HIV Cure Research Training Curriculum CUREiculum Early Antiretroviral ART Treatment Module by Scientific Leads Dr Jintanat Ananworanich US Military HIV Research Program MHRP ID: 226570
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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 2015Slide2
Understand why early ART is an important HIV cure research strategy
Explain that HIV latency is established very early during HIV infectionDescribe the Fiebig states during acute HIV infectionAppreciate that early ART can result in a smaller reservoir sizeIdentify examples of clinical studies involving early ART Module Objectives Slide3
The HIV infection pathwaySlide4
Natural
history of HIV infection Pantaleo G et al. NEJM, 1993Slide5
Why is early ART important?
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
Is essential to prevent sexual transmission of HIV during acute infection
May be a critical step in clinical research towards HIV cureSlide6
C
ell Death
R
esting
S
tate
HIV persistenceSlide7
Before
HIV InfectionViral LoadSuppressed“Shock and Kill”Eliminate Infected Cells
Vaccine
Chronic
HIV Infection
Possible interventions:
Latency reversing agents
Broadly neutralizing antibody
Gene-editing therapy
Acute
HIV Infection
ART
HIV RNA
Strategies to eliminate HIV persistenceSlide8
When is HIV latency established?
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
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 cureSlide9
HIV latency is established in acute HIV infection
Latency persists despite early and long-term ARTPool of latently infected cells is stable with little to no decay in the presence of long-term ARTWhen is HIV latency established?Archin N et al. PNAS, 2011Slide10
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 tissuesEarly ART at Days 3, 7 and 10 reduces the size of the viral reservoirs but does not prevent establishment of viral reservoirViral rebound occurred in all animals that were treated at Day 3When is HIV latency established?Whitney JB et al. Nature, 2014Slide11
What are the
Fiebig stages?Adapted from McMichael AJ, Nature Reviews Immunology, 2010
T
0
Limit of detection of assay for
Plasma viral RNA
10
-5
10
-4
10
-3
10
-2
10
-1
10
0
10
1
10
2
10
3
10
4
10
5
10
6
10
7
0
5
10
15
20
25
30
35
40
45
50
70
80
90
100
Virus concentration in extracellular fluid of plasma
(copies per ml)
Days following HIV-1 Transmission
Initial
infection
Stage 1
Eclipse PhaseSlide12
What are the
Fiebig stages?Adapted from McMichael AJ, Nature Reviews Immunology, 2010
Eclipse Phase
T
0
Reservoir Established
Symptoms Begin
Limit of detection of assay for
Plasma viral RNA
10
-5
10
-4
10
-3
10
-2
10
-1
10
0
10
1
10
2
10
3
10
4
10
5
10
6
10
7
0
5
10
15
20
25
30
35
40
45
50
70
80
90
100
Virus concentration in extracellular fluid of plasma
(copies per ml)
Days following HIV-1 TransmissionSlide13
Y
Y
Plasma Viral RNA (copies per ml)
Days following HIV-1 Transmission
RNA
P24 Antigen
Specific EIA
Possible presence
of P24 Antigen
Present on
Western Blot
Y
What are the
Fiebig
stages?
1
2
3
4Slide14
Y
RNA
P24 Antigen
Specific EIA
Possible presence
of P24 Antigen
Present on
Western Blot
Y
Y
STAGE 1
STAGE 2
STAGE 3
STAGE 4
What are the
Fiebig
stages?Slide15
Earlier ART = smaller reservoir size?
Benefits of early ART is maximal in the first few weeks of infection
2
But subset of latently infected cells may persist indefinitely
3
Earlier treatment = smaller reservoir size
1
Key points: Slide16
What do we measure with total HIV DNA?
Large
Very small
Small
Total
HIV DNA
Replication-
C
ompetent
Provirus
Integrated
HIV DNA
Ho YC
et al
.
Cell
, 2014Slide17
Ananworanich
J et al. Curr Opin HIV/AIDS, 2015Early ART also alters the distribution of the reservoir in CD4+ T cell subsetsSlide18
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
2
ART limits persistence of HIV reservoir in
all
CD4+ T cell subsets (
Chomont
)
3
Long-lived viral reservoir may be the biggest obstacle to HIV cure
1
Key points:
They may support latency through different mechanisms
6
But there is patient-to-patient variability
7
Resting CD4+ T cells also have different functional and phenotypic properties
5
When patients treated during primary infection, transitional memory T cells (with short half-life) contribute most to reservoir
4Slide19
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
, 2013Slide20
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 T
CM
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 subsetsSlide21
Nicolas
Chomont Updated from Ananworanich J, 2013 CROILong-lived central memoryCD4+ T cells100%63%
0%
Duration of HIV
a
t ART initiation
Early ART limits persistence of HIV reservoir in long-lived CD4+ T cell subsets (RV254/SEARCH010)
Fiebig
I
Fiebig I ChronicSlide22
Post-treatment control present at
sustained remission Sáez-Cirion et al. PLoS Pathogens, 2013V
iro
-
I
mmunological
S
ustained
CON
trol
after
T
reatment Interruption VISCONTI Slide23
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
VISCONTI
CohortSlide24
Pediatric studies: a form of early ARTSlide25
Long term remission
for 27 months
30 hours
HIV detected in blood plasma
BIRTH
18 months
Begins ART
Stops ART
46
months
No HIV detected in blood plasma
23
months
HIV detected in blood
at 2 separate time points
Mississippi child: timeline of events
Persaud
D
et al
.
NEJM
, 2013
Persaud
et al
. IAS 2014Slide26
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
Pediatric studies: a form of early ARTSlide27
Ethical and social considerations
How early is “early enough”
2
Treatment interruptions not medically recommended
(standardized and controlled clinical studies; active and frequent monitoring)
3
Early ART will not be “curative”
(e.g. adults will not be cured by early ART alone; risk of curative misconception)
1
Potential impacts (positive or negative) on interpersonal relationships
5
Perception of “vulnerability” vs. “healthy” patients
(e.g. medical vulnerability vs. how patients perceive themselves)
4Slide28
Implementation challenges
Difficult to identify people in AHIRecruitment and time of initiation of antiretroviral treatment
P
atient-to-patient variability given stochastic nature of rebound
Scalability
Difficult
to compare studies (variable timing of ART initiation and ways to measure reservoir)Slide29
Conclusions and key points
ART started during AHI can limit the size of the HIV reservoirTreatment 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 Slide30
Module collaborators