EARLY ANTIRETROVIRAL TREATMENT

HIV Cure Research Training Curriculum (CUREiculum)Early Antiretroviral (ART) Treatment Module by: Scientific Leads: Dr. Jintanat Ananworanich, U.S. Military HIV Research Program (MHRP)

with input from Sidaction team (France) Community Lead: Jeffrey Taylor, Collaboratory of AIDS Researchers for Eradication (CARE) Contributor: Karine Dubé, CARE The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure research science accessible to the community and the HIV research field.

Last updated April 2015

• Understand why early ART is an important HIV cure

research strategy

• Explain that HIV latency is established very early during

HIV infection

• Describe the Fiebig states during acute HIV infection

• Appreciate that early ART can result in a smaller

reservoir size

• Identify examples of clinical studies involving early ART

Module Objectives

The HIV infection pathway

Natural history of HIV infection

Pantaleo G et al. NEJM, 1993

Why is early ART important?

One of the most effective ways to contain the HIV

reservoir, preserve

immunity and reduce immune

activation

One of the most effective ways to contain the HIV

reservoir, preserve

immunity and reduce immune

activation

May optimize responses to

immune-based interventions

aimed at achieving HIV remission

May optimize responses to

immune-based interventions

aimed at achieving HIV remission

Is essential to prevent sexual transmission of

HIV during acute infection

Is essential to prevent sexual transmission of

HIV during acute infection

May be a critical step in clinical

research towards HIV cure

May be a critical step in clinical

research towards HIV cure

Cell Death

Resting State

HIV persistence

Before HIV Infection

Viral LoadSuppressed

“Shock and Kill”Eliminate Infected CellsVaccine

Chronic HIV Infection

Possible interventions:

• Latency reversing agents

• Broadly neutralizing antibody

• Gene-editing therapy

AcuteHIV Infection

ART

HIV RNA

Strategies to eliminate HIV persistence

When is HIV latency established?

HIV latency (or persistence) is established early in acute HIV

infection in all CD4+ T cell subsets

HIV latency (or persistence) is established early in acute HIV

infection in all CD4+ T cell subsets

These cells carry integrated but transcriptionally silent HIV

viral genome

These cells carry integrated but transcriptionally silent HIV

viral genome

Small number of dormant HIV infected cells (including central and transitional

memory CD4+ T cells) persist indefinitely and are not eliminated by ARV drugs or by the immune system

Small number of dormant HIV infected cells (including central and transitional

memory CD4+ T cells) persist indefinitely and are not eliminated by ARV drugs or by the immune system

HIV persistence is the main barrier to cure

HIV persistence is the main barrier to cure

HIV latency is established in acute HIV infectionLatency persists despite early and long-term ARTPool of latently infected cells is stable with little to no

decay in the presence of long-term ART

When is HIV latency established?

Archin N et al. PNAS, 2011

Establishment of the SIV reservoirs occurred as early as three days post-infection

Treatment with ART 3 days post-SIVmac51 in rhesus macaques blunts viremia (viral RNA and proviral DNA) in the PBMCs but proviral DNA was already detected in tissues

Early ART at Days 3, 7 and 10 reduces the size of the viral reservoirs but does not prevent establishment of viral reservoir

Viral rebound occurred in all animals that were treated at Day 3

When is HIV latency established?

Whitney JB et al. Nature, 2014

What are the Fiebig stages?

Adapted from McMichael AJ, Nature Reviews Immunology, 2010

T0

Limit of detection of assay forPlasma viral RNA

10-

5

10-4 10-3

10-2 10-1

100 101

102

103

104

105

106

107

0 5 10 15 20 25 30 35 40 45 50 70 80 90 100

Vir

us

conce

ntr

ati

on in e

xtra

cellu

lar

fluid

of

pla

sma

(co

pie

s per

ml)

Days following HIV-1 Transmission

Initial infection

Stage 1

Eclipse Phase

What are the Fiebig stages?

Adapted from McMichael AJ, Nature Reviews Immunology, 2010

Eclipse Phase

T0

Reservoir Established

Symptoms Begin

Limit of detection of assay forPlasma viral RNA

10-

5

10-4 10-3

10-2 10-1

100 101

102

103

104

105

106

107

0 5 10 15 20 25 30 35 40 45 50 70 80 90 100

Vir

us

conce

ntr

ati

on in e

xtra

cellu

lar

fluid

of

pla

sma

(co

pie

s per

ml)

Days following HIV-1 Transmission

Y Y

Plas

ma

Vira

l RN

A (c

opie

s pe

r ml)

Days following HIV-1 Transmission

RNA

P24 Antigen

Specific EIA

Possible presenceof P24 Antigen

Present on Western Blot

Y

What are the Fiebig stages?

1 

2 

3 4

YRNA

P24 Antigen

Specific EIA

Possible presenceof P24 Antigen

Present on Western Blot

Y

YSTAGE 1 STAGE 2

STAGE 3 STAGE 4

What are the Fiebig stages?

Earlier ART = smaller reservoir size?

Benefits of early ART is maximal in the first few weeks of infectionBenefits of early ART is maximal in the first few weeks of infection22

But subset of latently infected cells may persist indefinitelyBut subset of latently infected cells may persist indefinitely33

Earlier treatment = smaller reservoir sizeEarlier treatment = smaller reservoir size11

Key points:

What do we measure with total HIV DNA?

Large Very smallSmall

Total HIV DNA

Replication- Competent

Provirus

Integrated HIV DNA

Ho YC et al. Cell, 2014

Ananworanich J et al. Curr Opin HIV/AIDS, 2015

Early ART also alters the distribution of the reservoir in CD4+ T cell subsets

Early ART also alters the distribution of the reservoir in CD4+ T cell subsets

When patients treated during primary infection, the central memory T cells are preserved

When patients treated during primary infection, the central memory T cells are preserved22

ART limits persistence of HIV reservoir in all CD4+ T cell subsets (Chomont)

ART limits persistence of HIV reservoir in all CD4+ T cell subsets (Chomont)

33

Long-lived viral reservoir may be the biggest obstacle to HIV cureLong-lived viral reservoir may be the biggest obstacle to HIV cure11

Key points:

They may support latency through different mechanismsThey may support latency through different mechanisms66

But there is patient-to-patient variabilityBut there is patient-to-patient variability77

Resting CD4+ T cells also have different functional and phenotypic properties

Resting CD4+ T cells also have different functional and phenotypic properties55

When patients treated during primary infection, transitional memory T cells (with short half-life) contribute most to reservoir

When patients treated during primary infection, transitional memory T cells (with short half-life) contribute most to reservoir

44

Long-term ART initiated during AHI key to achieving low HIV reservoirs and normal T cell counts

Patients treated during chronic infection

Patients treated during primary acute infection

Hocqueloux L et al. JAC, 2013

Pivotal clinical early ART studies

Update from Thai Studies:

• Most participant enrolled at Fiebig I and III• Very early ART protects all memory CD4+ T cell subsets from infection,

including long-lived TCM cells• ART in Fiebig I is associated with preservation of poly-functional gut Th17

cells; however, elevated plasma biomarkers of gut repair and microbial translation persist

• Most participant enrolled at Fiebig I and III• Very early ART protects all memory CD4+ T cell subsets from infection,

including long-lived TCM cells• ART in Fiebig I is associated with preservation of poly-functional gut Th17

cells; however, elevated plasma biomarkers of gut repair and microbial translation persist

RV254/SEARCH010: Early ART limits persistence of HIV reservoir in long-lived CD4+ T cell subsetsRV254/SEARCH010: Early ART limits persistence of HIV reservoir in long-lived CD4+ T cell subsets

Nicolas Chomont Updated from Ananworanich J, 2013 CROI

Long-lived central memory

CD4+ T cells

100%

63%

0%

Duration of HIVat ART initiation

Early ART limits persistence of HIV reservoir in long-lived CD4+ T cell subsets (RV254/SEARCH010)

Fiebig I Fiebig I Chronic

Post-treatment control present at sustained remission

Sáez-Cirion et al. PLoS Pathogens, 2013

Viro-Immunological Sustained CONtrol after Treatment Interruption VISCONTI

VISCONTI cohort

Sáez-Cirion et al. PLoS Pathogens, 2013

• Durable control of HIV infection after treatment interruption initiated during primary infection

• Different from HIV controllers (natural viral control = never received treatment)

• Treated within the first 2 months of infection• Able to control viremia without ART > 9 years• Most of VISCONTI patients had no protective HLA class I alleles (but

neutral or high-risk alleles) and weak CD8+ T cell responses (no favorable genetic profile)

• Low HIV DNA level and shorter time to ART initiation from onset of infection predicted post-treatment control (PTC)

• Mechanism of viral control is different between PTC and elite controllers• Need more research to understand the mechanism of viral control

• Durable control of HIV infection after treatment interruption initiated during primary infection

• Different from HIV controllers (natural viral control = never received treatment)

• Treated within the first 2 months of infection• Able to control viremia without ART > 9 years• Most of VISCONTI patients had no protective HLA class I alleles (but

neutral or high-risk alleles) and weak CD8+ T cell responses (no favorable genetic profile)

• Low HIV DNA level and shorter time to ART initiation from onset of infection predicted post-treatment control (PTC)

• Mechanism of viral control is different between PTC and elite controllers• Need more research to understand the mechanism of viral control

VISCONTI CohortVISCONTI Cohort

Pediatric studies: a form of early ART

Long term remissionfor 27 months

30 hours

HIV detected in blood plasma

BIRTH18 m

onths

Begins ART Stops ART

46 months

No HIV detected in blood plasma

23 months

HIV detected in bloodat 2 separate time points

Mississippi child: timeline of events

Persaud D et al. NEJM, 2013Persaud et al. IAS 2014

• Started ART at <2 days of life, remained on ART for 18 months and was able to remain suppressed for 27 months without ART

• Transient but encouraging HIV remission• A remarkable progress for the field:

– Re-affirmed the concept that HIV could persist in latent HIV reservoirs– Evidence that early ART could prolong the time to viral load rebound– Showed that current HIV reservoir test may not be sensitive enough– Showed that only a small number of latently infected cells could

rekindle HIV infection

• Started ART at <2 days of life, remained on ART for 18 months and was able to remain suppressed for 27 months without ART

• Transient but encouraging HIV remission• A remarkable progress for the field:

– Re-affirmed the concept that HIV could persist in latent HIV reservoirs– Evidence that early ART could prolong the time to viral load rebound– Showed that current HIV reservoir test may not be sensitive enough– Showed that only a small number of latently infected cells could

rekindle HIV infection

Mississippi Child Mississippi Child

Pediatric studies: a form of early ART

Ethical and social considerations

How early is “early enough” How early is “early enough”

22

Treatment interruptions not medically recommended (standardized and controlled clinical studies; active and frequent monitoring)Treatment interruptions not medically recommended (standardized and controlled clinical studies; active and frequent monitoring)33

Early ART will not be “curative” (e.g. adults will not be cured by early ART alone; risk of curative misconception) Early ART will not be “curative” (e.g. adults will not be cured by early ART alone; risk of curative misconception)

11

Potential impacts (positive or negative) on interpersonal relationships

Potential impacts (positive or negative) on interpersonal relationships55

Perception of “vulnerability” vs. “healthy” patients (e.g. medical vulnerability vs. how patients perceive themselves) Perception of “vulnerability” vs. “healthy” patients (e.g. medical vulnerability vs. how patients perceive themselves) 44

Implementation challenges

Difficult to identify

people in AHI

Recruitment and time of initiation of

antiretroviral treatment

Patient-to-patient

variability given stochastic nature of rebound

Scalability

Difficult to compare studies

(variable timing of ART initiation and

ways to measure reservoir)

Conclusions and key points

ART started during AHI can limit the size of the HIV reservoir

Treatment in earliest AHI (Fiebig I) may skew distribution of latently infected cells to shorter lived memory CD4+ T cells

HIV persistence established early in AHI in memory CD4+ T cells and can persist indefinitely

ART in AHI may be the first critical step in clinical research aimed at HIV cure/remission

Module collaborators