Roy M. Gulick, MD, MPH Gladys and Roland Harriman Professor of Medicine Chief, Division of Infectious Diseases Weill Medical College of Cornell University.

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.

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

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

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 www.aidsinfo.nih.gov

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 www.aidsinfo.nih.gov

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;161:461 6052 NRTI + ATV/r88% 6012 NRTI + DRV/r89% 6032 NRTI + RAL94%* SINGLE Walmsley NEJM 2013;369:1807 + JAIDS 2015;70:515 414ABC/3TC + DTG80%* 419TDF/FTC/EFV72% FLAMINGO Molina Lancet 2014;383:2222 + Lancet HIV 2015;2:e127 2422 NRTI + DTG80%* 2422 NRTI + DRV/r68% * = significant difference

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 #947 -2.75 log cps/ml (PADDLE) vs. -2.5 (SPRING-1) and -2.6 (SINGLE) ACTG 5353 –Pilot study enrolling (N=120) –Treatment-Naïve Individuals with HIV RNA <500K

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 30-69 Pozniak JAIDS 2015 (epub 11/30/15)

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)

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

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-663068 cabotegravir Phase 2 apricitabine dexelvucitabine festinavir BILR 355cenicriviroc ibalizumab PF-232798 GS-9883BMS- 955176 Phase 1/2 elvucitabine TMC 310911 HGS004 Phase 1 MK-8591 CMX157 RDEA 806CTP-298 CTP-518 PPL-100 SPI-256 SCH532706 VIR-576 BI 224436 INH-1001 GSK- 2838232

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

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)

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)

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

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;58:1652-1663

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)

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+

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

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

of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. Cabotegravir (CAB, GSK 1265744) 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 21-50 days! Supports monthly or quarterly dosing Safety: ISR (all mild) and nodules with SC dosing Spreen JAIDS 2014;67:481

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)

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

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

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

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)

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

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;100:10598-10602. gp41gp41 gp120gp120 V3 loop CD4BindingCD4Binding CD4CD4 CellMembraneCellMembrane CoreceptorBindingCoreceptorBinding CCR5/CXCR4(R5/X4)CCR5/CXCR4(R5/X4) CCR5 Inhibitors maraviroc maraviroc enfuvirtideenfuvirtide BMS 663068

of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS-663068: Oral HIV Attachment Inhibitor Prodrug of BMS-626529 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)

of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS-663068: Phase 2b Lalezari Lancet HIV 2015;2:e427-37 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) ***

of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS-663068: Phase 2b Efficacy DeJesus CROI 2016 #472

of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS-663068: Phase 2b Safety DeJesus CROI 2016 #472Given FDA “Breakthrough Status” 7/15

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

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

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

of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS-955176: 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-955176 retained virologic activity Ray CROI 2016 #464

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

of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. BMS-955176 Exposure-Response Sevinsky CROI 2016 #425

of 40 From RM Gulick, MD, MPH, at New York, NY: March 23, 2016, IAS-USA. –2.5 –2 –1.5 –1 –0.5 0 0.5 1 Median change in VL (log 10 c/mL) TDF/FTC 300 mg/200 mg + ATV 300 mg + RTV 100 mg* BMS-955176 40 mg + ATV 300 mg + RTV 100 mg BMS-955176 40 mg + ATV 400 mg BMS-955176 80 mg + ATV 400 mg Study day 10152025 3035404550 5 0 Dosing period BMS-955176: Phase 2a (Part B) Hwang IAS 2015 #TUAB0106LB Study population: Subtype B, Rx-naïve, VL>5000, CD4>200 (N=28)

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!

Roy M. Gulick, MD, MPH Gladys and Roland Harriman Professor of Medicine Chief, Division of Infectious Diseases Weill Medical College of Cornell University.

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Roy M. Gulick, MD, MPH Gladys and Roland Harriman Professor of Medicine Chief, Division of Infectious Diseases Weill Medical College of Cornell University.

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Presentation on theme: "Roy M. Gulick, MD, MPH Gladys and Roland Harriman Professor of Medicine Chief, Division of Infectious Diseases Weill Medical College of Cornell University."— Presentation transcript:

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