Drug-Drug Interactions by Antiretroviral (ARV) Class - AIDS Institute Clinical Guidelines

Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, April 2019

Caveats: Many of the formal interaction studies involving ARVs are carried out in small samples of patients who do not have HIV or other known comorbid conditions. Although the results of such studies may be extrapolated to larger populations of patients with HIV, several important considerations should be kept in mind. The U.S. Food and Drug Administration has issued draft guidance on the design, analysis, and clinical implications of drug-drug interaction studies to aid in the interpretation of future interactions [FDA 2017].

Given the limited financial and clinical resources available to researchers, it is impossible to design and run randomized controlled trials to determine the effects of every possible drug-drug interaction. Therefore, many drug-drug interactions are theoretical—based not on evidence or data, but instead on what is known about the pharmacokinetic properties of the various individual agents. As a result, there is often an incomplete correlation between predicted drug-drug interactions and in vivo pharmacokinetics. There is also significant person-to-person variability in drug-drug interactions, and small sample sizes may not be adequate to identify the effects such an interaction may have on a specific patient.

Patients with HIV may be at greater risk of pharmacokinetic variability due to the nature of the infection itself or the drugs taken for antiretroviral therapy (ART). At the same time, both the medications and HIV itself may alter the physiologic processes of the liver, kidney, brain, gastrointestinal system, or other organ systems, which may affect absorption, distribution, metabolism, or elimination of pharmacologically active agents. Additionally, patients with HIV are at a greater risk of the effects of polypharmacy, and the effects of multiple drugs on the pharmacokinetic pathways or pharmacodynamic effects of a single agent are not well documented. Therefore, when treating patients who are taking several medications for multiple comorbid conditions, expert advice may be necessary and is often recommended to ensure appropriate management of drug-drug interactions.

ARVs can have complex interactions with other medications commonly used by patients with HIV. When questions arise regarding the management of drug-drug interactions not described here, a clinician cannot assume that no interaction exists. Several theoretical drug-drug interactions may exist given the unique nature of the pharmacokinetic and pharmacodynamic effects seen with each medication, and the clinical significance of these interactions is not always known. The interactions described here reflect medications used to treat comorbid conditions commonly seen in primary care or family health clinics.

Prescribers should become familiar with the potential for adverse effects and drug-drug interactions with all co-administered drugs they prescribe for their patients. Clinicians who manage the care of only a few patients with HIV may find it difficult to remember the potential mechanisms or effects of interactions between ARVs and other medications commonly seen in primary care settings, and drug-drug interactions may lead to symptoms attributed to ARV medications rather than the physiologic effect of an interaction. Consultation with a pharmacist or healthcare provider experienced in prescribing ART may assist in determining the true cause of symptoms and/or adverse effects. Adverse drug-drug interactions can be prevented when patients receive anticipatory guidance regarding possible interactions between prescribed medications and commonly available over-the-counter medications or supplements.

Boosted Protease Inhibitor (PI) Drug-Drug Interactions
- Table 2: Boosted Atazanavir (ATV) Interactions
- Table 3: Boosted Darunavir (DRV) Interactions
Integrase Strand Transfer Inhibitor (INSTI) Drug-Drug Interactions
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug-Drug Interactions
Nucleoside Reverse Transcriptase (NRTI) Drug-Drug Interactions

Reference

FDA. Clinical Drug Interaction Studies—Study Design, Data Analysis, and Clinical Implications. Guidance for Industry. 2017 Oct. https://www.fda.gov/files/drugs/published/Clinical-Drug-Interaction-Studies-%E2%80%94-Study-Design–Data-Analysis–and-Clinical-Implications-Guidance-for-Industry.pdf [accessed 2019 Jan 9]

Boosted Protease Inhibitors (PIs): ATZ, DRV

Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, April 2019

Table 2: Boosted Atazanavir (ATV) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Proton pump inhibitors (PPIs) [Falcon and Kakuda 2008; Kiser, et al. 2008; Brooks, et al. 2017]	ATV requires an acidic gastric pH for absorption, and acid-reducing agents interfere with the absorption of ATV. May markedly reduce ATV concentration and AUC.	Do not coadminister if alternatives are possible; use alternative acid-reducing agent, or alternative PI, or boost ATV with RTV or COBI. Treatment-naive: If use cannot be avoided, do not exceed omeprazole 20 mg per day or equivalent; administer 12 hours prior to ATV. Treatment-experienced: 1) Consult with an experienced HIV care provider or a GI specialist. 2) Administer at least 12 hours before RTV- or COBI-boosted ATV.
Histamine 2 receptor antagonist (H2RA) [Falcon and Kakuda 2008; Wang, et al. 2011; Brooks, et al. 2017]	ATV requires an acidic gastric pH for absorption, and acid-reducing agents interfere with the absorption of ATV.	Treatment-naive: 1) Administer ATV 300 mg + RTV 100 mg simultaneously with, or at least 10 hours after H2RA. 2) Do not exceed famotidine 20 mg twice per day or equivalent [a] if patient is not taking TFV. 3) Do not exceed famotidine 40 mg twice per day or equivalent [a] if patient is taking TFV. Treatment-experienced: 1) In second and third trimesters of pregnancy [b], increase dose to 400 mg per day. 2) H2RA use is contraindicated if pregnant patient takes TFV + boosted ATV. 3) If patient is taking TFV, ATV is dosed at 400 mg when boosted; unboosted ATV is not recommended. 4) Give drugs at the same time, or give ATV more than 10 hours after H2RA. 5) Administer ATV 300 mg + COBI 150 mg or RTV 100 mg simultaneously with and/or ≥10 hours after dose of H2RA. H2RA dose equivalents twice per day: famotidine 20 mg (40 mg), ranitidine 150 mg (300 mg), nizatidine 150 mg (300 mg). The volume of distribution increases as duration of pregnancy increases, which damages the PK parameters of medications such as some PIs. PK boosting protects some of these PIs, but caution is required during the second and third trimesters of pregnancy to ensure adequate therapeutic concentrations.
Antacids [Brooks, et al. 2017]	ATV requires an acidic gastric pH for absorption, and acid-reducing agents interfere with the absorption of ATV.	Give ATV 2 hours before or 1 to 2 hours after antacids (and all buffered medications).
Simvastatin, lovastatin [Chauvin, et al. 2013; Feinstein, et al. 2015]	Simvastatin and lovastatin are substrates for CYP3A4, CYP2D6, OATP1B1, and the drug transporter P-gP. Greatly increases concentrations. COBI is an inhibitor of CYP3A4, CYP2D6, OATP1B1, and P-gP.	Avoid concomitant use due to potential for myopathy, including rhabdomyolysis. Consider use of low doses of alternative statins less likely to be affected by boosted ATV use.
Pravastatin [Kis, et al. 2013]	Pravastatin is a substrate for OATP1B1. ATV is an inhibitor for OATP1B1.	Use the lowest effective dose of pravastatin and monitor for adverse events, including myopathy and rhabdomyolysis.
Atorvastatin [Vildhede, et al. 2014]	Atorvastatin is a substrate for CYP3A4 and OATP1B1. Boosted ATV inhibits both CYP3A4 and OATP1B1. May moderately increase concentrations.	Use with lowest effective doses; monitor closely for safety and efficacy before increasing statin dose. Avoid atorvastatin use when combined with COBI-boosted ATV due to an increased risk of rhabdomyolysis and myopathy. If atorvastatin use is necessary, do not exceed dose of 20 mg per day.
Rosuvastatin [Busti, et al. 2008]	Rosuvastatin is a substrate of OATP1B1/1B3. ATV is an inhibitor of OATP1B1. May moderately increase concentrations.	Use with lowest effective doses; monitor closely for safety and efficacy before increasing statin dose. If rosuvastatin use is necessary, start with 10 mg per day.
Fluvastatin	Interaction has not been studied, but potential for moderate increase is possible.	Do not use, but if clinical use is desired, use the lowest effective dose; monitor closely for safety and efficacy before increasing statin dose.
Pitavastatin, pravastatin	Although moderate increases are possible, low doses are considered safe when used with boosted PIs.	Use with lowest effective doses; dose adjustments are not necessary when using these statins with boosted EVG.
Anticoagulants, factor Xa inhibitors [Egan, et al. 2014]	Boosted PIs inhibit most factor Xa inhibitors (not dabigatran) via CYP3A or P-gP. ATV is a minor inhibitor of CYP2C8. Apixaban is a substrate of 2C8. Dabigatran is a P-gP substrate. RTV and COBI are inhibitors of P-gP. Warfarin: Could potentially decrease (or more rarely) increase metabolism of warfarin. Rivaroxaban, dabigatran, apixaban: May increase concentrations, increasing bleeding risk.	Avoid concomitant use or use the lowest effective dose of the factor Xa inhibitor to avoid increased bleeding risk. Apixaban: Reduce apixaban dose to 2.5 mg twice per day; if patient is already taking 2.5 mg twice per day, avoid concomitant use. Dabigatran: 1) Separate doses of dabigatran and boosted PIs by at least 2 hours. 2) RTV-boosted PIs may be safer than COBI boosting when using concomitant dabigatran [Kakadiya, et al. 2018]. 3) Avoid dabigatran in patients taking boosted PIs if the patient also has renal impairment (CrCl <50 ml/min). Warfarin: Use cautiously with warfarin, and if use is necessary, increase monitoring of INR. Decrease dose if INR increases. Increase dose slowly if INR decreases.
PY2-antagonists [Egan, et al. 2014; Teng 2015]	Ticagrelor is rapidly metabolized by CYP3A. May result in decreased concentrations of clopidogrel’s active metabolite.	To avoid increased bleeding risk, do not use ticagrelor with strong inhibitors of CYP3A. Do not use with clopidogrel unless an alternative antiplatelet drug cannot be used.
Aliskiren	Boosted PIs inhibit P-gP, which may decrease aliskiren elimination, increasing risk of adverse events.	Do not coadminister.
Atenolol	COBI-boosted PIs may increase atenolol concentrations via inhibition of MATE-1 elimination. Similar interaction is not seen with RTV-boosted PIs.	If atenolol must be used with boosted PIs, use RTV as the PK booster.
Calcium channel blockers (CCBs)	Boosted PIs may increase CCB concentrations by as much as 50%.	Decrease original dose of CCB by as much as 50% when using with boosted PIs and slowly titrate to effect.
Anti-arrhythmic drugs [Roden, et al. 2007]	Boosted PIs inhibit anti-arrhythmic drug metabolism via CYP3A and CYP2D6.	Avoid concomitant use to avoid increased risk of QT prolongation and other adverse events of anti-arrhythmic drugs.
Anti-mineral corticoid (eplerenone) [Keating and Plosker 2004]	ATV inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone.	Avoid concomitant use due to increased risk of hyperkalemia and hypotension.
Glyburide	Drug is mainly metabolized via CYP3A, so concentrations are increased with boosted ARVs.	Use the lowest effective dose of glyburide and monitor for signs of hypoglycemia.
Saxagliptin	Levels may be increased via inhibition of CYP3A.	Limit dose of saxagliptin to 2.5 mg once per day.
Canagliflozin	Could lead to reduced canagliflozin exposure as a result of ATV’s induction of UGT enzymes.	With RTV-boosted ATV and inadequate glycemic control, consider increasing dose to 300 mg per day if patient is tolerating 100 mg and has GFR >60 ml/min/1.73 m².
GLP-1 agonists	Exenatide may inhibit gastric secretion, reducing absorption of ATV.	Consider taking ATV 4 hours before exenatide.
Long-acting beta agonists	Inhibition of CYP3A increases plasma concentrations of these agents.	Concomitant use is contraindicated unless benefits outweigh the risks; consider use of alternative ARV agent. If coadministration is necessary, monitor frequently for QT prolongation, palpitations, and sinus tachycardia. Boosted PIs may also increase QT prolongation.
Inhaled, intranasal, and injected corticosteroids [Daveluy, et al. 2009; Saberi, et al. 2013]	Boosted PIs are strong inhibitors of CYP3A, and many corticosteroids are substrates of these enzymes. Risk of Cushing’s syndrome when coadministered with the following corticosteroids: Intranasal or inhaled: Fluticasone, mometasone, ciclesonide, budesonide, triamcinolone. Systemic: Betamethasone, budesonide, dexamethasone. Injectable: Betamethasone, triamcinolone.	Use beclomethasone if possible. This agent is less likely to be affected by boosted ATV use; thus is less likely to cause symptoms of Cushing’s syndrome and other systemic corticosteroid adverse events. Intranasal or inhaled fluticasone, mometasone, ciclesonide, budesonide, triamcinolone: Do not coadminister unless potential benefits outweigh risk; consider alternative corticosteroid (e.g., beclomethasone). Systemic betamethasone, budesonide: Do not coadminister unless potential benefits outweigh risk. Systemic prednisolone, prednisone: Contraindicated unless potential benefits outweigh risk; if use cannot be avoided, use for shortest effective duration. Injectable betamethasone, triamcinolone: Contraindicated unless potential benefits outweigh risk. Systemic dexamethasone: Contraindicated unless potential benefits outweigh risk; consider alternative corticosteroid.
Oral prednisone	Prednisone is a CYP3A4 and P-gP substrate. Boosted PIs are strong inhibitors of CYP3A4 and P-gP.	Short-term use is not contraindicated. For chronic use of prednisone, careful monitoring of immune function is warranted and dose adjustment may be considered with therapeutic efficacy and adverse events.
Benzodiazepines	Benzodiazepines are substrates of CYP3A and may be increased in the presence of strong inhibitors of this enzyme. Alprazolam: Boosted ARVs may increase alprazolam concentrations via CYP3A4 inhibition. Diazepam: Metabolism of diazepam may be reduced via inhibition of CYP3A4.	Alprazolam, clonazepam, diazepam: Consider alternative benzodiazepine (e.g., lorazepam, oxazepam, temazepam). If used, administer lowest effective dose; monitor closely for adverse events. Diazepam: Monitor for excess sedation.
Antipsychotics	Haloperidol: Potential for moderately increased haloperidol concentrations with boosted PIs. Aripiprazole, brexpiprazole: RTV-boosted PIs may increase levels of aripiprazole and brexpiprazole. Risperidone: Potential for moderate increase in risperidone levels. Clozapine: Interaction has not been studied but may theoretically increase concentrations of clozapine, increasing risk of adverse events.	Quetiapine: Reduce dose to 1/6 if initiating ARVs in patients on stabilized quetiapine; monitor for QT prolongation. If initiating in patient stabilized on boosted PI, use lowest dose and titrate slowly to desired effect; monitor for QT prolongation. Lurasidone: No data; avoid coadministration; consider alternative anti-psychotic or ARV agent. Haloperidol: Monitor for QT prolongation. Aripiprazole: Initiate at 50% of standard starting dose and titrate slowly; monitor carefully and adjust dose as necessary. Brexpiprazole: Monitor carefully and adjust dose as necessary. Risperidone: Initiate at low dose; titrate slowly; monitor for adverse events. Clozaril: Monitor carefully for adverse clozaril-related events.
HCV PIs (“-previr” drugs) [Soriano, et al. 2017]	Inhibition of CYP3A4 and OATP1B1 by ATV may increase the plasma concentrations of other PIs.	Avoid concomitant use to avoid adverse events of NS3/4A PIs.
Daclatasvir [Soriano, et al. 2017]	Boosted PIs inhibit daclatasvir metabolism via CYP3A4.	Decrease daclatasvir dose to 30 mg per day.
Etravirine (ETR) [Orrell, et al. 2015]	ETR is a substrate and inducer of CYP3A4. COBI is a substrate/inhibitor of CYP3A4. ATV is a substrate and inhibitor of CYP3A4.	Use with RTV-boosted ATV results in decreases in ATV exposure, but the decrease is not considered relevant; can be administered together without dose adjustments. Due to the potential for decreased ARV efficacy, avoid use of ETR with COBI. When these drugs are given together, concentrations of COBI are decreased. When possible, avoid concomitant use of ETR and unboosted ATV. ETR with unboosted ATV results in significant decreases in ATV exposure.
Sleep medications [Kishi, et al. 2015]	Suvorexant: CYP3A substrate. COBI: Inhibitor of CYP3A. Zolpidem, suvorexant: Potential for increased concentrations of zolpidem and suvorexant. Ramelteon: RTV-boosted PIs may reduce efficacy.	Zolpidem: Administer lowest effective dose; monitor for adverse effects, including excess sedation. Eszopiclone: Start with 1 mg per day; titrate slowly to effect; monitor for adverse effects, including excess sedation. Suvorexant: Coadministration is not recommended; use alternative sleep medication or ARV agent. Ramelteon: Monitor efficacy in cigarette smokers.
Non-opioid pain medications	Eletriptan: Metabolism inhibited by boosted PIs. TCAs: PIs and TCAs can both cause QT prolongation. Pregabalin: No significant interactions expected.	Eletriptan: Do not coadminister; use alternative triptan medication. TCAs: When using high-dose TCAs and PIs, consider monitoring for QT prolongation or other cardiac adverse events or using alternative medications.
Other antiplatelet drugs	Cilostazol: Metabolized by CYP3A, and boosted PIs will increase concentrations of this drug. Dipyridamole: RTV-boosted PIs may induce UGT enzymes, which are responsible for metabolism of dipyridamole (not seen with COBI).	Cilostazol: Monitor for antiplatelet effect. May be necessary to use an alternative antiplatelet drug or alternative ARV agent. Dipyridamole: Monitor for antiplatelet effect. Use another ARV agent or boost with COBI if necessary.
Antidiabetic drugs	Metformin: COBI is known to inhibit MATE1, which plays a role in the elimination of metformin, thus increasing metformin concentrations. Glyburide: Mainly metabolized by CYP3A, and thus concentrations are increased by inhibitors of this enzyme. Saxagliptin: Substrate of CYP3A, so levels may be increased. Canagliflozin: Use with ATV may decrease concentrations of canagliflozin. GLP-1 agonists: Caution needed when coadministering ATV and GLP-1 agonists, such as exenatide, due to their potential to inhibit gastric secretion, thereby reducing the absorption of ATV. Furthermore, exenatide has the potential to slow gastric emptying. TZDs, exenatide: No significant interactions expected.	Metformin: Monitor for metformin-related adverse events, and reduce dose as needed. Glyburide or alternative sulfonylureas: Use lowest effective doses with boosted PIs; monitor for signs of hypoglycemia. Saxagliptin: Limit dose to 2.5 mg once per day. Canagliflozin: With RTV-boosted ATV and inadequate glycemic control, consider increasing dose to 300 mg per day if patient is tolerating 100 mg per day and has GFR >60 mL/min/1.73 m². GLP-1 agonist: Consider taking ATV 4 hours before. TZDs: No dose adjustments necessary.
Trazodone	May increase trazodone concentrations.	Monitor antidepressant and/or sedative effects.
Anticonvulsants	Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Coadministration may significantly reduce concentrations of ARVs through induction of CYP450 system. Zonisamide: Zonisamide concentrations may be increased through CYP3A4 inhibition.	Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: 1) Coadministration is not recommended; use alternative anticonvulsant. 2) If benefit of use outweighs risk, monitor carefully for efficacy and toxicity. 3) Perform therapeutic drug monitoring. Zonisamide: Monitor efficacy and adverse effects; adjust dose as needed.
Opioid analgesics	Complex mechanisms of metabolism and the formation of both active and inactive metabolites create interactions of unclear significance between these drugs and boosted PIs.	Monitor for signs of opiate toxicity and analgesic effect, and dose these analgesics accordingly.
Tramadol	Tramadol exposure is increased with inhibition of CYP3A, but this reduces conversion to the more potent active metabolite seen when tramadol is metabolized by CYP2D6.	When tramadol is given with COBI or RTV, monitoring for tramadol-related side effects and for the analgesic effect may be required as clinically indicated; adjust tramadol dosage if needed.
Hormonal contraceptives	Complex drug interaction potential has been described. Drospirenone: Potential for hyperkalemia.	Etonogestrel: No data; consider alternative or additional contraceptive method or alternative ARV agent. Ethinyl estradiol; norgestimate and metabolites: Dose with at least 35 mcg (no data on other progestins). Drospirenone: Do not coadminister.
Erectile and sexual dysfunction agents	PDE5 inhibitor: Increased PDE5 inhibitor concentrations expected. Flibanserin: Increased flibanserin concentrations expected.	Sildenafil: Start with 25 mg every 48 hours; monitor for adverse effects. Tadalafil: Start with 5 mg; do not exceed 10 mg every 72 hours; monitor for adverse effects. Vardenafil: Administer 2.5 mg every 72 hours; monitor for adverse effects. Avanafil: Do not coadminister. Flibanserin: Do not coadminister.
Methadone, buprenorphine (BUP), naloxone (NLX)	RTV-boosted PIs: May greatly increase BUP concentrations, but clinical significance of this is unknown because dosing of buprenorphine is based on clinical opiate withdrawal scale. COBI-boosted PIs: 1) May increase BUP concentrations while decreasing NLX concentrations when given with sublingual BUP/NLX. 2) Does not appear to have any significant effect on the concentration of methadone.	RTV-boosted PIs: Monitor BUP for signs of increased opioid toxicity, including sedation, impaired cognition, and respiratory distress. COBI-boosted PIs: 1) Use careful dose titration of BUP/NLX when administering with COBI-boosted ARVs. Methadone: Based on efficacy and safety, initiate at lowest possible dose, and monitor for signs and symptoms of opiate withdrawal, and titrate dose to effect.
Immunosuppressants	Everolimus, sirolimus: Metabolism decreased by boosted PIs. Cyclosporine, tacrolimus: Metabolism decreased by boosted PIs.	Everolimus, sirolimus: Do not use with boosted PIs. Cyclosporine, tacrolimus: Dose based upon therapeutic drug monitoring. Monitor closely for adverse events.
Abbreviations: ARV, antiretroviral; ATV, atazanavir; AUC, area under the curve; BUP, buprenorphine; COBI, cobicistat; CrCl, creatinine clearance; CYP, cytochrome P450; EVG, elvitegravir; GFR, glomerular filtration rate; GLP-1, glucagon-like peptide-1; HCV, hepatitis C virus; INR, international normalized ratio; MATE, multidrug and toxin extrusion; NLX, naloxone; NS3/4A, nonstructural protein 3/4A; PK, pharmacokinetic; OATP, organic anion transporting polypeptide; PDE-5, phosphodiesterase type 5; P-gP, P-glycoprotein; PI, protease inhibitor; RTV, ritonavir; TCA, tricyclic antidepressant; TFV, tenofovir; TZD, thiazolidinedione; UGT, uridine diphosphate glucuronosyltransferase. No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive medicines; asthma and allergy medications; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate.

Table 3: Boosted Darunavir (DRV) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Simvastatin, lovastatin [Chauvin, et al. 2013; Feinstein, et al. 2015]	Simvastatin and lovastatin are substrates for CYP3A4, CYP2D6, OATP1B1, and the drug transporter P-gP. COBI is an inhibitor of CYP3A4, CYP2D6, OATP1B1, and P-gP. Greatly increases concentrations.	Avoid concomitant use due to potential for myopathy, including rhabdomyolysis. Consider use of low doses of alternative statins less likely to be affected by boosted DRV use.
Pravastatin [Aquilante, et al. 2012; Kellick, et al. 2014]	When combined with DRV, pravastatin levels are significantly increased. Pravastatin is an OATP1B1 substrate. COBI and RTV may modestly inhibit OATP1B1. Moderate increases are possible; low doses are considered safe when used with boosted PIs.	If pravastatin use is necessary, use the lowest effective dose and monitor for signs of toxicity.
Atorvastatin [McKeage, et al. 2009]	Atorvastatin is a substrate for CYP3A4. Boosted DRV inhibits CYP3A4. May moderately increase concentrations.	Use the lowest effective dose of atorvastatin when combined with RTV-boosted DRV. If concomitant use of atorvastatin and boosted DRV is necessary, monitor closely for signs of myopathy and rhabdomyolysis.
Rosuvastatin [Samineni, et al. 2012; Custodio, et al. 2014]	Rosuvastatin is a substrate of OATP1B1 and OATP1B3. COBI inhibits OATP. May moderately increase concentrations.	When possible, avoid concomitant use of rosuvastatin and boosted DRV. If rosuvastatin use is necessary, start with 10 mg per day. Dose should not exceed 20 mg per day.
Fluvastatin	Interaction has not been studied, but potential for moderate increase is possible.	Do not use, but if clinical use is desired, use the lowest effective dose; monitor closely for safety and efficacy before increasing statin dose.
Factor Xa inhibitors [Egan, et al. 2014]	Boosted PIs inhibit factor Xa inhibitors via CYP3A or P-gP. DRV is a minor inhibitor of CYP2C8. Apixaban: Substrate of CYP2C8. Warfarin: Could potentially decrease (or more rarely) increase metabolism of warfarin.	Avoid concomitant use, or use the lowest effective dose of the factor Xa inhibitor to avoid increased bleeding risk. Apixaban: Reduce apixaban dose to 2.5 mg twice per day, and if patient is already taking 2.5 mg twice per day, avoid concomitant use. Dabigatran: 1) Separate doses of dabigatran and boosted PIs by at least 2 hours. 2) RTV-boosted PIs may be safer than COBI boosting when using concomitant dabigatran [Kakadiya, et al. 2018]. 3) Avoid dabigatran in patients taking boosted PIs if the patient also has severe renal impairment. Warfarin: Use cautiously with warfarin, and if use is necessary, increase monitoring of INR. Decrease dose if INR increases. Increase dose slowly if INR decreases.
Antiplatelet drugs and PY2-antagonists [Egan, et al. 2014; Teng 2015]	Cilostazol: Metabolized by CYP3A, and boosted PIs will increase concentrations of this drug. Dipyridamole: RTV-boosted PIs may induce UGT enzymes, which are responsible for metabolism of dipyridamole (not seen with COBI). Ticagrelor: Results in increased exposure to ticagrelor. Clopidogrel: Results in decreased concentration of clopidogrel’s active metabolite.	Cilostazol: Monitor for antiplatelet effect. May be necessary to use an alternative antiplatelet drug or alternative ARV agent. Dipyridamole: Monitor for antiplatelet effect. Use another ARV agent or boost with COBI if necessary. Ticagrelor: Do not used with boosted PIs. Clopidogrel: Do not use with boosted PIs unless an alternative antiplatelet drug (or ARV agent) cannot be used.
Atenolol	Eliminated via OCT2 and MATE1, which are inhibited by DTG and BIC; limited potential for atenolol levels to increase if given with these INSTIs.	Start at lower dose and adjust until desired clinical effect is achieved. If patient is already on atenolol but starting DTG or BIC, monitor for atenolol-related adverse events. Reduce dose of atenolol if necessary or switch to another ARV agent.
Calcium channel blockers (CCBs)	Boosted PIs may increase CCB concentrations by as much as 50%.	Decrease the original dose of CCB by as much as 50% when using with boosted PIs and slowly titrate to effect.
Eplerenone [Keating and Plosker 2004]	DRV inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone.	Avoid concomitant use to avoid increased risk of hyperkalemia and hypotension.
Antidiabetic drugs	Metformin: COBI is known to inhibit MATE1, which plays a role in the elimination of metformin, thus increasing metformin concentrations. Glyburide: Mainly metabolized by CYP3A, and thus concentrations are increased by inhibitors of this enzyme. Saxagliptin: Substrate of CYP3A, so levels may be increased. Canagliflozin: Use with DRV may decrease concentrations of canagliflozin. GLP-1 agonists: Caution needed when coadministering DRV and GLP-1 agonists, such as exenatide, due to their potential to inhibit gastric secretion, thereby reducing the absorption of DRV. Furthermore, exenatide has the potential to slow gastric emptying. TZDs, exenatide: No significant interactions expected.	Metformin: Monitor for metformin-related adverse events and reduce dose as needed. Glyburide or alternative sulfonylureas: Use lowest effective doses with boosted PIs; monitor for signs of hypoglycemia. Saxagliptin: Limit dose to 2.5 mg once per day. Canagliflozin: With RTV-boosted DRV and inadequate glycemic control, consider increasing dose to 300 mg per day if patient is tolerating 100 mg per day and has GFR >60 mL/min/1.73 m². GLP-1 agonist: Consider taking DRV 4 hours before. TZDs: No dose adjustments necessary.
Long-acting beta-agonists	Inhibition of CYP3A increases plasma concentrations of these agents.	Concomitant use is contraindicated unless benefits outweigh the risks; consider use of alternative ARV agents. If coadministration is necessary, monitor frequently for QT prolongation, palpitations, and sinus tachycardia. Boosted PIs may also increase QT prolongation.
Inhaled and injected corticosteroids [Daveluy, et al. 2009; Saberi, et al. 2013]	Boosted PIs are strong inhibitors of CYP3A and many corticosteroids are substrates of these enzymes. Risk of Cushing’s syndrome when coadministered with the following corticosteroids: Intranasal or inhaled: Fluticasone, mometasone, ciclesonide, budesonide, triamcinolone. Systemic: Betamethasone, budesonide, dexamethasone. Injectable: Betamethasone, triamcinolone.	Intranasal or inhaled fluticasone, mometasone, ciclesonide, budesonide, triamcinolone: Do not coadminister unless potential benefits outweigh risk; consider alternative corticosteroid (e.g., beclomethasone). This agent is less likely to be affected by boosted DRV use and thus is less likely to cause symptoms of Cushing’s syndrome and other systemic corticosteroid adverse events. Systemic betamethasone, budesonide: Do not coadminister unless potential benefits outweigh risk. Systemic prednisolone, prednisone: Contraindicated unless potential benefits outweigh risk; if use cannot be avoided, use for shortest effective duration. Injectable betamethasone, triamcinolone: Contraindicated unless potential benefits outweigh risk. Systemic dexamethasone: Contraindicated unless potential benefits outweigh risk; consider alternative corticosteroid.
Oral prednisone	Prednisone is a CYP3A4 and P-gP substrate. Boosted PIs are strong inhibitors of CYP3A4 and P-gP.	Avoid concomitant use unless risk outweighs benefits, because of increased risk of corticosteroid-related adverse events.
Benzodiazepines	These benzodiazepines are substrates of CYP3A and may be increased in the presence of strong inhibitors of this enzyme. Alprazolam: Boosted ARVs may increase alprazolam concentrations via CYP3A4 inhibition. Diazepam: Metabolism of diazepam may be reduced via inhibition of CYP3A4.	Consider alternative benzodiazepine (e.g., lorazepam, oxazepam, temazepam). If used, administer lowest effective dose; monitor closely for adverse events. Diazepam: Monitor for excess sedation.
Antipsychotics	Haloperidol: Potential for moderately increased haloperidol concentrations with boosted PIs. Aripiprazole, brexpiprazole: RTV-boosted PIs may increase levels of aripiprazole and brexpiprazole. Risperidone: Potential for moderate increase in risperidone levels. Clozapine: Interaction has not been studied but may theoretically increase concentrations of clozapine, increasing risk of adverse events.	Quetiapine: Reduce dose to 1/6 if initiating ARVs in patients on stabilized quetiapine. Lurasidone: No data; avoid coadministration; consider alternative antipsychotic or ARV agent. Haloperidol: Monitor for QT prolongation. Aripiprazole: Initiate at 50% of standard starting dose and titrate slowly; monitor carefully and adjust dose as necessary. Brexpiprazole: Monitor carefully and adjust dose as necessary. Risperidone: Initiate at low dose; titrate slowly; monitor for adverse events. Clozaril: Monitor carefully for adverse Clozaril-related events. All other antipsychotics should be used at the lowest dose possible in patients taking boosted ARVs, and careful monitoring for adverse events is warranted.
HCV PIs (“-previr” drugs) [Soriano, et al. 2017]	Inhibition of CYP3A4, P-gP, and OATP1B1 by boosted PIs may increase the plasma concentrations of other PIs.	Avoid concomitant use to avoid adverse events of NS3/4A PIs.
Daclatasvir [Soriano, et al. 2017]	Boosted PIs inhibit daclatasvir metabolism via CYP3A4.	Decrease daclatasvir dose to 30 mg per day.
Sleep medications [Kishi, et al. 2015]	These drugs are CYP3A substrates and may be increased by strong inhibitors of this enzyme. Zolpidem, suvorexant: Potential for increased concentrations of zolpidem and suvorexant. Ramelteon: RTV-boosted PIs may reduce efficacy. COBI is an inhibitor of CYP3A.	Zolpidem: Administer lowest effective dose; monitor for adverse effects, including excess sedation. Eszopiclone: Start with 1 mg per day; titrate slowly to effect; monitor for adverse effects, including excess sedation. Suvorexant: Coadministration is not recommended; use alternative sleep medication or ARV agent (may increase somnolence, dizziness, and risk of sleep hangover). Ramelteon: Monitor efficacy in cigarette smokers.
Non-opioid pain medications	Eletriptan: Metabolism inhibited by boosted PIs. TCAs: PIs and TCAs can both cause QT prolongation. Pregabalin: No significant interactions expected.	Eletriptan: Do not coadminister; use alternative triptan medication. TCAs: When using high-dose TCAs and PIs, consider monitoring for QT prolongation or other cardiac adverse events or using alternative medications.
Omeprazole	No significant interactions noted.	Do not exceed omeprazole 40 mg per day.
Trazadone	May increase trazodone concentrations.	Monitor antidepressant and/or sedative effects.
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin	Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system.	Coadministration is not recommended; use alternative anticonvulsant. If benefit of use outweighs risk, monitor carefully for efficacy and toxicity. Perform therapeutic drug monitoring.
Zonisamide	Zonisamide concentrations may be increased through CYP3A4 inhibition.	Monitor efficacy and adverse effects; adjust dose as needed.
Opioid analgesics	Complex mechanisms of metabolism and the formation of both active and inactive metabolites create interactions of unclear significance between these drugs and boosted PIs.	Monitor for signs of opiate toxicity and analgesic effect and dose these analgesics accordingly.
Tramadol	Tramadol exposure is increased with inhibition of CYP3A, but this reduces conversion to the more potent active metabolite seen when tramadol is metabolized by CYP2D6.	When tramadol is given with COBI or RTV monitoring for tramadol-related side effects and for the analgesic effect may be required as clinically indicated; adjust tramadol dosage if needed.
Hormonal contraceptives	RTV-boosted: Combination appears to decrease oral norethindrone concentrations. COBI-boosted: Combination has not been studied, but since COBI does not induce glucuronidation, it is expected to increase concentration of norethindrone.	Norethindrone: Consider alternative or additional contraceptive method or alternative ARV agent.
Erectile and sexual dysfunction agents	PDE5 inhibitor: Increased PDE5 inhibitor concentrations expected. Flibanserin: Increased flibanserin concentrations expected.	Sildenafil: Start with 25 mg every 48 hours; monitor for adverse effects. Tadalafil: Start with 5 mg; do not exceed 10 mg every 72 hours; monitor for adverse effects. Vardenafil: Administer 2.5 mg every 72 hours; monitor for adverse effects. Avanafil: Do not coadminister. Flibanserin: Do not coadminister.
Methadone, buprenorphine (BUP), naloxone (NLX), and naltrexone	RTV-boosted: May greatly increase BUP concentrations, but the clinical significance of this is unknown because dosing of BUP is based on clinical opiate withdrawal scale. RTV-boosted, taken twice per day: May reduce methadone concentrations. COBI-boosted: 1) May increase BUP concentrations while decreasing NLX concentrations when given with sublingual BUP/NLX. 2) COBI does not appear to have any significant effect on the concentration of methadone.	RTV-boosted: Monitor BUP for signs of increased opioid toxicity, including sedation, impaired cognition, and respiratory distress. RTV-boosted, taken twice per day: Monitor methadone for signs of opiate withdrawal and increase dose of methadone if necessary. COBI-boosted: 1) Use careful dose titration when giving BUP/NLX with COBI-boosted ARV. 2) Based on efficacy and safety, initiate methadone at lowest possible dose and monitor for signs and symptoms of opiate withdrawal and titrate dose to effect.
Immunosuppressants	Everolimus, sirolimus: Metabolism decreased by boosted PIs. Cyclosporine, tacrolimus: Metabolism decreased by boosted PIs.	Everolimus, sirolimus: Do not use with boosted PIs. Cyclosporine, tacrolimus: Dose based upon therapeutic drug monitoring. Monitor closely for adverse events.
Abbreviations: ARV, antiretroviral; BIC, bictegravir; BUP, buprenorphine; COBI, cobicistat; CYP, cytochrome P450; DTG, dolutegravir; GFR, glomerular filtration rate; GLP-1, glucagon-like peptide-1; HCV, hepatitis C virus; INR, international normalized ratio; INSTI: integrase strand transfer inhibitor; MATE, multidrug and toxin extrusion; NLX, naloxone; NS3/4A, nonstructural protein 3/4A; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; P-gP, P-glycoprotein; PI, protease inhibitor; RTV, ritonavir; TCA, tricyclic antidepressant; UGT, uridine diphosphate glucuronosyltransferase. No significant interactions/no dose adjustments necessary: Common oral antibiotics; acid-reducing agents; polyvalent cations; asthma and allergy medications; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate.

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Integrase Strand Transfer Inhibitors (INSTIs): BIC, DTG, Boosted EVG, RAL

Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, April 2019

Table 4: Bictegravir (BIC) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Antacids	BIC chelates with cations, forming insoluble compounds that inactivate both drugs.	Administer BIC 2 hours before or 6 hours after taking antacids containing polyvalent cations
Other polyvalent cations	BIC chelates with cations, which can inactivate both drugs.	Calcium- or iron-containing supplements: If taken with food, BIC can be taken at the same time. If not taken with food, these supplements should be administered as with antacids.
Dofetilide [Feng and Varma 2016]	BIC inhibits renal OCT2 and MATE1, and these transporters eliminate dofetilide.	Avoid concomitant use (may cause QT prolongation or torsade de pointes).
Metformin [Custodio, et al. 2017]	BIC inhibits renal OCT2 and MATE1, which are involved in elimination of metformin.	Drug interaction studies suggest that a prospective dose adjustment of metformin is not required when using BIC. Administer at lowest dose possible to achieve glycemic control; monitor for adverse effects.
Atenolol	Atenolol is eliminated via OCT2 and MATE1, which are inhibited by BIC. Coadministration may increase levels of atenolol	Start at a lower dose of atenolol and adjust slowly until desired clinical effect is achieved. If patient is already on atenolol but starting DTG or BIC, monitor for atenolol-related adverse events. Reduce dose of atenolol if necessary or switch to another ARV agent
Valproic acid	Coadministration may significantly decrease BIC concentrations.	Coadministration is not recommended. If an alternative anticonvulsant cannot be used, therapeutic drug monitoring may be warranted. Coadministration with strong inducers of CYP3A is not recommended because they may reduce concentrations of INSTIs.
Cyclosporine	May increase BIC concentrations to a modest degree via P-gP inhibition.	Monitor for BIC-related adverse events.
Abbreviations: CYP, cytochrome P450; DTG, dolutegravir; INSTI, integrase strand transfer inhibitor; MATE, multidrug and toxin extrusion; OCT, organic cation transporter; P-gP, P-glycoprotein; TDM, therapeutic drug monitoring. No significant interactions/no dose adjustments necessary: Common oral antibiotics; anticoagulants; antiplatelet drugs; statins; acid-reducing agents; asthma and allergy medications; long-acting beta-agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction agents; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone.

Table 5: Dolutegravir (DTG) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Dofetilide [Max and Vibhakar 2014; Feng and Varma 2016]	DTG inhibits renal OCT2 and MATE1, and these transporters eliminate dofetilide.	Avoid concomitant use (may cause QT prolongation or torsade de pointes).
Metformin [Song, et al. 2016; Gervasoni, et al. 2017]	DTG inhibits renal OCT2, MATE1, and MATE2, which are involved in elimination of metformin.	Administer at lowest dose possible to achieve glycemic control; monitor for adverse effects. Titrate metformin and do not exceed 1,000 mg when coadministered with DTG; monitor for adverse effects, including lactic acidosis.
Pioglitazone [Fantauzzi, et al. 2013]	Pioglitazone is a weak inducer of CYP3A, and DTG is partially metabolized by this enzyme.	Avoid concomitant use because this may decrease DTG concentrations.
Divalent and trivalent cations (aluminum, magnesium, calcium, zinc, etc.) [Cottrell, et al. 2013; Song, et al. 2015]	DTG chelates with cations forming insoluble compounds that inactivate both drugs	Administer DTG 2 hours before or 6 hours after taking cations. Calcium-containing supplements may be used concomitantly if taken with food
Iron salts [Song, et al. 2015]	DTG chelates with cations, forming insoluble compounds that inactivate both drugs.	Administer DTG 2 hours before or 6 hours after taking iron salts. These drugs may be used concomitantly if taken with food.
Atenolol	Atenolol is eliminated via OCT2 and MATE1, which are inhibited by DTG. Coadministration may increase levels of atenolol.	Start at a lower dose of atenolol and adjust slowly until desired clinical effect is achieved. If patient is already on atenolol but starting DTG, monitor for atenolol-related adverse events. Reduce dose of atenolol if necessary or switch to another ARV agent.
Valproic acid	Coadministration may significantly decrease DTG concentrations. Coadministration with strong inducers of CYP3A (phenytoin, phenobarbital, etc.) may decrease DTG concentrations.	Coadministration is not recommended. If an alternative anticonvulsant cannot be used, monitor for safety and efficacy, including therapeutic drug monitoring. Coadministration with strong inducers of CYP3A are not recommended because they may reduce concentrations of INSTIs.
Abbreviations: ARV, antiretroviral; CYP, cytochrome P450; INSTI, integrase strand transfer inhibitor; MATE, multidrug and toxin extrusion; OCT, organic cation transporter. No significant interactions/no dose adjustments necessary: Common oral antibiotics; anticoagulants; antiplatelet drugs; statins; acid-reducing agents; asthma and allergy medications; long-acting beta-agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction agents; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; immunosuppressants.

Table 6: Boosted Elvitegravir (EVG) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Antacids	EVG chelates with polyvalent cations, which may reduce the efficacy of both agents.	Administer at least 2 hours before or 6 hours after EVG.
Factor Xa inhibitors [Egan, et al. 2014]	Factor Xa inhibitors are substrates of P-gP and CYP3A. COBI inhibits P-gP and CYP3A. May increase concentrations, increasing bleeding risk.	Rivaroxaban, edoxaban: Avoid concomitant use. Apixaban: Reduce apixaban dose to 2.5 mg twice per day, and if patient is already taking 2.5 mg twice per day, avoid concomitant use. Dabigatran: In patients with good renal function, no dose adjustments are necessary. Do not use this combination in patients with moderate to severe renal dysfunction.
Warfarin	Could potentially decrease (or more rarely) increase metabolism of warfarin.	Use cautiously with warfarin, and if use is necessary, increase monitoring of INR. Decrease dose if INR increases. Increase dose slowly if INR decreases.
Cilostazol, ticagrelor, clopidogrel [Egan, et al. 2014; Tseng, et al. 2017]	Cilostazol: Metabolized by CYP3A; boosted EVG will increase concentrations of this drug. Ticagrelor: Results in increased exposure to ticagrelor. Clopidogrel: Results in decreased concentration of clopidogrel’s active metabolite.	Cilostazol: Monitor for antiplatelet effect. May be necessary to use an alternative antiplatelet drug or alternative ARV agent. Ticagrelor: Do not use with boosted EVG. Clopidogrel: Do not use with boosted EVG unless an alternative antiplatelet drug (or ARV agent) cannot be used.
Aliskiren	COBI inhibits P-gP, which may decrease aliskiren elimination, increasing risk of adverse events.	Do not coadminister.
Other polyvalent cations (calcium, zinc, iron, etc.)	EVG chelates with polyvalent cations.	Administer at least 2 hours before or 6 hours after EVG.
Atenolol	COBI-boosted EVG may increase atenolol concentrations via inhibition of MATE-1 elimination.	Start patient at lowest possible dose and monitor for adverse events before slowly increasing dose to effect. If patient is already taking atenolol but starting COBI-boosted EVG, monitor for atenolol-related adverse events. Reduce dose of atenolol as needed.
Calcium channel blockers (CCBs)	COBI-boosted EVG may increase CCB concentrations by as much as 50%.	Decrease the original dose of CCB by as much as 50% when using with boosted EVG and slowly titrate to effect.
Eplerenone [Keating and Plosker 2004; Tseng, et al. 2017]	Eplerenone is metabolized by CYP3A. COBI inhibits CYP3A.	Avoid concomitant use (increased risk of hyperkalemia and hypertension). If concomitant use is required, use lowest possible effective dose of eplerenone.
Simvastatin, lovastatin [Perry 2014]	COBI is an inhibitor of CYP3A. Simvastatin and lovastatin are substrates of CYP3A. Greatly increases concentrations.	Avoid concomitant use (may increase muscle aches and risk of rhabdomyolysis).
Pitavastatin [Tseng, et al. 2017]	Pitavastatin is a substrate of OATP1B1. COBI inhibits OATP1B1. Although moderate increases are possible, low doses are considered safe when used with boosted PIs.	Use the lowest effective dose of pitavastatin and monitor for signs of toxicity, including myopathy. Dose adjustments are not necessary when using these statins with boosted EVG.
Pravastatin [Tseng, et al. 2017]	Pravastatin is a substrate of OATP1B1. COBI inhibits OATP1B1. Although moderate increases are possible, low doses are considered safe when used with boosted PIs	Use the lowest effective dose of pravastatin and monitor for signs of toxicity, including myopathy. Dose adjustments are not necessary when using these statins with boosted EVG.
Atorvastatin [Tseng, et al. 2017]	Atorvastatin is a substrate for CYP3A4 and OATP1B1. Boosted EVG inhibits both CYP3A and OATP1B1. May moderately increase concentrations.	Avoid concomitant use of COBI and atorvastatin. If atorvastatin use is necessary, do not exceed 20 mg per day.
Rosuvastatin [Custodio, et al. 2014]	Rosuvastatin is a substrate of OATP1B1 and OATP1B3. COBI inhibits OATP. Rosuvastatin is a substrate of CYP2C9. EVG is an inducer of CYP2C9. May moderately increase concentrations	When possible, avoid concomitant use of rosuvastatin and COBI-boosted EVG. If rosuvastatin use is necessary, start with 10 mg per day. Dose should not exceed 20 mg per day.
Fluvastatin	Interaction has not been studied, but potential for moderate increase is possible.	Do not use, but if clinical use is desired, use the lowest effective dose; monitor closely for safety and efficacy before increasing statin dose.
Antidiabetic drugs	Metformin: COBI is known to inhibit MATE1, which plays a role in the elimination of metformin, thus increasing metformin concentrations. Glyburide: Mainly metabolized by CYP3A; concentrations are increased by inhibitors of this enzyme. Saxagliptin: Levels may be increased via inhibition of CYP3A. Canagliflozin: Could lead to reduced canagliflozin exposure because of EVG’s induction of UGT enzymes	Metformin: Monitor for metformin-related adverse events and reduce dose as needed. Glyburide or alternative sulfonylureas: Use lowest effective doses with boosted EVG; monitor for signs of hypoglycemia. Saxagliptin: Limit dose to 2.5 mg once per day. Canagliflozin: Monitor glycemic control. With RTV-boosted EVG and inadequate glycemic control, consider increasing dose to 300 mg per day if patient is tolerating 100 mg and has GFR >60 ml/min/1.73m².
Long-acting beta-agonists (formoterol, salmeterol, etc.)	Inhibition of CYP3A increases plasma concentrations of these agents. Increased risk of salmeterol-associated cardiovascular events.	Concomitant use is contraindicated unless benefits outweigh the risks; consider use of alternative ARV agents. If coadministration is necessary, monitor frequently for QT prolongation, palpitations, and sinus tachycardia.
Inhaled and injected corticosteroids	Risk of Cushing’s syndrome when coadministered with the following: Intranasal or inhaled: Fluticasone, mometasone, ciclesonide, budesonide, triamcinolone. Systemic: Betamethasone, budesonide, prednisolone, prednisone, dexamethasone. Injectable: Betamethasone, triamcinolone	Intranasal or inhaled fluticasone, mometasone, ciclesonide, budesonide, triamcinolone: Do not coadminister unless potential benefits outweigh risk; consider alternative corticosteroid (e.g., beclomethasone). Systemic betamethasone, budesonide: Do not coadminister unless potential benefits outweigh risk. Systemic prednisolone, prednisone: Do not coadminister unless potential benefits outweigh risk; if use cannot be avoided, use for shortest effective duration. Injectable betamethasone, triamcinolone: Do not coadminister unless potential benefits outweigh risk. Systemic dexamethasone: Do not coadminister unless potential benefits outweigh risk; consider alternative corticosteroid.
Trazodone	May increase trazodone concentrations.	Monitor antidepressant and/or sedative effects.
Alprazolam, clonazepam, diazepam	These benzodiazepines are substrates of CYP3A and may be increased in the presence of strong inhibitors of this enzyme.	Consider alternative benzodiazepine (e.g., lorazepam, oxazepam, temazepam). If used, administer lowest effective dose; monitor closely for adverse events.
Antipsychotics	Several of these agents are substrates of CYP3A, and inhibitors of this enzyme may increase their concentrations.	Quetiapine: Reduce dose to 1/6 if initiating ARVs in patients on stabilized quetiapine. Use all other antipsychotics at the lowest dose possible in patients taking boosted ARVs, and careful monitoring for adverse events is warranted.
PDE5 inhibitors [Perry 2014]	COBI is an inhibitor of CYP3A. PDE5 inhibitors are substrates of CYP3A. Flibanserin: Increased flibanserin concentrations expected.	Avoid concomitant use or use with lowest effective dose of the PDE5 inhibitor (may increase risk of hypotension, syncope, priapism, and other adverse reactions). Sildenafil: Start with 25 mg every 48 hours; monitor for adverse effects. Tadalafil: Start with 5 mg; do not exceed 10 mg every 72 hours; monitor for adverse effects. Vardenafil: Administer 2.5 mg every 72 hours; monitor for adverse effects. Flibanserin: Coadministration is contraindicated
Suvorexant [Kishi, et al. 2015]	Suvorexant is a CYP3A substrate. COBI is an inhibitor of CYP3A.	Avoid concomitant use or use the lowest effective dose (may increase somnolence, dizziness, and risk of sleep hangover).
Zolpidem, eszopiclone	These drugs are CYP3A substrates and may be increased by strong inhibitors of this enzyme.	Zolpidem: Administer lowest possible dose of zolpidem and monitor for adverse events. Eszopiclone: Start with 1 mg of eszopiclone at bedtime and titrate slowly for maximum effect.
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin	Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system	Coadministration is not recommended; use alternative anticonvulsant. If benefit of use outweighs risk, monitor carefully for efficacy and toxicity. Perform therapeutic drug monitoring.
Eletriptan	Eletriptan is a CYP3A substrate and concentrations may be increased if given with strong inhibitors of this enzyme.	Do not coadminister. Select an alternative triptan medication.
Opioid analgesics	Complex mechanisms of metabolism and formation of both active and inactive metabolites create interactions of unclear significance between these drugs and boosted EVG.	Monitor for signs of opiate toxicity and analgesic effect and dose these analgesics accordingly.
Tramadol	Tramadol exposure is increased with inhibition of CYP3A, but this reduces conversion to the more potent active metabolite seen when tramadol is metabolized by CYP2D6.	When tramadol is given with COBI or RTV, monitoring for tramadol-related side effects and for the analgesic effect may be required as clinically indicated; adjust tramadol dosage if needed.
Hormonal contraceptives	Drospirenone: Potential for hyperkalemia.	Ethinyl estradiol, norgestimate, metabolites; norethindrone: Weigh risks/benefits; consider alternative contraceptive method. Drospirenone: Monitor for hyperkalemia; consider alternative contraceptive or alternative ARV agent. Etonogestrel: No data; consider alternative or additional contraceptive method or alternative ARV agent
Immunosuppressants	Everolimus, sirolimus: Metabolism decreased by boosted EVG. Cyclosporine, tacrolimus: Metabolism decreased by boosted EVG.	Everolimus, sirolimus: Do not use with boosted EVG. Cyclosporine, tacrolimus: Dose based upon therapeutic drug monitoring. Monitor closely for adverse events.
Abbreviations: ARV, antiretroviral; COBI, cobicistat; CYP, cytochrome P450; GFR, glomerular filtration rate; INR, international normalized ratio; MATE, multidrug and toxin extrusion; OATP, organic anion transporting polypeptide; P-gP, P-glycoprotein; PI, protease inhibitor; RTV, ritonavir; TDM, therapeutic drug monitoring; UGT, uridine glucuronosyltransferase. No significant interactions/no dose adjustments necessary: Common oral antibiotics; acid-reducing agents; asthma and allergy medications; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone.

Table 7: Raltegravir (RAL) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Antacids and other polyvalent cations [Kiser, et al. 2010; Calcagno, et al. 2015; Krishna, et al. 2016]	RAL chelates with cations, forming insoluble compounds that inactivate both drugs.	Administer RAL 2 hours before or 6 hours after taking antacids. CaCO₃ antacids are contraindicated with RAL HD (2 x 600 mg tablets). CaCO₃ antacids can be taken with twice-daily RAL (400 mg) with no dose adjustments
Anticonvulsants	Coadministration with strong inducers of UGT1A1 (phenytoin, phenobarbital, etc.) may decrease RAL concentrations.	Coadministration with strong inducers of UGT1A1 are not recommended
Abbreviation: UGT1A1, uridine diphosphate glucuronosyltransferase 1A1. No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive agents; anticoagulants; antiplatelet drugs; statins; antidiabetic drugs; acid-reducing agents; asthma and allergy medications; long-acting beta-agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction agents; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; immunosuppressants.

References

Calcagno A, D’Avolio A, Bonora S. Pharmacokinetic and pharmacodynamic evaluation of raltegravir and experience from clinical trials in HIV-positive patients. Expert Opin Drug Metab Toxicol 2015;11(7):1167-1176. [PMID: 26073580]

Cottrell ML, Hadzic T, Kashuba AD. Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir. Clin Pharmacokinet 2013;52(11):981-994. [PMID: 23824675]

Custodio J, Wang H, Hao J, et al. Pharmacokinetics of cobicistat boosted-elvitegravir administered in combination with rosuvastatin. J Clin Pharmacol 2014;54(6):649-656. [PMID: 24375014]

Custodio J, West S, Yu A, et al. Lack of clinically relevant effect of bictegravir (BIC, B) on metformin (MET) pharmacokinetics (PK) and pharmacodynamics (PD). Open Forum Infect Dis 2017;4(suppl_1):S429-S429. [Link]

Egan G, Hughes CA, Ackman ML. Drug interactions between antiplatelet or novel oral anticoagulant medications and antiretroviral medications. Ann Pharmacother 2014;48(6):734-740. [PMID: 24615627]

Fantauzzi A, Turriziani O, Mezzaroma I. Potential benefit of dolutegravir once daily: efficacy and safety. HIV AIDS (Auckl) 2013;5:29-40. [PMID: 23413040]

Feng B, Varma MV. Evaluation and quantitative prediction of renal transporter-mediated drug-drug interactions. J Clin Pharmacol 2016;56 Suppl 7:S110-121. [PMID: 27385169]

Gervasoni C, Minisci D, Clementi E, et al. How relevant is the interaction between dolutegravir and metformin in real life? J Acquir Immune Defic Syndr 2017;75(1):e24-e26. [PMID: 28114188]

Keating GM, Plosker GL. Eplerenone: A review of its use in left ventricular systolic dysfunction and heart failure after acute myocardial infarction. Drugs 2004;64(23):2689-2707. [PMID: 15537370]

Kiser JJ, Bumpass JB, Meditz AL, et al. Effect of antacids on the pharmacokinetics of raltegravir in human immunodeficiency virus-seronegative volunteers. Antimicrob Agents Chemother 2010;54(12):4999-5003. [PMID: 20921313]

Kishi T, Matsunaga S, Iwata N. Suvorexant for primary insomnia: A systematic review and meta-analysis of randomized placebo-controlled trials. PLoS One 2015;10(8):e0136910. [PMID: 26317363]

Krishna R, East L, Larson P, et al. Effect of metal-cation antacids on the pharmacokinetics of 1200 mg raltegravir. J Pharm Pharmacol 2016;68(11):1359-1365. [PMID: 27671833]

Max B, Vibhakar S. Dolutegravir: a new HIV integrase inhibitor for the treatment of HIV infection. Future Virol 2014;9(11):967-978.

Perry CM. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (Stribild(R)): a review of its use in the management of HIV-1 infection in adults. Drugs 2014;74(1):75-97. [PMID: 24338165]

Song I, Borland J, Arya N, et al. Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects. J Clin Pharmacol 2015;55(5):490-496. [PMID: 25449994]

Song I, Zong J, Borland J, et al. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Acquir Immune Defic Syndr 2016;72(4):400-407. [PMID: 26974526]

Tseng A, Hughes CA, Wu J, et al. Cobicistat versus ritonavir: Similar pharmacokinetic enhancers but some important differences. Ann Pharmacother 2017;51(11):1008-1022. [PMID: 28627229]

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): DOR, RPV, EFV, ETR

Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, April 2019

Table 8: Doravirine (DOR) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Strong inducers or inhibitors of CYP3A [Deeks 2018]	DOR is a substrate of CYP3A, and as such, drugs that affect its metabolism affect its concentrations.	Avoid concomitant use if possible. Dose adjustments of DOR are not recommended. Consider alternative concomitant agents.
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin	Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system.	Coadministration is not recommended; use alternative anticonvulsant. If benefit of use outweighs risk, monitor carefully for efficacy and toxicity. Perform therapeutic drug monitoring if use cannot be avoided.
Abbreviations: ARV, antiretroviral; CYP, cytochrome P450. No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive agents; anticoagulants; antiplatelet drugs; statins; antidiabetic drugs; polyvalent cations (Table 22); asthma and allergy medications (Table 23); long-acting beta-agonists (Table 24); inhaled and injected corticosteroids (Table 25); antidepressants (Table 26); benzodiazepines (Table 27); sleep medications (Table 28); antipsychotics (Table 28); non-opioid pain medications (Table 31); opioid analgesics and tramadol (Table 32); hormonal contraceptives (Table 33); erectile and sexual dysfunction agents (Table 34); tobacco and smoking cessation products (Table 35); alcohol, disulfiram, and acamprosate (Table 36); methadone, buprenorphine, naloxone, and naltrexone (Table 37); immunosuppressants (Table 38).

Table 9: Rilpivirine (RPV) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Proton pump inhibitors (PPIs) [Schafer and Short 2012]	PPIs inhibit secretion of gastric acid by proton pumps thereby increasing gastric pH. RPV requires an acidic environment for optimal absorption.	Avoid concomitant use; may decrease RPV absorption.
Histamine 2 antagonists (H2As) [Schafer and Short 2012]	H2As inhibit secretion of gastric acid by proton pumps, thereby increasing gastric pH. RPV requires an acidic environment for optimal absorption.	Give H2A at least 12 hours before or 4 hours after RPV. Concomitant use may decrease RPV absorption. Use lowest effective dose. Administer with food.
Antacids [Schafer and Short 2012]	Antacids increase gastric pH. RPV requires an acidic environment for optimal absorption. Concomitant use may decrease RPV absorption	Give antacids 2 hours before or 4 hours after RPV.
GLP-1 agonists	Caution should be exercised when coadministering with RPV and GLP-1 agonists, such as exenatide, due to their potential to inhibit gastric secretion, thereby reducing absorption of RPV. Furthermore, exenatide has the potential to slow gastric emptying.	Consider taking RPV 4 hours before exenatide.
Dexamethasone [Welz, et al. 2017]	Dexamethasone is an inducer of CYP3A, which is primarily responsible for the metabolism of RPV.	Systemic dexamethasone: 1) Contraindicated; consider use of alternative agents. 2) If using more than single dose, do not coadminister.
Anti-arrhythmic drugs [Sanford 2012]	Supratherapeutic doses of RPV have caused QT prolongation, and additive effects may be seen.	Avoid concomitant use (may cause QT prolongation and torsades de pointes).
Long-acting beta-agonists (LABAs)	RPV and drugs from the LABA class may both theoretically increase QT interval, especially at high doses.	No dose adjustment necessary. Do not use more LABA than recommended; this can increase risk of QT prolongation.
Antipsychotics	No significant interactions noted.	No dose adjustments necessary, but avoid excess doses of either antipsychotic or RPV because excess doses of both drugs may increase risk of QT prolongation.
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin	Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system.	Coadministration is not recommended; use alternative anticonvulsant. If benefit of use outweighs risk, monitor carefully for efficacy and toxicity. Perform therapeutic drug monitoring if use cannot be avoided.
Methadone, buprenorphine (BUP)	BUP: No significant interactions with are expected. Methadone: Mildly reduces methadone concentrations.	Methadone: Monitor for signs of methadone withdrawal and increase dose as necessary. Use methadone or BUP cautiously with RPV because supratherapeutic doses of RPV have been known to cause increase in QT prolongation.
Strong inducers or inhibitors of CYP3A	RPV is a substrate of CYP3A, and as such, drugs that affect its metabolism affect its concentrations.	Avoid concomitant use if possible. Dose adjustments of RPV are not recommended. Consider alternative concomitant agents.
Abbreviations: ARV, antiretroviral; BUP, buprenorphine; CYP, cytochrome P450 No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive agents; anticoagulants; antiplatelet drugs; statins; asthma and allergy medications; antidepressants; benzodiazepines; sleep medications; anticonvulsants not specifically stated above; non-opioid pain medications; opioid analgesics and tramadol; erectile and sexual dysfunction agents; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; naloxone and naltrexone; immunosuppressants.

Table 10: Efavirenz (EFV) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Warfarin	Could potentially increase (or, more rarely, decrease) metabolism of warfarin.	Use cautiously with warfarin, and if use is necessary, increase monitoring of INR. Increase dose slowly if INR decreases. Decrease dose if INR increases.
Bupropion [Robertson, et al. 2008]	EFV may induce CYP2B6, the enzyme that is primarily responsible for metabolism of bupropion.	Monitor clinical effect and increase as needed, but do not exceed recommended maximum dose.
Levonorgestrel/norgestimate, levonorgestrel [Carten, et al. 2012; Scarsi, et al. 2016]	EFV may induce CYP3A, the enzyme that is primarily responsible for metabolism of levonorgestrel.	Effectiveness of levonorgestrel or norgestimate may be decreased.
Cilostazol	May reduce concentrations of cilostazol.	Monitor for antiplatelet effect; may be necessary to use an alternative antiplatelet drug or alternative ARV agent.
Dipyridamole	EFV may induce UGT enzymes, which are responsible for metabolism.	Monitor for antiplatelet effect; use another ARV agent if necessary.
Ticagrelor, clopidogrel	EFV reduce ticagrelor concentrations and the conversion of clopidogrel to its active metabolite.	Use with EFV may reduce the antiplatelet effect; monitor closely and use an alternative ARV agent if necessary.
Statins	Simvastatin, lovastatin: Could potentially decrease concentrations. Atorvastatin, pravastatin, fluvastatin: May modestly reduce concentrations. Pitavastatin, rosuvastatin: No interactions expected.	Simvastatin, lovastatin: Monitor for efficacy. May warrant increases in statin dose. Do not increase dose above maximum recommended statin dose. Atorvastatin, pravastatin, fluvastatin: Monitor cholesterol-lowering effect of statins. May require increased dose. Pitavastatin, rosuvastatin: No dose adjustments necessary.
Pioglitazone	EFV may increase concentrations by inhibition of CYP2C8. No significant interactions expected.	Monitor for signs of adverse events with EFV; decrease dose if necessary.
Saxagliptin, sitagliptin	EFV may decrease concentration.	Monitor for efficacy; if necessary, increase dose of the DPP-4 inhibitor.
Inhaled and injected corticosteroids	Coadministration may reduce concentrations of corticosteroids.	Systemic dexamethasone: Consider alternative corticosteroid for long-term use; if benefits of use outweigh risks, monitor virologic response.
Trazodone	May decrease trazodone concentrations.	Monitor antidepressant and/or sedative effects.
Bupropion	EFV induces bupropion metabolism.	Monitor clinical effect and increase as needed, but do not exceed recommended maximum dose.
Benzodiazepines	Alprazolam, diazepam: Potential for reduced alprazolam and diazepam concentrations.	Alprazolam: Monitor for benzodiazepine withdrawal if EFV is added. Alprazolam, clonazepam, diazepam: Monitor for benzodiazepine efficacy; titrate slowly as needed for effect.
Sleep medications	Zolpidem: Potential for reduced concentrations of zolpidem.	Zolpidem, eszopiclone: Monitor for efficacy; no dose adjustments recommended. Suvorexant: Monitor for efficacy; do not exceed 20 mg per day.
Antipsychotics	Quetiapine: Concentrations of quetiapine may be reduced. Aripiprazole, brexpiprazole: Concentrations of aripiprazole and brexpiprazole may be decreased. Risperidone, olanzapine: May decrease efficacy of risperidone and olanzapine.	Quetiapine: Monitor for efficacy; titrate slowly as needed; monitor for adverse effects. Aripiprazole, brexpiprazole: Monitor for efficacy; titrate dose slowly as needed; monitor for adverse effects. Risperidone, olanzapine: Monitor for efficacy; titrate slowly as needed; monitor for adverse effects
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin	Coadministration may significantly reduce concentrations of antiretroviral agents through induction of CYP450 system.	Coadministration is not recommended; use alternative anticonvulsant. If benefit of use outweighs risk, monitor carefully for efficacy and toxicity. Perform therapeutic drug monitoring if use cannot be avoided
Lamotrigine, zonisamide	EFV may reduce efficacy of lamotrigine or zonisamide.	Monitor efficacy; titrate dose slowly as needed.
Opioid analgesics and tramadol	Morphine, hydromorphone: Metabolism could potentially be reduced by EFV. Oxycodone: May be metabolized faster to an inactive metabolite by EFV. Meperidine: Coadministration can potentially increase the amount of neurotoxic metabolite and thereby increase risk of seizures. Tramadol: May reduce concentration of tramadol without affecting pathway that increases development of more potent active metabolites.	Morphine, hydromorphone: Monitor for signs of opiate toxicity when using with EFV. Oxycodone: Dose adjustment of oxycodone may be required when dosing with EFV. Meperidine: If possible, avoid concomitant use; use alternative opiate pain medication or ARV agent. Tramadol: When given with tramadol, a priori dose adjustments are necessary.
Hormonal contraceptives	Decreased concentrations of combined progestins.	Ethinyl estradiol; norgestimate, metabolites: Use alternative or additional contraceptive methods; unintended pregnancies have been reported in individuals using levonorgestrel implant. Norethindrone, drospirenone, etonogestrel: Consider alternative or additional contraceptive method or alternative ARV agent. Ulipristal: Efficacy may be reduced; monitor closely.
Erectile and sexual dysfunction agents	PDE5 inhibitor: Potential for reduced effectiveness of PDE5 inhibitors (sildenafil, vardenafil, and tadalafil). Flibanserin: Potential for reduced concentrations of flibanserin.	PDE5 inhibitors: Monitor clinical effect; if dose increase is needed to achieve desired clinical effect, titrate under medical supervision to lowest effective dose. Flibanserin: Do not coadminister.
Methadone [Clarke, et al. 2001; Gruber and McCance-Katz 2010; Kharasch, et al. 2012]	EFV induces methadone metabolism via CYP3A4. Reduces methadone concentrations.	Monitor for signs and symptoms of opioid withdrawal and titrate methadone dose to effect.
Buprenorphine (BUP) [McCance-Katz, et al. 2006; Gruber and McCance-Katz 2010]	EFV induces BUP metabolism via CYP3A4. When given with BUP (monotherapy), significantly reduces BUP concentrations, but no patients developed opioid withdrawal.	When given with BUP, dose adjustments are unlikely to be required, but monitor for withdrawal symptoms. If withdrawal symptoms occur, increase BUP dose accordingly
NS3/4A inhibitors (glecaprevir, simeprevir, grazoprevir, etc.) [Soriano, et al. 2017; Garrison, et al. 2018]	EFV induces NS3/4A PI metabolism via CYP3A4.	Concomitant use is not recommended (may result in failure of HCV treatment regimens containing PIs, reducing SVR rates and increasing resistance).
Daclatasvir [Soriano, et al. 2017; Garrison, et al. 2018]	EFV induces daclatasvir metabolism via CYP3A4.	Increase daclatasvir dose to 60 mg per day.
Sofosbuvir/ velpatasvir (available as coformulated product) [Greig 2016]	EFV may decrease levels of velpatasvir through induction of CYP3A.	Coadministration of sofosbuvir/ velpatasvir is contraindicated.
Cyclosporine, tacrolimus	Concentrations may be lower when used with EFV.	Dose-adjust cyclosporine and tacrolimus based on efficacy and therapeutic drug monitoring (TDM). Conduct TDM more frequently for 2 weeks when starting or stopping NNRTI therapy.
Abbreviations: ARV, antiretroviral; BUP, buprenorphine; CYP, cytochrome P450; HCV, hepatitis C virus; INR, international normalized ratio; NNRTI, non-nucleoside reverse transcriptase inhibitor; NS3/4A, nonstructural protein 3/4A; PDE5, phosphodiesterase type 5; PI, protease inhibitor; SVR, sustained viral response; UGT, uridine diphosphate glucoronosyltransferase. No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive medicines; acid-reducing agents; polyvalent cations; asthma and allergy medications; long-acting beta-agonists; non-opioid pain medications; alcohol, disulfiram, and acamprosate.

Table 11: Etravirine (ETR) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Aliskiren	ETR is a minor inhibitor of P-gP and may minimally increase concentrations of aliskiren, but this has not been studied.	When using with ETR, monitor for aliskiren-related adverse events. If present, switch to alternative antihypertensive agent or ARV agent.
Warfarin	Could potentially increase (or more rarely decrease) metabolism of warfarin.	Use cautiously with warfarin, and if use is necessary, increase monitoring of INR. Increase dose slowly if INR decreases. Decrease dose if INR increases.
Antiplatelet drugs [Rathbun and Liedtke 2010; Kakuda, et al. 2011]	Cilostazol: May reduce concentrations of cilostazol. Dipyridamole: ETR may induce UGT enzymes, which are responsible for metabolism. Ticagrelor, clopidogrel: ETR reduces ticagrelor concentrations and the conversion of clopidogrel to its active metabolite because ETR inhibits 2C19.	Cilostazol: Monitor for antiplatelet effect; may be necessary to use an alternative antiplatelet drug or alternative ARV agent. Dipyridamole: Monitor for antiplatelet effect; use another ARV agent if necessary. Ticagrelor, clopidogrel: Use with ETR may reduce the antiplatelet effect; monitor closely and use an alternative ARV agent if possible.
Statins	Simvastatin, lovastatin: Could potentially decrease concentrations. Atorvastatin, pravastatin, fluvastatin: May modestly reduce concentrations.	Simvastatin, lovastatin: Monitor for efficacy. May warrant increases in statin dose. Do not increase dose above maximum recommended statin dose. Atorvastatin, pravastatin, fluvastatin: Monitor cholesterol-lowering effect of statins. May require increased dose.
Saxagliptin, sitagliptin	ETR may decrease concentration.	Monitor for efficacy; if necessary, increase dose of the DPP-4 inhibitor.
Inhaled and injected corticosteroids	Coadministration may reduce concentrations of corticosteroids.	Systemic dexamethasone: Consider alternative corticosteroid for long-term use; if benefits of use outweigh risks, monitor virologic response
Trazodone	May decrease trazodone concentrations.	Monitor antidepressant and/or sedative effects.
Bupropion	No significant interactions.	Monitor clinical effect and increase as needed, but do not exceed recommended maximum dose.
Alprazolam	Potential for reduced alprazolam concentrations.	Monitor for benzodiazepine withdrawal.
Diazepam	Potential for reduced diazepam concentrations.	No dose adjustments necessary.
Sleep medications	Zolpidem: Potential for reduced concentrations of zolpidem.	Zolpidem, eszopiclone: Monitor for efficacy; no dose adjustments recommended. Suvorexant: Monitor for efficacy; do not exceed 20 mg per day.
Antipsychotics	Aripiprazole, brexpiprazole: Concentrations of aripiprazole and brexpiprazole may be decreased. Risperidone: May decrease efficacy of risperidone.	Aripiprazole, brexpiprazole: Monitor for efficacy; titrate dose slowly as needed; monitor for adverse effects. Risperidone: Monitor for efficacy; titrate slowly; monitor for adverse effects.
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin	Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system.	Coadministration is not recommended; use alternative anticonvulsant. If benefit of use outweighs risk, monitor carefully for efficacy and toxicity. Perform therapeutic drug monitoring if use cannot be avoided.
Lamotrigine, zonisamide	May reduce efficacy of lamotrigine or zonisamide.	Monitor efficacy; titrate dose slowly as needed.
Hormonal contraceptives	Information is based on what is known with EFV drug interactions	Etonogestrel: No data; consider alternative or additional contraceptive method or alternative ARV agent. Ulipristal: Efficacy may be reduced; monitor closely.
Erectile and sexual dysfunction agents	PDE5 inhibitor: Potential for reduced effectiveness of PDE5 inhibitors (sildenafil, vardenafil, and tadalafil). Flibanserin: Potential for reduced concentrations of flibanserin.	PDE5 inhibitors: Monitor clinical effect; if dose increase is needed to achieve desired clinical effect, titrate under medical supervision to lowest effective dose. Flibanserin: Do not coadminister.
Bupropion	No significant interactions noted.	Monitor clinical effect and increase as needed, but do not exceed recommended maximum dose.
Buprenorphine	No significant interactions expected.	Monitor for signs of withdrawal or opioid toxicity and titrate dose of opioid or antagonist as required.
Methadone	May slightly increase concentrations of methadone.	Monitor for signs of withdrawal or opioid toxicity and titrate dose of opioid or antagonist as required. Monitor for signs of methadone toxicity and reduce dose if necessary.
Cyclosporine, tacrolimus	Concentrations may be lower when used with ETR.	Dose-adjust cyclosporine and tacrolimus based on efficacy and therapeutic drug monitoring (TDM). Conduct TDM more frequently for 2 weeks when starting or stopping NNRTI therapy.
HCV PIs (“-previr” drugs) [Kaur, et al. 2015; Yeh 2015; Mak, et al. 2018]	ETR may decrease levels of HCV PIs through induction of CYP3A.	Do not coadminister HCV PIs with ETR.
Sofosbuvir/ velpatasvir (available as coformulated product) [Greig 2016]	ETR may decrease levels of velpatasvir through induction of CYP3A and (weak) inhibition of P-gP.	Do not coadminister sofosbuvir/ velpatasvir with ETR.
Daclatasvir [Garrison, et al. 2018]	ETR induces CYP3A, lowering daclatasvir levels.	Increase dose of daclatasvir to 90 mg per day.
Atazanavir (ATV) [Orrell, et al. 2015; Marzolini, et al. 2016]	ETR is a substrate and inducer of CYP3A4. COBI is a substrate and inhibitor of CYP3A4. ATV is a substrate and inhibitor of CYP3A4	Use with RTV-boosted ATV results in decreases in ATV exposure, but the decrease is not considered relevant and ETR and RTV-boosted ATV can be administered together without dose adjustments. Due to the potential for decreased ARV efficacy, avoid use of ETR with COBI. When these medications are given together, COBI concentrations are decreased. When possible, avoid concomitant use of ETR and unboosted ATV. ETR with unboosted ATV results in significant decreases in ATV exposure.
Dolutegravir (DTG) [Green, et al. 2017]	ETR induces UGT1A1 and CYP3A enzymes. DTG is a substrate of UGT1A1 and CYP3A enzymes.	ETR reduces concentrations of DTG. Do not use concomitantly unless a boosted PI is also a part of the treatment regimen.
Abbreviations: ARV, antiretroviral; COBI, cobicistat; CYP, cytochrome P450; EFV, efavirenz; HCV, hepatitis C virus; INR, international normalized ratio; NNRTI, non-nucleoside reverse transcriptase inhibitor; P-gP, P-glycoprotein; PI, protease inhibitor; RTV, ritonavir; UGT, uridine diphosphate glucuronosyltransferase. No significant interactions/no dose adjustments necessary: Common oral antibiotics; acid-reducing agents; polyvalent cations; asthma and allergy medications; long-acting beta-agonists; non-opioid pain medications; opioid analgesics and tramadol; alcohol, disulfiram, and acamprosate.

References

Carten ML, Kiser JJ, Kwara A, et al. Pharmacokinetic interactions between the hormonal emergency contraception, levonorgestrel (Plan B), and Efavirenz. Infect Dis Obstet Gynecol 2012;2012:137192. [PMID: 22536010]

Clarke SM, Mulcahy FM, Tjia J, et al. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001;51(3):213-217. [PMID: 11298066]

Deeks ED. Doravirine: First global approval. Drugs 2018;78(15):1643-1650. [PMID: 30341683]

Garrison KL, German P, Mogalian E, et al. The drug-drug interaction potential of antiviral agents for the treatment of chronic hepatitis C infection. Drug Metab Dispos 2018;46(8):1212-1225. [PMID: 29695614]

Green B, Crauwels H, Kakuda TN, et al. Evaluation of concomitant antiretrovirals and CYP2C9/CYP2C19 polymorphisms on the pharmacokinetics of etravirine. Clin Pharmacokinet 2017;56(5):525-536. [PMID: 27665573]

Greig SL. Sofosbuvir/velpatasvir: A review in chronic hepatitis C. Drugs 2016;76(16):1567-1578. [PMID: 27730529]

Gruber VA, McCance-Katz EF. Methadone, buprenorphine, and street drug interactions with antiretroviral medications. Curr HIV/AIDS Rep 2010;7(3):152-160. [PMID: 20532839]

Kakuda TN, Scholler-Gyure M, Hoetelmans RM. Pharmacokinetic interactions between etravirine and non-antiretroviral drugs. Clin Pharmacokinet 2011;50(1):25-39. [PMID: 21142266]

Kaur K, Gandhi MA, Slish J. Drug-drug interactions among hepatitis C virus (HCV) and human immunodeficiency virus (HIV) medications. Infect Dis Ther 2015;4(2):159-172. [PMID: 25896480]

Kharasch ED, Whittington D, Ensign D, et al. Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 2012;91(4):673-684. [PMID: 22398970]

Mak LY, Seto WK, Lai CL, et al. An update on the toxicological considerations for protease inhibitors used for hepatitis C infection. Expert Opin Drug Metab Toxicol 2018;14(5):483-491. [PMID: 29718748]

Marzolini C, Gibbons S, Khoo S, et al. Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications. J Antimicrob Chemother 2016;71(7):1755-1758. [PMID: 26945713]

McCance-Katz EF, Moody DE, Morse GD, et al. Interactions between buprenorphine and antiretrovirals. I. The nonnucleoside reverse-transcriptase inhibitors efavirenz and delavirdine. Clin Infect Dis 2006;43 Suppl 4:S224-234. [PMID: 17109309]

Rathbun C, Liedtke MD. The next generation: etravirine in the treatment of HIV-1 infection in adults refractory to other antiretrovirals. Virus Adapt Treat 2010;2:91-102. [Link]

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Nucleoside Reverse Transcriptase Inhibitors (NRTIs): ABC, TDF/TAF, 3TC

Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, April 2019

Table 12: Abacavir (ABC) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Ethanol [McDowell, et al. 2000; Yuen, et al. 2008]	ABC is metabolized via alcohol dehydrogenase, and competitive metabolism may increase exposure to ABC.	Use cautiously and monitor for adverse events of ABC.
No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive medicines; anticoagulants; antiplatelet drugs; statins; antidiabetic drugs; acid-reducing agents; polyvalent cations; asthma and allergy medications; long-acting beta-agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; anticonvulsants; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction agents; tobacco and smoking cessation products; methadone, buprenorphine, naloxone, and naltrexone; immunosuppressants.

Table 13: Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF) Interactions (also see drug package inserts)
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Class or Drug	Mechanism of Action	Clinical Comments
Adefovir [Jafari, et al. 2014]	Similar mechanisms of action and elimination, and thus, similar adverse event profiles. Competitive inhibition of elimination results in additive adverse events.	Avoid concomitant use to avoid increased risk of hepatic steatosis and lactic acidosis.
Other nephrotoxic agents [Jafari, et al. 2014]	Competitive inhibition of elimination results in additive adverse events.	Avoid concomitant use or use the lowest effective dose of other drug to avoid renal impairment and kidney dysfunction. May be preferable to use TAF in these instances because TAF is less nephrotoxic.
Sofosbuvir/velpatasvir/ voxilaprevir [brand name Vosevi] [Garrison, et al. 2017]	TDF and TAF are substrates for BCRP and P-gP. Voxilaprevir is a BCRP inhibitor. Velpatasvir inhibits BCRP and P-gP.	Avoid concomitant use if possible to avoid TDF-associated adverse events. May be preferable to use TAF in these instances.
Potent CYP3A4 or P-gP inducers (phenytoin, rifampin, carbamazepine, St. John’s wort, etc.) [Gibson, et al. 2016]	CYP3A4 is a minor metabolic pathway for TAF, and as such, potent inducers of this enzyme may modestly reduce concentrations. TAF is also a substrate of P-gP, and inducers may decrease TAF concentrations.	Avoid coadministration of TAF with potent inducers of CYP3A4 or P-gP.
Zonisamide	TDF may increase concentration of zonisamide.	Monitor for adverse events of zonisamide with TDF.
Topiramate	No significant interactions noted.	Monitor renal function when coadministered (topiramate may cause kidney stones; TDF is associated with renal toxicity).
Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome P450; P-gP, P-glycoprotein. No significant interactions/no dose adjustments necessary: Common oral antibiotics; drugs used as antihypertensive medicines; anticoagulants; antiplatelet drugs; statins; antidiabetic drugs; acid-reducing agents; polyvalent cations; asthma and allergy medications; long-acting beta-agonists; inhaled and injected corticosteroids; antidepressants; benzodiazepines; sleep medications; antipsychotics; non-opioid pain medications; opioid analgesics and tramadol; hormonal contraceptives; erectile and sexual dysfunction drugs; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; immunosuppressants.

Table 14: Lamivudine (3TC) and Emtricitabine (FTC) Interactions (also see drug package inserts)
Class or Drug	Mechanism of Action	Clinical Comments
–	–	–
Note: There are no known clinically significant drug-drug interactions between 3TC or FTC and concomitant agents.

References

Garrison KL, Mogalian E, Zhang H, et al. Evaluation of drug-drug interactions between sofosbuvir/velpatasvir/voxilapevir and boosted or unboosted HIV antiretroviral regimens. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy; 2017 Jun 14-17; Chicago, IL. http://www.natap.org/2017/Pharm/Pharm_19.htm

Gibson AK, Shah BM, Nambiar PH, et al. Tenofovir alafenamide: A review of its use in the treatment of HIV-1 infection. Ann Pharmacother 2016;50(11):942-952. [PMID: 27465879]

Jafari A, Khalili H, Dashti-Khavidaki S. Tenofovir-induced nephrotoxicity: incidence, mechanism, risk factors, prognosis and proposed agents for prevention. Eur J Clin Pharmacol 2014;70(9):1029-1040. [PMID: 24958564]

McDowell JA, Chittick GE, Stevens CP, et al. Pharmacokinetic interaction of abacavir (1592U89) and ethanol in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 2000;44(6):1686-1690. [PMID: 10817729]

Yuen GJ, Weller S, Pakes GE. A review of the pharmacokinetics of abacavir. Clin Pharmacokinet 2008;47(6):351-371. [PMID: 18479171]