Roy M. Gulick, MD, MPH Gladys and Roland Harriman Professor of Medicine Chief, Division of Infectious Diseases Weill Medical College of Cornell University New York, New York Antiretroviral Therapy: What to Start and New Drugs FORMATTED: 03/08/16 New York, New York: March 23, 2016 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.

Slide 2 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Learning Objectives After attending this presentation, participants will be able to: List the current recommended and alternative ART regimens Describe research data to support these recommendations Describe at least 3 investigational antiretroviral drugs in the pipeline

Slide 3 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Question: Which is NOT a recommended ART regimen according to the DHHS Guidelines? 1.tenofovir (TDF)/emtricitabine + darunavir/r 2.tenofovir (TDF)/emtricitabine + dolutegravir 3.tenofovir (TAF)/ emtricitabine/elvitegravir/cobici stat 4.tenofovir (TAF)/ emtricitabine/rilpivirine 5.tenofovir (TDF)/emtricitabine + raltegravir

Slide 4 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Recommended ART Regimens (2 NRTI + 3 rd drug) Protease Inhibitor-based –tenofovir (TDF)/emtricitabine + darunavir/r Integrase Inhibitor-based –abacavir/lamivudine/dolutegravir –tenofovir (TDF)/emtricitabine + dolutegravir –tenofovir (TAF)/ emtricitabine/elvitegravir/cobicistat –tenofovir (TDF)/emtricitabine/elvitegravir/cobicistat –tenofovir (TDF)/emtricitabine + raltegravir U.S. DHHS Guidelines 1/28/16

Slide 5 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Alternative Initial Regimens (2 NRTI + 3 rd drug) NNRTI-based –tenofovir (TDF)/emtricitabine + efavirenz –tenofovir (TDF)/emtricitabine/rilpivirine PI-based –tenofovir (TDF)/emtricitabine + atazanavir/ritonavir (or cobicistat) –abacavir/lamivudine + darunavir/ritonavir (or cobicistat) –tenofovir (TDF)/emtricitabine + darunavir/cobicistat U.S. DHHS Guidelines 1/28/16

Slide 6 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Newer ART Rx-Naïve Studies Study (reference)NRegimenVL <50 (96 wks) ACTG 5257 Lennox Ann Intern Med 2014;161: NRTI + ATV/r88% 6012 NRTI + DRV/r89% 6032 NRTI + RAL94%* SINGLE Walmsley NEJM 2013;369: JAIDS 2015;70: ABC/3TC + DTG80%* 419TDF/FTC/EFV72% FLAMINGO Molina Lancet 2014;383: Lancet HIV 2015;2:e NRTI + DTG80%* 2422 NRTI + DRV/r68% * = significant difference

Slide 7 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Two drugs? PADDLE Study Figueroa EACS 2015 #LBPS4/1 –Treatment-naïve individuals with HIV RNA 5-100K (N=20) –2-drug regimen of DTG + 3TC –Results: All suppressed VL <50 by week 8  week 24 –HIV RNA decline Sued CROI 2016 # log cps/ml (PADDLE) vs (SPRING-1) and -2.6 (SINGLE) ACTG 5353 –Pilot study enrolling (N=120) –Treatment-Naïve Individuals with HIV RNA <500K

Slide 8 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Tenofovir alafenamide fumarate (TAF) TAF vs. TDF: Similar virologic efficacy –1733 pts on [TAF or TDF]/FTC/EVG/c Sax Lancet 2015;385:2606 –153 pts on TAF/FTC/DRV/c or TDF/FTC+DRV+cobi Mills JAIDS 2015;69:439 Switch TDF  TAF improved renal markers and BMD –1443 pts on TDF with GFR >50 cc/min Mills Lancet ID 2016;16:43 –663 pts on TDF with GFR >50 cc/min Gallant CROI 2016 #29 –242 pts on TDF (65%) or not (35%) with eGFR Pozniak JAIDS 2015 (epub 11/30/15)

Slide 9 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Tenofovir alafenamide (TAF) TAF dose will be 25 mg, despite other drugs Lawson ICAAC 2014 #H-1012 Co-formulations –TAF/FTC/EVG/c (FDA approved 11/5/15) –TAF/FTC/RPV (FDA approved 3/1/16) –TAF/FTC (FDA target action date: 4/7/16) –TAF/FTC/DRV/c (in clinical trials)

Slide 10 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Question: Which new class of drugs is in advanced clinical development? 1.Uncoating inhibitor 2.RNAase H inhibitor 3.Maturation inhibitor 4.CD8 attachment inhibitor 5.CXCR4 antagonist

Slide 11 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Newer Investigational ART Agents (partial list) NRTINNRTIPIEntry Inh IIMI Phase 3 doravirine BMS cabotegravir Phase 2 apricitabine dexelvucitabine festinavir BILR 355cenicriviroc ibalizumab PF GS-9883BMS Phase 1/2 elvucitabine TMC HGS004 Phase 1 MK-8591 CMX157 RDEA 806CTP-298 CTP-518 PPL-100 SPI-256 SCH VIR-576 BI INH-1001 GSK

Slide 12 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. NRTI Needs: More convenient

Slide 13 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. MK-8591 (EFdA) Grobler CROI 2016 #98 Friedman CROI 2016 #437LB 4’-ethynyl-2-fluoro-2’- deoxyadenosine; EFdA Non-obligate chain terminator Inhibits RT by preventing translocation (NRTTI) Potent antiviral activity (PBMC EC50 = 0.2 nM) with broad coverage (HIV-1, HIV-2, MDR strains)

Slide 14 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Grobler CROI 2016 #98 Friedman CROI 2016 #437LB MK-8591 (EFdA)

Slide 15 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. NNRTI Needs: Less toxicity and better tolerability Active against resistant viral strains Fewer drug interactions

Slide 16 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Doravirine (DOR; MK-1439) Investigational NNRTI Pre-clinical –Potent at low milligram dose –Metabolized by CYP3A4; not a CYP450 inhibitor or inducer –Active in vitro against viral strains with: K103N Y181C G190A E101K E138K K103N/Y181C Lai AAC 2014;58:

Slide 17 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Doravirine (DOR): Phase Ib Double-blind, randomized, placebo-controlled Study population: HIV+, treatment-naïve (N=18) Schurmann AIDS 2015 (epub 9/13/15)

Slide 18 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Doravirine – Phase 2 Gatell CROI 2016 #470 Randomized, double-blind, 2-part study Study population: Rx-naïve participants, VL >1000, CD4 >100 (N=216) TDF/FTC+

Slide 19 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Doravirine – Phase 2 Gatell CROI 2016 #470

Slide 20 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. INSTI Needs: More convenient

Slide 21 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Cabotegravir (CAB, GSK ) Integrase inhibitor similar to DTG; similar resistance Potent in HIV+ individuals (5, 10, 30, 60 mg oral) Margolis EACS 2013; Spreen HIV Clin Trials 2013;14:192 Nanotechnology formulation; SC + IM injections T ½ days! Supports monthly or quarterly dosing Safety: ISR (all mild) and nodules with SC dosing Spreen JAIDS 2014;67:481

Slide 22 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. LATTE-2: CAB + RPV IM Maintenance Margolis CROI 2016 #31LB Phase 2b multicenter, parallel group, open-label study Study population: Rx-naïve individuals (N=309)

Slide 23 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. LATTE-2: Virologic Suppression Margolis CROI 2016 #31LB

Slide 24 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. LATTE-2: Efficacy Margolis CROI 2016 #31LB

Slide 25 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. LATTE-2: Injection Site Reactions Margolis CROI 2016 #31LB

Slide 26 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Cabotegravir (CAB) for PrEP: Phase 2a Markowitz CROI 2016 #106 Study population: Low-risk HIV(-) men (N=127)

Slide 27 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. CD4 Attachment Inhibitor Needs: Novel mechanism of action

Slide 28 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. HIV Entry Inhibitors Virus-CellFusionVirus-CellFusion Adapted from Moore JP, PNAS 2003;100: gp41gp41 gp120gp120 V3 loop CD4BindingCD4Binding CD4CD4 CellMembraneCellMembrane CoreceptorBindingCoreceptorBinding CCR5/CXCR4(R5/X4)CCR5/CXCR4(R5/X4) CCR5 Inhibitors maraviroc maraviroc enfuvirtideenfuvirtide BMS

Slide 29 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS : Oral HIV Attachment Inhibitor Prodrug of BMS Inhibits CD4 binding by binding to gp120 PK suggest QD or BID dosing without boosting ↓ baseline susceptibility in 12% of pts due to envelope polymorphisms; screened by baseline IC 50 Nettles JID 2012;206:1002 Study pop: CD4 >200, VL >5000 off ART X >8 wks or ART-naive (N=50)

Slide 30 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS : Phase 2b Lalezari Lancet HIV 2015;2:e and DeJesus CROI 2016 #472 Phase 2b, randomized, controlled, partially blinded (to ‘068 dose) Study pop: Rx-experienced (>1 wk on >1 ART); IC 50 <100 nM for ‘529 (N=254) ***

Slide 31 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS : Phase 2b Efficacy DeJesus CROI 2016 #472

Slide 32 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS : Phase 2b Safety DeJesus CROI 2016 #472Given FDA “Breakthrough Status” 7/15

Slide 33 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Maturation Inhibitor Needs: Novel mechanism of action No baseline polymorphisms that confer resistance

Slide 34 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. HIV Maturation Inhibitors (MI)

Slide 35 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Lataillade CROI 2015, #114LB

Slide 36 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS : PI-resistant viral strains 21 clinical isolates from 15 patients –median 6 years on PI therapy –all had major PI resistance-associated mutations in protease –17 of 21 had 2 o changes in GAG associated with PI resistance (at positions 128, 431, 436, 437, 449, 452, 453) 7 highly PI-resistant virus strains BMS retained virologic activity Ray CROI 2016 #464

Slide 37 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Lataillade CROI 2015, #114LB No serious adverse events, grade 3/4 events, no d/c due to adverse events Plans for phase 2b Study population: HIV+, VL >5K, CD4 >200, PI and MI naive

Slide 38 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS Exposure-Response Sevinsky CROI 2016 #425

Slide 39 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. –2.5 –2 –1.5 –1 – Median change in VL (log 10 c/mL) TDF/FTC 300 mg/200 mg + ATV 300 mg + RTV 100 mg* BMS mg + ATV 300 mg + RTV 100 mg BMS mg + ATV 400 mg BMS mg + ATV 400 mg Study day Dosing period BMS : Phase 2a (Part B) Hwang IAS 2015 #TUAB0106LB Study population: Subtype B, Rx-naïve, VL>5000, CD4>200 (N=28)

Slide 40 of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Acknowledgments Cornell HIV Clinical Trials Unit (CCTU) Division of Infectious Diseases Weill Cornell Medical College AIDS Clinical Trials Group (ACTG) HIV Prevention Trials Network (HPTN) Division of AIDS, NIAID, NIH The patient volunteers!