Paediatric HIV: update

1

• Paediatric HIV update
• EACS Advanced HIV course
• Montpellier, 3-5th Sept 2008
• Carlo Giaquinto
• Department of Paediatrics,
• Padova, Italy

2
Presentation overview

• Children HIV in developed countries
• Women pregnancy HIV
• PMTCT / MTCT in developing countries
• Children HIV in developing countries

3
Two Pediatric Epidemics

• High-resource countries
• New perinatal infections are rare
• Effective treatment available
• Aging cohort of infected children
• Concerns long-term complications of treatment
• Low-resource countries
• 1,000 infants are newly infected each day
• Diagnosis of infection in infants problematic
• Problems with drug access
• Treatment when available is started late.

4
Pediatric HIV Infection in the West A success
story

• With effective prevention of most new perinatal
  HIV infection, it is estimated that lt250 newly
  infected infants are born annually in the U.S and
  about 500 in Europe.
• Effective therapies for HIV in children have
  prolonged life and quality of life1.
• The median age of over 3,500 HIV-infected
  children followed at US pediatric clinical trials
  sites is 14.8 years2 .

• Lee GM et al. Pediatrics 2006117273-83
• 219 study summary July 23 2007

5
In the USA, the Majority of HIV-Infected Children
Are Receiving ARTPediatric Spectrum of Disease
Project, 1994-2001
In 2001, 78 of HIV-infected children were on ARV
and 66 were receiving 3-drug HAART
100
Monotherapy
Triple Therapy
No Therapy
Dual Therapy
80
Unclassified
60
Percentage of children
40
HAART era
20
0
1994n2196
1995n2235
1996n2235
1997n2210
1998n2218
1999n2218
2000n2155
2001n2040
McConnell M et al. JAIDS 200538488-94 PSD
includes over 2,000 children from 6 areas US
6
Decrease in AIDS, Death, and Hospital Admissions
in HIV Children in the HAART Era, United Kingdom
Judd A et al. Clin Infect Dis 200745918-24
Same as US rate in 2006
7
Age at Death (1994-2006) in HIV-Infected Children
Enrolled in PACTG 219 Long-Term Follow-Up Study
Age at Death by Year of Deathfor Infected
Children
3,553 children Median f/u 5.3 yrs 298 deaths
22
20
18
16
14
12
Median Age at Death (IQR)
10
8
6
4
Mean age at death 2006 18.2 years
Mean age at death 1994 8.9 years
2
0
1994
1996
1998
2000
2002
2004
2006
Year
HAART Era
Courtesy Mike Brady, Paige Williams
8
Primary Causes of Death (1994-2006) in
HIV-Infected Children Enrolled in PACTG 219
AIDS OI
End Stage AIDS
Pheumonia
Sepsis
Cardiomyopathy
CNS disease
Malignancy
Renal failure
Stroke
Hepatitis
Accident / other
40
Increase 19942006 End stage Aids Sepsis Renal
Failure
30
20
10
0
19941996
19972000
20012006
N 3,553 children Median f/u 5.3 yrs 298 deaths
Courtesy Mike Brady, Paige Williams
9
Encephalopathy in Pediatric HIV InfectionVan Rie
A et al. Eur J Pediatr Neurol 2007111-9

• Prior to ART, 13-25 of children with HIV
  infection and 35-50 with AIDS were diagnosed
  with encephalopathy.
• Highest incidence 1st 2 years of life incidence
  rate 9.9 in 1st year, 4.2 in 2nd year, and lt1
  thereafter.
• Reported risk factors for neuroAIDS include
• Maternal advanced disease
• Low CD4 count in child
• Elevated plasma and CSF viral load
• Perinatal route of transmission
• Lack of ARV treatment

10
Decline in Progressive and Static Encephalopathy
Children with Perinatal Infection in HAART
EraShabhag MC et al. Arch Pediatr Adolesc Med
2008159651-6
P0.049
P0.02
146 children with perinatal infection followed
between 1990 and 2003 at Childrens Hospital
Philadelphia
11
Encephalopathy in Pediatric HIV Infection

• However, ART does not eliminate HIV-related CNS
  disease.
• Differential penetration of antiretroviral drugs
  into CNS (Mitchell C. Mental Retard Develop
  Disabil 200612216-22 Caparelli E. AIDS
  200519949-52 Antinori A. CID
  2005411787-93)).
• AZTgtd4TgtABCgt3TCgtddI
• NVPgtEFV
• IDVgtLPVgtSQVNFVRTVAPV (very low)

12
In the HAART era there was a 10-fold decrease in
the incidence of HIV encephalopathyPatel et al
WAIDS 2008
on HAART
Incidence rate
13
Comments on Mortality of HIV in Children Today

• Decline in mortality with HAART sustained over 10
  years, but there has not been further decrease
  since about 2000.
• Mortality in HIV-infected children is still gt30
  fold higher than similarly aged children (0.49
  per 100 infected children vs 0.02 per 100
  children aged 5-14 years in US, plt0.001).
• As in adults, there has been evolution in causes
  of death over time, with decrease in AIDS OI and
  increase in end stage AIDS multi-organ failure,
  sepsis and renal disease.

14
Challenges in the Treatment of Pediatric HIV
Infection in High Resource Settings
Effective Therapy is Prolonging Life Spectrum of
Disease Changed

• Drug resistance primary, acquired
• Pharmacokinetics
• Lack salvage drugs for children
• Complications of therapy
• Adherence
• Mental health
• Adolescence - transition to adult care.

15
Prevalence of Transmitted Primary ARVDrug
Resistance in New perinatal HIV Infection
58 increase
Non-subtype B virus found in 4.4 of infants
born 1998-9 16.7 of infants born 2001-02.
1 Parker MM, et al. JAIDS 200332292-7. 2
Karchava M, et al. JAIDS 200642614-9. 3 Persaud
D, et al. J Infect Dis 2007195140210.
16
Acquired Drug Resistance
Many older children had sequential mono dual
therapy prior to starting HAART may have had
periods of inadequate adherence
Leads to the development of multi-drug resistant
virus
Necessitates more complex regimens
Limits choices for effective therapy
However Newer drugs used for salvage in adults
often not available in children Lag in
development of pediatric formulations
17
Acquired drug resistance
After first line failure 88 of ART treated
children have at least 1 significant resistance
mutation (RM) - 88 NRTI RM - 52 NNRTI RM -
8 PI RM Sunpath H et al CROI 2008 Abs
587 After first line NNRTI failure 52 of
children have at least 1 significant resistance
mutation (RM) - 52 NRTI RM - 43 NNRTI
RM Sungaknuparph S et al CROI 2008 Abs 588
18
Antiretroviral Drugs Approved in Adults
but Not Yet Approved in Children
19
LPV/r pharmacokinetics in HIV-infected infants lt
6 weeks

• LPV/r exposure is initially low in infants lt 6
  weeks of age but increases dramatically during
  the first year of life

Despite the low initial LPV exposure, viral
suppression was achieved by most infants at 48
weeks
Capparelli, E Poster 573, CROI 2008
20
Recommended dose of LPV/r is sub-optimal in
PI-experienced children

• 47 paediatric patients on 52 weeks of study
  follow up.
• 51 achieved VLlt400 copies/mL
• LPV trough lt5.7 mg/L (p0.05) and baseline LPV
  resistance (p0.005) were independently and
  significantly associated with failure to achieve
  VLlt400 copies/mL
• Pharmacokinetic modelling and simulation
• Data from 33 patients was used to create a model,
  and this model was used to simulate 1000 children
  to determine the with trough LPV concentration
  lt5.7mg/L after standard dosing.
• Data from this model showed that in children
  given standard LPV dose (230 mg/m2), 49.3 would
  fail to reach the target trough.
• In PI pre-treated children, LPV plasma levels
  should be optimized in order to achieve maximal
  virologic suppression

Rahkmanina, N, Poster 574, CROI 2008
21
DELPHI Darunavir Evaluation in Paediatric
HIV-1-Infected Treatment-Experienced Patients

• Target treatment-experienced adult DRV exposures
  were achieved in children across weight bands and
  age groups
• Trough concentrations (C0h) were well above the
  protein-binding corrected EC50 value of 550
  ng/mL in all children

Estimated using populations pharmacokinetic
analysis For wild-type virus Primary
24-week analysis of integrated data from POWER 1
and 2 trials, Sekar V, et al., 13th CROI 2006 Abs
J-121

• In treatment-experienced HIV-1-infected children
  and adolescents at week 24, DRV/r showed
• good virologic response rates
• positive clinical outcomes
• favourable safety and tolerability
• comparable exposure to adults and confirmed
  appropriate dose-selection in this paediatric
  population

Spinosa-Guzman S, Oral Abstract 78LB, CROI 2008
22
Long-term Complications of HIV Infection of ART
in Children

• Metabolic complications
• Abnormal fat accumulation wasting
• Abnormal lipid profiles
• Insulin resistance
• Osteopenia/ bone disease
• Mitochondrial toxicity
• Liver disease
• Renal disease
• Adolescent obesity

23
Metabolic Complications of ART in
ChildrenMetabolic disorders reported in
HIV-infected children on ART

• Lipodystrophy 6 - 47
• Hyperlipidaemia 13 - 67
• Insulin resistance 0 - 13
• hyper-insulinaemia 60

Puberty is the time when children are most likely
to develop metabolic complications.
Tassiopoulos K et al. JAIDS. 2008 in
press Vigano A et al. Antivir Ther.
200712297-302 Ene L et al. Eur J Pediatr.
200716613-21 Ergun-Longmire B et al. Endocr
Prac. 200612514-21 Dzwonek AB et al. JAIDS.
200643121-3
Carter RJ et al. JAIDS. 200641453-60 Farley J
et al. JAIDS. 200538480-7 Beregszaszi M et
al. JAIDS. 200540161-8 European Paediatric
Lipdystrophy Group. AIDS. 2004181443-1451 McComs
ey G et al. Pediatrics. 2003111e275-81
24
Development of hypercholesterolaemia is more
frequent in children on pi-based HAART
tassiopoulos K et al. JAIDS 2008 in press
1.0
Cholesterol gt220 Entry 13 of 2123
children Follow-up additional 13 (median f/u
50.4 mos) Incidence 3.4/100 pt-yr
0.9
0.8
Prop. hyperchol free
0.7
0
6
12
18
24
30
36
42
48
54
60
Months to consecutive CHOL 220 or censoring
25
Probability of Developing Lipodystrophy in
HIV-Infected Children Increases with Tanner
Stage Taylor P et al. Pediatrics 2004114e235-42
100
90
80
70
60
Percent without lipodystrophy
50
40
30
20
10
0
0
1
2
3
4
5
Tanner Stage
26
Impaired glucose homeostasis
Impaired glucose tolerance was present in 20 of
adolescents and young adults infected perinatally
on ART from a mean of 13 years, suggesting an
increased risk of Type 2 diabetes and
cardiovascular diseases Hadigan C CROI 2008
Abs 591 Puberty is the primary determinant of
reduced insulin sensitivity in ART experienced
children and adolescents Vigano et al CROI
2008 Abs 592
27
Mental Health in HIV-Infected Children and
YouthScharko AM. AIDS Care 200618441-5

• Review of 8 studies including 328 HIV-infected
  children age 4-21 years data were compared to
  prevalence in overall population.

28
HIV-Infected Children Have Higher Rates of
Psychotropic or Behavioral Treatments Compared to
Uninfected Similarly Socioeconomic Controls P1055
Treatment, by HIV Status
45
HIV-uninfected
40
HIV-infected
35
30
25
20
15
10
5
0
Med orBehavTx
BehavTx
MedTx
Stimulant
SSRI
Neuro-leptic
Anti-Hypert
Other
Data provided by Sharon Nachman MD
29
Challenges in Adolescent HIV Care

• Knowledge of HIV infection.
• 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 continue to
engage in unprotected sex. High rate substance
use, smoking
Kadivar H et al. AIDS Care 200618544-9
Rotheram-Borus M et al. J Adoles
200124791-802 Lightfoot M et al. Am J Health
Behav 200529162-71.
Rice E et al. Prospect Sex Repro Health
200638162-7 Murphy DA et al . J Adol Health
200129S57-63 Sturdevant MS et al. J Adol
Health 200129S64-71
30
Short-cycle therapy in adolescents following
continuous therapy with established viral
suppression The effect on viral load suppression

• 32 subjects with viral suppression aged 12-24
  switched from continuous HAART to short-cycle
  therapy (SCT) with a schedule of 4 days on
  (mon-thurs) and 3 days off (fri-sun) HAART.
• Viral suppression was maintained in 62.5 of
  participants.
• Significantly more subjects infected before age 9
  discontinued SCT (p0.0155).
• No significant losses of CD4 T cells were noted
  in those with or without VL breakthrough.
  Adherence by self report was high for both groups
  ,with no difference in those with viral rebound.
• Of 12 patients with viral load rebound, 9
  re-suppressed after re-initiating continuous
  HAART.

Rudy, B Poster 580, CROI 2008
31
Cumulative Incidence of First Pregnancy in 174
Perinatally HIV-Infected Sexually Active Girls
Age gt13 Years, PACTG 219CBrogly SB et al. Am J
Public Health 20079710471052
45
40
35
30
25
Cumulative Incidence of First Pregnancy ()
20
By age 19 years, 24.2 of sexually active girls
had been pregnant at least once (6 had 2nd
pregnancy, 1 had 3rd)
15
10
5
0
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
105
110
115
120
125
130
135
Months Since 13th Birthday
32
Challenges in Management of Pediatric HIV
Infection in Low Resource Countries
1 Challenge in Low Resource Countries Continued
HIV Transmission to Women Poor Implementation
of PMTCT
33
of Female HIV-Infected Adults
By Geographic Location, 1990-2007
Caribbean
Source UNAIDS/WHO Dec 2007
5
34
Incidence of pregnancy and desire for children
12
100
90
10
80
p lt 0.001
70
8
60
Women
Incidence of pregnancy per 100 WY
6
50
40
4
p lt 0.04
30
20
2
10
0
0
Baseline
21
24
15
27
3
6
12
18
9
Months after ART Initiation
Wants more children
Partner wants more children
Sexually active
Weidle, P Oral Abstract 74, CROI 2008
35
Effectiveness of NNRTI-containing ART in women
previously exposed to a single dose of
nevirapine A multi-country cohort study

• A high proportion of women in this cohort
  responded to NNRTI-based HAART at 24 weeks
  whether previously exposed to SD-NVP or not.
• Increased risk of failure among women with
  exposure to SD-NVP within 6 months and perhaps 12
  months before initiation on NNRTI-based HAART.
• Women exposed to SD-NVP more than 12 months prior
  to initiation of NNRTI-based HAART did as well as
  women who were not exposed to SD-NVP.

P lt 0.001 vs unexposed
Success ()
Time since NVP exposure (months)
Weidle, P Oral Abstract 48, CROI 2008
36
Despite Effective Regimens to Prevent MTCT,
Globally Only 11 of Women Receive ARV
Prophylaxis
100
95
Regions with 95 of all MTCT
77
75
Percentage ()
50
37
29
28
25
16
15
14
12
8
3
2
0
India
West
East
Eastern
Central
Central
Central
South
Asia
South
Eastern
Africa
Africa
Pacific
America
Europe
HIV women identified 2005
HIV women given ARV 2005
Interagency Task Team on PMTCT Report Card Feb
2007 UNICEF/WHO/UNAIDS
37
Very low risk of MTCT in women on HAART who
achieve viral suppression the UK and Ireland,
2000 to 2006
There was no difference in MTCT rates according
to BHIVA guidelines HAART with elective CS,
HAART with planned vaginal delivery and AZT with
elective CS
Townsent, C Poster 653, CROI 2008
38
Prevention of postnatal infection
Extended infant post exposure prophylaxis
significantly reduces postnatal HIV
transmission NVP or NVP/ZDV for 14 weeks in
infants (7.2vs 13 MTCT at 9 mo) Taha T et al
CROI 2008 Abs 42LB NVP for 6 weeks in
infants (8.0 vs 11 MTCT at 6 mo) Sastry J et
al CROI 2008 Abs 43 HAART in women for 6 mo
(uncontrolled) (5.9 MTCT at 12 mo) Thomas T
et al CROI 2008 Abs 45aLB HAART in women for 12
mo (uncontrolled) (2.9 MTCT at 12 mo) Marazzi
M et al CROI 2008 Abs 239
Emergence of HIV drug resistance among
breastfeeding infants born to HIV infected mother
taking ART Zeh C et al CROI 2008 Abs 84LB
39
The Challenge of Pediatric HIV Infection in
Resource-Poor Countries

• While high rates of HIV infection in women, few
  women know they are infected and there is poor
  access to ARV to prevent MTCT.
• Children often present to health system with
  advanced disease.
• Rapid progression and high mortality due to HIV
  in children, yet few receive treatment.
• Early treatment would prevent many deaths but
  infant diagnosis not available.

40
Data from African perinatal prevention trials
from breastfeeding HIV transmission study
meta-analysis mortality in infected children was
53 at 2 years of ageNewell et al. Lancet
2004364123643
0.6
Mean survival 1.6 years
0.5
Infected
By age 2.5 years, 60 mortality
Overall
0.4
Unknown HIV status
Not infected
Cumulative probability of death
0.3
0.2
0.1
0
0
100
200
300
400
500
600
700
800
900
Age at last visit or at death (days)
41
Estimated Number of HIV-Infected Children Needing
and Number Receiving Antiretroviral Treatment By
Region as of December 2006
Needing ART
Receiving ART
800,000
600,000
400,000
200,000
0
Sub-Saharan Africa
Latin America/ Caribbean
E/S/SE Asia
Europe/ Central Asia
N Africa/ Middle East
ARV Coverage 13 67 21
20 lt1
Source World Health Organization, April 2007
42
Virologic Suppression in Children on HAART from
17 Studies in Sub-Saharan AfricaSutdiffe CG et
al. Lancet Infect Dis 20088447-89
Median viral load decrease approximately 2.0 log
within 1 year of starting ART.
43
Viral Suppression After 1 Year Was 49-81 17
Studies in Sub-Saharan AfricaSutdiffe CG et al.
Lancet Infect Dis 20088447-89
44
CD4 Increase in Children on HAART from 14
Studies in Sub-Saharan AfricaSutdiffe CG et al.
Lancet Infect Dis 20088447-89
CD4 increased in 1st year of treatment, seeming
to plateau after 12-18 months
45
However, Normalization of CD4 Percentageto gt25
with HAART was Uncommon
46
However, children in low-resource countries who
receive ART are starting at older ages than high
resource countries
47
Children in low-resource countries who receive
ART are starting treatment when already severely
immune deficient
48
Recovery of immune status with HAART is dependent
on CD4 at time HAART is initiatedPatel K et al.
Clin infect dis 2008 46 507-515
40
35
Notimmunedeficient
30
25
20
Immunedeficient
Mean CD4
15
10
CD4 lt15
CD4 1524
5
CD4 gt25
0
0
1
2
3
4
5
6
Years since HAART initiation
1,236 children enrolled in PACTG 219 not on HAART
at study initiation
49
Immune reconstitution syndrome in HIV-infected
children started on HAART

• Most commonly reported from low resource
  countries, likely because they are starting
  treatment at lower CD4 levels than in US.

19 of 153 children started on HAART had IRIS,
median onset 4 weeks 10 died. Thailand
(Puthanakit T et al. PIDJ 20062553-8) 17 of
148 children started on HAART had IRIS, median
onset 2 weeks most common BCG-related IRIS
disease. South Africa (Smith K et al. CROI 2008
Abs 75)
50
Implications for when to start antiretroviral
therapy in children

• Children lt1 year are at high risk of death
  aggressive treatment seems warranted.
• However
• Need to build capacity for early diagnosis
• Viral suppression with ART less in infants
• Limited pediatric formulations
• Minimal data on dosing in children
• Limited data on efficacy of early treatment

51
Clinical and Immunological Characteristics of
HIV-Infected Infants lt60 Days Old in South
Africa Evidence from CHER

• Few clinical characteristics are associated with
  severe immune suppression
• Certain clinical characteristics are highly
  specific for HIV infection in infants lt60 days of
  age - may be useful for early presumptive
  diagnosis
• Many HIV-infected infants will be missed
  therefore access to PCR in resource limited
  settings is essential.

• ROC of HIV infection in exposed infants (area
  under ROC curve 0.6624)
• Any of the following
• Oral thrush
• any LAD
• Hepatomegaly
• Splenomegaly
• clinical GERD
• Weight below 10th centile

Jaspan, H Oral Abstract 76, CROI 2008
52
Studies early HAART at age lt3-12 months show
viral suppression in 18-73
53
Early HAART at age lt3-12 months is associated
with no AIDS progression and
maintenance of immune
reconstitution
54
CHER 76 reduction in the risk of death with
immediate (arms 2 3) compared to deferred (arm
1) HAARTCROI 2008 Abs 76, Abs 600
1
Deferred
p 0.0002
Immediate
0.80
0.60
Failure probability
0.40
16
0.20
4
0
0
3
6
9
12
Time to death (months)
Patients at risk Arm 1 Arm 2 Arm 3
125 252
104 213
72 145
44 99
22 52
55
WHO 2008 Revised Guidelines When to Start
Antiretroviral Therapy in HIV-Infected Children
If lack ability for viral test, use WHO
presumptive diagnosis of severe HIV (thrush,
severe pneumonia or sepsis) in infants with HIV
antibody test and with clinical symptoms of
severe HIV need to confirm infection status as
soon as possible.
56
What to start with Implications of resistance
following Single-dose NVP prophylaxis Given 1st
line recommendation for NNRTI-based therapy In
low resource settings
57
Single-dose NVP prophylaxis is associated with
NVP resistance acquisition in infants failing
prophylaxis
SD NVP
SD NVP, no maternal SD NVP
AZT SD NVP
AZT SD NVP, no maternal SD NVP
with resistance

Clade E,B C A E,B
C E,B C C A,D C
C CRF01,
06
58
Infants who become HIV-infected despite
single-dose NVP prophylaxis may be more likely
to have viral failure with later nvp-based
HAARTLockman S, et al. Nejm 200735613547
80
Single dose of NVP
60
Median age at start HAART 8.5 months
with RNA gt400 c/mL
40
20
Placebo
0
0
6
12
18
24
30
36
Months since the Start of ART
Analysis after 6 months of HAART 10/13 in SD
NVP group and 1/12 placebo group had HIV RNA
gt400 copies/mL
59
Optimal initial ART trials for infants with SD
NVP exposure
60
What to start (WHO Paediatric HIV/ART working
group, Geneva April 2008)
For HIV infected infants with no exposure to
NNRTIs, or with unknown exposure to maternal or
infant ARVs, standard NVP-containing triple
therapy should be started Strong
recommendation For HIV infected infants with a
history of exposure to single dose nevirapine or
NNRTI containing maternal ART or preventive
antiretroviral regimens, a protease inhibitor
based triple ART regimen should be started. Where
protease inhibitors are not available, nevirapine
based therapy should be used Strong
recommendation
61
Challenges in Treatment of HIV-Infected Children
in Low Resource Settings

• Pediatric formulations
• Fewer ARV approved in children
• More costly than adult preparations
• FDC just becoming available
• Dosing weight/size based, change as child grows,
  problems for busy health clinic.
• Liquid drugs transport/storage problems.
• Complexity of therapy in context multiple
  co-moribidities (TB, malaria, malnutrition)

62
Improved therapeutic exposure of NVP using WHO
pediatric weight band dosing

• WHO weight band dosing of NVP
• results in therapeutic concentrations in 80 of
  subjects without incurring a high freq of
  excessive NVP exposure.
• achieves target exposure in a greater proportion
  of subjects than the FDA dose of 4-7mg/kg.
• The 50-mg tablet strength maximises the
  therapeutic index.
• WHO weight band dosing should be used in
  resource-limited settings.

Capparelli, E Poster 576, CROI 2008
63
Thank you for your attention
Courtesy Peter Havens MD