Outline

1. KITSO AIDS Training ProgramLecture 5:Pediatric Specific Issues and ARV Dosingdelivered byDr. Elizabeth D. LowenthalBotswana-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 15-19 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).

16. 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%

17. Symptoms: Clinical Categories (pg 64)

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

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 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).

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 – m2 • 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/m2 X patient BSA in m2.

32. Patient 1: First line Regimen

33. Calculation of 3TC dose

34. Calculation of NVP dose

35. Body Surface Area • BSA (m2) 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

38. Calculation of AZT dose

41. Patient 1: Second line Regimen

42. Calculation of d4T dose

43. Calculation of NFV dose

44. Calculation of ddI dose

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

47. Patient 2: Second line Regimen

48. Calculation of LPV/r dose

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.