HIV Advances and What Comes Next - ACTHIV

HIV Advances and What Comes Next

R.M. Gulick, MD, MPH

Rochelle Belfer Professor in Medicine

Chief, Division of Infectious Diseases

Weill Cornell Medicine

New York City

Learning Objectives

•Review current state-of-the-art HIV treatment.

•Describe advances in antiretroviral therapy that will enhance virologic activity, safety/tolerability, and convenience for patients.

Disclosures

•No pharmaceutical or device company relationships

•Co-Chair, U.S. DHHS Adult and Adolescent ART Treatment Guidelines Panel

ART in 2020

•Start ART at all stages of HIV infection

•33 approved drugs•5 broad mechanistic classes:

NRTI, NNRTI, PI, INSTI, EI

•Up to 7 recommended first-line regimens worldwide•1 standard strategy:

1-2 NRTI(s) + [INSTI, NNRTI, or PI]

•ART Properties•Antiretroviral activity•Safety and tolerability•Convenience

When to Start?: Chronic Infectionasymptomatic

AIDS/

symptoms

CD4

<200

CD4

200-

350

CD4

350-500

CD4

>500

US DHHS 2019www.aidsinfo.nih.gov

recommended

IAS-USA 2018JAMA 2018;320:379

recommended

WHO 2016http://www.who.int/hiv/pu

b/guidelines/en/

recommended

Antiretroviral Drug Approval:1987 - 2020

0

5

10

15

20

25

30

35

1987 1990 1993 1996 1999 2002 2005 2008 2011 2014 2017 2020

AZT ddI

ddC d4T

3TC

SQV

RTV

IDV

NVP

NFV

DLV

EFV

ABC

APV

LPV/r

TDF

ENF

ATV

FTC

FPV TPVDRV

ETR

RAL

MVCRPV

EVGDTG TAF

BIC

IBA

DORFTR

ART: What to Start? Recommended/Preferred: 1-2 NRTI + INSTI

NRTI NNRTI PI INSTI


TAF/FTC (or 3TC)

TDF/FTC (or 3TC)

ABC/3TC+

3TC+

-- -- BIC, DTG,

RAL

IAS-USA 2018JAMA 2018;320:379

TAF/FTC

ABC/3TC+

-- -- BIC, DTG

+ only with DTG

ART: What to Start? Alternative: 2 NRTI + 3rd Drug

NRTI NNRTI PI INSTI


ABCǂ/3TC* DOR

EFV 400 mg

EFV 600 mg

RPV*

ATV/c or /r

DRV/c or /r

EVG/c

IAS-USA 2018JAMA 2018;320:379

TDF EFV

RPV

DRV/c

DRV/r

EVG/c

RAL

ǂ if HLA-B*5701 negative

*performs less well/not recommended for baseline HIV RNA >100,000, CD4 <200

(except ABC/3TC/DTG)

Advance Study: TAF vs. TDF; DTG vs. EFV

• South African PLWH, ART-naïve randomized to:• TDF/FTC/EFV• TDF/FTC + DTG • TAF/FTC + DTG (N=~350 per arm)

• Results:• VL <50 c/ml (ITT, wk 96):

74% (EFV), 78% (TDF/DTG), 79% (TAF/DTG)

• More RTI resistance in EFV arm• Weight gain• Hip osteopenia:

16/351(5%) TAF vs.58/608(10%) TDF Venter NEJM 2019;381:803-815

Sokhela IAS 2020 #OAXLB0104

Switching ART and Weight Gain• NA-ACCORD adults switched from NNRTI- or PI-regimen to INSTI from

2007-2014 with virologic suppression 2 years before and after switch (N=870)

• Age at switch 50; 83% men; 41% non-white; BMI 26; CD4 620

• INSTI: 431 on RAL; 263 on EVG; 176 on DTG

• Results:

• Conclusions: with NNRTI→INSTI with in ♀, non-white, age >50Koethe CROI 2020 #668

ART Guidelines: What to Start? 2-drug ART: Alternative or “Other”

2-drug ART scenario regimens


when ABC, TAF, and

TDF cannot be used

or are not optimal

DRV/r + RAL*

DRV/r + 3TC

DTG + 3TCǂ

IAS-USA 2018JAMA 2018;320:379

when individuals

cannot take ABC, TAF,

or TDF

DRV/c or /r +

RAL or DTG or 3TC

or FTC

* performs less well/not recommended for baseline HIV RNA >100,000 or CD4 <200

ǂ except for VL>500,000 copies/mL, HBV co-infection, or before HIV genotype available

2-Drug Regimens

•PI/r + 3TC (or FTC)•GARDEL (LPV/r): Cahn Lancet Infect Dis 2014;14:572• ANDES (DRV/r): Sued IAS 2017 #MOAB0106LB

•PI/r + integrase inhibitor•NEAT-001 (DRV/r + RAL*) Raffi Lancet 2014;384:1942

* performs less well/not recommended for baseline HIV RNA >100,000 or CD4 <200

Antiretroviral Activity

ART Trials: Virologic Responses

Carr Glasgow AIDS 2019;33:443-453

354 studies through 2017: ITT analyses

N=77,999

0

20

40

60

80

100

1994 1998 2002 2006 2010 2014

Eff

icacy (

%)

Year of commencement

45%

77%

Virologic Responses – Newer Studies

Study (reference) Study arm (N)

Regimen HIV RNA <50 at 48 wks

GS-US-380-1490Sax Lancet 2017;390:2074

320325

TAF/FTC/BICTAF/FTC + DTG

89%93%

GS-US-380-1489Gallant Lancet 2017;390:2063

316315

TAF/FTC/BICABC/3TC/DTG

92%93%

AMBEREron AIDS 2018;32:1431

362 363

TAF/FTC/DRV/c TAF/FTC + DRV/c

91% 88%

GEMINI 1Cahn Lancet 2019;393:143

356359

DTG+3TCTDF/FTC + DTG

90%93%

GEMINI 2Cahn Lancet 2019;393:143

360359

DTG+3TCTDF/FTC + DTG

93%94%

Study (reference) N Regimen VL <50 (96 wks)

ACTG 5257Lennox Ann Intern Med 2014;161:461

605 2 NRTI + ATV/r 88%

601 2 NRTI + DRV/r 89%

603 2 NRTI + RAL 94%*

SINGLEWalmsley NEJM 2013;369:1807 + JAIDS 2015;70:515

414 ABC/3TC + DTG 80%*

419 TDF/FTC/EFV 72%

FLAMINGOMolina Lancet 2014;383:2222 + Lancet HIV 2015;2:e127

242 2 NRTI + DTG 80%*

242 2 NRTI + DRV/r 68%* = significant difference

Virologic Responses – Comparative Studies

HIV Entry Inhibitors

Virus-CellFusion

Adapted from Moore JP, PNAS 2003;100:10598-10602.

gp41

gp120

V3 loop

CD4Binding

CD4

Cell

Membrane

CoreceptorBinding

CCR5/CXCR4

(R5/X4)

CCR5 antagonist

maravirocenfuvirtide

fostemsavir

ibalizumab

Fostemsavir (FTR) • Fostemsavir (FTR): Small-molecule that binds to

gp120 – new antiretroviral class: CD4 attachment inhibitor

• BRIGHTE (Phase 3): heavily rx-exp. PLWH• n=272 with 1-2 remaining ART classes

randomized to FTR 600 mg bid or placebo• N=99 with no remaining ART classes

not randomized; all received FTR• day 8: mean HIV RNA ∆:

-0.2 log cps/ml (placebo) vs. -0.8 (FTR)

• 7/2/20: U.S. FDA approved for adults living with HIV who have tried multiple HIV meds and whose HIV infection cannot be successfully treated with other therapies because of resistance, intolerance or safety considerations.

Kozal NEJM 2020;382:1232-43 Lataillade IAS 2019 #MOAB0102

HIV Capsid Inhibitor

2

0

Capsid CoreAssembly

NUCLEUS

Reverse Transcription

Nuclear Translocation

Capsid Core Disassembly

PRODUCER

CELL

Gag-Pol

TARGET CELL

Pre-integration complex

NUCLEUS

Integration

Maturation

Gag

GS-CA1

Yant Nat Med 2019;25:1377-1384

Capsid Inhibitor: Lenacapavir (LEN, GS-6207)• Potent antiretroviral activity: EC50 140 pM in PBMC

• Active across all tested subtypes

• Resistant variants have low fitness

• ↓ clearance and solubility →very long ½ life: 30-43 days

• Oral and SC formulations

• Phase 1 in HIV- and HIV+ pts• Max VL ↓ 2.2 log cps/ml at day 10

• New sustained-delivery formulation: • Phase 1 in 30 HIV- pts

• 3 SC doses (10/group)

• Plans for ART and PrEP studies

Begley

IAS 2020

#PEB0265

Link Nature

(epub 7/1/20)

Safety and Tolerability

ART Trials: Discontinuations for Toxicity

Carr Glasgow AIDS 2019;33:443-453

354 studies, through 2017: ITT analyses

N=77,999

0

10

20

30

40

50

1994 1998 2002 2006 2010 2014

Ce

ss

ati

on

(%

)

10%

4%

Discontinuations for Adverse Events

Study (reference) Study arm (N)

Regimen % d/c for adverse events at 96 weeks

ACTG 5257Lennox Ann Intern Med 2014

603 2 NRTI + RAL <1%

SPRING-2Raffi Lancet Infect Dis 2013

411 2 NRTI + DTG 2%

GS-US-292-0104/0111Wohl JAIDS 2016

866867

TAF/FTC/EVG/cTDF/FTC/EVG/c

1%2%

GS-US-380-1489Gallant Lancet 2017;390:2063

316315

TAF/FTC/BICABC/3TC/DTG

0%1%

Safety and Tolerability: Newer ApproachesLower doses:

• ENCORE 1 (EFV 400 mg vs. 600 mg) double-blind randomized, noninferiority study of initial rx

Puls Lancet 2014;383:1474

• WRHI 052 (DRV/r 400/100)

• on LPV/r >6 months, VL <50, no hx of other PI use (N=300)• Randomized to:

• continue LPV/r (n=152) or switch to DRV/r 400/100 qd (n=148)

• VL <50 at wk 48 (ITT): 95% (LPV) vs. 97% (DRV) ∆ +1.2% (95% CI: -3.7, +6.2%) →non-inferiority• Conclusions: DRV/r 400/100 non-inferior and significantly

cheaper Venter Lancet HIV 2019;6:e428-e437

What to Start?: 2-Drug Regimens•DTG + 3TC

• GEMINI 1 and 2 (N=1441)• Randomized, double-blinded, international phase 3 study• Study population: Rx-naive, HIV RNA 1000-500,000, no chronic HBV

infection, no major resistance mutations

April 2019

93% TDF/FTC + DTG91% DTG + 3TC

∆ -1.7 (95% CI: -4.4, +1.1)→ 2 drugs non-inferior

no drug

resistance

Cahn Lancet 2019;393:143-155

Cahn JAIDS 2020;83:310-318

Maintenance 2-Drug ART Regimens (1)

•PI/r + 3TC (vs. PI/r + 2 NRTIs)•OLE (LPV/r, N=250) Arribas Lancet Infect Dis 2015;15:785

•ATLAS-M (ATV/r, N=266) Fabbiani JIAS 2014;17:19808

• SALT (ATV/r, N=286) Perez-Molina Lancet ID 2015;15:775

•DUAL (DRV/r, N=249) Pulido CID 2017;65;2112

•DTG + 3TC•ASPIRE: (N=90) Taiwo Clin Infect Dis 2018;66:1794–7

• LAMIDOL/ANRS 167: (N=110) Joly JAC 2019;74:739-745

• TANGO: (N=700) Van Wyk CID 2020 (epub 1/6/20)

Maintenance 2-Drug ART Regimens (2)• II + NNRTI

• SWORD 1 and 2 (DTG/RPV; N=1028) Llibre Lancet 2018;391:839

• LATTE 2 (CAB + RPV; N=309) Margolis Lancet 2017;390:1499-1510• ATLAS (CAB + RPV; N=616) Swindells NEJM 2020;382:1112-1123• FLAIR (CAB + RPV; N=629) Orkin NEJM 2020;382:1124-1135

• DRV/r + DTG• Tivista (Italian Cohort; N=113) Capetti Antivir Ther 2017;22:257-262 • Korean Cohort (N=31) Lee Infect Chemother 2018;50:252-262• Spanish Cohort (N=50) Navarro Pharmacotherapy 2019;39:501• DUALIS (N=269) Spinner IAS 2019 #MOPEB269

2017 2018

Convenience

ART: Convenience

2006

20112012

20142015

2016

2018 2018

2018

ATLAS-2M Study: CAB + RPV LA Q4 Versus Q8 Weeks• Phase 3b, open-label non-inferiority

(Δ4%) study (N=1045)

• Study pop: ATLAS pts – on SOC ART or CAB+RPV LA with VL <50

• Study rx: (po lead in of CAB+RPV X 4 wks if on SOC ART) • CAB 400 + RPV 600 LA q4 wks or CAB

600 + RPV 600 LA q8 wks

• Results:• Safety: ISR 98% were grade 1-2,

median duration 3 days

• Conclusion: q8 weeks was non-inferior to q4 weeks

• HPTN 083 PrEP Study: LA CAB

Overton CROI 2020 Abstract 34

Pa

tie

nts

(%

)

Efficacy at Week 48

HIV RNA≥50 Copies/mL

1% 2% 4%

94% 94%

6%

HIV RNA<50 Copies/mL

No VirologicData

Cabotegravir + Rilpivirine LA:

q4 weeks (n=523) q8 weeks (n=522)

Difference (%):0.8 (-2.1, 3.7)

HIV-1 Broadly Neutralizing Antibodies

Klein, Science 2013;341:1199

Islatravir (ISL): NRTTI

• EFdA – adenosine analogue• Active against NRTI-resistant virus• Half-life = 50-60 hours in plasma• Oral and parenteral formulations

• Phase 2b study of ISL+DOR+3TC vs. DOR/3TC/TDF; ISL: 3TC d/c at 24 wks• Treatment-naïve (N=120)

• Results• At week 48 viral suppression similar• VL too low for resistance testing • Adverse effects similar; mild HA more

common for ISL (11%), transient

• Phase 3 planned: rx-naïve, switch, rx-experienced (ISL dose 0.75 mg)

Molina J-M IAS 2019 #WEAB0402LBOrkin IAS 2020 #OAB0302DeJesus IAS 2020 #OAB0304

48 weeks: FDA Snapshot

Long-Acting Subdermal Implants:

Islatravir in Animal Studies

Barrett AAC 2018;62:e01058-18

Drug-eluting implants, both bioerodible and non-erodible

rats

non-human

primates

polylactic acid polycaprolactone ethylene vinyl

acetate

plasma PBMCs

Islatravir Implant

Matthews IAS 2019 #WEAB0402LB

Long-Acting Subdermal Implants:

Tenofovir Alafenamide (TAF) in Dogs

Gunawardana, AAC 2015;59:3913

Also: DTG, FTC, NVP, TAF-FTC, TDF-FTC

Rajabi PLoS 2016 https://doi.org/10.1371/journal.pone.0166330

Microneedle Patches

Estimated cabotegravir concentrations after applying a 30-60 cm2

microneedle patch (adults)

Rajoli Eur J Pharm Biopharm 2019;144:101-109

Microneedle Patches -- CAB

ART: Conclusions

•Antiretroviral Therapy•Activity

•Safety/tolerability

•Convenience

•Innovations will allow us to use ART to control HIV infection for our patients and reduce transmission in the community.

excellent; new MDR-active drugs

excellent; newer strategies

excellent; newer formulations

Acknowledgments• Weill Cornell Medicine• Cornell HIV Clinical Trials Unit (CCTU)

• Division of Infectious Diseases

• AIDS Clinical Trials Group (ACTG)

• HIV Prevention Trials Network (HPTN)

• NIH, NIAID, Division of AIDS

• The patient volunteers!

HIV Advances and What Comes Next - ACTHIV

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