Antiretroviral Drug
Interactions &
Polypharmacy
Elizabeth Sherman, PharmD, AAHIVE
HIV/AIDS Clinical Pharmacy Specialist,
Memorial Healthcare System
Assistant Professor,
Nova Southeastern University
Faculty, Florida/Caribbean AETC
Disclosure of Financial Relationships
This speaker has no financial relationships with
commercial entities to disclose.
This speaker will not discuss any off-label use or
investigational product during the program.
This slide set has been peer-reviewed to ensure that there are no
conflicts of interest represented in the presentation.
What is your profession?
A. Physician
B. Nurse
C. Pharmacist
D. Medical assistant
E. Case manager
F. Student
G. Other
0%
0%
0%
0%
0%
0%
A.
B.
C.
D.
E.
F.
0%
G.
Which best describes your patient setting?
A. Outpatient clinic
B. Hospital/Inpatient
C. Other
ie
pa
t
/In
ta
l
Ho
sp
i
r
ic
cli
n
nt
at
ie
Ou
tp
0%
Ot
he
0%
nt
0%
How comfortable are you in managing drug
interactions in HIV-infected patients?
A. Extremely comfortable: I wrote the
book on drug interactions.
B. Somewhat comfortable: I keep up
on the topic and/or have access to a
pharmacist.
C. Uncomfortable: I know they exist but
have a difficult time recognizing
them.
D. Drug interactions? Isn’t this clinical
trials/adherence?
0%
A.
0%
B.
0%
C.
0%
D.
Objectives
• Avoid pitfalls of unintentional
polypharmacy in HIV-infected patients
• Review clinically significant drug
interactions in patients with multiple
diagnoses
Objectives
• Recognize pitfalls of unintentional
polypharmacy in HIV-infected patients
• Review clinically significant drug
interactions in patients with multiple
diagnoses
Polypharmacy & HIV Infection
• Polypharmacy is “many drugs”
– Typically refers to 5+ medications1
• Polypharmacy occurs in 20-50% of HIVinfected patients2
– Adverse drug reactions more common and
serious in older patients
• Regular drug interaction screening is
essential
1. Wick JY. Pharmacy Times 2006.
2. The HIV and Aging Consensus Project. www.aahivm.org/hivandagingforum
AAHIVM Recommendations to Reduce
Unintentional Polypharmacy
• Medication reconciliation at every visit
– Ask patients to bring in all medications
– Obtain dispensing history from pharmacy
– Assess continued need for each medication
• Encourage use of one pharmacy
– HIV specialty pharmacy preferred
• Consult a clinical pharmacist
– AETC Consultation (www.fcaetc.org/consultation)
– UCSF HIV Warmline (800-933-3413)
The HIV and Aging Consensus Project, www.aahivm.org/hivandagingforum
Polypharmacy & Aging
HIV-Infected Patients
Antiretroviral therapy (ART) transformed HIV into
complex chronic disease with multimorbidity
Longer lifespan
Additional disease states
Additional medications
Increased risk of drug-drug
interactions (and side effects)
ART Undergoes Pharmacokinetic
Transformation
1. Absorption
2. Distribution
3. Metabolism
4. Elimination
• Setting for most ARV
drug interactions
• Cytochrome P450 drug
metabolizing enzyme
influences/influenced
by, many ARVs and
many other drugs
• PIs, NNRTIs,
maraviroc, and
elvitegravir/cobicistat
can be P450
substrates, inducers,
or inhibitors
Drug Metabolism Occurs via Hepatic
Cytochrome P450 Enzymes
Drug alone
Concentration
P450
Drug alone
Time
Drug Metabolism Occurs via Hepatic
Cytochrome P450 Enzymes
Drug + Inhibitor
Concentration
P450
Drug + Inhibitor
Drug alone
Time
Inhibitor blocks
P450 enzyme
Too
much
drug!
Drug Metabolism Occurs via Hepatic
Cytochrome P450 Enzymes
P450
Inducer increases
P450 enzyme production
Concentration
Drug + Inducer
Not
enough
drug!
Drug alone
Drug + Inducer
Time
ARV Metabolism and Drug Interaction Potential
ARV Drug Class Route of Metabolism
Drug Intxn Potential
NRTI
Mostly renal
Medium
NNRTI
Liver metabolism: P450 substrates, some are
P450 inducers/inhibitors
High
PI
Liver metabolism: P450 substrates, most are
P450 inhibitors
High
Integrase
Inhibitors
Liver metabolism
•Raltegravir: UGT1A1 enzyme (not P450)
•Elvitegravir: P450 substrate/inducer
(Cobicistat: P450 inhibitor)
Medium-High
Entry Inhibitor:
CCR5
Liver metabolism: P450 substrate
Medium
Entry Inhibitor:
Fusion
Peptide undergoes catabolism to amino acids:
No known drug interactions
Low
Objectives
• Recognize pitfalls of unintentional
polypharmacy in HIV-infected patients
• Review clinically significant drug
interactions in patients with multiple
diagnoses
Antiretrovirals Have Drug Interactions With
Multiple Medications
• Statins (HMG Co-A
reductase inhibitors)
• Anti-acid therapy
• Antiepileptics
• Phosphodiesterase
inhibitors
• Antiplatelets &
anticoagulants
• Hepatitis C protease
inhibitors
• Antimycobacterials
• Antifungals
• Benzodiazepines
• Hormonal
contraceptives
• Asthma medications
and corticosteroids
• Antiarrhythmics,
calcium channel
blockers
• Antipsychotics and
antidepressants
• Herbal and dietary
supplements
• Other antiretrovirals
ARV Interactions with Statins
• Statins (HMG Co-A reductase inhibitors)
– P450 substrates
– May be affected by NNRTIs, PIs, &
cobicistat
• March 2012: FDA updates statin dosing
recommendations with ARVs
Managing ARV Interactions with Statins
Statin
Interacting Antiretroviral(s)
Prescribing Recommendation
Atorvastatin
•Tipranavir + ritonavir
Avoid atorvastatin
•Lopinavir + ritonavir
Use with caution: lowest necessary
atorvastatin dose
•Darunavir + ritonavir
•Fosamprenavir ± ritonavir
•Saquinavir + ritonavir
Do not exceed 20mg atorvastatin daily
•Nelfinavir
Do not exceed 40mg atorvastatin daily
Lovastatin
•HIV protease inhibitors
•Cobicistat
CONTRAINDICATED
Pitavastatin
•Atazanavir ± ritonavir
•Darunavir + ritonavir
•Lopinavir + ritonavir
No dose limitations
Pravastatin
•Darunavir + ritonavir
•Lopinavir + ritonavir
No dose limitations
Rosuvastatin
•Atazanavir ± ritonavir
•Lopinavir + ritonavir
Limit rosuvastatin dose to 10mg once daily
Simvastatin
•HIV protease inhibitors
•Cobicistat
CONTRAINDICATED
FDA Drug Safety Communication. March 1,2012. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm.
Gilead Sciences, Inc. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) package insert. Foster City, CA; 2012.
ARV Interactions with Anti-Acid Therapy
• Medications decreasing stomach acidity can
interfere with ARVs requiring an acidic environment
for absorption (PI, NNRTI)
• Elvitegravir absorption is decreased by binding with
di/trivalent cations
• Indicated for GERD/peptic ulcer disease to decrease
gastric acidity
– Antacids: Aluminum, magnesium hydroxide, or calcium
carbonate
– H2 receptor antagonists: cimetidine, famotidine, ranitidine
– Proton pump inhibitors: esomeprazole, lansoprazole,
omeprazole, pantoprazole
Managing ARV Interactions
with Anti-Acid Therapy
Anti-acid
Atazanavir (ATV) Intxns
Rilpivirine (RPV) Intxns
Elvitegravir (EVG) Intxns
Al, Mg, Ca
Antacids
ATV 2 hrs before or 1 hour after
antacids
Antacids 2 hours before
or 4 hours after RPV
Separate EVG and antacids
by at least 2 hours
H2 Receptor
Antagonists
(H2RA)
•Atazanavir with ritonavir: ATV/r with
or 10 hours after H2RA (max
famotidine 40mg BID for treatment
naïve; 20mg BID for treatment
experienced)
•Atazanavir alone: ATV 2 hours before
or 10 hours after H2RA (max
famotidine 20mg BID for treatment
naïve; CONTRAINDICATED for
treatment experienced)
H2RA 12 hours before or
4 hours after RPV
No dose adjustment
Proton Pump
Inhibitors
(PPI)
Atazanavir must be boosted with
ritonavir: PPI 12 hours prior to ATV/r
(max omeprazole 20mg for treatment
naïve; CONTRAINDICATED for
treatment experienced)
CONTRAINDICATED
No dose adjustment
Bristol-Myers Squibb. Reyataz (atazanavir) package insert. Princeton, NJ; 2012.Tibotec Therapeutics. Edurant (rilpivirine) package
insert. Raritan, NJ; 2012. Gilead Sciences, Inc. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir) package insert. Foster City, CA; 2012.
ARV Interactions with Antiepileptics
• Antiepileptic drugs: Carbemazepine,
phenytoin, phenobarbital have two-way drug
interactions
– They are P450 inducers: may decrease levels of
ARVs that are P450 substrates (PI, NNRTI,
maraviroc, elvitegravir)
– They are P450 substrates: ARVs that are P450
inducers/inhibitors (PI, NNRTI, cobicistat) may
affect antiepileptic efficacy/toxicity
• Levetiracetam not metabolized by P450,
recommend as alternative
Managing ARV Interactions with Antiepileptics:
Carbemazepine, Phenytoin, & Phenobarbital
Antiretroviral
Effect on ARV/Antiepileptic Drug
Clinical Management
PI
•PIs inhibit P450, causing increased
antiepileptic levels
•Antiepileptics induce P450, causing lower
PI levels
Avoid; or monitor PI efficacy
(viral load) & antiepileptic
toxicity (drug levels)
NNRTI
•NNRTIs induce P450, causing lower
antiepileptic levels
•Antiepileptics induce P450, causing lower
NNRTI levels
EFV and NVP require close
monitoring of ARV
levels/efficacy; ETR and RPV
CONTRAINDICATED
Maraviroc
•Antiepiletics induce P450, causing lower
maraviroc levels
Increase maraviroc dose to
600mg BID
Elvitegravir/
cobicistat
•Cobicistat inhibits P450, causing
increased antiepileptic levels
•Antiepileptics induce P450, causing lower
elvitegravir & cobicistat levels
Consider alternative
anticonvulsant
DHHS panel on antiretroviral guidelines for adults and adolescents. March 27, 2012. Available at
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir)
package insert. Foster City, CA; 2012.
ARV Interactions with
Phosphodiesterase (PDE) Inhibitors
• Sildenafil, tadalafil & vardenafil
– Metabolized by P450 (are P450 substrates)
• NNRTIs induce P450, decreasing PDE inhibitor;
may need to increase PDE based on clinical effect
• PIs & elvitegravir/cobicistat inhibit P450, increasing
PDE inhibitor, increasing risk of adverse events
– Used to treat erectile dysfunction (ED),
pulmonary arterial hypertension (PAH) and
benign prostatic hyperplasia (BPH)
Managing ARV Interactions with
Phosphodiesterase (PDE) Inhibitors
PDE Inhibitor + ARV
PDE Inhibitor Dosing Recommendation Based on Indication
Sildenafil + PI
•ED: Start 25mg q48H
•PAH: CONTRAINDICATED
Sildenafil +
elvitegravir/cobicistat
•ED: Max 25mg q48H
•PAH: CONTRAINDICATED
Tadalafil + PI
•ED: Start 5mg, max 10mg q72H
•PAH: Increase dose to max 40mg daily based on tolerability,
may require tadalafil discontinuation prior to PI start
•BPH: Max dose 2.5mg daily
Tadalafil +
elvitegravir/cobicistat
•ED: Max 10mg q72H
•PAH: Increase dose to max 40mg daily based on tolerability,
may require tadalafil discontinuation prior to EVG/COBI start
Verdenafil + PI
•ED: Start 2.5mg q72H
Verdenafil +
elvitegravir/cobicistat
•ED: Max 2.5mg q72H
DHHS panel on antiretroviral guidelines for adults and adolescents. March 27, 2012. Available at
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir)
package insert. Foster City, CA; 2012.
ARV Interactions with
Antiplatelets/Anticoagulants
• Clopidogrel
– Prodrug activated by P450; active metabolite
decreased by NNRTI etravirine
• Warfarin
– Metabolized by P450; levels affected by
NNRTIs & PIs; elvitegravir/cobicistat unknown
– Requires cautious dosing and frequent INR
monitoring with ART change
• Rivaroxaban
– Metabolized by P450; May be affected by PIs
Managing ARV Interactions with
Antiplatelets/Anticoagulants
Antiplatelet/Anticoagulant
Clinical Management
Clopidogrel
Avoid coadministration with
etravirine, if possible
Warfarin
Monitor INR closely when starting or
stopping NNRTI, PI, or elvitegravir/
cobicistat & adjust warfarin accordingly
Rivaroxaban
Avoid use with ritonavir boosted PIs
DHHS panel on antiretroviral guidelines for adults and adolescents. March 27, 2012. Available at
http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir)
package insert. Foster City, CA; 2012.
Summary
• ART presents higher potential for drug
interactions
• Aging patients may present more
comorbidities and therefore greater
potential for drug interactions
• Review medications at every patient visit
– Check for drug interactions
– Ask about over the counter medications
ARV Drug Interaction Resources
• F/C AETC or HIV Warmline Consultation
[fcaetc.org/Consultation]
• DHHS HIV Guidelines (Tables 14-16)
[www.aidsinfo.nih.gov]
• University of Liverpool HIV iChart app for
iPhone and Android
[www.hiv-druginteractions.org]
Case from the Clinic
• 50 yo female, HIV/AIDS diagnosed this
month on hospital admission
• Creole-speaking, recently immigrated
from Bahamas
• CD4 155 (7%), HIV RNA 1,000,000
• Baseline genotype: K103N (resistance to
EFV and NVP)
• HBV co-infection, toxoplasmosis, oral
thrush, pulmonary arterial hypertension
and GERD
Case from the Clinic
• Presents to HIV clinic with her daughter
(caretaker) following hospital discharge
– Daughter has limited time to assist in care
– Daughter suggests patient has difficulty with
complex instructions
– Requests simplest ART regimen
• PI-based regimen is started:
tenofovir/emtricitabine + atazanavir +
ritonavir
Case from the Clinic
• Inpatient notes reviewed
• Discharge medication list from hospital:
– Phenytoin
– Leucovorin
– Sulfadiazine
– Pyrimethamine
– Pantoprazole
– Sildenafil
– Fluconazole
Which medication combination are you
concerned about?
89%
A. ATV/r + pantoprazole
B. ATV/r + sildenafil
C. ATV/r + phenytoin
D. All of the above
3%
A.
8%
1%
B.
C.
D.
Antiretroviral Drug
Interactions &
Polypharmacy
Elizabeth Sherman, PharmD, AAHIVE
HIV/AIDS Clinical Pharmacy Specialist,
Memorial Healthcare System
Assistant Professor,
Nova Southeastern University
Faculty, Florida/Caribbean AETC