Lifelong Monitoring of HIV-Exposed

Uninfected Infants is Jennifer Jao, MD, MPH

Icahn School of Medicine at Mount Sinai

CRUCIAL!

Increasing numbers of HEUs Worldwide

0

200.000

400.000

600.000

800.000

1.000.000

1.200.000

1.400.000

1.600.000

1.800.000

2002 2004 2006 2008 2010 2012

New HIV+ infections in children

HIV+ pregnant women requiring ARVs for PMTCT

UNAIDS 2013: AIDS by the numbers.

Increasing numbers of HEUs Worldwide

0

200.000

400.000

600.000

800.000

1.000.000

1.200.000

1.400.000

1.600.000

1.800.000

2002 2004 2006 2008 2010 2012

New HIV+ infections in children

HIV+ pregnant women requiring ARVs for PMTCT

UNAIDS 2013: AIDS by the numbers.

Do we need long term monitoring of HEUs?

“Follow-up of children with

exposure to ARVs should continue

into adulthood because of the

theoretical concerns regarding the

potential for carcinogenicity of

nucleoside analogue ARV drugs……….

Information regarding such exposure

should be part of ongoing

permanent medical records for

children, particularly those who are

uninfected.” (DHHS Panel on

Treatment of HIV-Infected Pregnant

Women and Prevention of Perinatal

Transmission, 2014)

“Long term follow up of symptomatic children

may be justified and should be guided by best

clinical practices. Families should alert the

child’s physician and/or the physician who

treated the child during the first months of life of

any significant clinical events.” (Medical

Management of Persons Living with HIV, Report

from Expert Panel of CNS and ANRS, 2013)

“…the potential long-term toxicity in healthy exposed

infants and the continuing emergence of new ARVs

make it advisable to devise a mechanism whereby the

identification and registration of potential adverse

long-term effects of such exposures may be

recorded..” (Recommendations by the Spanish Society

of Pediatric Infectious Diseases for the follow up of

the child exposed to HIV and to ARV drugs during

pregnancy and the neonatal period, 2012)

Drug/ Toxin, Stress, Infection

Reorganization/ Adaptation

Cellullar Epigenetic Organ

In utero milieu and Fetal Programming have lasting effects

Risk for Chronic Disease

Later in Life

Maternal Infection Drug/Toxin

Example:

Influenza,

Toxoplasmosis

Example:

Diethylstilbestrol

Metabolic Changes

Example:

IUGR

Schizophrenia

Insulin resistance,

Type 2 DM, CV

Disease Cervical, Vaginal, Breast

Cancer; Infertility

In Utero

HIV/ARV

Exposure

Preterm Birth

SGA

Mitochondrial

Toxicity

Metabolic

Complications?!

Cardiovascular

Disease?!

Mental Health

Problems?!Genotoxicity

Malignancy?!

Neurologic/

Cognitive

Complications?!

Diabetes?!

Poor Bone

Health?!

Short and Long Term Concerns for In Utero HIV/ARV Exposure

Congenital

anomalies

HIV/ARV is associated with Preterm Birth

Authors Cohort Sample size

Finding

Cotter et al 2006 JID U.S. 999 Increased risk with PI vs. non-PI

Sibiude et al 2012 CID French Perinatal Cohort 1253 Increased risk with boosted PI

Lopez et al 2012 AIDS Spain 1557 Increased risk with HIV exposure;

Increased risk with cART

Watts et al 2013 JID PHACS 1869 Increased risk with 1st trimester PI

ECS 2000 AIDS European Collborative

Study and Swiss

Mother+Child Cohort

3920 Increased risk with cART (PI and non-PI

based)

Increased risk with 1st trimester cART

Schulte et al 2007

Pediatrics

U.S. 8793 Increased risk with PI

Townsend et al 2010

BJOG

Pediatric Spectrum of

HIV Disease, European

Collaborative Study,

National Study of HIV in

Pregnancy and

Childhood

19,585 Increased risk with cART

Chen et al 2012 JID Botswana 33,148 Increased risk with HIV exposure;

increased risk with cART

n=19,585

Pediatric Spectrum of HIV Disease, European Collaborative

Study, National Study of HIV in Pregnancy and Childhood

Townsend C et al BJOG 2010

n=19,585

Pediatric Spectrum of HIV Disease, European Collaborative

Study, National Study of HIV in Pregnancy and Childhood

Townsend C et al BJOG 2010

“By the time HEU’s are

diagnosed as HEU’s at 4

months, most of the

significant medical issues

they might have such as

prematurity, low birth

weight, and congenital

defects are already

identified and managed

appropriately.”

SGA/Preterm Birth have long-lasting sequelae:

Adult Metabolic and Cardiovascular Disease

Author Study Finding

Barker et al 1989 Lancet Cohort Low BW associated with death from

ischemic heart disease in adulthood

De Jong et al 2012

Hypertension

Meta analysis Preterm birth and VLBW are

associated with HTN in adulthood

Hofman et al 2006

NEJM

Cohort Preterm birth is associated with

insulin resistance in adulthood

Rotteveel et al 2009

Pediatrics

POPS cohort Preterm birth is associated with

insulin resistance and HTN in

adulthood

Whincup et al 2008 JAMA Pooled

analysis

Lower BW and SGA are associated

with insulin resistance in adulthood

Lawlor et al 2006

Diabetologia

Cohort BW and GA are inversely associated

with diabetes in adulthood

In utero HIV/ARV perturbs intermediary metabolism

DIRECTLY, independent of SGA/ prematurity

Abnormal Fatty-Acid Oxidation in HIV-Exposed Uninfected Neonates in the United States. Kirmse B, Yao T, Hofher S, Williams P, Kacanek D, Hazra R, Borkowsky W, Van Dyke R, Summar M. CROI 2014; Boston.

Preterm Birth is well-documented to cause

neurocognitive sequelae

In Utero HIV/ARV exposure may confer an independent

risk for neurocognitive dysfunction later in life

Preterm Birth is well-documented to cause

neurocognitive sequelae

In Utero HIV/ARV exposure may confer an independent

risk for neurocognitive dysfunction later in life

Preterm Birth is well-documented to cause

neurocognitive sequelae

In Utero HIV/ARV exposure may confer an independent

risk for neurocognitive dysfunction later in life

Preterm Birth is well-documented to cause

neurocognitive sequelae

In Utero HIV/ARV exposure may confer an independent

risk for neurocognitive dysfunction later in life

Not all congenital defects are evident at birth.

Among 12,888 children, 1st

trimester AZT exposure was

significantly associated with

CHD (aOR=2.2; CI=1.3-3.7).

Not all congenital defects are evident at birth.

Among 12,888 children, 1st

trimester AZT exposure was

significantly associated with

CHD (aOR=2.2; CI=1.3-3.7).

In utero HIV/ARV is associated with

mitochondrial toxicityAuthors Study Sample

sizeFindings

Poirier et al 2003 WITS 30 Decreased mtDNA

Ross et al 2011 U.S. 46 Abnormal mtDNA levelsDecreased Complex II:IV

Gingelmaier et al 2009

Germany 77 Decreased mtDNADecreased Complex II:IV

Aldrovandi et al 2010

WITS, PACTG 1009

624 Abnormal mtDNA levels

Côté et al 2008 Canada 154 Increased mtDNA levelsAbnormal mitochondrial gene expression

McComsey et al 2008

ACTG 5084 136 Increased mtDNA levels

Torres et al 2009 U.S. 108 Increased mitochondrial mutations

In utero HIV/ARV is Associated with Clinically

Significant Mitochondrial Dysfunction

18 month incidence of

neuro-mitochondrial

disease was 0.26% (95% CI:

0.10 – 0.54) in HIV-exposed

children compared to 0.01%

in the general pediatric

population

In utero tenofovir exposure affects

postnatal growth and bone mineral content

CID June 2015 epub print

HEU’s have high rates of mental health problems

Mental health problems were

more prevalent in HEU children

than HIV-infected children

(38 vs. 25%, p<0.01) in the PHACS

cohort

Amongst HEUs, the prevalence

of any psychiatric disorder (57%)

remained high and mood

disorders INCREASED (4.4-8.8%,

p<0.05) over time compared to

HIV-infected children in the

CASAH cohort.

Both AZT and TDF confer genotoxicity

Elevations in GPA

N/N variants

persisted even up

to 1 year of age.

Both AZT and TDF confer genotoxicity

Frequency of aneuploidy

was significantly higher

with AZT exposure, but

both AZT and TDF

exhibited altered gene

expression for DNA repair

and telomere maintenance

pathways.

p<0.05

“Lifelong follow-up will

increase stigma to HEU

infants.”

Stigma is a small price to pay if lifelong

follow-up uncovers a serious late

adverse effect of in utero HIV/ARV

exposure!

“Lifelong follow up may not be

warranted in all settings. With

the scale up of PMTCT and

Pediatric ART programs there are

already competing resources in

resource-limited settings.”“Given that the HIV burden in women is greatest in

resource-constrained countries where rapid expansion in ARV

use in pregnancy is expected with implementation of WHO

guidelines, there is an ethical imperative to systematically

and critically evaluate the safety of these recommendations

for the fetus/infant both in terms of potential

teratogenicity but also long term outcomes.”

Mofenson LM & Watts DH. 2014. PLOS Medicine

Vote YES! for long term follow up of HEUs

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