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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/– [email protected]
• Right to Care Paediatric ARV Helpline– 0823526642
• Dr Leon Levin [email protected]• 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
