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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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PRacticalAntiretroviral Medications

in Paediatrics

Dr Leon J. Levin

Head - Paediatric HIV Programmes

Right to Care

new regimens for doh and private sector in sa

0-3 years

>3years and >10 kg

1st Line

Abacavir (ABC)

Lamivudine (3TC)


Abacavir (ABC)Lamivudine (3TC)


2nd Line

Zidovudine (AZT)



New Regimens for DOH and Private Sector in SA

Expert advice

first line
  • 3TC/ABC/Kaletra
abacavir 3tc backbone
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
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
impaact p10601

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



  • Headache
  • Fatigue
  • Nausea
  • Diarrhoea
  • Skin rash
  • Abdominal Pain
  • Pancreatitis
  • Peripheral neuropathy
  • Neutropaenia
  • Elevated Liver enzymes
  • Lactic acidosis
  • Pure Red Cell Aplasia




  • TMP/SMX increases 3TC levels
  • 3TC resistance delays or reverses ZDV resistance
  • Do not administer together with FTC


  • Can be given with or without food
  • Store at room temperature

Lamivudine ( 3TC) 3TC

Previous DOSAGES

  • At what weight should we change to adult tabs?
  • 150÷4=37.5kg
  • WHO 25kg
  • Some experts from 20kg
3tc dosage
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
can 3tc and abacavir be given once daily
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.


Lamivudine ( 3TC) 3TC




  • Nausea and vomiting
  • Fever
  • headache
  • Diarrhoea
  • Hypersensitivity Reaction
  • Lactic Acidosis
  • Pancreatitis
  • Liver enzymes
  • Blood glucose
  • Triglycerides
abacavir hypersensitivity reaction
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
abacavir hypersensitivity reaction1
Abacavir Hypersensitivity Reaction
  • Therefore
  • If you stop Abacavir for a suspected Hypersensitivity reaction, you can NEVER give the patient Abacavir again
abacavir hypersensitivity reaction2
Abacavir Hypersensitivity Reaction


  • Fever
  • Malaise, Aches
  • Rash
  • Vomiting
  • Diarrhoea
  • Abdominal pain
  • Cough
  • Dyspnoea
  • Sore throat
  • Multi system disorder
  • Usually occurs within 6 weeks of starting ABC
abacavir hypersensitivity reaction3
Abacavir Hypersensitivity Reaction

Differential Diagnosis

  • Measles
  • Influenza
  • Pneumonia
  • Streptococcal Pharyngitis
  • Scarlet Fever
  • TB
  • IRIS
abacavir hypersensitivity reaction4
Abacavir Hypersensitivity Reaction


  • Hypersensitivity linked to HLA B*5701
  • HLA B*5701 rare in Black population
  • HSR 5% in whites, 0.2% in Blacks


  • No significant interactions with other ARVs
  • Ethanol ABC levels


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


  • 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


  • Headache, GI disturbance, Skin Rashes

Peripheral neuropathy, Pancreatitis, Lactic Acidosis



  • 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

(d4T) Zerit BMS


lopinavir ritonavir1


lopinavir ritonavir2
  • 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.


what is the dose of kaletra aluvia
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
infants 6 months of age1
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

what about premature infants1
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

what about premature infants2
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

what about premature infants3
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.
can kaletra be given once daily in children
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]

can kaletra given once daily in children
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
lopinavir ritonavir3


  • Diarrhoea,headache,asthenia,nausea & vomiting
  • Cholesterol & Triglycerides, pancreatitis,hyperglycaemia, hepatitis, Lipodystrophy
  • Arrythmias


  • 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


  • 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.


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

(RTV) Norvir Abbott


  • 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

Adverse effects

  • Skin Rash
  • CNS effects
    • Insomnia,somnolence,nightmares,confusion,

amnesia, hallucinations,agitation,euphoria

  • Raised Liver enzymes
  • Teratogenic in monkeys (and humans)
  • Lipomastia


  • Supposed to be given on empty stomach but can generally be taken with or without food providing it is tolerated well.
  • Avoid high fat meals ( Absorption)
  • Capsules may be opened and added to soft foods. (Peppery taste)
  • Tablets cannot be crushed. Use generic capsules if child cant swallow tablets
  • Bedtime dosing especially 1st2-4 weeks
  • No data in children < 3 years and < 10kg


  • mixed inducer/inhibitor of Cytochrome P450 CYP3A4 (More Inhibitor)
  • concentrations of concomitant drugs can be increased or decreased depending on the specific enzyme pathway involved. There are multiple drug interactions with efavirenz.
  • Before efavirenz is administrated, the patient’s medication profile should be carefully reviewed for potential drug interactions with efavirenz.
  • Contra-indicated ,terfenadine,midazolam,triazolam,,cisapride, ergot alkaloids
  • Monitor carefully. Warfarin, ethinyloestradiol
  • Rifampicin, phenobarb, phenytoin may decrease EFV levels. Significance unknown Can still use EFV with TB treatment
  • EFV deceases Clarithromycin levels & increases its metabolite. Rather use Azithromycin with EFV
  • PI’s .EFV decreases levels of LPV and ATV. Therefore increase dose of LPV and only use RTV boosted ATV

EFV Stocrin MSD



EFV Stocrin MSD


weight based vs body surface area bsa based
Weight based vs Body Surface Area BSA based
  • Some drugs weight based eg 3TC,ABC,EFV
  • Some drugs BSA based eg LPV/r,NVP,AZT
  • BSA dosages more accurately follow growth of child
  • Weight based dosage Charts reasonably accurate and very convenient
  • Use weight based dosages except in special circumstances eg 3rd line, resistant virus, pt on rifampicin
weight base dosage chart1
Weight Base Dosage Chart



Developed for Western Cape – not necessarily ideal for rest of SA

Not that accurate for BSA dosed drugs

Different doses morning and evening may impact on adherence

Not all dosage forms catered for e.g. tabs and syrup

  • Only requires weight
  • Doses rounded off
weight base dosage chart2
Weight Base Dosage Chart
  • Needs work
  • Use should be encouraged especially with inexperienced nurses and doctors
  • Meeting of DOH and HIV Clinicians Society 2 December to discuss
  • Keep things simple
  • Accurate doses vs simplicity and ease of use
  • With post marketing research very often Package insert doses are no long reliable
  • Things aren't always as clear as they seem
  • Consult a recent good guideline


Buffered Tablets

  • Tablets can be chewed or dispersed in 30ml of water or clear apple juice
  • Administer tablets on empty stomach ½ hour before or 1 hour after a meal
  • Tablets contain Buffer. Always give at least 2 tablets together to get the right dose of buffer
  • Give Lopinavir/ritonavir 1 hour after or 2 hours before ddI
  • Limited data for once daily dosing in children but does aid adherence


  • Oral solution needs to be reconstituted with antacid. Shake well. Is stable for 30 days in Fridge

EC capsules

  • Must still be given on empty stomach
  • Can be given together with Aluvia tablets on an empty stomach
  • Kaletra solution must still be separated from Videx EC by 1-2 hours


  • ddI serum concentrations are increased when ddI is coadministered with TDF. Avoid this combination if possible
  • Mitochondrial toxicity increased if given with d4T-AVOID
  • Absorption of Tetracyclines & Fluoroquinolines. Separate by 2 hours
  • ddI Absorption of Protease Inhibitors. Separate by 1-2 hours or use EC ddI



(ddI) Videx BMS




Renal toxicity

  • FDA USA and WHO advocate using TDF from 12 years and 35kg
    • USA DHHS guidelines age 12 and > Tanner stage IV
  • SA package insert- from 18 years
  • Most experts are reluctant to use it routinely in children so young.
  • Best to reserve for patients with resistance or Hep B > 12years or routinely from 18 years
  • Can be administered with or without food
  • Can be given concurrently with ddI
  • Rash normally occurs in 1st 6 weeks
  • If rash occurs, do not increase dose until rash resolves
  • Discontinue with severe rash or constitutional symptoms
  • Monitor liver functions 2 weekly for the first 8 weeks and 3 monthly thereafter
  • If child reaches 8years, don’t decrease the dose. Let the child grow into the correct dose
  • If NVP dosing is interrupted for more than 7 days, restart with once-daily dosing for 14 days and increase if rash resolved


  • Induces Cytochrome P450 CYP3A Therefore numerous potential interactions
  • Before nevirapine is administered, the patient’s medication profile should be carefully reviewed for potential drug interactions with nevirapine
  • Rifampicin -lowers NVP levels significantly. Don’t use together
  • Anticonvulsants – monitor levels
  • Oral contraceptives –use other means of birth control
  • Don’t use NVP together with Atazanavir boosted or unboosted

Drug interactions

  • ATV is both a substrate and an inhibitor of the CYP3A4 enzyme system and has significant interactions with drugs highly dependent on CYP3A4 for metabolism.
  • There is potential for multiple drug interactions with atazanavir. .
  • Before atazanavir is administered, the patient’s medication profile should be carefully reviewed for potential drug interactions with atazanavir.
  • Tenofovir decreases atazanavir plasma concentrations. Only ritonavir-boosted atazanavir should be used in combination with tenofovir.
  • NNRTIs: Efavirenz, etravirine, and nevirapine decrease atazanavir plasma concentrations significantly. Nevirapine and etravirine should not be coadministered to patients receiving ATV . Efavirenz should not be coadministered with atazanavir in treatment-experienced patients but may be used in combination with atazanavir 400 mg plus ritonavir boosting in treatment-naive adults.
  • Atazanavir absorption is dependent on low gastric pH. When atazanavir is administered with medications that alter gastric pH, dosage adjustment is indicated

Special Instructions

  • Generally only use boosted with RTV esp in children< 13 years
  • Administer ATV with food to enhance absorption.
  • Use ATV with caution in patients with pre-existing cardiac conduction system disease or with other drugs known to prolong the PR interval (e.g., calcium channel blockers, beta-blockers, digoxin, verapamil).
  • ATV absorption is dependent on low gastric pH; therefore, when ATV is administered with medications that alter gastric pH, special dosing information is indicated
  • Give ATV at least 2 hours before or 1 hour after antacid or ddI tablet administration.
  • Only RTV-boosted ATV should be used in combination with TDF or EFV
  • Nevirapine and etravirine should not be coadministered to patients receiving atazanavir (with or without ritonavir



  • Keep things simple
  • Accurate doses vs simplicity and ease of use
  • With post marketing research very often Package insert doses are no long reliable
  • Things aren't always as clear as they seem
  • Consult a recent good guideline
practical resources
Practical Resources
  • SA HIV Clinicians Society
  • Right to Care Paediatric ARV Helpline
    • 0823526642
  • Dr Leon Levin
  • SA HIV Clinicians Paeds Guidelines

  • American Guidelines
  • PENTA (European) Guidelines
  • WHO Guidelines www.who.intDOH Guidelines
  • Liverpool drug interactions Website: