1. Overview of Ongoing Cure Research Globally
Jintanat Ananworanich, MD, PhD
Associate Director for Therapeutics Research, U.S. Military HIV Research Program
Co-director, SEARCH, The Thai Red Cross AIDS Research Center
Professor of Internal Medicine, University of Amsterdam
Professor of Pediatrics, University of Maryland School of Medicine

2. Disclosures
Jintanat Ananworanich has received honorarium for advisory meeting participation from Gilead, Merck, Roche, AbbVie and ViiV Healthcare

3. Outline HIV remission and eradication strategies Ongoing cure research
What are they?
How and where are they done?
Examples of cure clinical trials
Acknowledgement
Study Participants

4. From Treatment to HIV Eradication
Living with HIV
36 million
HIV remission
~ 100+ cases, early treated
( %)
HIV eradication
1 case, the Berlin pt
( %)
VL suppressed
No therapy
Need VL monitoring
Transmission risk?
No HIV replication
No therapy
No VL monitoring
No transmission risk
Impact on stigma and discrimination?

5. Cure Research Ethics, Socio-behavioral Bench Science
Understand persistence and immune control
Population
Age
Sex
Viral subtype
Genetics
Tissues OI
Tropical diseases
Malnutrition
Timing and regimens
Intervention Trials
Animal and human studies
Single or combination interventions
Early ART
Latency
modifying agents
Immune
therapies
Gene- and
cell-based
Ethics, Socio-behavioral
Decision-making
Perceptions of risks and benefits
Attitudes about research
Individual and societal impact

6. Where Current Cure Trials are Conducted
Information from Treatment Action Group (

7. Design of Clinical Trials in HIV Cure
Small numbers
Single arm or randomized
With or without control arm
With or without analytical treatment interruption (ATI)

8. Evaluating HIV Remission Strategies with Treatment Interruption
Biomarkers
currently unknown
Suppressive ART
Sustained viremia
ART
Viral Load
Interventions
Time

9. Decision Making in HIV Remission Trials: Interviews of Thais who Joined and Declined Trials with ART Interruption+/-Experimental Agents
Joiners
Decliners
I don’t want to do everything in the study
I trust the doctors and nurses
Other people will benefit
from me
There is no guarantee that it will work
It’s too risky
I could be one of the few to control HIV
I want to know how strong
my immunity is
My anti-HIV test might turn positive
I have a special body. Others don’t get
to try this
I don’t want to be the first one to do this
R01AI27024 (Henderson and Peay)

10. Understand persistence and immune control Ethics, Socio-behavioral
Cure Research
Bench Science
Understand persistence and immune control
Population
Age
Sex
Viral subtype
Genetics
Tissues OI
Tropical diseases
Malnutrition
Timing and regimens
Intervention Trials
Early ART
Latency
modifying agents
Immune
therapies
Gene- and
cell-based
Ethics, Socio-behavioral
Decision-making
Perceptions of risks and benefits
Attitudes about research
Individual and societal impact

11. The “Shock and Kill” Model
Latency
reversing agents
Antibodies
Vaccines
Engineered cells
More than one drugs
New classes (e.g.TLR7 agonist)
RIVER study: vorinostat + ChAdV63.MVA vaccine (2018 IAS, Abstract 12977)
Vorinostat plus expanded HIV-specific T cell1 or dendritic cell2
TLR7 agonist in virally suppressed people on ART3
: 1NCT ; 2NCT ; 3NCT /NCT

12. The “Block and Lock” Model
Block & Lock
Transcription
inhibitor
Tat inhibitor1
RNA interference2
1Kessing, Cell Report 2017; 2Ahlenstiel, Mol Ther Nucleic Acid 2015

13. Broadly Neutralizing Antibodies (bNAbs)
bNAbs can bind
many HIV strains
bNAbs facilitate
antibody-dependent
cell cytotoxicty (ADCC)
CD8
Enhance
CD8 T cell
function NK NK
Main obstacle
- Pre-existing resistance
Strategies
- Broad and potent
- Multiple
- Tri-specific
- Long-acting
- Novel delivery platforms
- Early administration
- Combine with other agents
Kong, J Virol 2015; Barr, NEJM 2016; Scheid, Nature 2016; Caskey, Nature Med 2017; Hessell, Nature Med 2016; Liu, Science 2016;
Nishimura, Nature 2017; Pardi, Nature Communications 2017; Gardner, Nature 2015; Pitman, Lancet 2018

14. bNAbs in Ongoing/New Cure Clinical Trials
Dose, safety, antiviral effects
(People without HIV and
Those with chronic HIV)
Combination
3BNC117-LS / LS1
PGT121 /PGDM14002
New delivery system
AAV8-VRC073
New bNAbs
Z258-N6-LS
10e8v5R-LS
CAP256-LS
Tri-specific-LS
Safety and antiviral effects
(People in acute HIV)
VRC014
Viral control post-ART interruption
(People with chronic HIV)
3BNC117 / /TLR9 agonist5
PGT121 /VRC07-LS6
: 1NCT ; 2NCT ; 3NCT ; 4NCT
5Ole Sogaard (Aarhus); 6Dan Barouch (BIDMC)

15. Anti-α4β7 Antibody (Vedolizumab) in Clinical Trials
madCAM on
gut epithelial cells
α4β7 on
CD4+ cells
anti-α4β7 (treatment for inflammatory bowel disease)
50% of acutely treated monkeys had viral remission
Mechanisms for remission are unknown
Byrareddy, Science 2016
(Also see Di Mascio M, 2018 IAS, Abstract 13267)
Dose, safety, and antiviral effects post ART interruption
People with chronic HIV
Ottawa1: 12 people (Randomized to 75, 150, 300mg dosing groups)
NIAID2: 40 people (Single arm, 300mg)
People with primary or chronic HIV
Inserm-ANRS3: two-stage study of 192 people (DNA/MVA HIV vaccines vs. vedolizumab vs. vaccines plus vedolizumab vs. placebo)
: 1NCT ; 2NCT ; 3NCT

16. Improve CD8+ T cell killing of HIV-infected cells
Vaccines
HIV+
cells
In people with cancer/HIV5
Anti-PD1 or PDL1
Anti-CTLA-4
Immune checkpoint
blockers
PD-1
T-cell trafficking to LN
CD8
CXCR5
IL-15 superagonist6
CD8
CD8
CD8
CD8
CD8 NK NK
ChAdV63/MVA (HIVconsv)1
Ad26/MVA or protein2
DNA/MVA3
Dendritic cell+/-LRA3
Anti-inflammation
mTOR inhibitors7
:1NCT ; 2NCT /3NCT ;4NCT /NCT
5NCT /NCT ; 6NCT ; 7NCT /NCT

17. Genetic Engineered T cells: Creating Killer T Cells
HIV-infected cell
with surface
expression of
HIV envelope
CD8+ T cells
Single chain variable fragments derived from bNAbs
CAR-T cell therapy in
virally suppressed people on ART
(China; NCT )
Chimeric Antigen Receptor (CAR) T cells
Modified from a slide by Dr. Thor Wagner (U Washington)
Hale and Wagner, Mol Ther 2017; Ali, J Virol 2016; Liu, J Virol 2016; Hale, Mol Ther 2017

18. Gene Therapy to Make Cells Resistant to HIV
Leukapharesis
CD4+ T-cell isolation
CCR5-
Strategies
Use stem cells
Conditioning therapies
CCR5 and other anti-HIV genes
Newer editing technologies
CCR5+
ZFN cut
CCR5 gene
Re-infuse
People with HIV/no cancer
SB-728mR-T+cyclophosphamide1
shRNA-modified stem cells2
People with HIV and cancer
Stem cells gene-modified to encode multiple anti-HIV RNAs3
CRISPR CCR5 modified CD34+ cells4
Tebas P, NEJM 2014
: 1NCT ; 2NCT ; 3NCT /NCT ; 4NCT

19. Clinical Trials in Children with HIV
Early treatment cohorts
Canada1 (EPIC4), Botswana2 (EIT), S. Africa3 (Leopard), France4 (CLEAC), China5, Thailand (HIV-NAT 194/209)6
IMPAACT P11157
bNAbs
VRC01 with early ART in infants (IMPAACT P2008)8
VRC01-LS in virally suppressed, early treated children (Botswana)9
HIV vaccines
HIVIS DNA/MVA-CMDR vaccines in Thailand, South Africa and Italy in virally suppressed, early treated adolescents (EPIICAL network)10
: 1CTNS281; 2NCT ; 3NCT ; 4NCT ; 5NCT
6R01AI114236; 7NCT ; 8NCT ; 9U01AI135940; 10U01AI135941

20. The role of HIV cure research in improving therapy and health for people living with HIV
Opportunity to advance therapy with cure research
Even the best and long-acting ART cannot significantly
Reduce reservoir
Reduce immune activation
Improve HIV-specific immunity
Cure research leads to discovery science
“Play the long game” towards better therapy and health

21. Study Participants and Investigators
NIH
John Mascola
U California San Francisco
Steven Deeks
Harvard
Dan Barouch
Roger Shapiro
MHRP
Merlin Robb
Lisa Reilly
Jamie Livengood
Treatment Action Group
Richard Jefferys
Thai Red Cross
Praphan Phanuphak
Nittaya Phanuphak
Eugene Kroon
Thidarat Jupimai
U North Carolina
Gail Henderson
RTI
Holly Peay
Aarhus University
Ole Sogaard
U Melbourne
Sharon Lewin
Acknowledgements
Study Participants and Investigators