs discovered in 1940s, 1950s,
armamentarium dwindling
• Cumbersome - direct monitoring by healthcare
workers, <50% of smear+ cases receive
standard of care
• Poor results - Incomplete treatment results in
drug-resistant strains, and relapse
• TB and HIV treatment not easily coadministered
We need a new treatment!
TB and HIV
• A total of 12 million people worldwide are coinfected with both diseases, with a majority of
them living in Southern Africa.
• In sub-Saharan Africa, two-thirds of TB patients
are co-infected with AIDS.
• When someone with latent TB becomes coinfected with HIV, the risk of developing active
TB increases by a factor of 30 - 50.
• For those who are HIV+, risk is almost 10% per
year. (In some countries, over 70% of TB
patients are also HIV+)
TB and HIV
The are several important associations between
epidemics of HIV and TB:
• TB is harder to diagnose in HIV positive people
• TB progresses faster in HIV-infected people
• TB in HIV positive people is more likely to be fatal if
undiagnosed or left untreated
• TB occurs earlier in the course of HIV infection than
other opportunistic infections
• TB is the only major AIDS-related opportunistic infection
that poses a risk to HIV-negative people.
History of the TB Alliance
• Cape Town Declaration – Feb 2000
– Hosts: Rockefeller Foundation & MRC S. Africa
– Over 120 organizations (health, science,
philanthropy and private industry)
• Results
– Support goals of Stop TB Initiative
– Create Scientific Blueprint
– Develop Pharmacoeconomic Analysis
Build a global alliance for
TB drug development
The TB Alliance
• International Public-Private Partnership
(PDP)
• Independent, not-for-profit organization
• Based in New York, Brussels and
Pretoria
• Entrepreneurial, virtual R&D approach
– Out-source R&D to public or private partners
The TB Alliance
Mission
Develop new, better drugs for TB
Ensure affordability, access and
adoption (AAA)
Coordinate and catalyze TB drug
development activities worldwide
Affordability, Access and Adoption
(AAA)
• Develop cost effective, affordable new antituberculosis drugs for all those who need them
most
• Ensure equitable access of new TB treatments,
especially for patients in high-burden countries.
• Working closely with communities, governments
and National TB Programme coordinators to
ensure the future drugs will be adopted into TB
Programmes
TB Alliance Priorities
Based on impact and feasibility
1. Active disease
2. TB/HIV co-infection
3. MDR-TB
4. Latent infection (LTBI)
Active TB – Near Term Goal
Shorten: 6 months to 2-3 months
Simplify: daily to weekly
130 doses
10 doses
Long-term Goal
Active Disease
7-10 days of treatment
But - very difficult to achieve without
advances in understanding the biology of
“persistence”
TB Alliance Portfolio
Discovery
Nitroimidazole Analogs
(University of Auckland/Novartis Institute for Tropical Diseases/
National Institute of Allergy & Infectious Diseases)
Compounds, Analogs and Derivatives
Quinolones
Preclinical
Nitroimidazole Backup Compound
(Otsuka)
Nitroimidazole PA-824
(Chiron)
Diamine SQ-109
Moxifloxacin
(Bayer)
(KRICT/Yonsei University)
(Sequella)
Macrolides
Quinolone DW-224
(University of Illinois at Chicago)
Clinical Testing
(Dongwha)
Nitroimidazole OPC-67683
(Otsuka)
InhA Inhibitors
(GlaxoSmithKline)
Isocitrate Lyase Inhibitors
(GlaxoSmithKline)
Pleuromutilins
(GlaxoSmithKline)
Focused Screening
(GlaxoSmithKline)
Screening and Target Identification
(AstraZeneca)
Oxazolidinones
(Pfizer)
Bifunctional Molecules
(Cumbre)
Malate Synthase Inhibitors
(GlaxoSmithKline/Rockefeller University)
Protease Inhibitors
(Medivir)
Riminophenazines
(Institute of Materia Medica)
Capuromycins
(Sankyo/Sequella)
Contracted Program
Program in discussion
New Targets
(University of Pennsylvania/Evotec)
Proteasome Inhibitors
(Cornell University)
Global Alliance for TB Drug Development
www.tballiance.org
March 2006
Global TB Drug Portfolio
September 2005
Discovery
Preclinical
Clinical Testing
Carboxylates
TB Alliance, Wellesley College
Nitrofuranylamides
NIAID, University of Tennessee
Diamine SQ-109
Sequella Inc.
Diarylquinoline TMC207
Johnson & Johnson
Cell Wall Inhibitors
Colorado State University, NIAID
Nitroimidazole Analogs
Dipiperidines (SQ-609)
Sequella Inc.
Gatifloxacin
NIAID, Novartis Institute for Tropical Diseases,
TB Alliance
OFLOTUB Consortium, Lupin, NIAID TBRU,
Tuberculosis Research Centre, WHO TDR
Dihydrolipoamide Acyltransferase
Inhibitors
Cornell University, NIAID
Novel Antibiotic Class
GlaxoSmithKline, TB Alliance
Non-Fluorinated Quinolone
TaiGen
Moxifloxacin
InhA Inhibitors
GlaxoSmithKline, TB Alliance
Picolinamide Imidazoles
NIAID, TAACF)
Synthase Inhibitor FAS20013
FASgen Inc.
Nitroimidazole PA-824
Chiron Corporation, TB Alliance
Isocitrate Lyase Inhibitors (ICL)
GlaxoSmithKline, TB Alliance
Pleuromutilins
GlaxoSmithKline, TB Alliance
Translocase I Inhibitors
Sequella Inc., Sankyo
Nitroimidazo-oxazole OPC-67683
Otsuka
Macrolides
TB Alliance, University of Illinois at Chicago
Quinolones
Nitroimidazo-oxazole Back-up
Otsuka
Pyrrole LL-3858
Lupin Limited
Methyltransferase Inhibitors
Anacor Pharmaceuticals
Screening and Target Identification
AstraZeneca
Natural Products Exploration
Thiolactomycin Analogs
NIAID, NIH
BIOTEC, California State University, ITR, NIAID,
TAACF, University of Auckland
KRICT/ Yonsei University, NIAID,
TAACF, TB Alliance
Bayer Pharmaceuticals, CDC TBTC, Johns
Hopkins University, NIAID TBRU, TB Alliance
STOP TB New Drugs Working Group
TB and HIV
While policymakers are currently
developing better technical
frameworks to improve today’s
strategies for TB control in HIV
hotspots, better drugs that eliminate
TB in HIV patients are key to halting
the dual infection.
Antituberculosis drugs and HIV
• Rifampicin should be avoided because of its
strong inducing effect resulting in an
increased risk of virological failure and
development of resistance.
• Serious side effects can occur in combination
with Protease inhibitors
• Rifampin should be avoided if concurrent
ART with NNRTIs (nucleoside reverse
transcriptase inhibitors.)
Accelerating
the development of faster acting and
affordable drug combinations
to fight tuberculosis.