Challenges in Pediatrics Taking 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 Development National 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% for Early vs Deferred ART

N= 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 old Age at Virologic Control: HIV DNA (copies/million PBMCs) <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 P-value PHIV+ vs HEU: <0.001 <

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 P-value PHIV+ vs HEU: <0.001 < 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: Thailand Ananworanich J et al. AIDS 2014;28: 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/ copies/10 6 None detectable 60% had <20 c/10 6

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:  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 mo/o>12 yr/o Age at viral suppression post cART 3-8 months Median age at study 16.9 ( )22.5 ( ) Median cART duration 16.7 ( )9.6 ( ) Ultrasensitive plasma RNA (LLD <2 c/mL) Undetectable8 copies/mL Median PBMC proviral load ( copies/10 6 PBMC) 7 (4-12)181 (68-345) Replication-competent virus (LLD <0.1 IU/10 6 cells) 1/44/4 HIV antibody positive 1/44/4 HIV-specific CD4 and CD8 0/44/4

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 Children With Early Treatment, by Age at Sample p=0.02p=0.03 p=0.01p=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 Findings Luzuriaga 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 Trial Cotton M et al. Lancet 2013;382: 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 1 st -line ART: LPV/r+ZDV+3TC

CHER Study: Early Time-Limited ART Cotton M et al. Lancet 2013;382: Deferred Start ART Immediate x 40 wk Immediate x 96 wk Restart ART after interruption Median time to start ART 20 wks IQR Median time to restart ART 33 wks IQR % not restarted Median time to restart ART 70 wks IQR % 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  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:  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 Survival Emerging 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:57-63 Sturdevant 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: Lightfoot M et al. Am J Health Behav 2005;29:

Perinatally-Infected Youth are Sexually Active Tassiopoulos K et al. Clin Infect Dis 2013;56:  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/JournalYear (place)# Perinatal Girls# Pregnancies# Infected Crane Ob/Gyn 1998 (Boston) Case rpt: 110 CDC MMWR 2003 (Puerto Rico) Case rpt: 8100/7 live birth Chibber Arch Gyn/Ob 2005 (India) Case rpt: 30300/26 live birth Bernstein J Adol Health 2006 (Wash DC) Cohort: 6/43 (14%)6Unk Ezeanolue J Adol Health 2006 (Newark) Cohort: 5/28 (18%)5Unk Levine J Adol Health 2006 (Philadelphia) Case rpt: 220 Brogley Am J Pub Health 2007 (US) Cohort: 38/638 (6%)451/32 live birth Koenig Am J Ob/Gyn 2007 (US) Case rpt: 1515Unk Thorne AIDS 2007 (Europe) Case rpt: 9110/8 live birth Meloni AIDS Care 2009 (Italy) Case rpt: 220 Williams Am J Ob/Gyn 2009 (Newark) Case rpt: 10131/7 live birth Kenny J HIV Med 2012 (UK/Ireland) Cohort: 30/252 (12%)420/3 live birth Jao AIDS 2012 (NYC) Case rpt: 14170/17 live birth Millery J Ass Nurs AIDS Care 2012 (NYC) Cohort: 25/97 (26%)330/19 live birth Croucher Sex Trans Inf 2013 (UK) Cohort: 6/31 (19%)80/3 live birth Munjal Adol Health Med Th 2013 (Bronx) Case rpt: 30371/37 live birth  Between , 16 publications on 277 pregnancies in 231 perinatally-infected girls.

Challenge: Pregnancy in Perinatally-Infected Females Author/JournalYear (place)# Perinatal Girls# Pregnancies# Infected Crane Ob/Gyn 1998 (Boston) Case rpt: 110 CDC MMWR 2003 (Puerto Rico) Case rpt: 8100/7 live birth Chibber Arch Gyn/Ob 2005 (India) Case rpt: 30300/26 live birth Bernstein J Adol Health 2006 (Wash DC) Cohort: 6/43 (14%)6Unk Ezeanolue J Adol Health 2006 (Newark) Cohort: 5/28 (18%)5Unk Levine J Adol Health 2006 (Philadelphia) Case rpt: 220 Brogley Am J Pub Health 2007 (US) Cohort: 38/638 (6%)451/32 live birth Koenig Am J Ob/Gyn 2007 (US) Case rpt: 1515Unk Thorne AIDS 2007 (Europe) Case rpt: 9110/8 live birth Meloni AIDS Care 2009 (Italy) Case rpt: 220 Williams Am J Ob/Gyn 2009 (Newark) Case rpt: 10131/7 live birth Kenny J HIV Med 2012 (UK/Ireland) Cohort: 30/252 (12%)420/3 live birth Jao AIDS 2012 (NYC) Case rpt: 14170/17 live birth Millery J Ass Nurs AIDS Care 2012 (NYC) Cohort: 25/97 (26%)330/19 live birth Croucher Sex Trans Inf 2013 (UK) Cohort: 6/31 (19%)80/3 live birth Munjal Adol Health Med Th 2013 (Bronx) Case rpt: 30371/37 live birth  Between , 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 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 years, Pediatric0.2 ( ) years, Pediatric0.3 ( )1.3 ( ) years, Adult0.5 ( )2.7 ( ) >21 years, Adult0.9 ( )4.9 ( )  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 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 years, Pediatric0.2 ( ) years, Pediatric0.3 ( )1.3 ( ) years, Adult0.5 ( )2.7 ( ) >21 years, Adult0.9 ( )4.9 ( )  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

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