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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
US DHHS 2019www.aidsinfo.nih.gov
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
US DHHS 2019www.aidsinfo.nih.gov
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
US DHHS 2019www.aidsinfo.nih.gov
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
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!