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An Update on New HIV Antiretroviral Agents This activity is supported by an educational grant from Faculty: Edwin DeJesus, M.D., F.A.C.P. Medical Director.

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Presentation on theme: "An Update on New HIV Antiretroviral Agents This activity is supported by an educational grant from Faculty: Edwin DeJesus, M.D., F.A.C.P. Medical Director."— Presentation transcript:

1 An Update on New HIV Antiretroviral Agents This activity is supported by an educational grant from Faculty: Edwin DeJesus, M.D., F.A.C.P. Medical Director of the Orlando Immunology Center in Orlando, Fla. Edwin DeJesus, M.D., F.A.C.P. Copyright © 2008 Body Health Resources Corporation. All rights reserved.

2 The Body PRO An Update on New HIV Antiretroviral Agents 1 Faculty For This Activity Edwin DeJesus, M.D., F.A.C.P. Dr. DeJesus is Medical Director of the Orlando Immunology Center in downtown Orlando, Fla., and the medical director of the HUG-Me Program's adult clinic at Orlando Regional Medical Center. Since 1993, Dr. DeJesus has devoted most of his time to caring for HIV- and hepatitis-infected patients. He is also deeply involved in HIV-related research: He is the principal investigator for the Orlando Immunology Center Research Facility, where he oversees several phase 1-4 clinical trials. In this capacity, he has presented study results at major international conferences, including the International AIDS Conference, International AIDS Society Conference, Interscience Conference on Antimicrobial Agents and Chemotherapy, Conference on Retroviruses and Opportunistic Infections and European AIDS Conference. Disclosures Dr. DeJesus has received grants and research support from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb Company, Gilead Sciences, GlaxoSmithKline, Hoffman- LaRoche Inc., Merck & Co., Inc., Pfizer, Inc., Schering-Plough Corporation and Tibotec Therapeutics. He has been a consultant to Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Tibotec and Vertex Pharmaceuticals, Inc., and he serves on speakers bureaus for Gilead, GlaxoSmithKline, Merck and Tibotec.

3 The Body PRO An Update on New HIV Antiretroviral Agents 2 What Drives the Search for New Antiretroviral Agents? 1. Sabine Yerly et al. Lancet. August 28, 1999;354(9180): Bluma Brenner et al, and the Quebec Primary Infection Study Team. Int J Antimicrob Agents. December 2000;16(4): Daniel Boden et al. JAMA. September 22, 1999;282(12): William Wheeler et al. CROI 2007; abstract Katherine Samaras. Diabetes Care. January 2007;30(1): Julio Montaner et al. AIDS. January 5, 2001;15(1): Strategies for Management of Antiretroviral Therapy (SMART) Study Group et al. N Engl J Med. November 30, 2006;355(22): HIV Drug ResistanceSafety and TolerabilityCost and Convenience Five to 15% of newly diagnosed patients have drug resistance 1-4 A proportion of treatment-experienced patients have multi- class resistance 4 Metabolic side effects: lipoatrophy, dyslipidemia, insulin resistance 5 Other side effects: bone, hematologic, central nervous system, renal, reproductive and gastrointestinal Treatment-experienced patients may need mega-HAART with as much as seven agents or more 6 Patients must take lifelong therapy 7

4 The Body PRO An Update on New HIV Antiretroviral Agents 3 Goals of Therapy for Treatment- Experienced Patients 1. Scott M. Hammer et al. JAMA. 2006;296: DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1Infected Adults and Adolescents. January 29, Available at: Accessed June 11, IAS-USA Guidelines, August : US DHHS Guidelines, January 29, : “Trials with newer antiretroviral agents have shown that it is possible to achieve plasma HIV-1 RNA levels below 50 copies/mL even in highly treatment-experienced patients.” “The goal of treatment for patients with prior drug exposure and drug resistance is to re- establish maximal virologic suppression, HIV-1 RNA < 50 copies/mL.”

5 The Body PRO An Update on New HIV Antiretroviral Agents 4 Timeline of Antiretroviral Development 1987zidovudine 1991didanosine 1992zalcitabine 1994stavudine 1995lamivudine, saquinavir 1996nevirapine, ritonavir, indinavir 1997delavirdine, nelfinavir 1998efavirenz, abacavir 1999amprenavir 2000lopinavir/ritonavir 2001tenofovir 2003emtricitabine, atazanavir, enfuvirtide, fosamprenavir 2005tipranavir 2006darunavir 2007raltegravir, maraviroc 2008etravirine Key NRTI NNRTI PI Entry Inhibitor Integrase Inhibitor

6 The Body PRO An Update on New HIV Antiretroviral Agents 5 Etravirine (TMC125): Next-Generation NNRTI

7 The Body PRO An Update on New HIV Antiretroviral Agents 6 Need for Next-Generation NNRTIs  Tolerability and toxicity  CNS adverse effects, rash  Hypersensitivity reactions (HSRs)  Limits on prescribing to the target population  Women of childbearing potential (i.e., efavirenz)  Individuals with higher CD4+ cell counts (i.e., nevirapine)  HIV drug Resistance  Broad cross-resistance among first-generation NNRTIs  Transmitted NNRTI resistance in up to 10% of treatment- naive individuals * * Potential importance of minority variants that cannot be detected currently in clinical practice

8 The Body PRO An Update on New HIV Antiretroviral Agents 7 Etravirine  In vitro characteristics  EC 50 WT HIV-1: 1.4 nmol/L  < 5-fold reduction in susceptibility against  K103N, Y181C, Y188L, and L100I  Phase I pharmacokinetics  Elimination half-life: hours  Steady state attained within 5 days  Metabolized by cytochrome P450 CYP3A  Phase IIa  2.0 log 10 decline in plasma HIV-1 RNA over 7 days Adapted from Marie-Pierre de Bethune et al. ICAAC 2000; abstract Adapted from Stephen Piscitelli et al. Pharmacology Workshop 2002; abstract 5.3. Adapted from Boris Gruzdev et al. AIDS. 2003;17: NH 2 H3CH3C CH 3 Br N NH O N N N

9 The Body PRO An Update on New HIV Antiretroviral Agents 8 Etravirine: Proof-of-Principle Trial in Treatment-Experienced Patients *Etravirine 900 mg BID + continued NRTIs for seven days 0.86 log Time (Days) HIV-1 RNA (Log 10 Copies/mL) -10 Failing NNRTI therapyEtravirine*New Tx Adapted from Brian Gazzard et al. AIDS. 2003;17:F49-F54. N = 16 Patients

10 The Body PRO An Update on New HIV Antiretroviral Agents 9 DUET: Study Design and Major Inclusion Criteria 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 (600/100 mg/mL) with optimised NRTIs and optional enfuvirtide Etravirine (TMC125) (200 mg BID) + BR* Placebo + BR* Follow up 4 weeks * BR = background regimen; RAM = resistance-associated mutation † Primary endpoint HIV-1 RNA < 50 copies/mL (TLOVR) Adapted from Pedro Cahn et al. ICAAC 2007; abstract H-717.

11 The Body PRO An Update on New HIV Antiretroviral Agents 10 DUET: Patients with Viral Load < 50 Copies/mL at Week 48 (ITT-TLOVR) Richard Haubrich et al. CROI 2008; abstract 790. Reprinted with permission. * Pooled DUET data included for comparison; ‡ Logistic regression model; TLOVR = time to loss of virologic response imputation algorithm. CI = confidence interval

12 The Body PRO An Update on New HIV Antiretroviral Agents 11 DUET: Response (<50 Copies/mL) by PSS (DRV FC < 10 and < 40)* at Week 48 Richard Haubrich et al. CROI 2008; abstract 790. Reprinted with permission. *PSS = phenotypic sensitivity score; DRV = darunavir; FC = fold change; ETR = etravirine; BR = background regimen; ARVs = antiretrovirals; VL = viral load ‡ Analysis excludes pts who DC except for virologic failure; ENF counted as sensitive if used de novo <10 FC < 40 FC

13 The Body PRO An Update on New HIV Antiretroviral Agents 12 DUET: Overview of Adverse Events (Regardless of Causality) at Week 48 Richard Haubrich et al. CROI 2008; abstract 790. Reprinted with permission. No consistent or clinically relevant trends in lab, vital signs or ECGs observed Lab abnormalities, including hepatic and lipid parameters similar between arms ‡ All deaths in the ETR group were considered not or doubtfully related to trial medication. One death in the pooled placebo group was considered possibly related to the background regimen (BR); AE = adverse event; ETR = etravirine

14 The Body PRO An Update on New HIV Antiretroviral Agents 13 DUET: Response (< 50 Copies/mL) According to Number of TMC125 RAMS The greatest added benefit in the TMC125 versus placebo group was seen in patients with <3 TMC125 RAMs 86% of patients had <3 TMC125 RAMs Patients with Viral Load < 50 Copies/mL at Week 24 (%) Number of TMC125 RAMs Present at Baseline 75% 58% 60% 41% Analysis excludes patients who used de-novo enfuvirtide or discontinued except for virological failure BR = background regimen; RAM = resistance-associated mutation ≥ 73/121 59/157 38% 25% 44% Placebo + BR (n=414)TMC125 + BR (n=406) % 17% 121/161 64/147 37/64 17/68 13/32 6/24 7/28 3/18 Pedro Cahn et al. ICAAC 2007; abstract H-717. Reprinted with permission.

15 The Body PRO An Update on New HIV Antiretroviral Agents 14 Etravirine  Recommended dose of etravirine is 200mg BID with a meal  It can be dispersed in a glass of water  Substrate CYP3A4, CYP2C9, CYP2C19  Rash: main AE in clinical studies  Grade (9%), discontinuation from study (2%), Stevens-Johnson Syndrome (<.1%)  Mutations V179F/I and Y181C/I most commonly selected on virologic failure  Fold change (FC) susceptibility: 27.6 (Virco)  Populations:  Pregnancy Category B  No renal dose adjustment needed  OK for mild to moderate liver disease

16 The Body PRO An Update on New HIV Antiretroviral Agents 15 ARV Drug-Drug Interactions: Etravirine  No dose adjustment required  Didanosine  Tenofovir  Saquinavir/r  Lopinavir + Saquinavir 2  Darunavir/r  Raltegravir  Elvitegravir/r 3  Co-administer with caution 1  Lopinavir/r a  Dose modification 1  Maraviroc 4 (modify dose)  Co-administered contraindicated with 1  Tipranavir/r  Atazanavir/r b  Fosamprenavir/r c  Full dose ritonavir  Unboosted PIs  Atazanavir  Fosamprenavir  Indinavir  Nelfinavir  Delavirdine  Nevirapine  Efavirenz a AUC of ETR after co-administration with LPV/r is anticipated to be ~85% higher than AUC of ETR observed in DUET trials. 1 b AUC of ETR after co-administration with ATV/r is anticipated to be ~100% higher than AUC of etravirine observed in DUET trials. 1 c Due to a significant increase in AUC of APV, the appropriate doses of the combination of ETR and FPV/r have not been established. 1 1 Intelence [package insert]. Raritan, NJ: Tibotec, Inc.; January Marianne Harris et al. CROI 2006; abstract 575b. 3 Srinivasan Ramanathan et al. ICAAC 2007; abstract H J. Davis et al. EACS Abstract P4.3/02.

17 The Body PRO An Update on New HIV Antiretroviral Agents 16 Protease Inhibitors

18 The Body PRO An Update on New HIV Antiretroviral Agents 17 Similar Efficacy of Protease Inhibitors in Treatment-Naïve Patients at 48 Weeks Percent With HIV-1 RNA < 50 Copies/mL Approximated Difference, % ARTEMIS (ITT: TLOVR) 1 Intent to Treat: Time to Loss of Virologic Response Darunavir/ritonavir (800/100) mg QD (N = 343) (95% CI:-0.3, 11.2) Lopinavir/ritonavir (400/100) mg BID or (800/200) mg QD + tenofovir/emtricitabine* (N = 346) 78 CASTLE (ITT-CVR: NC = F) 2 Intent to Treat-Confirmed Virologic Response: Non-completer = Failure Atazanavir/ritonavir (300/100 mg) QD + tenofovir/emtricitabine (N = 440) (95% CI:-3.8, 7.1) Lopinavir/ritonavir soft-gel capsule (400/100 mg) BID + tenofovir/emtricitabine (N = 443) 76 GEMINI (ITT) 3 Intent to Treat Lopinavir/ritonavir soft-gel capsule (400/100 mg) BID + tenofovir/emtricitabine (N = 170) (96% CI:-9.6, 11.9) Saquinavir/ritonavir (1000/100 mg) BID + tenofovir/emtricitabine (N = 167) 64 KLEAN (ITT-E: TLOVR) 4 Intent to Treat-Exposed: Time to Loss of Virologic Response Fosamprenavir/ritonavir (700/100 mg) BID + abacavir/lamivudine (N = 434) 66 n/a Lopinavir/ritonavir soft-gel capsule (400/100 mg) BID + abacavir/lamivudine (N = 444) 65 1 Adapted from Nathan Clumeck et al. CROI 2008; abstract Adapted from Jean-Michel Molina et al. CROI 2008; abstract Adapted from Sharon Walmsley et al. EACS 2007; abstract PS1/4. 4 Adapted from Joseph Eron Jr et al. Lancet. 2006;368: *77% of patients received BID dosing throughout study, 83% of patients switched from soft-gel capsule to tablet formulation.

19 The Body PRO An Update on New HIV Antiretroviral Agents 18 The Evolution of Darunavir/r in the Treatment of HIV Infection  Patients With Heavy ARV Experience  POWER 1 and POWER 2  POWER 3  DUET 1 and DUET 2  Patients With Limited ARV Experience  TITAN  Patients Naïve to Therapy  ARTEMIS

20 The Body PRO An Update on New HIV Antiretroviral Agents 19 TITAN (TMC114-C214): Study Design Jose Valdez Madruga et al. IAS 2007; abstract TUAB101. Reprinted with permission.

21 The Body PRO An Update on New HIV Antiretroviral Agents 20 TITAN: Baseline Characteristics Jose Valdez Madruga et al. IAS 2007; abstract TUAB101. Reprinted with permission.

22 The Body PRO An Update on New HIV Antiretroviral Agents 21 TITAN: Viral Load < 50 Copies/mL to Week 48 (TLOVR) — All Patients Jose Valdez Madruga et al. IAS 2007; abstract TUAB101. Reprinted with permission.

23 The Body PRO An Update on New HIV Antiretroviral Agents 22 TITAN: Viral Load < 50 Copies/mL at Week 48 by Baseline LPV FC (TLOVR) Jose Valdez Madruga et al. IAS 2007; abstract TUAB101. Reprinted with permission. * DRV/r 600/100mg bid † Estimated from a logistic regression model including treatment and stratification factors: baseline log 10 HIV-RNA and use of NNRTIs in the optimised background regimen

24 The Body PRO An Update on New HIV Antiretroviral Agents 23 TITAN: Most Common Adverse Events Jose Valdez Madruga et al. IAS 2007; abstract TUAB101. Reprinted with permission.

25 The Body PRO An Update on New HIV Antiretroviral Agents 24 ARTEMIS: Phase III Study Design Dosing was based on regulatory approval; switch was made according to local regulatory approval and drug availability DRV/r 800/100mg QD + TDF 300mg and FTC 200mg (N=343) LPV/r 400/100mg bid or 800/200mg QD + TDF 300mg and FTC 200mg (N=346) LPV dosingLPV formulation QD = 15%Capsule only = 15% BID = 77%Tablet only = 2% BID/QD = 7%Capsule/tablet switch = 83% 689 ARV-naïve patients VL > 5,000; no CD4 entry Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.

26 The Body PRO An Update on New HIV Antiretroviral Agents 25 ARTEMIS: Viral Load < 50 Copies/mL to Week 48 (ITT-TLOVR) Estimated difference in response vs LPV/r for non-inferiority: PP = 5.6% (95% CI –0.1;11.3) p<0.001 Estimated difference in response vs LPV/r for non-inferiority: PP = 5.6% (95% CI –0.1;11.3) p<0.001 Estimated difference in response vs LPV/r for superiority: ITT = 5.5% (95% CI –0.3;11.2) p= % 78% Time (weeks) Patients with VL < 50 Copies/mL (% [±SE]) LPV/r QD or BID (N=346) DRV/r QD (N=343) 2 Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission.

27 The Body PRO An Update on New HIV Antiretroviral Agents 26 ARTEMIS: Week 48 Response by QD and BID Dosing (ITT-TLOVR) Adapted from Edwin DeJesus et al. ICAAC 2007; abstract H-718b. 346 N = Patients with VL < 50 Copies/mL (%) 343 DRV/r QD 84 LPV/r overall 78 *Difference rounded † 27 patients receiving LPV/r BID and QD during the study were excluded from this analysis. 267 LPV/r BID † LPV/r QD † 71 Difference 9% * (95% CI -3; 21) Difference 13% (95% CI 1; 24; p<0.05) Difference 3% (95% CI -3; 9)

28 The Body PRO An Update on New HIV Antiretroviral Agents 27 ARTEMIS: Grade 2–4 Adverse Events Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission. Gr 2–4 AEs † ≥ 2% Incidence, n (%) DRV/r QDLPV/r QD or BID (N=343)(N=346) GI (all AEs) 23 (7) 47 (14) Diarrhea 14 (4) 34 (10) Nausea 6 (2)10 (3) Rash (all types) 9 (3) 4 (1) † At least possibly related to study drug, excluding laboratory-related events No renal SAEs and no treatment discontinuations due to renal AEs p < 0.01 p < 0.05

29 The Body PRO An Update on New HIV Antiretroviral Agents 28 ARTEMIS: Mean Fasting Lipid Levels Over Time Edwin DeJesus et al. ICAAC 2007; abstract H-718b. Reprinted with permission. Mean Triglyceride Concentration ( ± SE) Time (weeks) DRV/r n= LPV/r n= Mean Triglycerides DRV/r QD (n=343) LPV/r QD or BID (n=346) Total Cholesterol/HDL Ratio DRV/r QD (n=343) LPV/r QD or bid (n=346) Mean Total Cholesterol/HDL Ratio (± SE) NCEP cut-off mM ng/mL

30 The Body PRO An Update on New HIV Antiretroviral Agents 29 Raltegravir: Integrase Inhibitor

31 The Body PRO An Update on New HIV Antiretroviral Agents 30 BENCHMRK-1 & -2: Study Design Randomized, double-blind, placebo-controlled with Data and Safety Monitoring Board Primary analysis at Week 16; secondary analysis at Week 48 Raltegravir 400 mg BID + OBT P018* (n=232) P019* (n=230) Placebo + OBT P018* (n=118) P019* (n=119) HIV-1-infected Triple-class resistant HIV-1 RNA > 1,000 copies/mL No CD4 cell cut-off Protocol 018* (N=352) Europe, Asia/Pacific and Peru Protocol 019* (N=351) North and South America 2:1 OBT was selected by investigator based on baseline resistance testing and prior treatment history. Selected investigational ARTs, darunavir and tipranavir, were permitted. *Protocol 018 (P018) is BENCHMRK-1; Protocol 019 (P019) is BENCHMRK-2 Primary endpoints Week 16 Planned duration Week 156 David Cooper et al. CROI 2008; abstract 788. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Stations, New Jersey, USA, All Rights Reserved

32 The Body PRO An Update on New HIV Antiretroviral Agents 31 BENCHMRK-1 & -2: Patients With HIV-1 RNA < 50 Copies/mL at Week 48 *+OBR; P <.001 for RAL vs placebo, derived from a logistic regression model adjusted for baseline HIV-1 RNA level (log 10 ), first ENF use in OBR, first DRV use in OBR, active PI in OBR. BENCHMRK-1 [1] BENCHMRK-2 [2] 1 David Cooper et al. CROI 2008; abstract 788. Reprinted with permission. 2 Roy Steigbigel et al. CROI 2008; abstract 789. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Stations, New Jersey, USA, All Rights Reserved

33 The Body PRO An Update on New HIV Antiretroviral Agents 32 BENCHMRK-1 & -2 Combined Efficacy: Percent of Patients With HIV RNA <50 Copies/mL at Week 48 by Selected ARTs in OBT David Cooper et al. CROI 2008; abstract 788. Reprinted with permission. Copyright © 2008 Merck & Co., Inc., Whitehouse Stations, New Jersey, USA, All Rights Reserved

34 The Body PRO An Update on New HIV Antiretroviral Agents 33 BENCHMRK-1 and -2: Drug-Related Adverse Events at Week 48 BENCHMRK-1 1 BENCHMRK-2 2 Placebo + OBT (N = 118) RAL + OBT (N = 232) Placebo + OBT (N = 119) RAL + OBT (N = 230) Diarrhea14.4%6.9%10.1%13.9% Fatigue0%2.2%2.5%5.2% Headache6.8%3.0%5.0%8.7% Nausea6.8%3.9%9.2%9.6% Rates of all-cause, serious and drug-related AEs, death and laboratory abnormalities did not differ significantly between treatment arms. Malignancy rate: RAL 3.5/100 person-years vs. placebo 2.3/100 person-years RR: 1.5 (95% CI: ) 1 Adapted from David Cooper et al. CROI 2008; abstract Adapted from Roy Steigbigel et al. CROI 2008; abstract 789. Copyright © 2008 Merck & Co., Inc., Whitehouse Stations, New Jersey, USA, All Rights Reserved

35 The Body PRO An Update on New HIV Antiretroviral Agents 34 Study Design: MK-0518 Protocol patients treated Mean age 36, 80% male, 69% non-white, 34% AIDS, Mean HIV RNA at baseline log 10 EFV (TDF + 3TC) 48 Week Phase II Multicenter Double-Blind, Randomized Study MK-518 (100, 200, 300, 400 BID) (TDF + 3TC) *Virologic failure defined as early (rebound or lack of suppression by 1 log 10 ) or late (failure to suppress to <200 c/mL or rebound) MK weeks monotherapy Adapted from Martin Markowitz et al. IAC 2006; abstract THLB0214.

36 The Body PRO An Update on New HIV Antiretroviral Agents 35 Protocol 004: Percent (95% CI) of Patients with HIV RNA < 50 Copies/mL (NC=F) * P < for MK-0518 at each dose vs. EFV Martin Markowitz et al. IAC 2006; abstract THLB0214. Reprinted with permission Week Percent of Patients withHIV RNA < 50 Copies/mL * * MK mg 39 MK mg 40 MK mg 41 MK mg 40 Efavirenz 38 37

37 The Body PRO An Update on New HIV Antiretroviral Agents 36 MK-0518 vs. EFV: Adverse Events MK-0518 (all doses) N=160 (%)Efavirenz* N=38 (%) Nausea 1113 Headache924 Dizziness826 Diarrhea711 Insomnia711 Abnormal dreams618 Flatulence6- Adapted from Martin Markowitz et al. IAC 2006; abstract THLB0214. Additional adverse events seen at ≥ 5% in efavirenz group: Nightmare (11%) Vomiting (8%) Malaise (8%) Fatigue (5%) Disturbance in attention (5%) Lethargy (5%) Anxiety (5%) * With TFV/3TC

38 The Body PRO An Update on New HIV Antiretroviral Agents 37 Raltegravir vs. EFV: Serum Lipids Hedy Teppler et al. ICAAC 2006; abstract H-0256a. Reprinted with permission. N = number of patients with data * p-value < 0.05 for comparison to efavirenz ** MK-0518 and EFV were given in combination with TFV/3TC

39 The Body PRO An Update on New HIV Antiretroviral Agents 38 Maraviroc: CCR5 Entry Inhibitor

40 The Body PRO An Update on New HIV Antiretroviral Agents 39 CCR5 Inhibitors: The Good, The Bad, The Unknown Dan Kuritzkes. Infectious Disease Grand Rounds Feb. 2008, University of Colorado. Reprinted with permission. X4 (SI)R5 (NSI) CXCR4 CCR5 CD4 T-cell lines Primary lymphocytesMonocyte/macrophages CD4 Naïve CD4 memory Dual tropic

41 The Body PRO An Update on New HIV Antiretroviral Agents 40 Tropism Testing Panel on Antiretroviral Guidelines for Adults and Adolescents. Washington, DC: US Dept of Health and Human Services; December 1, 2007.

42 The Body PRO An Update on New HIV Antiretroviral Agents 41 Tropism Testing Standard Trofile Assay The Trofile test, which was used to establish eligibility for clinical trials of maraviroc, has been proven an effective test for identifying individuals with X4-tropic virus. 1 However, the test sometimes fails to identify X-4 tropic minority subpopulations. Enhanced Trofile Assay It identified D/M tropism in more patients in ACTG 5211 than the standard assay: 2 25 of the 116 patients who were believed to have changed from CCR5-only to D/M tropism while taking vicriviroc, were found to have D/M virus at study entry when the enhanced Trofile assay was used. 1. Jeannette M. Whitcomb et al. Antimicrob Agents Chemother. February 2007;51(2): Jacqueline Reeves et al. CROI 2008; abstract 869.

43 The Body PRO An Update on New HIV Antiretroviral Agents 42 MOTIVATE-1 & -2: Study Design Randomization 1:2:2 MOTIVATE 1 N=601 MOTIVATE 2 N=474 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) Planned interim analysis Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission.

44 The Body PRO An Update on New HIV Antiretroviral Agents 43 MOTIVATE 1 & 2: Combined Virologic Efficacy at Week 48 David Hardy et al. CROI 2008; abstract 792. Reprinted with permission. Percentage of Patients with HIV-1 RNA Suppression (solid lines, HIV-1 RNA <400 copies/mL; dashed lines, HIV-1 RNA <50 copies/mL)

45 The Body PRO An Update on New HIV Antiretroviral Agents 44 MOTIVATE-1 & -2: HIV-1 RNA < 50 Copies/mL at Week 24 by Number of Active Drugs in OBT N= Number of Active Drugs in OBT Adapted from Mark Nelson et al. CROI 2007; abstract 104aLB. Adapted from Jacob Lalezari et al. CROI 2007; abstract 104bLB.

46 The Body PRO An Update on New HIV Antiretroviral Agents 45 MOTIVATE 1 & 2: Virologic Outcomes Based on Tropism Elna van der Ryst et al. ICAAC 2007; abstract H-715. Reprinted with permission. N= MVC QD + OBT MVC BID + OBT OBT alone D/MR5 Patients (%) Tropism result at baseline: HIV-1 RNA <50 c/mL

47 The Body PRO An Update on New HIV Antiretroviral Agents 46 MOTIVATE 1 & 2: 48-Week Safety Unadjusted for Duration of Exposure *Includes all patients who received at least one dose of study medication. † Includes deaths reported up to 28 days after stopping study drug. No deaths were related to study drug according to the investigator. Similar frequency of serious, all-grade adverse events, toxicity-driven discontinuations, laboratory abnormalities, AIDS-defining events among MVC and placebo arms at Week 48. David Hardy et al. CROI 2008; abstract 792. Reprinted with permission. All casualties and severities, n (%)Placebo + OBT N=209 Maraviroc QD + OBT N=414 Maraviroc BID + OBT N=426 Total exposure to study treatment, patient-years Treatment-emergent adverse events177 (84.7)375 (90.6)393 (92.3) Discontinuation due to adverse events11 (5.3)24 (5.8)21 (4.9) Serious adverse events35 (16.7)62 (14.9)72 (16.9) Grade 3 adverse events46 (22.0)84 (20.3)104 (24.4) Grade 4 adverse events16 (7.7)37 (8.9)45 (10.6) Category C events16 (7.7)29 (7.0)23 (5.4) Category C malignancies5 (2.4)3 (0.7)4 (0.9) Non-HIV malignancies11 (5.3)12 (2.9)19 (4.5) Deaths*2 † (1.0)6 (1.4)9 (2.1)

48 The Body PRO An Update on New HIV Antiretroviral Agents 47 MERIT: Comparison of Efavirenz and Maraviroc in ARV-Naïve Patients Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission. Randomization 1:1 Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)* Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)* Primary analysis 0 48 wk 96 wk Screening (6 weeks) Patients stratified by: HIV-1 RNA < and ≥ 100,000 copies/mL at screening Geographic location: Northern Hemisphere and Southern Hemisphere Patient eligibility criteria: ≥ 16 years of age Treatment naive R5 HIV-1 infection HIV-1 RNA ≥ 2,000 copies/mL No evidence of resistance to EFV, ZDV, or 3TC First patient visit Nov, 2004 *Patients experiencing toxicity to ZDV or 3TC were permitted to substitute an alternative NRTI MVC QD arm discontinued at end of Phase 2b (week 16) for failure to meet protocol-defined criteria to continue (205 pts completed 16 weeks)

49 The Body PRO An Update on New HIV Antiretroviral Agents 48 MERIT: Summary of Discontinuations Through 48 Weeks Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission. Reason for Discontinuation EFV + CBV N=361 MVC + CBV N=360 All, N (%)91 (25.2)97 (26.9) Adverse event, N (%)49 (13.6)15 (4.2) Lack of efficacy, N (%)15 (4.2)43 (11.9) Other reason, N (%)9 (2.5)14 (3.9) Withdrew consent or lost to follow-up, N (%)18 (5.0)25 (6.9)

50 The Body PRO An Update on New HIV Antiretroviral Agents 49 MERIT: Percentage of Patients with Undetectable HIV-1 RNA at Week 48 (Primary Endpoint) Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission Patients (%) N= MVC + CBV EFV + CBV < 400 Copies/mL < 50 Copies/mL –3.0* (–9.5 † ) –4.2* (–10.9 † ) †Lower bound of 1-sided 97.5% confidence interval; noninferiority margin = –10% Per-protocol analysis: <400 copies/mL difference = -4.1 (-10.5 † ), <50 copies/mL difference = -4.4 (-11.2 † ) Mean ∆ CD4+ from baseline: EFV +144 vs. MVC +170 cells/mm 3 Difference: +26 (95% CI: +7, +46) *Difference (adjusted for randomization strata) Intent-to-treat (ITT) analysis

51 The Body PRO An Update on New HIV Antiretroviral Agents 50 MERIT: Percentage of Patients with HIV-1 RNA < 50 Copies/mL by HIV-1 RNA at Screening Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission Patients (%) N= < 100,000 copies/mL≥ 100,000 copies/mL Difference in < 50 noted in Southern Hemisphere (71% vs. 62%); No difference in Northern Hemisphere (67% vs. 68%) Missing values classified as failures/non-responders MVC + CBV EFV + CBV

52 The Body PRO An Update on New HIV Antiretroviral Agents 51 Summary of Dose Modifications with Maraviroc Concomitant TreatmentA.M. Dose P.M. Dose 150 mg 300 mg Includes a Potent CYP3A4 Inhibitor PIs ± ritonavir (except tipranavir), clarithromycin, delavirdine, elvitegravir, itraconazole, ketoconazole, nefazadone, telithromycin Includes a CYP3A4 Inducer efavirenz, etravirine, rifampicin No CYP3A4 Inhibitors or Inducers NRTIs, nevirapine, tipranavir/r NO YES 300 mg Adapted from Maraviroc [package insert]. New York, NY: Pfizer Labs; 2007.

53 The Body PRO An Update on New HIV Antiretroviral Agents 52 Take Home Message  ARV development has been very successful in the past decade.  The availability of new agents and new classes have increased treatment options for our treatment experienced patients.  The potential use of these agents earlier in therapy have opened the door for new treatment strategies.  There are several other agents in development that can further complement the enhanced activity of these new agents.


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