There are significant drug interactions between antiretroviral drugs and other medications that must be carefully managed. An introductory case involves a woman taking phenytoin and cotrimoxazole who is starting antiretroviral therapy including nevirapine, lamivudine and zidovudine. Nevirapine may decrease phenytoin levels, so phenytoin dosing may need adjustment to avoid loss of seizure control. Cotrimoxazole interacts with phenytoin as well, but discontinuing it is not necessary as the patient has been stable on both medications. The document discusses mechanisms of antiretroviral drug interactions and provides examples of interactions between classes of

1. Significant Drug Interactions with
Antiretroviral Drugs
Unit 7
HIV Care and ART: A Course for
Pharmacists by Salahadin M.Ali

2. 2
Introductory Case: Aida
 Aida, a 25 year-old HIV+ woman, comes to your
pharmacy with prescriptions for her routine therapy of
phenytoin and cotrimoxazole
 Her recent labs indicate that her repeat TLC is 1000
and she is going to begin treatment with ART
 Today she is given prescriptions for the first line
regimen in Ethiopia: nevirapine, lamivudine and
zidovudine.

3. 3
Introductory Case: Aida (cont.)
 Which of the following statements is true about an
interaction between these medications?
1. There is no interaction between antiretroviral drugs and
phenytoin. They can safely be administered together
2. An interaction exists between phenytoin and nevirapine.
The dose of nevirapine must be increased to account for
increased metabolism due to phenytoin
3. An interaction exists between phenytoin and cotrimoxazole.
They should not be administered together
4. Nevirapine may decrease phenytoin levels and therefore
the dose of phenytoin may need to be increased to avoid
loss of seizure control

4. 4
Unit Learning Objectives
 Identify basic drug interaction concepts
 Describe types and mechanisms of interactions
 Identify drug interactions commonly encountered
with antiretroviral drugs
 Describe how to manage known interactions
 Discuss pharmacokinetic enhancement and protease
inhibitor combinations
 Review the role of the pharmacist in drug interaction

5. 5
Basic Definitions
 Pharmacokinetic:
 Refers to what the body does
to the drug
 Associated with the length of
time the drug stays in the body
 “LADME” principle
• Liberation
• Absorption
• Distribution
• Metabolism
• Elimination
 Pharmacodynamic:
 Refers to what the drug does
to the body
 Can change the
pharmacological effect of
drugs
 Examples
• Bone marrow toxicity
caused by ganciclovir or
AZT
• Peripheral neuropathy –
ddI, d4T,
• Pancreatitis – ddI, alcohol

6. Mechanisms of ARVs Interaction
 Two types
 Pharmacokinetic interaction
• Resulted in a change in serum conc. of the interacting drugs
• Occurs at absorption(e.g. ketoconazole and antacids)
distribution (TMP/SMX and warfarin), metabolism (e.g.
rifampcin & NVP) and excretion ( e.g. TDF&DDI)
 Pharmacodynamic interaction
• Resulted in a change in pharmacological response with no
change in serum conc.
• Occurs at receptor level (e.g. DDI & INH) in causing
peripheral neuropathy

7. Drug-Drug Interaction Clinical
Consequences
 Some interactions increase beneficial effects (eg ritonavir +
lopinavir)
 Some interactions increase harmful effects (ritonavir +
simvastatin)
 Some interactions decrease therapeutic effects (eg, rifampin
+ protease inhibitors, rifampin + coumadin anticoagulant)
 Some interaction may result in a new effect not previously
observed with either drug alone (ritonavir + amitriptyline)
 Some interactions have unclear clinical significance(e.g. TDF
& ritonavir)

8. ARVs Drug interaction
 Pharmacodynamic type: NRTIS
 Pharmacokinetic type: NNRTIS and PIs

9. NRTIs Drug Interaction
 Drug interaction with this class of drugs is not
common as compared to PIs and NNRTIs
 The interaction is mainly pharmacodynamic type

10. NRTI Drug Interactions(2)
 Zidovudine:
 Agents that cause additive bone marrow suppression
(i.e. ganciclovir, flucytosine)
 Antagonism with stavudine (competition for intracellular
activation)
 Didanosine (ddI):
 Inhibition of absorption of other agents due to ddI
buffer in Videx® ( tetracyclines, dapsone, ketoconazole)

11. NRTI Drug Interactions(3)
 Didanosine, Stavudine,
 Agents causing additive neurotoxicity (vincristine, cisplatin,
isoniazid) and causes peripheral neuropathy
 Agents causing additive pancreatoxicity (alcohol, valproic
acid)
 Abacavir
 Metabolized by alcohol dehydrogenase (alcohol can
increase abacavir levels and toxicity)

12. Tenofovir (TDF) Drug Interactions
  ddI levels
 The Cmax and AUC of didanosine (buffered formulation or
enteric coated) increased when given with tenofovir.
Increases in didanosine concentrations could increase risk
of adverse events, including pancreatitis and peripheral
neuropathy
 TDF decrease serum level of atazanavir
 Boost ATV (300 mg qd ) with RTV 100 mg qd) when given
together

13. NNRTIs and PIs drug interaction
 Drug interaction in these classes of drugs are very
common problem
 The interaction could be between themselves and
with other drugs
 Interactions occur mainly during metabolism by CYP
system and it is pharmacokinetic type

14. 14
Drug Metabolism in Context to Drug Interaction
 The goal of metabolism is to change the active form
of drugs
 Making them more water soluble and more readily
excreted by kidney or other organs
 Drug metabolism occurs via two types of reactions:
 Phase I; oxidation
 Phase II; conjugation
 The oxidation reaction (phase I) is catalyzed by CYP
450 system and responsible for the metabolism of
NNRTIs and PIs
Refer to enlarged image at end of handout

15. Drug Metabolism/Elimination
Refer to enlarged image at end of handout

16. 16
Cytochrome P450 (CYP450)
 >36 isoenzymes identified in
humans
 Isoenzymes:1A2, 2C9/19,
2D6, 3A4 are primarily
responsible for drug
metabolism,
 3A4 accounts the metabolism
of 50% of marketed drugs
 Enzyme 3A4 (3 =family, A=
subfamily, 4= isoenzyme)
 Knowledge of substrates,
inhibitors and inducers helps
predict drug interactions
particularly CYP 3A4 system

17. 17
P450 Drug Interactions
 Substrate
 Medication depends on enzymatic pathway(s) for
metabolism
 Object drug which is affected by inducer or inhibitor
 Inducer
 Speeds up metabolism
 Decreases substrate level (lack of efficacy is concern)
 Gradual onset/offset
 Inhibitor
 Slows metabolism
 Increases substrate level (toxicity is concern)
 Quick onset/offset

18. 18
In general beware that
 A drug interaction can occur whenever a:
 New medication is started
 Medication is discontinued
 Dose is changed
 Drug is changed
 Remember:
 Inducing interactions
• Gradual onset/offset
 Inhibiting interactions
• Quick onset/offset

19. CYP 3A4: Substrates
 Alpra, mida -zolam
 Calcium channel blockers
 Carbamazepine
 Corticosteroids
 Digoxin
 Methadone
 Protease inhibitors
 Statins
 Amitriptyline
 Quinidine
 Pimozide
 Many, many more

20. 20
CYP 3A4: Inhibitors
 Erythro-, > clarithromycin
 Efavirenz (moderate)
 Fluoxetine
 Fluvoxamine
 Grapefruit juice
 Keto-, itra- > fluconazole
 PIs: ritonavir >>> atazanavir, nelfinavir > saquinavir

21. 21
CYP 3A4: Inducers
 Inducers
 Carbamazepine, phenytoin, phenobarbital
 Rifampin
 St. John’s wort, garlic
 Efavirenz, nevirapine

22. 22
Introductory Case: Aida (cont.)
1. There is no interaction between ART and
phenytoin. They can safely be administered
together
FALSE
The interaction between phenytoin and nevirapine
is unknown. Both drugs are cytochrome P450 3A4
inducers and therefore an interaction can be
anticipated

23. 23
2. An interaction exists between phenytoin and
nevirapine. The dose of nevirapine must be
increased to account for increased metabolism due
to phenytoin
FALSE
 Phenytoin may decrease the levels of nevirapine,
however, the interaction is unknown
 Levels of nevirapine should not be increased empirically
 If there are no other options for anti-seizure medications
for this patient, and this combination must be used, the
patient should be monitored for loss of virologic control
Introductory Case: Aida (cont.)

24. 24
CYP 2C9/19
 Substrates
 Diazepam
 NSAIDs
 Phenobarbital
 Phenytoin
 Tolbutamide
 S-warfarin
 Inhibitors
 Ritonavir
 Efavirenz
 Cimetidine
 Fluoxetine
 Fluvoxamine
 Omeprazole
 TMP/SMX
 Inducers
 Rifampin
 Carbamazepine
 Phenobarbital
Refer to enlarged image at end of handout

25. 25
3. Part 1: An interaction exists between phenytoin and
Cotrimoxazole
TRUE
3. Part 2: They should not be administered together
FALSE
 Cotrimoxazole is an inhibitor of CYP 2C9 and phenytoin
is a substrate of the same enzyme. The levels of
phenytoin may be increased when Cotrimoxazole is
started (after a few weeks)
 This patient has been taking both medications together
and is stable on therapy. She can continue to receive
these medications together
Introductory Case: Aida (cont.)

26. 26
Red Flags for Potential Interactions
 PIs or NNRTIs and
 Statins
 Ergot alkaloids
 Azole antifungals
 Antihistamines
 Anticonvulsants
 Anti-tuberculars
(rifamycins)
 Warfarin
 Benzodiazepines
 Alternative medicine
 Cardiac medicine
• Amiodarone, quinidine
 Oral contraceptives
• Containing estradiol
 Macrolide antibiotics
 Methadone

27. 27
PI/ NNRTI/ Antidepressant
Drug Interactions
Antidepressant Potential for
Interaction
Effects Management
Amitriptyline ritonavir,
lopinavir/r,
Levels of
amitriptyline may be
increased via 2D6
inhibition
Start with lower dose
(50%) of amitriptyline,
adjust dose when addIng
ritonavir. Monitor for side
effects
Fluoxetine ritonavir,
lopinavir/r, all other
PIs, efavirenz
Levels of both
fluoxetine and
ARVs may be
increased via 2D6
inhibition
As above

28. 28
Ritonavir: Do NOT Co-administer
 Antiarrhythmics
 Amiodarone, quinidine
 Antihistamines – terfenadine,*
 Ergot derivatives* (ergotamine)
 Herbal Preparations
 HMG-CoA Reductase Inhibitors – lovastatin*,
simvastatin*
 Neuroleptic – Pimozide* (Orap)
 Benzodiazepines – midazolam,* triazolam*
* These drugs must also never be co-administered with any PIs

29. 29
PI: Safer Choices
 Anxiety/insomnia
 Use Diphenhydramine, Diazepam, chlordiazepoxide
 MAI prophylaxis/treatment
 Use Azithromycin
 Antidepressants
 Start low and go slow!
 Amitriptyline: 2D6 and 3A4 substrate
 Fluoxetine and Fluvoxamine: broad CYP450 inhibition
(serotonin syndrome)

30. 30
PI: Safer Choices (2)
 Anticonvulsants
 Use sodium valproate, if possible.
 If use with phenytoin, phenobarbitol, or carbamazepine,
need to monitor antiseizure activity as well as antiviral
activity
 Migraine therapy
 Use paracetamol, sumatriptan, or narcotic analgesics
 Antihistamines
 Use loratadine or cetirizine or diphenhydramine
 Rifampicin (only use with EFZ)

31. 31
4. Nevirapine may decrease phenytoin levels and
therefore the dose of phenytoin may need to be
increased to avoid loss of seizure control
TRUE
 The patient would need to be monitored closely for loss of seizure
control and then the dose would need to be adjusted accordingly by the
physician
 The best option would be to gradually switch the patient from phenytoin
to another drug for seizure control, one that does not interact with ART.
Options may include sodium valproate or gabapentin
Introductory Case: Aida (cont.)

32. 32
NNRTIs: Do NOT Co-administer
 Ergot derivatives (ergotamine)
 Benzodiazepine: midazolam, triazolam
 Rifampicin (Nevirapine) – unless there is NO
alternative
 Herbal – St. Johns wort

33. Nevirapine interactions
 Drug interactions (induces liver enzymes)
 NVP reduces AUC for ethinyl estradiol (EE) by ~30%. An
alternate or additional form of birth control should be
used
 NVP reduces ketoconazole levels by 63% and NVP levels
increase 15% - 30%. Do not co-administer
 Rifampicin reduces NVP 37%. Do not combine NVP and
Rifampicin
 NVP drug interactions with PIs
• May need to increase dose of the PI but NVP levels are
generally unaffected
• LPV/r, IDV
33

34. EFV Drug interactions (induces liver
enzymes)
 EFV increases levels of ethinyl estradiol by 37% 
encourage women to use an alternate contraceptive
method
 Rifampicin decreases EFV levels 25%  No
change in EFV dose
 EFV decreases levels of phenytoin, phenobarbital,
and carbamazepine  Need to monitor
anticonvulsant levels
 EFV decreases clarithromycin levels by 39% and
rate of rash increases to 46% do not combine EFV
and clarithromycin 34

35. 35
PI and NNRTI Drug Interactions:
Nevirapine (NVP)
 NVP (standard dose) +
 Ritonavir (dose RTV standard)
 Nelfinavir (NFV dose standard)
 Lopinavir/r (use 4 caps bid or 3 tablets bid)
 Atazanavir (no data, most clinicians would use with
ritonavir)

36. 36
PI and NNRTI Drug Interactions:
Efavirenz (EFV)
 EFV (standard dose) +
 Ritonavir (dose standard)
 Nelfinavir (dose standard)
 Atazanavir (use ATV 300 mg with RTV 100 mg qd
 Lopinavir/r (use 4 caps of LPV/r bid or 3 tablets bid)

37. 37
Antiretroviral/Food Interactions
Take with food:
 Lopinavir (capsules or
solution):  50-130%
 Nelfinavir: 2-3 fold 
 Ritonavir: 15% 
 Itraconazole caps
 Atazanavir 70 % 
 Ganciclovir  up to 5%
Avoid taking food:
 ddI: 47%  with meal
 Efavirenz:  79% high fat
meal increases toxicity
 Rifampin: food may  levels
 Isoniazid

38. 38
Avoid Antacids
 PIs
 Atazanavir
 Ketoconazole
 Fluoroquinolones
 Isoniazid
 Dapsone

39. Atazanavir with
Acid-reducing Agents
 Dosing must be separated by 2 hours from traditional
antacids (e.g. calcium carbonate )
 Take 2 hours before or 10 hours after H-2 blockers (e.g.
famotidine,)
 Should not be used with proton pump inhibitors (PPIs) (e.g.
omeprazone)

40. ATV/r 300/100
ATV/r 300/100 + 40 mg OMP
ATV/r 300/100 + 40 mg OMP + cola
ATV/r 400/100 + 40 mg OMP
100
1000
10,000
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hr)
Atazanavir
Trough
(ng/mL)
 N = 48 HIV(-) subjects
 ATV exposures
substantially reduced by
coadministration with
OMP 40 mg
 Not corrected by
increased ATV dose or
8 oz cola
 OMP exposures not
significantly altered
 Effect of OMP 20 mg
(OTC dose) not known
 Do not coadminister
Interaction Between Atazanavir +
Omeprazole

41. 41
Alternative Medicine
 Some alternative medicine or herbal therapies have
been shown to interact with ART
 Pharmacists and providers must be aware of the
potential interaction should their patient wish to take
alternative medicine
 The interactions may increase or decrease ART
levels leading to either an increase in toxicity or loss
of efficacy

42. 42
Recreational Drugs
 Drug interactions involving recreational drugs are of
particular concern
 Limited Data
 Amphetamine
 Ketamine
 Marijuana [Tetrahydrocanabinol (THC)]
 Alcohol
 LSD
 Cocaine
 Chat

43. Pharmacokinetic Enhancement

44. 44
Pharmacokinetic Enhancement
 Ritonavir used to
“boost” Cmin and
increase t½ of other
protease inhibitors
 Allows extended dosing
intervals
 Decreases pill burden
 Reduces adverse effects
 May allow salvage in
patients with resistance
and reduced
susceptibility
 Ritonavir (cont)
 Overcomes enzyme
induction caused by other
drugs
 Increase drug exposure
 Remove meal
requirements
 Activity primarily via
inhibition of CYP450 3A4
 May also inhibit MDR-
PGP efflux pumps

45. 45
Pharmacokinetics Principles
0
2
4
6
8
10
Concentration
(ug/mL)
2 4 10 12
6 8
Cmax
maximum concentration
correlates with some short-term
side effects, e.g. nausea
AUC
area under the curve
overall drug exposure

46. 46
Pharmacokinetics Principles (2)
0
2
4
6
8
10
Concentration
(ug/mL)
2 4 10 12
6 8
Cmin
minimum, or trough concentration
occurs at the end of the dosing interval
correlates with anti-HIV effect for all PIs

47. 47
Pharmacokinetic Rationale for Dual
Protease Inhibitor Therapy
 When a single PI is used, its peaks may reach well
above the desired concentration for effectiveness
and this may lead to drug toxicity.
 When PIs are used together, you are able to achieve
lower peak levels
 Reduces the chance of side effects
 Achieves higher trough levels, increasing potency and
reducing the chance of viral replication.

50. 50
Dual Protease Inhibitors
 Lopinavir + ritonavir*
 3 Co-formulated capsules BID
or 2 tablets BID
 Atazanavir + ritonavir*
 ATV 300mg/RTV 100mg QD

51. 51
The Role of a Pharmacist in
Drug Interactions
 Pharmacists must be knowledgeable about
potential drug-drug, drug-food interactions
 Pharmacists should question a patient about
their current medications whenever filling a
prescription that is new for them
 Patients should be educated that drug
interactions can also occur if they stop or
receive a change in dose of their medications
 Pharmacists should ask patients about their use
of herbal preparations and other recreational
drugs as they can interact with ARV therapy

52. Discuss in small groups on drug-
interaction checklist

53. Drug Interaction Case Studies

54. Case 1

55. 55
Case Study: Ermias
 Ermias is 45 year-old HIV+ male presenting for
routine follow-up. He has been on HAART for two
years
 CD4 count: 480 cells/mm3 HIV RNA < 50 copies/mL.
 He comes into your pharmacy after seeing a
physician for his migraines. He is glad to try a new
medication as his headaches have been a problem
for years. He is so distraught about them that he
has begun to take an herbal product to help with his
mood

56. 56
Case Study: Ermias (2)
 You ask him his current medication regimen, which
is:
 Nevirapine 200 mg bid
 Lamivudine 150mg bid
 Zidovudine 300 mg bid
 An herbal medicine when he feels “down”
 New medications prescribed today: Ergotamine +
caffeine

57. 57
Case Study: Ermias (3)
1. Which of the following combinations represents a
potential drug-drug interaction?
A. Nevirapine and herbal medicine
B. Zidovudine and ergotamine
C. Ergotamine and nevirapine
D. Caffeine and zidovudine

58. 58
Case Study: Ermias (4)
 Herbal medicines
 Concomitant use with herbal medicine may decrease or increase
serum levels of NNRTIs.
• e.g. St. John's Wort can increase the oral clearance of nevirapine
(viramune) by 35%
 Sub-therapeutic concentrations are associated with therapeutic failure,
development of viral resistance, and development of drug class
resistance, high therapeutic concentrations are associated with toxicity
• e.g. St. John's Wort induces intestinal and hepatic cytochrome
P450 3A4 (CYP3A4) and intestinal P-glycoprotein/MDR-1, a drug
transporter
 Avoid use with any NNRTI or PI

59. 59
Case Study: Ermias (5)
2. What would you recommend to Ermias for his
depression?
3. What would you recommend to him for his
migraines?

60. Case 2

61. 61
Case Study: Sara
 Sara is a 41 year-old female with esophageal
candida and has just completed a 10 day course of
fluconazole. She has lost weight because symptoms
of thrush made it difficult to swallow. She weighs 62
kg. She is to begin ARV therapy today. She comes to
your pharmacy to fill her prescriptions.

62. 62
Case Study: Sara (2)
 She presents you with the following:
 Zidovudine 300 mg bid
 Stavudine 40 mg bid
 Nevirapine 200 mg once daily for the first 2 weeks, then
increase to 200 mg bid
 Cotrimoxazole DS, 1 tablet daily
1. Is this an appropriate regimen for her? Can you identify
any possible drug interactions?

63. 63
Case Study: Sara (3)
2. How would you communicate the change that you
recommended to the physician who wrote the
prescription?
3. What would you say to the physician?

64. Case 3

65. 65
Case Study: Lake
 Lake, a 50 year-old male who has been HIV+ for 5
years and is stable on therapy, presents to the clinic
to get more medication to treat his thrush
 He has been taking his brother’s medication, which
seemed to help at first and then stopped working. He
would like to get some more to clear the white
plaques on his tongue

66. 66
Case Study: Lake (2)
Oral Thrush

67. 67
Case Study: Lake (3)
 His current ARV regimen is:
 Nevirapine 200 mg bid
 Stavudine 30 mg bid
 Lamivudine 150 mg bid
 He has one pill of his brother’s medication left. The
physician brings it to your pharmacy to determine
what medication it is
 You identify the tablet as ketoconazole 200 mg

68. 68
Case Study: Lake (4)
1. Is this an appropriate medication to use with his
current ARV regimen?
2. What are some counseling points for this patient?

69. Case 4

70. 70
Case Study: Fatima
 Fatima is a 30 year-old female patient who has just completed
9 months of TB therapy (regimen was rifampicin and isoniazid
along with pyridoxine) 3 weeks ago. She has also been on
ARVs (EFV 600 mg qhs, 3TC 150 mg bid and ZDV 300 mg
bid) during this time. She presents with a bloody nose and
bruises on her arm. She was also on oral contraceptive to
which she perfectly adhered but she becomes pregnant
 Other current medications include:
 Coumadin for atrial fibrillation
 Atenolol for blood pressure
 Oral contraceptive (ethinyl estradiol and norethindrone)

71. 71
Case Study: Fatima (2)
 What do you suspect has happened?
 How should this patient have been counseled
before the TB medication was discontinued?

72. 72
Case Study: Fatima (3)
 If it is necessary to use enzyme inducers and drugs
that are substrates of those enzymes. Monitor for
altered response if the inducer is initiated,
discontinued, or changed in dosage

73. 73
Key Points
 Pharmacokinetic interactions refer to what the body
does to the drug
 Pharmacodynamic interactions refer to what the drug
does to body
 A drug interaction can occur whenever a medication
is started or discontinued or whenever a dose is
changed.
 Pharmacists play a critical role in detecting drug
interactions before they happen

74. 74
Key Points (2)
 Pharmacists must be knowledgeable about potential
drug-drug and drug-food interactions
 Pharmacists should question a patient about their
current medications whenever filling a new
prescription, changing dose, or discontinuing a
medication
 Patients should be educated that drug interactions
can also occur if they stop or change a medication or
dose

75. 75
Key Points (3)
 Pharmacists should ask patients about their use of
herbal preparations as they can interact with ARV
therapy
 Pharmacokinetic enhancement combines agents
from different classes or various agents from similar
classes to:
 Improve ARV pharmacokinetics
 Improve adherence
 Minimize side effects
 Enhance antiviral activity and prevent resistance