Tuesday, May 14, 213 12:3pm 1:3pm ALL PARTICIPANTS MUST CALL THE CONFERENCE LINE PLEASE MUTE ALL MICROPHONES AND SPEAKERS TO MUTE PRESS *6, TO UNMUTE PRESS #6 <<DO NOT PLACE PHONE ON HOLD>> CONFERENCE NUMBER: Toll Free 1-888-67-3525 Other +1-72-389-1212 CODE: 5-177-6856 then # Continuing Education Disclosure The activity planners do not have any financial relationships with commercial entities to disclose. This slide set has been peer reviewed to ensure that there are no conflicts of interest represented in the presentation. 1
Continuing Education Disclosure The following have no financial relationships with commercial entities to disclose: o Beata Casanas, DO, FACP (Program Planner / Facilitator / Case Facilitator) Associate Professor, Division of Infectious Diseases and International Medicine, USF Health - Morsani College of Medicine Executive Medical Director, Hillsborough County Health Department Faculty Member, Florida/Caribbean AIDS Education and Training Center o Joanne J. Orrick, PharmD, AAHIVP (Case Facilitator) Associate Director, Florida/Caribbean AIDS Education and Training Center These facilitators will not discuss any off-label use or investigational product during the program. This slide set has been peer reviewed to ensure that there are no conflicts of interest represented in the presentation. Continuing Education Disclosure The following have financial relationships with commercial entities to disclose: o Todd S. Wills, MD (Didactic Presenter / Case Facilitator) Vice-Chair for Operations, Research and Education, Department of Internal Medicine Fellowship Program Director, Division of Infectious Disease and International Medicine, USF Health - Morsani College of Medicine Faculty Member, Florida/Caribbean AIDS Education and Training Center Grant/Research Support: Gilead Sciences, Pfizer Dr. Wills will not discuss off-label use or investigational product during the program. This slide set has been peer reviewed to ensure that there are no conflicts of interest represented in the presentation. 2
Continuing Education (up to 1. hour of CE/CME) Continuing Medical Education This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Florida AHEC Network and the Florida/Caribbean AIDS Education and Training Center. The Florida AHEC Network is accredited by the Florida Medical Association to provide continuing medical education for physicians. The Florida AHEC Network designates this live activity for a maximum of 5. AMA PRA Category 1 Credits. Each physician should claim only the credit commensurate with the extent of their participation in the activity. Continuing Education Suwannee River Area Health Education Center, Inc., is a Florida Board of Nursing approved provider of continuing nursing education (CE Broker Provider ID #5 1922); a Florida Board of Clinical Social Work, Marriage and Family Therapy, and Mental Health Counseling approved provider of continuing education (BAP #5 1922), and a Florida Board of Pharmacy approved provider of continuing education (BAP #5 1922). This program meets the requirements for up to 5. contact hours. For questions regarding CE or CME, please contact our Professional Education Manager at ce@srahec.org or 386 462 1551. Continuing Education Disclosure In order to receive CE or CME credit, participants must complete a participant information survey and evaluation survey which includes a request for CE/ CME within 1 week of participation in each session, as well as be present for the entire session (at least 6 minutes). Participants will receive their CE/CME certificate approximately 6 weeks after the program. For questions regarding CE or CME, please contact our Professional Education Manager at ce@srahec.org or 386-462-1551. This slide set has been peer reviewed to ensure that there are no conflicts of interest represented in the presentation. 3
HIV Case Conference: Overview of Hep C Protease Inhibitors Todd S. Wills, MD Vice-Chair for Operations, Research and Education, Department of Internal Medicine Fellowship Program Director, Division of Infectious Disease and International Medicine, USF Health - Morsani College of Medicine Faculty Member, Florida AIDS Education and Training Center Today s Facilitator Beata Casanas, DO, FACP Faculty Florida/Caribbean AETC Associate Professor of Medicine Division of Infectious Diseases and International Medicine University of South Florida Morsani College of Medicine 4
HIV Case Conference: Overview of Hep C Protease Inhibitors Todd S. Wills, MD Vice-Chair for Operations Research and Education Department of Internal Medicine USF Health - Morsani College of Medicine Fellowship Program Director Division of Infectious Disease and International Medicine USF Health - Morsani College of Medicine Faculty Member Florida/Caribbean AIDS Education and Training Center Our Challenge A fraction of those with HCV are diagnosed A fraction of those diagnosed are treated A fraction of those treated are cured Adapted from Kim, Arthur, HIV/HCV Coinfection Update, Mass Gen Hosp. 212 5
The Need to Cure Cirrhosis: Survival in Patients With HCV and Cirrhosis 1 Survival Probability Compensated After first major complication Patients (%) 6 4 2 Pts at Risk, n 384 376 65 39 12 24 36 48 6 72 84 96 18 Mos 342 21 288 11 236 7 Fattovich G, et al. Gastroenterology. 1997;112:463 472. 165 4 126 4 79 3 52 3 39 2 12 25 1 To Treat or Not to Treat: A Constellation of Considerations Genotype: virus, patient (IL28B) Histologic stage 2%+ lifetime risk of cirrhosis Duration of infection Personal plans (marriage, pregnancy) Age Family and other support Patient mindset ALT Occupation Extrahepatic features (fatigue, EMC, PCT) from Clinical Care Options HIV coinfection Contraindications & comorbidities; insulin resistance 6
Potential HCV antiviral targets C E1 E2/NS1 NS2 NS3 NS4A NS4B NS5A NS5B 5 3 Internal ribosomal entry site RNA binding site Envelope glycoproteins Signal peptide Serine protease/ helicase telaprevir, boceprevir RNA dependent RNA polymerase Evolution of HCV Therapy: Where Are We in 212? 21 211 Beyond PegIFN/RBV Protease inhibitor Nucleos(t)ide polymerase inhibitor Nonnucleoside polymerase inhibitor NS5A inhibitor Host targeting agent From Clinical Care Options Chung RF,HCV the Road Ahead 7
Telaprevir and Boceprevir Both target HCV serine proteases Common resistance mutations and cross resistance described Telaprevir NS3/NS4 protease inhibitor Boceprevir NS3 protease inhibitor Studies in HCV monoinfection are complete Studies in HIV/HCV co-infection ongoing Study 11: SVR24 With TVR + PegIFN/RBV in HCV GT1/HIV-Coinfected Patients Higher SVR24 rate with TVR-based therapy Telaprevir + PR 1 Placebo + PR SVR24 (%) 6 4 2 n/n = 74 71 69 45 28/ 1/ 38 22 5/ 7 33 2/ 6 11/ 16 5 5 4/ 8 12/ 15 4/ 8 No significant drug drug interactions with TVR and ART TVR plasma levels similar in patients with or without ART EFV and ATV/RTV plasma levels similar in patients with or without TVR No HIV breakthroughs in patients using ART during HCV treatment Safety and tolerability similar to treatment in patients with HCV monoinfection Sulkowski MS, et al. AASLD 212. Abstract 54 8
Higher SVR12 Rates With BOC + P/R vs P/R Alone in HIV/HCV Coinfection Interim data reported (3 pts in BOC arm had not reached SVR12) 1 SVR12 (%) 6 4 2 26.5 6.7 n/n = 9/34 37/61 P/R BOC + P/R HIV-1 RNA breakthrough observed in 7 pts BOC plus P/R: n = 3 (all receiving boosted PIs) Placebo plus P/R: n = 4 SVR12 by ARV Regimen, % BOC + PegIFN/RBV (n = 61) PegIFN/ RBV (n = 34) ATV/RTV 67 62 LPV/RTV 67 DRV/RTV 67 Other RTVboosted PI* 57 Raltegravir 43 33 Other *SQV, FPV, TPV. MVC, EFV. Sulkowski MS, et al. CROI 212. Abstract 47. Adverse Events of BOC + P/R vs P/R Alone in HIV/HCV Coinfection Overall and serious AE rates similar between arms Anemia, pyrexia, asthenia, decrease appetite, diarrhea, dysgeusia, vomiting, neutropenia more common among BOC recipients Most cases of anemia and neutropenia mild (WHO grade 1/2) Flu-like illness more common among placebo recipients More patients discontinued study because of toxicity in BOC vs placebo arm BOC plus pegifn/rbv: 2% Placebo plus pegifn/rbv: 9% Sulkowski MS, et al. CROI 212. Abstract 47. 9
Pharmacokinetic Effects of RTV- Boosted HIV PIs on BOC and TVR Similar reductions in BOC and TVR exposures observed with coadministration of ATV/RTV, DRV/RTV, and LPV/RTV Prescribing information for TVR does not recommend coadministering TVR with DRV/RTV, FPV/RTV, or LPV/RTV; prescribing information for BOC does not recommend coadministering BOC with any HIV PI Change in Steady State HCV PI C min, % (9% CI) 2 18 4 ( 2 to 32) 35 ( 24 to 44) 6 1 BOC [1] TVR [2] 57 ( 47 to 64) 15 ( 2 to 25) 32 (-26 to -37) 52 ( 44 to 6) ATV/RTV DRV/RTV LPV/RTV 1. Hulskotte EGJ, et al. CROI 212. Abstract 771LB. 2. van Heeswijk R, et al. CROI 211. Abstract 119. Pharmacokinetic Effects of BOC and TVR on RTV-Boosted HIV PIs Change in Steady State HIV PI C min, % (9% CI) 1 6 4 2 2 4 6 ATV/RTV 49 ( 39 to 56) 85 (4 to 144) LPV/RTV 43 ( 35 to 51) 14 ( 4 to 36) DRV/RTV 42 ( 37 to 48) BOC [1] TVR [2] 59 ( 55 to 62) 1 1. Hulskotte EGJ, et al. CROI 212. Abstract 771LB. 2. van Heeswijk R, et al. CROI 211. Abstract 119. 1
BOC Plus PegIFN alfa-2b/rbv: Adverse Events Higher rates of anemia, neutropenia, and dysgeusia in BOC arms vs control Adverse Event, % PR48 (n = 467) BOC + PR RGT/48* (n = 1225) Anemia* 3 5 Neutropenia 19 25 Dysgeusia 16 35 *Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24% of PR). Boceprevir [US package insert]. July 212. TVR Plus PegIFN alfa-2a/rbv: Adverse Events Higher rates of rash, anemia, and anorectal signs and symptoms in TVR arms vs control Adverse Event, % PR48 (n = 493) TVR + PR RGT/48* (n = 1797) Rash 34 56 Anemia 17 36 Anorectal events 7 29 *Pooled results from TVR arms. Anemia was managed with RBV dose modification; epoetin alfa was not permitted. In most subjects, rash was mild to moderate Severe rash in 4%; discontinuation due to rash in 6% of subjects Telaprevir [US package insert]. October 212. 11
Improved Dosing of Current Therapy: TVR BID Noninferior to TID in Tx-Naive GT1 1 73 74 78 81 TVR q8h + pegifn/rbv TVR BID + pegifn/rbv SVR12 (%) 6 4 59 58 2 n/ N = 27/ 371 274/ 369 Overall 29/ 268 213/ 264 No, Minimal, or Portal Fibrosis 61/ 13 61/ 15 Bridging Fibrosis or Cirrhosis Adverse events similar between treatment arms No differences in efficacy with 2 strategies in patients with more advanced disease Buti M, et al. AASLD 212. Abstract LB-8. Limited Efficacy With Telaprevir and Boceprevir in Some Patient Groups 1 75 83 [1,2] 68 75 [3,4] SVR (%) 6 4 42 62 [3,4] 53 62 [3,4] 4 59 [1,2] 29 4 [1,5] 2 14 [6] * Relapser Naive White/ Nonblack Naive Cirrhotic Naive Black Partial Responder Null Responder Cirrhotic Null Responder *Pooled TVR arms of REALIZE trial. 1. Zeuzem S, et al. N Engl J Med. 211;364:2417 2428. 2. Bacon BR, et al. N Engl J Med. 211;364:127 1217. 3. Jacobson IM, et al. N Engl J Med. 211;364:245 2416. 4. Poordad F, et al. N Engl J Med. 211;364:1195 126. 5. Bronowicki J, et al. EASL 212. Abstract 11. 6. Zeuzem S, et al. EASL 211. Abstract 5. 12
Likelihood of SVR With Current Therapies Related to IFN Responsiveness 1 HCV RNA Reduction After 4-Wk Lead-in < 1 log decline 1 log decline 1 76 82 SVR (%) 6 4 33 SVR (%) 6 4 33 2 2 RESPOND 2* (BOC) [1] REALIZE (TVR) [2] *Pooled data from RGT and arm 3. 1. Vierling JM, et al. EASL 211. Abstract 481. 2. Foster G, et al. EASL 211. Abstract 6. 15 8 HCV DAA Agents in Late Stage Development NS3/4A Pis NS5A replication complex inh Nucleotide NS5B poly inh Non-nuc NS5B Pol inh ABT-45/r ABT-267 Sofosbuvir ABT-333 Asunaprevir Daclatasvir Mericitabine Faldaprevir GS5885 Simeprevir 13
Summary HCV therapy for monoinfected and HIVcoinfected patients has revolutionized therapy Data regarding drug efficacy, toxicity and drug-drug interactions is helping to refine the role of the HCV PIs in treatment of coinfected patients New regimens including RBV and IFN sparing regimens create new questions about timing of treatment 14