MH
RP
The views expressed are those of the authors and should not be construed to represent the
positions of the U.S. Army or the Department of Defense.
Towards an HIV Cure: Clinical Strategies and Trials
Jintanat Ananworanich, MD, PhDProfessor of Internal Medicine, University of Amsterdam
Co-director, SEARCH, The Thai Red Cross AIDS Research CenterAssociate Director for Therapeutics Research, US Military HIV Research Program
MH
RP
What do We Want?
Without
ART
Eradication
(Sterilizing Cure)
Elimination of
all HIV capable of replicating
Remission (Functional Cure)
Undetectable VL
Healthy
No increased risk of transmission
Viral lo
ad
ART
1 20
Typical
rebound
< 2months
Boston A
3 months
Boston B
8 months
Mississippi child
28 months
Timothy
Brown
6 7
Post treatment controllers
No rebound
Visconti (n=14)
SPARTAC (n=4)
Swiss 1 (n=3)
Primo SHM (n=4)
Cascade (n=11)
Seattle (n=1)
French teenager (n=1)
Seattle ACTG mixed (n=1)
Limit of detection
From the slide collection of Dr. Nicolas Chomont (U Montreal)
G. Hütter et al. NEJM 2009; D. Persaud et al. NEJM 2013; K. Luzuriaga et al. NEJM 2015; T. Henrich et al. JID 2013; T. Henrich et al. Ann Intern Med
2014; W. Stöhr et al. Plos One 2013; L. Hocqueloux et al. AIDS 2010; A. Saez-Cirion et al. Plos Path 2013; W. Stöhr et al. Plos One 2013; V. Von Wyl
et al. PlosOne 2011; ML. Grijsen et al. Plos Medicine 2012; S. Lodi et al. Arch Intern Med 2012; J. Maenza et al. Antivir Ther 2015; J. Li et al.
CROI2015; P. Frange Lancet HIV 2016. Adapted from J. Cohen, Science 2015.
years
All started ART early after infection
So Far, Two Ways to Achieve HIV Remission
Bone marrow transplantation
Early ART
MH
RP HIV remission is uncommon
even in early treated people
VISCONTI (Hocqueloux L, 2010; Saez-Cirion A, 2013): SPARTAC (Fidler S, 2013, Stohr 2013); Swiss 1 (Gianella S, 2011)
Primo SHM (Grijsen ML, 2012); Cascade (Lodi S, 2012) Seattle (Maenza J, 2015); ACTG mixed (Li J, CROI 2015)
San Diego (Gianella S, 2015); Swiss 2 (von Wyl V, 2011); A371 (Volberding P, 2009); Ped (Ananworanich J, 2015)
VISCONTIn=14 (15%)
Primo-SHM
n=4 (5%)
CASCADEn=11 (5%)
Seattlen=1 (5%)
San Diego
0%
SPARTACn=4 (9%)
Swiss 1n=3 (9%)
Swiss2 0%
A3710%
ACTG mixed
n=1 (5%)Pedcase
reports
MH
RP HIV Remission:
Complex Interplay between Reservoir and Immunity
immunity
latent
virus
Host
Broad T cell responses
Less exhausted T cells
Strong NK cytotoxicity
Rapid ART initiation
Low HIV DNA and HIV RNA
Absence of residual viremia
Poor viral replicative fitness
Williams JP, eLife 2014; Etemad B, 2015 CROI; Hurst J, Nature Communications 2015;
Frater J, AIDS 2014; Scott-Algara D, 2015 CROI; van Gulck E, Plos One 2012
Gossez M, 2016 CROI (Abstract 87)
African Spartac
5 in 22 PTC (22%)
MH
RP
Strategies to Limit and Reduce HIV Persistence
After VL Suppression
ChronicHIV Infection
AcuteHIV Infection
ART
HIV RNA
At ART initiation
Limit reservoir
establishment
Possible strategies
• Reactivate reservoir
• Deplete infected cells
• Make cells resistant to HIV
Stark Differences in HIV Reservoir in Untreated vs. Treated Acutely HIV-Infected Thai Adults
Ananworanich, Robb, 2016 CROI (Abstract 349), manuscript submitted
20-fold300-fold
Reservoir “set-point” is established early in acute infection and determines
reservoir size in chronic infection
Window of opportunity to significantly alter reservoir size is with early ART
MH
RP High Seronegativity in Very Early Treated Thais
(RV254/SEARCH010)
de Souza M, Ananworanich J, Clin Infect Dis (in press)
4th generation antigen-antibody combo immunoassay
Very early treated individuals can remain HIV antibody negative more than 6 months
from onset of infection
Virally suppressed children have higher proportion of naïve cells (and less memory
cells) than adults
Early Treated Children have More HIV Resistant Cells Possibly Less HIV Persistence than Adults
Ananworanich, AIDS 2014
HIV-NAT 194/RV254 (Chomont, Marssanella, Puthanakit, Ananworanich)
Early treated children vs. adultsEarly treated children
Disulfiram Reactivates Latent HIV
Elliott JH, Deeks S, Lewin SR, Lancet HIV 2015
Prolonged increase in cell-associated and plasma HIV RNA after disulfiram
Cell-associated HIV RNA Plasma HIV RNA
2
0
0
0
m
g
/
d
o
s
e
d
i
s
u
l
f
i
r
a
m
One of the Most Potent Latency Reversing Agents“TLR7 agonist”
in rhesus monkeys
Blood
SIV DNA
LN Gut
Pre and post TLR-7 agonist
Whitney J, 2016 CROI (Abstract 95LB)
Reduced reservoir size in all 3 monkeys and viral remission in 1 of 3 monkeys
Latency Reversing Agent (Romidepsin) plus HIV Vaccine (Vacc-4x/GM-CSF)
M
e
d
i
a
n
t
i
m
e
t
o
V
L
>
5
0
c
o
p
i
e
s
/
m
l
Leth S and Sogaard OS, 2016 CROI
Romidepsin reactivated latent reservoir and significantly reduce HIV DNA (p=0.012)
Vaccine did not generate strong HIV-specific immune responses
Combination did not lead to prolonged time to viral rebound
MH
RP Novel CMV-based vaccine given before exposure
may aid in viral control: SIV/macaque model
Hansen SG, Nature 2011 and 2013
No protection
but
Virus
eradicated in
50%
Controllers
(n=9)
Time post infection (weeks)
Early mucosal immune responses
Broad immune responses that did not target immuno-dominant epitopes
Cell deathViral
clearance
HIV viral load after 3BNC117 antibody
Broadly neutralizing antibody can reduce HIV viremia in people
Ability to reduce reservoir size is not well understood
Broadly Neutralizing Antibody
Caskey M and Nussenzweig M, Nature 2015
VRC01 Broadly Neutralizing Antibody
Barr K and Tebas P, 2016 CROI
0 2 4 6 8 10 12
Weeks post-ATI
100
1000
10000
100000
HIV
-1 R
NA
(c
op
ies
/ml)
14
13
12
10
9
8
7
6
5
4
3
2
1
enrollee
VRC01 antibody did not prevent viral rebound in chronic HIV infection likely due to
pre-existing viral escape (resistance)
VRC01 in virally suppressed people
before and after treatment interruption
Gene therapy to eliminate CCR5
Leukapharesis
CD4+ T-cell isolation
ZFN cut
CCR5 gene
Re-infuse
Tebas P, NEJM 2014
CCR5-
CCR5+
CCR5 gene-editing reduced HIV reservoirs
There was plasma viral load control post ART interruption in people with high
engraftment of CCR5-negative cells (e.g. CCR5 heterozygotes)
Animal Safety Study
6 – 12 months
Combination A
Combination B
Combination C
Combination D
Combination E
ControlCombination A
Combination D
Control
Phase 2 Human Study
Parallel social, behavioral and ethics research ...
12- 24 months
Phase I Human Study
Animal Efficacy Study
12-15 months
12-15 months
Combination A
Combination B
Combination D
Control
A Possible Roadmap to Combination Cure Research for HIV
Ananworanich J and Barre Sinoussi F, Lancet HIV 2015
MH
RP What might HIV remission treatment
look like?
Time
Suppressive
ART
Biomarkers
Repeat doses of immunotherapeutics
Latency modifying agents
ART ART
Cost-effectiveness of HIV Remission Treatment
HIV remission treatment will be
cost effective if $1400 or less 6 months
Remission treatment
ART ≥ 6 monthsVL suppress
High CD4
ART and monitoring
2020 2040
95% controlq 3 mo VL
ART
interruption
Phillips, Lewin, Deeks, Hallett, J Infect Dis 2016
HIV remission interventions would have to be inexpensive and highly effective to be
cost-effective for the general HIV population
VL suppression
RV254 Cohort
Acute HIV Infection
No additional intervention
• Treated Fiebig 1 (RV411)
Single interventions
• VRC01 (RV397)
• Ad26/MVA (RV405)
Combination interventions
• Romidepsin+3BNC117 (RV438)
Low frequency of latently infected
cells in blood/tissue
Preserved HIV-specific immune
responses
HIV Remission Trials in the Thai RV254/SEARCH 010 Participants
Analytical treatment interruption
ART
Goals
Prolong time to viral rebound
Identify biomarkers for viral control without ART
MH
RP What the potential trial Thai participants in RV254
were told about “viral suppression trial”
…participants in the study may be asked to start using an
experimental intervention (like a medicine) and stop
taking their ART.
Researchers don’t have much experience with using the
intervention, how safe it is, and whether it works.
It is not likely that the clinical trial will lead to better
health…..
Jupimai, Kroon, Henderson, Peay (2016 IAS)
65%Personal
benefits1%
71%Scientific
benefits
37%4%
Personal
harm
Definite/big chance No/small chance
2%
Very/somewhat
Not at all likely/not very likely
Stop ART
57%
Take experiment
drug
16%
64%
5%
Jupimai, Kroon, Henderson, Peay (2016 IAS)
Benefit/risk perceptions and intentions among potential remission trial participants (n=229)
The Journey towards HIV Remission
ART
ART
optimization
Combination remission
therapy
Parallel social, behavioral and ethics research ...
Modified from Nicolas Chomont (2015 IAS)
Persistent immune
surveillance
MH
RP
The views expressed are those of the authors and should not be construed to represent the
positions of the U.S. Army or the Department of Defense.
MHRP
Nelson Michael
Merlin Robb
Sodsai Tovanabutra
Suteera Pinyakorn
Lisa Reilly
U Melbourne
Sharon Lewin
U North Carolina
Gail Henderson
Joe Eron
RTI International
Holly Peay
Arthus University
Ole Sogaard
U Pennsylvania
Pablo Tebas
Katharine Barr
RTI International
Holly Peay
Harvard Medical School
James Whitney
Thai Red Cross
Praphan Phanuphak
Nittaya Phanuphak
Nipat Teeratakulpisarn
Mark de Souza
Frits van Griensven
James Fletcher
Eugene Kroon
Donn Colby
Carlo Secdalan
Nitiya Chomchey
Tippawan Pankam
AFRIMS
Robert O’ Connell
Alexandra Schuetz
Sandhya Vasan
Rapee Trichavaroj
Bessara Nantapinit
Siriway Akapirak
U Montréal
Nicolas Chomont
Remi Fromentin
Marta Massanella
RV254 The study
participants
Acknowledgements
ARV sponsorsThai GPO
ViiV HealthcareGileadMerck
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