PEDIATRIC HIV “CURE” HIV Cure Research Training Curriculum Pediatric HIV Cure module by: Kaitlin...
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Transcript of PEDIATRIC HIV “CURE” HIV Cure Research Training Curriculum Pediatric HIV Cure module by: Kaitlin...
PEDIATRIC HIV “CURE”
HIV Cure Research Training Curriculum
Pediatric HIV Cure module by: Kaitlin Rainwater-Lovett, PhD, MPH, Priyanka Uprety, and Deborah Persaud, MDJohns Hopkins University Martha Sichone-Cameron, Community Lead
February 2015
The HIV CURE training curriculum is a collaborative project aimed at making HIV cure research science accessible to the community and the HIV research field.
Table of Contents
Perinatal HIV InfectionBarrier to Cure: The Latent ReservoirAntiretroviral Therapy (ART) and the Latent ReservoirCases of Virologic RemissionEthics of ART CessationChallenges
Perinatal HIV Infection
Perinatal HIV Infection
HIV infection that is transmitted from mother to child
3 routes of perinatal HIV transmission1. In utero: during the pregnancy2. Intrapartum: during delivery3. Postpartum: during breastfeeding
Prevention of Mother-to-Child Transmission (PMTCT)
Mother-to-child transmission of HIV is preventable
Antiretroviral Therapy (ART) for mother during pregnancy + ART for baby after birth prevent HIV transmission from the mother to the baby
ART during breastfeeding prevents transmission through the breast milk
Formula feeding, when safe and affordable, prevents further exposure of the baby to HIV
Risk of perinatal transmission during pregnancy and delivery:When mother does not receive ART: 15-37% of infants acquire HIVWhen mother receives ART that suppresses HIV viral load: 1-4%
Rollins et al 2012 Sex Transm Infect
What are risk factors for mother-to-child transmission?
• Knowledge of HIV status• Acquiring HIV infection during pregnancy• Low CD4 count, high viral load• Maternal ART and infant prophylaxis• Access to care• Stigma
Barrier to Cure: The Latent Reservoir
HIV is not curable: Prompt formation of latent reservoir in long-lived cells
Resting Memory
CD4+ T cell
ActivatedCD4+ T cell
HIV
CellDeath
Latent Reservoir
Naïve CD4+ T cell
CellSurvival
- Reservoir expands with delay in
treatment- Virus not expressed- Cells survive for life
Latent Reservoir Reactivation
Latent Reservoir ReactivatedCD4+ T cell
Approaches to HIV CureDrugs that reactivate HIV-infected resting cells Latency reversing agents
Genetic modification of CD4+ T cells to prevent HIV entry and replicationZinc-finger nucleases: delete part of CCR5 co-receptor
Boosting the immune system to kill residual virus expressing cellsTherapeutic vaccines; Broadly neutralizing antibodies
Early ART initiation to limit the size of the reservoir
Antiretroviral Therapyand the Latent Reservoir
Perinatal HIV Infection and Latency
Unique aspect of in utero or intrapartum HIV: Time of exposure is known Allows for timely intervention
http://birthwithoutfearblog.com/2012/01/31/the-beauty-of-pregnant-women/
Early ART is Life-Saving
Decreases morbidity and mortalityReduces the size of the latent HIV reservoirFirst step to long-term remissionMay permit ‘functional cure’ when combined with immune-based therapies
Control of HIV in the absence of ART
Longer ART duration, smaller reservoir
0 5 10 15 200.0
0.5
1.0
1.5
2.0
P-1042
Age (yrs)
log
10
DN
A c
op
ies
/ 10
6 PB
MC
0 5 10 15 200.0
0.5
1.0
1.5
2.0
P-1043
Age (yrs)
log
10
DN
A c
op
ies
/ 106 P
BM
C
0 5 10 15 200.0
0.5
1.0
1.5
2.0
P-1048
Age (yrs)
log
10
DN
A c
op
ies
/ 10
6 PB
MC
0 5 10 15 200.0
0.5
1.0
1.5
2.0
P-1049
Age (yrs)
log
10
DN
A c
op
ies
/ 10
6 PB
MC
Luzuriaga et al 2014 J Infect Dis
Begin ART earlier, smaller latent reservoir
Rainwater-Lovett et al 2015 Curr Opin HIV AIDS
Very Early(within 2 days)
Late(>3 months)
No Treatment
Timing Of ART Initiation
Early (3 days to 3 months)
LatentReservoir
Viremia Re-Establishment
RemissionDuration
MinimalHIV
Exposure
LimitedHIV
Exposure
ArrestedHIV
Exposure
ExtensiveHIV
Exposure
Cases of Virologic Remission
The Mississippi Child
Well-known case of perinatal HIV remission
How does cure and long-term remission occur?
Persaud et al 2013 NEJM; Luzuriaga et al 2015 NEJM
Long term remission
for 27 months
30 hours
HIV detected in blood plasma
BIRTH
18 month
s
Begins ART Stops ART
46 month
s
No HIV detected in blood plasma
23 month
s
HIV detected in bloodat 2 separate time points
Mississippi Child: Timeline of Events
Persaud et al 2013 NEJM; Luzuriaga et al 2015 NEJM
Mississippi Child: The ScienceThe inability to detect HIV in blood plasma while the child was not receiving ART is called long-term remission
Detection of HIV after long-term remission in the absence of any immune response to HIV shows that the child had a dormant reservoir
The close match to the mother’s virus supports HIV latency prevented cure
Mississippi Child: What we learnedStarting ART very early in the time course of HIV infection likely led to few HIV-infected cells that could become dormant
The small number of dormant cells took more than 2 years to re-kindle HIV infection
This permitted long-term HIV remission but not cure
Virologic Rebound within 14 Days of ART Cessation in 3 Children Treated Within 4 days of birth
Butler et al 2014 Pediatr Infect Dis J; Bitnun et al 2014 CID; Giacomet et al 2014 Lancet; Luzuriaga et al 2015 NEJM
Days to viral rebound after treatment cessation0
HIV
-1 R
NA
(co
pie
s/m
L)
14
Dublin Child (8 days; VL=11,230 c/ml))
Canadian Child (14 days; VL=7797 c/ml)
828
Mississippi Child (828 days; VL=16 copies/ml)
Milan Child (14 days; VL 36,840 c/ml)
What could explain differences between Mississippi Child’s prolonged duration of remission and other children’s faster rebounds?
Case Initial VL(c/mL)
ART Initiation
ART Duration
Remission Duration
Rebound VL
Mississippi Child
19,812 30 hours 18 months 27 months 16
Dublin Child 653 <24 hours 4 years 8 days 11,230
Canadian Child
808 <24 hours 3 years 14 days 7,797
Milan Child 152,560 4 days 3 years 14 days 36,840
• Stage of in-utero infection• Viral load of mother• HIV exposure duration and VL• Genetic differences in immune
response• ART adherence• Co-infections
Butler et al 2014 Pediatr Infect Dis J; Bitnun et al 2014 CID; Giacomet et al 2014 Lancet; Luzuriaga et al 2015 NEJM
• Latent reservoir size• Viral strain• ART regimen and dose
Perinatal Remission StoriesAll started ART within hours of birth
None had detectable HIV in blood by standard clinical or ultrasensitive assays
None had immune responses to HIV
Those who stopped ART experienced viral rebound
Ethics of ART Cessation
Long Beach ChildStarted ART within 4 hours of birth
Undetectable HIV and immune responses to HIV in blood for >9 months, BUT
Child remains on ART
This case highlights that very early therapy can limit the reservoir in early infancy
Unclear if child is capable of long-term remission
Given other cases of rebound viremia, ethical concerns with ART cessation?
Persaud, Deveikis et al CROI 2014
Perinatal HIV Remission Cases and Biological Plausibility
Potential benefit to millions of perinatally-infected infants, children and adolescents
Justifies development of clinical trial to test whether very early ART can lead to long-term remission
Organized by the International Maternal and Perinatal Adolescent AIDS Clinical Trials (IMPAACT) Networkwww.ImpaactNetwork.org
IMPAACT P1115 Trial
Study Objective: To study HIV remission (48 or more weeks off ART) among HIV-infected neonates who begin ART within 48 hours of birth
Design: Small, proof-of-concept exploratory study in US, sub-Saharan Africa, and Thailand
Ethics of Empiric ARTEthical consideration of ‘functional cure’ regimen for neonates:
Very early treatment with aggressive drug regimen can have toxic side effects
Therapy discontinuation to assess remission can lead to:
Drug resistanceIncreased HIV reservoir size
Shah et al. 2014 Lancet Infect Dis
What could be other ethical implications of very early ART initiation?
• Consent during labor and delivery• Pressure to discontinue ART• Drug fatigue in adolescence• Frequency of viral rebound assessment• Ability to emotionally support parents
Many Remaining Questions
How early is early enough for ART initiation?
What biomarkers should be used to indicate ART cessation? HIV remission?
What duration of remission is appropriate to refer to one as cured?
ChallengesImplementation of early ART
Early infant HIV diagnosis, particularly in low-income settingsNeed for point-of-care diagnostic tests
Low blood volumes restrict ability to study perinatal HIV remission as thoroughly as adults
Reservoirs in other bodily sites (e.g., central nervous system, gastrointestinal tract)
Conclusions for InfantsVery early ART to achieve HIV remission in perinatal infection:
Biologically plausible, as shown by the Mississippi ChildPotential for widespread global implementation given existing structure for delivery of PMTCTPotential to further lengthen HIV remission and the need for lifelong ART if combined with immunotherapeutics
Conclusions for Older Children and Youth
Need immunotherapeutic interventions that are safe and plausible for HIV-infected adults
Some will have the advantage of low reservoir size from long-term virologic control
Most will benefit from the capacity of the immune response to reconstitute due to thymic reserve
Acknowledgements