guidelines for the use of antiretroviral agents in pediatric hiv infection
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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
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