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Therapeutic issues
John B. Ziegler
Sydney Children’s Hospital
Randwick
j.ziegler@unsw.edu.au
Paediatric HIV
•Epidemiology
•Perinatal transmission
•Special features
•Management
PERINATALLY ACQUIRED HIV
Special features
• Higher viral load
• Diagnostic difficulty; lymphocytosis in infants; DD
• More rapid disease progression
• Failure-to-thrive
• Recurrent bacterial infection
• PCP in infancy with preserved CD4
• Pulmonary lymphoid hyperplasia, parotitis
• Kaposi’s sarcoma rare; leiosarcoma
• Neurological involvement, developmental delay
• Seroconverting illness infrequent
• Immunisation issues
• Multigenerational disease
• Pharmacological issues
SURVIVAL BY BIRTH COHORT
Martino et al.
JAMA 2000;284:190-7
Paediatric HIV
Modes of transmission
• Mother to child transmission
• Blood, blood products, tissues
• “Medically acquired”
• Child sexual abuse
• ALSO:
♦Sharing of injecting equipment
♦Unprotected sex
Mother to child
transmission of HIV
• In utero (in the womb)
• Intrapartum (during
birth)
• Breastfeeding
HIV may be transmitted as
• viral particles and/or
• HIV infected cells
UNAIDS GIobal summary of the HIV/AIDS
epidemic, December, 2004
• 640,000 children newly infected with HIV in
2004 (1,700/day; 1 every 50 seconds)
• 2,200,000 children < 15 living with HIV
• 510,000 children < 15 died from HIV-related
causes in 2004
• > 5,000,000 AIDS deaths in children since the
beginning of the epidemic
• Almost entirely attributable to perinatal
transmission
• More than 17,000,000 women living with HIV
• Numbers increasing by about 5% per year
Children (<15 years) estimated to be living
with HIV as of end 2004
Source: Roeland Monasch and J. Ties Boerma, Orphanhood and childcare patterns in sub-Saharan Africa: an analysis of
national surveys from 40 countries. AIDS 2004, 18 (suppl 2): S55-S65. 4.7
AUSTRALIAN HIV SURVEILLANCE
Data to 31 March, 2006
Children under 13 years at diagnosis/death
HIV:
Mother at risk 43 39 82 # 0.4
Blood products etc. 78 9 87 0.4
# 358 exposed
TIMING OF PERINATAL INFECTION
(No zidovudine prophylaxis)
25
TRANSMISSION RISK (%)
20
15
10
0
In utero At birth Early breast Late breast
feeding feeding
SERODIA HIV ANTIBODY TITRES IN INFANTS WITH PERINATAL
EXPOSURE TO HIV
Modified from Palasanthiran et al., JID
1994;170:1593-6
30 Infected infants
25
Uninfected
infants
20
15
10
0
0 200 400 600 800
Plot of log base 2 HIV antibodies in infants born to HIV seropositive mothers against age in days .
Thin lines represent the uninfected infants and thick lines the infected infants.
DEFINITION OF PERINATAL
HIV INFECTION
36.7%
30 ? exclusive
25 breast feeding
20
20.5%
15 ? NilNB:
breast feeding
Compliance = 70%
10
5
0
0 6 12 18 24
Age (months)
ACTG 076
Transmission rates
p = 0.0006
Infection at 14-16 w
NVP: 13.1% inf.
AZT: 22.1% inf.
At 18 m: 24% v. 14.7%
Kwor et al. Durban LbOr1
DRUG COST: ~ $5
MATERNAL POTENT ANTIVIRAL THERAPY
AND VIRAL LOAD
Effects on perinatal tranmission
WITS prospective study: Blattner, LbOr4
40
25
20.7 21.1
20
15
11.3
10 7.7
6.4
5 3.9
1.1 0.9
0
< 400 400-3 K 3-40 K 40-100 K > 100 K
b.
ed
I
py
.P
m
at
ra
w
co
re
he
b.
nt
PI
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om
U
on
C
M
N
What is the risk of MTCT?
• Historically, up to 60%, falling with time
• Less developed settings, 30-40%
• Currently, in developed countries, as low as 1-2% or less
RISK OF MTCT OF HIV
Advanced HIV, breast feeding
Breast fed infant
Formula feeding
Breast feeding, Nevirapine
Formula, AZT - 3 periods ("076")
Formula, HAART
Formula, HAART, VL<50
Formula, HAART, VL<50, C/S
0 10 20 30 40 50 60
Transmission (%)
BROAD PRINCIPLES OF HIV
PREGNANCY MANAGMENT
• Maternal antiviral therapy as indicated for
non-pregnant patients
• Recommend antiviral regimen for 3rd
trimester, labour, newborn
• ECS may reduce risk, especially if VL high
• Breast feeding doubles MTCT risk
• Exclusive breast feeding appears to be
safer than mixed feeding
PREVENTION OF PERINATAL
TRANSMISSION OF HIV
Current status
• Rate of perinatal transmission can be 1% or less
when
♦ Maternal viraemia well controlled
♦ Potent antiretrovirals used
♦ Delivery by caesarean section
♦ Infant bottle fed
• Strategies depend on identifying HIV positive
women before, or early in, pregnancy
• Best strategy is to prevent women becoming HIV
infected
CLINICAL DIAGNOSIS
OF HIV
PAEDIATRIC HIV:
MANAGEMENT
ISSUES
Children are not just small adults !
Differences:
• Immunology Differences
in ART
- Developing immune system
- Functioning thymus
Early or late
disease
No clear set point
200
80
Percentage of adult function
body water
gastric acid
50 20
body fat
0 0
H. Lyall
PAEDIATRIC ARV FORMULATIONS
LIQUID ARVs TABs, CAPs ONLY
NRTIs NRTIs
• Zidovudine (AZT/ZDV) • ddI/didanosine
• 3TC/lamivudine • Tenofovir (TDV)
• D4T/stavudine (powder) • FTC/emtricitabine
NNRTIs PIs
• Nevirapine (NVP) • Saquinavir (SQV)
• Efavirenz (EFV) • Atazanavir
PIs • Darunovir, tipranavir (TPV)
• Ritonavir (RTV) COMBOs
• Lopinavir/r • Combivir (AZT, 3TC)
• Fosamprenavir • Trizivir (AZT, ABC, 3TC)
• Nelfinavir (powder) • Kivexa (ABC, 3TC)
COMBOs • Truvada (TDV, FTC)
• Kaletra • Atripla (FTC, TDV, EFV)
(Not licensed in Australia)
ARV SYRUPS
ADVANTAGES DISADVANTAGES
• Ease of administration, • Cost
adherence • Availability
• Dosage calculation • Refrigeration
• Dosage adjustment • Storage, transport
• Taste
• Lack of combinations
(except Kaletra)
COMBINATION TABLETS
TRIOMUNE
• D4T 40 mg + 3TC 150 mg + NVP 200 mg
• Adult dose: 1 twice daily
• 40 Kg child (age ~ 11 y): 1 twice daily
• 20 Kg child (age 6 y):
D4T 20 mg bd (in ½ tab)
3TC 80 mg bd (in ½ tab)
NVP 140 mg (½ tab = 100 mg)
PAEDIATRIC HIV: Other Issues
Nutrition
Neurodevelopment
Testing
Prevention of infections
Opportunistic infections and
prophylaxis
Immunisations
AGE AT PCP DIAGNOSIS
Perinatally acquired HIV, USA, 1981-90
250
200
Number of cases
150
100
50
0
0-2 3-5 6-8 9-11 12-14 15-17 18-20 21-23 24-26 27-29 30-32 33-35 > 35
Age (months) at PCP diagnosis
HIV and CHILDHOOD
IMMUNISATION
• http://www.ctu.mrc.ac.uk/penta/
• Pediatric AIDS: The challenge of HIV infection in
infants, children & adolescents (3rd Ed). Eds Pizzo PA,
Wilfert CM. Williams & Wilkins, Baltimore, 1998
• Medical Management of AIDS in Children. Shearer WT,
Hanson IC. Saunders, Philadelphia, 2003
• http://www.aids-ed.org/ppt/nrc_pediatric_arv_guidelines_9-03.ppt