November 2004

Guidelines for the Use of Antiretroviral Agents in

Pediatric HIV Infection

11/04

About this Presentation

These slides were developed using the November 2004 Pediatric Guidelines. The intended audience is clinicians involved in the care of patients with HIV.

The user is cautioned that, due to the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent.

-AETC NRC

http://www.aids-etc.org

11/04

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Developed by the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children

François-Xavier Bagnoud Center, UMDNJ, the Health Resources and Services Administration (HRSA); and the National Institutes of Health (NIH)

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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

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

Drug distribution, metabolism and clearance Drug dosing and toxicities

Lead to potential differences in:

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Diagnostic Issues

Early identification means all pregnant women must be offered HIV 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 (<48 hours)

14 days (optimal)

1–2 months

3–6 months

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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 IgGs at >6 months

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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%)

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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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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

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Likelihood of Developing AIDS Within 12 MonthsBy Age and CD4+ Percentage in Children

Receiving No Therapy or ZDV Monotherapy

% withAIDS

64.9%

56.2%

45.6%

30.8%

20.5%

51.4%

40.5%

28.6%

14.7%

7.4%

40.0%

28.8%

18.0%

7.6%3.4%

31.2%

20.9%

12.0%4.7%

2.2%

24.9%

15.9%

8.8%3.6% 1.9%

20.5%

12.8%

7.2%3.1% 1.8%

0%

10%

20%

30%

40%

50%

60%

70%

6 mos 1 yr 2 yr 5 yrs 10 yrs

30%

25%

20%

15%

10%

5%

Age of Child

Figure 1

CD4 %

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Likelihood of Death Within 12 MonthsBy Age and CD4+ Percentage in Children

Receiving No Therapy or ZDV Monotherapy

Age of Child

% Mortality

CD4 %

Figure 2

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Obtain baseline CD4 assays when child is clinically stable

Confirm CD4 changes with a second test before making therapy changes

Immunologic Parameters in Children

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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

For HIV RNA, 5-fold change in infants or 3-fold change in children is biologically and clinically significant

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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

Very slow decline over several years to reach “set point”

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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

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Likelihood of Developing AIDS Within 12 MonthsBy Age and HIV-1 RNA Log10 Copy Number in Children

Receiving No Therapy or ZDV Monotherapy

Age of Child

% with AIDS

23.7%20.9%

18.8%17.0% 16.2%

17.1%

14.1%11.8%

9.8%8.9%

13.6%

10.5%8.1%

6.0% 5.1%

11.8%

8.7%6.2%

4.1% 3.2%

11.0%

7.8%5.3%

3.2% 2.2%

10.5%

7.3%4.8%

2.7% 1.8%

0%

5%

10%

15%

20%

25%

30%

6 mos 1 yr 2 yrs 5 yrs 10 yrs

3.5

4.0

4.5

5.0

5.5

6.0

HIV-1 Log10 RNA

Figure 3

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Likelihood of Death Within 12 Months By Age and HIV-1 Log10 RNA Copy Number in Children

Receiving No Therapy or ZDV Monotherapy

9.7%8.8%

8.2%7.8% 7.7%

6.0%5.0%

4.4%4.0% 3.9%

4.1%3.1%

2.5% 2.1% 2.0%3.1%2.2%

1.5% 1.1% 1.0%2.7%1.7%

1.1% 0.7% 0.6%2.5%1.5%

0.9% 0.5% 0.3%

0%

2%

4%

6%

8%

10%

12%

6 mos 1 yr 2 yrs 5 yr 10 yrs

3.5

4.0

4.5

5.0

5.5

6.0

HIV-1 Log10 RNA

Age of Child

% Mortality Figure 4

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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

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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

November 2004

Antiretroviral Treatment Guidelines for Children

with HIV Infection

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Decision Factors about ARV Initiation in Children

Disease severity and risk of progression—presence/hx of serious illness, CD4+ count, HIV RNA

Availability of appropriate, 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 child’s other meds

Ability of the child and caregiver to adhere to the regimen

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Early Therapy Controversies

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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Early Therapy Controversies

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 <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

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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:

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Indications for Initiation of ARV Therapy in Children <12 Months of Age

Clinical CategoryCD4+ 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

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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 >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

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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:

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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 <100,000 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 (>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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Indications for Initiation of ARV Therapy in Children Age >1 Year

Clinical CategoryCD4+ Cell

Percentage

Plasma HIV RNA Copy

Number Recommendation

AIDS (Clinical Category C)

OR

<15%

(Immune

Category 3)

Any Value Treat

Mild-Moderate

Symptoms (Clinical Category A or B)

OR

15–25%

(Immune

Category 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

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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

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Choice of Initial ARV Therapy

Maximal suppression of viral replication to undetectable if possible for as long as possible

Preservation or restoration of immune function

The goal of ARV therapy is:

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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:

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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:

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Types of ARV Regimens for Children

PI-based (2 NRTIs + PI)

NNRTI-based(2 NRTIs + NNRTI)

NRTI-based(3 NRTIs)

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Drug Regimen Categories for Initial Therapy

Strongly recommended

Recommended as an alternative

Offered in special circumstances

Not recommended

Insufficient data for recommendation

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PI-Based Regimens Advantages Disadvantages

Highly potent

NNRTI-sparing

Targets HIV at 2 steps

Resistance requires multiple mutations

High pill burden

Potential for multiple drug interactions

Poor palatability

Metabolic complications

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Initial ARV Therapy:Recommended (PI-Based)

Strongly recommended:

2 NRTIs1 + lopinavir/ritonavir or nelfinavir or ritonavir

Alternative recommendation:

2 NRTIs1 + indinavir or amprenavir (children >4 years old)2

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NNRTI-Based Regimens Advantages Disadvantages

Effective

Palatable

Less dyslipidemia/fat maldistribution

PI-sparing

Lower pill burden

Cross resistance among NNRTIs

Rare, but serious life-threatening skin rashes

Hepatic toxicity Multiple drug

interactions

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Initial ARV Therapy:Recommended (NNRTI-Based)

Strongly

Recommended:

Children >3 years:

2 NRTIs1 + efavirenz5

Children <3 years or who can’t swallow capsules:

2 NRTIs1 + nevirapine3

Alternative

recommendation:

2 NRTIs + nevirapine in children >3 years old

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NRTI & NtRTIAdvantages Disadvantages

Spares other classes of drugs

Minimal drug-drug interactions

Limited NRTI cross resistance

Palatable

Lower pill burden

May be less potent than other regimens

Rare, but serious lactic acidosis/hepatic steatosis

Potential for ABC hypersensitivity

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Initial ARV Therapy:Recommended (NRTI-Based)

Strongly recommended:

None

Alternative recommendation:

Zidovudine + lamivudine + abacavir

Use only in special circumstances:

2 NRTIs1

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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

Saquinavir: requires RTV boost to achieve adequate drug level; pediatric dose unknown

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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

Tenofovir Enfuvirtide (T-20) Emtricitabine (FTC) Atazanavir Fosamprenavir

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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

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Virologic Considerations for Changing ARV Therapy

Less than 1.0 log10 decrease in HIV RNA from baseline after 8-12 weeks

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

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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

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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

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Clinical Considerations for Changing ARV Therapy

Progressive neurodevelopmental deterioration

Growth failure despite adequate nutritional support

Disease progression

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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

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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 trial Discuss quality of life issues

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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

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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

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Adherence Issues in Children

Families’ reluctance to disclose HIV diagnosis may limit medication administration at daycare/school

Children’s developmental level influences ability and willingness to take medications

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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

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Adherence Issues in Adolescents

Adolescents’ readiness

Reminder systems, beepers, timers

Stylish pill boxes

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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