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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

jananworanich@hivresearch.org

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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%)

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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

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(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

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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