CBSK ZNA Koningin Paola Kinderziekenhuis ARC: ZNA/UZA/ITG Philip Maes – Bart Peeters – Myriam Willems – Elke De Belder 21 December 2006 HIV in Children

CBSK ZNA Koningin Paola Kinderziekenhuis

ARC: ZNA/UZA/ITG

Philip Maes – Bart Peeters – Myriam Willems – Elke De Belder

21 December 2006

HIV in Children and early detection

00003-E-1 – December 2005

Global summary of the HIV and AIDS epidemic, December 2005

The ranges around the estimates in this table define the boundaries within which the actual numbers lie, based on the best available information.

Number of people living with HIV in 2005 Total 40.3 million (36.7 – 45.3 million)

Adults 38.0 million (34.5 – 42.6 million)

Women 17.5 million (16.2 – 19.3 million)

Children under 15 years 2.3 million (2.1 – 2.8 million)

People newly infected with HIV in 2005 Total 4.9 million (4.3 – 6.6 million)


Children under 15 years 700 000 (630 000 – 820 000)

AIDS deaths in 2005 Total 3.1 million (2.8 – 3.6 million)


Children under 15 years 570 000 (510 000 – 670 000)

00003-E-4 – December 2005

Adults and children estimated to be living Adults and children estimated to be living with HIV as of end 2005with HIV as of end 2005

Total: 40.3 (36.7 – 45.3) million

Western & Central Europe

720 000720 000[570 000 [570 000 –– 890 000]890 000]

North Africa & Middle East510 000510 000

[230 000 [230 000 –– 1.4 million]1.4 million]

Sub-Saharan Africa25.8 million25.8 million

[23.8 [23.8 –– 28.9 million]28.9 million]

Eastern Europe & Central Asia1.6 million 1.6 million

[990 000 [990 000 –– 2.3 million]2.3 million]

South & South-East Asia7.4 million7.4 million[4.5 [4.5 –– 11.0 million]11.0 million]

Oceania74 00074 000

[45 000 [45 000 –– 120 000]120 000]

North America1.2 million1.2 million

[650 000 [650 000 –– 1.8 million]1.8 million]

Caribbean300 000300 000

[200 000 [200 000 –– 510 000]510 000]

Latin America1.8 million1.8 million

[1.4 [1.4 –– 2.4 million]2.4 million]

East Asia870 000870 000

[440 000 [440 000 –– 1.4 million]1.4 million]

00003-E-7 – December 2005

ChildrenChildren (<15 years)(<15 years) estimated to be living estimated to be living with HIV as of end 2005with HIV as of end 2005

Western & Central Europe5 3005 300

[4 200 [4 200 –– 6 800]6 800]


[12 000 [12 000 –– 130 000]130 000]

Sub-Saharan Africa2.1 million2.1 million

[1.8 [1.8 –– 2.5 million]2.5 million]

Eastern Europe & Central Asia7 8007 800[5 300 [5 300 –– 14 000]14 000]

East Asia5 0005 000[1 900 [1 900 –– 14 000]14 000]South

& South-East Asia130 000130 000[73 000 [73 000 –– 250 000]250 000]

Oceania3 3003 300

[1 000 [1 000 -- 13 000]13 000]

North America9 0009 000

[4 600 [4 600 –– 14 200]14 200]

Caribbean17 00017 000

[9 900 [9 900 –– 34 000]34 000]

Latin America50 00050 000

[35 000 [35 000 –– 91 000]91 000]

Total: 2.3 (2.1 – 2.8) million

00003-E-8 – December 2005

Estimated deaths in children (<15 years) from AIDS during 2005

Western & Central Europe< 100< 100[< 200][< 200]


[4 100 [4 100 –– 33 000]33 000]

Sub-Saharan Africa520 000520 000

[460 000 [460 000 –– 610 000]610 000]

Eastern Europe & Central Asia2 100 2 100 [1 400 [1 400 –– 3 600]3 600]

East Asia1 3001 300[470 [470 –– 3 600]3 600]South

& South-East Asia31 00031 000[18 000 [18 000 –– 60 000]60 000]

Oceania700700

[180 [180 –– 3 100]3 100]

North America< 100< 100[< 200][< 200]

Caribbean3 6003 600

[1 800 [1 800 –– 7 900]7 900]

Latin America3 2003 200

[2 400 [2 400 –– 6 600]6 600]

Total: 570 000 (510 000 – 670 000)

00003-E-10 – December 2005

About 14 000 new HIV infections a day in 2005

More than 95% are in low and middle income countries

Almost 2000 are in children under 15 years of age

About 12 000 are in persons aged 15 to 49 years, of

whom:

— almost 50% are women

— about 50% are 15–24 year olds

Tyl

Child with HIV: what to do?

Child with HIV: what to do?

Don’t panic and Phone: 03/280.21.12!

HAART

Highly Active Anti Retroviral Therapy

Dramatic fall in child and adult mortality from HIV infection in Europe

Very expensive major impact on the family Wide variation in prescribing practice across

Europe: from 50% to 97% in different countries

Problems of compliance/adherence

Diagnosis

ELISA Western Blott PCR virale lading

Guidelines for HAART in HIV + children

U.S.A.:1993: Working Group on Antiretroviral Therapy and Medical

Management of HIV-Infected Children:convened by the NPHRC, HRSA & NIH

1998: CDC: MMWR: April 17, 1998/Vol.47/No. RR-42005: Most recent update Nov. 05, 2005.Europe:09/99: Current evidence for the use of Pediatric Antiretroviral

Therapy - A PENTA AnalysisBelgium:National Pediatric Working group every 3 monthswith review of the guidelines once a year

When to start HAART ?

What HAART to start with ?



When to change HAART ?



- No randomised trial evidence is available

- So decisions to start are based on:

clinical disease stage?

viral load ?

CD4% ?

cfr.: CDC 1994 Revised classification system for HIV infection in children less than 13 years of age.

- AIDS stadium or not ?

- Age ?

Basic principles for HAART in HIV + children

1. Importance of clinical trials in children

2. Management of prescribing HAART is becoming increasingly complex and should wherever possible be directed in specialised centres by a multidisciplinary team

3. Regular monitoring (clinical/biochemical/psycho-social)

4. Factors to be considered before starting HAART:

- availability, tolerability, efficacy, formulation, and side effect profile of currently available drugs, including dosage frequency, and impact on school, family, and social life

- dosage in function of the farmacokinetic, complex differences in absorbtion, distribution and metabolism

between neonates, infants, children, adolescents and adults


4. Other factors to be considered before starting HAART:

- interactions with other medications and food

- development of antiretroviral resistance, and planning for subsequent drug regimens when virological or clinical failure occurs

- a detailed understanding of the families medical and social circumstances are critical to the successful introduction

and maintenance of combination antiretroviral therapy


Personal conclusions HAART in HIV + children

HAART, 95% compliance necessary 50% success is very good universal problem motivation

– if you try to get ideality, you get realityif you try to get reality, you get shit

– hit hard, hit early compliance - adherence - ? Another way to look at it: “living met HIV”

Personal conclusions Adherence in HIV + children

Bad taste of the medication Difficult medicationscheme Food advise Quantity of pills, size of pills Adverse events Child Adaption of living to the medicationscheme Environment is not aware of the diagnosis Therapy duration

daily confrontation with sickness daily struggle with the medication altered motivation when the child is going better Child is sometimes to young to understand the necessity

of the medication QOL The weather Sleep/rest Fight with partner Seasons Relation doctor- patient Function of the multidisciplinary team Accesability of the hospital Influence of alternative medicines, healers, religious

leaders, gossip in the community

Table 1: 1994 Revised HIV pediatric classification system: Immune categories based on Age-specific CD4+ T-cells count and %

<12 months 1-5 years 6-12 years Immune category No./µL % No./µL % No./µL %

Category 1- No suppression

1500 25% 1000 25% 500 25%

Category 2- Moderate suppression

750-1499 15%-24% 500-999 15%-24% 200-499 15-24%

Category 3- Severe suppression

< 750 < 15% > 500 < 15% < 200 < 15%

Table 2: 1994 Revised HIV pediatric classification system: Clinical categories

Category N: Not symptomaticChildren who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in Category A

Category A: Mildly symptomaticChildren with 2 or more of the following conditions but none of the conditions listed in categories B and C.

- lymfadenopathy ( 0.5 cm at more than two sites; bilateral = 1 site)

- hepatomegaly

- splenomegaly

- dermatitis

- parotitis

- recurrent of persistent upper respiratory infection, sinusitis or otitis media

Table 2: 1994 Revised HIV pediatric classification system: Clinical categories

Category B: Moderately symptomaticChildren who have symptomatic conditions, other than those listed for category A or category C, that are attributed to HIV infection. Examples of conditions in clinical category B include, but are not limited to, the following:- Anemia (<8gr/dl), neutropenia (<1000/mm³), or thrombocytopenia (<100000/mm³) for 30 dd- bacterial meningitis, pneumonia or sepsis (single episode)- candidiasis, orofaryngeal persisting for > 2 mm in children aged > 6 mm- cardiomyopathy- CMV infection with onset before age 1 month- diarrhea, recurrent or chronic- hepatitis, nephropathy- HSV stomatitis, recurrent (I.e. > 2 episodes/year)- HSV bronchitis, pneumonitis or esofagitis with onset before age 1 month- Herpes Zoster involving at least two distinct episodes or more than one dermatome- LIP or pulmonary lymphoid hyperplasia complex- ...

Category C: Severe symptomaticChildren who have any condition listed in the 1987 surveillance case definition for acquired immunodeficiency syndrome, with the exception of LIP

Table 3:Association of baseline CD4 T cell % with long-term risk for death in HIV- infected children

DEA THS

BASELINE # PATIENTS # %

< 5% 5%-9%

10%-14% 15%-19% 20%-24% 25%-29% 30%-34% 35%

33 29 30 41 52 49 48 92

32 22 13 18 13 15 5

30

97 76 43 44 25 31 10 33

Table 4:Association baseline # HIV RNA Copy with long-term risk for death in HIV-infected children

DEA THS

BASELINE # PATIENTS # %

4000 4001-50000

50001-100000 100001-500000

500001-1000000 1000000

Total

25 69 33 72 20 35

254

6 19 5

29 8

25

92

24 28 15 40 40 71

36

Table 5:Association baseline # HIV RNA copy & CD4 T cell % with long term risk for death in HIV infected children

DEA THS

Baseline HIV RNA / Baseline CD4 T cell %

# PATIENTS # %

100000 15% < 15%

100000 15% < 15%

103 24

89 36

15 15

32 29

15 63

36 81

Table 8: Indications for initiation of antiretroviral therapy in children >12 mm with HIV infection (Nov 26,2003)

Clinical category CD4+ Cell % Plasma HIV RNA copy number

Recommendation

AIDS

(Clinical cat. C)

<15%

(Immune cat. 3)

Any value Treat

Mild-moderate symptoms

(Clinical cat. A or B)

15-25%

(Immune cat.2)

>= 100.000 c/ml Consider treatment

Asymptomatic

(Clinical cat.N)

>25%

(Immune cat. 1)

< 100.000 c/ml Many experts would defer therapy with closely FU

OR

OR OR

AND AND

Concensus Belgian National Pediatric Group

< 6 mm of age:

Start a treatment from the moment the infection has been confirmed by:

- 2 positive elements: - Clinical status (Cat. C)

- DNA-PCR

- RNA-PCR

- Culture

- 2 positive virological results taken on 2 different samples


> 6 mm of age:

decision to treat depends on clinical criteria and/or biological criteria

- clinical: Cat. C and B (except 1 pneumonia)

- immunological: - CD4 <20% if > 1y

- CD4 <25% if < 1y

- abs. # CD4 ( >30% in <6months)

- virological: - <1y: V.L. > 100.000 c/ml

- >1y: V.L. > 150.000 c/ml


Nucleoside Reverse Transcriptase Inhibitors

Non-Nucleoside reverse Transcriptase Inhibitors

Nucleotide reverse transcriptase Inhibitors

Protease Inhibitors

Fusion Inhibitors

Mechanism of Action

Adapted from HIV/AIDS Handbook. 4th ed. Boston: Total Learning Concepts, 1999; Ritchie DJ. In: Powderly WG, ed. Manual of HIV Therapeutics. Philadelphia: Lippincott-Raven, 1997:33-41.

NNRTIworks here

PIworks here

RNA and reversetranscription

Injectionof capsidcontents

HIV particle BindingCompletedHIV particle

Maturation

Viralassembly

Protease

Translation

Proteincleavage

Integrase

Transcription

RNA DNA Provirus(circular

structure)

Integration of ProvirusDNA into Host DNA

NRTIworks here

FIworks here


< 6 mm of age:

2 NRTIs + NVP

>6 mm of age:

advanced stage: - Cat. C

- Immunological stage 3

- V.L. > 300.000 c/ml

2NRTIs + 1 PI

mild stage:

2NRTIs + 1 NNRTI

“Doctors should pay attention with the fact that patients often lie when they are telling that they’ve taken their medication.”

Hippocrates (460-377 BC)

Mother to child transmission of HIV: impact of measures of prevention

Pregnancy and HIV infection in 2005Pregnancy and HIV infection in 2005

> 90% of pediatric infections are acquired by mother to > 90% of pediatric infections are acquired by mother to child transmission child transmission

40.1040.106 persons are infected by HIV globally persons are infected by HIV globally

In BelgiumIn Belgium 35% of the HIV infected persons are women.35% of the HIV infected persons are women.80 % in childbearing age (15-40 years)80 % in childbearing age (15-40 years)

% women% women

– Subsaharian AfricaSubsaharian Africa 50% 50%

– SE Asia SE Asia 30%30%

– EuropeEurope 20%20%

HIV mother to child transmission rates in prospectively followed cohorts

When does mother to child transmission occur ?

late in utero 34%

early in utero

2%

intrapartum64%

Postpartum transmission through breast feeding: riskestimated at 3 to 9 % /year, about 25 to 40 % of the total risk

How is the timing of HIV vertical transmission established ?

in utero transmission

peripartum transmission

transmission by breastfeeding

HIV detection(PCR DNA)

+ at < 48 hoursneg at < 48 h

+ after 1 week

neg at < 1 month+ thereafter

If breastfeeding

Risk factors for mother to child transmission of HIV

Demographic and behavioural

- age - ethnicity- parity

- unprotected sexual intercourse during pregnancy- IV drug abuse

no correlationwith risk

Increased riskclinicalimmunologicalvirological

Severity of illness in the mother evaluated by:- clinical stage- immunodeficiency- viremia

- acute HIV infection- STD

Risk factors for mother to child transmission of HIV

obstetricalincreased risk

- cervico-vaginal infection- chorioamnionitis

invasive interventions- amniocentesis- episiotomy

rupture of membranes > 4 hours

- vaginal delivery- C section during labor

premature delivery

Risk of vertical transmission according to viral load

% périnatal transmission

0

16,621,3

30,9

40,6

0

10

20

30

40

50

<1 K 1 K-10 K 10 K-50 K 50 -100 K >100 K

HIV RNA

Source: Garcia et al. NEJM 1999;341:394-402

The risk of vertical transmission is increased by:

• the severity of the maternal illness.

• the exposure of the child to maternal fuids during labor and delivery.

• breastfeeding.

The risk of vertical transmission can be reduced by

formula feeding

obstetrical interventions

antiretroviral treatment

Nduati et al, JAMA 2000

A randomised trial of breast versus formula feeding

425 women enrolled MTCT was 37% in the BF arm and 21% in FF arm at

24 months, an absolute difference of 16% BF was associated with a 44% increased risk of

transmission

ACTG 076:

25,5

8,3

0

10

20

30

Placebo ZDVTra

nsm

issi

on (

%)

Source: Connor et al. NEJM 1994;331:1173-80.

ZDV reduces the risk of perinatal transmission by 67 %Excellent short term tolerance

HIVNET 012 (at 14-16 weeks)HIVNET 012 (at 14-16 weeks)

25,1

13,1

0

5

10

15

20

25

30

ZDV(1 week) NVP

Tra

nsm

issi

on (

%)

Source: Guay et al. Lancet 1999;354:795802.

Cost of antiretroviral regimen to prevent vertical transmission of HIV

800

280

40

200

400

600

800

1000

ACTG 076 Thai HIVNET 012

Cos

t (U

S $)

VIH transmission and mode of delivery

% transmission (1) (2)

Vaginal, no ZDV 19.5 19

Vaginal + ZDV 4.3 7.3

Elective C-section, no ZDV 3.9 10.4

Elective C-section + ZDV 0.8 2

(1) Metaanalysis of 15 studies, 8533 mother-child pairs - The International Perinatal HIV Group NEJM 1999; 340:977

(2) Randomised study, 370 deliveriesThe European Mode of Delivery CollaborationLancet 1999; 353:1035

European collaborative study: Trends over time in antiretroviral administration during pregnancy

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1999 2000 2001 2002 2003

Triple+ therapy Double therapy Monotherapy

European collaborative study: Trends over time in mode of delivery

0

10

20

30

40

50

60

70

80

1997 1998 1999 2000 2001 2002 2003

%

elective Csection emergency Csection Vaginal delivery

European collaborative study: Trends over time in vertical transmission rates

14,5

8,5

5,4

2,2

13,713,4

0

2

4

6

8

10

12

14

16

85-87 88-90 91-93 94-96 97-99 00-03

%

N= 4064 women and 4047 infants

Trends over time in HIV vertical transmission rates in industrialised countries

Transmission %

PACTG 247 (2/3 combination ) 2.7 PACTG 367 (USA cohort, 78% HAART) 3 WITS cohort (250 with HAART) 1.2 Europe C/S trial (ZDV+C/S) 2 PACTG 316 1.5 Meta-analysis: 1000 HIV-RNA copies 1

Prevention of the vertical transmission of HIV by HAART and obstetrical interventions

• Highly active antiretroviral therapy during pregnancy, associated with an elective C-section, allows to reduce transmission rates to < 2 %.

• There is no situation in which the risk of transmission is absent.

Long term side-effects observed in children exposed in utero to ARV agents..

No excess of malformations.

Excess of mitochondriopathy ?

Excess of febrile seizures ?

Excess prematurity in relation with HAART ?

FDA class

Exposition during 1st

trimestre in ARV pregnancy

registerclinical studies

transplacental passage

NUCLEOSIDESZidovudine C 2,80% PACTG 076 0,8Lamivudine C 3% yes 1Abacavir C no yesDidanosine B PACTG 249 0,5Stavudine C 2,20% PACTG 332 0,76

NUCLEOTIDETenofovir B no yes animal

NON NUCLEOSIDESNevirapine C 2% PACTG 250 1Efavirenz C no 1

Anti protéasesNelfinavir B PACTG 353 minimalSaquinavir B PACTG 386 minimalRitonavir B PACTG 354 minimalIndinavir C PACTG 358 minimalLopinavir C no ?Amprenavir C no ?Atazanavir B no ?

Toxicity for the fœtus of antiretroviral agents Toxicity for the fœtus of antiretroviral agents administered during pregnancyadministered during pregnancy

Lancet 1999;354:1084-89Lancet 1999;354:1084-89

Study ANRS 075 “tolerance of ZDV+3TC administered to prevent MCT of HIV”

ZDV (ACTG076) + 3TC starting at 32 weeks.

Discontinuation of the study after the death of 2 children with a mitochondriopathy

Review of the french cohort 6 other cases of mitochondrial impairment (4 had received only ZDV)

What’s next? Important to participate into ECS & Penta-trials

Volgend jaar : les 7 op 11 januari

Leven met HIV ?!, Sensoa Verpleegkundige zorgen, Geert Peuskens,

UZA

Documents

CBSK ZNA Koningin Paola Kinderziekenhuis ARC: ZNA/UZA/ITG Philip Maes – Bart Peeters – Myriam Willems – Elke De Belder 21 December 2006 HIV in Children