1. Pediatric HIV “Cure” HIV Cure Research Training Curriculum
Pediatric HIV Cure module by: Kaitlin Rainwater-Lovett, PhD, MPH, Priyanka Uprety, and Deborah Persaud, MD
Johns 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.

2. Table of Contents Perinatal HIV Infection
Barrier to Cure: The Latent Reservoir
Antiretroviral Therapy (ART) and the Latent Reservoir
Cases of Virologic Remission
Ethics of ART Cessation
Challenges

3. Perinatal HIV Infection

4. Perinatal HIV Infection
HIV infection that is transmitted from mother to child
3 routes of perinatal HIV transmission
In utero: during the pregnancy
Intrapartum: during delivery
Postpartum: during breastfeeding

5. 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%
Important to remember that mother to child transmission of HIV is preventable with currently available antiretroviral drugs. This should still be our primary focus. Just requires mother knowing her HIV infection status, which requires testing during pregnancy; if negative, needs to maintain barrier protection during pregnancy and the breast-feeding period as risk of transmission is much higher during acute (early) HIV infection in the mother as the viral load is very high during this period.
Antiretroviral therapy (ART) given during pregnancy, during birth and breastfeeding period can prevent HIV transmission from the mother to the baby.
Rollins et al 2012 Sex Transm Infect

6. 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

7. Barrier to Cure:
The Latent Reservoir

8. HIV is not curable: Prompt formation of latent reservoir in long-lived cells
Naïve CD4+ T cell
Activated
CD4+ T cell
- Reservoir expands with delay in treatment
- Virus not expressed
- Cells survive for life
In every infected person, a so-called viral reservoir for HIV forms almost immediately after infection. One reservoir is in a special pool of CD4+ T cells known as memory CD4+ T cells. Memory cells are a key part of your immune system. They allow you body to remember what infections or vaccines you encountered during your life to help protect you for your lifetime.
 GO THRU DIAGRAM
ART and immune system cannot detect infected resting cells to clear HIV
The unique difference in pediatric infection is that this memory cell pool is rapidly expanding in the first few years of life, therefore since we know when babies are exposed to the virus, and since the reservoir expands when virus replication is not controlled, if we can stop the virus from replicating, we can definitely limit the size of the reservoir. Limiting the size of these reservoirs is the fundamental aspect of cure research.
Cell
Death
Cell
Survival
Resting
Memory
CD4+ T cell

9. Latent Reservoir Reactivation
Resting cells can re-activate at a later time. When this occurs, HIV DNA also become activated and creates new virus particles.
If this occurs while an individual is taking effective ART, virus particles cannot infect cells fully to produce more virus.
Importantly, when patients stop taking their ART , these virus particles can re-ignite the infection
Reactivated
CD4+ T cell
Latent Reservoir

10. 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
Relevance for children and youth with longstanding infection

11. Antiretroviral Therapy and the Latent Reservoir

12. Perinatal HIV Infection and Latency
Unique aspect of in utero or intrapartum HIV: Time of exposure is known  Allows for timely intervention
READ SLIDE

13. 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
When mother is HIV+, early ART is highly beneficial to infant

14. Longer ART duration, smaller reservoir
Promising finding: Small study of 4 perinatally-infected 14-18y.o., continuous virologic suppression since infancy (median17yrs)
Reservoir size decreased over time
Also,
Final reservoir sizes of these adolescents <<< 4 perinatally-infected young adults y.o., median10yrs virologic suppression
Longer ART duration assoc’d smaller latent HIV reservoir in memory CD4+ T cells
Luzuriaga et al 2014 J Infect Dis

15. Begin ART earlier, smaller latent reservoir
Very Early
(within 2 days)
Late
(>3 months)
No Treatment
Timing
Of ART Initiation
Early
(3 days to 3 months)
Latent
Reservoir
Viremia
Re-Establishment
Remission
Duration
Minimal
HIV
Exposure
Limited
Arrested
Extensive
Schematic of timing of ART initiation, hypothesized size of latent reservoir, duration of remission following ART discontinuation, capacity of reservoir to re-establish viremia
GO THRU DIAGRAM
Time frames estimated from published literature, some of which we’ll discuss in the upcoming slides
Rainwater-Lovett et al 2015 Curr Opin HIV AIDS

16. Cases of Virologic Remission

17. 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

18. at 2 separate time points
Mississippi Child: Timeline of Events
BIRTH
30 hours
18 months
23 months
46 months
Long term remission
for 27 months
Begins ART
Stops ART
No HIV detected in blood plasma
The only known case of long-term HIV remission in a child
The child was born to an HIV-infected mother who was unaware of her HIV status before giving birth
Within 24 hours of birth, the infant tested positive for HIV by two different tests
The doctor immediately began treating this child with 3 antiretroviral drugs
The child received antiretroviral therapy for the first 18 months of life
At 18 months, ART was stopped against medical advice and the child missed several clinic visits
When the child returned to the clinic at 23 months, doctors and researchers were unable to find HIV in the child’s blood
Multiple blood tests over the next two years were unable to detect HIV
HIV was detected in the child’s blood 28 months after stopping ART and ART was re-started
HIV detected in blood
at 2 separate time points
HIV detected in blood plasma
Persaud et al 2013 NEJM; Luzuriaga et al NEJM

19. Mississippi Child: The Science
The 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
READ SLIDE

20. Mississippi Child: What we learned
Starting 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
READ SLIDE

21. Days to viral rebound after treatment cessation
Virologic Rebound within 14 Days of ART Cessation in 3 Children Treated Within 4 days of birth
Days to viral rebound after treatment cessation
HIV-1 RNA (copies/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)
GO THRU DIAGRAM
Dublin Child:
Started ART immediately after birth and continued for 4 years
Standard HIV diagnostic tests (VL, antibody) were negative for 4 years
ART discontinued, HIV detected one week later
Italian (or Milan) Child:
Started ART within 4 days of birth
Undetectable HIV or immune responses to HIV in blood for 3 years
After hearing of Mississippi Child, doctors stopped ART and closely monitored the child
Canadian Child
HIV-infected child began ART within 24 hours of birth
ART discontinued, but HIV detected in <2 weeks and ART re-started
Series of Canadian children who remain on ART - Physicians and researchers were unable to detect HIV in the blood or cells for years
IN contrast, MS child had >2 years of remission
MS Child’s rebound viremia was quite low compared to the other children
Butler et al Pediatr Infect Dis J; Bitnun et al 2014 CID; Giacomet et al 2014 Lancet; Luzuriaga et al 2015 NEJM

22. 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
3 years
14 days
7,797
Milan Child
152,560
4 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
Latent reservoir size
Viral strain
ART regimen and dose
Butler et al Pediatr Infect Dis J; Bitnun et al 2014 CID; Giacomet et al 2014 Lancet; Luzuriaga et al 2015 NEJM

23. 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
These cases all demonstrate that negative results on standard diagnostic tests are not sufficient evidence for ART discontinuation

24. Ethics of ART Cessation

25. 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?
READ SLIDE
Persaud, Deveikis et al CROI 2014

26. 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) Network
MS child has provided hope and biological plausibility
READ SLIDE

27. 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
READ SLIDE

28. 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
There are a lot of ethical consideration that one needs to keep in mind when conducting clinical trials with focus on attaining ‘functional cure’. One of the main side effects of very early and aggressive treatment could be the toxic side effects of antiretroviral drugs on neonates.
Most importantly to study the effect of early therapy on HIV remission , we would have to take infants off of ART. This can have some other side-effects like it can lead to drug resistance forms of the virus and increase HIV reservoir size which can further preclude cure.
2014 article on ethics of ART discontinuation for children in The Lancet Infect Dis by Shah
Shah et al Lancet Infect Dis

29. 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
Answer:

30. 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?

31. Challenges Implementation of early ART
Early infant HIV diagnosis, particularly in low-income settings
Need 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)
READ SLIDE

32. 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 the need for lifelong ART if combined with immunotherapeutics
READ SLIDE

33. 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
READ SLIDE

34. Acknowledgements The Persaud Lab’s research has been supported by:
NIH – Institutes of Allergy & Infect Dis + Child Health & Human Development
Elizabeth Glazer Pediatric AIDS Foundation
Hopkins CFAR
IMPAACT Network
Doris Duke Foundation
American Foundation for AIDS Research