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TRANSCRIPT
From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Investigational Approaches to
Antiretroviral Therapy
Rajesh T. Gandhi, MD Massachusetts General Hospital
Professor of MedicineHarvard Medical SchoolBoston, Massachusetts
Slide 2 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Financial Relationships With Commercial Entities
Dr Gandhi has served as a consultant or advisor to Merck &
Co, Inc. (Updated 11/11/19)
Slide 3 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Learning Objectives
After attending this presentation, learners will be able to:
• Describe investigational approaches for treating people
with HIV infection
• Discuss the pipeline for novel antiretroviral agents
Slide 4 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Investigational Approaches to Antiretroviral Therapy
• Have we moved into the era of 2-drug therapy? New,
emerging and investigational 2-drug regimens.
• What are the ART options in someone who has difficulty
taking daily drugs? Long-acting ART.
• What about new medicines for treating someone with
multi-drug resistant HIV?
• What’s on the horizon?
Slide 5 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
What to Start in Most People with HIV:
Integrase Inhibitor + 2 NRTI
IAS-USA (7/2018)
Recommended Initial Regimens
• Bictegravir/TAF/FTC
• Dolutegravir/abacavir/3TC
• Dolutegravir + TAF/FTC
DHHS (10/2018)
Recommended for Most People with HIV
• Bictegravir/TAF/FTC
• Dolutegravir/abacavir/3TC
• Dolutegravir + TAF/FTC or TDF/FTC
• Raltegravir + TAF/FTC or TDF/FTC
DHHS. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision October 25, 2018.; Saag MS, et al. JAMA. 2018;320:379-396.
• If substantial cost difference, TDF (with FTC or 3TC) is effective and generally well-tolerated, esp. if patient not at high risk for bone, renal disease
• Differences between TAF and TDF accentuated when TDF is used with ritonavir or cobicistat
Slide 6 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
GEMINI-1 and -2: DTG + 3TC vs DTG + TDF/FTC in
Treatment Naïve People with HIV
Cahn et al. IAS 2019; Mexico City, Mexico. Slides WEAB0404LB.
DTG + 3TC (N=716)
Day 1
Screening (28 days)
DTG + TDF/FTC (N=717)
DTG + 3TC
Week48
Double-blind phase
Open-labelphase
Continuation phase
Week144
Week 24
Week96
• ART-naive adults
1:1
• International, double-blind phase III noninferiority studies
ART-naive adults VL 1000-500,000
No major RT or PI resistanceNo HBV infection
(N = 1433)
Who was in GEMINI?Male: 85%.Age: 32-33 years.Black: 12%.HIV RNA level: Mean: 4.4 log10 c/mL; >100K: 20%.CD4 count: Mean: 462; ≤200 8%.
Slide 7 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
70.284.4
93.4 93.3 89.4 89.5
72.0
87.093.2 91.5
87.2 86.0
0
20
40
60
80
100
HIV
-1 R
NA
<50 c
/mL, %
(95%
CI)
Wks
Snapshot
Treatment Responders, n (%)
Adjusted difference, %
(95% CI)a
DTG + 3TC 616/716 (86.0) −3.4 (−6.7, 0.0)
DTG + TDF/FTC 642/717 (89.5)Snapshot
• No treatment emergent resistance (INSTI or NRTI) in either arm
• Blips not more frequent in 2-drug arm.
• Proportion of viral load <40/target not-detected similar in 2- and 3-drug arms
0 4 8 12 16 24 36 48 60 72 84 96
Cahn et al. IAS 2019; Mexico City, Mexico. Slides WEAB0404LB. Underwood. IAS 2019. Abstr MOPEB231
DTG + 3TC Non-inferior to DTG + TDF/FTC:
Snapshot VL <50 at Week 96
Slide 8 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Other 2-drug options for treatment of HIV
• Initial therapy
▫ DRV/r + RAL: but not as good as 3-drug therapy when CD4 <200, VL
>100K1-3
• Maintenance therapy (once VL suppressed on 3-drug therapy)
▫ DTG/RPV (SWORD)4-5 INSTI/NNRTI
▫ LPV/r + 3TC/FTC (OLE)6
▫ ATV/r + 3TC (SALT, ATLAS-M)7-8 PI + 3TC
▫ DRV/r + 3TC (DUAL)9
1 F Raffi Lancet 2014; 384:1942-51; 2Lambert-Niclot S, JAC 2016; 3 Bernardino J Lancet HIV. 2015 Nov;2(11):e464-73 ; 4Llibre JM et al, Lancet, 2018; 5Aboud et al, Lancet HIV, 2019; 6Arribas JR et al, Lancet ID, 2015; 7Perez-Molina JA et al, Lancet ID, 2015; 8Di Giambenedetto S et al, J Antimicrob Chemother 2017; 9Pulido T HIV Drug Therapy 2016 Glasgow, O331
Slide 9 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Emerging and investigational
2-drug options for treatment of HIV
• Initial therapy
▫ DRV/r + 3TC (ANDES): promising in small randomized trial1
▫ Islatravir + Doravirine: investigational
• Second-line therapy
▫ DRV/r + DTG (vs. 2 NRTI + DRV/r or DTG) (D2EFT). N=1010. Ongoing.2
• Maintenance therapy (once VL suppressed on 3-drug therapy)
▫ DRV/r + RPV (n=60)3
▫ DRV/r + DTG (DUALIS): similar 48 wk results as 3-drug therapy (n=265)4
▫ LA Cabotegravir/Rilpivirine (ATLAS, FLAIR, ATLAS-2M)
1 Figueroa, CROI 2018, abstract 489; 2clinicaltrials.gov #NCT03017872 3Maggiolo F, JAIDS, 2016; 4Spinner, IAS 2019, abstract MOPEB269
Slide 10 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
ART Options in Someone Who Has Difficulty Taking Daily Drugs
• 55 yo M with HIV, achalasia, dysphagia
• Long-standing difficulty swallowing pills
• Virologically suppressed on dolutegravir and rilpivirine
• He asks whether there are long-acting HIV medicines that he can take instead of a daily oral regimen
A. Yes
B. No
C. Not yet
D. I don’t know
How do you respond?
Slide 11 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Long-acting Cabotegravir and Rilpivirine
• Cabotegravir (CAB), an INSTI, and rilpivirine (RPV), an NNRTI, available in long-acting nanosuspension formulations; half-lives of months
Slide 12 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Phase 3 Clinical Trials: ATLAS/FLAIR Week 48
• ATLAS: virologicallysuppressed; switch to monthly IM LA CAB/RPV vs. continue oral ART
• FLAIR: Treatment naïve; suppress with oral ART; switch to monthly IM LA CAB/RPV vs. continue oral ART
Overton E IAS 2019 MOPEB257; Swindells S, et al. CROI 2019; #139; Orkin C, et al. CROI 2019; #140.
Slide 13 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
ATLAS/FLAIR Week 48 Pooled Results
*Adjusted for sex and baseline third agent class.
CAB, cabotegravir; CAR, current antiretroviral; CI, confidence interval; ITT-E, intention-to-treat exposed; LA, long-acting; NI, noninferiority; RPV, rilpivirine.
Virologic outcomes
1.9
93.1
5.11.7
94.4
3.9
0
20
40
60
80
100
Pro
port
ion o
f Part
icip
ants
(%
)
CAB + RPV LA
(n=591)
CAR (n=591)
Virologic
Nonresponse
(≥50 c/mL)
Virologic
Success
(<50 c/mL)
No Virologic
Data
Adjusted treatment difference (95% CI)*
Primary Endpoint:
LA noninferior to CAR
(HIV-1 RNA ≥50 c/mL)
at Week 48
Difference (%)
-10 -8 -6 -4 -2 0 2 4 6 8 10
-1.4 1.7
0.2
CARCAB + RPV LA
4% NI
margin
Key Secondary
Endpoint:
LA noninferior to
CAR (HIV-1 RNA <50
c/mL) at Week 48
Difference (%)
-10 -8 -6 -4 -2 0 2 4 6 8 10
-4.1 1.4
-1.4
CAR CAB + RPV LA
−10% NI
margin
Overton E, IAS 2019 MOPEB257; Swindells S, CROI 2019; #139; Orkin C, CROI 2019; #140.
Slide 14 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Treatment Emergent Resistance (CAB/RPV Groups)
Site/HIV subtypeBaseline Resistance
(HIV DNA)Resistance at Virologic
failure
RT IN RT IN
ATLAS
Russia/A1 E138E/A L74I E138A L74I
France/AG V108V/I, E138K None V108I, E138K None
Russia/A1 None I74I E138E/K N155H, L74I
FLAIR
Russia/A1 None L74I E138E/A/K/T L74I, Q148R
Russia/A1 None L74I K101E L74I, G140R
Russia/A1 None L74I E138K L74I, Q148R
L74I more common in people with HIV subtype A but did not affect treatment response.CAB, RPV conc at time of failure below population means but within range for majority who maintained suppression.
Overton E IAS 2019 MOPEB257; Swindells S, et al. CROI 2019; #139; Orkin C, et al. CROI 2019; #140.
Slide 15 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
LA CAB/RPV: Questions
• Is the 4-week oral lead-in needed? What about direct to inject?
• What about the long tail in people who stop the drugs? CAB detectable up to
48 wks after single injection, longer in women
• Will the drugs be useful in people who have difficulty adhering to oral ART?
• Can LA CAB/RPV be used in someone who is viremic?
▫ Case: person with bowel resection; not able to absorb oral ART; suppressed on IM
CAB/RPV
• What will the cost of the drugs be? Will the cost of the administration be
reimbursed?Orkin C, IAS 2019 TUSY0403; Landovitz, R, HIV R4P, Madrid, 2018. Abstract #OA15.06LB; Saman R, EACS 2019
Slide 16 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Ongoing CAB/RPV Studies
• 2 monthly IM: ATLAS 2M (n=1049)
• Phase 3 open-label 48 wk results in persons suppressed on oral ART or on every 4 wk CAB/RPV LA
• Randomized 1:1 to CAB/RPV LA every 4 weeks
or every 8 weeks
• Every 8 wk therapy was non-inferior
• Poor Adherers ACTG 5359 (n=350)
‒ VL >200 at entry
‒ No RPV or INSTI mutations
‒ Phase 1: 24 weeks of standard of care oral ART (conditional financial incentives)
‒ Then open label switch CAB/RPV 48 weeks
Slide 17 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Practical Aspects of Using CAB/RPV
• Loading dose: CAB LA 600 mg (one 3-mL injection)
and RPV LA 900 mg (one 3-mL injection)
• Monthly maintenance: CAB LA 400 mg (one 2-mL
injection) and RPV LA 600 mg (one 2-mL injection)
• RPV LA requires cold chain
• Injection into gluteus medius (upper outer
quadrant of buttock)
• Need a private place for injections
• What about people with buttock implants?Orkin C, et al. IAS 2019 TUSY0403; Landovitz, R et al. HIV R4P, Madrid, 2018. Abstract #OA15.06LB; Saman R et al, EACS 2019
Slide 18 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Practical Aspects of Using CAB/RPV: Continued
• Staffing and physical space to deliver injections
• In 3000 patient clinic, if 10% want injections: 15 visits/day, 30
injections/day (if monthly)
• Are there alternative places to deliver injections? Pharmacies? Home
healthcare?
• How will people remember to come in for visits? How will we remind people
to come in for visits? Might pharmacies play a role?
• If people are late in coming in, will need oral ARV bridging
Orkin C, et al. IAS 2019 TUSY0403; Landovitz, R et al. HIV R4P, Madrid, 2018. Abstract #OA15.06LB; Saman R et al, EACS 2019
Slide 19 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
My take on LA Cabotegravir/Rilpivirine
• For most people, oral daily ART will remain effective and convenient option
• LA CAB/RPV may be good option for people who struggle with taking daily oral regimen
(e.g., swallowing difficulties; stigma – external or internal)
• In people who struggle with adherence with oral ART, LA CAB/RPV may be helpful as
long as the person comes back for appointments
• Combining visits with other appointments may be helpful, e.g. when picking up methadone
refills, psychiatrist/psychologist/support group visits
• Every 8 wk dosing (if safe and effective) will make LA CAB/RPV more attractive but
adherence, long pharmacokinetic tail, oral bridging for missed injections, reminders,
administration logistics, and cost will still be important considerations
Slide 20 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
New Drugs for Multi-drug Resistant HIV
Slide 21 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Case Scenario
• 60 yo F diagnosed with HIV in 1990. Multiple previous regimens
• HIV RNA 20,000; CD4 cell count 150
• HIV phenotype: resistance to NRTI, NNRTI, PIs. Sensitive to INSTI
Slide 22 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
ARS Question
• Which of following classes are in or have completed phase 3 trials for treatment?
A. Entry/attachment inhibitors
B. Maturation inhibitors
C. Capsid inhibitors
D. Broadly neutralizing antibodies
Slide 23 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
HIV Entry Inhibitors
Virus-CellFusion
Slide courtesy of Trip Gulick, MD; Adapted from Moore JP, PNAS 2003;100:10598-10602.
gp41
gp120
V3 loop
CD4Binding
CD4
CellMembrane
CoreceptorBinding
CCR5/CXCR4(R5/X4)
CCR5 Inhibitorsmaraviroc*
enfuvirtide*
* FDA approved
FostemsavirIbalizumab*
Slide 24 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Ibalizumab: Post-Attachment Inhibitor
Emu B et al, Abstract 1686, IDWeek 2017; Weinheimer S et al, CROI 2018
Emu B et al, NEJM, 2018
• Humanized monoclonal Ab: binds CD4 on host cells; blocks HIV entry (post attachment inhibitor)
• Active against CCR5 and CXCR4 tropic HIV
• In phase 3 clinical trial (n=40), 50% of those who received ibalizumab + optimized background regimen achieved VL <200
• IV infusion: 2,000 mg loading dose then 800 mg every 2 wks
• Duration of infusion: 15-30 min
Slide 25 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Fostemsavir (FTR): Oral HIV Attachment Inhibitor
• Prodrug of temsavir: binds to gp120, inhibits HIV attachment to CD4
• Phase 3 trial in heavily treatment experienced patients with virologic failure (BRIGHTE)
Lataillade, IAS 2019. MOAB0102
• Randomized- 272 pts with ≥1 fully active drug in 1 or 2 classes. 8 days blinded therapy (FTR or pbo), then FTR + OBT
• Non-Randomized-99 pts with no fully active approved drug. FTR + OBT
Slide 26 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
BRIGHTE: Most Common ARVs in Initial
Optimized Background Therapy (OBT)
Slide credit: clinicaloptions.comLataillade. IAS 2019. Abstr MOAB0102. Reproduced with permission.
Slide 27 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
BRIGHTE: ITT-E Virologic Response Through Wk 96
Slide credit: clinicaloptions.com
Slide 28 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
• Islatravir
• Capsid inhibitor
• CD4 antibody
• CCR5 antibody
• Broadly neutralizing Ab
• Other novel agents
• Novel delivery systems
On the Horizon
Slide 29 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Islatravir (MK-8591)
• Nucleoside RT translocation inhibitor (NRTTI)
• Potent at low doses: single oral dose as low as 0.5 mg suppressed HIV RNA for >7 days
• High barrier to resistance• Long half-life (about 120 h)
▫ Potential for once daily, once weekly or less frequent dosing
Grobler et al CROI 2017 #435Matthews et al IAS 2017 #TUPDB0202LB
Slide 30 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Phase 2b study for treatment: DRIVE2Simplify: ISL + DOR vs. DOR/3TC/TDF
Molina J-M IAS 2019 WEAB0402LB
Participants initially received ISL+DOR+3TC; then switched to ISL+DOR during week 24-48 after achieving virologic suppression. Week 48 virologic outcomes (FDA Snapshot)
• All participants with protocol defined virologic failure had confirmatory VL <80
• No participants met criteria for resistance testing
Slide 31 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
ISL + DOR
• Phase 3 treatment program being launched:▫ Trial for treatment-experienced participants.▫ Two trials for participants switching therapy.▫ Trial for treatment naïve participants.
Future possibilities:• Based on pharmacokinetics (PK), ISL has potential for once weekly dosing
for treatment.• Also being considered for PrEP (promising PK results with ISL implant).
Molina J-M IAS 2019 WEAB0402LBMolina J-M, EACS 2019, PE3/21
Slide 32 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
HIV Capsid Inhibitor: Sustained levels for >24 weeks
after single subcutaneous injection
Ganser-Pornillos BK, Yeager M, Sundquist WI, Curr Opin Struct Biol, 2008Sager et al CROI 2019 abstract 141
Slide 33 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Start of B/F/TAFSingle SC GS-6207 dose
HIV Capsid Inhibitor: Antiviral activity after single subcutaneous dose in people with HIV
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1 2 3 4 5 6 7 8 9 10
Mean C
hange i
n H
IV-1
RN
A,
Log
10
copie
s/m
L (
95%
CI)
Day
Placebo (n=6)
GS-6207 50 mg (n=6)
GS-6207 150 mg (n=6)
GS-6207 450 mg (n=6)
Mean reduction of HIV RNA: -1.4 to 2.2 log10 c/mL over 10 days1
Recently announced2: • Phase 2/3 study in treatment
experienced/multi-drug resistant HIV• Phase 2 trial in treatment naïve • Capsid inhibitor: two-week oral lead-
in followed by subcutaneous injection every 6 mo.
1Daar E IAS 2019 LBPEB13; Daar E EACS 2019 PE3/17
2clinical trials.gov: NCT04150068; NCT04143594
Slide 34 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
HIV Entry Inhibitors: Novel Antibodies
Virus-CellFusion
Slide courtesy of Trip Gulick, MD; Adapted from Moore JP, PNAS 2003;100:10598-10602.
gp41
gp120
V3 loop
CD4Binding
CD4
CellMembrane
CoreceptorBinding
CCR5/CXCR4(R5/X4)
CCR5 Inhibitorsmaraviroc*
enfuvirtide*
* FDA approved
UB-421
Leronlimab(PRO 140)
FostemsavirIbalizumab*
Slide 35 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
UB-421: Antibody against CD4
• 29 people with virologic suppression on oral ART
• Received up to 8 infusions of UB-421▫ Weekly: cohort 1▫ Every 2 wks: cohort 2
• Oral ART stopped after first infusion
• All participants remained virologically suppressed during infusions
• Rash: 52%: mild and transitory; 1 person stopped Ab because of more severe rash
• Approval in China for a phase 3 ART substitution trialWang, C-Y et al, N Engl J Med 2019; 380:1535-1545; http://www.unitedbiopharma.com/news_detail.php?id=365
Plasma VL
Slide 36 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Leronlimab (PRO 140)
• Monoclonal antibody against CCR5
• Weekly subcutaneous injection
• Being studied as a single agent for maintenance of suppression and for people with drug resistant HIV
• Single agent for maintenance of suppression
▫ Participants with virologic suppression and R5 tropic HIV (Trofile DNA)
▫ Virologic failure rate: 14-66%
▫ Participants who had virologic failure re-suppressed on baseline ART
▫ No tropism shiftsDhody C et al, CROI 2019, Abstr 486
Slide 37 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
• Treatment-experienced people with multi-drug resistant R5-tropic HIV
• Randomized to receive PRO140 + baseline ART vs. placebo + baseline ART
• All participants then start open label PRO140 + optimized background regimen
• Results:▫ >0.5 log reduction in VL after single
injection: 64% in PRO 140 treated group vs. 23% in placebo group
▫ Week 25: 81% of participants with VL <50 Dhody K, ASM 2019, Abstract AA-713
Leronlimab (PRO 140) in people with
drug-resistant HIV
Slide 38 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Broadly Neutralizing Antibodies against HIV
Slide courtesy of Pablo Tebas, MD
Slide 39 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
(n=15)
0 5 10 15 20 25 300
25
50
75
100
Weeks of ATI
% B
elo
w 2
00 c
opie
s/m
l
p < 0.0001No bNAb
3BNC117
3BNC117 +
10-1074
Mendoza et al, Nature (2018) 561; 479-484
Combination of 2 Antibodies Maintained HIV suppression in Absence of ART in Some People
• 15 participants received a combination of 2 bNAband then stopped ART after first dose
• Combination of 2 bNAbs maintained viral suppression for median of 15 wk after last dose
• 2 participants maintained HIV suppression > 24 weeks
Will need to combine antibodies with multiple specificities
Slide 40 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Antibodies with improved potency and breadth:Reduction in VL after VRC01LS or VRC07-523LS Infusion
VRC01LS VRC07-523LS
0 2 4 6 8 10 12 141
2
3
4
5
6
LOD
Days post infusion
log
10 v
iru
s lo
ad
(co
pie
s/m
l)
Subject 1
Subject 2
Subject 3
Subject 4
Subject 5
Subject 6
Subject 7
0 2 4 6 8 10 12 141
2
3
4
5
6
LOD
Days post infusion
log
10 v
iru
s lo
ad
(co
pie
s/m
l)
Subject 8
Subject 9
Subject 10
Subject 11
Subject 12
Subject 13
Subject 14
Subject 15
Subject 16
- Day 7: 2/7 decrease of at least 0.9 log10- Day 14: 2/7 decrease of at least 1.6 log10
(all subjects off ARVs)
- Day 7: 8/9 decrease of at least 1.2 log10; 2/9 decrease of least 2 log10
- Day 14: 6/9 decrease of at least 1.6 log10; 7/9 decrease of at least 0.6 log10 (all subjects off ARVs until after Day 14)
Chen G IAS 2019 WEAA0305LB
Study of LA cabotegravir + VRC07-523 LS being launched (ACTG)
Slide 41 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Selected other investigational drugs in the pipeline
http://i-base.info/htb/wp-content/uploads/2019/07/PIPELINE-2019-FINAL-full-version.pdf
Slide 42 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
New Delivery Systems (in development)
Long acting injectables: o Elsulfavirine (NNRTI); raltegravir; atazanavir/ritonavir; combinectin (entry inhibitor)
o Considerations: managing toxicities if they develop; what to do if recipients
become pregnant; what happens if doses missed
Implants:o Islatravir: NRTTI
o TAF: NRTI
o Biodegradable, removable, polymer-based implants with multiple drugs
Patches
Oral once-weekly delivery system
Novel antibody delivery systems: viral vectors; synthetic DNAGulick R & Flexner C. Ann Rev Med 2019;70:137-50; Flexner C. Curr Opin HIV AIDS 2018; Benhabbour SR et al, Nature Comm 2019; Rajoli et al. Eur J of Pharma and Biopharm 2019. Giardiello M
Nature Comm 2016; Kirtane A, et al. Nature Comm 2018. Wise M et al, JCI, 2019
Slide 43 of 44 From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Investigational Approaches to Antiretroviral Therapy
• Have we moved into era of 2-drug therapy? Dolutegravir/3TC is an approved
option; new & investigational regimens under evaluation.
• What are the ART options in someone who has difficulty taking daily drugs?
Long-acting IM cabotegravir/rilpivirine may be approved soon.
• What do you give to someone with highly drug resistant HIV? Ibalizumab
approved; fostemsavir (attachment inhibitor): promising results in phase 3 trial.
• What’s on the horizon? Islatravir, capsid inhibitor, antibodies against CCR5 or
CD4, broadly neutralizing antibodies, new delivery systems, and more!
From RT Gandhi, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Question-and-Answer Period