Indications for Initiation of ARV Therapy in Children Age >1 Year

Clinical CategoryCD4+ Cell

Percentage

Plasma HIV RNA Copy

NumberRecommendation

AIDS (Clinical Category C)

OR

<15%

(Immune

Category 3)Any Value Treat

Mild-Moderate

Symptoms (Clinical Category

A or B)

OR

15–25%

(ImmuneCategory 2)

OR>100,000

copies/mL2

Consider

Treatment

Asymptomatic (Clinical

Category N)AND

>25%

(Immune

Category 1)

AND

<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

• 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

The goals of ARV therapy are:

Choice of Initial ARV Therapy

• Consideration of resistance testing before initiation of therapy in newly diagnosed infants <12 months

• Particularly if mother has known or suspected drug-resistant virus

The Working Group recommends:

Recommendations on ARV Regimens for Initial Therapy

• 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

Working Group criteria:

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• Potent

• NNRTI-sparing

• Targets HIV at 2 steps

• Resistance requires multiple mutations

Disadvantages• High pill burden

• Multiple drug interactions

• 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 life-threatening skin rashes

• Hepatic toxicity

• Multiple drug interactions

Initial ARV Therapy:Recommended (NNRTI-Based)

Strongly recommended:

•Children >3 years:

Efavirenz3 + 2 NRTIs1

•Children <3 years or who cannot swallow capsules: Nevirapine3 + 2 NRTIs1

Alternative recommendation:

Nevirapine + 2 NRTIs in children >3 years old

NRTI-Based Regimens

Advantages

• Spares other classes of drugs

• Minimal drug-drug interactions

• Limited NRTI cross resistance

• Palatable

• Lower pill burden

Disadvantages

• May be less potent than other regimens

• 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)

11/26/03 AETC NRC 16

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

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

• 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)

Immunologic Considerations for Changing ARV Therapy

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– Review patient medications

• Perform resistance testing– 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

• Misinformation

• Distrust of the medical establishment

• Fear of ARV

• Lack of belief in the effectiveness of ARV

• Low self-esteem

• Unstructured and chaotic lifestyle

• 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