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4/5/16 Disclosures
¨ 
¨ 
Clinically Relevant Drug
Interactions in HIV Treatment
¨ 
Presenter has no financial interest to disclose
This continuing education activity is managed and
accredited by Professional Education Services Group
(PESG) in cooperation with the NIH Pharmacy
Department. PESG, NIH, and all accrediting
organizations do not support or endorse any product
or service mentioned in this activity.
PESG and NIH staff have no financial interest to
disclose
Kristina M. Brooks, PharmD
Pharmacokinetics Fellow, NIH Clinical Center Pharmacy Dept.
Objectives
¨ 
¨ 
¨ 
Review mechanisms behind drug interactions with
antiretroviral drugs (ARVs)
Discuss recently approved ARV agents and key
interactions of concern Identify interactions between ARVs and commonly
prescribed medications and OTC products
HIV Overview
¨ 
¤ 
Single stranded, positive sense, enveloped RNA virus
Infects CD4+ T cells, macrophages, and dendritic cells
Chronic, untreated HIV infection progresses to acquired
immunodeficiency syndrome (AIDS)
¤ 
AIDS status defined by
n 
n 
¨ 
HIV Infection Course
HIV is a retrovirus that infects essential cells within the
immune system
¤ 
¨ 
Mechanisms of ARV Interactions
CD4 count <200 cell/mm3
Development of ≥1 opportunistic infection
No effective cure has been discovered à lifelong
treatment with antiretroviral drugs (ARVs) is necessary
Image from: https://upload.wikimedia.org/wikipedia/commons/thumb/0/0e/Hivtimecourse_copy.svg/2000px-Hiv-timecourse_copy.svg.png
1 4/5/16 Enfuvirtide (T-20)
NRTIs
Abacavir (ABC)
Didanosine
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine
Zidovudine
Maraviroc (MVC)
INSTIs
Elvitegravir (EVG)
Dolutegravir (DTG)
Raltegravir (RAL)
NtRTIs
Tenofovir (TDF or TAF)
NNRTIs
Efavirenz (EFV)
Etravirine (ETR)
Nevirapine (NVP)
Rilpivirine (RPV)
PIs
Amprenavir
Atazanavir (ATV)
Darunavir (DRV)
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Saquinavir
Tipranavir
Recommended HIV Regimens for
Treatment-Naïve Patients
NRTI
Backbone
3rd Agent
Complete Regimens
Integrase Inhibitor
(INSTI)
DTG + TDF/FTC (Tivicay + Truvada)
DTG/ABC/3TC (Triumeq)
Abacavir/lamivudine
(ABC/3TC)
Tenofovir disoproxil
fumarate/
emtricitabine
(TDF/FTC)
Tenofovir
alafenamide/
emtricitabine
(TAF/FTC)
PK Enhancers (“Boosters”)
Cobicistat* (COBI or /c)
Ritonavir (RTV or /r)
Dolutegravir (DTG)
Elvitegravir (EVG)
Raltegravir (RAL)
Protease Inhibitor (PI)
Darunavir/ritonavir
(DRV/r)
NRTI
Backbone
Fundamentals of HIV Management
¨ 
3rd Agent
Complete Regimens
Non-nucleoside reverse
transcriptase inhibitors
(NNRTI)
Atripla
(EFV/TDF/FTC)
DRV/r + TDF/FTC (Prezista + Norvir + Truvada)
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016
Image from: http://www.nature.com/nrd/journal/v6/n12/fig_tab/nrd2424_F1.html
Alternative Regimen Options for
Treatment-Naïve Patients
EVG/c/TAF/FTC (Genvoya)
EVG/c/TDF/FTC (Stribild)
RAL + TDF/FTC (Isentress + Truvada)
All HIV-infected patients should be treated with
ARV therapy
¤  No
Efavirenz (EFV)
Abacavir/lamivudine
(ABC/3TC)
Rilpivirine (RPV)
Tenofovir disoproxil
fumarate/emtricitabine
(TDF/FTC)
Protease Inhibitor (PI)
Tenofovir alafenamide/
emtricitabine
(TAF/FTC)
Atazanavir/ritonavir
(ATV/r)
Darunavir/cobicistat
(DRV/c)
Atazanavir/cobicistat
(ATV/c)
Darunavir/ritonavir
(DRV/r)
longer based on CD4 count thresholds
2-3 fully active agents from different drug
classes
¤  Need
Complera
RPV/TDF/FTC
Evotaz + Truvada
(ATV/c + TDF/FTC)
¨ 
Treatment goals
Reyataz + Norvir + Truvada
(ATV/r + TDF/FTC)
¤  Suppress
Prezista + Norvir + Epzicom
(DRV/r + ABC/3TC)
¤  Restore
plasma HIV RNA
and preserve immunologic function
¤  Reduce HIV-associated morbidity and mortality
¤  Prevent transmission of HIV
Prezcobix + Epzicom
(DRV/c + ABC/3TC)
Prezcobix + Truvada
(DRV/c + TDF/FTC)
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016
Selecting an ARV Regimen
¨ 
Pre-treatment HIV RNA level (viral load) and CD4 cell count
¨ 
HIV drug resistance genotype
¨ 
Drug Interactions in HIV
¨ 
¤  ARV-ARV
interactions very common
concomitant non-HIV medications are also
affected
¤  Other
HLA-B*5701 status
¤ 
If positive, abacavir cannot be used
¨ 
¨ 
Patient preference, tolerance, and anticipated adherence
¨ 
Comorbidities and coinfections
¨ 
Concomitant medications
ARVs are substrates, inhibitors, and inducers of
several metabolic enzymes and transporters
Increased longevity of HIV-infected patients à
shifted need to management of comorbid conditions
¤  Estimated
that >50% of HIV-infected persons are 50
years of age or older
disease, metabolic disorders, non-HIV malignancies,
and renal/liver dysfunction now more of a concern
¤  CV
2 4/5/16 Types of Drug Interactions
Pharmodynamic
• Additive
• Synergistic
• Antagonistic
Pharmacokinetic Interactions
Pharmacokinetic
• Absorption
• Distribution
• Metabolism
• Elimination
GI motility
pH
Chelate formation
GI transport proteins (P-gp)
Transport proteins
(P-gp, OATP, MDR1)
Plasma protein binding
Phase I (CYP450 enzymes)
Transport proteins (OATP)
Phase II (conjugation)
Transport proteins
(OCT2, OAT1/3)
Glomerular filtration
Tubular secretion
Image from: http://www.nature.com/nrc/journal/v5/n6/images/nrc1629-f1.jpg
Absorption
¨ 
pH dependence for drug dissolution
¤ 
¨ 
¨ 
Intestinal Tract
Ex: atazanavir, rilpivirine
Blood
Chelation of drugs that bind to cationic
active sites
¤ 
¨ 
Transporters
Ex: integrase inhibitors
Ex: OATP
Expression of CYP enzymes in the
small intestine
Ex: P-gp
Intestinal transporters
¤ 
¤ 
Efflux: P-glycoprotein (P-gp) and breast
cancer resistance protein (BCRP)
Uptake: organic anion transporter (OAT)
Images from: http://www.pnas.org/content/109/7/2251/F1.large.jpg (top), http://www.nature.com/nrd/journal/v9/n3/images/nrd3028-f1.jpg (bottom)
Distribution
Transporters
Transporter
Substrates
Inhibitors
Inducers
Efflux
P-gp
Aliskiren, colchicine, dabigatran
etexilate, digoxin, DPP4-inhibitors,
fexofenadine, immunosuppressants,
maraviroc, posaconazole, ranolazine,
talinolol, tolvaptan
Cardiac medications (ACEIs, ARBs,
antiarrhythmics, CCBs), cobicistat,
macrolides, cyclosporine,
itraconazole, ketoconazole,
lopinavir, ritonavir
Avasimibe, carbamazepine,
phenytoin, rifampin, St John’s wort,
tipranavir/ritonavir
BCRP
Many antineoplastics (topotecan),
rosuvastatin, sulfasalazine
Cobicistat, cyclosporine, ritonavir
Not known
Uptake
Lipid-lowering agents (statins,
ezetimibe), glyburide, rifampin,
valsartan, olmesartan
Atazanavir, cobicistat, cyclosporine,
gemfibrozil, lopinavir, rifampin,
ritonavir, saquinavir, tipranavir
OATP1B3
Some statins, ARBs
Atazanavir, cobicistat, cyclosporine,
lopinavir, rifampin, ritonavir
OCT2
H2RAs, metformin, NMDA-antagonists,
pindolol, varenicline
Cimetidine, quinidine
OAT1
Captopril, furosemide, lamivudine,
methotrexate, oseltamivir, tenofovir,
zidovudine
Probenecid
OAT3
Acyclovir, ciprofloxacin, famotidine,
furosemide, methotrexate, zidovudine,
penicillin G, some statins
Probenecid, cimetidine, diclofenac
OATP1B1
Image from: http://www.nature.com/nrd/journal/v9/n3/images/nrd3028-f1.jpg
Not known
Not known
Not known
Not known
Not known
Full list can be found on the FDA website: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm093664.htm
3 4/5/16 Metabolism
Elimination
Percent Contribution of Phase I and II Enzymes to Drug Metabolism
¨ 
NRTIs primarily renally eliminated
¤ 
Require dose adjustments in patients
with renal insufficiency
n 
¨ 
¤ 
¤ 
¨ 
MATE1 by cobicistat
OCT2 by dolutegravir, rilpivirine, ritonavir
Inhibition of renal uptake
transporters can increase drug levels
¤ 
ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CYP, cytochrome P450; DPD, dihydropyrimidine dehydrogenase; NQO1, NADPH:quinone
oxidoreductase or DT diaphorase; COMT, catechol O-methyltransferase; GST, glutathioneS-transferase; HMT, histamine methyltransferase; NAT,Nacetyltransferase; STs, sulfotransferases; TPMT, thiopurine methyltransferase; UGTs, uridine 5′-triphosphate glucuronosyltransferases.
Exception: abacavir
Creatinine secretion inhibited by
some ARVs à transient SCr increase
P-gp and OATP1B1/3 by cobicistat,
ritonavir
Evan WE, Relling MV. Science. 1999 Oct 15;286(5439):487-491.
ARV Interaction Overview
Agent
Metabolism
PK Enhancers/Boosting Agents
Transporter
Cobicistat
3A4, 2D6 (minor)
OCT2
Ritonavir
3A4, 2D6
P-gp, MRP1/2
Protease Inhibitors (PIs)
Amprenavir
3A4
P-gp
Atazanavir
P-gp, MRP1/2
3A4
P-gp,
OATP1A2/1B1
3A4
P-gp
3A4
P-gp, MRP1/2
3A4
P-gp, MRP1/2
2C19, 3A4 (M8
Nelfinavir
P-gp
metabolite), 2D6
Saquinavir
3A4
P-gp
Tipranavir
3A4
P-gp
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz
2B6 (major), 2A6, 3A4
Etravirine
3A4, 2C9, 2C19
Nevirapine
3A4, 2B6 (minor)
3A4 (major),
Rilpivirine
2C8/9/10/19 and
OCT1
1A2 (minor)
Darunavir
3A4
Fosamprenavir
Indinavir
Lopinavir
ARV Interaction Overview
Inhibitor
3A4 > 2D6
P-gp, BCRP, OATP1B1/3, MATE1
3A4, 2D6* > 2C9/19 > 2A6 >
1A2 > 2E1
P-gp, BCRP, OATP1B1/3, MATE1
Raltegravir
1A2, 2B6, 2C8, 2C9/19,
UGT1A1
3A4
3A4, 1A2, UGT1A1>2C8, 2C9
P-gp*
P-gp
3A4, P-gp
-
3A4, P-gp
3A4
3A4
3A4 (weak)
UGT, 1A2
3A4, 2B6 (in vitro)
UGT, 1A2, 3A4, 2C9, P-gp
3A4, P-gp
2D6
3A4, 1A2, 2C19, P-gp
2C9/19, 3A4
2C9/19
-
Agent
Integrase Inhibitors (INSTIs)
Inducer
-
3A4 (potent), 2B6, UGT1A1
3A4, P-gp
3A4, 2B6
2C19*, 1A2*, 2B6*, 3A4*
Kis O, et al. Trends Pharmacol Sci. 2010 Jan;31(1):22-35.
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
Department of Health and Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
Transporter
P-gp, OAT1,
PEPT1
Inhibitor
Inducer
-
-
Dolutegravir
OCT2, MATE
(renal)
-
Elvitegravir
-
2C9
UGT1A1 (major); 3A4 (minor)
? BCRP, P-gp
? UGT1A3/9
3A4 (major), UGT1A1/3
P-gp
(minor)
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs/NtRTIs)
Abacavir
ADH, UGT1A1*
P-gp
Didanosine
Renal elimination
BCRP
Emtricitabine
Renal elimination
MRP1
Lamivudine
Renal elimination
BCRP
Stavudine
Renal elimination
BCRP
Tenofovir
P-gp, BCRP,
Renal elimination
diphosphate (TFV-DP)
OAT1/3
Tenofovir disoproxil
Renal elimination
P-gp
fumarate (TDF)
Tenofovir
Cathepsin A (intracellular)
P-gp, BCRP,
alafenamide (TAF)
Renal elimination
OATP1B1/3
Zidovudine
Glucoronidation*
Entry Inhibitors
Non-NADP-dependent
Enfuvirtide
hydrolysis
Maraviroc
3A4
P-gp
P-gp
*Inhibition/induction observed at higher concentrations than those achieved with clinical doses.
Metabolism
UGT1A1
OCT1, MATE1 (weak)
Cathepsin A
*Metabolite and parent undergo renal and hepatobiliary excretion!
Kis O, et al. Trends Pharmacol Sci. 2010 Jan;31(1):22-35.
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
Department of Health and Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
!
Cobicistat (COBI)
Recently Approved ARVs
¨ 
Newer PK enhancer without HIV activity
¤  Dose
of 150 mg once daily
inhibitor of 3A4 > 2D6
¤  Similar AEs to RTV-boosted regimens
¤  Strong
¨ 
Coformulated into fixed dose combinations (FDCs)
¤  EVG/c/TDF/FTC
(Stribild) – approved Nov 2012
(Evotaz) – approved Jan 2015
¤  DRV/c (Prezcobix) – approved Jan 2015
¤  EVG/c/TAF/FTC (Genvoya) – approved Nov 2015
¤  ATV/c
4 4/5/16 COBI Interactions
¨ 
Potent inhibitor of CYP3A4
¤ 
¤ 
¤ 
Similar potency of 3A4 inhibition, weaker 2D6 vs. RTV
Similar interactions to RTV assumed with 3A4 substrates
RTV and COBI both inhibit transporters
n 
¨ 
¨ 
Newly available prodrug form of tenofovir (TFV)
¤  Converted
inside target cell by cathepsin A
lower systemic concentrations of TFV à less
renal and bone toxicity vs. TDF
¤  90%
P-gp, BCRP, OATP1B1/3, MATE
Interaction profile between RTV and COBI may vary
¤ 
No induction of CYP enzymes
¤ 
COBI may yield stronger MATE inhibition than RTV
n 
n 
¨ 
Tenofovir alafenamide (TAF)
Substrates for enzymes induced by RTV may not be affected with a
transition to COBI
Similar IC50, but higher intracellular accumulation via OCT2 uptake into
renal tubular cells
Drug interaction studies comparing differences between RTV- and
COBI-boosted atazanavir and darunavir are lacking at this time
Marzolini C, et al. J Antimicrob Chemother. 2016 Mar 5. pii: dkw032. [Epub ahead of print]
TAF Formulations
¨ 
TAF available at two different doses depending on
concomitant ARVs
10 mg à boosted with RTV or COBI
¤  25 mg à unboosted regimens
Ray AS, et al. Antiviral Research. 2016 Jan; 125: 63-70.
TAF Interactions
¨ 
TAF is increased 2.5-fold by boosted ARVs
¤  Use
10 mg dose (not 25 mg)
¤ 
¨ 
¨ 
¤  TAF
also inhibits cathepsin A in vitro à contraindicated
with certain hepatitis C protease inhibitors
Four FDC formulations at various stages of development
¤  Genvoya®
n 
¤  Odefsey®
n 
(EVG/c/TAF/FTC) – approved Nov 2015
Alternative for Stribild
¤ 
DRV/c/TAF/FTC – Ph3 trials, possible approval later in 2016
Alternative for Truvada
Substrate for P-gp, BCRP, OATP1B1/3
¤  Inhibitors
¤  Inducers
Alternative for Complera
Descovy® (TAF/FTC) – application submitted
n 
¨ 
(RPV/TAF/FTC) – approved March 2016
¤ 
Intracellular metabolism by cathepsin A
¨ 
may increase TAF levels
may decrease TAF levels
Weak inhibitor of OCT1 and MATE1
¤  In
vitro studies show weak inhibition of CYP3A
AIDSinfo Drug Database. “Tenofovir alafenamide.” 17 Dec 2015. Accessed 13 Mar 2015. <https://
aidsinfo.nih.gov/drugs/514/tenofovir-alafenamide/0/professional>
Patient Case #1
Common Interactions with ARVs
¨ 
53 yo HIV-infected male presents to clinic with complaints
of dizziness, disturbing dreams after restarting therapy
with Atripla
¤ 
¨ 
Contains efavirenz/tenofovir/emtricitabine
Current medication list
Atorvastatin 40 mg po daily
Atripla 1 tab po q HS
¤  Lisinopril 20 mg po daily
¤  Metformin 1000 mg BID with food
¤ 
¤ 
¨ 
The patient would like to change his ARV regimen
¤ 
¤ 
What would you recommend?
What interactions are you concerned about?
5 4/5/16 Metformin
¨ 
Statins
Cautioned use with dolutegravir (DTG) specifically
¤  DTG
alone (Tivicay®)
¤  DTG/abacavir/lamivudine (Triumeq®)
¨ 
¨ 
PIs and elvitegravir/COBI (EVG/c) can increase statin exposure
Efavirenz (EFV), etravirine (ETR), nevirapine (NVP) primarily
decrease exposure
¤ 
¨ 
DTG inhibits the renal transporter responsible for
eliminating metformin (OCT2)
¤  79%
n  vs.
increase in metformin AUC with DTG 50 mg q 24 hrs
metformin 500 mg BID alone
¤  145%
¨ 
increase in metformin AUC with DTG 50 mg q 12 hrs
Maximum metformin dose = 1,000 mg/day with
concomitant use of DTG
Do not exceed maximum statin doses to overcome induction
Statins
Metabolism
Boosted PIs
¨ 
Regimen change from Atripla (efavirenz/tenofovir/emtricitabine)?
¨ 
Atorvastatin 40 mg daily
•  Contraindicated
•  EFV: 68% AUC decrease
•  Contraindicated
Lovastatin
3A4
•  Contraindicated
•  Titrate to effect
•  Contraindicated
Atorvastatin
3A4
•  Reduce dose by 50%
•  Titrate to effect
•  +DRV/r = max 20 mg
•  EFV, ETR: 32-43% AUC
decrease
•  Titrate to effect
•  Titrate to effect
Fluvastatin
2C9
•  No data – possible increase
with ATV?
•  ETR: increases statin
•  Reduce dose
•  No data – possible
decrease?
•  Max dose of 10 mg
•  Titrate to effect
•  No data - possible increase
by EFV or ETR?
•  Increases AUC by 38%
•  Titrate to effect
Rosuvastatin
2C9/19
Pravastatin
UGT
•  Titrate to effect
•  EFV decreases AUC by 44%
•  No adjustment
Pitavastatin
UGT, 2C9
•  No adjustment
•  No adjustment
•  No adjustment
¤ 
¤ 
Efavirenz à darunavir/cobicistat or elvitegravir/cobicistat?
n 
n 
¨ 
¨ 
Reduce dose to 20 mg to achieve similar effects
¨ 
Monitor INR and adjust warfarin dose accordingly
n 
¨ 
¨ 
Avoid with 3A4 inhibitors & inducers
Dabigatran: P-gp and MATE1
¤ 
Maximum daily dose of 1000 mg
Decreased warfarin levels possible with RTV-boosted PIs
Increased warfarin levels possible with etravirine
Rivaroxaban, apixaban, edoxaban: CYP3A4 and Pgp
¤ 
¨ 
Efavirenz à dolutegravir?
n 
Warfarin: CYP2C9 > 3A4
n 
No change necessary
Metformin 2000 mg daily with food
¤ 
Anticoagulants & Antiplatelets
Reduce dose to 10 mg daily due to 3A4 inhibition
Lisinopril 20 mg daily
¤ 
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
¤ 
40 mg ≈ 20 mg due to 3A4 induction by efavirenz
Efavirenz à dolutegravir or raltegravir?
¤ 
INSTIs (EVG/c)
3A4
Song IH, et al. J Acquir Immune Defic Syndr. 2016 Mar 11.
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
Department of Health and Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
Patient Case #1
NNRTIs (EFV, ETR, and NVP)
Simvastatin
COBI increases and prolongs thrombin time, no effect with RTV
Clopidogrel: 2C9/19
¤ 
Etravirine may prevent activation à do not coadminister
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
Antacids & Acid Suppressants
¨ 
Integrase inhibitors can chelate with Ca, Mg, and
Al-containing antacids
Mineral Supplements
¨ 
¤  INSTIs are the only ARV drug class
Mg2+ in the HIV integrase enzyme
¤  Give
ARVs 2 hour before or 6 hours after antacid
¤  H2RAs and PPIs are acceptable to use
¨ 
Atazanavir and rilpivirine require an acidic
environment for absoprtion
¤  PPIs
contraindicated with rilpivirine
¤  DHHS Guidelines should be consulted for appropriate
dosing and spacing of acid suppressants
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
Cationic minerals can reduce integrase inhibitor
(INSTI) levels by 40-74% when coadministered
¤  Applies
of concern à binds to
to Ca2+, Fe2+, Al2+, Mg2+, and Zn2+ supplements
n  Sucralfate
n  Extent
¨ 
and liquid bismuth subsalicylate can also interact
of interaction with daily multivitamins unclear
INSTIs must be taken 2 hrs before or 6 hrs after
mineral supplements
¤  Exception: dolutegravir can be given at the same
Fe2+ or Ca2+ supplements if given with food
time as
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
6 4/5/16 Anticonvulsants
¨ 
Phenytoin, phenobarbital, carbamazepine, oxcarbazepine
metabolized via CYP450 system
All are capable of CYP induction à dual interaction with RTVboosted PIs and NNRTIs
¤  Many combinations are contraindicated or cautioned against
Antidepressants
SSRIs, SNRIs, and TCAs metabolized via CYP2D6
¨ 
¤ 
¤ 
Boosted PIs: start with lowest dose and titrate to effect
Darunavir/RTV: decreases paroxetine and sertraline AUC by 39-49%
¤ 
¨ 
Consider alternatives if boosted PIs or NNRTIs required
¤ 
Low interaction potential with renally eliminated drugs
n 
¤ 
n 
Bupropion via 2B6
¨ 
Trazodone via CYP3A4
¤ 
Efavirenz decreases levels by 55% à titrate to effect
¤ 
3-4 fold AUC increase with RTV administration
¤ 
May be used at low dose for sleep, titrate to effect
Levetiracetam, lacosamide
n 
Agents that undergo glucoronidation may be decreased by RTVboosted PIs à monitor drug levels
Valproic acid (>90% by UGT and beta-oxidation)
n  Lamotrigine (UGT1A4)
n 
Effects with COBI unknown
¨ 
n 
No data with COBI but increased levels expected
Mirtazapine could be considered as an alternative
Modifications to ARV regimen may require further dose
adjustments in psych medications
¨ 
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
Anxiolytics & Hypnotics
¨ 
Anxiolytics
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
Antipsychotics
¨ 
¤  Alprazolam:
avoid with PIs, no data with NNRTIs
¤  Midazolam and triazolam: do not coadminister oral dose
with efavirenz, or COBI or RTV-boosted ARVs
¤  Low interaction potential with lorazepam, oxazepam,
temazepam à alternative treatment options
¨ 
Hypnotics
(Belsomra®): contraindicated with 3A4
inhibitors
¤  Zolpidem (Ambien®): 3A4 and other pathways à
increased levels possible with boosted PIs
¤ 
Nearly all are substrates for 3A4 and/or 2D6, some for 1A2, 2C19
Ritonavir (RTV)
¤ 
Cobicistat
¤ 
n 
n 
n 
¨ 
¤  Suvorexant
PIs and PK enhancers can alter concentrations of atypical
antipsychotics
Inhibits 3A4, 2D6 à increased levels
Induces 1A2 and 2C19 à decreased levels (ex: olanzapine)
Inhibits CYP3A4, 2D6 à increased levels expected, no data available
Numerous case reports documenting AEs following
coadministration of antipsychotics + RTV-boosted PIs
¤ 
¤ 
EPS side effects, sedation, disorientation, significant weight gain
develop quickly
Reversal of symptoms accomplished with discontinuation of
antipsychotic or boosted PI
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
Patient Case #2
¨ 
34 yo male with recent diagnosis of HIV/AIDS
on Stribild (elvitegravir/cobicistat/tenofovir/
emtricitabine)
¤  Presented with cryptococcal meningitis, CMV
encephalopathy
Kennedy WK, et al. CNS Drugs (2013); 27, 1021-1048.
Hill L, et al. Ann Pharmacother (2013); 47, 75-89.
Patient Case #2
¨ 
n  Neurological
response, further dose increases desired
over boosting by COBI à guideline
recommendation to use 1/6th dose
¤  Concern
¨ 
n  No
¨ 
What agent would you recommend?
Transitioned to olanzapine 12.5 mg daily
¤  Metabolized
changes, agitation present despite effective
therapy
n  Medical team decides to add on an antipsychotic
¨ 
Treatment was initiated with quetiapine 50 mg daily
¤  Partial
¤  Initiated
by UGT, 1A2, 2D6 à lower interaction risk
data with COBI-boosted regimens
Changed ARV regimen to Triumeq (dolutegravir/
abacavir/lamivudine)
¤  Reduce
risk of drug interactions with future psych
medications
7 4/5/16 Azole Antifungals
¨ 
¨ 
Low dose fluconazole can be used with ARV regimens
¨ 
¤ 
Rifamycins: induction of CYP and UGT enzymes1
¤  Rifampin
Itra-, keto-, posa- and isavuconazole are 3A4 substrates and
inhibitors à bi-directional interactions with PIs and NNRTIs
¤ 
n 
not use rifampin with PI-based regimens
metabolized by 3A4 à two-way interaction with
inhibitors/inducers of 3A4
n  Rifapentine data is limited à not recommended at this time
n  Rifabutin
PIs: increased azole and PI levels may result, monitor for PI toxicity
NNRTIs: decreased azole and increased NNRTI levels possible
n 
Exception: rilpivirine
¨ 
RTV decreases AUC by 39% à monitor levels or consider alternatives
¤ 
Efavirenz decreases AUC by 77%: increase voriconazole to 400 mg BID
n 
n 
COBI-boosted ARVs may increase levels
Clarithromycin: 3A4 substrate and potent inhibitor1
¤  PIs
Voriconazole metabolized by 2C19 > 3A4
¤ 
> rifapentine > rifabutin
n  Do
Certain combinations should be avoided or require dose adjustments
Consult guidelines and monitor azole levels
n 
¨ 
Opportunistic Infections
¨ 
and NNRTIs: consider alternative (e.g., azithromycin)
Atovaquone: UGT substrate2
¤  Efavirenz
decreases levels by 44-47%
does not alter concentrations
¤  Atazanavir/RTV
Decrease efavirenz from 600 mg to 300 mg daily (bi-directional interaction)
1Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.
Department of Health and Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
2Calderón MM, et al.. Clin Infect Dis. 2016 Jan 20.
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
Corticosteroids
¨ 
Systemic corticosteroids altered by boosted PIs and NNRTIs
¤ 
¤ 
Patient Case #3
¨ 
Prednisone AUC changes by 30% with 3A4 inhibition/induction
Dexamethasone decreases NNRTI AUCs – consider alternatives if >1
dose needed
35 yo male received epidural injections of triamcinolone
acetonide (x2) for lumbosacral back pain at outside facility
¤ 
¤ 
¤ 
¨ 
Inhaled and nasal corticosteroids are boosted by RTV and COBI à
do not coadminister, concern for iatrogenic Cushing’s syndrome
¤ 
¤ 
Inhaled fluticasone + PI/r = 368-fold increase in AUC
Beclomethasone is currently the only alternative if a boosted regimen
is necessary
n 
¨ 
ARV regimen: lopinavir/RTV BID + tenofovir/emtricitabine
Reported facial swelling within 1 week of injection
1 month post-injection: BP 157/100, weight gain of 1.4 kg, “moon
face” and “buffalo hump”, poor wound healing
•  Triamcinolone half-life normally ~2-3 hrs
•  Absorption from intra-articular sites can
occur for 2-3 wks after injection
•  Estimated half-life in this patient was
21.3 days à 170-fold increase
Metabolized by esterases (NOT CYP450) à 2-fold increase with RTV alone
(not clinically significant), unchanged with darunavir/RTV
Intraarticular steroid injections can also be boosted with RTV or
COBI-containing regimens à do not coadminister
Boyd SD, et al. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3)355-61
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
Patient Case #4
¨ 
57 yo male with HIV on ARV regimen of darunavir/
RTV + emtricitabine/tenofovir
intraarticular steroid injection into the shoulder
2 days prior to clinic visit
¤  Review of safety labs revealed elevated WBC 12.35,
glucose 181 (normally 80-100)
Ramanathan R, et al. Clin Infect Dis. 2008 Dec 15;47(12):e97-9. doi: 10.1086/593314.
Hormones
¨ 
¤ 
¤ 
¤  Received
¨ 
Barrier methods needed if levels are decreased
Depomedroxyprogesterone and IUDs do not appear to have
significant interactions with ARVs
n 
¨ 
¤  Patient
¨ 
May be preferred methods, but further studies are needed
Ethinyl estradiol (EE)
¤ 
Decreased with PI/r, EFV, and NVP, (?)COBI
¤ 
Increased with ATV 400 mg daily à max dose 30 mcg
n 
Darunavir/RTV switched to dolutegravir
counseled on monitoring for facial swelling,
hypertension, weight gain
¤  Labs normalized at 1 month follow-up visit, no other side
effects reported
Oral contraceptives can be affected
ATV/r: use OC with 35+ mcg EE
Progestins
¤ 
Increased with ATV/r, (?)COBI
¤ 
Decreased with EFV and NVP
n 
Monitor for acne, decreased HDL, and insulin resistance
Tseng A, Hills-Nieminen C. Expert Opin Drug Metab Toxicol. 2013 May;9(5):559-72.
8 4/5/16 PDE5 Inhibitors
¨ 
AUC increases by 2- to 50-fold with concomitant
PI/r administration due to 3A4 inhibition
¤  No
Conclusions
¨ 
¤ 
data with COBI à use lowest dose
data with NNRTIs à may require higher doses
¤  Little
¨ 
¨ 
Use lowest available doses and monitor for
orthostatic hypotension
(Viagra) – max 25 mg q 48 hrs
(Levitra) – max 2.5 mg daily
¤  Tadalafil (Cialis) – max 10 mg q 72 hrs
Aging HIV population is requiring chronic medication therapy
for non-HIV-associated conditions
Several drug interactions have been identified and
characterized
Many more are based on known interactions mediated by
similar mechanisms à not always clear if similar or different
¤  Further research is still needed
¤ 
¤  Sildenafil
¤  Vardenafil
Drug interactions can pose significant problems for HIVinfected patients on ARV therapy
¨ 
Full evaluations of all concomitant medications need to
be conducted at every patient encounter
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and
Human Services. Accessed 13 Mar 2016 [Drug Interactions L-1]
Resources for HIV Drug Interactions
¨ 
¨ 
¨ 
¨ 
DHHS Guidelines:
http://aidsinfo.nih.gov/guidelines
Liverpool: www.hiv-druginteractions.org
Toronto General Hospital:
http://www.hivlcinic.ca/main/drugs_interact.html
Questions?
Obtaining CME/CE Credit
If you would like to receive continuing
education credit for this activity, please visit:
http://nih.cds.pesgce.com
Micromedex: www.micromedexsolutions.com
References
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
¨ 
AIDSinfo Drug Database. “Tenofovir alafenamide.” AIDSinfo. National Institutes of Health, 17 Dec 2015. Accessed 13
Mar 2015. <https://aidsinfo.nih.gov/drugs/514/tenofovir-alafenamide/0/professional>
Boyd SD, Hadigan C, McManus M, Chairez C, Nieman LK, Pau AK, Alfaro RM, Kovacs JA, Calderon MM, Penzak SR.
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beclomethasone. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):355-61. doi: 10.1097/QAI.0b013e31829260d6.
Calderón MM, Penzak SR, Pau AK, Kumar P, McManus M, Alfaro RM, Kovacs JA. Efavirenz but Not Atazanavir/Ritonavir
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SLC transporters. Trends Pharmacol Sci. 2010 Jan;31(1):22-35. doi: 10.1016/j.tips.2009.10.001. Epub 2009 Dec 11.
Marzolini C, Gibbons S, Khoo S, Back D. Cobicistat versus ritonavir boosting and differences in the drug-drug
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Immunodeficiency Virus. Antiviral Research. 2016 Jan; 125: 63-70. doi:10.1016/j.antiviral.2015.11.009
Ramanathan R, Pau AK, Busse KH, Zemskova M, Nieman L, Kwan R, Hammer JH, Mican JM, Maldarelli F. Iatrogenic
Cushing syndrome after epidural triamcinolone injections in an HIV type 1-infected patient receiving therapy with
ritonavir-lopinavir. Clin Infect Dis. 2008 Dec 15;47(12):e97-9. doi: 10.1086/593314.
Song IH, Zong J, Borland J, Jerva F, Wynne B, Zamek-Gliszczynski MJ, Humphreys JE, Bowers GD, Choukour M. The
Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects. J Acquir Immune Defic Syndr. 2016
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