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Key HIV Research From ICAAC 2007: Antiretrovirals in Development and Salvage Chicago, Illinois | September 17-20, 2007 Faculty: Cal Cohen, M.D., M.S. Eric.

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Presentation on theme: "Key HIV Research From ICAAC 2007: Antiretrovirals in Development and Salvage Chicago, Illinois | September 17-20, 2007 Faculty: Cal Cohen, M.D., M.S. Eric."— Presentation transcript:

1 Key HIV Research From ICAAC 2007: Antiretrovirals in Development and Salvage Chicago, Illinois | September 17-20, 2007 Faculty: Cal Cohen, M.D., M.S. Eric Daar, M.D. This activity is supported by an educational grant from:

2 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Cal Cohen, M.D., M.S. Eric Daar, M.D. Dr. Daar is the chief of HIV medicine at Harbor-UCLA Medical Center in Los Angeles, Calif., and a professor of medicine at the University of California- Los Angeles' David Geffen School of Medicine. He has been an active HIV physician and researcher since the 1980s; during the past three decades, he has led dozens of studies on a vast range of HIV-related issues, with a particular focus on coinfections and other health complications associated with HIV and HIV treatment, including hepatitis C, metabolic complications, cardiovascular disease and psychosocial issues such as depression. Dr. Cohen is the research director of the Community Research Initiative of New England and teaches at Harvard Medical School in Boston, Mass. In addition, he works as a HIV clinical management consultant and internist at Harvard Pilgrim Health Care, Boston, Mass., and is affiliated with Harvard Vanguard Medical Associates. Dr. Cohen was co-chair of the Scientific Advisory Committee of amfAR community-based clinical trials network, and served as co-principal investigator of the Harvard/BCH AIDS Clinical Trials Unit, AIDS Clinical Trials Group. He holds appointments at Brigham and Women's Hospital and Beth Israel Hospital, both in Boston, Mass. Faculty for This Activity

3 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage About this slide presentation This presentation is one of three slide sets created to accompany The Body PRO's podcast summary of key research presented at ICAAC 2007, featuring interviews with Cal Cohen, M.D., M.S., and Eric Daar, M.D. To download the remaining slide sets or learn more about this CME/CE program, please visit us on the Web at: TheBodyPRO.com/ICAAC2007 Please feel free to use this slide presentation for personal reference or for your own presentations; however, we ask that you not modify any aspects of the slides contained within this presentation, so proper attribution can be retained. If you would like to publish all or part of this presentation, or repost any of these slides online, permission must first be obtained from Body Health Resources Corporation. Our gratitude goes out to all who granted permission for their slides to be adapted for this presentation. Disclaimer Knowledge about HIV changes rapidly. Note the date of this presentation's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this presentation.

4 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Antiretrovirals in Development for Treatment-Experienced Patients

5 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Antiretrovirals in Advanced Development Drug NameClassDevelopment Stage Notes elvitegravir (GS-9137, JTK-303) Integrase inhibitor Phase II Regimens including boosted PIs could have greater antiviral activity. No clinically relevant drug interaction with etravirine. When boosted, increases maraviroc exposure. Showed synergistic interactions with enfuvirtide (T- 20, Fuzeon), darunavir (TMC114, Prezista) and efavirenz (Sustiva, Stocrin) in vitro. etravirine (TMC125) NNRTIPhase III No clinically relevant drug interaction with elvitegravir. maraviroc (Selzentry) CCR5 inhibitorPhase III Patients failing regimen had higher mean CD4 increases even with D/M or X4-tropic virus. Exposure increases when used with boosted elvitegravir; use reduced dose of 150mg twice daily. raltegravir (MK- 0518) Integrase inhibitor Phase III In patients with limited treatment options, all doses had potent and durable effects. vicriviroc (SCH 417690, SCH-D) CCR5 inhibitorPhase II No adverse effect on white blood cell counts. Not associated with an increased risk of infections.

6 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage 24-week primary analysis DUET-1 and -2 differed only in geographical location; pooled analysis was pre-specified Plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for 8 weeks 1 NNRTI RAM, at screening or in documented historical genotype 3 primary PI mutations at screening Patients recruited from Thailand, Australia, Europe and the Americas Screening 6 weeks 600 patients target per trial 48-week treatment period with optional 48-week extension *BR = darunavir/ritonavir with optimised NRTIs and optional enfuvirtide TMC125 + BR* Placebo + BR* Follow up 4 weeks DUET: Study Design and Major Inclusion Criteria BR = background regimen; RAM = resistance-associated mutation Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.

7 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage DUET: Viral Load Reduction From Baseline (ITT NC=F) BR = background regimen; SE = standard error; ITT = intent-to-treat population; NC=F = noncompleter equals failure imputation algorithm; changes below the detection limit (<50 copies/mL) were imputed as 49 copies/mL –1.7 –2.4 Mean change in viral load from baseline (log 10 copies/mL) ± SE 0.0 –0.5 –1.0 –1.5 –2.0 –2.5 –3.0 –3.5 Time (weeks) 04812162024 p<0.0001 TMC125 + BR (n=599) Placebo + BR (n=604) Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.

8 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage DUET: Change in CD4 Cell Count From Baseline (ITT NC=F) +86 +67 Mean change in CD4 cell count from baseline (cells/mm 3 ) ± SE Time (weeks) p<0.0001 BR = background regimen; SE = standard error; ITT = intent-to-treat population; NC=F = noncompleter equals failure imputation algorithm 100 75 50 25 0 04812162024 TMC125 + BR (n=599) Placebo + BR (n=604) Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.

9 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage DUET: Response (<50 copies/mL) According to Enfuvirtide (ENF) Use (Primary Analysis) Patients with viral load <50 copies/mL at Week 24 (%) p<0.0001 Using de novo ENF DRV FC category, % TMC125 + BRPlacebo + BR <2 2027 2–104039 10–4026 >40158 Placebo + BR (n=604)TMC125 + BR (n=599) 67% Using de novo ENF p=0.427 34% 56% Unadjusted response rates 0 20 40 60 80 Re-using or not using ENF 62% DRV = darunavir FC = baseline fold change Using de novo ENF p<0.05 62% 73% Adjusted for differences in baseline DRV FC between groups Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.

10 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage DUET: Response (<50 copies/mL) According to Number of Active Background Antiretrovirals Patients with viral load <50 copies/mL at Week 24 (%) Number of fully active background ARVs (PSS) 45% 60% 8%a 30% 67% 74% Analysis excludes patients who discontinued except for virological failure; PSS = phenotypic sensitivity score; darunavir and enfuvirtide are counted as fully active if FC<10 or used de novo, respectively 7/91 40/88 63/211 120/199 171/257 191/258 Placebo + BR (n=559)TMC125 + BR (n=545) Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.

11 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage DUET: Conclusions In treatment-experienced patients, including those with NNRTI resistant virus, TMC125 consistently demonstrated superiority over placebo –59% of patients achieved confirmed undetectable VL (<50 copies/mL) with TMC125 plus BR at Week 24 Even in the absence of any other fully active background agents, with TMC125, 45% of patients achieved undetectable (<50 copies/mL) viral load –response rates increased as more active agents were used in the background regimen 13 TMC125 resistance-associated mutations (TMC125 RAMs) were identified –the greatest added benefit in the TMC125 versus placebo group was seen in patients with <3 TMC125 RAMs –86% patients had <3 TMC125 RAMs Except for rash, incidence and severity of AEs with TMC125 were similar to placebo TMC125 has the ability to extend and enhance the NNRTI class and provide a new treatment option for patients with resistance to other NNRTIs Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.

12 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Protocol 004: Study Design Interim Analysis of Part I Before Initiating Part II Raltegravir 600 mg BID Raltegravir 400 mg BID Raltegravir 200 mg BID Raltegravir 100 mg BID Placebo BID Part I cohort: Rx-naive patients stratified and randomized to integrase monotherapy or placebo for 10 days Integrase Monotherapy for 10 Days Part II cohort: Rx-naive patients stratified and randomized to combination therapy for 48 weeks ~ 30 pts Combination Therapy Total ~ 38 pts Part IPart II ~ 8 pts Raltegravir 600 mg BID + TDF/3TC Raltegravir 400 mg BID + TDF/3TC Raltegravir 200 mg BID + TDF/3TC Raltegravir 100 mg BID + TDF/3TC Efavirenz 600 mg QD + TDF/3TC Adapted from Martin Markowitz et al. IAS 2007; abstract TUAB104.

13 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Protocol 005: Study Design Raltegravir 200 mg BID* (43) Raltegravir 400 mg BID* (45) Raltegravir 600 mg BID* (45) Placebo BID* (45) Raltegravir 400 mg BID* (178) Weeks 1-24Weeks 25-48 All 178 HIV-infected participants had an HIV RNA > 5,000 copies/mL and documented resistance to three classes of oral ARTs at baseline. *All patients received optimized background therapy. All 178 HIV-infected participants had an HIV RNA > 5,000 copies/mL and documented resistance to three classes of oral ARTs at baseline. *All patients received optimized background therapy. Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713.

14 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Protocol 005: Patient and Optimized Background Therapy (OBT) Characteristics Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713. Raltegravir (MK-0518) + OBTPlacebo + OBT 200 mg N = 43 400 mg N = 45 600 mg N = 45 Percentage Male Median Age in Years Median Years of Prior Antiretrovirals Mean CD4 Count in mm 3 Mean HIV RNA in log 10 copies/mL 84 43 10 245 4.6 89 43 11 221 4.8 91 44 9 220 4.7 89 43 10 274 4.7 OBT: Median Number of Antiretrovirals Phenotypic Sensitivity Score*: 0 to Protease Inhibitors Phenotypic Sensitivity Score*: 0 to All Antiretrovirals Genotypic Sensitivity Score*: 0 to All Antiretrovirals Number of Patients With Enfuvirtide (T-20, Fuzeon) as New OBT 4 42 (98%) 20 (47%) 27 (63%) 13 (30%) 4 42 (93%) 26 (58%) 38 (84%) 8 (18%) 4 40 (89%) 22 (49%) 35 (78%) 13 (29%) 4 38 (84%) 18 (40%) 28 (62%) 10 (22%) *By Phenosense GT Note: Enfuvirtide is not included in the phenotypic sensitivity score since there is no clinical cut-off.

15 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Protocol 005: Time to Loss of Virologic Response to Week 72: Raltegravir (MK- 0518) All Doses Combined vs. Placebo Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713. Placebo 4511 998655431 133122 120113100959286694312 0248 1624324048566472 Week 0 20 40 60 80 100 % of Patients Remaining HIV RNA <400 copies/mL # of Patients at Risk Raltegravir All Doses Combined Placebo Raltegravir All Doses Combined* Placebo* * Plus optimized background therapy. Patients who never achieved HIV RNA <400 copies/mL were considered failures. Non-responders assigned failure at time 0.

16 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Protocol 005: Analysis of Raltegravir (MK-0518) Resistance Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713. Study found no association between dose and/or drug concentration and resistance. The factors decreasing likelihood of developing mutations at amino acids 148 alone, 155 alone, and either 148 or 155 were found to be: Phenotypic sensitivity score > 0. Lower viral load ( 100,000 copies/mL vs. > 100,000 copies/mL). New use of enfuvirtide (T-20, Fuzeon) in optimized background therapy. From: Hazuda et al, XVI International HIV Drug Resistance Workshop, 2007, Barbados

17 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Protocol 005: Safety During Double-Blind Study Period Adapted from Beatrice Grinsztejn et al. ICAAC 2007; abstract H-713. Raltegravir (MK-0518) safety profile for all doses similar to placebo Liver function test abnormalities were uncommon No grade 4 abnormalities for aspartate aminotransferase (AST), alanine transaminase (ALT) or alkaline phosphatase (ALP) Grade 3 AST: 2/133 patients (1.5%) in all MK-0518 groups Grade 3 ALT: 1/133 patients (0.8%) in all MK-0518 groups Most clinical adverse events (AEs) were mild to moderate 4 serious, drug-related clinical AEs Acute pancreatitis after 2 doses, considered 2º to optimized background therapy (200 mg group) Metabolic acidosis and renal insufficiency; sepsis; death (600 mg group) Lacunar infarction by CT (placebo) Worsening lipoatrophy (placebo) 2 discontinuations due to drug-related AE Elevated AST/ALT, considered 2º to optimized background therapy (200 mg group) Lipoatrophy (placebo)

18 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Elvitegravir (EVG) Phase 2 Study Schema Andrew Zolopa et al. ICAAC 2007; abstract H-714. Reprinted with permission.

19 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Elvitegravir Study: HIV RNA < 50 copies/mL at Week 16 for Patients With First Use of T-20 Andrew Zolopa et al. ICAAC 2007; abstract H-714. Reprinted with permission.

20 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Week 16 HIV RNA < 50 copies/mL for Patients Receiving EVG/r 125 mg: Impact of Gradations in Activity of Optimized Background Therapy Andrew Zolopa et al. ICAAC 2007; abstract H-714. Reprinted with permission.

21 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage * versus OBT alone HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 24 weeks Last observation carried forward MOTIVATE 1 and 2: Summary of Week 24 Efficacy Results Includes all patients who received at least one dose of study medication Mean change from baseline in CD4 count (cells/mm 3 ) MVC QD + OBT (N=414) MVC BID + OBT (N=426) OBT alone (N=209) P <0.0001* Patients (%) P <0.001* Difference: +51 (95% CI: 33, 69) P <0.001* Difference: +49 (95% CI: 31, 67) HIV-1 RNA <50 copies/mL Mean Change from Baseline in CD4 Count Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.

22 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Characterization of Maraviroc Resistance in MOTIVATE 1 and 2: Study Overview OBJECTIVE: To study changes in HIV-1 tropism in patients who experienced treatment failure in the MOTIVATE 1 and 2 studies MOTIVATE 1 and MOTIVATE 2 Phase 3 studies in treatment-experienced patients (N=1,075) Assessment of CD4 count at failure, time of failure, and occurrence of Category C events by tropism result NR/NP Non-reportable/ non-phenotypable D/M* Dual/mixed tropic virus population R5* Only CCR5-tropic virus detected X4 Only CXCR4-tropic virus detected Tropism determined for all patients at screening, baseline, and all visits where VL>500 c/mL (Trofile assay, Monogram Biosciences) * CCR5-using virus; CXCR4-using virus Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.

23 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage R5 X4 A) Pure B) Mixed MOTIVATE 1 and 2: Viral Populations That May Exist Within a Patient R X X X X X X X X X X X X X X X X X X R R R R R R R R R R R R R R R R R R R R D D D D D D D D D D D D D D D D D D DD R X X X X X X X X XX X X X X XX X X X X X X X X X X X X X X X X X X R R R R R R R R R R R R R R R R R R R R R R R R R R R D D D D D D Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission. Dual/mixed (D/M) tropism

24 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage -1000100200300 0 100 200 300 400 500 MOTIVATE 1 and 2: CXCR4-Using Clones Were Detected at Low Frequency in the Baseline Sample Time Since First Administration (Day) CXCR4-using clones detected at baseline (7%) No CCR5-tropic clones on treatment R5 DM R5 1 2 3 4 5 6 HIV-1 RNA (log 10 copies/mL) CD4 Count (cells/mm 3 ) Patient T6 Lewis M et al. XVI International HIV Drug Resistance Workshop, June 2007, Abstract 56 Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.

25 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage MOTIVATE 1 and 2: Selective Inhibition of R5 Viruses Can Lead to a Change in Tropism Result to D/M or X4 RRRR RRRR RRRR RRDR RRRR RRRR RRRR RRDR RRRR RRRR RRRR RRDR RRRR RRRR RRRR RRDR RRRR RRRR RRRR RRDR RRRR RRRR RRRR RRXR RRRR RRRR RRRR RRDR RRRR RRRR RRRR RRDR D X D D D D D D R5 D/M Trofile (like all resistance tests) measures relative proportions (not absolute amounts) of different viruses (Panel A) Selective inhibition of a majority virus type, increases the sensitivity to detect the minor variant (Panel B) A B MVC Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.

26 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage MOTIVATE 1 and 2: Selective Inhibition of R5 Viruses Can Lead to a Change in Tropism Result to D/M or X4 Maraviroc selectively inhibits R5 virus If maraviroc is administered as part of a sub-optimal regimen, pre-existing low (undetected) levels of D/M or X4 virus will emerge as the dominant viral population Since the D/M or X4 virus is pre-existing, time to failure is shorter than with R5 virus (where maraviroc resistance must be selected de novo) Similar to the rapid outgrowth of pre-existing (archived) drug-resistant virus when failed ARV therapy is reinitiated after treatment interruption After withdrawal of maraviroc, selective pressure on R5 virus is removed, allowing R5 virus to re-emerge as the dominant population Reversion to R5 takes approximately 16 weeks, consistent with loss of 3TC 1 or enfuvirtide 2 resistance after withdrawal of these ARVs 1. Deeks S, et al. J Infect Dis 2005; 192:1537-44. 2. Deeks et al. J Infect Dis 2007;195:387-91. Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.

27 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Randomization 1:2:2 N=601 MOTIVATE 1: Trial Design OBT* + maraviroc (150 mg BID) OBT* + maraviroc (150 mg QD) OBT* + placebo 0 24w * OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of RTV not counted as an ARV) Patients receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients received 300 mg dose of MVC Screening (6 weeks) 48w Patients stratified by: Enfuvirtide use in OBT HIV-1 RNA < and 100,000 copies/mL at screening Patient eligibility criteria: R5 HIV-1 infection HIV-1 RNA 5,000 copies/mL Stable pre-study ARV regimen, or no ARVs for 4 weeks Resistance to and/or 6 months experience with one ARV from three classes ( two for PIs) Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.

28 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage MOTIVATE 1 – Week 48: Mean Change From Baseline in HIV-1 RNA Includes all patients who received at least one dose of study medication HIV-1 RNA value imputed as baseline if patient discontinued before 48 weeks *Treatment difference vs OBT alone Mean change in HIV-1 RNA from baseline (log 10 copies/mL) Difference: -0.85* (97.5% CI: -1.22, -0.49) Difference: -1.02* (97.5% CI: -1.39, -0.66) MVC QD + OBT (N=232) MVC BID + OBT (N=235) OBT alone (N=118) Study week Difference: -0.79* (97.5% CI: -1.14, -0.44) Difference: -0.92* (97.5% CI: -1.28, -0.57) 2448 Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.

29 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage MOTIVATE 1 – Week 48: Percentage of Patients With Undetectable HIV-1 RNA Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.

30 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Patients (%) N= Maraviroc QD + OBT Maraviroc BID + OBT OBT alone MOTIVATE 1 and 2: Proportion of Patients Receiving ENF With Undetectable HIV-1 RNA at Week 48 According to ENF First Use <400 copies/mL<50 copies/mL Last observation carried forward ENF first useENF experienced/ resistance 9110859307572 ENF first useENF experienced/ resistance 9110859307572 Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.

31 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage MOTIVATE 1 and 2 – Week 48: Change in CD4+ Cell Count From Baseline by Tropism Result at Time of Failure Tropism result, Baseline Treatment Failure Mean change from baseline in CD4+ count in patients with treatment failure (cells/mm 3 ) OBT alone N=271 MVC QD + OBT N=477 MVC BID + OBT N=487 All treatment failures* +24 (n=111) +64 (n=92) +74 (n=96) R5 +25 (n=89) +77 (n=33) +133 (n=24) R5 D/M or X4 +61 (n=6) +47 (n=35) +57 (n=41) * Includes patients with non-reportable/non-phenotypable tropism result at baseline and patients with non-reportable/non-phenotypable/missing tropism result at time of failure Jacob P. Lalezari et al. ICAAC 2007; abstract H-718a. Reprinted with permission.

32 The Body PRO ICAAC 2007: Antiretrovirals in Development and Salvage Visit The Body PRO for Comprehensive Coverage of ICAAC 2007. This presentation is one of three slide sets created to accompany The Body PRO's podcast summary of key research presented at ICAAC 2007, featuring interviews with Cal Cohen, M.D., M.S., and Eric Daar, M.D. To download the remaining slide sets or learn more about this, please visit us on the Web at: TheBodyPRO.com/ICAAC2007 In addition, be sure to browse through The Body PROs extensive coverage of ICAAC 2007, which includes: –Downloadable MP3s and full transcripts –Expert discussion of key research –Slides and in-depth data analyses Visit TheBodyPRO.com/ICAAC2007 today for a full listing of our conference materials!


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