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Natural History of HIV Infection in Children

HAIVNHarvard Medical School AIDS

Initiative in Vietnam

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Learning Objectives

By the end of this session, participants should be able to:

Describe the characteristic, structure of HIV

Describe the and transmission route of HIV

Describe the HIV life cycle Explain HIV pathogenesis Describe the natural history of HIV

disease progression in children

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Basic Concepts

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HIV Virology HIV: Human Immunodeficiency Virus HIV is an RNA virus HIV is a “retrovirus”:

• replication occurs from RNA to DNA using the enzyme “reverse transcriptase”

• the DNA created is then integrated into the host cell genome (T lymphocyte)

• further HIV virus is then produced using this DNA complex

• Two types: HIV1 and HIV2

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HIV Virion

HIV virion taken withelectronic microscope

p24

Source of pictures: wikipedia

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CD4 Cell – Definition

CD4 cell is one type of T-Lymphocyte HIV binds with receptors on the CD4

cell to enter and infect the cell After infection, the number of CD4

cells gradually declines over time

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CD4 Count - Definition

The CD4 cell count is the number of CD4 cells in a cubic millimeter of blood

The CD4 cell count indicates extent of HIV-induced immune damage

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Viral Load – Definition

The viral load is the amount of HIV in the blood

The level of HIV in the blood indicates the magnitude of HIV replication and rate of destruction of CD4 cells

The viral load test measures the amount of HIV RNA in the plasma

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How is HIV Transmitted?

Blood/Parentally• IV drug use• Occupational exposure (needle sticks)

Unprotected sexual contact with infected partner/s • Heterosexual or homosexual

Perinatally (mother to child) • During pregnancy and labor• Through breastfeeding

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Transmission Activity

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Estimated HIV Risk for a Single Exposure to HIV Source

Blood Transfusion

Mother to child

IDU needle sharing

Occupational needle stick

Receptive anal sex

Receptive vaginal sex

Insertive anal sex

Insertive vaginal sex

Receptive oral sex

Insertive oral sex

(CDC, MMWR, 2005)

90%

25-35%

0.67%

0.3%

0.5%

0.1%

0.065%

0.05%

0.01%

0.005%

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What Characterizes HIV Transmission?

HIV is spread only through exposure to certain bodily fluids: • Blood• Semen• Vaginal secretions• Breast milk

In order for HIV to be spread, infected fluids need to be exposed to:• a mucous

membrane (vagina, eye, mouth)

• broken skin• blood (needle stick,

infusion)

HIV is difficult to transmit even through risky behaviors

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How is HIV not Spread?

HIV is NOT transmitted through casual contact such as:• Hugging or kissing• Coughing or sneezing• Sharing utensils, cups or bowls• Sharing toilets• Swimming pools• Insect bites

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How Does HIV Infect the Human Cell?

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1

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3

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Reverse tran-

scriptaseHIV RNA

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HIV Pathogenesis

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What Happens after HIV Virus Enters the Bloodstream?

Virus: • enters dendritic cells and macrophage and • is carried to regional lymph nodes, and:

infects CD4 cells produces virions, which in turn infect other CD4

cells

• also goes into other body compartments

Virus causes deaths of massive number of memory CD4 cells (impairing ability

to fight infections later on)

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Pathogenesis of HIV-infection:Compartments

Dendritic cells, macrophage

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Pathogenesis of HIV-infection (1)

Rapid HIV virus production results in:• depletion of CD4 lymphocytes and • a weakened immune system

HIV may also lay dormant in the host cell after integration into host DNA (the reservoir)• These viruses are not affected by ARVs

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Pathogenesis of HIV-infection (2)

Two main types of injury caused by HIV

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Natural History of HIV Infection in Children

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Natural History Untreated HIV infection

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Bimodal Progression of AIDS and Deaths in HIV-infected Children

1 year 5 yearDeaths 10 - 35% 40 – 50%

AIDS 25 – 30% 40 – 43%

Immune suppression 10 -20% >50%

AIDSDeaths

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Patterns of HIV Disease Progression in Children (1)

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Patterns of HIV Disease Progression in Children (2)

Long-term non-progressors:• Prevalence: about 2%, similar to adults• Definition:

Age ≥10 Never have CDC category B/C disease

(=WHO stage 3/4) CD4 > 25% Never been on ARV except AZT

Source: Warszawski et al. Clinical Infectious Diseases 2007; 45:785–94

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What are Risk Factors for Disease Progression in Children?

In utero or perinatal transmission High viral load and advanced disease

in mother Stage III/IV conditions, esp.

encephalopathy Low CD4 cells/percentage High plasma viral load

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Risk Factors for Disease Progression in Children

NOTE: Normal CD4 or low VL does not have predictive value in young children < 2, i.e. those with normal CD4 or low VL can still develop severe disease and die.

This is the basis for treating all HIV-infected children under 2 y.o

regardless of clinical and immunological stage

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Common OIs/Conditions in Vietnamese Children

• Respiratory infections, including PCP

• Tuberculosis• Oral candidiasis• Diarrhea

• PPE/dermatitis• Herpes varicella zoster• Otitis media• Hepatosplenomegaly• Failure to thrive

Infants may be symptomatic in the 1st year, after that, the majority of them tend to be:

• asymptomatic or• only with mild symptoms

Below is the list of common OIs/conditions:

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Plasma Viremia in Vertically HIV-infected Infants

Time

Viral Load

(Copies/ml

Birth – 6 months

≥106

18 months

105 -105.5

5 years ≤ 105

Copies/ml

Vir

al lo

ad

6 months

Viremia is extremely highin the first 6 months,

then gradually declines

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CD4 Percentage/Count: Which to Use?

Age Parameter to use

Comment

< 5 y.o

CD4 percentage (%) is preferred

the absolute CD4 count is generally not used due to:

• high inter-measurement variability and

• age-related decline

CD4% is more constant

≥ 5 y.o CD4 count

the CD4 count pattern is similar to that of adults in this age group

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Role of CD4 Percentage/Count

CD4 is extremely useful for:• when to start prophylactic medications• when to start ARV treatment• monitoring response to treatment• predicting risk for OI’s

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Natural History ofHIV infection treated with ART

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HIV infection treated with ART

Combination ART is associated with improvement in:• virologic, • immunologic, and • clinical health for HIV-infected adults

and children

34Brady MT, Oleske JM, Williams PL, et al. Declines in mortality rates and changes in causes of death in HIV-1-infected children during the HAART era. J Acquir Immune Defic Syndr 2010; 53:86.

7.2

0.8

Between 1994 and 2000, the mortality rate decreased 7.2 to 0.8 deaths per 100 person-years; mortality rate was inversely associated with HAART treatment

Declines in mortality rates in HIV infected children during the HAART era

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Ciaranello AL, Chang Y, Margulis AV, et al. Effectiveness of pediatric antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis. Clin Infect Dis 2009; 49:1915.

70 % of children attained virologic suppression increase of 13.7 percent in CD4 percentage

Effectiveness of pediatric antiretroviral therapy in resource-limited settings

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Key Points After infecting CD4 cells, HIV multiplies

rapidly, resulting in:• depletion of CD4 lymphocytes • weakened immune system

3 patterns of HIV disease progression in children are :• Rapid progressors• Slow progressors• Long-term non-progressors

In infants infected perinatally, viremia is extremely high in the first 6 months, then gradually declines

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CD4 count is the best way to:• Determine degree of immune suppression• Make treatment decisions• Monitor for treatment response

Combination ART is associated with improvement in: • Virologic• Immunologic• Clinical health for HIV-infected children.

Key Points

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Thank you!

Questions?