1. Tuberculosis Program at NIAID
Christine Sizemore, PhD* & Barbara Laughon, PhD#
*Program Officer for Tuberculosis, Leprosy and Other Mycobacterial Diseases
#Chief, Complications and Co-Infections Research Branch, TRP
Division of Microbiology and Infectious Diseases (DMID)
Division of Acquired Immunodeficiency Syndrome (DAIDS)
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health (NIH)
US Department of Health and Human Services (DHHS)
NIAID – WHO TB/HIV February 14-15, 2005

2. New Therapeutics for Tuberculosis / HIV Co-infections
Basic Research Preclinical Development Clinical Trials
New
Concepts
for
Therapeutics
Growth Inhibition Screening
Drug Libraries
Mechanism-Based Screening
In Vitro Spectrum
In Vivo Efficacy
Pharmacology
Toxicology
Multi-center Clinical Studies
NIAID TBRU
TB Alliance
CDC TBTC
ACTG International Sites
IUATLD
In Vivo Evaluation, Chemical Synthesis, Reagent Support, Data Bases
NIH Roadmap Initiatives
Direct Assistance and Interaction with the Scientific Community

3. NIAID Project Officer: Robert Goldman, www.taacf.org

4. Geographical Distribution
of Compound Suppliers

5. Candidates Advancing >75,000 unique structures in database
7,157 active at < 6.25 ug/ml
2,000 MIC < 4 ug/ml
20 Actives in Gamma Knock Out Mouse
11 Actives in Standard Model
3 Actives in both GKO and Standard
182 Compounds in queue for in vivo testing
Candidates = Compounds with SI >= 10, structural novelty, supportive assay results, meet drug-like criteria.
NIAID Project Officer: Robert Goldman,

6. Global Alliance for TB Drug Development (TB Alliance)
TB Alliance founded in 2000
Global public private partnership
NIAID - a founding stakeholder, in kind contributor
NIAID staff – Board of Directors, Scientific Advisory Committee

7. Advanced Drug Development
Moxifloxacin (Bayer)
R Diarylquinoline Johnson & Johnson
PA-824 (TB Alliance)
Oxazolidinone Ranbaxy Research Labs
LL-3858 Lupin Pharmaceuticals
SQ-109 Sequella, Inc
KRQ KRICT/TB Alliance
OSA FASgen, Inc
PD Fluoroquinolone
Thiolactomycin -GlaxoSmithKline/NIAID/St. Jude Children’s Hospital
ActivBiotics

8. PA-824: Efficacy Review Bactericidal against replicating MTB
New mechanism of action
Active against MDR strains of MTB
Potency similar to INH
Other analogs show greater in vitro activity than PA-824, less in vivo
Orally bioavailable with formulation

9. NIAID-supported TB HIV Co-infection Studies
R Chaisson – “Novel TB Prevention Regimens for HIV-Infected Adults”, Hopkins, University of the Witwatersrand.
R Oberhelman – “Practical Diagnostics for AIDS-Related Pediatric TB, Peru”, Tulane, Instituto de Salud del Nino, Lima.
R Semba – “Adjunct Vitamin Therapy for TB and HIV/AIDS”, Hopkins, Zomba Central Hospital, Malawi
C Whalen – “Punctuated ARV Therapy”, Case Western, Uganda JCRC, Kampala, Uganda
A Salim Karim – “CIPRA:CAPRISA – Implementing ARV therapy in resource constrained settings”, Durban.
D Havlir – AACTG 5221 "A Phase IV study of immediate versus delayed initiation of antiretroviral therapy for HIV-infected adults presenting with pulmonary tuberculosis.“
Sok Thim – “A Cambodian Clinical Research Network for HIV”, CAMELIA, Cambodian Health Committee (NGO), ANRS, Institute Pasteur Cambodia, Harvard.
J Pape – “A randomized clinical trial to determine the efficacy of early versus delayed antiretroviral therapy in HIV-infected adults with CD4+ T cell counts between 200 and 350 cells/mm3”, GHESKIO, Haiti
PACTG 1041 – “A Phase II/III Randomized DB Trial to Determine the Efficacy of INH in TB Disease in South African Infants Perinatally exposed to HIV”, University of the Witwatersrand, South Africa.
J McIntyre – “CIPRA: The Effect of ART on Rates and Transmission of TB in a peri-urban community in South Africa”

10. TB HIV Co-Infection Treatment Issues
Appropriate treatment of both infections
When to Start ARVs in active TB
What ARVs to Start – CYP interactions with PIs and with RIF
How to effectively protect against infection (or re-infection) of HIV+
Extended INH over 6 months
Lifetime INH
Rifapentine
Management and better understanding of the IRIS reaction in HIV/TB co-infections

13. Preclinical Efficacy Safety
NIAID’s TB and other Mycobacterial Diseases Program
Research Grants
Fundamental and Clinical Science
Vaccines
Drugs
Diagnostics
Basic
Research
Target
Identification
Target
Validation
Candidate
Identification
Preclinical Efficacy Safety
Optimization
Scale-up
GLP Pharm
GLP Tox
Formulation
IND Studies
Partners
Clinical Trials
Contracts