brooks pharmacotherapy frontiers - hiv drug...

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Clinically Relevant Drug Interactions in HIV Treatment Kristina M. Brooks, PharmD Pharmacokinetics Fellow, NIH Clinical Center Pharmacy Dept.

Disclosures

¨  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

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

Mechanisms of ARV Interactions

HIV Overview

¨  HIV is a retrovirus that infects essential cells within the immune system ¤  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  CD4 count <200 cell/mm3 n  Development of ≥1 opportunistic infection

¨  No effective cure has been discovered à lifelong treatment with antiretroviral drugs (ARVs) is necessary

HIV Infection Course

Image from: https://upload.wikimedia.org/wikipedia/commons/thumb/0/0e/Hiv-timecourse_copy.svg/2000px-Hiv-timecourse_copy.svg.png

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NNRTIs Efavirenz (EFV) Etravirine (ETR)

Nevirapine (NVP) Rilpivirine (RPV)

NRTIs Abacavir (ABC)

Didanosine Emtricitabine (FTC) Lamivudine (3TC)

Stavudine Zidovudine

NtRTIs

Tenofovir (TDF or TAF)

INSTIs Elvitegravir (EVG) Dolutegravir (DTG) Raltegravir (RAL)

PIs Amprenavir

Atazanavir (ATV) Darunavir (DRV) Fosamprenavir

Indinavir Lopinavir Nelfinavir Saquinavir Tipranavir

PK Enhancers (“Boosters”) Cobicistat* (COBI or /c)

Ritonavir (RTV or /r)

Enfuvirtide (T-20)

Maraviroc (MVC)

Image from: http://www.nature.com/nrd/journal/v6/n12/fig_tab/nrd2424_F1.html

Recommended HIV Regimens for Treatment-Naïve Patients

Complete Regimens 3rd Agent NRTI Backbone

Abacavir/lamivudine (ABC/3TC)

Tenofovir disoproxil fumarate/

emtricitabine (TDF/FTC) Tenofovir

alafenamide/emtricitabine

(TAF/FTC)

Integrase Inhibitor (INSTI)

Dolutegravir (DTG) Elvitegravir (EVG) Raltegravir (RAL)

DTG/ABC/3TC (Triumeq)

DTG + TDF/FTC (Tivicay + Truvada)

EVG/c/TAF/FTC (Genvoya) EVG/c/TDF/FTC (Stribild)

RAL + TDF/FTC (Isentress + Truvada)

Protease Inhibitor (PI) Darunavir/ritonavir

(DRV/r) 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

Alternative Regimen Options for Treatment-Naïve Patients

Complete Regimens 3rd Agent NRTI Backbone

Abacavir/lamivudine (ABC/3TC)

Tenofovir disoproxil fumarate/emtricitabine

(TDF/FTC) Tenofovir alafenamide/

emtricitabine (TAF/FTC)

Non-nucleoside reverse transcriptase inhibitors

(NNRTI) Efavirenz (EFV) Rilpivirine (RPV)

Atripla (EFV/TDF/FTC)

Complera RPV/TDF/FTC

Protease Inhibitor (PI) Atazanavir/cobicistat

(ATV/c) Atazanavir/ritonavir

(ATV/r) Darunavir/cobicistat

(DRV/c) Darunavir/ritonavir

(DRV/r)

Evotaz + Truvada (ATV/c + TDF/FTC)

Reyataz + Norvir + Truvada (ATV/r + TDF/FTC)

Prezista + Norvir + Epzicom (DRV/r + ABC/3TC)

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

Fundamentals of HIV Management

¨  All HIV-infected patients should be treated with ARV therapy ¤ No longer based on CD4 count thresholds ¤ Need 2-3 fully active agents from different drug

classes

¨  Treatment goals ¤ Suppress plasma HIV RNA ¤ Restore and preserve immunologic function ¤ Reduce HIV-associated morbidity and mortality ¤ Prevent transmission of HIV

Selecting an ARV Regimen

¨  Pre-treatment HIV RNA level (viral load) and CD4 cell count

¨  HIV drug resistance genotype

¨  HLA-B*5701 status ¤  If positive, abacavir cannot be used

¨  Patient preference, tolerance, and anticipated adherence

¨  Comorbidities and coinfections

¨  Concomitant medications

Drug Interactions in HIV

¨  ARVs are substrates, inhibitors, and inducers of several metabolic enzymes and transporters ¤  ARV-ARV interactions very common ¤  Other concomitant non-HIV medications are also

affected

¨  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 ¤  CV disease, metabolic disorders, non-HIV malignancies,

and renal/liver dysfunction now more of a concern

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Types of Drug Interactions

Pharmodynamic

• Additive • Synergistic • Antagonistic

Pharmacokinetic

• Absorption • Distribution • Metabolism • Elimination

Pharmacokinetic Interactions

Image from: http://www.nature.com/nrc/journal/v5/n6/images/nrc1629-f1.jpg

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

Absorption

¨  pH dependence for drug dissolution ¤  Ex: atazanavir, rilpivirine

¨  Chelation of drugs that bind to cationic active sites ¤  Ex: integrase inhibitors

¨  Expression of CYP enzymes in the small intestine

¨  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)

Transporters

Ex: OATP

Ex: P-gp

Intestinal Tract Blood

Distribution

Image from: http://www.nature.com/nrd/journal/v9/n3/images/nrd3028-f1.jpg

Transporters

Full list can be found on the FDA website: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm

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

OATP1B1 Lipid-lowering agents (statins, ezetimibe), glyburide, rifampin, valsartan, olmesartan

Atazanavir, cobicistat, cyclosporine, gemfibrozil, lopinavir, rifampin, ritonavir, saquinavir, tipranavir

Not known

OATP1B3 Some statins, ARBs Atazanavir, cobicistat, cyclosporine, lopinavir, rifampin, ritonavir

Not known

OCT2 H2RAs, metformin, NMDA-antagonists, pindolol, varenicline Cimetidine, quinidine Not known

OAT1 Captopril, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, zidovudine

Probenecid Not known

OAT3 Acyclovir, ciprofloxacin, famotidine, furosemide, methotrexate, zidovudine, penicillin G, some statins

Probenecid, cimetidine, diclofenac Not known

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Metabolism

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,N-acetyltransferase; STs, sulfotransferases; TPMT, thiopurine methyltransferase; UGTs, uridine 5′-triphosphate glucuronosyltransferases.

Evan WE, Relling MV. Science. 1999 Oct 15;286(5439):487-491.

Percent Contribution of Phase I and II Enzymes to Drug Metabolism

Elimination

¨  NRTIs primarily renally eliminated ¤  Require dose adjustments in patients

with renal insufficiency n  Exception: abacavir

¨  Creatinine secretion inhibited by some ARVs à transient SCr increase ¤  MATE1 by cobicistat ¤  OCT2 by dolutegravir, rilpivirine, ritonavir

¨  Inhibition of renal uptake transporters can increase drug levels ¤  P-gp and OATP1B1/3 by cobicistat,

ritonavir

ARV Interaction Overview

Agent Metabolism Transporter Inhibitor Inducer PK Enhancers/Boosting Agents

Cobicistat 3A4, 2D6 (minor) OCT2 3A4 > 2D6 P-gp, BCRP, OATP1B1/3, MATE1 -

Ritonavir 3A4, 2D6 P-gp, MRP1/2 3A4, 2D6* > 2C9/19 > 2A6 > 1A2 > 2E1 P-gp, BCRP, OATP1B1/3, MATE1

1A2, 2B6, 2C8, 2C9/19, UGT1A1

Protease Inhibitors (PIs) Amprenavir 3A4 P-gp 3A4 P-gp

Atazanavir 3A4 P-gp, MRP1/2 3A4, 1A2, UGT1A1>2C8, 2C9 P-gp*

P-gp

Darunavir 3A4 P-gp, OATP1A2/1B1 3A4, P-gp -

Fosamprenavir 3A4 P-gp 3A4, P-gp 3A4 (weak) Indinavir 3A4 P-gp, MRP1/2 3A4 - Lopinavir 3A4 P-gp, MRP1/2 3A4 UGT, 1A2

Nelfinavir 2C19, 3A4 (M8 metabolite), 2D6 P-gp 3A4, 2B6 (in vitro) UGT, 1A2, 3A4, 2C9, P-gp

Saquinavir 3A4 P-gp 3A4, P-gp - Tipranavir 3A4 P-gp 2D6 3A4, 1A2, 2C19, P-gp Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz 2B6 (major), 2A6, 3A4 2C9/19, 3A4 3A4 (potent), 2B6, UGT1A1 Etravirine 3A4, 2C9, 2C19 2C9/19 3A4, P-gp Nevirapine 3A4, 2B6 (minor) - 3A4, 2B6

Rilpivirine 3A4 (major), 2C8/9/10/19 and 1A2 (minor)

OCT1 2C19*, 1A2*, 2B6*, 3A4*

*Inhibition/induction observed at higher concentrations than those achieved with clinical doses. 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]

ARV Interaction Overview

Agent Metabolism Transporter Inhibitor Inducer Integrase Inhibitors (INSTIs)

Raltegravir UGT1A1 P-gp, OAT1, PEPT1 - -

Dolutegravir UGT1A1 (major); 3A4 (minor) ? UGT1A3/9 ? BCRP, P-gp OCT2, MATE

(renal) -

Elvitegravir 3A4 (major), UGT1A1/3 (minor) P-gp - 2C9

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 diphosphate (TFV-DP) Renal elimination P-gp, BCRP,

OAT1/3

Tenofovir disoproxil fumarate (TDF) Renal elimination P-gp

Tenofovir alafenamide (TAF)

Cathepsin A (intracellular) Renal elimination

P-gp, BCRP, OATP1B1/3

OCT1, MATE1 (weak) Cathepsin A

Zidovudine Glucoronidation* Entry Inhibitors

Enfuvirtide Non-NADP-dependent hydrolysis

Maraviroc 3A4 P-gp *Metabolite and parent undergo renal and hepatobiliary excretion!

!Kis O, et al. Trends Pharmacol Sci. 2010 Jan;31(1):22-35.


Recently Approved ARVs

Cobicistat (COBI)

¨  Newer PK enhancer without HIV activity ¤ Dose of 150 mg once daily ¤ Strong inhibitor of 3A4 > 2D6 ¤ Similar AEs to RTV-boosted regimens

¨  Coformulated into fixed dose combinations (FDCs) ¤ EVG/c/TDF/FTC (Stribild) – approved Nov 2012 ¤ ATV/c (Evotaz) – approved Jan 2015 ¤ DRV/c (Prezcobix) – approved Jan 2015 ¤ EVG/c/TAF/FTC (Genvoya) – approved Nov 2015

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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  P-gp, BCRP, OATP1B1/3, MATE

¨  Interaction profile between RTV and COBI may vary ¤  No induction of CYP enzymes

n  Substrates for enzymes induced by RTV may not be affected with a transition to COBI

¤  COBI may yield stronger MATE inhibition than RTV n  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]

Tenofovir alafenamide (TAF)

¨  Newly available prodrug form of tenofovir (TFV) ¤ Converted inside target cell by cathepsin A ¤ 90% lower systemic concentrations of TFV à less

renal and bone toxicity vs. TDF

Ray AS, et al. Antiviral Research. 2016 Jan; 125: 63-70.

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

¨  Four FDC formulations at various stages of development ¤  Genvoya® (EVG/c/TAF/FTC) – approved Nov 2015

n  Alternative for Stribild ¤  Odefsey® (RPV/TAF/FTC) – approved March 2016

n  Alternative for Complera ¤  Descovy® (TAF/FTC) – application submitted

n  Alternative for Truvada ¤  DRV/c/TAF/FTC – Ph3 trials, possible approval later in 2016

TAF Interactions

¨  TAF is increased 2.5-fold by boosted ARVs ¤  Use 10 mg dose (not 25 mg)

¨  Intracellular metabolism by cathepsin A ¤  TAF also inhibits cathepsin A in vitro à contraindicated

with certain hepatitis C protease inhibitors

¨  Substrate for P-gp, BCRP, OATP1B1/3 ¤  Inhibitors may increase TAF levels ¤  Inducers 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>

Common Interactions with ARVs

Patient Case #1

¨  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?

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Metformin

¨  Cautioned use with dolutegravir (DTG) specifically ¤  DTG alone (Tivicay®) ¤  DTG/abacavir/lamivudine (Triumeq®)

¨  DTG inhibits the renal transporter responsible for eliminating metformin (OCT2) ¤  79% increase in metformin AUC with DTG 50 mg q 24 hrs

n  vs. 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

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]

Statins ¨  PIs and elvitegravir/COBI (EVG/c) can increase statin exposure

¨  Efavirenz (EFV), etravirine (ETR), nevirapine (NVP) primarily decrease exposure ¤  Do not exceed maximum statin doses to overcome induction

Statins Metabolism Boosted PIs NNRTIs (EFV, ETR, and NVP) INSTIs (EVG/c)

Simvastatin 3A4 •  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?

Rosuvastatin 2C9/19 •  Max dose of 10 mg •  Titrate to effect

•  No data - possible increase by EFV or ETR?

•  Increases AUC by 38% •  Titrate to effect

Pravastatin UGT •  Titrate to effect •  EFV decreases AUC by 44% •  No adjustment

Pitavastatin UGT, 2C9 •  No adjustment •  No adjustment •  No adjustment


Patient Case #1

¨  Regimen change from Atripla (efavirenz/tenofovir/emtricitabine)?

¨  Atorvastatin 40 mg daily ¤  40 mg ≈ 20 mg due to 3A4 induction by efavirenz ¤  Efavirenz à dolutegravir or raltegravir?

n  Reduce dose to 20 mg to achieve similar effects ¤  Efavirenz à darunavir/cobicistat or elvitegravir/cobicistat?

n  Reduce dose to 10 mg daily due to 3A4 inhibition

¨  Lisinopril 20 mg daily ¤  No change necessary

¨  Metformin 2000 mg daily with food ¤  Efavirenz à dolutegravir?

n  Maximum daily dose of 1000 mg

Anticoagulants & Antiplatelets

¨  Warfarin: CYP2C9 > 3A4 ¤  Monitor INR and adjust warfarin dose accordingly

n  Decreased warfarin levels possible with RTV-boosted PIs n  Increased warfarin levels possible with etravirine

¨  Rivaroxaban, apixaban, edoxaban: CYP3A4 and Pgp ¤  Avoid with 3A4 inhibitors & inducers

¨  Dabigatran: P-gp and MATE1 ¤  COBI increases and prolongs thrombin time, no effect with RTV

¨  Clopidogrel: 2C9/19 ¤  Etravirine may prevent activation à do not coadminister


Antacids & Acid Suppressants

¨  Integrase inhibitors can chelate with Ca, Mg, and Al-containing antacids ¤ 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]

Mineral Supplements

¨  Cationic minerals can reduce integrase inhibitor (INSTI) levels by 40-74% when coadministered ¤  INSTIs are the only ARV drug class of concern à binds to

Mg2+ in the HIV integrase enzyme ¤  Applies to Ca2+, Fe2+, Al2+, Mg2+, and Zn2+ supplements

n  Sucralfate and liquid bismuth subsalicylate can also interact n  Extent 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 time as

Fe2+ or Ca2+ supplements if given with food


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Anticonvulsants

¨  Phenytoin, phenobarbital, carbamazepine, oxcarbazepine metabolized via CYP450 system ¤  All are capable of CYP induction à dual interaction with RTV-

boosted PIs and NNRTIs ¤  Many combinations are contraindicated or cautioned against

¨  Consider alternatives if boosted PIs or NNRTIs required ¤  Low interaction potential with renally eliminated drugs

n  Levetiracetam, lacosamide ¤  Agents that undergo glucoronidation may be decreased by RTV-

boosted PIs à monitor drug levels n  Valproic acid (>90% by UGT and beta-oxidation) n  Lamotrigine (UGT1A4)


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%

n  Effects with COBI unknown

¨  Bupropion via 2B6 ¤  Efavirenz decreases levels by 55% à titrate to effect

¨  Trazodone via CYP3A4 ¤  3-4 fold AUC increase with RTV administration

n  No data with COBI but increased levels expected ¤  May be used at low dose for sleep, titrate to effect

n  Mirtazapine could be considered as an alternative

¨  Modifications to ARV regimen may require further dose adjustments in psych medications


Anxiolytics & Hypnotics

¨  Anxiolytics ¤  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 ¤  Suvorexant (Belsomra®): contraindicated with 3A4

inhibitors ¤  Zolpidem (Ambien®): 3A4 and other pathways à

increased levels possible with boosted PIs Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and


Antipsychotics

¨  PIs and PK enhancers can alter concentrations of atypical antipsychotics ¤  Nearly all are substrates for 3A4 and/or 2D6, some for 1A2, 2C19 ¤  Ritonavir (RTV)

n  Inhibits 3A4, 2D6 à increased levels n  Induces 1A2 and 2C19 à decreased levels (ex: olanzapine)

¤  Cobicistat n  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

Kennedy WK, et al. CNS Drugs (2013); 27, 1021-1048. Hill L, et al. Ann Pharmacother (2013); 47, 75-89.

Patient Case #2

¨  34 yo male with recent diagnosis of HIV/AIDS ¤  Initiated on Stribild (elvitegravir/cobicistat/tenofovir/

emtricitabine) ¤ Presented with cryptococcal meningitis, CMV

encephalopathy n Neurological changes, agitation present despite effective

therapy n Medical team decides to add on an antipsychotic

¨  What agent would you recommend?

Patient Case #2

¨  Treatment was initiated with quetiapine 50 mg daily ¤  Partial response, further dose increases desired ¤  Concern over boosting by COBI à guideline

recommendation to use 1/6th dose

¨  Transitioned to olanzapine 12.5 mg daily ¤  Metabolized by UGT, 1A2, 2D6 à lower interaction risk

n  No data with COBI-boosted regimens

¨  Changed ARV regimen to Triumeq (dolutegravir/abacavir/lamivudine) ¤  Reduce risk of drug interactions with future psych

medications

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Azole Antifungals

¨  Low dose fluconazole can be used with ARV regimens

¨  Itra-, keto-, posa- and isavuconazole are 3A4 substrates and inhibitors à bi-directional interactions with PIs and NNRTIs ¤  Certain combinations should be avoided or require dose adjustments ¤  Consult guidelines and monitor azole levels

n  PIs: increased azole and PI levels may result, monitor for PI toxicity n  NNRTIs: decreased azole and increased NNRTI levels possible

n  Exception: rilpivirine

¨  Voriconazole metabolized by 2C19 > 3A4 ¤  RTV decreases AUC by 39% à monitor levels or consider alternatives

n  COBI-boosted ARVs may increase levels ¤  Efavirenz decreases AUC by 77%: increase voriconazole to 400 mg BID

n  Decrease efavirenz from 600 mg to 300 mg daily (bi-directional interaction)


Opportunistic Infections

¨  Rifamycins: induction of CYP and UGT enzymes1 ¤  Rifampin > rifapentine > rifabutin

n  Do not use rifampin with PI-based regimens n  Rifabutin metabolized by 3A4 à two-way interaction with

inhibitors/inducers of 3A4 n  Rifapentine data is limited à not recommended at this time

¨  Clarithromycin: 3A4 substrate and potent inhibitor1 ¤  PIs and NNRTIs: consider alternative (e.g., azithromycin)

¨  Atovaquone: UGT substrate2 ¤  Efavirenz decreases levels by 44-47% ¤  Atazanavir/RTV does not alter concentrations

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.

Corticosteroids

¨  Systemic corticosteroids altered by boosted PIs and NNRTIs ¤  Prednisone AUC changes by 30% with 3A4 inhibition/induction ¤  Dexamethasone decreases NNRTI AUCs – consider alternatives if >1

dose needed

¨  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  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


Patient Case #3

¨  35 yo male received epidural injections of triamcinolone acetonide (x2) for lumbosacral back pain at outside facility ¤  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

Ramanathan R, et al. Clin Infect Dis. 2008 Dec 15;47(12):e97-9. doi: 10.1086/593314.

•  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

Patient Case #4

¨  57 yo male with HIV on ARV regimen of darunavir/RTV + emtricitabine/tenofovir ¤  Received 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)

¨  Darunavir/RTV switched to dolutegravir ¤  Patient counseled on monitoring for facial swelling,

hypertension, weight gain ¤  Labs normalized at 1 month follow-up visit, no other side

effects reported

Hormones

¨  Oral contraceptives can be affected ¤  Barrier methods needed if levels are decreased ¤  Depomedroxyprogesterone and IUDs do not appear to have

significant interactions with ARVs n  May be preferred methods, but further studies are needed

¨  Ethinyl estradiol (EE) ¤  Decreased with PI/r, EFV, and NVP, (?)COBI

n  ATV/r: use OC with 35+ mcg EE ¤  Increased with ATV 400 mg daily à max dose 30 mcg

¨  Progestins ¤  Increased with ATV/r, (?)COBI

n  Monitor for acne, decreased HDL, and insulin resistance ¤  Decreased with EFV and NVP

Tseng A, Hills-Nieminen C. Expert Opin Drug Metab Toxicol. 2013 May;9(5):559-72.

4/5/16

9

PDE5 Inhibitors

¨  AUC increases by 2- to 50-fold with concomitant PI/r administration due to 3A4 inhibition ¤ No data with COBI à use lowest dose ¤ Little data with NNRTIs à may require higher doses

¨  Use lowest available doses and monitor for orthostatic hypotension ¤ Sildenafil (Viagra) – max 25 mg q 48 hrs ¤ Vardenafil (Levitra) – max 2.5 mg daily ¤ Tadalafil (Cialis) – max 10 mg q 72 hrs


Conclusions

¨  Drug interactions can pose significant problems for HIV-infected patients on ARV therapy ¤  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

¨  Full evaluations of all concomitant medications need to be conducted at every patient encounter

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

¨  Micromedex: www.micromedexsolutions.com

Obtaining CME/CE Credit If you would like to receive continuing

education credit for this activity, please visit: http://nih.cds.pesgce.com

Questions?

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.

Influence of low-dose ritonavir with and without darunavir on the pharmacokinetics and pharmacodynamics of inhaled 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 Significantly Reduces Atovaquone Concentrations in HIV-Infected Subjects. Clin Infect Dis. 2016 Jan 20. pii: ciw028. [Epub ahead of print]

¨  Evan WE, Relling MV. Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics. Science. 1999 Oct 15;286(5439):487-491. doi: 10.1126/science.286.5439.487

¨  Kis O, Robillard K, Chan GNY, Bendayan R. The complexities of antiretroviral drug–drug interactions: role of ABC and 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 interaction profiles with co-medications. J Antimicrob Chemother. 2016 Mar 5. pii: dkw032. [Epub ahead of print]

¨  Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 13 Mar 2016 [Drug Interactions L-1]

¨  Ray AS, Fordyce MW, Hitchcock MJM. Tenofovir alafenamide: A novel prodrug of tenofovir for the treatment of Human 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 Mar 11. [Epub ahead of print]

¨  Tseng A, Hills-Nieminen C. Drug interactions between antiretrovirals and hormonal contraceptives. Expert Opin Drug Metab Toxicol. 2013 May;9(5):559-72. doi: 10.1517/17425255.2013.772579. Epub 2013 Feb 21.

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