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KITSO AIDS Training Program

Lecture 5:

Pediatric Specific Issues and ARV Dosing

delivered by

Dr. Elizabeth D. LowenthalBotswana-Baylor Children’s Clinical Centre of

Excellence, Baylor International Pediatric AIDS Initiative

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Outline• Background

• Diagnosis of HIV infection in children

• Common manifestations of HIV infection in children

• Management of HIV infection in children– Nutritional needs of children

• ARV Therapy in children– When to start– Which regimens– What to monitor

• Dosing guidelines/tools – facilitate accurate prescribing

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Background (1)

• >50 million people or 1% of the world’s population infected with HIV.

• Each day > 15,000 people newly infected.

• 1,600 HIV-infected children are born every day due to peri-natal transmission.

• High prevalence among 15-19 years old women in Botswana increases risk of MTCT.

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Background (2)Pathogenesis and general immunologic and virologic principles are similar in adults and children, BUT…

• Perinatal infection– Maternal antibodies DNA PCR

• Infection in a developing body– Immature immune system CD4%– Immature liver and kidneys Dose of ARVs– Weight of growing body Dose of ARVs– Immature physiology Formulations, taste

of ARVs

• Vulnerable member of community– Dependent on others Adherence

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Diagnosis

• Antenatal Care – HIV+ pregnant mothers will expose their fetus/baby to

HIV

• Between Birth and 18 Months– DNA-PCR– 2 separate positive test results to confirm infection– 1 positive DNA-PCR can be confirmed with RNA-PCR

• Beyond 18 months (same as adults)– ELISA (antibody test)

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Pathophysiology

Because of immature immune systems at birth, control of viral replication in infants is poor. Thus, higher viral loads are reached and persist for a longer duration before steady-state levels are reached.

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Common Presenting Features of Pediatric HIV Infection

• Infectious Diseases – Oral Candidiasis, – Respiratory illnesses (PCP, Tuberculosis), – Diarrheal illnesses

• Lymphadenopathy, Hepatosplenomegaly, Parotitis

• Growth failure: Kwashiorkor, Marasmus • Malignancies (Kaposi’s sarcoma) • Developmental delay or regression • Peripheral neuropathy

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Diarrheal Illnesses

• Prevalence of specific stool pathogens is similar in HIV infected and uninfected children.

• Outcomes for HIV-infected children are worse.

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Respiratory Tract Infections

• Death from respiratory tract infections:– PCP most common

pathogen in HIV-infected children below 6 months of age.

– Acute pyogenic pneumonia and tuberculosis common in both HIV-infected and uninfected children.

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Malnutrition

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Progression of HIV Disease in Untreated Children

‘Rapid Progressor’ ‘Long-Term- Non-Progressor’

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Management of Pediatric HIV Exposure• Continue AZT begun during PMTCT for four weeks.

• All children fully/appropriately immunized. • Treatment and prophylaxis of opportunistic

infections.

• PCP prophylaxis with Cotrimoxazole™ (Trimethoprim/sulfamethoxazole-TMP-SMX). – From ages 6 weeks to 12 months (unless proven to be

HIV negative or allergic). Continue TMP-SMX if found to be HIV+

– Discontinue over 12 months of age only when CD% >15%

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Nutrition• Nutrition is a major element of child care

– Increased caloric requirements during time of infection.

• Consistent sources of healthy food may be a problem in HIV affected families– Poverty and employment– Loss of wage earners– Changing caregivers

• Traditional beliefs– Often underestimate food requirements of children

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When to Start HAART in Children

–In contrast to adults, immunologic and virologic predictors of progression in asymptomatic children and infants are not well defined.

–High viral load and low CD4% are both independent predictors of disease progression, but are of low predictive value for an individual child.

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When to Start HAART in Children (2)

• The youngest children are at greatest risk for rapid deterioration.

– In the first year:• 15-20% develop AIDS or die. • 50% develop moderate immune suppression.• Infants can progress to AIDS even with high CD4%

values.

• Risk of disease progression slows down in children over one year of age.

– 10% will survive for a prolonged period (over 5-6 years).

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2005 Botswana ART Guidelines

• All infants < age 12 months.

• Any child with clinical symptoms of disease. – Clinical Category A, B, or C (pg 64)

• Any child with immune suppression.– Immune Category 2 or 3 (pg 63)

– i.e., CD4% < 25%

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Symptoms: Clinical Categories (pg 64)

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Immune Categories by CD4 Count and CD4 % (pg 63)

Age of Child Age Age

Immunologic

Category

< 1 Year 1- 5 Years 6 – 12 Years

Category I

No evidence of suppression

> 1500 cells

>25%

> 1000 cells

>25%

> 500 cells

>25%

Category II

Moderate suppression

750 – 1499

15 – 24%

500 – 999

15 – 24%

200 – 499

15 – 24%

Category III

Severe suppression

< 750 cells

< 15%

< 500 cells

< 15%

< 200 cells

< 15%

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When to Defer Treatment

• ARV treatment may be deferred in children above 12 months of age who are asymptomatic (clinical category N) and who have a CD4% ≥ 25.

• BUT regular monitoring is required.– CD4% every three months.

– Clinical status with Ht, Wt, HC every three months.

– Developmental stages (milestones).

– For children under 2 years, head circumference every 3 months.

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Recommended Drug Regimens (1)

First- line Drug Regimens

UNDER AGE 3 YEARS:

AZT / 3TC / NVP

OVER AGE 3 YEARS:

AZT / 3TC / EFV

or

AZT / 3TC / NVP

(D4T should be used in place of AZT if baseline anemia is present)

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Recommended Drug Regimens (2)

Second-Line Drug Regimens:• DDI / D4T / NFV (same as adult 2nd line)

• DDI / D4T/Kaletra (new guidelines)

Third-Line Drug Regimens:• SQV boosted with RTV• Plus two recycled NRTIs

(depending on resistance assay and specialist

consultation – same as adult 3rd line).

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Recommended Drug Regimens (3)

Second line Regimen:

If NRTI backbone of first line regimen was d4T/3TC, then second line NRTI backbone should be AZT/ddI, if anemia is not significant.

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Longitudinal Monitoring• ART Efficacy

– Immunological response: increase in CD4% (CD4 % may fluctuate widely over time: confirm unusual value before changing regimen)

– Virological response: decrease in Viral load

• Clinically– Weight gain– Developmental stages every 3-6 months– Assess for potential side effects

• Adherence– Need for one designated caregiver responsible for ART– Assess the family situation

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When to Change a Regimen • Virologic Failure: same definition as for adults

– Inadequate suppression after treatment initiation– Viral load rebound after initially adequate suppression

• Immune Failure– Significant and persistent decline in CD4%

• Clinical Criteria – Progressive neurodevelopmental deterioration– Growth failure– Disease progression– ARV toxicity

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Pediatric Dosing Guides

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Outline of Learning Exercise

• Familiarize participants with ARV drugs dosed by body weight and body surface area in children.

• Introduce the Dosage Recommendation Chart and Confirmatory Dosage Chart to assist with accurate dosing.

• Introduce the use of a nomogram to calculate BSA.

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Dosing Medication in Children

• Infants and children have immature liver and kidney function and their body metabolism changes as growth and development occurs.

• Accordingly ARV drug dosages depend on the infant’s/child’s body weight or body surface area.

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Calculating Pediatric ARV Doses

• In children, most ARV drugs are dosed by body weight:

– 3TC, NVP, EFV, d4T, NFV, LPV/r and SQV*

• Some ARV drugs are dosed by BSA—body surface area – m2

– AZT, ddI, and RTV*

*third line drugs

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Principles of dose calculation

• Calculation of ARV drug doses for infant and children involve the same general principle as dosage calculation for other drugs:

– ARV drug dosed on body weight• Patient dose = recommended dose in mg/kg X patient

weight in kg.

– ARV drug dosed on Body Surface Area (BSA)• Patient dose = recommended dose in mg/m2 X patient

BSA in m2.

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Patient 1: First line RegimenAZT 3TC NVP EFV

Dose 240mg/m2/ds BD

Peds:

4mg/kg/ds BD

Adolescents < 50 kg: 2mg/kg/ds BD

Peds < 8 yrs: 7mg/kg/ds*

Peds > 8 yrs: 4mg/kg/ds*

Refer to

Botswana

National

Guidelines

Formulation 10mg/ml liq

100mg cap 300mg tab

10mg/ml liq

150mg tab

10mg/ml liq

200mg tab

Patient:

4.5 kg

48 cm

0.22 m2

5.3 ml/ds BD 1.8 ml/ds BD 3.2 ml/ds*

(if < 8yrs)

*Start OD for 2 weeks, then BD.

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Calculation of 3TC dose

3TC dose Weight Dose

4 mg/kg/dsBD

X 4.5 kg = 18 mg

18 mg Divided by 10mg/ml

= 1.8 ml BD

(q12 hrs)

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Calculation of NVP dose

NVP dose Weight Dose

7 mg/kg/dsBD

X 4.5 kg = 31.5 mg

31.5 mg Divided by 10mg/ml

= 3.15 ml

Or

3.2 ml

BD*

*Initiate at OD, for two weeks, then increase to BD.

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Body Surface Area

• BSA (m2) can be estimated by:

height (cm) X weight (kg)

3600

• Nomograms for BSA

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Nomogram for Estimation of BSA(Body Surface Area)

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BSA: Nomogram or Formula

height weight Nomogram

48 cm 4.5 kg = 0.22 m2 BSA

48 X 4.5 =

3600

0.25 m2 BSA

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Calculation of AZT dose

AZT dose BSA Dose

240 mg/m2/ds BD

X 0.22 m2 = 52.8 mg

52.8 mg Divided by 10mg/ml

= 5.28 ml or

5.3 ml

BD

(q12 hrs)

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Patient 1: Second line Regimen  ddI d4T LPV/r NFV

Dose Recommendation: 90-150mg/m2/ds BD

Authors choose: 120mg/m2/ds BD

1mg/kg/ds BD

7-15kg:

12/3mg/kg/ds BD

15-40kg:

10/2.5mg/kg/ds BD

Recommendation:20-55 mg/kg/ds BD

Authors choose: 55mg/kg/ds BD

Form-ulation

10mg/ml liq

25mg tab50mg tab

1mg/ml liq

15mg cap20mg cap30mg cap40mg cap

80mg LPV +

20mg RTV / ml liq

133mg LPV + 33mg RTV /cap

50mg/scoop

250mg tab

Patient:4.5 kg48 cm0.22 m2

BSA

2.6 ml/ds BD

No single tab

4.5 ml/ds BD No recommended dose for children < 7kg.

(247.5 mg/ds)5 scoops/ds BD or 1 tab/ds BD

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Calculation of d4T dose

d4T dose weight Dose

1 mg/kg/dsBD

X 4.5 kg = 4.5 mg

4.5 mg Divided by 1mg/ml

= 4.5 ml BD

q12 hrs

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Calculation of NFV dose

NFV dose weight Dose

55 mg/kg/dsBD

X 4.5 kg = 247.5 mg

247.5 mg Divided by 50mg/

scoop

= 4.95 scp

Or

5 scoops

BD

q12 hrs

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Calculation of ddI dose

ddI dose BSA Dose

120 mg/m2/ds

(twice daily)

X 0.22 m2 = 26.4 mg

26.4 mg Divided by 10mg/ml

= 2.64 ml or

2.6 ml

BD

No single tab

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Special Considerations for Pediatric Dosing:

• NVP dose is first given once daily for 2 weeks and then increased to twice a day.

• EFV should only be used with children three years of age and older.

• There is no recommended dosage of Kaletra (LPV/r) for pediatric patients with a weight of < 7 kg.

• ddI cannot be given as a single tablet due to an inadequate amount of buffer in a single tablet. All ddI doses should involve two tablets, taken together, to ensure an adequate amount of buffer.

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Patient 2: First line RegimenAZT 3TC NVP EFV

Dose 240mg/m2/ds

BD

Peds:

4mg/kg/ds BD

Adolescents <50 kg: 2mg/kg/ds BD

< 8 yrs: 7mg/kg/ds*

> 8 yrs: 4mg/kg/ds*

15-20 kg:

250 mg OD

Formu-lation

10mg/ml liq

100 mg cap 300mg tab

10mg/ml liq

150mg tab

10mg/ml liq

200mg tab

50mg cap

200 mg cap

Patient:

15.5 kg

102 cm

0.65 m2 BSA

15.6 ml/ds BD

or

½ 300mg tab

BD

6.2 ml/ds BD 10.9 ml*

or

½ 200mg tab*

(if < 8yrs)

*Start OD for first two weeks. Then BD.

200mg cap + 50mg cap OD, at bedtime.

(if > 3 years)

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Patient 2: Second line Regimen  ddI d4T LPV/r NFV

Dose Recommendation:90-150mg/m2/ds BD

Authors choose: 120mg/m2/ds BD

1mg/kg/ds BD 10mg LPV / 2.5mg RTV / kg/ds BD

Recommendation:20-55 mg/kg/ds q 8-12 hrs

Authors choose: 55mg/kg/ds BD

Formulation 10mg/ml liq

25mg tab50mg tab

1mg/ml liq

15mg cap20mg cap30mg cap40mg cap

80mg LPV +

20mg RTV / ml liq

133mg LPV + 33mg RTV / cap

50mg/scoop

250mg tab

Patient:15.5 kg102 cm0.65 m2

7.8 ml/ds BD or 50mg tab + 25mg tab BD

15.5 ml/ds BD or 15mg cap BD

1.9 ml/ds BD (852.5 mg/ds) 17 scoops BD or 3 to 4 tabs/ds BD

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Calculation of LPV/r dose

LPV/r dose Weight Dose

10/2.5mg/kg/ds BD

(child > 15 kg)

X 15.5 kg =

155mg

LPV/

38.75mg RTV

155mg LPV/ 38.8mg RTV

Divided by

80mg LPV/ 20mg RTV per ml =

1.9 ml BD

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Calculation of LPV/r dose

• Because all LPV/r (Kaletra) preparations have LPV and low-dose RTV in a 4:1 dosage strength ratio, calculations of Kaletra doses can be based on only the LPV dose.

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Use of Dosing Guidelines

• Clinicians should calculate all doses.

• Dosing guides are a supplement to ensure accuracy. Guides should never replace clinician calculations.

• Increase dose as a child’s weight increases by 10 % from the weight at which the present dose was calculated.

• When a child receiving NVP at 7mg/kg dose turns 8 years of age, the dose should be maintained until the child’s weight catches up with the dose of 4mg/kg.

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Summary

• Principles of treating children

• Early identification – testing options

• Nutritional needs of children

• Pediatric HIV and AIDS – common presentations

• Starting ARV’s in pediatrics

• Follow up care/monitoring

• Dosing guidelines/tools – facilitate accurate prescribing