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

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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

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Special Considerations in Pediatric ARV
Therapy

• Diagnostic issues
• Pharmacokinetic changes
• Availability of pediatric formulations
• Natural history differences in virologic and
  immunologic markers
• Adherence issues

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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
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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

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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 (lt48 hours)
• 14 days (optimal)
• 12 months
• 36 months

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Diagnostic Issues in Infants

• HIV is reasonably excluded with
• 2 or more negative virologic tests
• One at age gt1 month
• One at age gt4 months
• 2 or more negative HIV antibody tests at gt6
  months (in the absence of breast feeding)

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Pediatric HIV ClassificationAge-Specific CD4
Immunologic Categories
Age of Child Age of Child Age of Child
lt12 months 15 years gt6 years
Immune Category Number/µL () Number/µL () Number/µL ()
Category 1 gt1,500 (gt25) gt1,000 (gt25) gt500 (gt25)
Category 2 7501,499 (1524) 500999 (1524) 200499 (1524)
Category 3 lt750 (lt15) lt500 (lt15) lt200 (lt15)
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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

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Immunologic Parameters in Children

• 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 lt6 years

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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.)

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HIV RNA and ChildrenClinical 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

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HIV RNA and ChildrenClinical Considerations

• Low levels at birth rise to gt100,000 copies/mL to
  several million copies within the first 12
  months of life
• Without treatment, very slow decline over several
  years to reach set point

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HIV RNA and ChildrenClinical Considerations

• Children gt12 months with HIV RNA gt100,000
  copies/mL are at higher risk for disease
  progression and death
• Predictive value of HIV RNA in infants lt12 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 lt12 months than HIV
  RNA in older children both parameters are useful

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HIV RNA in ChildrenClinical 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

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HIV RNA and ChildrenClinical 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

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Antiretroviral Treatment Guidelines for Children
with HIV Infection
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Decision Factors about ARV
Initiation in Children

• Disease severity and risk of progressionpresence/
  hx of serious illness, CD4 count, HIV RNA
• Availability of appropriately formulated and
  palatable drugs

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Decision Factors about ARV
Initiation in Children

• Complexity of regimen and potential adverse
  effects
• Effect of initial choice on later therapeutic
  options

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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 childs other
  medications
• Ability of the child and caregiver to adhere to
  the regimen

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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

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Delayed Initiation of Therapy Potential
Advantages

• Delaying 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

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ARV Therapy for Infants lt12 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

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ARV Therapy for Infants lt12 Months
The Working Group recommends

• Initiate treatment for any infant with clinical
  or immunologic symptoms
• Consider treatment for infants who are
  asymptomatic with normal immune function

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Indications for Initiation of ARV Therapy in
Children lt12 Months of Age
Clinical Category CD4 Cell Percentage Plasma HIV RNA Copy Number1 Recommend
Symptomatic (Clinical Category A, B, or C) OR lt25 (Immune Category 2 or 3) Any Value Treat
Asymptomatic (Clinical Category N) AND gt25 (Immune Category 1) Any Value Consider Treatment2
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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 gt12 months, plasma HIV RNA may
  provide information about progression risk as an
  adjunct to clinical/immune parameters and can
  assist in making ARV decisions

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ARV Therapy for Children Age 12 Months and Older
The Working Group recommends

• 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 gt100,000 copies/mL

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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 lt100,000 copies/mL) when
  adherence factors favor postponing
• Monitor virologic, clinical, and immunologic
  status

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ARV Therapy for Children Age 12 Months and Older

• Factors to consider in deciding when to initiate
  therapy
• Increasing HIV RNA levels (gt100,000 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