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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. Pediatric HIV Cure Research HIV Cure Research Training Curriculum Pediatric HIV Cure Research Presented by: Priyanka Uprety,MSPH, PhD Laboratory of Deborah Persaud, MD Johns Hopkins University July 2016

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Page 1: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

TheHIVCUREresearchtrainingcurriculumisacollaborativeprojectaimedatmakingHIVcureresearchscienceaccessibletothecommunityandtheHIVresearchfield.

Pediatric HIV Cure ResearchHIV Cure Research Training Curriculum

Pediatric HIV Cure Research

Presented by: Priyanka Uprety,MSPH, PhD

Laboratory of Deborah Persaud, MD Johns Hopkins University

July 2016

Page 2: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Objectives

●Understand the current state of HIV cure research in pediatric populations

●Summarize the challenges of working with pediatric populations

●Explain the major cases of virologicremission

Page 3: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What is an HIV Cure?

How Do We Define “Cure”?

Page 4: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

How Do We Define “Cure”?

●Sterilizing/Eradication-● HIV is completely removed from every cell in the

body ● Person is HIV-free (virus free)● No need for medication

●Functional/Remission-● HIV is NOT completely gone from the body ● All requirements from previous slide met● No need for medication● HIV has potential to resurface

Page 5: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What is an HIV Cure?

Why is HIV so Hard to Cure?

Page 6: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Why is HIV so Hard to Cure?

●HIV enters a cell and integrates into the cell’s DNA

●Most cells recognize infection - causing cell death

●A few infected cells become “long-lived” memory cells or “resting memory” cells

●The collection of long-lived memory cells is called the Latent Reservoir

Page 7: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Why is HIV so Hard to Cure?

Page 8: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Why is it so Hard to Cure HIV: Establishing the Latent Reservoir

ActivatedCD4+ T cell

HIV

Naïve CD4+ T cell

Adapted from D. Persaud

Page 9: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Why is it so Hard to Cure HIV: Establishing the Latent Reservoir

ActivatedCD4+ T cell

HIV

CellDeath

Naïve CD4+ T cell

Adapted from D. Persaud

Page 10: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Why is it so Hard to Cure HIV: Establishing the Latent Reservoir

Resting Memory

CD4+ T cell

ActivatedCD4+ T cell

HIV

CellDeath

Naïve CD4+ T cell

CellSurvival

Adapted from D. Persaud

Page 11: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Why is it so Hard to Cure HIV: Establishing the Latent Reservoir

Resting Memory

CD4+ T cell

ActivatedCD4+ T cell

HIV

CellDeath

Latent Reservoir

Naïve CD4+ T cell

CellSurvival

Adapted from D. Persaud

Page 12: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Why is it so Hard to Cure HIV: Establishing the Latent Reservoir

Latent Reservoir ReactivatedCD4+ T cell

Adapted from D. Persaud

Page 13: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Why is it so Hard to Cure HIV: Establishing the Latent Reservoir

Latent Reservoir ReactivatedCD4+ T cell

Adapted from D. Persaud

Page 14: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Approaches to HIV Cure

● Drugs that reactivate HIV-infected resting cells ● Latency reversing agents

● Genetic modification of CD4+ T cells to prevent HIV entry and replication● Zinc-finger nucleases: delete part of CCR5 co-

receptor

● Boosting the immune system to kill residual virus expressing cells● Therapeutic vaccines; Broadly neutralizing

antibodies

● Early ART initiation to limit the size of the reservoir

Page 15: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Difference Between Adults and Children?

Infants have unique immune systems that:● Discourage the inflammatory response●Have fewer long lived memory cells●Increased immune activation after birth can

increase risk of infectionAdults have immune systems:●Increased long lived memory cells from long term

exposure to pathogens●Increased number of differentiated cells

Page 16: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Perinatal HIV Infection

●HIV infection that is transmitted from mother to child

●Three routes of perinatal HIV transmission● In utero: during the pregnancy● Intrapartum: during delivery● Postpartum: during breastfeeding

Page 17: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Perinatal HIV Infection and Latency

Unique aspect of in utero orintrapartum HIV●Time of exposure is known

●Allows for timely intervention

Page 18: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What is an HIV Cure?

What are risk factors for mother-to-child transmission?

Page 19: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

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

Page 20: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

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

HIV● When mother receives ART that suppresses HIV viral load: 1-4%

Rollins et al 2012 Sex Transm Infect

Page 21: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Early ART is Life-Saving

●Decreases morbidity and mortality●Reduces the size of the latent HIV

reservoir●First step to long-term remission●May permit ‘functional cure’ when

combined with immune-based therapies● Control of HIV in the absence of ART

Page 22: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Longer ART Duration, Smaller Reservoir

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Luzuriaga et al 2014 J Infect Dis

Page 23: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Early ART in Infants

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

Page 24: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What is an HIV Cure?

Mississippi Child

Page 25: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Mississippi Child

●HIV-positive at birth●Started triple drug therapy 30 hours after

birth●Lost to follow-up and returned into care

after 18 months off treatment●Remained off treatment with no

detectable virus for 27 months●Rebounded and successfully restarted

treatment at 28 months post-treatment

Page 26: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Mississippi Child

Long term remissionfor 27 months

HIV detected in blood plasma

Begins ART Stops ART

No HIV detected in blood plasma

HIV detected in bloodat 2 separate time points

Persaud et al 2013 NEJM; Luzuriaga et al 2015 NEJM

Page 27: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What Can We Learn From the Mississippi Child?

●Proof that sustained viral remission is possible

●Early treatment prevented a large viral reservoir from forming

●Even a small amount of reservoir cells can reestablish infection

Page 28: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What is an HIV Cure?

Other Cases of Pediatric Viral Suppression

Page 29: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Long Beach Child

● Started 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

Page 30: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Cases of Short Virologic Remission

Days to viral rebound after treatment cessation0

HIV

-1 R

NA

(cop

ies/

mL)

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)

Butler et al 2014 Pediatr Infect Dis J; Bitnun et al 2014 CID; Giacomet et al 2014 Lancet; Luzuriaga et al 2015 NEJM

Page 31: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What Makes the Mississippi Child Different?

Case Initial VL(c/mL)

ART Initiation

ART Duration

Remission Duration

ReboundVL

Mississippi Child

19,812 30 hours 18 months 27 months 16

Dublin Child 653 <24 hours 4 years 8 days 11,230Canadian Child

808 <24 hours 3 years 14 days 7,797

Milan Child 152,560 4 days 3 years 14 days 36,840

Butler et al 2014 Pediatr Infect Dis J; Bitnun et al 2014 CID; Giacomet et al 2014 Lancet; Luzuriaga et al 2015 NEJM

Page 32: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What Makes the Mississippi Child Different?

● Stages of in-utero infection

● Viral load of mother

● HIV Exposure duration and viral load

● Genetic differences in immune response

● ART adherence Co-infections

● Latent reservoir size

● Viral strain

● ART regimen and dose

Page 33: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What is an HIV Cure?

Post-Treatment Control

Page 34: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

The VISCONTI Child

●ART initiated at 3 months●Two separate episodes of ART non-

adherence in the second year that resulted in viral rebound

●ART discontinued a third time with sustained viral suppression

●Small viral blips at 11 years old and 13 years old

●Remains a post-treatment controller

Page 35: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Innate Ability to Control HIV in Adults

Elite Controllers● Individuals who can:

● control their virus- sometimes to undetectable levels- without antiretroviral treatment

● They generally have regular CD4 and CD8 counts.

Long Term Non-Progressors● Individuals who may:

● have low levels of virus but maintain normal T-cell counts with no disease progression

Page 36: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Perinatal Remission Stories

●All 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

Page 37: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Ethics of Empiric ART

Ethical 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 resistance• Increased HIV reservoir size

Shah et al. 2014 Lancet Infect Dis

Page 38: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What is an HIV Cure?

What Are Other Ethical Considerations?

Page 39: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

What Are Other Ethical Considerations?

●Consent during labor and delivery●Pressure to discontinue ART●Drug fatigue in adolescence●Frequency of viral rebound assessment●Ability to emotionally support parents

Page 40: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

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”?

Page 41: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Challenges

●Implementation of early ART● Early infant HIV diagnosis, particularly in

low-income settings● Need for point-of-care diagnostic tests

●Low blood volumes

●Treatment cessation

●Reservoirs other than blood● Sampling challenges in bodily sites

Page 42: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Conclusions for Infants

Very early ART to achieve HIV remission in perinatal infection:●Biologically plausible, as shown by the

Mississippi Child●Potential for widespread global

implementation given existing structure for delivery of PMTCT

●Potential to further lengthen HIV remission and/or encourage post-treatment control

Page 43: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

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 virologiccontrol

●Most will benefit from the capacity of the immune response to reconstitute due to thymic reserve

Page 44: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Acknowledgements

Page 45: pediatric cure SLIDES - AVAC · The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure ... All requirements from previous slide met ... delivery

Questions

www.avac.org/CUREiculumFor additional information visit:

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