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 transcript:

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: New Drugs and New Guidelines FORMATTED: 03/08/16 Chicago, Illinois: May 9, 2016 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 2 of 41 Financial Relationships With Commercial Entities Dr Gulick has no relevant financial affiliations to disclose. (Updated 05/9/16) From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 3 of 41 Learning Objectives After attending this presentation, participants will be able to: List the current recommended and alternative antiretroviral therapy regimens Describe research data to support these recommendations Describe at least 3 investigational antiretroviral drugs in the pipeline From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 4 of 41 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/cobicstat 4.tenofovir (TAF)/emtricitabine/rilpivirine 5.tenofovir (TDF)/emtricitabine + raltegravir From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 5 of 41 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 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 6 of 41 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 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 7 of 41 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 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 8 of 41 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 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 9 of 41 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 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 10 of 41 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 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 11 of 41 NRTI Needs: More convenient From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 12 of 41 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) From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 13 of 41 Grobler CROI 2016 #98 Friedman CROI 2016 #437LB MK-8591 (EFdA) From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 14 of 41 NNRTI Needs: Less toxicity and better tolerability Active against resistant viral strains Fewer drug interactions From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 15 of 41 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: From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 16 of 41 Doravirine (DOR): Phase Ib Double-blind, randomized, placebo-controlled Study population: HIV+, treatment-naïve (N=18) Schurmann AIDS 2015 (epub 9/13/15) From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 17 of 41 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+ From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 18 of 41 Doravirine – Phase 2 Gatell CROI 2016 #470 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 19 of 41 INSTI Needs: More convenient From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 20 of 41 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 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 21 of 41 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) From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 22 of 41 LATTE-2: Virologic Suppression Margolis CROI 2016 #31LB From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 23 of 41 LATTE-2: Efficacy Margolis CROI 2016 #31LB From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 24 of 41 LATTE-2: Injection Site Reactions Margolis CROI 2016 #31LB From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 25 of 41 Cabotegravir (CAB) for PrEP: Phase 2a Markowitz CROI 2016 #106 Study population: Low-risk HIV(-) men (N=127) From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 26 of 41 CD4 Attachment Inhibitor Needs: Novel mechanism of action From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 27 of 41 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 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 28 of 41 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) From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 29 of 41 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) *** From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 30 of 41 BMS : Phase 2b Efficacy DeJesus CROI 2016 #472 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 31 of 41 BMS : Phase 2b Safety DeJesus CROI 2016 #472 Given FDA “Breakthrough Status” 7/15 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 32 of 41 Maturation Inhibitor Needs: Novel mechanism of action No baseline polymorphisms that confer resistance From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 33 of 41 HIV Maturation Inhibitors (MI) From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 34 of 41 Lataillade CROI 2015, #114LB From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 35 of 41 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 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 36 of 41 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 From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 37 of 41 –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) From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.

Slide 38 of 41 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! From RM Gulick, MD, MPH at Chicago, IL: May 9, 2016, IAS-USA.