Download Beware: Clinically Significant Drug Interactions in the Treatment of HIV

Beware: Clinically Significant
Drug Interactions in the
Treatment of HIV
Betty J. Dong, PharmD, FCCP, FASHP, FAPHA, AAHIVP
Professor of Clinical Pharmacy and Family and
Community Medicine, University of California Schools of
Pharmacy and Medicine, San Francisco
HIV and HCV Consultant, Clinicians’ Consultation Center
2
Disclosures
• Betty J. Dong, PharmD declares no conflicts of interest,
• Target Audience: Pharmacists
real or apparent, and no financial interests in any
company, product, or service mentioned in this program,
including grants, employment, gifts, stock holdings, and
honoraria.
• ACPE#: 0202-0000-16-010-L02-P
• Activity Type: Application-based
The American Pharmacists Association is accredited by the Accreditation
Council for Pharmacy Education as a provider of continuing pharmacy
education.
3
• Examine common pharmacologic mechanisms of drug-drug
•
•
interactions with non-nucleoside reverse transcriptase
inhibitors (NNRTIs), protease inhibitors (PIs), and integrase
strand transfer inhibitors (INSTIs).
Evaluate the consequences of drug interactions associated
with antiretroviral drugs and determine the incidence of
clinical adverse effects from interactions.
Formulate a list of drugs that have a high potential to interact
with antiretroviral drugs.
Establish monitoring parameters and strategies that can be
used to minimize the incidence of adverse drug interactions
5
© 2016 by the American Pharmacists Association. All rights reserved.
•
•
• ARV= antiretroviral agent
•
• ART= antiretroviral therapy
•
• PI= Protease inhibitor
• NNRTI= non nucleoside
•
Glossary
Learning Objectives
•
4
•
•
•
•
reverse transcriptase
inhibitor
INSTI= integrase inhibitor
DRV/r= darunavir/ritonavir
ATV/r =atazanavir/ritonavir
RPV = riprivirine
•
•
•
•
•
/cobi= cobicistat
/r = ritonavir
TDF=tenofovir
TAF= tenofovir
alafenamide
FTC= emtricitabine
3TC = lamivudine
ABC= abacavir
DTG= dolutegravir
RAL=raltegravir
EVG=elvitegravir
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Self-Assessment Question
Self-Assessment Question
Proton pump inhibitors are contraindicated
with which antiretroviral agent?
Which of the following would pose the
lowest risk of drug interactions?
1.
2.
3.
4.
5.
1.
2.
3.
4.
5.
Raltegravir
Dolutegravir
Rilprivine
Elvitegravir/cobistat
Darunavir/ritonavir
Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress,
Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID
Metformin 1000 mg BID, lorazepam 2 mg prn anxiety
Raltegravir
Rilpivirine
Dolutegravir
Atazanavir/cobicistat
Darunavir/ritonavir
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8
Self-Assessment Question
Self-Assessment Question
Which is the most appropriate action if
dolutegravir, abacavir, and lamivudine
(Triumeq) is selected as initial ART?
Which of the following should be considered if
elvitegravir, emtricitabine, tenofovir (Stribild) or
Tenofovir alafenamide (Genvoya) is started?
1.
2.
3.
4.
5.
1.
2.
3.
4.
5.
Reduce metformin dose
Increase amlodipine dose
Give CA+ w/DTG on empty stomach
Stop esomeprazole
Give Al-Mg antacids at same time
Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress,
Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID
Metformin 1000 mg BID, lorazepam 2 mg prn anxiety
9
Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress,
Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID
Metformin 1000 mg BID
Which of the following hepatitis agents
would result in the lowest risk of ARV
drug interactions?
1. Sofosbuvir/ledispasvir (Harvoni)
2. Paritaprevir/ritonavir/ombitasvir/dasabuvir
What can occur if ledipasvir/sofosbuvir
(Harvoni) is given with tenofovir,
emtricitabine, and darunavir/r regimen?
1.
2.
3.
4.
5.
(ViekiraPak or PROD)
3. Sofosbuvir/simeprevir
4. Sofosbuvir/daclastasvir
5. Grazoprevir/elbasvir
© 2016 by the American Pharmacists Association. All rights reserved.
10
Self-Assessment Question
Self-Assessment Question
Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin,
warfarin, indomethacin, OTC ranitidine
Reduce metformin dose
Reduce amlodipine dose
Change lorazepam to triazolam
Separate esomeprazole by 6 hr
Give Al-Mg antacids at same time
11
HCV treatment failure
HIV treatment failure
Darunavir hepatic toxicity
Tenofovir renal toxicity
Emtricitabine lipid toxicity
Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin,
warfarin, indomethacin, OTC ranitidine
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Some Pharmacokinetic Basics...
Prevalence of Clinically Significant Drug
Interactions
•
•
•
•
•
• 27-41% of HIV+ persons
• Risk factors:
–
–
–
–
Age >50yr (aOR 2.5)
Polypharmacy: >5 non-HIV agents (OR 2.7 to 15.1)
Co-morbidities: dyslipidemia (aOR 1.96), anxiety (aOR 1.78)
Protease (OR 5.3) or NNRTI regimen
• Low recognition of CSDI--36%
–
–
–
–
Substrates
CYP450 inhibition
CYP450 induction
AUC: area under the curve = drug exposure
Cmin/trough: lowest drug concentration = ARV
efficacy
Lower ARV concentrations
Suboptimal therapy
Toxicity
Death
J AIDS 2006;42:52; Ann Pharmacoth 2008;42:1048; Ther Drug Monit 2007;687
HIV Med 2015;16:273. Pharmacotherapy 2007;27:1379; AIDS Care 2015; 27:1443
13
CID 2006;43:933; J Clin Pharm Ther 2004;29:121;CID 2010;50:1419.
Hepatic Metabolism
CYP 450 and Drug Metabolism
• Substrates refers to agents metabolized via the hepatic
• Majority of medications are 3A4 substrates
metabolized by 3A4 hepatic enzymes
CYP2C
14
enzyme (CYP 450, UGT1A1) system agents
• Nonnucleosides (NNRTIs), protease inhibitors (PIs),
integrase inhibitor elvitegravir, statins, warfarin are
metabolized via CYP 450 3A4 and associated
isoenzymes
• Integrase inhibitors (INSTI) raltegravir and dolutegravir
are primarily metabolized by glucuronidation via the
UGT1A1 enzyme (UDP-glucuronosyltransferases)
• Most NRTIs (nucleoside reverse transcriptase inhibitors)
are renally eliminated and do not undergo liver
metabolism. Exceptions: zidovudine, abacavir
CYP3A4
CYP2D6
CYP
1A2
15
16
Slide 17 of 39
CYP450 Inhibition
CYP450
• Slower onset and
• Quick onset and offset
of effect when stopped
Drug
Concentration
(few days)
• Reduces metabolism
of CYP 450 enzyme
substrates
•  levels of substrates
( toxicity/efficacy)
• Examples of inhibitors:
Inhibiting
protease inhibitors,
cobicistat
CYP 450 Induction
drug added
Time
17
© 2016 by the American Pharmacists Association. All rights reserved.
Slide 18 of 39
Drug
offset of action
Concentration
when stopped
~ 7 to 14 days
•  levels/efficacy
of CYP 450
substrate
• Examples of
Inducing drug added
inducers:
efavirenz, rifampin
Time
18
Mechanism of ARV Drug Interactions
• Most clinically relevant antiretroviral (ARV) drug
Drug Transporters
• Several medications in each ARV class are affected by
interactions occur because of alterations in CYP450
metabolism (e.g. inhibition or induction) of CYP 450
substrates
drug transporters present in multiple cell lines
• P-glycoprotein (P-gp):
– efflux pump present in the intestinal epithelium,
hepatocytes, renal, and other cells
– Increasing recognition as an important factor in
influencing drug pharmacokinetics and efficacy
– Many ARVs are P-gp substrates that can be
transported across cellular membranes by this protein,
with potential for clinically relevant drug interactions
• May also result from the action of drug transporters
involved in moving ARVs across cellular membranes
• Renal elimination is not a common cause of ARV drug
interactions
19
Drug Transporters
P-Glycoprotein (P-gp) Interactions
• Renal Transporters
• Can significantly affect disposition of medications
•
•
•
20
– Dolutegravir:
• Inhibits renal transporter, organic cation transporter2
(OCT2)
• Decreased tubular secretion of creatinine and nonprogressive SCr elevations (not progressive or true
renal impairment)
• Potentially inhibits multidrug and toxin extrusion
transporter (MATE1)
– absorption, elimination, entry into CNS, testes
P-gp substrates: digoxin
P-gp inducers: PB, phenytoin, rifampin, St John’s wort
P-gp inhibitors– erythromycin, clarithromycin, diltiazem,
felodipine, intraconazole, ketoconazole, nicardipine, grapefruit
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Recognizing Potential for ARV Drug Interactions
Protease Inhibitors
HIGH
CCR5 Inhibitors
Nucleoside Reverse
Transcriptase Inhibitors
High potential
CYP450 substrates
Mixed induction and inhibition effects
Efavirenz and etravirine: induction >>> inhibition
– Efavirenz: 3A4, 2B6 induction; 2C9, 2C19 inhibition
– Etravirine: 3A4 induction, 2C9, 2C19 inhibition
MEDIUM
• Rilpivirine is a CYP 3A4 substrate
• Nevirapine is an inducer of CYP 3A4 and 2B6
LOW
23
© 2016 by the American Pharmacists Association. All rights reserved.
Nonnucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
•
•
•
•
Nonnucleosides
Reverse Transcriptase
Inhibitors
Integrase
Inhibitors
22
24
Protease Inhibitors (PIs) and
Cobicistat
Protease Inhibitors (PIs)
• High potential
• CYP3A4 inducers
• High potential
• CYP 3A4 and p-gp substrates
• CYP 3A4 inhibitors
•
– Ritonavir: 1A2, 2C8, 2C9
– Fosamprenavir 3A4
– Tipranavir 3A4, 1A2, 2C19
– Ritonavir (/r): 3A4, 2D6
– Cobicistat (/cobi) = ritonavir: 3A4, 2D6:
pharmacoenhancer to  PI
– LPV/r, TPV/r>>ATV/r, DRV/r >> SQV/r
Variable P-gp inhibition
• Glucuronidation ( estinyl estradiol)
• Mixed effects; not always possible to determine
overall effects
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Potential for ARV Drug Interactions
Integrase Inhibitors (INSTI)
•
•
•
•
•
•
26
Protease Inhibitors
Low to medium potential
EVG> DTG> RAL are metabolized by UGT1A1
CYP 450 enzyme effects vary.
Dolutegravir is a 3A4 substrate.
Raltegravir and dolutegravir are not inducers nor inhibitors
Elvitegravir
– CYP 3A4, 2D6, 2C9, 2C19, 2B6, and 1A2 substrate.
– modest CYP2C9 inducer
– Co-formulated with cobicistat, a CYP 450 inhibitor.
HIGH
Nonnucleosides
Reverse Transcriptase
Inhibitors
CCR5 Inhibitors
Integrase
Inhibitors
Nucleoside Reverse
Transcriptase Inhibitors
LOW
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ARVs and Interacting Drugs/Classes
Anticoagulants/Anti-platelet
Acid Reducing Agents
Antifungals; azoles
Antiarrhythmics
Antimycobacterial/macrolides
Anti-epileptics
Anti-depressants/psychotics
Anti-hypertensives
Asthma agents
Benzodiazepines
Cardiac medications
Chemotherapeutic agents
Cisapride
Corticosteroids
Protease Inhibitor/Cobicistat Contraindications
Ectasy/illicit drugs
Ergots
Erectile dysfunction
Gout agents
HCV Direct Acting Agents
Herbals
Immunosuppressives
Methadone/Opiates
Oral contraceptives
Pimozide
Pulmonary hypertension
Statins
29
© 2016 by the American Pharmacists Association. All rights reserved.
28
Medication
Potential Consequences
Alpha-1 blocker; alfuzosin
Hypotension
Anticonvulsants:carbamazepine
oxcarbazepine, phenytoin, Pb
Loss of virologic efficacy d/t lower PI/cobi levels.
Consider gabapentin or levetiracetam
Rifampin, rifapentin
Loss of virologic efficacy d/t lower PI/cobi levels
Consider rifabutin with PI. Avoid with cobi.
Ergots: ergotamine, dihydroergotamine, methylergonovine
acute ergot toxicity characterized by
peripheral vasospasm and tissue ischemia
St. John’s wort
Loss of virologic efficacy d/t lower PI/cobi levels
Corticosteroids: nasal
fluticasone, budesonide,
injectable triamcinolone
Risk of Cushings’ causing adrenal insufficiency with
both systemic and nasal fluticasone/budesonide.
Consider montelukast or less potent steroid (e.g.
beclomethasone)
Dexamethasone
Avoid chronic co-administration. Loss of virologic
efficacy d/t lower PI/cobi levels
30
Protease Inhibitor/Cobi Contraindications
Case 1 Presentation
• PJ is a 38-yr-old HIV positive woman who has never taken
Medication
Potential Consequences
Benzodiazepines: triazolam, oral
midazolam
Potential for life threatening/serious risk of
increased sedation and respiratory depression.
Consider lorazepam, temazepam or oxazepam.
Neuroleptic: pimozide, lurasidone
GI motility: cisapride
Potential for life threatening/serious risk of cardiac
arrhythmias
Statins: simvastatin, lovastatin, red
rice yeast
 statin’s risk of myopathy and rhabdomyolysis.
Use lowest dose of other statins (e.g. atorvastatin,
pitavastatin, pravastatin, rosuvastatin)
Inhaled -agonists: salmeterol
Avoid co-administration d/t  risk of CV ADR
(QT, palpitations, sinus tachycardia).
Consider formoterol
•
•
•
•
antiretroviral therapy (ART) before (“treatment naive“)
PMH: GERD, type 2 diabetes, hypertension, anxiety
Social history: smokes 1 PPD, denies alcohol, illicit agents
Allergy: cough on lisinopril
Medications:
–
–
–
–
–
–
PDE-5 inhibitor:sildenafil (Revatio) sildenafil ADRs (visual, hypotension, prolonged
for pulmonary artery hypertension
erection or priapism, syncope)
Esomeprazole 20 mg daily
Aluminum magnesium antacids prn gastric distress
Calcium carbonate (TUMS) bid
Amlodipine 10 mg daily
Lorazepam 2 mg prn anxiety
Metformin 1000 mg BID
31
Case 1 Presentation:
32
Questions to Consider
PE: BP 130/80, HR 62 beats/min, R 12. 02 sat 95%
Labs:
BUN 8/Scr 1.0
A1c 6.5%
Baseline HIV Genotype: Wild type, no mutations
HLA-B5701 negative
HBV and HCV AB negative
CD4 500 cells/mm3
HIV RNA: 247,500 copies/ml
• Can we honor PJ’s request for a single tablet ARV?
• If so, which single dose antiretroviral co-formulation would
be most appropriate?
• Identify if any drug interactions are expected with the
•
addition of each single dose co-formulated first line
recommended regimen?
If so, what modifications to her DM, HTN, or GERD therapy
would be necessary to incorporate antiretroviral therapy?
She is ready to start but would prefer a single dose
tablet once daily if possible
33
DHHS Guidelines: 2015 Recommended Firstline Antiretroviral (ART) Regimens
Recommended ART
Regardless of BL VL or CD4+ Count
Class
INSTI





NNRTI
#Only
*Only if CrCl ≥ 70 mL/min.
†Only if HLA-B*5701 negative.
Considerations for Selecting The
Initial Antiretroviral Regimen
Lifestyle
Adherence
Dosing
Pill Burden
Preference
Resistance
Testing
RAL + TDF/FTC
EVG/COBI/TDF/FTC (Stribild)*
EVG/COBI/TAF/FTC (Genvoya)#
DTG/ABC/3TC (Triumeq)†
DTG + TDF/FTC
Boosted  DRV/r + TDF/FTC
PI
‡Avoid
Alternative Regimens
34
Co-morbid
Conditions





ATV/r + TDF/FTC
ATV/COBI (Evotaz)+TDF/FTC*
DRV/r + ABC/3TC†
DRV/COBI (Prezcobix)+ ABC/3TC†
DRV/COBI (Prezcobix)+ TDF/FTC*
 EFV/TDF/FTC (Atripla)
 RPV/TDF/FTC (Complera)‡
(e.g. Hepatitis
CV Disease,
Mental illness)
Potency
Drug
Interactions
Initial ART
Treatment
Toxicity
Short Term
Long Term
if CrCl > 30 ml/min
if initial VL >100,000 c/mL and CD4+ < 200 c/mm3.
© 2016 by the American Pharmacists Association. All rights reserved.
35
36
Single Dose Combinations (SDC)
One Pill Once Daily ART Regimens
Advantages and Disadvantages of SDC
Advantages
Product
Components
Food Requirements
Drug interaction
Atripla
Efavirenz 600 mg
Tenofovir 300 mg
Emtricitabine 200 mg
YES, Empty stomach
3A4 inducer> inhibition
Complera
Rilpivirine 25 mg
Tenofovir 300 mg
Emtricitabine 200 mg
YES: > 400 Kcal meal
3A4 substrate
Stribild
YES
Elvitegravir (EVG) 150
mg/cobicistat 150 mg
tenofovir 300 mg
Emtricitabine 200 mg
YES
EVG150mg/cobi 150 mg
tenofovir alafenamide 10mg
emtricitabine 200 mg
NO
Dolutegravir 50 mg
Abacavir 600 mg
Lamivudine 300 mg
Genvoya
Triumeq
cobi 3A4 interactions =
protease inhibitors
Disadvantages
 Simplicity
 Convenience
 Fewer copays
 Reduces selective nonadherence to regimen
components
• Inability to adjust dosage
component if needed
• drug–drug interactions
• tolerability
• renal or hepatic insufficiency
 Not available for all ART
regimens
cobi 3A4 interactions =
protease inhibitors
OCT-2 interactions
37
Self-Assessment Question
Which is the most appropriate
recommendation if dolutegravir, abacavir,
and lamivudine (Triumeq) is selected as her
initial ART?
1.
2.
3.
4.
5.
Reduce metformin dose
Increase amlodipine dose
Give CA+ w/DTG on empty stomach
Stop esomeprazole
Give Al-Mg antacids at same time
Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress,
Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID
Metformin 1000 mg BID, lorazepam 2 mg prn anxiety
38
Dolutegravir Drug Interactions
Medication
Interaction
Recommendation
Polyvalent cations
(e.g., Mg, Al, Fe, or
Ca) Antacids,
laxatives, sulcrafate,
or buffered meds
Concurrent Al+ Mg+
antacids  DTG AUC
76% vs 26% if
staggered.
Administer Al++, Mg++, or
Ca++-containing antacids,
laxatives, iron, or sulcrafate
six hours before or two
hours after DTG
Fasting: DTG AUC
37%-39% with CA+
 54% to 57% iron
Food: normal AUC
Take DTG and calcium
supplements or iron
together with food.
Multivitamins
DTG AUC  33%
when co-administered
with a multivitamin.
Standard DTG dosage
PPI and H2
blockers
No interaction
Standard DTG dosage
39
40
Self-Assessment Question
Selected Dolutegravir Drug Interactions
Medication
Interaction
Anticonvulsants  DTG
Dofelitide
 dofelitide
Recommendation
Which of the following should be considered if
elvitegravir, emtricitabine, tenofovir (Stribild) or
Tenofovir alafenamide (Genvoya ) is selected as
her initial ART?
Avoid co-administration
Avoid co-administration
Carbamazepine  DTG AUC 49%
and Cmin 73%
 DTG 50 mg bid in naïve pts.
Consider oxcarbamazepine
Rifampin
 DTG
 DTG 50 mg BID in treatmentnaïve or treatment experienced if
INSTI-naïve. Consider rifabutin.
Metformin
 Metformin AUC
79%, Cmax 66%,
Cmin 9%
Adjust metformin to maximum of
1000 mg daily. Adjust metformin
dose when stopping/starting DTG
BID DTG metformin
AUC 2.4 fold, Cmax
2 fold, Cmin 14%
41
© 2016 by the American Pharmacists Association. All rights reserved.
1.
2.
3.
4.
5.
Reduce metformin dose
Reduce amlodipine dose
Change lorazepam to triazolam
Separate esomeprazole by 6 hr
Give Al-Mg antacids at same time
Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress,
Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID
Metformin 1000 mg BID
42
Cobicistat 150 mg (/cobi)
•
•
•
•
•
•
•
Stribild: CrCL >70 cc/min with tenofovir
Genvoya: CrCL >30cc/min tenofovir alafenamide (TAF)
Pharmacokinetic booster = ritonavir but no HIV activity
Take with food to increase absorption
Mean Scr  0.14 mg/dl, max 0.4 mg/dL
– Interference with creatinine tubular secretion
– eGFR before starting, urine prot/gluc, P04 with tenofovir
ADR: HA, GI distress, nausea, lipid changes
FDC: atazanavir 300 mg/cobi 150 mg (Evotaz)
darunavir 800 mg/cobi 150 mg (Prezcobix)
Clin Pharmacok: April 2011; 50:229; Lancet. 2012 Jun 30;379:2429
Interaction
Agent
Interaction
Recommendations
Antacids (Al and
Mg hydroxide, Ca
carbonate)
Cmax, and 41% Cmin.
CardiacAntiarrhythmics:
(amiodarone,digoxindi
antiarrhythmics and
digoxin levels (41% Cmax;
8% AUC).
Separate by >2hr.
Use PPI or H2 blockers
EVG AUC 45%, 47%
Separate 2 hr, EVG 1020%; NS if separate by 4hr
Monitor antiarrhythmic levels
and adjust as necessary.
sopyramide,
flecainide,lidocaineme
xiletine,quinidine,
propafenone
43
Elvitegravir/Cobi (Genvoya, Stribild) DI
Agent
Elvitegravir/Cobi (Genvoya, Stribild)
Drug Interactions (DI)
44
Elvitegravir/Cobi (Genvoya, Stribild) DI
Recommendations
Agent
Antifungals
(itraconazole,
ketoconazole,
voriconazole
 Antifungal levels
Ketoconazole and
itraconazole: NTE 200 mg/day.
Voriconazole: evaluate risks vs
benefits
Antihypertensives
-β blockers
-calcium channel
blockers (CCB)
β blockers (2D6):
(metoprolol,carvedilol
timolol);
3A4 CCB (amlodpine,
diltiazem, felodipine,
nifedipine, verapamil)
Monitor BP/HR and β-blockers
and CCB toxicity; dose prn.
Consider labetalol, naldolol,
atenolol
Antidepressants,
Anxiety
Neuroleptics
 SSRI (except sertraline), Monitor for toxicity.
TCA, buspirone, trazodone,  doses as warranted
risperidone, perphenazine,
thioridazine
Interaction
Recommendations
Colchicine
colchicine. Avoid
in renal/hepatic
dysfunction
Acute: 0.6 mg x1, 0.3 mg po one hr later,
repeat no earlier than q 3 days.
Prophylaxis:0.3mg daily or QOD
PDE5 inhibitors
for erectile
PDE5 levels
Avoid co-administration with avanafil.
DNE 25 mg sildenafil/48 hr, 2.5 mg
vardenafil or 10mg tadalafil /72 hrs
Hormonal
contraceptives
EE AUC 25%,  2
Consider alternative contraception or
use at least 30 mcg EE contraceptive
Narcotics:
(buprenorphine,
naloxone,
methadone)
Watch for 
sedative and
cognitive opioid
effects.
dysfunction
fold AUC/Cmax
norgestimate active
metabolite
Monitor for opioid toxicity. Normal
opioid doses, adjust as needed
45
Summary: Selected INSTI Drug Interactions
Agent
Elvitegravir/
cobi
Dolutegravir
46
Summary: Selected INSTI Drug Interactions
Potential Drug–Drug Interactions
COBI increases levels of 3A4 substrate drugs
Give EVG/c 2 hr before or 6 hr after AL+and/or Mg+-antacids, Fe+, CA+, Zn+
supplements
Administer Al++, Mg++, Ca++antacids/laxatives,
iron or sulcrafate six hours before or two hours
after DTG or take DTG and Ca++ supplements
or iron together with food.
 metformin 2 fold; maximum 1000 mg daily;
monitor clinically when starting/stopping DTG
47
© 2016 by the American Pharmacists Association. All rights reserved.
Agent
Raltegravir
Potential Drug–Drug Interactions
 Avoid AL+-and/or Mg-containing antacids,
 no interaction with CA+
 Give RAL at least 2 hr before or 6 hr after
polyvalent cations
 Rifampin decreases RAL levels;  RAL
800 mg BID
Raltegravir [package insert]. EVG/COBI/TDF/FTC [package insert].
Dolutegravir [package insert].
48
Case 1 Presentation
Questions to Discuss
• PJ is a 38-yr-old HIV positive woman who has never taken
• Which SDC would be most appropriate for PJ?
antiretroviral therapy (ART) before (“treatment naive“)
PMH: GERD, type 2 diabetes, hypertension, anxiety
Social history: smokes 1 PPD, denies alcohol, illicit agents
Allergy: cough on lisinopril
Medications:
•
•
•
•
–
–
–
–
–
–
– Stribild, Genvoya, Triumeq
– Avoid Complera since baseline VL > 100,000 c/ml
• What drug interactions are expected with each SDC first line
regimen?
• What modifications to her DM, HTN, or GERD therapy would
be necessary?
Esomeprazole 20 mg daily
Aluminum magnesium antacids prn gastric distress
Calcium carbonate (TUMS) bid
Amlodipine 10 mg daily
Lorazepam 2 mg prn anxiety
Metformin 1000 mg BID
Continue PPI and lorazepam and CA
Separate Al/Mg antacids by at least 6 hr after or stop
Reduce metformin to 500 mg bid with Triumeq, if A1c @goal
Monitor BP/HR with amlodipine and Genvoya and Stribild
49
Case 2 Presentation:
Case 2 Presentation
RJ is a 55 year old HIV-infected male lawyer with
multiple co-morbidities who is reluctant to start ART
due to concerns about side effects affecting his ability to
function and think clearly.
•
Allergy: NKA
• PMH/Medications:
–
–
–
–
–
–
50
Hemophiliac: weekly Factor 7 transfusions
Allergic rhinitis—nasal fluticasone BID
Hypertension—lisinopril 40 mg + diltiazem 300 mg daily
Dyslipidemias—simvastatin 20 mg daily
Severe GERD—pantoprazole 20 mg BID
Depression— sertraline 100 mg daily
PE: BP 140/90, HR 62 beats/min, R 12. 02 sat 95%
Labs:
BUN 18/Scr 1.3, CrCL 60 cc/min
AST 14 ALT 16
Tchol 294 mg/dl, LDL 130 mg/dl, HDL 45 mg/dl
Baseline HIV Genotype: Wild type, no mutations
HLA-B5701 positive
HBV and HCV AB negative
CD4 500 cells/mm3
HIV RNA: 147,500 copies/ml
51
Self-Assessment Question
Efavirenz, TDF/FTC (Atripla)
Which is most appropriate action to
consider if efavirenz,tenofovir, emtrictabine
(Atripla) is selected as RJ’s initial ART?
1.
2.
3.
4.
5.
Reduce diltiazem by 50%
Increase simvastatin dose
Reduce sertraline dose
Stop nasal fluticasone
Change pantoprazole to ranitidine
Factor 7 transfusions, nasal fluticasone BID
lisinopril 40 mg + diltiazem 300 mg daily simvastatin 20 mg daily,
pantoprazole 20 mg BID, sertraline 100 mg daily
© 2016 by the American Pharmacists Association. All rights reserved.
52
53
• No longer recommended as first line therapy
• Side effects concerns:
– CNS: depression, cognitive impairment, insomnia,
“weird dreams”, suicidal tendencies
– Rash
– Dyslipidemia:  TC , LDL, HDL
– Vitamin D deficiency
• Potential drug interactions 3A4 induction
– simvastatin, diltiazem, sertraline levels/efficacy
– no interactions: lisinopril, pantoprazole, nasal
fluticasone
54
Selected Efavirenz (EFV) Induction Drug
Interactions
Association Between EFV as Initial
Therapy and Suicidality
• Analysis of 4 ACTG
(95% CI: 1.27-4.10; p = .006)
Agent
Interaction
Recommendations
Antidepressants
 sertraline AUC 39%
and buproprion AUC 55%
Monitor clinical response
and increase dose if
warranted
Anticonvulsants
 EFV, phenytoin,
Monitor anticonvulsant level.
carbamazepine, phenobarb Avoid efavirenz or use other
anticonvulsants
0.10
Cumulative Incidence
studies in ART-naive pts
randomly assigned to
initial therapy with EFV vs
EFV-free regimens
• HR for suicidality
increased with EFV vs
EFV-free regimens: 2.28
Cumulative Incidence of Suicidality (ITT)
EFV
EFV free
0.08
0.06
Calcium channel diltiazem AUC 69%
blockers (CCBs) other CCBs ??
Gray P = .004
0.04
0.02
48
96
144
Wks to Suicidality
3241
2091
2949
1917
2703
1760
1782
1107
192
522
298
55
Mollan KR, et al. Ann Intern Med. 2014;161:1-10.
56
Rilpivirine (RPV) Drug Interactions
and Absolute Contraindications
Self-Assessment Question
Which is most appropriate action in RJ if
rilpivirine, tenofovir, emtrictabine (Complera)
is being considered as his initial ART?
1.
2.
3.
4.
5.
• CYP3A substrate, no inhibition, slight induction
• Absolute contraindications: RPV levels
– Proton Pump Inhibitors:  gastric pH
– Potent 3A4 inducers:
• St John’s wort, ginko biloba
• Anticonvulsants: carbamazeprine, oxcarbazeprine,
phenobarbital, phenytoin
• Antimycobacterials: rifampin, rifapentine
– Exception: rifabutin
• More than one dose of dexamethasone
Reduce diltiazem by 50%
Increase simvastatin dose
Reduce sertraline dose
Stop nasal fluticasone
Stop pantoprazole
Meds: Factor 7 transfusions, nasal fluticasone BID
lisinopril 40 mg + diltiazem 300 mg daily simvastatin 20 mg daily,
pantoprazole 20 mg BID, sertraline 100 mg daily
57
58
Rilpivirine (RPV) vs Efavirenz
(EFV) in Treatment-Naïve Pts
Selected Ripivirine Drug Interactions
Agent
Interaction
Recommendations
Antacids
 RPV
Administer antacids 2 hrs
before or 4 hrs after RPV
Administer RPV 4 hr before
or 12 hrs after famotidine
 RPV Cmax 31%, AUC Give additional 25 mg dose
42%, Cmin 48%.
of rilpivirine = 50 mg daily
50 mg=Cmax 43%,
AUC  16%, Cmin 7%
Azole antifungals  RPV;  azoles
Macrolides
% < 50 copies/mL at Week 96  macrolides
Monitor for fungal infection
breakthru.
Consider azithromycin
Rilpivirine 77%
Wk 96 Outcome, %
Efavirenz 77%
100
80
Patients (%)
RPV AUC 76% if RPV
H2-Receptor
Antagonists(HRA) given 2 hr after HRA
Rifabutin
 simvastatin AUC 58%
Require higher statin doses
atorvastatin 43%,
Prefer simvastatin,
pravastatin 44%, lovastatin atorvastatin, rosuvastatin, or
pitavastatin
Statins
0
0
Titrate CCB dose based on
clinical responses
68
72
83
80
74
71
DC for ADR
5
Most Common AEs of Interest, %
Dizziness
1
7
Depression
2
2
Abnormal dreams
1
3
Any psychiatric
5
7
40
Any rash
1
5
20
0
VL <100,000
VL >100,000
•
•
•
© 2016 by the American Pharmacists Association. All rights reserved.
Efavirenz
(n = 546)
2
60
CD4 <200
59
Rilpivirine
(n = 550)
*** RPV failure if
HIV VL>100K c/mL and
CD4 <200 c/mm3
Cohen C, et al. Lancet 2011; 378: 229–37; Molina JM et al. Lancet 2011;378:238‐46 . 60
Self-Assessment Question
Ritonavir (or Cobicistat) Boosted Darunavir
Which is most appropriate action in RJ if
ritonavir (or cobi) boosted darunavir,
tenofovir, and emtrictabine is selected as
initial ART?
1.
2.
3.
4.
5.
•
•
•
•
Increase diltiazem dose
Change simvastatin to pitavastatin
Reduce sertraline dose
Change to nasal budesonide
Separate pantoprazole co-administration
from ritonavir (or cobi) boosted darunavir
Factor 7 transfusions, nasal fluticasone BID
lisinopril 40 mg + diltiazem 300 mg daily simvastatin 20 mg
daily, pantoprazole 20 mg BID, sertraline 100 mg daily
– Contraindications: simvastatin, nasal fluticasone, and
nasal budesonide
– DRV/r  sertraline levels
– Diltiazem and CCB levels may increase
– No interaction with lisinopril or pantoprazole
61
Darunavir/r Statin Drug Interactions
DRUG
EFFECT
Recommendations
Statins
Simvastatin/lovastatin AUC 5003000% (myositits, rhabdomyolysis)
Contraindicated with
simvastatin and lovastatin
(red rice yeast).
DRV/r
atorvastatin AUC 70-836%
DRV/r + atorvastatin 10 mg =
40 mg/day, DNE 20 mg/day.
Pravastatin AUC 81% (single dose) Use lowest effective dose
Pravastatin AUC 26% (steady state)
rosuvastatin AUC 48%, Cmax 139%
Use lowest effective dose.
no significant effects on pitavastatin
Use normal doses
Sensitive regimen since no PI or other mutations
Not best option unless medication changes occur
No sulfa allergy—okay to consider DRV/r
Drug interactions:
62
Selected Darunavir/r Drug Interactions
DRUG
EFFECT
CCBs:
Amlodipine
Diltiazem
 risk of CCB and diltiazem
Monitor BP/HR and titrate
levels—no studies except with
to response (diltiazem
indinavir: amlodipine AUC  90% dose 50% w/ ATV/r)
and diltiazem AUC  27%
COMMENTS
Inhaled
steroids
NS AUC with beclomethasone;
case reports of Cushingnoid with
DRV/r and TAC injections
Beclomethasone preferred,
use cautiously.
C/I:fluticasone, budesonide
SSRI
 paroxetine AUC 39%
 sertraline AUC 49%
 bupropion AUC  50-60% by
Higher SSRI/bupropion
may be required. Monitor
for antidepressant efficacy
LPV/r, TPV/r
63
64
DHHS ART Guidelines 2013; http://www.hivclinic.ca/main/drugs_interact.html/
Case 2 Presentation
RJ is a 55 year old HIV-infected male lawyer with
multiple co-morbidities who is reluctant to start ART
due to concerns about side effects affecting his ability to
function and think clearly.
•
Allergy: NKA
• PMH/Medications:
–
–
–
–
–
–
Hemophiliac: weekly Factor 7 transfusions
Allergic rhinitis—nasal fluticasone BID
Hypertension—lisinopril 40 mg + diltiazem 300 mg daily
Dyslipidemias—simvastatin 20 mg daily
Severe GERD—pantoprazole 20 mg BID
Depression— sertraline 100 mg daily
65
© 2016 by the American Pharmacists Association. All rights reserved.
Self-Assessment Question
In RJ, which of the following initial ART regimen is
most appropriate to achieve the lowest risk of drug
interactions and side effects?
1.
2.
3.
4.
5.
6.
Darunavir 800 mg/ritonavir 100 mg),TDF/FTC
Dolutegravir, TDF/FTC)
Atripla (efavirenz, TDF/FTC)
Genvoya (elvitegravir/cobi, TAF/FTC)
Complera (rilpivirine, TDF/FTC)
Triumeq (dolutegravir, ABC/3TC)
TDF/FTC = tenofovir/emtricitabine; ABC abacavir,
3TC lamivudine; TAF= tenofovir alafenamide,
66
Case 3: Interactions Among ARVs
• You receive a new prescription for an new ARV regimen
prescribed for a treatment experienced HIV+ person who
has failed multiple regimens. His medication profile shows
the following:
– Depression: bupropion 15 mg TID PO
– Insomnia: trazodone 100 mg @ bedtime PO
– Methadone maintenance: 30 mg daily PO
New prescription:
dolutegravir (Tivicay) 50 mg –take one tablet daily
tenofovir/emtricitabine (Truvada) one tablet daily
etravirine (Intelence) 200 mg one tablet bid
Which of the following would be the
most appropriate to recommend to the
prescriber about the new ARV regimen?
A. Bupropion dose increase may be
warranted
B. Watch for methadone withdrawal
C. Watch for increased trazodone
side effects
D. HIV VL suppression may be
insufficient
E. Monitor for increased risk of renal
toxicity from tenofovir
67
Which would be the most appropriate
to add and co-administer with
etravirine?
Dolutegravir (DTG) and Antiretroviral Drug
Interactions
ARVs
Interaction
Recommendation
ATV/r, DRV/r,
LPV/r, RPV
No interaction
Usual DTG dosage
Nevirapine
 DTG
Avoid co-administration
Etravirine
 DTG
A.
B.
C.
D.
E.
Avoid co-administration
Need to co-administer with PI
Efavirenz,
fosamprenavir/r,
tipranavir/r
 DTG
68
Tipranavir/ritonavir
Atazanavir/cobicistat (Evotaz)
Fosamprenavir/ritonavir
Darunavir/cobicistat (Prezcobix)
Darunavir/ritonavir
DTG 50 mg bid if integrase
naïve, otherwise, avoid
69
Etravirine (ETR) and PI Drug Interactions
• ETR Pharmacokinetics
70
Etravirine (ETR) Administration with
Protease Inhibitors (PI)
• Cautious co-administration of ETR and “SALoD”:
– 3A4, 2C9 and 2C19 substrate
– 3A4 inducer (weak)
– 2C9 . 2C19, and p-gp inhibitor
• Cautious administration ETR with:
– SAQ 1 gm /r 100 mg bid
 ETR Cmin 29%
NS SAQ levels
 ATV 300 mg /r 100 mg daily
 ETR AUC/Cmin 30%
 ATV Cmin18%
 ETR AUC 76%, Cmin 82%
 TPV AUC 18% and Cmin 24%
– Fosamprenavir/r
 APV AUC 69% and Cmin 77%
– Atazanavir/cobicistat  ATV and cobi
– Darunavir/cobicistat  DRV and cobi
– Tipranavir/r
*Kakuda TN et al. 13thth Int Workshop Clin Pharm, 2012, Abst 0_24, Barcelona
© 2016 by the American Pharmacists Association. All rights reserved.
71
– LPV 400mg/r 100 mg bid 
 ETR AUC 35%
 LPV AUC 13% (NS)
– DRV 600 mg/r 100 mg bid
600 mg bid/ r 100 mg bid
 ETR AUC 37%,
 Cmin 49% (ok DUET trial)
72
Dolutegravir (DTG) and Antiretroviral Drug
Interactions
ARVs
Interaction
Recommendation
ATV/r, DRV/r,
LPV/r, RPV
No interaction
Usual DTG dosage
Nevirapine
 DTG
Avoid co-administration
Etravirine
 DTG
Avoid co-administration
Case 4 Presentation
• Mr RJ is a 63 yr old male who in interested in taking new HCV
agents that can cure HCV. He is reluctant to change his HIV
regimen “since it works better than his past regimens of 8
tablets daily and he notices no side effects”.
PMH:
•
– Hep C genotype 1a, no cirrhosis –failed pegylated interferon, ribavirin
– HIV infection–CD4 585 c/mm3 with undetectable HIV viral load on
tenofovir/emtricitabine (Truvada) plus atazanavir 300/r 100 mg daily
– Dyslipidemia—on atorvastatin 40 mg daily
– Hx Afib and s/p CVA on warfarin 6 mg daily (INR stable at 2.5)
– Gout—indomethacin 500 mg every 8hr prn acute flares
– GERD- prn OTC ranitidine
Need to co-administer with
ATV/r, DRV/r or LPV/r
Efavirenz,
fosamprenavir/r,
tipranavir/r
 DTG
DTG 50 mg bid if integrase
naïve, otherwise, avoid
73
74
Case Presentation
•
•
•
•
•
•
•
Ritonavir Boosted Atazanavir (ATV/r)
• No longer recommended as initial ART therapy
• Side effects concerns:
PE: BMI 32; BP 140/80
Labs: Scr 1.0 mg/dL; CrCL > 60 mL/min
CBC, AST, ALT and liver ultrasound are normal
HLA-B*5701 negative
CD4+ cell count 585 cells/mm3 (30 %)
HCV RNA 5,890,670 IU/mL
Immune to hepatitis A and B
•
75
Self-Assessment Question
Considering his ART therapy, which of the
following is the most appropriate to
recommend to RJ’s doctor?
1.
2.
3.
4.
5.
6.
Change atorvastatin to rosuvastatin
Start rivaroxaban for warfarin
Substitute colchicine for indomethacin
Start omeprazole 40 mg daily
atazanavir 400 mg/r 100 mg daily
Change ranitidine to ATC with ART
Meds: Tenofovir/emtricitabine, atazanavir/ritonavir,
atorvastatin, warfarin, indomethacin, OTC ranitidine
© 2016 by the American Pharmacists Association. All rights reserved.
77
– GI effects (n,v,d)
– Jaundice (“stigma”) 43% (ACTG 5257)
Adverse effects
– Dyslipidemia:
• lower FBS, TC, non-HDL cholesterol, TG. vs LPV/r
• similar lipid changes as DRV/r but worse than RAL
– Hyperglycemia
•  FBS 4.8 mg/dl (EFV) vs 0.4 mg/dl (ATV/r)@96 wks
– Others: renal stones, 2x cholethiasis (onset 42 mo)
Clin Infect Dis. (2015) 60:1842;
Ann Intern Med. 2014 October 7; 161: 461
76
Atazanavir (ATV/r) and Acid Reducing
Agents
• Acid reducing agents
– increase gastric pH
– can significantly reduce atazanavir absorption
• Atazanavir requires acidic PH for optimal
absorption
– Solubility is 1.1 mg/ml at pH <1 vs. <0.002 at
pH5
• Give ATV 2 hr before or 1 hr after antacid
78
Atazanavir/ritonavir or cobi interaction with
Acid Reducing Agents
• H2 RA
– ARV naïve: DNE famotidine 40 mg BID (ranitidine 300 mg
bid, cimetidine 800 mg bid, nizatidine 300 mg bid)
– ARV experienced: DNE famotidine 20 mg BID (ranitidine150
mg bid, cimetidine 400 mg bid, nizatidine 150 mg bid)
Atazanavir and Proton Pump Inhibitors (PPI)
• Use PPI only in ARV-naïve persons
– DNE 20 mg/day of omeprazole
– Administer PPI 12 hours before ATV 300/r 100 mg
• Avoid PPI in treatment-experienced persons
ATV dose
OMP Dose
Cmin
ATV/r 300/100 mg daily
40 mg/day
20 mg/day
↓ 78%
↓ 46%
ATV/r 400/100 mg daily
20 mg/day
↓ 31%
– Give ATV/r with and/or ≥10 hours after the H2RA
– ATV 400 mg/r 100 mg daily if given with tenofovir + H2RA
in ART experienced persons.
79
Atazanavir/r and PI Anticoagulant
Drug Interactions
PK EFFECTs
Recommendations
Rivaroxaban
(Xarelto®)
rivaroxaban with  bleeding risk Contraindicated
Apixaban
(ELIQUIS®)
apixaban with  bleeding risk
Reduce apixaban dose by
50% or avoid use
Dabigatran
Dabigatran (p-gp substrate)
Cautious use. Avoid if
CrCl < 50 mL/min.
DRUG
ATV/r
 or  warfarin possible
Monitor INR and adjust
DHHS ART Guidelines 2013; http://www.hivclinic.ca/main/drugs_interact.html/
80
Atazanavir/r Statin Drug Interactions
PK EFFECTs
Statins Simvastatin/lovastatin AUC 500-3000%
DRUG
Warfarin
Reyataz package insert
Recommendations
(myositits, rhabdomyolysis)
Contraindicated with
simvastatin and lovastatin
(red rice yeast).
Atorvastatin possible
Use lowest dose
 rosuvastatin AUC 3 fold; Cmax 7 fold
Use lowest dose,
DNE 10 mg/day
pitavastatin AUC 31%, Cmax 60%
Use normal doses
No interaction with pravastatin
Use normal doses
DHHS ART Guidelines 2013; http://www.hivclinic.ca/main/drugs_interact.html/
81
Selected Atazanavir/r or PI DI
DRUG
EFFECT
CCBs:
 risk of CCB and diltiazem
Amlodipine levels—no studies
Diltiazem
Questions to Discuss
COMMENTS
• What drug interactions are expected with appropriate DAA
Monitor BP/HR and titrate
to response (diltiazem
dose 50% w/ ATV/r)
Colchicine
RTV 100 mg BID  colchicine Colchicine 0.6 mg x 1
AUC 296%, Cmax 184%
dose, then 0.3 mg 1 hour
later. Do not repeat dose
for at least 3 days. Reduce
prophylaxis to daily or
every other day
SSRI
 paroxetine AUC 39%
 sertraline AUC 49%
 bupropion AUC  50-60%
82
for his hepatitis C infection?
• What modifications to his co-morbid conditions would be
necessary to accommodate the HCV therapy?
Higher SSRI/bupropion
may be required. Monitor
for antidepressant efficacy
by LPV/r, TPV/r
83
© 2016 by the American Pharmacists Association. All rights reserved.
84
Genotype 1 HCV Agents
Polymerase Inhibitors
Protease
Inhibitors
Nucleotide
Simeprevir
Sofosbuvir
Paritaprevir
ritonavir
Nonnucleoside
Dasabuvir
Self-Assessment Question
NS5A
Inhibitors
Other
Ledipasvir
Ribavirin
1. Sofosbuvir/ledispasvir (Harvoni)
2. Paritaprevir/ritonavir/ombitasvir/dasabuvir
Ombitasvir
Daclatasvir
(DCV)
(ViekiraPak or PROD)
3. Sofosbuvir/simeprevir
4. Sofosbuvir/daclastasvir
5. Grazoprevir/elbasvir
85
www.hcvguidelines.org
Which is the most appropriate action in RJ
if ledipasvir/sofosbuvir (Harvoni) is
selected as his hepatitis C therapy ?
86
• LDV/SOF are p-gp and BRCP substrates
• LDV but not SOF are pgp and BRCP inhibitors
• Avoid co-administration:
•
•
•
•
•
Change HRA to omeprazole 20 mg daily
Consider using abacavir for tenofovir
Change atorvastatin to rosuvastatin
Stop warfarin and indomethacin
Change PI to NNRTI
Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin,
warfarin, indomethacin, OTC ranitidine
Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin,
warfarin, indomethacin, OTC ranitidine
Ledipasvir/Sofosbuvir (LDV/SOF) Drug
Interactions
Self-Assessment Question
1.
2.
3.
4.
5.
Which of the following HCV GT 1a
recommendations would result in RJ’s
lowest risk of drug interactions?
Amiodarone
St. John’s wort:  ledipasvir/sofosbuvir
Anticonvulsants: Pb, phenytoin, carbamazepine
Anti-mycobacterials: rifampin, rifabutin, rifapentine
Rosuvastatin: risk myopathy
• Use atorvastatin, pravastatin, simvastatin
87
Update to sofosbuvir and ledipasvir/sofosbuvir US package inserts
88
Ledipasvir/Sofosbuvir (LDV/SOF) Drug
Interactions with Acid Reducing Agents
•  pH  ledipasvir solubility
LDV/SOF.
Update to simeprevir US package insert
simeprevir.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205834s001lbl.pdf.
89
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205123s008lbl.pdf.
© 2016 by the American Pharmacists Association. All rights reserved.
• Antacids: separate from LDV/SOF by 4 hrs
• H2 RA: together or 12 hr apart, max of 40 mg
famotidine bid
• PPI: concurrent omeprazole 20 mg max/day
• Target Study: no PPI: 3.02 OR of achieving SVR
• Try to avoid all, especially PPI despite current
labeling
90
Tenofovir (TDF) Drug interaction with
Ledipasvir (LDV)/Sofosbuvir (SOF)
No Baseline PPI Use on Ledipasvir Sofosbuvir
SVR Results (HCV-TARGET)
No PPI @
baseline
OR 3.02
(1.516.05)
PPI
No PPI
0.001
100
98
93
98
93
•  TDF AUC 20-30% with boosted PI
• Addition of LDV  TDF AUC
• Mechanism: ?? LDV p-glycoprotein or BCRP inhibition
SVR12 (%)
80
60
40
20
n/N =
0
122/
124
28/
30
8-Wk
456/
464
TDF AUC
Efavirenz
98%
Rilpivirine
40%
Darunavir/ritonavir
38-60%
• Clinical outcome of  TDF AUC with LDV/SOF is unknown
• Cautious use if borderline low GFR or taking boosted PI
• Consider changing to ABC/3TC or INSTI regimen if feasible
151/
163
12-Wk
91
Slide credit: clinicaloptions.com
Terrault N, et al. AASLD 2015. Abstract 94
ARV withTDF/FTC
ARV Interactions:
Ledispasvir/Sofosbuvir (Harvoni)
German P et al, 22nd CROI 2015, Abstr 82; 15th Internat
Workshop Clin Pharm HepC and HIV, 2014
ARV Interactions:Paritaprevir-Ritonavir +
Ombitasvir, Dasabuvir (PROD,Viekira Pak)
ARV
Outcome
Tenofovir (TDF)
Use cautiously:  TDF AUC and risk of
renal dysfunction. Lowest risk with INSTI
vs NNRTI and PI (highest risk)
NRTI
Maraviroc
 MVC
Elvitegravir/cobicistat (Stribild)
•
• Source: Viekira Pak Prescribing Information. AbbVie Inc.
ARV
Source: Viekira Pak Prescribing Information. AbbVie Inc.
NRTI, TAF (except tenofovir)
NNRTI
INSTI: dolutegravir, raltegravir
INSTI: dolutegravir, raltegravir
NNRTI:efavirenz, etravirine, rilpivirine,
nevirapine
No interactions, standard dosing
Protease inhibitors: fosamprenavir/r,
tipranavir/r, lopinavir/r, saquinavir/r
Maraviroc
Protease inhibitors (ATV/r,
DRV/r, LPV/r)
Elvitegravir/cobicistat (Stribild)
Not recommended,  risk TDF toxicity
Tipranavir/ritonavir
Contraindicated
Protease Inhibitors: Atazanavir
Darunavir/r
Outcome
No interactions
Contraindicated
Liver elevations with efavirenz
 Risk QT with rilpivirine
 MVC to 150 mg BID
300 mg atazanavir, no ritonavir
800 mg darunavir if no PI
mutations
93
ARV Interactions: Daclatasvir (DCV,Daklinza)
ARV
92
Outcome
94
Antiretroviral Interactions with Sofosbuvir
NRTI
ARVs
Sofosbuvir
Interaction
Rilpivirine
Protease Inhibitors
DRV/r
No interaction
Avoid TPV/r
sofosbuvir
NNRTI
EFV, RPV
OK
No interaction
INSTI
Raltegravir
OK
No data w/ dolutegravir and
Elvitegravir/cobicistat
Maraviroc
No interactions, standard 60 mg DCV
INSTI: dolutegravir, raltegravir
PI: darunavir/r, lopinavir/r
EVG/cobicistat (Stribild)
PI: atazanavir/r, fosAPV/r,
Saquinavir/r
 DCV 30 mg d/t 3A4 inhibition
NNRTI: Efavirenz, etravirine,
nevirapine
 DCV 90 mg d/t 3A induction
Tipranavir/r
Contraindicated if co-administered with
DCV and sofosbuvir
95
© 2016 by the American Pharmacists Association. All rights reserved.
NRTI
OK
No interaction
CCR5: maraviroc
OK
No interaction
96
Antiretroviral Interactions with Simeprevir
ARVs
Simeprevir
ARV Interactions: Grazoprevir (GZR)
and Elbasvir (EBR)
• GZR is 3A, p-gp, and OATP substrate, weak 3A inhibitor
• EBR is 3A and p-gp substrate
Interaction
Protease Inhibitors
Avoid
 or Simeprevir
NNRTI (EFV, NVP,
ETR)
Avoid.
 Simeprevir
INSTI
Raltegravir
OK
ARV
Outcome
NRTI: Tenofovir
Rilpivirine OK No interaction
NNRTI: rilpivirine
No data with
dolutegravir
No interactions, standard dosing
INSTI: dolutegravir, raltegravir
Cobicistat
Avoid Stribild  Simeprevir
NRTI
OK
No interaction
Protease inhibitors (ATV/r,
DRV/r, LPV/r)
Elvitegravir/cobicistat (Stribild)
CCR5: maraviroc
OK
No interaction
Efavirenz
Not recommended
97
98
HIV Drug Interaction Website
Strategies to Identifying and Reducing
Risk of Drug Interactions
• Review risk factors for DI
• Review list of all medications, including herbals, OTC,
•
•
•
•
•
•
•
supplements
Understand metabolism for all medications
If feasible, design INSTI regimens; avoid PI and NNRTI
Ultilize medication management services (e.g. pharmacists)
Check drug interaction drug data bases
Hold drug or adjust dose, therapeutic interchange
Counsel patient about interacting agents
Inform prescriber about potential interactions
99
100
Additional HIV and HCV Resources
HCV Drug Interaction Websites
• Clinicians’ Consultation Center:
• 1-800-933-3413 http://www.nccc.ucsf.edu/
• Conference on Retrovirus and Opportunistic Infections (CROI
2016) http://retroconference.org/
• AIDS Education and Training Centers National Resource
Center http://www.aids-ed.org
• Clinical Care Options HIV and HCV :
http://www.clinicaloptions.com
• HIV Insite: http://hivinsite.ucsf.edu
• HIV-Associated Resources on the Web.
(http://www.iasusa.org)
• El-Sherif O et al. Key drug–drug interactions with direct-acting
•
101
© 2016 by the American Pharmacists Association. All rights reserved.
antiviral in HIV–HCV coinfection. Curr Opin HIV AIDS
2015,10:348–54
Drug interactions-Toronto Immunodeficiency Clinic.
http://www.hivclinic.ca/main/drugs_interact.html
102
Self-Assessment Question
Key Points
Which of the following would pose the
lowest risk of drug interactions?
• Drug Interactions are common with ART
• Drug Interactions can lead to ART failure and/or toxicity
• The CYP450 system are major reasons for ART drug
interactions.
• Important to review all medications, including OTC, herbal
• Pharmacists can play a major role in preventing drug
•
interactions and improving HIV care
Difficult to know all drug interactions, use drug interaction
websites and drug metabolism to identify potential drug
interactions.
1.
2.
3.
4.
5.
Raltegravir
Dolutegravir
Rilprivine
Elvitegravir/cobistat
Darunavir/ritonavir
103
Self-Assessment Question
Self-Assessment Question
Proton pump inhibitors are contraindicated
with which antiretroviral?
1.
2.
3.
4.
5.
Raltegravir
Rilpivirine
Dolutegravir
Atazanavir/cobicistat
Darunavir/ritonavir
Self-Assessment Question
Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress,
Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID
Metformin 1000 mg BID, lorazepam 2 mg prn anxiety
106
Which of the following hepatitis agents
would result in the lowest risk of ARV
drug interactions?
Reduce metformin dose
Reduce amlodipine dose
Change lorazepam to triazolam
Separate esomeprazole by 6 hr
Give Al-Mg antacids at same time
© 2016 by the American Pharmacists Association. All rights reserved.
Reduce metformin dose
Increase amlodipine dose
Give CA+ w/DTG on empty stomach
Stop esomeprazole
Give Al-Mg antacids at same time
Self-Assessment Question
Which of the following should be considered if
elvitegravir, emtricitabine, tenofovir (Stribild) or
Tenofovir alafenamide (Genvoya) is started?
Meds: Esomeprazole 20 mg daily, Al-Mg antacids prn GI distress,
Amlodipine 10 mg daily, HCTZ 25 mg daily. Ca+ (TUMS) BID
Metformin 1000 mg BID
Which is the most appropriate
recommendation if dolutegravir, abacavir,
and lamivudine (Triumeq) is selected as
initial ART?
1.
2.
3.
4.
5.
105
1.
2.
3.
4.
5.
104
1. Sofosbuvir/ledispasvir (Harvoni)
2. Paritaprevir/ritonavir/ombitasvir/dasabuvir
(ViekiraPak or PROD)
3. Sofosbuvir/simeprevir
4. Sofosbuvir/daclastasvir
5. Grazoprevir/elbasvir
107
Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin,
warfarin, indomethacin, OTC ranitidine
108
Self-Assessment Question
What can occur if ledipasvir/sofosbuvir
(Harvoni) is given with tenofovir,
emtricitabine, and darunavir/r regimen?
1.
2.
3.
4.
5.
HCV treatment failure
HIV treatment failure
Darunavir hepatic toxicity
Tenofovir renal toxicity
Emtricitabine lipid toxicity
Tenofovir/emtricitabine, atazanavir/ritonavir, atorvastatin,
warfarin, indomethacin, OTC ranitidine
© 2016 by the American Pharmacists Association. All rights reserved.
109