HIV in Paediatrics

22.07.15

Juan Ambrosioni, Noémie Wagner

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

• HIV: Human immunodeficiency Virus

– HIV-1: Pandemic

– HIV-2: Endemic in West Africa

• AIDS: Acquired immunodeficiency

syndrome

• ART: Antiretroviral therapy

Definitions

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

• First cases of AIDS described in early1980s

• Since then, more than 30 millions deaths

• In 2013: 35 million people infected

– Sub-saharian Africa: 1/20 adult is infected

• In 2013: 3,2 million children infected

• Since 1995: 14 million lives saved thanks to ART

WHO /UNAIDS 2013

Epidemiology

• Carte du monde avec prévalence HIV

Epidemiology: HIV-2

-Geographically restricted

-Less transmissible

-Less aggressive

-Some antiretroviral drugs (NNRTI, see later), not active

Nicolas et al. ERAIT 2015

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

Risk of getting infected with HIV (blood, body fluids):

•Transfusion: close to 100%

•MTCT (untreated mother): 30% (< 1% on ART and

undetectable VL)

•Vaginal/anal intercourse: 0,01 à 8 %

•Almost cero for oral sex (except menses or ejaculation)

•Needle injury: 0,3 %

☛ risk related to VL!!! ↗↗ during primary infection !!!

☛ circumcision: 40% decrease of risk (women to men)

☛sexual intercourse: Increased risk if local inflammation, (genital ulcer: x 10!)

Transmission

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

• The virus can infect:

- CD4 lymphocytes

- Dendritiques cells

- Monocytes and monocytes-derived cells

• HIV is also neurotropic and infect CNS!!!

Attachment of viral particles

(gp120) to CD4 and co-

receptors (CCR5, CXCR4)

Pathogenesis

1) Transmission through the mucosae (genital tract/rectum/placenta/digestive tract)

2) Depletion of lymphoid tissue in digestive tract (GALT)

=> translocation of bacterial products

☛ INCREASED IMMUNE ACTIVATION

3) progressive decrease of CD4 cell count and immune

collapse due to: - ↗ in CD4 cell turn-over

- ↗ destruction of CD4 cells

=> collapse of immune system

☛ OPPORTUNISTIC INFECTIONS (final step)

Pathogenesis (2)

Pathogenesis(3)

• Effect on the immune system

– ↗ HIV infection (the virus infect preferably activated cells)

– ↗ Increased T cell turnover immune collapse

– Fibrosis of lymphoid tissue dysfunction

• Effect on the organism (inflammation and increased replication)

– ↗ CV risk

– Neurological, bone and kidney involvement

– Increased risk of non-AIDS defining tumors

Frailty and Immune senescence =

development of typical complication of

uninfected population 10-20 years older

➤ Chronic increased immune activation

Pathogenesis (3)

Evolution clinique naturelle de

-A newborn infected in-uterus can progress much faster

-Since adolescence, clinical presentation is similar to that of adults

Natural history of HIV infection in adults

Evolution clinique naturelle de Viral markers kynetics

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

• Clinical presentation varies according to age

• Frequently the same pathogens than in HIV-neg

patients but:

– More frequently or repeated

– More severe

• Some diseases, highly specific of HIV-infected

children, e.g.:

– Pneumocystis jirovecii pneumonia (PCP)

– Esophagic candidiasis

– Lymphoid interstitial pneumonia (LIP)

– Kaposi Sarcoma

– Severe CMV infections

Clinical presentation in children (1)

Type of evolution in untreated children:

•Category 1 (25 – 30%): in general, infection acquired in-utero

• Very rapid disease progression

• Death before one year of life

•Cateegory 2 (50 – 60%)

• Symptomes appear during first years of life

• Death between 3 to 5 years old

•Cateegory 3 (5 – 25%): « long term survivors »

• children living without treatment beyond 8-y.o.

Clinical presentation in children(2)

• PCP

• LIP

• Delayed growing and repeated diarrheal episodes

• Lymphadenopathies, liver and spleen increase

• CMV Infection

• Hepatitis, retinitis, pneumonia, digestive disease,

encephalopathy, haematological involvement

• HIV-encephalopathy

• Tuberculosis

• Toxoplasmosis

• BCG-itis

Clinical presentation: infants (1)

- Severe infections / mild recurrent infections

- Chronic bilateral parotiditis

- Severe presentation of childhood infections (VZV)

- Herpes Zoster

-Repeated, extender cutaneous Infections

-HEENT recurrent Infections (Otitis, sinusitis)

-Lymphadenopathies, liver and spleen increase

☛ involution of lymphoid organs with advanced HIV infection

-Tuberculosis

Also frequent:

- Delayed puberty

- Delayed cognitive development (1/3 des patients)

Penta course, Rome 2013

Clinical presentation: children

THINK ABOUT HIV!!!!!!!!!!!!!

• Congenital infections can be evident only at that

time!!!!!!

• HIV/AIDS complications have the same clinical

presentation than in adults

Clinical presentation: adolescents

• Remember that a mononucleosis-

like syndrome can be a primary HIV

infection!!!

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

• The most frequent clinical presentation

• In general < 12 months (peak 4 – 6 months)

• Frequently associated with other infections (CMV!)

• 20-30% of mortality rate

Clinical presentation:

•Non-productive cough

and respiratory distress

•Fever (can be absent)

Radiography:

Interstitial bilateral

infiltrates

(although RX can be

normal in up to 20% of

cases)

PCP (1)

Treatment of PCP

– Start Co-trimoxazol orally or, if available, IV for

three weeks (dose 15mg/kg/d of TMP, tid or qid)

– Add prednisone 1-2 mg/kg (first week, then

decrease progressively, total 15-20 days) if

pO2<70mmHg, or clear respiratory insufficiency

– Start ART during the first two weeks of PCP

treatment

– Continue secondary prophylaxis with Co-

trimoxazol until CD4 T cell improvement

PCP (2)

•20% of infected infants, generally at the end of first year of life

•Related to EBV infection

•Exclusion Diagnosis

Clinical presentation:

Persistent cough

Bilateral Parotiditis

Persistent generalised lymphadenopathies

Hepatomegaly and other signs of cardiac insufficiency

TxRx: interstitial reticulonodular infiltrates

Interstitial Lymphoid Pneumonia (1)

Treatment ILP

• Antibiotics-Co-trimoxazole (exclude infectious causes)

• Once antimicrobials started and in presence of at least

one of the following:

• Respiratory distress

• Cyanosis

• Saturation < 90%

Add prednisone (1-2 mg/kg/d during 2 weeks, then decreasing doses)

• Start ART, if still not done

Interstitial Lymphoid Pneumonia(2)

ILP

•Hiliar Lymphadenopathy and more central infiltrates

PCP

PCP and/or ILP?

• Think TB in every HIV + patient!!

• Frequently difficult to confirm

• If immunity not compromised:

– Same clinical presentation than HIV negative children

• If advanced immunedeficiency:

– Frequently disseminated or meningeal TB

• Start 4 drugs as soon as possible

• Start ART asap, once tolerated

(within 2 weeks if severe immunodeficiency, and no more than 8

weeks after in every case for less immunosuppressed patients)

Tuberculosis (1)

Tuberculosis (2)

NCBI bookshelf

Miliary TB

– Severe delayed neurological development affecting

up to 10% of HIV infected infants

– Dysfonction similar to CP

– Motor disorders (spastic diplegia) +/- cognitive disorders

HIV-related encephalopathy

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

Stade 1 Asymptomatic or generalized adenopathies

Stade 2 Recurrent HEENT infections

HPV and molluscum extended infections. Nails mycoses.

Zoster (1 dermatome)

Chronic parotiditis

Stade 3 Moderate malnutrition

Recurrent pulmonary Infections

Recurrent oral candidiasis

TB (lungs, lymph nodes)

Chronic ILP

Unexplained haematological involvements (anemia,

thrombopenia, leucopenia)

Unexplained fever and/or diarrhea

Stade 4 Severe malnutrition

Recurrent severe bacterial infections

Oesophagic candidiasis

TB (extrapulmonary, entranodal)

PML

Zoster (multi-metameric)

PCP, CMV organ diseases

Kaposi

WHO 2006: Clinical classification (abstract)

CD4 selon âge

Immunosuppression

< 11

monts

(%)

12-35

months

(%)

36-59 months

(%)

> 5 y.o.

(/mm3)

Not significative > 35 >30 >25 >500

Mild 30-35 25-30 20-25 300-499

Advanced 25-30 20-25 15-20 200-349

Severe < 25 <20 <15 <200

WHO 2006: immunological Classification

The European collaborative study

PIDJ, 1992

Proportion of CD4 cells in

uninfected children (born from

HIV-infected mothers)

CD4 cells in healthy children (2)

The European collaborative study PIDJ,

1992

CD4 cells in healthy children(1)

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

• HIV infection in adults is based on Ab

detection +/- viral Ag P24 detection:

Diagnosis

Serologic tests according to generation:

• Tests of 1st, 2nd, 3rd generation: Only

detection of Ab (3rd G more sensitive,

pos around 4-6 weeks post-infection)

• Test of 4th generation: Simultaneous

detection of Ab and P24 Ag (pos

around 3-4 weeks post-infection)

Diagnosis

• In newborns, diagnosis cannot be based in Ab detection,

due to maternal IgGs

• IgM not useful either

Diagnostic

• Diagnosis in then based in direct detection of the virus

(genome) and the lost of maternal Abs (See later MTCT)

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

ART: targeting the replication cycle steps

• Every children < 5 y.o.

• Every children ≥ 5 y.o. with:

– CD4 < 500

–Clinical stages 3 & 4

Indications for ART (WHO 2013)

• ART: always combined therapy(SOC, three drugs)

Avoid resistance development

• First line drugs in children -Nucleoside RT inhibitors(NRTI)

-Non-Nucleoside RT inhibitors(NNRTI)

-Protease inhibitors (PI)

-Integrase inhibitors and entry inhibitors (very poor availability in Africa, thus not recommended by WHO in first line regimens)

Classic regimens:

• 2 NRTI + 1 NNRTI

• 2 NRTI + 1 PI

ART: regimens

• Choice according to:

- Age (authorized? Paediatric formulation?)

- Risk of resistance development

- Simplicity

- Side effects

- Limited experience with the more recently

developed molecules

ART : choice of regimen

Class Drug

NRTI zidovudine (AZT)

abacavir (ABC)

tenofovir (TDF)

lamivudine (3TC)

Emtricitabine (FTC)

NNRTI efavirenz (EFV)

Nevirapine (NVP)

PI Lopinavir (LPV)

Ritonavir (/r)

First line drugs in children

0-3 y.o. 3 - 10 y.o. >10 y.o. (> 35 kg)

Back-

bone ABC + 3TC

Alternative:

-AZT + 3TC

ABC + 3TC

Alternative:

-AZT + 3TC

-TDF + 3TC (or FTC)

TDF + 3TC (or

FTC)

Alternative:

-AZT + 3TC

-ABC + 3TC

3rd

agent LPV/r

Alternative: NVP

EFV

Alternative: NVP

EFV

Alternative: NVP

ART in children: 1st line regimens

WHO guidelines 2013

• NNRTI

– More paediatric formulations available

– Lower genetic barrier (resistance easily selected)

– Co-formulation

• PI

– Higher genetic barrier (‘resistant to resistance’)

– Fewer paediatric formulations available

NNRTI or PI based-regimens?

– Paradoxical worsening of clinical symptoms of a pre-

existent disease (diagnosed or not!!!), following

immunity improvement

– Up to 25% of cases following ART initiation

– More frequently seen with mycobacteria and some

fungi (crypto)

– Coud be fatal (E.g. Crypto, PML)

– Never stop ART!!! Provide anti-inflammatory treatment

IRIS (immune reconstitution inflammatory syndrome )

Age Indication

Infants of HIV-pos mothers Every child since 4-6 weeks until exclusion of

HIV infection

Infected children 0 - 5 y.o. all

≥ 5 y.o. Stage WHO 3 or 4

Or

CD4 < 350

Some experts recommend PCP prophylaxis

for every infected children in poor-resource

settings and high morbidity-mortality

countries

PCP prophylaxis

WHO guidelines 2014

• In untreated patients, production of millions virions per day

• Mutation rate 1/1000, most not functional, some potentially

resistant to drugs

• Risk of development in patients with poor adherence or low

drug exposure

• Resistant strains can also be transmitted!!!!

ART: Resistance(1)

• △ An acquired resistance will never be lost

• Every effort must be made to avoid the onset of

resistance

Drug adherence!!!!!!

• △ Resistance can be seen only under drug pressure

→ Always consider previous genotypes

ART: Resistance

ART resistance

Detection requires molecular techniques (genome amplification

and sequencing, followed by interpretation of mutations found)

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

Mother to child transmission risk:

▶ Without ARV (30%) Pregnancy: +

Delivery: +++

Lactation: +

▶ With ARV (< 1%) -If undetectable viremia during pregnancy, delivery and

breest feeding

Thanks to mother to child transmission prevention program, 500 000 new

cases have been avoided since the beginning of HIV pandemia.

MTCT transmission

Image: OMS 2013

Pregnant or breastfeeding

women HIV exposed infant

Treatment for all

TDF + 3TC (or FTC) + EVF

Breastfeeding Replacement

feeding

6 weeks ofNVP 4-6 weeks of NVP or AZT

• Option B+: Provide lifelong ART to all pregnant and

breastfeeding women with HIV regardless WHO staging or

CD4 count.

Option B: After delivery and lactation, continue ART only for

those meeting treatment eligibility criteria.

Mother to child prevention recommandations

WHO guidelines 2013

• ART for all breastfeeding mother

• Exclusive breastfeeding for the first 6 months of life

• Introduction of appropriate complementary foods

after 6 months and continued breastfeeding for the

first 12 months of life.

• Stop breastfeeding only once a nutritionally adequate

and safe diet without breast-milk can be provided

Breastfeeding recommandation

• Maternal HIV antibodies can persist in the child up to 15–

18 months of age

• A positive antibody test in a child < 18 months old is not

reliable to diagnose HIV infection

• HIV infection can only be definitively confirmed using

virological test (PCR) in children < 18 months

• In case of a positive virological test, start ART without

delay and repeat the virological test to confirm the

infection

HIV diagnosis in children < 18 mois

WHO guidelines 2013

HIV

-exp

ose

d in

fan

t o

r ch

ild <

18

mo

nth

s

Infected

In case of positive viral test - Start ART - Repeat viral test to confirm HIV infection

Uninfected. Remains at risk

until breastfeeding cessation

Infected

PCR at 1 month Antibodies

test at 9 months

Viral test

Antibody test at 18 months of age and/or 6 weeks after cessation of

breastfeeding

uninfected

+

-

+

+

-

- +

-

Infant diagnosis (virological –PCR- test available)

Uninfected. Remains at risk

until breastfeeding cessation

WHO guidelines 2013

Probable infection

periodic clinical monitoring

Antibodies

test at 9 months

Antibody test at

18 months of age and/or 6 weeks after cessation of

breastfeeding

Antibodies test

- Start ART. - Check antibodies at 9 months. If positive, repeat antibody test at 18 months of age and/or 6 weeks after cessation of breastfeeding

- Assume infected if sick - Assume uninfected if well

Possible infection

Start ART

-

+

+ -

+

-

Infant diagnosis (virological –PCR- test available) H

IV-e

xpo

sed

infa

nt

or

child

<1

8 m

on

ths

Uninfected. Remains at risk

until breastfeeding cessation

uninfected

Infected

WHO guidelines 2013

1. Definitions

2. Epidemiology

3. Transmission

4. Pathogenesis

5. Clinical presentation in paediatrics

- Presentation according to age

- Some selected diseases

6. WHO classification

7. Diagnosis

8. Antiretroviral therapy and resistance

9. Mother to child transmission

10. Take-home messages

Content

• HIV is frequent in Africa

• Think about HIV in case of repeted, severe or

uncommun infection(s)

• The standard ART is based on a combination of 2 NRTI

and 1 NNRTI or PI.

• Be aware of resistance risk. An acquired resistance will

never diseapear.

• Mother to child transmisison prevention:

– Mother ARV treatement + NVP (or AZT) in infant

during 6 weeks + exclusive breatfeeding

– Rule out infection in all exposed infant

Take-home messages

• G. Maartens, C. Celum, S. lewin. HIV infection: epidemiology,

pathogenesis, treatment and prevention Lancet 2014; 384:

258–71

• Penta Course, Roma 2013

• Consolidated guidelines on the use of antiretroviral drugs for

treating and preventing hiv infection (WHO 2013)

• Guidelines on post-exposure prophylaxis for HIV and the use of

co-trimoxazole prophylaxis for HIV-related infections among

adults, adolescents and children (WHO 2014)

• Pocket book of hospital care for children (Second edition): guidelines for the management of common childhood

illnesses (WHO 2013)

Bibliography