PR actical A ntiretroviral M edications in Paediatrics Dr Leon J. Levin Head - Paediatric HIV...

PRactical Antiretroviral Medications in Paediatrics

Dr Leon J. LevinHead - Paediatric HIV ProgrammesRight to Care

New Regimens for DOH and Private Sector in SA

0-3 years >3years and >10 kg

 1st Line

Abacavir (ABC)

Lamivudine (3TC)Kaletra®

Abacavir (ABC)

Lamivudine (3TC)Efavirenz

 2nd Line

Zidovudine (AZT)DDIKaletra®

Expert advice

FIRST LINE

• 3TC/ABC/Kaletra• 3TC/ABC/EFV

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 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

3TC,Lamivudine

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

WEL

L TOLE

RATE

D

LamivudineDRUG INTERACTIONS TMP/SMX increases 3TC levels 3TC resistance delays or reverses ZDV resistance Do not administer together with FTCSPECIAL INSTRUCTIONS Can be given with or without food Store at room temperature

Lamivudine

Neonates 2 mg/kg/dose 12 hourly

Paediatrics ( >1 month) 4mg/kg/dose 12 hourly

Adolescent/Adult BW>50kg 150mg 12hrlyBW<50kg 4mg/kg/dose 12 hourly

Previous DOSAGES

Lamivudine ( 3TC) 3TC

Lamivudine

Lamividine

• At what weight should we change to adult tabs?

• 150÷4=37.5kg• WHO 25kg• Some experts from 20kg

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?• 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)

Antivir Ther. 2010;15(3):297-305., Antivir Ther. 2010;15(8):1115-1124.Antivir Ther. 2005;10(2):239-246.

Lamivudine

Neonates 2 mg/kg/dose 12 hourly

Paediatrics ( >1 month) 4-6 mg/kg/dose 12 hourly (aim for higher dose)From 3 years can give 8-12mg/kg/dose once dailyChange to full adult dose at 25kg (some say at 20kg)

Adolescent/Adult 150mg 12hrlyOr 300mg OD

DOSAGELamivudine ( 3TC) 3TC

Abacavir

Abacavir

Nausea and vomiting Fever headache Diarrhoea Hypersensitivity Reaction Lactic Acidosis Pancreatitis Liver enzymes Blood glucose Triglycerides

ADVERSE EFFECTS

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 Reaction

• Therefore• If you stop Abacavir for a suspected

Hypersensitivity reaction, you can NEVER give the patient Abacavir again

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

Symptoms

Abacavir Hypersensitivity Reaction

• Measles • Influenza• Pneumonia• Streptococcal Pharyngitis• Scarlet Fever• TB• IRIS

Differential Diagnosis

Abacavir Hypersensitivity Reaction

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

Incidence

Abacavir 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 after Hypersensitivity

Reaction Therapy should not be interrupted and then restarted

DRUG INTERACTIONS

Abacavir

• At what weight should we change to adult tabs?

• 300÷8=37.5kg• WHO 25kg• Some experts from 20kg

Abacavir

0-3 months No data

Paediatrics/Adolescents>3 months

8-10mg/kg/dose bd(max 300mg bd)16-20mg/kg/dose once daily in > 3years(Max 600mg daily)Adult dose from 25kg (some say from 20kg)

Adult dose 300mg bd or 600mg daily

DOSAGE

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

Stavudine

Stavudine

Headache, GI disturbance, Skin Rashes Peripheral neuropathy, Pancreatitis, Lactic Acidosis

LIPOATROPHYSPECIAL 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

ADVERSE EFFECTS

Stavudine

Neonatal birth to 13 days 0.5mg/kg/dose 12 hourly

Paediatrics > 14 days(up to 30 kg)

1mg/kg/dose 12 hourly

Adolescent/Adult 30mg 12 hourly

DOSAGE

(d4T) Zerit BMS

Lopinavir/ritonavir

Lopinavir/ritonavirPREPARATION Adult dose

Oral solution80mg LPV & 20mg RTV per ml

Aluvia 200/50200mg LPV and 50mg RTV per capsule

2 tabs bd

Aluvia 100/25100mg LPV and 25mg RTV per capsule

4 tabs bd

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

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 Age

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 infants?

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 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 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

• 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

• 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/ritonavir

• 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

ADVERSE EFFECTS

Lopinavir/ritonavirDOSAGEPrematures Avoid till 2 weeks after due date

Neonates No data < 14 days. Avoid

PaediatricsPatients > 6 months not on NVP or EFV

230mg/m2/dose of LPV component 12 hrly

PaediatricsInfants < 6 monthsPatients on NVP or EFV Or PI expOr some say all paediatric patients

300mg/m2/dose of LPV component 12 hrly

Adult/AdolescentPatients not on NVP or EFV

400mg of LPV component 12 hrly

Adult/AdolescentPatients on NVP or EFV or PI experienced

500mg of LPV component 12 hrly

Ritonavir

Ritonavir 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.

SPECIAL INSTRUCTIONS

Ritonavir

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

ADVERSE EFFECTS

Ritonavir

With comcommitant TB Rx- ¾ Kaletra volumeAs PI booster-Depends on PI being boostedGenerally 100mg bd or dailyIf child can swallow capsules give capsule even

if overdose

DOSAGE (RTV) Norvir Abbott

Efavirenz

Efavirenz

Skin Rash CNS effects

• Insomnia,somnolence,nightmares,confusion, amnesia, hallucinations,agitation,euphoria

Raised Liver enzymes Teratogenic in monkeys (and humans) LipomastiaSPECIAL INSTRUCTIONS 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 1st 2-4 weeks No data in children < 3 years and < 10kg

Adverse effects

Efavirenz

• 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, ethinyl oestradiol 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

DRUG INTERACTIONS

Efavirenz

DOSAGE

Paediatric Dose(> 3 years)

15mg/kg/dose nocte or10- <15kg 200mg nocte 15- <20kg 250mg nocte20- <25kg 300mg nocte25-<32.5kg 350mg nocte32.5-<40kg 400mg nocte>= 40kg 600mg nocte

Adult /Adolescent dose 600mg nocte

EFV Stocrin MSD

Efavirenz

New WHO DOSAGE

Paediatric Dose(> 3 years and > 10kg)

10- <15kg 200mg nocte 15- <25kg 300mg nocte25-<35kg 400mg nocte> 35kg 600mg nocte

Adult /Adolescent dose 600mg nocte

EFV Stocrin MSD

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 Chart

Weight Base Dosage Chart

Advantages• Only requires weight• Doses rounded off

Disadvantages• 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

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

Conclusion

• 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

Zidovudine

Zidovudine

DOSAGEPremature infants <35 weeks

1.5mg/kg/dose(ivi) or 2mg/kg/dose po 12 hourly. Inc to 8hrly at 2 weeks(> 30 weeks) or 4 weeks (<30 weeks)

Neonates (< 6 weeks) 2mg/kg/dose po 6hrly or4mg/kg/dose 12 hourly

Paediatrics 180-240mg/m2 /dose 12 hrly

Adolescent/Adult 300mg 12 hourly

AZT,ZDV) - Retrovir GlaxoSmithKline

Didanosine

DidanosineSPECIAL INSTRUCTIONSBuffered 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

Solution 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

Didanosine DRUG INTERACTIONSddI 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

Didanosine

Neonates (2 weeks to <3 months)

50mg/m2/dose 12hourly

Infants 3 months to 8 months 100 mg/m2/dose 12hourly

Paediatrics 90–150mg /m2/dose 12 hourlySome experts give 180-300 mg/m2/dose once daily

Adolescent/Adult BW>60kg 400mg once dailyBW<60kg 250mg once daily

DOSAGE (ddI) Videx BMS

Tenofovir

ADVERSE EFFECTSOsteopaeniaRenal toxicity

Tenofovir• 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

NNRTIS

Nevirapine

Nevirapine

• , SPECIAL INSTRUCTIONS• 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

Nevirapine 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

Nevirapine

Neonates prophylaxis BW <2.5kg 1ml daily

BW> 2.5kg 1.5ml daily

Paediatrics > 15 days Age < 8 year200mg /m2 /dose 12 hrlyAge >8 year 120-150mg /m2 bd . Start daily X 14 days then increase to full dose

Adolescent/Adult 200 mg daily X 14 days , then 200mg 12 hrly

DOSAGE

Protease Inhibitors (PIs)

Atazanavir

Atazanavir• 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

Drug interactions

Atazanavir• 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

Special Instructions

AtazanavirAGE weight Dosage given with food

Neonates Dont administer to neonates because of risks associated with hyperbilirubinemia (kernicterus)

Paediatric: 6 - 18 years 205 mg/m2 OD

15 - <25 kg ATV 150mg + RTV 80 mg OD

25 - <32 kg ATV 200mg + RTV 100 mg OD

32 - <35 kg ATV 300mg + RTV 100 mg OD

>35 kg ATV 300 mg+ RTV 100 mg OD

Adolescent (≥18–21 years of age)/adult dose:

Antiretroviral-naive patients:ATV 300 mg + RTV 100 mg OD or ATV 400 mg ODAntiretroviral-experienced patients:ATV 300 mg + RTV 100 mg ODATV +EFV adults in therapy-naive patients only:ATV 400 mg + RTV 100 mg + EFV 600 mg OD

Dosages

Conclusion

• 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• SA HIV Clinicians Society

– http://www.sahivsoc.org/– sahivsoc@gomail.co.za

• Right to Care Paediatric ARV Helpline– 0823526642

• Dr Leon Levin leon.levin@righttocare.org• SA HIV Clinicians Paeds Guidelineshttp://www.sajhivmed.org.za/index.php/sajhivmed • American Guidelines www.aidsinfo.nih.gov• PENTA (European) Guidelines   www.ctu.mrc.ac.uk/PENTA• WHO Guidelines www.who.int

DOH Guidelines http://www.doh.gov.za/docs/hiv-f.html• Liverpool drug interactions Website:

www.hiv-druginteractions.org