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

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

3. Initiating first line ART in relationship to starting anti-TB therapy CD4 Cell Count ART recommendations Timing of ART in relation the start of TB treatment CD4  200 cells/mm 3 Recommend ART a Between 2-8 weeks b CD4 between 200-350 cells/mm 3 Recommend ARTAfter 8 weeks CD4  350 cells/ mm 3 Do not initiate ART c Re-evaluate patient at 8 weeks and at the end of TB treatment CD4 not availableRecommend ART d Between 2-8 weeks WHO Guidelines, 2006

4. Validating the optimal time to start ART: ongoing efforts TrialCD4regimenstiming CAMELIA ANRS 1295/NIH <200 N=570 EFV/D4T/3TC2 vs. 8 weeksStarted in January 2006 AA5221 NIH <200 N=800 EFV/TDF/FTC2 vs. 8-12 weeks START NIH >50 N=592 EFV/3TC/DDIImmediate vs. 8 weeks TB Early arm within the TB programme Start date? EDCTP/TDR Uganda/Tanzania N=1800EFV/3TC/AZTimmediate vs. after TB treatment Due to start in March 2007 Haiti (not only TB)>200 or 350AZT/3TC/EFVCD cell count driven Recruitment not started yet PART Study Uganda >350 or < 200ABC/AZT/3TCCD4 count drivenRecruitment started in 2005

5. What to start

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

7. Rifampin Interactions: Is dose adjustment required? EFV and NVP are reduced 20-40% with rifampin 1,2,3,4 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 metabolism 7 Clinical outcome studies to date do not support dose adjustment of EFV or NVP 1 Ribera, JAIDS, 2001; 2 Lopez-Cortes, Clinical PK, 2002; 3 Manosuthi, AIDS, 2005 ; 4 Manosuthi, CID, 2006 5 Lopez-Cortes, Clinical PK, 2002; 6 Ramachandran, JAIDS, 2006; 7 Haas, AIDS, 2004; Friedland J, Antimicrob. Chemotherapy 2006.

8. Efavirenz vs. Nevirapine TrialCD4regimensTimingcomments South Africa (Khayelitsha) EFV vs NVPA 6 arm trial Not powered to determine safety Virological outcome India (National AIDS control org) < 250EFV or NVP/ddI/3TC 8 weeksStarted in March 2006 HIV/NAT Multicentre study n/aNVP 400 mg vs. 600 mg 2-6 weeks A 48 week, randomized, open-label, 2 arm study to compare the efficacy, safety and tolerability. Started in 2005 Mozambique (Epicentre/MSF/MoH) ANRS <200 and <350 EFV or NVP4 weeksViral load at 12 mo and safety. To start in June 2007. Burkina Faso< 200EFV or NVP /3TC/AZT Malawi Two sites N=3820RIF vs RFB with NVP/3TC/d4T 2 weeks vs 8 weeks A four arm, double blinded, randomized

9. Potential toxicity between ART and TB medications Overlapping toxicityAntiretroviral agentAnti-TB agent HepatitisNVP, EFVRIF, PZA. INH, Eto/Pto, PAS, E, FQ HaematologicalAZTlinezolid CNSEFVCS, H, FQ, Eto/Pto GIAllRif, Pza, Eto/Pto, PAS, Cfz, Lzd Neuropathyd4TCS, INH, E

10. ART THERAPY 0 MONTH ON ARV 964862 TB in patients receiving ART NEW TB Undiagnosed TB Activation of latent TB IRIS Transmitted TB New Pulmonary TB Treatment failure if: CD4 guided Other conditions

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

12. RMP vs. RFB with PI based regimens DrugUnit costTB Treatment regimen cost Rifampicin + boosted ritonavir Rifabutin + standard dose of RTN * Rifabutin 0.85 USD 61-122 USD Rifampicin0.049USD8.82 USD Ritonavir price 0.374 USD 210.78 USD 61-122 USD *Toxicity: marrow suppression, contraindicated WBC <1000, Plts <50k, also arthralgias, uveitis

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

14. Future directions More research 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.