1 KITSO AIDS Training Program Lecture 5: Pediatric Specific Issues and ARV Dosing delivered by Dr. Elizabeth D. Lowenthal Botswana-Baylor Children’s Clinical Centre of Excellence, Baylor International Pediatric AIDS Initiative

2 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

3 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 years old women in Botswana increases risk of MTCT.

4 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

5 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)

6 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.

7 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

8 Diarrheal Illnesses Prevalence of specific stool pathogens is similar in HIV infected and uninfected children. Outcomes for HIV- infected children are worse.

9 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.

10 Malnutrition

11 Progression of HIV Disease in Untreated Children ‘Rapid Progressor’ ‘Long-Term- Non-Progressor’

12 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%

13 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

14 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.

15 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).

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%

17 Symptoms: Clinical Categories (pg 64)

18 Immune Categories by CD4 Count and CD4 % (pg 63) Age of ChildAge Immunologic Category < 1 Year1- 5 Years6 – 12 Years Category I No evidence of suppression > 1500 cells >25% > 1000 cells >25% > 500 cells >25% Category II Moderate suppression 750 – – 24% 500 – – 24% 200 – – 24% Category III Severe suppression < 750 cells < 15% < 500 cells < 15% < 200 cells < 15%

19 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.

20 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)

21 Recommended Drug Regimens (2) Second-Line Drug Regimens: DDI / D4T / NFV (same as adult 2 nd 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 3 rd line).

22 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.

23 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

24 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

25 Pediatric Dosing Guides

26 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.

27 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.

28 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 – m 2 –AZT, ddI, and RTV* *third line drugs

29 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/m 2 X patient BSA in m 2.

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32 Patient 1: First line Regimen AZT3TCNVPEFV Dose240mg/m 2 /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 m ml/ds BD1.8 ml/ds BD3.2 ml/ds* (if < 8yrs) *Start OD for 2 weeks, then BD.

33 Calculation of 3TC dose 3TC doseWeightDose 4 mg/kg/ds BD X4.5 kg =18 mg Divided by 10mg/ml = 1.8 mlBD (q12 hrs)

34 Calculation of NVP dose NVP doseWeightDose 7 mg/kg/ds BD X4.5 kg =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.

35 Body Surface Area BSA (m 2 ) can be estimated by: height (cm) X weight (kg) 3600 Nomograms for BSA

36 Nomogram for Estimation of BSA (Body Surface Area)

37 BSA: Nomogram or Formula heightweightNomogram 48 cm4.5 kg = 0.22 m 2 BSA 48 X 4.5 = m 2 BSA

38 Calculation of AZT dose AZT doseBSADose 240 mg/m 2 /ds BD X0.22 m 2 =52.8 mg Divided by 10mg/ml = 5.28 ml or 5.3 ml BD (q12 hrs)

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41 Patient 1: Second line Regimen ddId4TLPV/rNFV Dose Recommendation: mg/m2/ds BD Authors choose: 120mg/m 2 /ds BD 1mg/kg/ds BD 7-15kg: 12/3mg/kg/ds BD 15-40kg: 10/2.5mg/kg/ds BD Recommendation: mg/kg/ds BD Authors choose: 55mg/kg/ds BD Form- ulation 10mg/ml liq 25mg tab 50mg tab 1mg/ml liq 15mg cap 20mg cap 30mg cap 40mg cap 80mg LPV + 20mg RTV / ml liq 133mg LPV + 33mg RTV /cap 50mg/scoop 250mg tab Patient: 4.5 kg 48 cm 0.22 m 2 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

42 Calculation of d4T dose d4T doseweightDose 1 mg/kg/ds BD X4.5 kg =4.5 mg Divided by 1mg/ml = 4.5 mlBD q12 hrs

43 Calculation of NFV dose NFV doseweightDose 55 mg/kg/ds BD X4.5 kg =247.5 mg Divided by 50mg/ scoop = 4.95 scp Or 5 scoops BD q12 hrs

44 Calculation of ddI dose ddI doseBSADose 120 mg/m 2 /ds (twice daily) X0.22 m 2 =26.4 mg Divided by 10mg/ml = 2.64 ml or 2.6 ml BD No single tab

45 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.

46 Patient 2: First line Regimen AZT3TCNVPEFV Dose 240mg/m 2 /ds BD Peds: 4mg/kg/ds BD Adolescents <50 kg: 2mg/kg/ds BD < 8 yrs: 7mg/kg/ds* > 8 yrs: 4mg/kg/ds* 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 m 2 BSA 15.6 ml/ds BD or ½ 300mg tab BD 6.2 ml/ds BD10.9 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)

47 Patient 2: Second line Regimen ddId4TLPV/rNFV Dose Recommendation: mg/m2/ds BD Authors choose: 120mg/m2/ds BD 1mg/kg/ds BD10mg LPV / 2.5mg RTV / kg/ds BD Recommendation: mg/kg/ds q 8-12 hrs Authors choose: 55mg/kg/ds BD Formulation10mg/ml liq 25mg tab 50mg tab 1mg/ml liq 15mg cap 20mg cap 30mg cap 40mg cap 80mg LPV + 20mg RTV / ml liq 133mg LPV + 33mg RTV / cap 50mg/scoop 250mg tab Patient: 15.5 kg 102 cm 0.65 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

48 Calculation of LPV/r dose LPV/r doseWeightDose 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

49 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.

50 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.

51 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