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HIV treatment for TB patients: priorities and ongoing research efforts

TB/HIV meeting at 14 th conference on retroviruses and opportunistic infections Sunday, 25 February 2007. HIV treatment for TB patients: priorities and ongoing research efforts. Fabio Scano Stop TB, WHO. outline. WHEN to start ART WHAT to start Other areas of research

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HIV treatment for TB patients: priorities and ongoing research efforts

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  1. TB/HIV meeting at 14th conference on retroviruses and opportunistic infections Sunday, 25 February 2007 HIV treatment for TB patients:priorities and ongoing research efforts Fabio Scano Stop TB, WHO

  2. outline • WHEN to start ART • WHAT to start • Other areas of research • TB in patients on ART • Rifabutin • New drugs • Future directions

  3. WHO Guidelines, 2006

  4. Validating the optimal time to start ART: ongoing efforts

  5. What to start

  6. 2006 WHO Guidelines:First Line ART Regimens and Active TB *Patient education, bi-weekly visits, ALT/AST at 0,2,4,8 and 12 weeks 1 ZDV/3TC/ABC or ZDV/3TC/TDF 2 Hypersensitivity reaction

  7. Rifampin Interactions: Is dose adjustment required? • EFV and NVP are reduced 20-40% with rifampin1,2,3,4 • Small PK studies support dose increase of EFV (800 mg) and NVP(300 mg bid) 5,6 • Large interpatient variability due to genetic determinants of metabolism7 • Clinical outcome studies to date do not support dose adjustment of EFV or NVP 5 Lopez-Cortes, Clinical PK, 2002; 6Ramachandran, JAIDS, 2006; 7Haas, AIDS, 2004; Friedland J, Antimicrob. Chemotherapy 2006. 1Ribera, JAIDS, 2001; 2Lopez-Cortes, Clinical PK, 2002; 3Manosuthi, AIDS, 2005 ; 4Manosuthi,CID, 2006

  8. Efavirenz vs. Nevirapine

  9. Potential toxicity between ART and TB medications

  10. TB in patients receiving ART New Pulmonary TB NEW TB ART THERAPY 2 6 48 96 0 MONTH ON ARV Undiagnosed TB Activation of latent TB Treatment failure if: CD4 guided Other conditions Transmitted TB IRIS

  11. Second Line ART • Drug interactions between rifampin and protease inhibitors • Drug toxicity/tolerability • Drug Cost

  12. RMP vs. RFB with PI based regimens *Toxicity: marrow suppression, contraindicated WBC <1000, Plts <50k , also arthralgias, uveitis

  13. Discovery - 17 Preclinical - 4 Clinical Testing - 5 Cell Wall Inhibitors NIAID, Colorado State University Nitroimidazole Analogs Novartis Institute for Tropical Diseases, NIAID, TB Alliance Diamine SQ-109 Sequella Inc. Diarylquinoline R207910 Johnson & Johnson Dihydrolipoamide Acyltransferase Inhibitors NIAID, Cornell University Novel Antibiotic Class GlaxoSmithKline, TB Alliance Nitroimidazole PA-824 Chiron Corporation, TB Alliance Gatifloxacin OFLOTUB – TDR, Tuberculosis Research Centre, NIAID, TBRU Dipiperidines Sequella Inc. Picolinamide Imidazoles NIAID, TAACF) Synthase Inhibitor FAS20013 FASgen Inc. Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID, TBRU InhA Inhibitors GlaxoSmithKline, TB Alliance Pleuromutilins GlaxoSmithKline, TB Alliance Translocase I Inhibitors Sequella Inc., Sankyo Proprietary Compound Otsuka Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance Pyrroles (TB Alliance, Private Sector Partner) Pyrrole LL-3858 Lupin Limited Macrolides TB Alliance, University of Illinois at Chicago Quinolones KRICT/ Yonsei University, NIAID, TAACF, TB Alliance Methyltransferase inhibitors Anacor Pharmaceuticals Proprietary Compounds AstraZeneca Natural Products Exploration NIAID, TAACF, California State University, University of Auckland Thiolactomycin Analogs NIAID, NIH Nitrofuranylamides NIAID, University of Tennessee

  14. Future directions Moreresearch to optimize: Time of initiation, First line ART (safety and tolerability) Urgent research for new ART friendly-drugs, rifabutin, implications for M-XDR/TB. Questions: 1 How ANRS, NIH, EDCTP can ensure that HIV trials are well designed to reflect TB issues 2. How to ensure that these research priorities are well prioritised within the funding streams.

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