Eric S. Daar, MD Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California The Clinical Role of Integrase Inhibitors This program is supported by an educational grant from

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clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management Overview  Safety and efficacy of raltegravir demonstrated –Phase II data available for antiretroviral-naive patients –Phase III data available for antiretroviral-experienced patients –Current indication: for treatment-experienced adult patients with evidence of viral replication and resistance to multiple antiretrovirals  Elvitegravir studied predominantly in treatment- experienced patients to date (phase IIb)

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management Management of Virologic Failure in Multiclass-Experienced Patients  Newer drugs and those in novel classes provide options for patients with multidrug-resistant virus –Enfuvirtide –Tipranavir –Darunavir  Renewed expectation that patients with extensive treatment experience can achieve HIV-1 RNA < 50 copies/mL –Maraviroc –Raltegravir –Etravirine

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management DHHS Guidelines for Antiretroviral- Experienced Patients  Assessment of which available agents are likely to be partially or fully active based on treatment history, resistance data, and tropism testing [1]  Regimen optimization in experienced patients should involve standard assessments: potential toxicity, drug-drug interactions, likelihood of adherence  Regimens prescribed to treatment-experienced patients should include ≥ 2 new active agents, as illustrated in DUET (below) and other trials 1. DHHS. Available at: 2. Madruga JV, et al. Lancet. 2007;370: Placebo Etravirine ≥ 3 VL < 50 c/mL at Wk 24 (%) n = Response Rate by Active Background Agents in DUET-1 [2] Number of Active Agents in Optimized Background Regimen

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management 1. Nelson M, et al. J Acquir Immune Defic Syndr. 2005;40: Hicks CB, et al. Lancet. 2006;368: Clotet B, et al. Lancet. 2007;369: Haubrich R, et al. CROI Abstract Johnson M, et al. CROI Abstract Lalezari J, et al. ICAAC Abstract H-718a. 7. Cooper DA, et al. N Engl J Med. 2008;359: Steigbigel R, et al. N Engl J Med. 2008;359: StudyDrug RegimenHIV-1 RNA < 50 copies/mL, % TORO [1] Enfuvirtide + OBR OBR alone RESIST [2] Tipranavir/ritonavir + OBR Comparator PI + OBR POWER [3] Darunavir/ritonavir + OBR Comparator PI + OBR DUET [4,5] Etravirine + darunavir/ritonavir-containing OBR Placebo + darunavir/ritonavir-containing OBR MOTIVATE [6] Maraviroc QD + OBR Maraviroc BID + OBR Placebo + OBR BENCHMRK [7,8] Raltegravir + OBR Placebo + OBR Virologic Efficacy When Adding New Drugs to OBR (Week 48)

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management Pharmacology of Raltegravir: Implications for Dosing & Interactions  Raltegravir administered as one 400-mg pill BID without regard to food  Raltegravir metabolized by glucuronidation –May have fewer interactions with drugs metabolized by cytochrome P450 –Strong inducers or inhibitors of UGT1A1 (enzyme responsible for raltegravir glucuronidation) –Atazanavir: increases raltegravir levels—but increases not shown to be clinically relevant [1] –Tipranavir: reduces plasma levels of raltegravir [2] —but comparable efficacy observed in 100 patients receiving raltegravir plus either tipranavir/ritonavir or a control PI [1] 1. Raltegravir package insert. 2. Wenning LA, et al. ICAAC Abstract A-0374.

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management Principles for Use of Raltegravir in ARV-Resistant Patients  Greater likelihood of achieving virologic suppression if raltegravir introduced earlier rather than later  Regimen containing raltegravir + 2 other active agents appears more effective than regimen containing raltegravir + 1 other active agent  High rates of integrase resistance at virologic failure highlights importance of prescribing raltegravir with other active agents Cooper DA, et al. N Engl J Med. 2008;359:

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management BENCHMRK 1 & 2: HIV-1 RNA < 50 c/mL at Week 48, Overall, and by GSS 0 GSS Raltegravir ≥ 2 nPatients (%) Placebo Total Subgroup Cooper DA, et al. N Engl J Med. 2008;359:

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management BENCHMRK 1 & 2: HIV-1 RNA < 50 c/mL by New Agents in OBR, Week n Patients (%) 92 Enfuvirtide Darunavir Cooper DA, et al. N Engl J Med. 2008;359:

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management TRIO Study: RAL + ETR + DRV/RTV Highly Effective as 3 Active Agents  Multicenter, phase II study of darunavir/ritonavir + etravirine + raltegravir (N = 103); addition of NRTIs, enfuvirtide at discretion of physician –Inclusion criteria included susceptibility to darunavir and ETR based on ≤ 3 darunavir and ≤ 3 ETR RAMs –59% of patients had < 1 active agent in OBR, as assessed by GSS  HIV-1 RNA < 50 copies/mL at Week 24 in 90% (95% CI: 85% to 96%) of patients –Of 10 patients with detectable HIV-1 RNA at Week 24, only 3 confirmed at > 400 copies/mL  Median CD4+ cell count increase from BL to Week 24: 99 cells/mm 3 (IQR: )  Two possibly drug-related grade 4 AEs; only 1 led to treatment discontinuation Yazdanpanah Y, et al. IAC Abstract THAB0406.

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management Raltegravir in ARV-Experienced Patients With Virologic Suppression  Raltegravir licensed for use only in experienced patients with uncontrolled viremia –Interest in using raltegravir in other settings (eg, substitution for agents associated with toxicity)  Switch studies enrolled for patients on ritonavir-boosted PI therapy (eg, lopinavir/ritonavir)  Placebo-controlled trials of adding raltegravir to PI- or NNRTI-based HAART in virologically suppressed patients currently recruiting –To determine if raltegravir further decreases HIV-1 RNA in HAART-suppressed patients

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management Switching Enfuvirtide to Raltegravir in Virologically Suppressed Patients StudyNHIV-1 RNA < 50 copies/mL at Week 24 After Switch, % CHEER [1] 5294 Montreal cohort [2] 2596 Harris et al [3] 3597  3 case reports of hepatic cytolysis after switching enfuvirtide → raltegravir in virologically suppressed, heavily treatment–experienced men receiving tipranavir/ritonavir + enfuvirtide [4] –1 subject had higher tipranavir level after switch 1. Towner W, et al. IAC Abstract TUPE Talbot A, et al. IAC Abstract TUPE Harris M, et al. AIDS. 2008;22: Khanlou H, et al. IAC Abstract TUPE0087.

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management Raltegravir in Treatment-Naive Patients  Currently approved for use only in viremic patients with multidrug-resistant HIV [1]  Ongoing studies in antiretroviral-naive patients  Rationale for use in treatment-naive patients [2] –Potency –Does not require ritonavir boosting –Can be used as basis for NNRTI- and PI-sparing regimens –Neutral effect on lipids 1. Raltegravir package insert. 2. Markowitz M, et al. J Acquir Immune Defic Syndr. 2007;46:

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management Implications for Clinical Practice (cont’d)  Efficacy of integrase inhibitors in experienced patients improved when combined with other active agents  Relatively high rates of emergent integrase mutations associated with raltegravir virologic failure –Sequencing of raltegravir and elvitegravir not likely to be beneficial  Integrase inhibitors not associated with significant treatment-limiting, class-related toxicities  Role of integrase inhibitors in treatment-naive patients and as switch therapy for those suppressed on other regimens being investigated

clinicaloptions.com/hiv The Role of Integrase Inhibitors in HIV Management Implications for Clinical Practice (cont’d)  DHHS guidelines –HIV-1 RNA < 50 copies/mL goal of therapy in treatment- experienced patients –Regimens for experienced patients should include ≥ 2 new active agents, based on resistance testing and treatment history –Optimization of therapy in experienced patients should also involve consideration of potential toxicity, drug-drug interactions, and likely adherence

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