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PR actical A ntiretroviral M edications in Paediatrics

PR actical A ntiretroviral M edications in Paediatrics. Dr Leon J. Levin Head - Paediatric HIV Programmes Right to Care. 0-3 years. >3years and >10 kg. 1 st Line. Abacavir (ABC) Lamivudine (3TC) Kaletra®. Abacavir (ABC) Lamivudine (3TC) Efavirenz. 2 nd Line. Zidovudine (AZT)

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PR actical A ntiretroviral M edications in Paediatrics

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  1. PRacticalAntiretroviral Medications in Paediatrics Dr Leon J. Levin Head - Paediatric HIV Programmes Right to Care

  2. 0-3 years >3years and >10 kg 1st Line Abacavir (ABC) Lamivudine (3TC) Kaletra® Abacavir (ABC)Lamivudine (3TC) Efavirenz 2nd Line Zidovudine (AZT) DDI Kaletra® New Regimens for DOH and Private Sector in SA Expert advice

  3. FIRST LINE • 3TC/ABC/Kaletra • 3TC/ABC/EFV

  4. Abacavir +3TC Backbone • Can’t use Tenofovir routinely in children because of osteopaenia and nephrotoxicity • Very good long term data from PENTA 5 • Spares Thymidine analogue for next regimen • Volume of solution is same for both drugs eg 4ml bd • Can be given once daily in > 3 years

  5. IMPAACT P1060 • 452 children ages 2 to 35 months from India, Malawi, South Africa, Tanzania, Uganda, Zambia and Zimbabwe. • Cohort 1: 164 children SD NVP at birth • Cohort 2: 287 children who did not receive SD-NVP • Children in each cohort were randomly selected to receive AZT/3TC/NVP or AZT/3TC/LPV/r

  6. IMPAACT P1060 Cohort 1 (SD-NVP) • 2009, interim review showed that the LVP/r-based regimen was more effective than the NVP-based regimen in children previously exposed to SD-NVP. Cohort 2 (No SD-NVP) • study defined failure occurred in : • 40.1% of children taking the NVP-based regimen • only 18.6% of children taking the LPV/r-based regimen NEJM. 14 Oct 2010

  7. 3TC,Lamivudine

  8. Lamivudine ADVERSE EFFECTS • Headache • Fatigue • Nausea • Diarrhoea • Skin rash • Abdominal Pain • Pancreatitis • Peripheral neuropathy • Neutropaenia • Elevated Liver enzymes • Lactic acidosis • Pure Red Cell Aplasia WELL TOLERATED

  9. Lamivudine DRUG INTERACTIONS • TMP/SMX increases 3TC levels • 3TC resistance delays or reverses ZDV resistance • Do not administer together with FTC SPECIAL INSTRUCTIONS • Can be given with or without food • Store at room temperature

  10. Lamivudine Lamivudine ( 3TC) 3TC Previous DOSAGES

  11. Lamivudine

  12. Lamividine • At what weight should we change to adult tabs? • 150÷4=37.5kg • WHO 25kg • Some experts from 20kg

  13. 3TC dosage • Don't know if lower exposure to 3TC in < 6yrs is related to reduced virological activity of 3TC containing ART • Don't know effects of lower 3TC exposure on intracellular concentrations • Prudent to aim for higher dose especially in <6 years until more data

  14. Can 3TC and Abacavir be given once daily? • Standard adult dosage 3TC 300 mg once daily & Abacavir(ABC) 600mg once daily, • Few data regarding once-daily administration of 3TC & ABC in children. • PENTA-13 trial HIV-infected children 2 to 13 years of age • PENTA 15 trial children 3 to 36 months of age • Both trials were crossover design with doses of lamivudine of 8 mg/kg/once daily or 4 mg/kg/twice daily and ABC 16mg/kg/dose once daily or 8mg/kg/dose bd. • Area under the curve (AUC)0-24 and clearance values were similar and most children maintained an undetectable plasma RNA value after the switch. • Arrow Trial substudy. 41 children 3 to 12 years of age (median age 7.6 years) in Uganda Stable on twice-daily 3TC and ABC- switch to once-daily3TC & ABC, with median follow-up of 1.15 year. • Equivalent (AUC)0-24 and good clinical outcome (disease stage and CD4 cell count) after a switch • All three studies enrolled only patients who had low viral load or were “clinically stable” on twice-daily 3TC & ABC before changing to once-daily dosing • Therefore, some experts support switching to once-daily dosing of 3TC & ABC in clinically stable patients with undetectable viral load and stable CD4 cell count, (USA) • Others support the use of once daily 3TC ABC from age 3 years (PENTA) AntivirTher. 2005;10(2):239-246. AntivirTher. 2010;15(3):297-305., AntivirTher. 2010;15(8):1115-1124.

  15. Lamivudine Lamivudine ( 3TC) 3TC DOSAGE

  16. Abacavir

  17. Abacavir ADVERSE EFFECTS • Nausea and vomiting • Fever • headache • Diarrhoea • Hypersensitivity Reaction • Lactic Acidosis • Pancreatitis • Liver enzymes • Blood glucose • Triglycerides

  18. Abacavir Hypersensitivity Reaction • What is a Hypersensitivity Reaction? • An Allergy • Has anyone ever died of Penicillin Allergy? • Do we still use penicillin? • Has anyone ever died of Abacavir Hypersensitivity Reaction? • No • But there have been deaths from rechallenging with Abacavir after a reaction

  19. Abacavir Hypersensitivity Reaction • Therefore • If you stop Abacavir for a suspected Hypersensitivity reaction, you can NEVER give the patient Abacavir again

  20. Abacavir Hypersensitivity Reaction Symptoms • Fever • Malaise, Aches • Rash • Vomiting • Diarrhoea • Abdominal pain • Cough • Dyspnoea • Sore throat • Multi system disorder • Usually occurs within 6 weeks of starting ABC

  21. Abacavir Hypersensitivity Reaction Differential Diagnosis • Measles • Influenza • Pneumonia • Streptococcal Pharyngitis • Scarlet Fever • TB • IRIS

  22. Abacavir Hypersensitivity Reaction Incidence • Hypersensitivity linked to HLA B*5701 • HLA B*5701 rare in Black population • HSR 5% in whites, 0.2% in Blacks

  23. Abacavir DRUG INTERACTIONS • No significant interactions with other ARVs • Ethanol ABC levels SPECIAL INSTRUCTIONS • Can be given without regard to meals • Warn patient about Hypersensitivity Reaction • Don’t stop ABC until discussed with HCW • Do NOT rechallenge with ABC afterHypersensitivity Reaction • Therapy should not be interrupted and then restarted

  24. Abacavir • At what weight should we change to adult tabs? • 300÷8=37.5kg • WHO 25kg • Some experts from 20kg

  25. Abacavir DOSAGE

  26. Kivexa® • Fixed dose Combination tablet 3TC & Abacavir • 300mg 3TC/600mg Abacavir per tablet • Dose: 1 tablet once a day • Very large tablet • Use from 20kg if child can swallow it • Expensive

  27. Stavudine

  28. Stavudine ADVERSE EFFECTS • Headache, GI disturbance, Skin Rashes Peripheral neuropathy, Pancreatitis, Lactic Acidosis LIPOATROPHY SPECIAL INSTRUCTIONS • Can be administered with or without food • Decrease dose with renal impairment • Oral solution needs refrigeration • Oral solution stable in fridge for 30 days • Powder from capsules stable in water for 24 hours • Do not administer together with ZDV

  29. Stavudine (d4T) Zerit BMS DOSAGE

  30. Lopinavir/ritonavir

  31. Lopinavir/ritonavir PREPARATION Adult dose

  32. Lopinavir/ritonavir • Numerous interactions due to potent inhibition of Cytochrome P450 CYP3A4 by RTV • Check every drug that patient is on for interactions with LPV/RTV • Interactions as for Ritonavir • EFV & NVP serum concentrations of LPV/RTV. dose of LPV/RTV . • Interactions with other PIs. Appropriate doses not established. • Solution contains 42% alcohol. Avoid Disulphuram or metronidazole. DRUG INTERACTIONS

  33. What is the Dose of Kaletra®/Aluvia® • Ideally Children < 2 years should receive a dose of LPV of 300mg/m2 • Some paediatricians use a dose of LPV of 300mg/m2 in all paediatric patients • Dont don't exceed 400mg LPV (unless on concomitant NNRTI (not > 500mg LPV)) • WHO recommends 230-350mg/m2/dose bd • Rather aim for upper end of range especially in younger children

  34. Infants < 6 months of Age

  35. Infants < 6 months of Age 300/75 mg/m2/dose LPV/r provides similar exposure to that seen in older children, albeit slightly less than seen in adults No data in infants < 14 days of age AIDS 2008, 22:249–255

  36. What about premature infants?

  37. What about premature infants? • Kaletra oral solution contains 356.3 mg/mL (42% v/v) ethanol and 152.7 mg/mL propylene glycol. • LPV is metabolized by CYP3A; both ethanol and propylene glycol are initially metabolized by alcohol dehydrogenase. • Reduced hepatic metabolism and renal clearance in newborns, especially preterm infants, can lead to accumulation of all 3 ingredients. • Propylene glycol toxicity can cause bradycardia and cardiac arrhythmias, central nervous system (CNS) depression, acute renal failure, and lactic acidosis. • Acute ethanol toxicity can lead to AV block, cardiac arrhythmias, CNS depression, and lactic acidosis. • LPV has been associated with cases of heart block, and PR and QT interval prolongation. • Cases of toxicity in neonates, mostly premature, have been reported to FDA. CROI 2011. Poster 708

  38. What about premature infants? • Methods: • Searched the FDA Adverse Event Reporting System (AERS) for all reports of toxicity in children ≤2 years of age after administration of Kaletra oral solution. • Results: • Found 10 cases in neonates, 8 of whom were premature. • The gestational age was between 28 and 35 weeks in infants born prematurely. • Documented events included cardiac toxicity (bradycardia, complete AV block, bundle branch block, or cardiac failure; n = 7), acute renal failure (n = 5), increased serum creatinine (n = 1), elevated serum lactate level (n = 2), hyperkalemia (n = 4), respiratory failure (n = 2), hypotonia (n = 1), abnormal EEG (n = 1), and CNS depression (n = 1). • Acute overdoses were described in 2 cases, 1 resulting in death. • Therapy was initiated on the day of birth in 7 neonates, day after birth in 1, day 34 in 1, and unknown in 1. Onset of symptoms occurred within 1 to 6 days (n = 8); • discontinuation of Kaletra resulted in clinical improvement within 1 to 5 days (n = 6). • Conclusions:  • This case series shows that premature neonates are at increased risk of LPV, ethanol, and/or propylene glycol toxicity associated with Kaletra oral solution administration. CROI 2011. Poster 708

  39. What about premature infants? • RECOMMENDATION: The use of Kaletra oral solution should be avoided in premature babies until 14 days after their due date, or in full-term babies younger than 14 days of age unless a healthcare professional believes that the benefit of using Kaletra oral solution to treat HIV infection immediately after birth outweighs the potential risks. In such cases, FDA strongly recommends monitoring for increases in serum osmolality, serum creatinine, and other signs of toxicity.

  40. Can Kaletra be given once daily in children • Adult data conflicting • Some studies suggest only effective in PI naive patients with low viral loads • Adults – only use if < 3 LPV mutations • Paeds- PI says dont use once daily CROI 2008. Poster 775; 11th European AIDS Conference, Madrid, 2007. [Abstract LBPS7/5] ; 11th European AIDS Conference, Madrid, 2007 [Abstract LBPS7/4]

  41. Can Kaletra given once daily in Children • Sample sizes have been small • Awaiting KONCERT trial • High viral load issue not fully resolved • Vomiting seems to be a problem early on • Probably best if not done routinely until more data • In selected cases may be appropriate

  42. Lopinavir/ritonavir ADVERSE EFFECTS • Diarrhoea,headache,asthenia,nausea & vomiting • Cholesterol & Triglycerides, pancreatitis,hyperglycaemia, hepatitis, Lipodystrophy • Arrythmias SPECIAL INSTRUCTIONS • Administer solution with food • Dose solution in ml not mg and Aluvia in tablets not mg • Aluvia can be given with or without food (food may enhance tolerabilty) • Do NOT crush or halve Aluvia tablets • Give ddI 1 hour before or 2 hours after LPV/RTV • Solution.Refrigerate. Stable for 6 weeks at room temperature • Give a drink straight after dose of solution. • Aluvia does not require refrigeration • Do not administer to premature babies or infants < 14 days old • Once daily dosing generally not recommended

  43. DOSAGE Lopinavir/ritonavir

  44. Ritonavir

  45. Ritonavir SPECIAL INSTRUCTIONS • Only used as a booster or in addition to Kaletra with TB Rx • Should never be used as a sole PI • High incidence of resistance and cross resistance if used as sole PI • Check every drug that patient is on for interactions with RTV • If child can swallow capsules give capsule even if dose is high • Administer with food • Give ddI and RTV 1-2 hours apart • Keep oral solution at room temperature • Oral solution has 6 month shelf life • Terrible taste can be disguised by giving RTV with milk, chocolate milk, vanilla or chocolate pudding, or ice cream.Coating mouth with peanut butter. Give maple syrup,cheese or chewing gum after dose.

  46. Ritonavir ADVERSE EFFECTS • Nausea, Vomiting , Diarrhoea & abd pain • Headache • anorexia • circumoral paresthesias • Liver enzymes • Pancreatitis • Cholesterol and Triglycerides • Hyperglycaemia • Lipodystrophy

  47. Ritonavir (RTV) Norvir Abbott DOSAGE • With comcommitant TB Rx- ¾ Kaletra volume • As PI booster-Depends on PI being boosted • Generally 100mg bd or daily • If child can swallow capsules give capsule even if overdose

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