Transcript Indications for Initiation of ARV Therapy in Children Age >1 Year Clinical Category AIDS (Clinical Category C) Mild-Moderate Symptoms (Clinical Category A or B) Asymptomatic (Clinical Category N) OR OR CD4+ Cell Percentage (Immune Category 3) 15–25% (Immune OR Category 2) AND >25% AND (Immune Category.

Indications for Initiation of ARV
Therapy in Children Age >1 Year
Clinical Category
AIDS (Clinical
Category C)
Mild-Moderate
Symptoms
(Clinical Category
A or B)
Asymptomatic
(Clinical
Category N)
OR
OR
CD4+ Cell
Percentage
<15%
(Immune
Category 3)
15–25%
(Immune
OR
Category 2)
AND
>25%
AND
(Immune
Category 1)
Plasma HIV
RNA Copy
Number
Recommendation
Any Value
Treat
>100,000
copies/mL2
Consider
Treatment
<100,000
copies/mL2
Many experts
would defer
therapy and
closely monitor
clinical, immune
and viral
parameters
Choice of Initial ARV Therapy
• Use ZDV monotherapy only for
prophylaxis in indeterminate infant in
first 6 weeks of life
• Use combination ARV therapy with at
least 3 drugs
• Slows disease progression
• Improves survival
• Sustains virologic response better
• Delays development of resistance
Choice of Initial ARV Therapy
The goals of ARV therapy are:
•
Maximal suppression of viral replication
to undetectable levels, if possible, for as
long as possible
•
Preservation or restoration of immune
function
•
Prevention of complications of HIV
infection, including opportunistic
infections
Choice of Initial ARV Therapy
The Working Group recommends:
•
Consideration of resistance
testing before initiation of
therapy in newly diagnosed
infants <12 months
•
Particularly if mother has known
or suspected drug-resistant virus
Recommendations on ARV
Regimens for Initial Therapy
Working Group criteria:
• Data demonstrating durable viral
suppression, immunologic and clinical
improvement
• Incidence and types of drug toxicity
• Availability/palatability of formulations for
children
• Dosing frequency, food and fluid needs
• Potential for drug interactions
Types of ARV Regimens for
Children
• PI-based
(2 NRTIs + PI)
• NNRTI-based
(2 NRTIs + NNRTI)
• NRTI-based
(3 NRTIs)
Drug Regimen Categories
for Initial Therapy
• Strongly recommended
• Recommended as an alternative
• Offered in special circumstances
• Not recommended
• Insufficient data for recommendation
PI-Based Regimens
Advantages
Disadvantages
• Potent
• High pill burden
• NNRTI-sparing
• Multiple drug
interactions
• Targets HIV at 2
steps
• Resistance
requires multiple
mutations
• Metabolic
complications
• Poor palatability
• Few pediatric
formulations
Initial ARV Therapy:
Recommended (PI-Based)
Strongly
recommended:
Lopinavir/ritonavir or nelfinavir
or ritonavir + 2 NRTIs1
Alternative
recommendation:
Amprenavir (children >4 years old)2
or indinavir + 2 NRTIs1
NNRTI-Based Regimens
Advantages
•
Effective
•
Palatable
•
Less
dyslipidemia/fat
maldistribution
•
PI-sparing
•
Lower pill burden
Disadvantages
• Cross resistance
among NNRTIs
• Rare, but serious lifethreatening skin
rashes
• Hepatic toxicity
• Multiple drug
interactions
Initial ARV Therapy:
Recommended (NNRTI-Based)
Strongly
recommended:
Alternative
recommendation:
•Children >3 years:
Efavirenz3 + 2 NRTIs1
•Children <3 years or who cannot
swallow capsules: Nevirapine3 +
2 NRTIs1
Nevirapine + 2 NRTIs in children
>3 years old
NRTI-Based Regimens
Advantages
Disadvantages
• Spares other classes
of drugs
• May be less potent
than other regimens
• Minimal drug-drug
interactions
• Limited NRTI cross
resistance
• Palatable
• Lower pill burden
• Rare, but serious
lactic
acidosis/hepatic
steatosis
• Potential for ABC
hypersensitivity
Initial ARV Therapy:
Recommended (NRTI-Based)
Strongly
recommended:
None
Alternative
recommendation:
Zidovudine + lamivudine +
abacavir
Use only in special
circumstances:
2 NRTIs1
Initial ARV Therapy:
Not Recommended
• Monotherapy—except ZDV prophylaxis for HIV
exposed infants during the first 6 weeks of life
• Certain 2 NRTI combinations
– Antagonistic: ZDV/d4T
– Overlapping toxicities: d4T/ddC, ddI/ddC, 3TC/ddC
– Similiar structure and identical resistance: 3TC/FTC
• Saquinavir: requires RTV boosting to achieve
adequate drug level; pediatric dose unknown
Initial ARV Therapy:
Insufficient Data to Recommend
• Two NRTIs + delavirdine
• Dual PIs (except lopinavir/ritonavir)
• NRTI + NNRTI + PI (except EFV + NFV +
1 or 2 NRTIs)
• Regimens containing
–
–
–
–
–
–
Emtricitabine (FTC)
Tenofovir
Atazanavir
Fosamprenavir
Tipranavir/ritonavir
Enfuvirtide (T-20)
Changing ARV Therapy
• Failure based on virologic,
immunologic, or clinical parameters
• Toxicity or intolerance on the current
therapy
• Consider change if there is new data
demonstrating that another regimen
is superior to the current regimen
11/26/03
AETC NRC
16
Virologic Considerations for
Changing ARV Therapy
• Less than 1.0 log10 decrease in HIV
RNA from baseline 8-12 weeks after
start of ARV therapy
• HIV RNA not suppressed to
undetectable levels after 4-6 months
• Repeated detection in HIV RNA levels
after undetectable levels on ARVs
• A reproducible increase in HIV RNA
after substantial response
Monitoring Virologic Response
to Therapy Change
• Assess virologic response within 4
weeks after initiating or changing
therapy
• Measure HIV RNA levels at least every
3 months
• Resistance testing is recommended for
persistent or increasing HIV RNA levels
Immunologic Considerations
for Changing ARV Therapy
•
•
•
Change in immune classification
For children with <15% CD4+, persistent
decline of ≥5%
Rapid and substantive decrease in CD4+
count (ie, >30% decline in <6 months)
Clinical Considerations for
Changing ARV Therapy
•
Progressive neurodevelopmental
deterioration
•
Growth failure despite adequate
nutritional support
•
Disease progression
Changing ARVs for
Toxicity/Intolerance
•
•
•
Choose drugs from same class with
different toxicity/side effect profiles
Change of a single drug is permissible if
a single drug can be identified as a
cause of toxicity
Do not reduce dose below lower end of
therapeutic dose range for the particular
drug
Changing ARVs for Treatment
Failure/Disease Progression
•
Assess and review adherence
–
•
Perform resistance testing
–
•
•
•
Review patient medications
Consider overlap in resistance
Change ARVs to contain at least 2 or 3 new
ARVs
Consider clinical trials of investigational
ARVs
Discuss quality of life issues
Adherence is Critical
•
•
•
•
ARV most effective in initial therapy
Poor adherence may enhance drug
resistance
Child and caregiver participation is
crucial
Assess, discuss and address
adherence issues before initiating
therapy
Adherence Issues in Children
• Availability of drugs in palatable,
liquid or mixable formulations
• Difficulty of giving drugs that have
food restrictions, because of
children’s (particularly infant) eating
schedules
• Children’s dependence on caregivers
for administration
Adherence Issues in Children
• Timing issues, e.g., during school
hours
• Families’ reluctance to disclose HIV
diagnosis may limit medication
administration at daycare/school
• Children’s developmental level
influences ability and willingness to
take medications
Adherence Issues in Adolescents
• Denial and fear of
their HIV infection
• Lack of belief in the
effectiveness of ARV
• Misinformation
• Low self-esteem
• Distrust of the
medical
establishment
• Unstructured and
chaotic lifestyle
• Fear of ARV
• Lack of familial and
social support
Adherence Issues in
Adolescents
• Adolescents’ readiness
–
Reminder systems, beepers, timers
–
Stylish pill boxes
Conclusion

Clinical care and treatment changes

U.S. Pediatric Guidelines Working Group
meets monthly and reviews clinical trials
result

Published text posted on
www.aidsinfo.nih.gov

Current slide set with speaker notes posted
on www.aidsetc.org