DHS/HIV/PP HIV/AIDS 2007 Update David H. Spach, MD Clinical Director Northwest AIDS Education and Training Center Professor of Medicine Division of Infectious Diseases University of Washington, Seattle

HIV/AIDS 2007 Update DHHS Antiretroviral Recommendations Data Regarding Preferred Antiretroviral Regimens New and Future Medications Strategies for Patients with Multi-Drug Resistant HIV DHS/PP

Antiretroviral Therapy Current DHHS Recommendations

HIV: Antiretroviral Therapy HIV RNAHIV DNA HIV Nucleus Host Cell Non-Nucleoside RTI Nucleoside RTI Integrase Inhibitors Protease Inhibitors Entry Inhibitors

Starting Antiretroviral Therapy Acute HIV Infection Year DHS/PP

DHHS Panel: October 2006 ARV Therapy Guidelines Initial Therapy: Preferred Regimens Picture NNRTI Efavirenz Source: Column B 2-NRTI Tenofovir/Emtricitabine Zidovudine/Lamivudine Column A DHS/PP PI Atazanavir + Ritonavir Fosamprenavir + Ritonavir BID Lopinavir/ritonavir BID Construct Regimen by choosing one component from Column A and one component from Column B

DHHS Panel: October 2006 ARV Therapy Guidelines Initial Therapy: Preferred Regimens Picture NNRTI Efavirenz Source: Column B 2-NRTI Tenofovir/Emtricitabine Zidovudine/Lamivudine Column A DHS/PP PI Atazanavir + Ritonavir Fosamprenavir + Ritonavir BID Lopinavir/ritonavir BID Construct Regimen by choosing one component from Column A and one component from Column B

DHHS Panel: October 2006 ARV Therapy Guidelines Initial Therapy: Alternative Regimens Picture NNRTI Nevirapine Source: Column B 2-NRTI Abacavir/Lamivudine Didanosine + Lamivudine Column A DHS/PP PI Atazanavir (unboosted) Fosamprenavir (unboosted) Fosamprenavir + ritonavir qd Lopinavir/ritonavir qd Construct Regimen by choosing one component from Column A and one component from Column B

DHS/PP DHHS Guidelines Why no Update Since October 2006?

DHS/PP Antiretroviral Therapy Data with Preferred Regimens

Tenofovir + Emtricitabine + Efavirenz (Atripla) Classification: (2) nRTI + (1) nNRTI Dose: 1 pill qd - Tenofovir 300 mg - Emtricitabine 200 mg - Efavirenz: 600 mg Meal Restrictions: without food Strong data from Study 934 Adverse Effects: CNS (efavirenz) DHS/PP Atripla

From: Gallant JE et al. N Engl J Med. 2006;354: Tenofovir + Emtricitabine + Efavirenz versus Zidovudine + Lamivudine + Efavirenz  Patients (N = 517 randomized) - ARV naïve, HIV RNA > 10,000 copies/ml - Randomized trial  Regimens (N = 487) - Tenofovir + Emtricitabine + Efavirenz - Zidovudine + Lamivudine + Efavirenz Study Design: GS 934Results: 48 Weeks (ITT) DHS/PP TDF= Tenofovir FTC = Emtricitabine ZDV = Zidovudine 3TC = Lamivudine EFV = Efavirenz P = 0.002P = 0.02

From: Eron J et al. Lancet 2006;368: ABC + 3TC + (Fos-Amp-RTV or LPV-RTV) KLEAN-ESS  Patients (N = 887) - ARV naïve, HIV RNA > 1,000 copies/ml - Randomized trial  Regimens (backbone ABC + 3TC qd) - FosAmp 700 mg bid + RTV 100 mg bid - LPV-RTV ( mg bid) Study DesignResults*: 48 Weeks (TLOVR) DHS/PP * No differences in response in patients with HIV RNA > 100K * TLOVR = Time to Loss of Virologic Response

From: Smith K, et al. IAS, 2007: WEPEB023. TDF + FTC + (Fos-Amp-RTV or ATZ-RTV) ALERT Study  Patients (N = 106) - ARV naïve - HIV RNA > 1,000 copies/ml - Randomized trial  Regimens* - All patients: Tenofovir + Emtricitabine qd - FosAmp 1400 mg qd + RTV 100 mg qd - ATZ 300 mg qd + RTV 100 mg qd Study DesignResults: 48 Weeks (ITT) DHS/PP Abbreviations TDF = Tenofovir FTC = Emtricitabine FosAmp = Fosamprenavir RTV = Ritonavir ATZ = Atazanavir P = 0.30 P = 0.34

From: Madruga JV, et al. Lancet 2007;370: Darunavir + RTV vs. Lopinavir-RTV in Salvage TITAN  Patients (N = 595) - Highly treatment experienced* - HIV RNA > 1,000 copies/ml - Randomized trial (non-blinded) - Lopinavir and darunavir naïve  Regimens (All Received OBT) - Darunavir-RTV: 600/100 mg bid - LPV-RTV: 400/100 mg bid Study DesignResults*: 48 Weeks (ITT-TLOVR) DHS/PP * Baseline Data Overall 31% were PI-naïve Baseline Resistance - 2% with phenotypic resistance to Darunavir - 10% with phenotypic resistance to Lopinavir-RTV *TLOVR-Time to Loss of Virologic Response; Non-completer = Failure P < 0.001P < 0.005

DHS/PP HIV Entry

HIV DHS/PP gp120 gp41 Envelope Spikes

HIV: Envelope DHS/PP gp41 HIV gp120 CD4 Binding Groove V3 Region

HIV: Envelope DHS/PP HIV gp120 gp41

HIV: gp41 DHS/PP HIV Cytoplasmic tail Membrane-Proximal External Region Membrane-Spanning Domain N-heptad Repeat Region (Heptad Repeat 1) C-heptad Repeat Region (Heptad Repeat 2) Fusion Peptide

Host Cellular Receptors CD4 Receptor DHS/PP Intracellular Space Extracellular Space CD4 Receptor Host Cell Membrane

Host Cellular Receptor Cysteine-Cysteine Chemokine Receptor 5 (CCR5) DHS/PP CCR5 Intracellular Space Extracellular Space Host Cell Membrane C C

Host Cellular Receptor Chemokine C-X-C Motif Receptor (CXCR4) DHS/PP CXCR4 Intracellular Space Extracellular Space Host Cell Membrane C C

Host Cellular Receptors CD4, CCR5, & CXCR4 DHS/PP Host Cell Membrane CCR5 CD4 Receptor Extracellular Space Intracellular Space CXCR4

HIV Cell Binding and Entry DHS/PP Host Cell Membrane CD4 Receptor Extracellular Space Intracellular Space HIV CCR5 CD4 Receptor

HIV Cell Binding and Entry DHS/PP Host Cell Membrane Extracellular Space HIV CCR5 CD4 Receptor Intracellular Space

HIV Cell Binding and Entry DHS/PP Host Cell Membrane Extracellular Space HIV CCR5 CD4 Receptor Intracellular Space

HIV Cell Binding and Entry DHS/PP Host Cell Membrane Extracellular Space HIV Intracellular Space N-heptad Repeat Region (Heptad Repeat 1) C-heptad Repeat Region (Heptad Repeat 2) Fusion Peptide

HIV Cell Binding and Entry DHS/PP Host Cell Membrane HIV HIV Membrane

CCR5-∆32 DHS/PP CCR-∆32 Intracellular Space Extracellular Space Host Cell Membrane C C CCR5 C C

HIV Cell Binding and Receptor Tropism DHS/PP HIV CCR5 CD4 Receptor Host Cell Membrane Extracellular Space Intracellular Space CXCR4

HIV Cell Binding and Receptor Tropism DHS/PP HIV CCR5 CD4 Receptor Host Cell Membrane Extracellular Space Intracellular Space CXCR4 V3 Region

Entry Inhibitors CCR5 Inhibitors DHS/PP Host Cell Membrane CCR5 CD4 Receptor Extracellular Space Intracellular Space CCR5 Inhibitor

DHS/PP HIV Co-Receptor Tropism Assay Monogram Biosciences Trofile Assay  Assay Measures HIV Tropism - R5 Tropic - X4 Tropic - Dual Tropic/Mixed Tropic  Utilizes Entire Envelope Gene - Generates pseudoviruses  Viral Load Required - Above 1,000 copies/ml  Detection of Minor Species - Reliably detected at 5-10% R5-Tropic X4-Tropic R5X4 (Dual)-Tropic Mixed Tropic From: Whitcomb JM, et al. Antimicrob Agents Chemo 2007;51: HIV-1 Strains

HIV Infection: Natural History AIDS Year 1 DHS/PP R5 X4 R5X4 (Dual) Mixed HIV Tropism

From: Hunt PW, et al. J Infect Dis. 2006;194: Prevalence of CXCR4 Tropism among HIV-Infected Patients with Detectable Viremia  Patients (N = 1152) - ARV-naïve patients: n = ARV-experienced patients: n = 182  Measurement - PhenoSense HIV entry assay Study Design Patients with Dual/Mixed/X4 DHS/PP P <.001 P =.001 P =.005

Entry Inhibitors Fusion Inhibitors DHS/PP HIV N-heptad Repeat Region (Heptad Repeat 1) C-heptad Repeat Region (Heptad Repeat 2) Fusion Peptide C-heptad Repeat Region (Heptad Repeat 2) Enfuvirtide

DHS/PP Host Cell Membrane Extracellular Space HIV Intracellular Space N-heptad Repeat Region (Heptad Repeat 1) C-heptad Repeat Region (Heptad Repeat 2) Fusion Peptide Entry Inhibitors Fusion Inhibitors

DHS/PP Host Cell Membrane Extracellular Space HIV Intracellular Space Entry Inhibitors Fusion Inhibitors

DHS/PP Integration of HIV Into Host DNA

Integrase Inhibitors HIV RNAHIV DNA HIV Nucleus Host Cell Integrase Inhibitors

HIV: Integrase RNA DNA HIV Nucleus Host Cell Integrase 1 1 Integrase binding to HIV DNA

DNA HIV Nucleus Host Cell Integrase 2 3’ 2 3’ Processing of HIV DNA HIV: Integrase

DNA HIV Nucleus Host Cell Integrase Nuclear Translocation HIV: Integrase

HIV Nucleus Host Cell Integrase 3 3 Strand Transfer HIV: Integrase

HIV Nucleus Host Cell Gap Repair HIV: Integrase 4 4

HIV: Integrase Inhibitor HIV Nucleus Host Cell Integrase Inhibitor Strand Transfer

DHS/PP Data with New Antiretroviral Agents

Maraviroc (Selzentry) Mechanism: CCR5 Inhibitor Activity: Requires R5-tropic HIV & Screening with HIV Tropism Assay Data: MOTIVATE-1 and 2 (Maroviroc plus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients) Dose: mg bid (dose adjustments required with many other medications) Adverse Effects: well-tolerated; long term adverse effects unknown FDA-approved August 6, 2007 DHS/PP

OBT + Placebo Eligibility - HIV-infected: R5-tropic - Treatment Experienced - HIV RNA > 5,000 copies/ml - Randomized, double-blind - Resistance to (and/or) > 6 months of 3 classes of ARV drugs OBT + Maraviroc qd (150 or 300*) OBT + Maraviroc bid (150 or 300*) From: Lalezari J, et al. 14th CROI Abstract 104b-LB. Nelson M, et al. 14th CROI Abstract 104a-LB. Maraviroc in ARV-Experienced Patients MOTIVATE-1& 2 Study Motivate 1: N = 601 (Canada, US) Motivate 2: N = 475 (Europe, Australia, US) * Maraviroc 300 mg dose reduced to 150 mg in patients receiving RTV (except with Tipranavir) 1x 2x

From: Lalezari J, et al. 14th CROI Abstract 104b-LB. Nelson M, et al. 14th CROI Abstract 104a-LB. Maraviroc in ARV-Experienced Patients MOTIVATE-1 & 2 Studies Motivate 1: Results: 24 Weeks DHS/PP Motivate 2: Results: 24 Weeks

HIV Tropism at Time of Virologic Failure MOTIVATE-1 & 2 Studies DHS/PP From: Lalezari J, et al. 14th CROI Abstract 104b-LB. Nelson M, et al. 14th CROI Abstract 104a-LB. OBT + Placebo OBT + Maraviroc qdOBT + Maraviroc bid R5 at Baseline & at Failure R5 at Baseline; Dual, Mixed or X4 at Failure Non-R5 at Baseline or No Tropisms Data at Failure

Raltegravir (Isentress) Class - Integrase Inhibitor Dose mg PO bid (400 mg tabs) Adverse Effects - Diarrhea most common - No adverse effects on lipids Data - Excellent results in ARV-naïve and in salvage therapy - BENCHMARK 1& 2 Studies Approval - FDA advisory board to review September 2007 DHS/PP INVESTIGATIONAL

From: Markowitz M, et al. JAIDS Raltegravir versus Efavirenz in ARV-Naive Protocol 004, Part 2 Study DesignResults: 48 Weeks DHS/PP P = 0.04P = * CD4 counts higher in LPV-RTV arms INVESTIGATIONAL  Background - N = ARV-naïve - HIV RNA > 5,000 copies/ml - CD4 count > 100 cells/mm 3 - Randomized, double-blind  Regimens (all include TDF + 3TC*) - Efavirenz: 600 mg qd - Raltegravir: 100 mg bid - Raltegravir: 200 mg bid - Raltegravir: 400 mg bid - Raltegravir: 600 mg bid *Tenofovir + Lamivudine

Percent of Patients with HIV RNA < 50 copies/mL (NC = F) *P <.001 for MK-0518 at each dose vs EFV Week Raltegravir 100 mg39 Raltegravir 200 mg40 Raltegravir 400 mg41 Raltegravir 600 mg40 Efavirenz Pts With VL < 50 c/mL (%) * * Markowitz M, et al. XVI International AIDS Conference Abstract THLB0214. Raltegravir vs Efavirenz in ARV-Naïve Patients Backbone of Tenofovir + Lamivudine INVESTIGATIONAL

DHS/PP OBT + Placebo Eligibility - HIV-infected - Treatment Experienced - HIV RNA > 1,000 copies/ml - Randomized, double-blind - Resistance to 3 classes of ARV drugs OBT + Raltegravir 400 mg bid From: Cooper DA, et al. 14th CROI Abstract 105a-LB. Steigbigel R, et al. 14th CROI Abstract 105b-LB. Raltegravir in ARV-Experienced Patients BENCHMRK-1 & 2 Studies BENCHMRK 1: N = 350 (Europe, Asia, Peru) BENCHMRK 2: N = 349 (North & South America) 1x 2x INVESTIGATIONAL

From: Cooper DA, et al. 14th CROI Abstract 105a-LB. Steigbigel R, et al. 14th CROI Abstract 105b-LB. Raltegravir in ARV-Experienced Patients BENCHMRK-1 & 2 Study BENCHMRK 1: 16 Week Result DHS/PP P = 0.04P = P < BENCHMRK 2: 16 Week Result P = 0.04P = * CD4 counts higher in LPV-RTV arms P < INVESTIGATIONAL

DHS/PP Raltegravir in ARV-Experienced Patients BENCHMRK-1 & 2: Combined Data Week 16: HIV RNA < 400 copies/ml From: Cooper DA, et al. 14th CROI Abstract 105a-LB. Steigbigel R, et al. 14th CROI Abstract 105b-LB. INVESTIGATIONAL

Etravirine, formerly TMC-125 Class - 2nd Generation NNRTI Resistance Properties - Active against NNRTI-resistant HIV - High genetic barrier to resistance Dose mg PO bid (100 mg tabs) Adverse Effects - Rash most common Data - Good response in heavily pretreated patients (Duet I and II) Approval - Submitted to FDA in July 2007 DHS/PP INVESTIGATIONAL

DHS/PP Etravirine (TMC-125): Study C223 Response Related to Number of NNRTI Mutations  Background - Phase II trial  Patients (N = 199) - ARV experienced - Failed NNRTI regimen - 3 or more PI mutations - HIV RNA > 1,000 copies/ml  Regimens - Etravirine: 400 mg bid + OBR - Etravirine: 800 mg bid* + OBR - Placebo (OBR alone) Study Design 24 Week Data From: TMC-Writing Group. AIDS 2007;21(6):F1-10. *Comparable to 200 mg bid in new formulation used in Phase III trials INVESTIGATIONAL No single mutation associated with > 10-fold mean change

DHS/PP OBT* + Placebo Eligibility - Treatment Experienced - HIV RNA > 5,000 copies/ml - Randomized, double-blind, Phase 3 - Resistance to approved NNRTIs - At least 3 PI mutations OBT* + Etravirine 200 mg bid From: DUET-1. Madruga JV, et al. Lancet 2007;370: DUET-2. Lazzarin A, et al. Lancet 2007;370: Etravirine in ARV-Experienced Patients DUET 1 & 2 Studies DUET 1: N = 612 (Multinational) DUET 2: N = 591 (Multinational) * OBT - Darunavir + Ritonavir (600/100 mg bid) - Investigator Chosen NRTIs - Optional Enfuvirtide 1x INVESTIGATIONAL 1x

Etravirine in ARV-Experienced Patients DUET 1 & 2 Studies DUET 1: Results: 24 Weeks DHS/PP DUET 2: Results: 24 Weeks INVESTIGATIONAL From: Madruga JV, et al. Lancet 2007;370: From: Lazzarin A, et al. Lancet 2007;370: P = 0.001P < 0.005P = 0.001P = 0.003

Strategies for Treating Multi-Resistant HIV DHS/PP

QUESTION A 46-year-old HIV-infected man returns for further evaluation to discuss salvage therapy. He has a CD4 count of 118 cells/m 3 and an HIV RNA of 57,000 copies/ml. He is highly experienced with antiretroviral therapy and has extensive multi-drug resistant HIV. Specifically, he has high level resistance to all NRTIs and NNRTIs. In addition, he has resistance to all protease inhibitors except darunavir and tipranavir. He is currently taking tenofovir + emtricitabine (Truvada) + Lopinavir-ritonavir (Kaletra). He does not want to take enfuvirtide (Fuzeon). What would you recommend for this patient? DHS/HIV/PP

Options for Antiretroviral Medications NRTIs - Lamivudine or Emtricitabine; Tenofovir? Abacavir? Protease Inhibitor - Darunavir + Ritonavir Integrase Inhibitor - Raltegravir NNRTI - Etravirine Entry Inhibitors - Maraviroc? - Enfuvirtide DHS/PP INVESTIGATIONAL

Strategies for Deep Salvage in 2007 Goal - Undetectable HIV Key Medications to Build Regimen Around - Darunavir + Ritonavir - Raltegravir (if available via expanded access) - Etravirine (if available via expanded access) Possible Other Medications - Maraviroc (if patient has pure R5 HIV) - Enfuvirtide (if patient willing to do) - NRTIs (partial response only) OBTAIN EXPERT CONSULTATION DHS/PP