1. Guidelines published as an update on 2003 guidelines. About 8-9 pages. New data only Guidelines published as an update on 2003 guidelines. About 8-9 pages. New data only Look at new “backbones of therapy?” Look at new “backbones of therapy?” Tenofovir/FTC O/D Tenofovir/FTC O/D New combinations of drugs; ie Abacavir/3TC O/D New combinations of drugs; ie Abacavir/3TC O/D Warn against combinations; ie Tenofovir/DDI… Warn against combinations; ie Tenofovir/DDI… Brian West: BHIVA Guidelines What’s new:

2. Tenofovir/FTC in preference to AZT/3TC, or even Kivexa? Tenofovir/FTC in preference to AZT/3TC, or even Kivexa? New drugs since 2003; new ways to build 1 st combo? New drugs since 2003; new ways to build 1 st combo? Still NNRTI as support to Combivir/Truvada/Kivexa in 1 st line, or maybe Fosamprenavir/Reyataz? (Importance of resistance testing…) Still NNRTI as support to Combivir/Truvada/Kivexa in 1 st line, or maybe Fosamprenavir/Reyataz? (Importance of resistance testing…) Emphasise that all PIs to be boosted? (Unlike US) Emphasise that all PIs to be boosted? (Unlike US) BHIVA Guidelines What’s new:

3. Presently deals with drugs now in use such as Enfuvirtide, Atazanavir, Tenofovir Presently deals with drugs now in use such as Enfuvirtide, Atazanavir, Tenofovir New drugs to be looked at include the new PIs TMC114 and Tipranavir, New drugs to be looked at include the new PIs TMC114 and Tipranavir, The new RTI Reverset (D-D4FC) The new RTI Reverset (D-D4FC) The new NNRTI TMC125 The new NNRTI TMC125 BHIVA Guidelines, New Drugs:

4. Shown to be effective in a PI experienced population with resistant virus Shown to be effective in a PI experienced population with resistant virus 50 people randomised. After 8 weeks of treatment the median difference in VL and absolute drop in VL among people switching to TMC114/RTV significantly exceeded VL changes in people staying with the same PI 50 people randomised. After 8 weeks of treatment the median difference in VL and absolute drop in VL among people switching to TMC114/RTV significantly exceeded VL changes in people staying with the same PI Monika Peeters CROI 2004 abstract 533 Monika Peeters CROI 2004 abstract 533 a new boosted PI New Drugs: TMC114 a new boosted PI

5. RESIST1 and RESIST 2 Different continents; similar results - promising RESIST1 and RESIST 2 Different continents; similar results - promising Evaluated the efficacy and safety of TPV/Ritonavir(RTV) in comparison to 4 different RTV-boosted PIs Evaluated the efficacy and safety of TPV/Ritonavir(RTV) in comparison to 4 different RTV-boosted PIs People with multiple PI resistance mutations had better virological outcomes on Tipranavir 34% vs. 13%with VL<400; 23% vs. 9%<50 People with multiple PI resistance mutations had better virological outcomes on Tipranavir 34% vs. 13%with VL<400; 23% vs. 9%<50 Expanded access in UK. Launched this year Expanded access in UK. Launched this year Pedro Cahn: Foundación Huesped, Buenos Aires, Argentina, PL14.3 RESIST 2: phase 3 study, Glasgow 7 th International Congress on Drug Therapy in HIV Infection Pedro Cahn: Foundación Huesped, Buenos Aires, Argentina, PL14.3 RESIST 2: phase 3 study, Glasgow 7 th International Congress on Drug Therapy in HIV Infection a new boosted PI New Drugs: Tipranavir a new boosted PI

6. Low mitochondrial toxicity O/D drug Low mitochondrial toxicity O/D drug May have activity against many viral strains with NRTI resistance May have activity against many viral strains with NRTI resistance 10 day trial Small numbers; 10 treatment experienced people with VL>1000 enrolled. 2 given placebo 10 day trial Small numbers; 10 treatment experienced people with VL>1000 enrolled. 2 given placebo 7/8 had VL drop of at least 0.5 log 4 with VL below 400. Next phase sees 180 recruited 7/8 had VL drop of at least 0.5 log 4 with VL below 400. Next phase sees 180 recruited 44th ICAAC (Slide H-1130) Tolerance and anti-HIV-1 activity of Reverset following 10 days as add-on therapy to current regimens in treatment experienced HIV-infected individuals: RL Murphy et al 44th ICAAC (Slide H-1130) Tolerance and anti-HIV-1 activity of Reverset following 10 days as add-on therapy to current regimens in treatment experienced HIV-infected individuals: RL Murphy et al 44th ICAAC Tolerance and anti-HIV-1 activity of Reverset following 10 days as add-on therapy to current regimens in treatment experienced HIV-infected individuals 44th ICAAC Tolerance and anti-HIV-1 activity of Reverset following 10 days as add-on therapy to current regimens in treatment experienced HIV-infected individuals a new RTI New Drugs: Reverset a new RTI

7. Drugs in this class have problems with cross resistance Drugs in this class have problems with cross resistance TMC 125 could be used against viral strains with NNRTI resistance TMC 125 could be used against viral strains with NNRTI resistance Brian Gazzard’s (1) 7 day substitution study on16 people with efavirenz resistance showed at day 7, the median decrease in viral load was -0.9 log from baseline Brian Gazzard’s (1) 7 day substitution study on16 people with efavirenz resistance showed at day 7, the median decrease in viral load was -0.9 log from baseline In vitro data from CROI 2001 (2) showed high activity against key resistant strains such as K103N In vitro data from CROI 2001 (2) showed high activity against key resistant strains such as K103N 1.Gazzard B et al. abstract 5, TMC125, a Next-Generation NNRTI, Demonstrates High Potency after 7 Days Therapy in Treatment-Experienced HIV-1-Infected Individuals with Phenotypic NNRTI Resistance. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, 2002. 1.Gazzard B et al. abstract 5, TMC125, a Next-Generation NNRTI, Demonstrates High Potency after 7 Days Therapy in Treatment-Experienced HIV-1-Infected Individuals with Phenotypic NNRTI Resistance. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, 2002. 2.Gruzdev B et al. Abstract I-668. TMC125 is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI) in antiretroviral therapy (ART)-naive, HIV-1 infected subjects. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, Ill. 2.Gruzdev B et al. Abstract I-668. TMC125 is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI) in antiretroviral therapy (ART)-naive, HIV-1 infected subjects. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, Ill. a new NNRTI New Drugs: TMC125 a new NNRTI

8. Other new drugs under investigation such as the CXCR4 and CCR5 antagonists are not sufficiently advanced to be dealt with yet. (They’re also not so well supported by Brian Gazzard!) Thanks for your attention: Brian West contact details: brian.west@hivscotland.com Tel: 0131 558 3713Other new drugs under investigation such as the CXCR4 and CCR5 antagonists are not sufficiently advanced to be dealt with yet. (They’re also not so well supported by Brian Gazzard!) Thanks for your attention: Brian West contact details: brian.west@hivscotland.com Tel: 0131 558 3713