Challenges in PediatricsTaking Toddlers to Teens and Beyond

Lynne M. Mofenson, M.D.Maternal and Pediatric Infectious Disease Branch

Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of Health

Topics to Discuss

Infants– Early treatment– Viral reservoir

Perinatally-infected adolescents‒ Complications‒ Transition

Infants

How Early Must Early ART Be?

Importance of Early Therapy in HIV-Infected Infants

• We know that early ART – in the first 3 months of life – significantly decreases morbidity and mortality.

Probability of Death

Probability of Death or Progression

75% Reduction in Mortality:4% vs 16% for

Early vs Deferred ART

77% Reduction in Death/Progression:

6% vs 26% forEarly vs Deferred ART

N= 14 53 77

Proviral Load (copies/million PBMCs)

[IQR]

4.2 [2.6, 8.6]

19.4 [5.5, 99.8]

70.7 [23.2, 70.7]

144 Youth with Perinatal

Infection and Suppressed

Virus in PHACS

Median Age: 14.3 Yrs

Median cART duration: 10.2 yrs

<1 yr old 1-5 yrs old >5 yrs oldAge at Virologic Control:

HIV

DN

A (

copi

es/m

illio

n P

BM

Cs) <1 yr >5 yr

Proviral Reservoir Size & Age at Virologic Control in Perinatal Youth

Early Treatment Restricts the Proviral Reservoir

Persaud D et al. JAMA Pediatr 2014;in press

However - Sustained Elevation of Immune Activation Markers Regardless of Starting ART Age <1 Yr with Durable Suppression

Persaud D et al. JAMA Pediatr 2014;in press

0.0

1.0

2.0

3.0

soluble CD14 (x106pg/ml)

GMCSF (pg/ml) IL-1beta (pg/ml)

< 1 yr (N=14) 1-5 yrs (N=53) >5 yrs (N=77) HIV-exposed uninfected

P-value PHIV+ vs HEU: <0.001 <0.001 0.004

However - Sustained Elevation of Immune Activation Markers Regardless of Starting ART Age <1 Yr with Durable Suppression

Persaud D et al. JAMA Pediatr 2014;in press

0.0

1.0

2.0

3.0

soluble CD14 (x106pg/ml)

GMCSF (pg/ml) IL-1beta (pg/ml)

< 1 yr (N=14) 1-5 yrs (N=53) >5 yrs (N=77) HIV-exposed uninfected

P-value PHIV+ vs HEU: <0.001 <0.001 0.004

Early ART (starting <1 year) led to

smaller proviral reservoir but did

not reverse immune activation

(elevated in all 3 groups vs HIV-

exposed uninfected controls)

Restricted Viral Reservoir with Early ART: ThailandAnanworanich J et al. AIDS 2014;28:1015-20

15 children, median 6.3 yrs, who started ART age <6 mos (median 17 wks); median duration viral suppression 6 years.

Early ART results in restricted viral reservoir

Restricted immune response: 93% had no HIV-specific CD4 or CD8 response

47% non-reactive on EIA

Median 17 copies/106 132 copies/106 None detectable

60% had <20 c/106

Latent CD4 Reservoir Dynamics in Infants Starting ART Age <6 Months - Lower Reservoir if Starting Age <6 Weeks

Persaud D, et al. AIDS 2012;26:1483-90

Lower reservoir size in infants treated before six weeks of age

Reservoir decays during the first 2 years of life but remains detectable in most at 2 years of age

‒ half-life of 11 months [95% CI: 6 to 30 mos]

P1030 LPV/r infant PK study: 17 infants, median age 8.1 wks at start of ART, with RNA <400 by 24 wks ART, <400 through 96 wks

Start ART <6 wk/o Start ART >6 wk/o

Restricted Proviral Reservoir in Children Receiving Early Treatment with Sustained Viral Control

Luzuriaga K et al. J Infect Dis 2014 May 21; Epub ahead print

Early-Treated N=4

Late-Treated N=4

Started cART 0.5-2.6 mo/o >12 yr/o

Age at viral suppression post cART 3-8 months

Median age at study 16.9 (14.5-17.7) 22.5 (19.8-23)

Median cART duration 16.7 (14.4-17.5) 9.6 (5.7-10.5)

Ultrasensitive plasma RNA (LLD <2 c/mL)

Undetectable 8 copies/mL

Median PBMC proviral load (copies/106 PBMC)

7 (4-12) 181 (68-345)

Replication-competent virus (LLD <0.1 IU/106 cells)

1/4 4/4

HIV antibody positive 1/4 4/4

HIV-specific CD4 and CD8 0/4 4/4

Proviral Reservoirs Have Continuous Decay in Children with Early Therapy

Luzuriaga K et al. J Infect Dis 2014 May 21; Epub ahead print

Age at sample (yr)

HIV Proviral Decay Cures Among Individual ChildrenWith Early Treatment, by Age at Sample

p=0.02 p=0.03

p=0.01 p=0.17

Median proviral load (IQR) in early-treated youth, by age

Early Therapy is Associated with Loss of HIV-Specific Immune Response - Western Blot Antibody FindingsLuzuriaga K et al. J Infect Dis 2014 May 21; Epub ahead print

Late-treated youth retain strong response

to all HIV proteins

Early-treated youth lose response to HIV proteins over time

Early Treatment (<1 yr, <6 mos, <6 wks) Restricts Reservoir - What About Treatment Starting at Birth?

Very Early Treatment = Potential “Functional Cure”?

“Viral Remission” as Opposed to “Cure”?

“The fact that this child was able to remain off antiretroviral treatment for two years and maintain quiescent virus for that length of time is unprecedented.”

“The prolonged lack of viral rebound, in the absence of HIV-specific immune responses, suggests…the very early therapy not only kept this child clinically well but also restricted the number of cells harboring HIV infection.”

“The case of the Mississippi child indicates early antiretroviral treatment…did not completely eliminate the reservoir….but may have considerably limited its development and averted the need for antiretroviral medication overs a considerable period”

HIV diagnosed before 12 wks (median 7.4 wks) & CD4% ≥25%

N=375

Is Early Time-Limited ART Possible? CHER TrialCotton M et al. Lancet 2013;382:1555-63

ART-Deferred

Defer ART until clinical progression

or CD4% drop

N=125

Immediate ART x 40 WKS

Early ART to 40 weeks; then STOP,

until progression

N=125

Immediate ART x 96 WKS

Early ART to 96 weeks; then STOP,

until progression

N=125

Median follow-up 4.8 years

Primary endpoint: time to failure of first line ART

ART (start or re-start) when CD4% <20% or clinical event 1st-line ART:

LPV/r+ZDV+3TC

CHER Study: Early Time-Limited ART Cotton M et al. Lancet 2013;382:1555-63

DeferredStart ART

Immediate x 40 wk Immediate x 96 wkRestart ART after

interruption

Median time to start ART

20 wksIQR 16-25

Median time to restart ART

33 wksIQR 26-45

19% not restarted

Median time to restart ART

70 wksIQR 35-109

32% not restarted

ART-Defer N=125

ART-40 Wks N=126

ART-96 Wks N=126

P value

Deaths (rate 100 p-yr)

23 (4.6)

11 (2.0)

11 (2.0)

0.02

Clinical events (rate 100 p-yr)

66 (13.1)

38 (7.0)

29 (5.3)

<0.001

# Pts with clinical event (%)

38 (30%)

22 (17%)

17 (13%)

0.02

# Hospital admission (# pt)

139 (70)

90 (50)

78 (50)

<0.001

# Days in hospital 1018 533 414 0.004 Early time-limited ART superior to deferred ART over an extended period Deferred ART had more time on ART yet highest # deaths, clinical

events, hospital admissions

CHER Study: Early Time-Limited ART Cotton M et al. Lancet 2013;382:1555-63

Similarities with Mississippi baby? Consistent with early ART potentially restricting viral reservoir, longer duration ART before interruption

Early Treatment and “Functional Cure” Early ART studies and Mississippi baby have shown:

‒ Potential significant restriction (but not yet elimination) of viral reservoir with very early ART

‒ Continuing decline in reservoir over time‒ Loss of HIV-specific immune responses‒ “Remission” of HIV off ART

Many questions remain:– How to measure the latent pool in infants?– If reservoir establishment can’t be blocked, when

should eradication attempts begin?– Should immune approaches be studied to increase

HIV-specific immune response?– How long can viral “remission” be prolonged?

Adolescents

Prolonged SurvivalEmerging Issues

Jim Oleske, UMDNJ Newark Long-term survivors, 2003

But “elimination” does not mean these youth are going away!

Estimated Number of Children Aged <15 Years Living with HIV in Sub-Saharan Africa

WHO March 2014 Supplement

to 2013 Guidelines

2020: 1,931,768 (1,905,934 – 1,933,598)

Children with Perinatal HIV Infection are Now Surviving for Prolonged Periods

HIV-infected children now aging into adolescence.

HIV has become a chronic disease with all its concomitant challenges such as adherence to therapy, psychosocial challenges, sexual activity.

Newly recognized late complications are being detected with chronic HIV infection as well as a consequence of its therapies.

Complications of HIV and Antiretroviral Therapy in Children

Metabolic complications- Abnormal fat accumulation & wasting- Abnormal lipid profiles- Insulin resistance

Osteopenia/bone disease

Mitochondrial toxicity

Liver disease

Renal disease

Cardiac disease

Mental health

Obesity

Challenges in Adolescent HIV Care

• Knowledge of HIV infection (disclosure).• Linking to (and retaining in) health care.• Accepting (and adhering to) therapy.• Mental health issues.• Complexities of transition to adult care.• High risk population for HIV transmission.

– 40-60% of HIV-infected adolescents may engage in unprotected sex.

– High rate substance use, smoking.Rice E et al. Prospect Sex Repro Health 2006;38:162-7 Murphy DA et al . J Adol Health 2001;29S:57-63Sturdevant MS et al. J Adol Health 2001;29S:64-71

Kadivar H et al. AIDS Care 2006;18:544-9 Rotheram-Borus M et al. J Adoles 2001;24:791-802Lightfoot M et al. Am J Health Behav 2005;29:162-71.

Perinatally-Infected Youth are Sexually ActiveTassiopoulos K et al. Clin Infect Dis 2013;56:283-990

28% were sexually active at initial/follow-up ACASI.

67% of 18-year olds had initiated sex.

Mean age of initiation=13 yrs for males, 14 yrs for females

Annual audio computer-assisted interviews (ACASI) in 377 youth >10 years with perinatal HIV infection

in Pediatric HIV/AIDS Cohort Study in US.

Age (yrs) at most recent ACASI

Challenge: Pregnancy in Perinatally-Infected Females

Author/Journal Year (place) # Perinatal Girls # Pregnancies # Infected

Crane Ob/Gyn 1998 (Boston) Case rpt: 1 1 0

CDC MMWR 2003 (Puerto Rico) Case rpt: 8 10 0/7 live birth

Chibber Arch Gyn/Ob 2005 (India) Case rpt: 30 30 0/26 live birth

Bernstein J Adol Health 2006 (Wash DC) Cohort: 6/43 (14%) 6 Unk

Ezeanolue J Adol Health 2006 (Newark) Cohort: 5/28 (18%) 5 Unk

Levine J Adol Health 2006 (Philadelphia) Case rpt: 2 2 0

Brogley Am J Pub Health 2007 (US) Cohort: 38/638 (6%) 45 1/32 live birth

Koenig Am J Ob/Gyn 2007 (US) Case rpt: 15 15 Unk

Thorne AIDS 2007 (Europe) Case rpt: 9 11 0/8 live birth

Meloni AIDS Care 2009 (Italy) Case rpt: 2 2 0

Williams Am J Ob/Gyn 2009 (Newark) Case rpt: 10 13 1/7 live birth

Kenny J HIV Med 2012 (UK/Ireland) Cohort: 30/252 (12%) 42 0/3 live birth

Jao AIDS 2012 (NYC) Case rpt: 14 17 0/17 live birth

Millery J Ass Nurs AIDS Care 2012 (NYC) Cohort: 25/97 (26%) 33 0/19 live birth

Croucher Sex Trans Inf 2013 (UK) Cohort: 6/31 (19%) 8 0/3 live birth

Munjal Adol Health Med Th 2013 (Bronx) Case rpt: 30 37 1/37 live birth

Between1998-2013, 16 publications on 277 pregnancies in 231 perinatally-infected girls.

Challenge: Pregnancy in Perinatally-Infected Females

Author/Journal Year (place) # Perinatal Girls # Pregnancies # Infected

Crane Ob/Gyn 1998 (Boston) Case rpt: 1 1 0

CDC MMWR 2003 (Puerto Rico) Case rpt: 8 10 0/7 live birth

Chibber Arch Gyn/Ob 2005 (India) Case rpt: 30 30 0/26 live birth

Bernstein J Adol Health 2006 (Wash DC) Cohort: 6/43 (14%) 6 Unk

Ezeanolue J Adol Health 2006 (Newark) Cohort: 5/28 (18%) 5 Unk

Levine J Adol Health 2006 (Philadelphia) Case rpt: 2 2 0

Brogley Am J Pub Health 2007 (US) Cohort: 38/638 (6%) 45 1/32 live birth

Koenig Am J Ob/Gyn 2007 (US) Case rpt: 15 15 Unk

Thorne AIDS 2007 (Europe) Case rpt: 9 11 0/8 live birth

Meloni AIDS Care 2009 (Italy) Case rpt: 2 2 0

Williams Am J Ob/Gyn 2009 (Newark) Case rpt: 10 13 1/7 live birth

Kenny J HIV Med 2012 (UK/Ireland) Cohort: 30/252 (12%) 42 0/3 live birth

Jao AIDS 2012 (NYC) Case rpt: 14 17 0/17 live birth

Millery J Ass Nurs AIDS Care 2012 (NYC) Cohort: 25/97 (26%) 33 0/19 live birth

Croucher Sex Trans Inf 2013 (UK) Cohort: 6/31 (19%) 8 0/3 live birth

Munjal Adol Health Med Th 2013 (Bronx) Case rpt: 30 37 1/37 live birth

Between1998-2013, 16 publications on 277 pregnancies in 231 perinatally-infected girls. Majority of pregnancies were unplanned.

Elective termination was not uncommon (15%-

42% in 5 studies reporting).

Repeat pregnancy was not uncommon: 32 had

2 pregnancies; 4 had three pregnancies.

Adverse pregnancy outcomes: miscarriage (6-

14% 4 studies), preterm (7-44% 4 studies),SGA

(47% 1 study), low birth weight (1 study).

MTCT uncommon (3 infections/159 live birth,

2%).

Transition to Adult Care: Mortality in Perinatally-HIV-Infected Youth In UK/Ireland

Fish R et al. HIV Med 2013 Sept 25 (Epub ahead print)

Evaluated mortality 2006-2011 in UK/Ireland in 996 perinatally-infected youth >13 years, including 248 cared for in14 adult clinics. Median age at transfer 17 years and at death 21 years.

Age Group/Type Care

Mortality Rate/100 Pt-Yr

Rate Ratio

13-15 years, Pediatric 0.2 (0.1-0.6) 1.0

16-20 years, Pediatric 0.3 (0.1-1.0) 1.3 (0.2- 8.6)

16-20 years, Adult 0.5 (0.2-1.3) 2.7 (0.6-12.2)

>21 years, Adult 0.9 (0.3-2.3) 4.9 (1.1-22.0)

Estimated minimum mortality by age and type care in perinatally HIV-infected young people UK/Ireland:

Transition to Adult Care: Mortality in Perinatally-HIV-Infected Youth In UK/Ireland

Fish R et al. HIV Med 2013 Sept 25 (Epub ahead print)

Evaluated mortality 2006-2011 in UK/Ireland in 996 perinatally-infected youth >13 years, including 248 cared for in14 adult clinics. Median age at transfer 17 years and at death 21 years.

Age Group/Type Care

Mortality Rate/100 Pt-Yr

Rate Ratio

13-15 years, Pediatric 0.2 (0.1-0.6) 1.0

16-20 years, Pediatric 0.3 (0.1-1.0) 1.3 (0.2- 8.6)

16-20 years, Adult 0.5 (0.2-1.3) 2.7 (0.6-12.2)

>21 years, Adult 0.9 (0.3-2.3) 4.9 (1.1-22.0)

Estimated minimum mortality by age and type care in perinatally HIV-infected young people UK/Ireland:

Complex medical and psychosocial

issues in perinatally infected young

adults – 82% of deaths associated with

poor adherence and advanced HIV

disease, 9 with mental health diagnoses

and 2 deaths due to suicide!

Wednesday July 23

Living with HIV – Transitions to Adulthood

13:00-14:00 Room 105-106

Summary: From Tots to Teens

While we don’t have a “cure”, very early ART of infected neonates has promise in significantly restricting the viral reservoir and “remission”.

Potential utility of stimulating HIV-specific immune response in such children to prolong “remission”.

Even with “elimination” of pediatric HIV, millions of perinatally-infected youth will continue to survive into adolescence and young adulthood for many years to come.

We need to address new challenges with such youth, including late complications HIV/ART, sexual activity, transition to adult care.

Thanks For Your Attention