HIV infection in children

Paediatrics

Paediatric HIV Infection: Epidemiology, biology, and

pathophysiology

Adapted from the National AIDS Control Program Curriculum

THE UNITED REPUBLIC OF TANZANIA

MINISTRY OF HEALTH & SOCIAL WELFARE

2.5 million children, 90% in SSA

3LPM

8.7% of pregnant

12000 New HIV infections yearly in

• 1.3 million people (5.7%)

• 10% < age 15

• 12000 infant infections annually

Tanzania

• Prevalence 1.9%

Kilimanjaro region

Introduction: HIV epidemiology

UNGASS/TACAIDS (2010).

Modes of HIV Transmission to Children

• MTCT – responsible for 95% of infected infants

• Sexual transmission (adolescents/abuse)

• Transfusion of infected blood

• Unsterile injection procedures (2.5% in both adult and paediatric population)

• Scarification

Factors Contributing To High HIV Prevalence In Children In Sub-saharan Africa

• High prevalence of infection in women of childbearing age

• Efficiency of MTCT where infection rates among women (15-49 yrs) in Tanzania range from 2% (Manyara) to 15.2% (Mbeya)

Consequences of the HIV Epidemic on Children

AIDS impacts children in many ways

• Increased infant and childhood morbidity

• Increased infant and childhood mortality

• Increase in number of orphaned children

• Increased deprivations in various forms;

– Mental

– Psychological

– School dropouts

• Abuse : Physical, Sexual

HIV epidemiology - summary

• Over the past 2 decades HIV has spread worldwide with devastating epidemiological consequences particularly in Sub Saharan Africa

• MTCT is the greatest mode of transmission of HIV infection in children.

• The burden of HIV/AIDS among Tanzanian children is high: 72,000 new infections each year, 140,000 total infections, and a high proportion of orphaned children (11% of children under 18)

HIV biology

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The Biology of the Human Immunodeficiency Virus

HIV – 1

• Is found worldwide• Is the main cause of

the worldwide pandemic

NB: Unless otherwise specified, ‘HIV’ in this training refers to HIV-1

HIV – 2

• Mainly found in West Africa, Mozambique and Angola.

• Causes a similar illness to HIV – 1

• Less efficiently transmissible, rarely causing vertical transmission

• Less aggressive, slower disease progression

There are two types of HIV:

4/23/2015

HIV-1 SUBTYPES

• HIV-1 has many subtypes: A-K• A-E are the predominant subtypes

– A: W. Africa, E. Africa, Central Africa East Europe & Middle East

– B: N. America, Europe, Middle East, E. Asia, Latin America

– C: S. Africa, S. Asia, Ethiopia– D: E. Africa– E: S. E. Asia

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HIV-1 Subtype Distribution in Africa

• East and Central Africa has mainly subtype A and D.

• Southern Africa mainly subtype C.

• West Africa mainly A

• Different subtypes can combine to form diverse recombinants.

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HIV SUBTYPE C

• This is the most virulent subtype.

• It has higher transcription rates.

• In Tanzania is associated with higher MTCT rates than subtype A.

• Is associated with faster disease progression in adults.

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Viral Enzymes

• The most important are Reverse Transcriptase (RT), Protease and Integrase.• RT converts viral single-stranded RNA into a single strand deoxyribonucleic

acid (DNA).– DNA polymerizes to form a double stranded DNA (dsDNA)– DNA is incorporated into host nucleus as the proviral DNA.

• Integrase facilitates integration of the dsDNA into the host’s chromosomal DNA.

• Protease enzyme splits generated macro-proteins into smaller viral proteins (core, envelope & regulatory proteins and enzymes) which are then incorporated into the new viral particles.

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HIV - ReplicationFusion & viral entry

Reversetranscription

Integration

Transcription -Translation

Protease activity

Assembly& budding

HIV Life Cycle

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HIV biology - summary

• Rapid replication of HIV causes genetic diversity of the virus

• Knowledge of HIV structure is important in understanding the mechanism of ARV drugs

• Current ARV drugs act mainly by antagonizing various HIV enzymes necessary for viral replication

HIV pathophysiology

Cells Of The Immune System

• Found in blood and tissues

• In blood mostly are white blood cells (WBC)

– Macrophages act as clearing cells

– Neutrophils attack bacteria

– Eosinophils attack helminths (and mediate

allergies)

– B-lymphocytes make antibodies

Cells of the Immune System

– T-lymphocytes

• Responsible for attacking viruses, fungi and

some bacteria

• T helper cells central in orchestrating

function of other immune cells

– T killer cells are able to destroy infected cells

How HIV Affects the Immune System

• HIV attaches to cells of the immune system with special surface markers called CD4 receptors

• The following immune cells have CD4 receptors

• T-Lymphocytes – CD4 Cells

• Macrophages

• Monocytes

• Dendritic cells

HIV Effect on Immune System

• The hallmark of HIV/AIDS is profound immunodeficiency as a result depletion of CD4+ T lymphocytes.

• The CD4+ T cell dysfunction is two fold:– Reduction in numbers

– Impairment in function

HIV Effect On Immune System

• Reduction in the CD4 cell number and the

effects on their function reduces the capacity

of the body to fight infectious diseases

• Individuals with HIV infection are therefore

increasingly susceptible to many infections

especially at later stages of HIV infection

HIV Effect On Other Parts Of Immune System

• Lymphoid tissue destruction

• CD8+ cell dysfunction

• B cell abnormalities

• Thymic dysfunction

• Autoimmune abnormalities

Immunological Parameters in Children: Background

Immunological Parameters

• Absolute CD4 count higher in healthy children than in adults.

• Absolute CD4 count varies with age

• Normal absolute CD4 counts slowly decline to adult levels

• CD4 percentage does not change with age.

• In children < 5 yr CD4 percentage is the preferred immunological parameter for monitoring disease progression.

Immunological Parameters in Children: Background

Age-related Decrease in CD4+ Number

0

2000

4000

6000

Age in Months

CD

+ N

um

ber/m

m3

5th percentile

95th percentile

4 12 24 6090

Immunological Parameters in Children: Background

Age-related Decrease in CD4+

Percentage

0

20

40

60

80

Age in Months

CD

4+

% 5th percentile

95th percentile

4 12 24 6090

Natural History: Immunologic Parameters

• CD4 count/percentage declines with disease progression

• Rapid decline results in risk of developing AIDS or death as CD4+ cell percentage decreases below 15–20%.

– Prognosis poorer in infants <12 months than in older children

Natural History: Immunologic Parameters

• CD4+ T cell count and CD4% are useful when caring for HIV-infected infants and children

• The CD4+ T cell count or percentage value is used in conjunction with clinical indicators to guide antiretroviral treatment decisions

– CD4+ T cell values can be associated with considerable intra-patient variation.

– Transient decreases may be associated with intercurrent illnesses & vaccinations

– CD4+ T cell values are best measured when patients are clinically stable.

HIV RNA in Children

The HIV RNA pattern in perinatally infected infants

differs from infected adults (90% pediatric HIV is perinatally-

acquired)

In Infants:

• RNA levels are low at birth.

• Increase to high levels > 100,000-millions of copies/ml by 2 months of age.

• Remain high throughout the first year of life.

• Decline slowly over the next few years to “set point”.

VL VL

Adults Infants

“Set point”

3 months 1 yr

HIV RNA Response in Infants Compared to

Adults

•The mortality in young children under 2 years is very high

•Infants have much higher viral loads than adults

HIV RNA In Children

• This pattern is due to inability of the infant’s immature immune system to contain viral replication.

• There is also a greater number of HIV susceptible cells.

• High RNA levels and low CD4 counts (<15%) are independently predictive of increased risk of progression to AIDS and death.

HIV RNA in Children

• Children > 12 months with HIV RNA >100,000 copies/ml are at

higher risk for disease progression and death

• Prognostic value of RNA in infants < 12 months old is less than in older children

– CD4 percentage therefore is a better prognostic indicator of risk of disease progression and death in infants < 12 months

HIV Disease Progression In Children In Africa

Category 1 (25 – 30%):

Rapid disease progression; infants die within 1 year. Disease acquired in utero or perinatally.

Category 2 (50 – 60%):

Children who develop symptoms early in life.

Deteriorate and die by 3 to 5 years.

Category 3 (5 – 25%):

Long-term survivors who live beyond 8 years of age.

Progression

Early Severe Form Characterized by• Low birth weight• Developmental delay• Persistent oral candidiasis• Recurrent/persistent diarrhoea• Recurrent bacterial/fungal infections• Severe encephalopathy before 18 months• High viral load at birth• Rapidly decreasing CD4 counts

Progression

Slow Progression• Opportunistic Infections after 2 - 10 years• No encephalopathy, growth stunting common• Lymphoid interstitial pneumonitis (LIP), parotitis• Recurrent bacterial and fungal infections• Skin problems• AIDS related cancers• Low viral loads at birth, stable CD4 counts for 2 - 10 years then

slow decline

Natural History of HIV

Factors that related to disease progression are:

• The child’s immature immune system

• Size of infecting viral dose

• Maternal disease status

• Infant peak viremia

• Infant CD4+ cell counts