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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
Lead to potential
differences in:
– Enzyme maturation
•
•
Drug distribution, metabolism and
clearance
Drug dosing and toxicities
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 Classification
Age-Specific CD4+ Immunologic Categories
Age of Child
Immune
Category
Category 1
Category 2
Category 3
<12 months
1–5 years
>6 years
Number/µL
(%)
Number/µL
(%)
Number/µL
(%)
>1,500
(>25%)
750–1,499
(15–24%)
>1,000
(>25%)
500–999
(15–24%)
>500
(>25%)
200–499
(15–24%)
<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
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 <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.)
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 decisionmaking
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 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
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
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
Indications for Initiation of ARV
Therapy in Children <12 Months of
Age
Plasma HIV
RNA Copy Recommend
Number1
Clinical
Category
CD4+ Cell
Percentage
Symptomatic
(Clinical
Category A, B,
or C)
<25%
(Immune
Category 2 or 3)
Any Value
Treat
>25%
(Immune
Category 1)
Any Value
Consider
Treatment2
OR
Asymptomatic
AND
(Clinical
Category N)
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
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 >100,000
copies/mL
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