Didactic Series. CROI New Antiretroviral Therapies. Daniel Lee, MD Clinical Professor of Medicine UCSD Medical Center Owen Clinic July 14, 2016

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1 Didactic Series CROI New Antiretroviral Therapies Daniel Lee, MD Clinical Professor of Medicine UCSD Medical Center Owen Clinic July 14, 2016 This project is supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant number and title for grant amount (# U1OHA , Regional AIDS Education and Training 1 Centers,

2 New Antiretroviral Therapies 3

3 Question #1: Where do you feel is the need for new antiretroviral therapies for the future? 1) New single tablet regimens 2) ART with novel mechanisms of action 3) ART for experienced patients 4) Parenteral ART (non-tablet formulations) 5) ART with longer dosing intervals 6) Reductive ART (<3 meds per regimen) 4

4 Study 007: DOR 100 mg QD vs. EFV +TDF/FTC in Naive HIV+ Patients Week 48 Results Study Design RCT,DB, dose-finding, 2-part study Patients: HIV-1+ ART naïve RNA 1,000 c/ml CD4 100 cells/µl Stratified by screening RNA ( />100k c/ml) Part 2 began after dose selection based on Part 1 week 24 results. Part 1 Dose Ranging Phase (N=210) DOR 25 mg DOR 50 mg DOR 100 mg (n=42) DOR 200 mg EFV 600 mg (n=43) Part 1 Extension Phase DOR 100 mg Continue EFV Part 2: Additional Patients, DOR Selected Dose vs EFV (N=132) DOR 100 mg (n=66) EFV 600 mg (n=66) Week 48 Week 48 Week 96 Week 96 Gatell J, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 470.

5 % of patients (95% CI) Study 007: Results HIV RNA <40 copies/ml 100 (NC=F Approach) ,1 72,9 63,0 57,5 47,2 42,1 27,8 26,9 15,7 6,5 12,0 3,7 81,5 78,7 77,8 77, Treatment Week Week 48 n/n (%) DOR 84/108 (77.8) EFV 85/108 (78.7) Difference (95% CI): -1.1 (-12.2, 10.0) DOR 100 mg + TDF/FTC EFV 600 mg + TDF/FTC Gatell J, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 470.

6 Percent of Subjects (95% CI) Study 007: Results Virologic Response by Screening RNA Week 48 (OF Approach) ,000 c/ml >100,000 c/ml ,6 87,1 89,6 91,9 74,3 83,8 91,4 91, n/n: 58/67 54/62 60/67 57/62 26/35 31/37 32/35 34/37 % <40 c/ml % <200 c/ml % <40 c/ml % <200 c/ml DOR 100 mg + TDF/FTC EFV 600 mg + TDF/FTC Gatell J, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 470.

7 Study 007: Adverse Events DOR 100 mg (N=108) EFV 600 mg (N=108) Difference [DOR EFV] (95% CI) One or more adverse events (AE) (-10.9, 7.1) Serious AE (-9.5, 5.6) Death 0 0 Discontinued due to AE (-9.2, 3.0) Drug-related AE (-37.3, -11.8) Diarrhea Nausea Dizziness Headache Abnormal dreams Insomnia Nightmares Sleep disorder Gatell J, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 470.

8 LATTE-2 Study: Maintenance Therapy with Injectable Cabotegravir and Rilpivirine Induction period Maintenance period CAB 30 mg + ABC/3TC for 20 weeks (N=309) CAB loading dose at Day 1 CAB 400 mg IM + RPV 600 mg IM Q4W (n=115) CAB 600 mg IM + RPV 900 mg IM Q8W (n=115) CAB loading doses at Day 1 and Week 4 CAB 30 mg + ABC/3TC PO QD (n=56) Add RPV 4 weeks Day 1 Randomization 2:2:1 Week 32 Primary analysis Dosing regimen selection Week 48 Analysis Dosing regimen confirmation Week 96 Margolis D, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 31LB.

9 HIV-1 RNA <50 c/ml, % LATTE-2 Study: Week 32 Primary Endpoint: HIV-1 RNA <50 c/ml by Snapshot (ITT-ME) Virologic Outcomes Treatment Differences (95% CI) * 94* 91 Oral Q8W IM 80 Q8W (n=115) 60 Q4W (n=115) oral CAB (n=56) Virologic success <1 <1 Virologic non-response No virologic data Q4W No resistance detected in any study arm 82% experienced grade 1 injection site reactions, 17% grade 2 (moderate) most commonly pain, swelling, or nodules; one death (epilepsy), cause unclear Suppressive ART with IM cabotegravir and rilpivirine appears safe and effective; further studies planned Margolis D, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 31LB.

10 Patient Percent LATTE-2 Study: Patient Outcomes Comparing Maintenance with Oral Induction Treatment How satisfied are you with your current treatment? How satisfied would you be to continue with your present form of treatment? 100% 80% 1% 3% 100% 2% 3% 29% 80% 1% 1% 29% 60% 60% 40% 40% 20% 20% 0% 97% 96% 71% Q8W (n=106) Q4W (n=100) Oral CAB (n=49) More Neutral Less 0% 98% 98% 71% Q8W (n=106) Q4W (n=100) Oral CAB (n=49) More Neutral Less Margolis D, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 31LB.

11 AI Study: BMS Oral HIV Attachment Inhibitor 96 Week Results Study Design BMS mg BID + RAL +TDF N=50 BMS mg BID + RAL +TDF N=50 BMS mg QD + RAL +TDF N=50 BMS mg QD + RAL +TDF N=50 ATV/r 300/100 mg OD + RAL +TDF N=50 BMS monotherapy sub-study: 10 subjects per study arm Day 1 Primary study start of combination therapy Day 8 Data monitoring committee assessment Week 24 Primary endpoint Week 48 Long-term follow-up through Week 48 (secondary endpoint) BMS mg QD was selected as the open-label continuation dose after Week 48 Week 96 Long-term follow-up through Week 96 (BMS mg QD) DeJesus E, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 472.

12 Proportion of subjects achieving HIV-1 RNA <50 c/ml, % (95% Cl) AI Study: Results Proportion of subjects with <50 c/ml through Week 96 BMS ,200 mg QD 90% ATV/r 300 mg/ 100 mg QD 90% Week DeJesus E, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 472.

13 Change From Baseline HIV-1 RNA (log 10 c/ml) Grobler J, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 98; Friedman E, et al. 23rd CROI; Boston, MA; February 22-25, Abst. 437LB. MK-8591: Long-acting NRTI NRTI with unique mechanism of action and unusual PK Active phosphorylated metabolite has prolonged intracellular persistence in human PMBCs, with half-life of hours Exploratory study of single 10 mg dose in HIV infected volunteers MK-8591, a novel NRT translocation inhibitor, suppresses HIV RNA by 1.75 log after a single dose long half life could lead to novel dosing or administration strategies Time (days) TDF mg QD TAF - 25 mg QD MK mg QW

14 From: Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society USA Panel JAMA. 2016;316(2): doi: /jama Table Title: Recommended Initial Antiretroviral Therapy Regimens a Date of download: 7/13/2016 Copyright 2016 American Medical Association. All rights reserved.

15 From: Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society USA Panel JAMA. 2016;316(2): doi: /jama Table Title: Advantages and Disadvantages of Currently Available Integrase Strand Transfer Inhibitors Date of download: 7/13/2016 Copyright 2016 American Medical Association. All rights reserved.

16 From: Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2016 Recommendations of the International Antiviral Society USA Panel JAMA. 2016;316(2): doi: /jama Table Title: Advantages and Disadvantages of Initial Antiretroviral Therapy Options for Patients in Whom InSTIs Are Not an Option a Date of download: 7/13/2016 Copyright 2016 American Medical Association. All rights reserved.

17 References Slides are courtesy from ViralEd CME Internet Symposium: CROI 2016 Expert Review _symposium_croi_2016_expert.html Clinical Care Options Conference on Retroviruses and Opportunistic Infections 18