Guidelines for the Use of Antiretroviral Agents in

Pediatric HIV Infection

DR. S.K CHATURVEDI

DR. KANUPRIYA CHATURVEDI

Antiretroviral (ARV) Therapy in Adults and Children

• Similar pathogenesis of HIV infection

• General virologic and immunologic principals for antiretroviral therapy apply

• Unique considerations in infants, children, and adolescents

Special Considerations in Pediatric ARV Therapy

• Diagnostic issues

• Pharmacokinetic changes

• Availability of pediatric formulations

• Natural history differences in virologic and immunologic markers

• Adherence issues

Changing Pharmacokinetics• Age-related differences between children &

adults

– Body composition

– Renal excretion

– Liver metabolism

– Gastrointestinal function

– Enzyme maturation

• Drug distribution, metabolism and clearance

• Drug dosing and toxicities

Lead to potential differences in:

Diagnostic Issues

• Early identification = all pregnant women must be offered HIV counseling and testing

• Perinatal infection = primary infection

• Early diagnosis = starting therapy during primary/early infection

Diagnostic Issues in Infants

• HIV is diagnosed by 2 positive HIV virologic tests performed on blood samples 2 separate dates

• Use DNA PCR or HIV culture for diagnosing at:

– Birth (<48 hours)

– 14 days (optimal)

– 1–2 months

– 3–6 months

Diagnostic Issues in Infants

• HIV is reasonably excluded with:

– 2 or more negative virologic tests

• One at age >1 month

• One at age >4 months

– 2 or more negative HIV antibody tests at >6 months (in the absence of breast feeding)

Pediatric HIV ClassificationAge-Specific CD4+ Immunologic Categories

Age of Child

<12 months 1–5 years >6 years

Immune Category

Number/µL

(%)

Number/µL

(%)

Number/µL

(%)

Category 1>1,500

(>25%)

>1,000

(>25%)

>500

(>25%)

Category 2750–1,499

(15–24%)

500–999

(15–24%)

200–499

(15–24%)

Category 3<750

(<15%)

<500

(<15%)

<200

(<15%)

Pediatric HIV Classification Clinical Categories

• Category E: Perinatally Exposed

• Category N: Not Symptomatic

• Category A: Mildly Symptomatic

• Category B: Moderately Symptomatic

• Category C: Severely Symptomatic

• Absolute CD4+ counts in healthy children are much higher than in adults

• Normal absolute CD4+ counts slowly decline to adult levels by age 6

• If using CD4+ count for ARV decision, use appropriate levels

• CD4 percent varies less with age and may be a better immunologic parameter to follow in children <6 years

Immunologic Parameters in Children

• Obtain baseline CD4 assays when child is clinically stable

• Confirm CD4 changes with a second test before making therapy decisions (when to initiate therapy, when to change therapy, etc.)

Immunologic Parameters in Children

HIV RNA and Children:Clinical Considerations

• HIV RNA and CD4 assays are independently predictive of risk of disease progression

• Both help determine when to start and when to change ARV therapy

• A 5-fold change in HIV RNA copies/mL in infants or 3-fold change in children is biologically and clinically significant

HIV RNA and Children:Clinical Considerations

• Low levels at birth rise to >100,000 copies/mL to several million copies within the first 1–2 months of life

• Without treatment, very slow decline over several years to reach “set point”

HIV RNA and Children:Clinical Considerations

• Children >12 months with HIV RNA >100,000 copies/mL are at higher risk for disease progression and death – Predictive value of HIV RNA in infants <12 months old

less than older children

– In infants, HIV RNA levels are much higher and overlap with rapid and non-rapid progressors

– CD4+ counts/percentages may be more useful in evaluating risk in infants <12 months than HIV RNA; in older children both parameters are useful

HIV RNA in Children:Clinical Considerations

• Moderate predictive value of specific HIV RNA levels for disease progression/death in individual child

• HIV RNA levels difficult to interpret in first year of life

• CD4+ and HIV RNA level provide complimentary and independent information about prognosis

• Assess HIV RNA every 3-4 months

HIV RNA and Children:Clinical Considerations

• Obtain 2 baseline HIV RNA tests when child is clinically stable

• Confirm HIV RNA changes with a second test before making therapy changes

• Consult pediatric HIV specialist when interpreting HIV RNA for clinical decision-making

Antiretroviral Treatment Guidelines for Children

with HIV Infection

Decision Factors about ARV Initiation in

Children

• Disease severity and risk of progression—presence/hx of serious illness, CD4+ count, HIV RNA

• Availability of appropriately formulated and palatable drugs

Decision Factors about ARV Initiation in Children

• Complexity of regimen and potential adverse effects

• Effect of initial choice on later therapeutic options

Decision Factors about ARV Initiation in Children

• Presence of comorbidities (e.g. TB, Hep B or C, or chronic renal/liver disease)

• Potential ARV interaction with child’s other medications

• Ability of the child and caregiver to adhere to the regimen

Early Initiation of Therapy: Potential Advantages

Starting ARVs in the asymptomatic patient:– Controls viral replication while genetic quasispecies

are relatively homogeneous and before significant viral mutations occur

– Could control development of heterogeneous viral strains/mutations

– Potentially leads to less drug resistance

– Could lower “viral setpoint”fewer viral strains

– Slows immune system destruction preserving immune function and preventing clinical progression

Delayed Initiation of Therapy:

Potential AdvantagesDelaying ARV therapy until symptomatic:

– Could reduce evolution of drug-resistant virus due to lack of drug selection pressure exerted by early ARV use

– May support greater adherence when symptomatic

– Reduces or delays adverse effects of ARVs

ARV Therapy for Infants <12 Months

• Risk of disease progression is inversely correlated with age

• Limited data on rapid v. slower disease

• Limited clinical trial data on early aggressive therapy

• Limited information on drug dosing

• Potential ARV toxicities over the long term

ARV Therapy for Infants <12 Months

• Initiate treatment for any infant with clinical or immunologic symptoms

• Consider treatment for infants who are asymptomatic with normal immune function

The Working Group recommends:

Indications for Initiation of ARV Therapy in Children <12 Months of

Age

Clinical Category

CD4+ Cell Percentage

Plasma HIV RNA Copy Number1

Recommend

Symptomatic (Clinical

Category A, B, or C)

OR<25%

(Immune Category 2 or 3)

Any Value Treat

Asymptomatic (Clinical

Category N)AND

>25%

(Immune Category 1)

Any ValueConsider

Treatment2

ARV Therapy for Children Age 12 Months and Older

• Risk of disease progression is less in older children than in infants

• Children with fewer clinical symptoms or only moderate immune suppression are at lower risk for progression than those with more advanced clinical symptoms/immune disease

• In children >12 months, plasma HIV RNA may provide information about progression risk as an adjunct to clinical/immune parameters and can assist in making ARV decisions

ARV Therapy for Children Age 12 Months and Older

• Start treatment in children with AIDS or severe immune suppression

• Consider treatment for children with – Mild-moderate clinical symptoms

– Moderate immune suppression and/or

– Confirmed plasma HIV RNA level >100,000 copies/mL

The Working Group recommends:

ARV Therapy for Children Age 12 Months and Older

• Defer treatment in asymptomatic children with normal immune status with low risk of clinical disease (HIV RNA <100,000 copies/mL) when adherence factors favor postponing

• Monitor virologic, clinical, and immunologic status

ARV Therapy for Children Age 12 Months and Older

• Factors to consider in deciding when to initiate therapy

– Increasing HIV RNA levels (>100,000 copies/mL)

– Rapidly declining CD4+ count or percentage to values approaching severe suppression

– Development of clinical symptoms

– Ability of caregiver and child to adhere to regimen