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