5/17/2018

UPDATE ON ANTIRETROVIRAL THERAPIES Dr. Alftan D. Dyson, PharmD, BCACP, AAHIVP Director of Pharmacy Services Medical Advocacy and Outreach (MAO)

Disclosures

■ Janssen Therapeutics- Community Speaker’s Bureau ■ Viiv Healthcare- Pharmacy Advisory Board

Learning Objectives

■ Identify newly approved ART regimens and discuss appropriate use of these agents ■ Describe new approaches for treating PLWH

1 5/17/2018

KNOWING THE PAST TO UNDERSTAND THE PRESENT AND PLAN FOR THE FUTURE

ABC/3TC, TDF/FTC (‘04)

TAF/FTC, RPV + DTG + ABC + TAF + FTC (‘16) FDC , RPV, RPV + +3TC TDF +FTC (‘14) ABC + AZT +3TC STR EFV +TDF +FTC (‘11) AZT + 3TC , (‘06) , ELV + COBI + ELV + COBI + FTC (‘03) RAL, SELZ TDF + FTC EFV, ABC (‘98) (‘12) TAF + FTC, ATZ (‘09) DTG, RPV AZT Approved + COBI, DRV + (‘17) COBI DTG TDF (‘01) Ritonavir (‘13) (‘96) HIV-1 Discovered

AIDS Reported

1981 1984 19871990 1995 2000 2005 2010 2015 NOW Beyond…

Initial ART Selection

A. Boosted DRV plus tenofovir/FTC B. DTG/ABC/3TC C. DTG plus tenofovir/FTC D. EVG/c/tenofovir/FTC E. RPV/tenofovir/FTC F. RAL HD/tenofovir/FTC G. I like something else H. It depends

NEW OPTIONS FOR INITIAL TREATMENT

2 5/17/2018

Bictegravir/TAF/FTC

■Indications: – Initial treatment in adults with HIV – Replacement therapy in persons who have achieved virologic suppression (<50 copies per mL) for at least 3 months and have no history of treatment failure or known resistance to its components ■Pharmacology and dosing: – One-pill, once a day, with or without food – Half-life 17.3 hours – Excretion- feces 60.3%, urine 35%; Not recommended if CrCL <30 mL/minute ■Drug resistance: – Active in vitro against HIV isolates that carry some integrase resistance mutations – Efficacy in people with prior INSTI failure or resistance is unknown

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf , http://www.gilead.com/~/media/files/pdfs/medicines/hiv/descovy/descovy_pi.pdf?la=en

Bictegravir/TAF/FTC

■DrugDrugDrug- Drug ---DrugDrug Interactions: – Contraindications: Rifampin; Dofetilide – Special considerations: – Medications or oral supplements containing polyvalent cations; 2 hours before antacids, simultaneously with food with Ca++ or FeSO4 supplements – Metformin AUC increased 39%; assess risk vs. benefit

■Side effects: – Diarrhea, nausea and headache – Inhibition of tubular secretion ‰ increase in serum creatinine (median 0.1 mg/dL)

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf , http://www.gilead.com/~/media/files/pdfs/medicines/hiv/descovy/descovy_pi.pdf?la=en

Bictegravir/TAF/FTC: Treatment Naïve Trials

------3.5% 1,2 -0.6% Study 1489 (((-(--- 7.9 to 1.0%)7.9 1.0%) B/F/TAF (n=320) (-4.8 to 3.6%) B/F/TAF (n=314) 100 92.9 100 ABC/3TC/DTG (n=315) 92.492.492.4 93.093.093.0 89.4 ABC/3TC/DTG (n=315) 80 80

60 60

40 40

20 20 Proportion of Participants, % ProportionParticipants,of% ProportionParticipants,of Proportion of Participants, % ProportionParticipants,of% ProportionParticipants,of 6.76.76.7 6.3 5.8 4.44.44.4 4.4 111 2.52.52.5 1.2 0 0 HIV-1 RNA HIV-1 RNA No HIV-1 RNA HIVHIVHIV-HIV ---11 RNA1 RNA HIV-1 RNA No HIV-1 RNA < 50 c/mL ≥ 50 c/mL Data < 50 c/mL< c/mL ≥ 50 c/mL Data

BIC non-inferior to DTG- containing regimen in terms of virologic suppression at Week 48 1,2 Gallant J et al, Lancet 2017; Sax P et al Lancet 2017

3 5/17/2018

Bictregravir (BIC)

■ Unboosted (INSTI) ■ High genetic barrier to resistance ■ Low potential for drug-drug interactions ■ Co-formulated with TAF/FTC

■ 32 y/o AAF diagnosed with HIV 3 years ago A.C. after ex-husband passed away from AIDS- related illness. Tx naïve, “doesn’t like taking pills.” Urged to come in by new partner who is not HIV-infected.

■ PMH: HTN- previously on medication, but took it intermittently and finally stopped completely ~ 5 months ago. Depression- untreated

■ SH: Single mother with 3 small children (6mo,2y,8y); some assistance from family members; Works as a manager at a fast food restaurant, works all shifts; limited transportation; no tob, ETOH, or illicit drug use.

4 5/17/2018

Bictegravir/TAF/FTC: Virologically Suppressed Switch

■Randomized switch studies in virologically suppressed persons: –Switching to BIC/FTC/TAF non-inferior to continuing boosted PI 1 or a DTG, ABC, 3TC-containing regimen 2

1Daar E et al IDWeek 2017; 2Molina J-M et al, CROI 2018 abstract 22

■ 20 y/o AAM presents for initial visit after being diagnosed 2 weeks ago. He decided to K.B. get tested after he learned that his current partner has been living with HIV since 2006. He goes on to share that since his diagnosis, he and his partner now communicate more regularly about HIV. His partner has been helping him learn about different treatment options, and suggested K.B. start with one pill, but stay away from “the one that causes weird dreams.” You also learn that K.B.’s partner had problems with adherence on ”that one.”

■ PMH: No history

■ SH: In a monogamous relationship now, currently a junior in college studying music, smokes ½ ppd, social drinker, lives off fast food

Doravirine (DOR)

■ New NNRTI ■ Active in vitro against HIV that is resistant to first-generation NNRTI (K103N, Y181C, G190A, E138K, K103N/Y181C) 1 ■ Metabolized by CYP3A4, but not an inhibitor or inducer ■ Not impacted by PPIs ■ No specific food requirements

1Lai AAC 2014;58:1652-1663

5 5/17/2018

DRIVE-AHEAD: DOR/3TC/TDF in Treatment-Naïve PLWH

Doravirine/3TC/Tenofovir DF (n=364) Phase 3 /FTC/Tenofovir DF (n=364) Double-blind, Randomized 1:1, 96 Wk Week 0 48 96 HIV RNA ≥1000 copies/mL Primary Endpoint Stratified by: HIV RNA <50 copies/mL • HIV RNA ( 100K) and • Hepatitis B/C co-infection Doravirine/3TC/TDF Efavirenz/FTC/TDF 100 Difference (%): 91% 3.5 (-2.0, 9.0) 91% 84% 81% 81% 81% • Primary outcome: HIV RNA <50 copies/mL (FDA snapshot algorithm) 80 • Non-inferior efficacy DOR (84%); EFV (81%) ∑ 60 • Virologic failures in DOR arm (6%) ∑ Primary NNRTI resistance: (1.6%) ∑ Primary NRTI resistance (1.4%) 40 • Superior safety profile for neuropsychiatric events and lipids Patients (%) 20

0 DOR/3TC/FDF and DOR submitted Jan 2018, PDUFA Oct 2018 Overall ≤100K >100K ITT (n=277/258) (n=69/73) (n=364/364) HIV RNA (copies/mL) (Observed Failure Approach) Squires KE, et al. J Int AIDS Soc . 2017;20(suppl 4):110-111. Abstract TUAB0104LB; Orkin C et al, CROI 2018, abstract 491

DRIVE with DORAvirine

■DRIVEDRIVEDRIVE- DRIVE ---AHEADAHEADAHEADAHEAD – DOR/3TC/TDF vs. EFV/FTC/TDF

■DRIVEDRIVEDRIVE- DRIVE ---FORWARDFORWARD – DOR vs. DRV/r (non-inferior, lipids)

■DRIVEDRIVEDRIVE- DRIVE ---SHIFTSHIFTSHIFTSHIFT – Switch to DOR/3TC/TDF

AMBER: PI-based STR for Initial Therapy

■ Phase 3 randomized, double-blind study designed to assess safety and efficacy of DRV/c + 3TC/TAF vs. DRV/c + 3TC/TDF ■ Primary endpoint: non-inferiority of STR vs. control to achieve vial suppression (VL < 50 copies/mL) at 48 weeks

D/C/F/TAF (N= 362) Control (N= 363) 100 91.4% 88.4%

80

60

40

Patients Patients (%) AE leading to D/C- Rash @ 2% 20 One- M184V 8.3% 4.4% 3.3% 4.1% 0 Virologic VL > 50 c/mL No virologic data response (VL <50 c/mL) Orkin EACS 2017

6 5/17/2018

Early Initiation/Rapid Start/TNT

■ No, we need resistance testing before initiating treatment. ■ Yes, my preferred regimen is Boosted DRV/tenofovir/FTC. ■ Yes, my preferred regimen is DTG/ABC/3TC. ■ Yes, my preferred regimen is DTG/tenofovir/FTC. ■ No, I prefer to schedule to patient for a visit later to begin treatment. ■ What, people do that?

Challenging Tradition: 2-drug Therapies Nukes getting Nuked?

■ Initial therapy – LPV/r + 3TC (GARDEL) – DRV/r + RAL (NEAT001) – DTG + 3TC (PADDLE; ACTG A5353; GEMINI-1,2) – DRV/r +3TC (ANDES)

■ Switch therapy – LPV/r + 3TC/FTC (OLE) – ATV/r + 3TC (SALT, ATLAS-M) – DRV/r + 3TC (DUAL) – DRV/r + RPV – DTG + RPV – DRV/r + DTG (DUALIS)* – DTG + 3TC (LAMIDOL, ASPIRE, TANGO*)

* Currently being studied

7 5/17/2018

Dolutegravir + 3TC

■PADDLEPADDLEPADDLE: PADDLE open-label, single arm study, 20 patients, ARV-naïve, VL >5000<100K copies/mL, CD4 >200 cells/mL, HBV negativenegative; primary endpoint <50 copies/mL at week 48 (FDA snapshot algorithm) outcome: 90% at week 48

■ACTG A5353A5353: Phase 2 single-arm study, 120 patients, VL >1000<500K copies/mL, at week 24: 90% at <50 copies/mL, no difference in VL, VF uncommon (adherence n=1)

■GEMINIGEMINIGEMINI- GEMINI ---1,21,21,21,2: Large RCT, phase III; results likely summer 2018

Figueroa MI et al, 15 th EACS, 2015. Taiwo BO et al, Clin Infect Dis, 2017 .

ANDES: DRV/r + 3TC

■ DRV/r + 3TC vs. DRV/r + 3TC/TDF – Randomized, open-label, phase IV – Primary endpoint: VL < 50 copies/mL at week 48 (FDA snapshot algorithm) – 145 patients: DT (n=75),TT (n=70)

Adverse Events HIV RNA <50 (ITTe) AEs%AEs%AEs%DualDualDual TherapyTherapyTherapy TripleTripleTriple TherapyTherapyTherapy Gastrointestinal (GI) 7% 14% DRV/r+ 3TC DRV/r +3TC/TDF Difference (%): Rash 8% 7% -1.0% (-7.5 ; 5.6%) 100 93% 94% 91% 92% TC 19% 4% 80 LDL 14% 6%

60 TRG 25% 14% 40 • Discontinuation rare, similar

Patients (%) Patients 20 • No SAEs or death 0 Overall Baseline HIV RNA (n=70/66 ) >100K copies/mL (n=20/12) Figueroa et al, CROI 2018, Abstract 489

Challenging Tradition: 2-drug Therapies Nukes getting Nuked?

■ Initial therapy – LPV/r + 3TC (GARDEL) – DRV/r + RAL (NEAT001) – DTG + 3TC (PADDLE; GEMINI-1,2) – DRV/r +3TC (ANDES)

■ Switch therapy – LPV/r + 3TC/FTC (OLE) – ATV/r + 3TC (SALT, ATLAS-M) – DRV/r + 3TC (DUAL) – DRV/r + RPV – DTG + RPV – DRV/r + DTG (DUALIS)* – DTG + 3TC (LAMIDOL, ASPIRE, TANGO*)

* Currently being studied

8 5/17/2018

Dolutegravir + RPV

■ Approved November 2017 ■ First complete treatment regimen with only two drugs ■ Co-formulated INSTI + NNRTI ■ Switch/maintenance therapy

SWORD-1 and 2: Switching to DTG + RPV

Virologic outcomes at week 48 100 95 95 ■ Stable on standard 3DR suppressive ART, VL <50 for >6 mo., 80 no h/o VF or resistance to DTG or DTG + RPV (n=513) RPV 60 CAR (n=511) ■ Randomized 1:1 to continue CAR or HIV RNA <50, <50, HIV % RNA 40 switch to DTG +RPV ■ Primary endpoint: # of subjects VL 20 5 4 <50 copies/mL at Wk 48 <1 1 0 ■ Non-inferiority to CAR Virologic Virologic No virologic success non-response data

Llibre JM et al. CROI 2017; Abstract 44LB.; Llibre JM et al, Lancet 2018

DTG + RPV ■Indications: – Replacement therapy in persons who have achieved virologic suppression (<50 copies per mL) for at least 6 months and have no history of treatment failure or known resistance to its components

■Pharmacology and dosing: – One-pill, once a day with a meala meal – Can be used in patients with severe renal impairment, increased monitoring for AEs

■DrugDrugDrug- Drug ---DrugDrug Interactions: – Contraindications: Dofetilide, Rifampin, PPIs – Special considerations: – Rifabutin requires additional 25-mg of RPV with DTG/RPV – Antacids, administer DTG/RPV 4 hours before or 6 hours after; H2RA, administer DTG/RPV 4 hours before or 12 hours after – Metformin dose limited to 1000 mg when starting DTG/RPV or metformin

■Side effects: – Diarrhea, headache

https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Juluca/pdf/JULUCA-PI-PIL.PDF#page1

9 5/17/2018

■ 56 y/o AAM presents for follow-up after S.S. being discharged from the hospital. While in hospital, patient was diagnosed with ESRD requiring dialysis. Current ART of DTG + TAF/FTC.

■ PMH: Cryptococcal meningitis (2001, 2014), Genital Herpes (2014), CKD (2010), Depression, R DVT (2015), HTN (2015) ■ Medications: Rivaroxaban, Hydralazine, Amlodipine, Fluconazole, Valacyclovir

■ SH: Married, wife is supportive, past smoker 1 ppd, social drinker

What can TWO do?

■ ”Nuc-sparing” Rationale – Renal disease – TFV or ABC intolerance – Minimize ARV exposure (Aging population, co-morbidities) – Cost (Less agents)

Ibalizumab

CD4 Coreceptor Virus-Cell Binding Binding Fusion

CD4CD4

Cell Membrane CCR5/CXCR4 (R5/X4) Slide courtesy of Trip Gulick, MD; Adapted from Moore JP, PNAS 2003;100:10598-10602.

10 5/17/2018

Ibalizumab

■ Approved March 6, 2018 ■ Humanized monoclonal Ab ■ Binds CD4 on the host cell to block HIV entry into the cell (post-attachment inhibitor) 1 ■ Active against CCR5 and CXCR4 tropic HIV

1Emu B et al, Abstract 1686, IDWeek 2017

Ibalizumab

■Indications: – Treatment in heavily treatment-experiences adults with multidrug resistant HIV infection failing their current regimen – In combination with other antiretroviral(s) ■Pharmacology and dosing: – Administered intravenously, Infusion time 15-30 minutes – Diluted in 250 mL of 0.9% Sodium Chloride Injection – 2000 mg loading dose (10 vials), followed by 800 mg q 2 weeks (4 vials) – Half-life 2.7-64 hours ■Drug resistance: – No cross resistance with any classes of ART – Active against HIV resistant to all approved antiretroviral agents

https://drive.google.com/viewerng/viewer?embedded=true&url=https://theratechnologies.s3.amazonaws.com/prod/media/TrogarzoPrescribingInformation.pdf

Ibalizumab

■DrugDrugDrug- Drug ---DrugDrug Interactions: – None

■Side effects: – Diarrhea, dizziness, nausea and rash

https://drive.google.com/viewerng/viewer?embedded=true&url=https://theratechnologies.s3.amazonaws.com/prod/media/TrogarzoPrescribingInformation.pdf

11 5/17/2018

Ibalizumab at Work

■ Phase 3: 40 patients with 3-class ARV resistance, at least 1 active drug

■ Primary Endpoint: VL drop > 0.5 log 10 c/mL – 3% during control period – 83% after loading dose ■ After loading dose, regimen optimized at day 14 – Week 24: 50% had VL <200 – Expanded access: Week 48 viral suppression

Emu B et al, Abstract 1686, IDWeek 2017; Weinheimer S et al, CROI 2018, #561

Fostemsavir (FTR)

CD4 Coreceptor Virus-Cell Binding Binding Fusion

Prodrug of temsavir: binds to gp120, inhibits HIV attachment to CD4CD4CD4

gp120gp120

CD4CD4

Cell Membrane CCR5/CXCR4 (R5/X4)

Slide courtesy of Trip Gulick, MD; Adapted from Moore JP, PNAS 2003;100:10598-10602 .

Fostemsavir (FTR): Oral

Phase 3 trial with heavily treatment experienced patients with virologic failure (BRIGHTE)

Randomized (3:1) Cohort: FTR 600 mg Patients failing current regimen with VL of at least 400 c/mL and: BID + FR • 1 or 2 ARV classes remaining with at Open Label FTR 600 mg BID + OBT least 1 fully active agent per class • Unable to construct viable regimen PCB + FR otherwise

Day 1 Day 8 (PE) Day 9 (OL) W24 W48 W96 End of Study Non-randomized Cohort: Patients failing current regimen with VL of at least 400 c/mL and: Open Label FTR 600 mg BID + OBT • 0 ARV classes remaining and no fully active agents

Day 1 W24 W48 W96 End of Study

Kozal M et al, 16th EACS, 2017

12 5/17/2018

Fostemsavir (FTR): BRIGHTE Results

Mean VL Change at day 8 N=69 N=201 § 0 Placebo FTR 600mg -0.1 BID -0.2 -0.3 (95% CI) (95%

† -0.4 -0.17 -0.5 -0.6 -0.7 -0.8 Adjusted Adjusted Mean -0.79 -0.9 -1 Difference † (95% CI) = -0.625 (-0.810, -0.441) P<0.0001 ‡

Week 24: 5454%% of randomized and 36% of nonnon---- randomized patients who received FTR + OBT achieved VL https://www.viivhealthcare.com/media/press-releases/2017/october/viiv-healthcare-announces-positive-phase-3-results- <40 from-the-brighte-study-of-fostemsavir-in-heavily-treatment-experienced-patients-with-hiv.aspx <40<40 Kozal M et al, 16th EACS, 2017 Regulatory submission expected 2019/2020 Slide courtesy of Rajesh Ghandi, Atlanta, GA, March 2018

■ 32 y/o AAF, poor to no adherence. T.Y. Previous regimens: DRV/r + TDF/FTC, DTG + DRV/r, DTG + TDF/FTC, DRV/c + FTC/TAF, Current DTG + FTC/TAF. Continued non- adherence X 5 years.

■ PMH: Depression, Developmental Delay

■ SH: In a relationship, partner unaware of status, non-smoker, social drinker

Long-acting Injectable: CAB/RPV

■ (CAB) is an HIV-1 integrase inhibitor – Oral 30 mg tablet (t 1/2 , ~ 40 hours) – LA nanosuspension 200 mg/mL (t 1/2 , ~ 20-40 days)

■ (RPV) is an HIV-1 NNRTI – Oral 25 mg tablet (t 1/2 , ~ 50 hours) – LA nanosuspension 300 mg/mL (t 1/2 , ~ 30-90 days)

■ Oral and injectable forms studied: – LATTE-1: Oral CAB + RPV – LATTE-2: Oral induction, injection maintenance

13 5/17/2018

LATTE-2: Long-Acting Cabotegravir + Rilpivirine as Maintenance Therapy

Induction period Maintenance period

Cabotegravir 400 mg + Rilpivirine 600 mg IM q 4 weeks (n=115)

Cabotegravir 30mg + ABC/3TC Cabotegravir 600 mg + Rilpivirine 900 mg IM q 8 weeks (n=115)

Oral Cabotegravir 30 mg + ABC/3TC QD (n=56) Oral RPV

96 Week 0 16 20 0 32 48 Primary Endpoint: HIV RNA <50 InclusionInclusion criteria:criteria: copies/mL Randomized 2:2:1 • 18 years or older VL <50 c/mL Wk 16 IP • Tx Naïve to D1 MP • CD4+ at least 200 cells/mm 3

Exclusion criteria: • HBV+ • ALT >5x ULN • CrCL <50mL/min

1. Spreen HIV Clin Trials 2013;14:192; 2. Spreen JAIDS 2014;67:481; 3. Margolis DA, et al. Lancet. 2017Jul 21. [Epub ahead of print].

LATTE-2: Long-Acting Cabotegravir + Rilpivirine as Maintenance Therapy at Week 96

Oral cabotegravir + 3TC/ABC daily (n=56) IM cabotegravir + IM rilpivirine 100 94% Every 4 weeks (n=115) 87% Every 8 weeks (n=115) 84% 80

60

40

20 14% 13% HIV RNA <50 Copies/mL (%) Copies/mL<50 RNA HIV 2% 4% 2% 0% 0 Success Failure No Virologic Data

1. Eron J, et al. J Int AIDS Soc . 2017;20(suppl 4):107-108. Abstract MOAX0205LB.; 2. Margolis DA, et al. Lancet. 2017Jul 21. [Epub ahead of print].

Long-Acting Cabotegravir + Rilpivirine as Maintenance Therapy

■ Ongoing studies – FLAIR, ATLAS: Q 4 week dosing (2018) – ATLAS-2M: Q 8 week dosing (2019)

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■NRTINRTINRTI ■Maturation Inhibitor ■Capsid Inhibitor ■Protease Inhibitor ■Entry Inhibitor ■Monoclonal antibodies ■Broadly neutralizing aaantibodiesantibodies

Questions?

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