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Tuberculosis Program at NIAID

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Presentation on theme: "Tuberculosis Program at NIAID"— Presentation transcript:

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,

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

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