PAEDIATRIC HIV:

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

Western & Central Eastern Europe

Europe & Central Asia
North America 6 200 8 800
[7 100 – 13 000]
11 000 [4 900 – 7 900]
East Asia
[5 600 – 17 300]
North Africa & Middle East 9 400
Caribbean South [3 300 – 27 000]
23 000 24 000
[7 100 – 82 000] & South-East Asia
[12 000 – 49 000]
170 000
Sub-Saharan Africa [95 000 – 320 000]
Latin America 1.9 million Oceania
26 000 [1.7 – 2.3 million]
700
[21 000 – 43 000]
[< 2 500]

Total: 2.2 (2.0 – 2.6) million

00003-E-7 – December 2004
Estimated number of children (<15 years)
newly infected with HIV during 2004

Western & Central Eastern Europe

Europe & Central Asia
North America < 100 1 800
< 100 [< 200] [1 200 – 3 700]
East Asia
[< 200]
North Africa & Middle East 4 100
Caribbean South [1 500 – 11 000]
6 100 9 100
[2 800 – 30 000] & South-East Asia
[3 100 – 13 000]
51 000
Sub-Saharan Africa [30 000 – 95 000]
Latin America 560 000 Oceania
6 800 [500 000 – 650 000]
< 300
[5 400 – 11 000]
[< 1 000]

Total: 640 000 (570 000 – 750 000)

00003-E-9 – December 2004
Estimated deaths in children (<15 years)
from AIDS during 2004

Western & Central Eastern Europe

Europe & Central Asia
North America < 100 1 100
[800 – 2 200]
< 100 [< 200] East Asia
[< 200]
North Africa & Middle East 2 400
Caribbean South [900 – 6 900]
5 300 5 600
[1 700 – 19 000] & South-East Asia
[2 700 – 11 000]
37 000
Sub-Saharan Africa [22 000 – 70 000]
Latin America 450 000 Oceania
6 000 [400 000 – 540 000]
< 200
[4 800 –9 800]
[< 600]

Total: 510 000 (460 000 – 600 000)

00003-E-8 – December 2004
HIV IN DEVELOPING COUNTRIES
Demographic effects on children

• Reduced child survival

• Orphans
• Lack of education
• Economic impact - agriculture and
business
• Competing demands on health system
 Impact of orphanhood on school attendance
among 10–14-year-olds (%)

West Central Eastern Southern All

(9 countries) (6 countries) (9 countries) (10 countries) (34 countries)
Percentage in
school 67 75 70 88 74
Non-orphans 58 69 54 84 69
Orphans 57 58 49 80 64
Double orphans
Ratios
Double vs. non-
0.86 0.94 0.72 0.90 0.87
orphans
0.96 0.96 0.82 0.93 0.94
Boys
0.91 0.94 0.88 0.96 0.93
Girls

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

Male Female Total % Nat. AIDS

Total Deaths
AIDS:
Mother at risk 15 17 32 0.3 19
Blood products etc. 16 3 19 0.2 16
TOTAL CHILDREN 31 20 51 0.5 35

HIV:
Mother at risk 43 39 82 # 0.4
Blood products etc. 78 9 87 0.4

TOTAL CHILDREN 120 47 167 0.8

# 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

• Persistence of HIV antibody beyond

18 m (? 12 m in some settings)
OR
• Repeatedly positive virological tests
(DNA PCR, viral load or HIV culture)
OR
• Diagnosis of HIV-related disease
 Perinatal transmission of HIV
is preventable
• Prevention of HIV infection in women
• Antiretroviral therapy
♦ during pregnancy
♦ during labour
♦ to infant
• Elective caesarean section
• Avoidance of breast feeding

• ? Avoidance of invasive obstetric procedures

• ? Vaginal douching
• ? washing, sucking out infant
RANDOMISED, CONTROLLED TRIAL OF BREAST v.
FORMULA FEEDING, NAIROBI
Nduati et al. JAMA 2000;283:1167-1174

Breast fed (N=212) Formula fed (N=213)

40
35
% Transmission

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

GROUP No. No. Infection 95% CI

infants infected rate
PLACEBO 184 47 25.5% 18.3% - 33.7%
ZIDOVUDINE 180 15 8.3% 3.8% - 13.8%

p = 0.0006

DRUG COST: ~ $500

BANGKOK PERINATAL AZT STUDY
Kaplan-Meier Analysis

Placebo infection risk 18.9% (13.0 - 24.0)

AZT infection risk 9.4% (5.0 - 13.5)
Reduction (p=0.006) 50.1% (15 - 71)

DRUG COST: ~ $50

HIVNET 012 randomised trial: Guay LA et al. Lancet 1999;354:795-802 (N=626)
Nevirapine 200 mg po at onset labour and 2 mg/kg to babies within 72 h
v. AZT q3h in labour and bd for 7 days to infant

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

35 Therapy Viral Load

30.1
30
Probability of infection (%)

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
ot

om
U

Independent factors: Tmt, VL, C/S, ROM, NOT CD4

-
on

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

• Patterns of HIV RNA

response
- High viral load between
- “natural” decline of HIV-RNA
up to 5 yrs
adults and
children
• Pharmacokinetics
- Developing metabolic
pathways Age is a
major
• Acceptability/tolerability
- need for different formulations variable
as children grow H. Lyall
Pattern of viraemia in HIV infected adult:
Viral load - log scale

Initial peak >106 copies/ml

Late
disease

‘Set point’ = 103 - 105 /ml

Time from infection (years)

Pattern of viraemia in HIV infected infant:
Viral load - log scale

Initial peak >>106 copies/ml

Early or late
disease
No clear set point

Time from infection (years)

Plasma HIV-1 RNA in Multiple Samples from 106 Infants with HIV-1, According to Age. The solid line connects
the median values of the individual data points. The vertical bars represent the 95 percent confidence intervals .
From: Shearer: N Engl J Med, Volume 336(19).May 8, 1997.pp 1337-1342.
PAEDIATRIC MEDICATION ISSUES
• Drug licensing
• Dosing information
• Formulations
• Palatability
• Toxicities
• Pharmacokinetics
• Growth
• Disclosure issues
• Adherence
Changing pharmacokinetics with age

200
80
Percentage of adult function

body water

percent body weight

150
60
liver function
100 40
renal

gastric acid
50 20
body fat

0 0

preterm full 1 m 3m 1y 6y Adult

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

Other areas of health

‹ Dentition

‹ 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

• All routine immunisations

except:
♦ IPV instead of OPV
♦ No BCG
• Pneumococcal conjugate vaccine
• Varicella vaccine
• ? Influenza vaccine
 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
FURTHER READING, RESOURCES
• http://www.bhiva.org/
• www.aidsinfo.nih.gov/
• http://www.womenchildrenhiv.org/
♦ http://www.womenchildrenhiv.org/wchiv?page=pi-10-02

• 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