Guidelines for the Use of Antiretroviral Agents in HIV1Infected Adults and Adolescents
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Drug Interactions
Drug Interactions between Integrase Inhibitors and Other Drugs
Last Updated: July 14, 2016; Last Reviewed: July 14, 2016
Table 19d. Drug Interactions Between Integrase Strand Transfer Inhibitors and Other Drugs
This table provides information on known or predicted pharamacokinetic interactions between INSTIs (DTG, EVG, or RAL) and nonARV drugs. EVG is always coadministered with either COBI or RTV. In this table, the drug interactions with EVG/c products and those with EVG plus PI/r are presented separately. When EVG is given with a PI/r, clinicians should refer to Table 19a for recommendations on the management of drug interactions of concomitant medications and the specific PI/r used with EVG.
Concomitant Drug Class/Name  INSTI  Effect on INSTI or Concomitant Drug Concentrations  Dosing Recommendations and Clinical Comments 

Acid Reducers  
Aluminium, Magnesium +/ CalciumContaining Antacids Please refer to the Miscellaneous Drugs section of this table for recommendations on use with other polyvalent cation products (eg, iron, calcium supplements, multivitamins). 
DTG  DTG AUC ↓ 74% if given simultaneously with antacid; DTG AUC ↓ 26% if given 2 hours before antacid  Give DTG at least 2 hours before or at least 6 hours after antacids containing polyvalent cations. 
EVG/c EVG plus PI/r 
EVG AUC ↓ 40% to 50% if given simultaneously with antacid EVG AUC ↓ 15% to 20% if given 2 hours before or after antacid; ↔ with 4hour interval 
Separate EVG/c/TDF/FTC and antacid administration by more than 2 hours.  
RAL  AlMg Hydroxide Antacid:

Do not coadminister RAL and AlMg hydroxide antacids. Use alternative acid reducing agent.
No dosing separation necessary when coadministering RAL and CaCO_{3} antacids. 

H2Receptor Antagonists  EVG/c  No significant effect  No dosage adjustment necessary. 
EVG plus PI/r  ↔ EVG  No dosage adjustment necessary for EVG. Refer to Table 19a for information on PI/r interactions.  
PPIs  DTG  No significant effect  No dosage adjustment necessary. 
EVG/c  No significant effect  No dosage adjustment necessary.  
EVG plus PI/r  ↔ EVG  No dosage adjustment necessary for EVG. Refer to Table 19a for information on PI/r interactions.  
RAL  RAL AUC ↑ 212% and C_{min} ↑ 46%  No dosage adjustment necessary.  
Anticoagulants and Antiplatelets  
Apixaban 
EVG/c EVG plus PI/r 
↑ apixaban expected  Avoid concomitant use. 
Dabigatran 
EVG/c EVG plus PI/r 
↑ dabigatran possible  No dosage adjustment for dabigatran if CrCl >50 mL/min. Avoid coadministration if CrCl <50 mL/min. 
Edoxaban 
EVG/c EVG plus PI/r 
↑ edoxaban expected  Avoid concomitant use. 
Rivaroxaban 
EVG/c EVG plus PI/r 
↑ rivaroxaban expected  Avoid concomitant use. 
Ticagrelor 
EVG/c EVG plus PI/r 
↑ ticagrelor expected  Avoid concomitant use. 
Vorapaxar 
EVG/c EVG plus PI/r 
↑ vorapaxar expected  Avoid concomitant use. 
Warfarin 
EVG/c EVG plus PI/r 
Warfarin levels may be affected  Monitor INR and adjust warfarin dose accordingly. 
Anticonvulsants  
Carbamazepine
Phenobarbital Phenytoin 
DTG  ↓ DTG possible  Consider alternative anticonvulsant. 
EVG/c 
carbamazepine AUC ↑ 43%
EVG AUC ↓ 69% and Cmin ↓ >99% ↓ COBI expected 
Contraindicated. Do not coadminister.  
EVG plus PI/r  ↓ EVG  Consider alternative anticonvulsant.  
Ethosuximide 
EVG/c EVG plus PI/r 
↑ ethosuximide possible  Clinically monitor for ethosuxamide toxicities. 
Oxcarbazepine 
DTG EVG/c EVG plus PI/r 
↓ INSTI possible  Consider alternative anticonvulsant. 
Antidepressants/Anxiolytics/Antipsychotics Also see Sedative/Hypnotics section below. 

Bupropion  EVG/c  ↑ or ↓ bupropion possible  Titrate bupropion dose based on clinical response. 
EVG plus PI/r  ↓ bupropion possible  Titrate bupropion dose based on clinical response.  
Buspirone 
EVG/c EVG plus PI/r 
↑ buspirone possible  Initiate buspirone at a low dose. Dose reduction may be necessary. 
Fluvoxamine 
EVG/c EVG plus PI/r 
↑ or ↓ EVG possible  Consider alternative antidepressant or ARV. 
Quetiapine 
EVG/c EVG plus PI/r 
↑ quetiapine AUC expected  Initiation of quetiapine in a patient receiving EVG/c:

SSRIs Citalopram Escitalopram Fluoxetine Paroxetine Sertraline 
EVG/c  ↑ SSRI possible  Initiate with lowest dose of SSRI and titrate dose carefully based on antidepressant response. 
EVG plus PI/r  ↑ or ↓ SSRI possible  Titrate SSRI dose based on clinical response.  
RAL 
↔ RAL ↔ citalopram 
No dosage adjustment necessary.  
TCAs Amitriptyline Desipramine Doxepin Imipramine Nortriptyline 
EVG/c  Desipramine AUC ↑ 65%  Initiate with lowest dose of TCA and titrate dose carefully. 
EVG plus PI/r  ↑ TCA expected  Initiate with lowest dose of TCA and titrate dose carefully based on antidepressant response and/or drug levels.  
Trazodone 
EVG/c EVG plus PI/r 
↑ trazodone possible  Initiate with lowest dose of trazodone and titrate dose carefully. 
Antifungals  
Isavuconazole  EVG/c 
↑ isavuconazole expected ↑ EVG and COBI possible 
If coadministered, consider monitoring isavuconazole concentrations and assess virologic response. 
EVG plus PI/r  Changes in isavuconazole and EVG possible  Refer to Table 19a for PI recommendations.  
Itraconazole  EVG/c 
↑ itraconazole expected ↑ EVG and COBI possible 
Consider monitoring itraconazole level to guide dosage adjustments. High itraconazole doses (>200 mg/day) are not recommended unless dose is guided by itraconazole levels. 
EVG plus PI/r  ↑ EVG possible  Refer to Table 19a for PI recommendations.  
Posaconazole  EVG/c 
↑ EVG and COBI possible ↑ posaconazole possible 
If coadministered, monitor posaconazole concentrations. 
EVG plus PI/r  ↑ EVG possible  Refer to Table 19a for PI recommendations.  
Voriconazole  EVG/c 
↑ voriconazole expected ↑ EVG and COBI possible 
Risk/benefit ratio should be assessed to justify use of voriconazole. If administered, consider monitoring voriconazole level. Adjust dose accordingly. 
EVG plus PI/r  Changes in voriconazole and EVG possible  Refer to Table 19a for PI recommendations.  
Antimycobacterials  
Clarithromycin  EVG/c 
↑ clarithromycin possible ↑ COBI possible 
CrCl 50−60 mL/min:

Rifabutin  DTG  Rifabutin (300 mg once daily):

No dosage adjustment necessary. 
EVG/c  Rifabutin 150 mg every other day with EVG/c once daily compared to Rifabutin 300 mg once daily alone:
↔ rifabutin AUC 25Odesacetylrifabutin AUC ↑ 625% EVG AUC ↓ 21%, C_{min} ↓ 67% 
Do not coadminister.  
EVG plus PI/r 
↔ EVG ↔ rifabutin AUC 25Odesacetylrifabutin AUC ↑ 951% 
Refer to Table 19a for dosing recommendations for rifabutin with PI.  
RAL  RAL AUC ↑ 19% and C_{min} ↓ 20%  No dosage adjustment necessary.  
Rifampin  DTG  Rifampin with DTG 50 mg BID compared to DTG 50 mg BID alone: DTG AUC ↓ 54%, C_{min} ↓ 72% Rifampin with DTG 50 mg BID compared to DTG 50 mg once daily alone: DTG AUC ↑ 33%, C_{min} ↑ 22% 
Dose:
DTG 50 mg BID (instead of 50 mg once daily) for patients without suspected or documented INSTI mutation. Alternative to rifampin should be used in patients with certain suspected or documented INSTIassociated resistance substitutions. Consider using rifabutin. 
EVG/c EVG plus PI/r 
Significant ↓ EVG and COBI expected  Do not coadminister.  
RAL  RAL 400 mg:
RAL AUC ↓ 40%, C_{min} ↓ 61% Compared with RAL 400 mg BID alone, Rifampin with RAL 800 mg BID: RAL AUC ↑ 27%, C_{min} ↓ 53% 
Dose: RAL 800 mg BID Monitor closely for virologic response or consider using rifabutin as an alternative rifamycin. 

Rifapentine  DTG  Significant ↓ DTG expected  Do not coadminister. 
EVG/c EVG plus PI/r 
Significant ↓ EVG and COBI expected  Do not coadminister.  
RAL  Rifapentine 600 mg once daily:
RAL C_{min} ↓ 41% Rifapentine 900 mg once weekly: RAL AUC ↑ 71%, C_{min} ↓ 12% 
Do not coadminister with oncedaily rifapentine. For onceweekly rifapentine, use standard doses. 

Cardiac Medications  
Antiarrhythmics
Amiodarone Bepridil Digoxin Disopyramide Dronedarone Flecainide Systemic lidocaine Mexilitine Propafenone Quinidine 
EVG/c 
↑ antiarrhythmics possible digoxin C_{max} ↑ 41% and AUC no significant change 
Use antiarrhythmics with caution. Therapeutic drug monitoring, if available, is recommended for antiarrhythmics. 
EVG plus PI/r  ↑ antiarrhythmics possible  Refer to Table 18 and 19a for use of antiarrhythmics and PI/r.  
Bosentan  EVG/c  ↑ bosentan possible;  In patients on EVG/c ≥10 days:

EVG plus PI/r  ↑ bosentan possible  Refer to Table 19a for recommendations on bosentan dosing when used with PI/r.  
Betablockers (eg, metoprolol, timolol) 
EVG/c EVG plus PI/r 
↑ betablockers possible 
Betablocker dose may need to be decreased; adjust dose based on clinical response.
Consider using betablockers that are not metabolized by CYP450 enzymes (eg, atenolol, labetalol, nadolol, sotalol). 
CCBs 
EVG/c EVG plus PI/r 
↑ CCBs possible  Coadminister with caution. Titrate CCB dose and monitor for CCB efficacy and toxicities.
Refer to Table 19a for diltiazem plus ATV/r and SQV/r recommendations. 
Dofetilide  DTG  ↑ dofetilide expected  Do not coadminister. 
Eplerenone 
EVG/c EVG plus PI/r 
↑ eplerenone expected  Contraindicated. Do not coadminister. 
Ivabradine 
EVG/c EVG plus PI/r 
↑ ivabradine expected  Contraindicated. Do not coadminister. 
Corticosteroids  
Dexamethasone (systemic) 
EVG/c  ↓ EVG and COBI possible 
Use systemic dexamethasone with caution. Monitor virologic response to ART. Consider alternative corticosteroid. 
EVG plus PI/r  ↓ EVG possible  
Fluticasone Inhaled/Intranasal 
EVG/c EVG plus PI/r 
↑ fluticasone possible  Coadministration may result in adrenal insufficiency and Cushing’s syndrome. Consider alternative therapy (eg, beclomethasone), particularly for longterm use. 
Methylprednisolone, Prednisolone, Triamcinolone Local injections, including intraarticular, epidural, intraorbital 
EVG/c EVG plus PI/r 
↑ glucocorticoids expected 
Coadministration may result in adrenal insufficiency and Cushing’s syndrome. Do not coadminister. 
Hepatitis C Direct Acting Antivirals 

Daclatasvir 
DTG  Daclatasvir ↔  No dosage adjustment necessary. 
EVG/c  ↑ Daclatasvir  Decrease daclastavir dose to 30 mg once daily.  
EVG plus PI/r  ↑ Daclatasvir expected  Decrease daclastavir dose to 30 mg once daily, regardless of which PI/r is used, except for TPV/r. Do not coadminister EVG plus TPV/r with daclastavir.  
RAL  No data  No dosage adjustment necessary.  
Dasabuvir plus Ombitasvir/ Paritaprevir/r 
DTG  No data  No dosing recommendations at this time. 
EFG plus PI/r EVG/c 
No data  Do not coadminister.  
RAL  RAL AUC ↑ 134%  No dosage adjustment necessary.  
Elbasvir/Grazoprevir  DTG 
Elbasvir ↔ Grazoprevir ↔ DTG ↔ 
No dosage adjustment necessary. 
EVG plus PI/r  Refer to Table 19a for PI dosing recommendations.  
EVG/c  ↑ elbasvir, grazoprevir expected  Coadministration is not recommended.  
RAL 
Elbasvir ↔
Grazoprevir ↔ RAL ↔ with elbasvir RAL AUC ↑ 43% with grazoprevir 
No dosage adjustment necessary.  
Ledipasvir/Sofosbuvir  EVG/c/TDF/FTC  ↑ TDF and ↑ ledipasvir expected  Do not coadminister. 
EVG/c/TAF/FTC  ↔ EVG/c/TAF/FTC expected  No dosage adjustment necessary.  
EVG plus PI/r  ↔ EVG expected  Refer to Table 19a for PI dosing recommendations.  
DTG
RAL 
↔ DTG or RAL  No dosage adjustment necessary.  
Simeprevir 
DTG  ↔ DTG expected  No dosage adjustment necessary. 
EVG/c 
↑ simeprevir expected 
Coadministration is not recommended. 

EVG plus PI/r 
↔ EVG expected 
Coadministration is not recommended. 

RAL 
No significant effect 
No dosage adjustment necessary. 

Sofosbuvir 
All INSTIs  No significant effect expected  No dosage adjustment necessary. 
Herbal Products  
St. John's Wort  DTG  ↓ DTG possible 
Do not coadminister. 
EVG/c EVG plus PI/r 
↓ EVG and COBI possible 
Do not coadminister. 

Hormonal Contraceptives 

Hormonal Contraceptives  RAL  No clinically significant effect  No dosage adjustment necessary. 
Norgestimate/ Ethinyl Estradiol 
DTG  No significant effect 
No dosage adjustment necessary. 
EVG/c 
Norgestimate AUC, C_{max}, and C_{min} ↑ >2fold Ethinyl estradiol AUC ↓ 25% and C_{min} ↓ 44% 
The effects of increases in progestin (norgestimate) are not fully known and can include insulin resistance, dyslipidemia, acne, and venous thrombosis. Weigh the risks and benefits of the drug, and consider alternative contraceptive method. 

EVG plus PI/r  ↔EVG 
Refer to Table 19a for recommendations when used with PI/r. 

HMGCoA Reductase Inhibitors 

Atorvastatin 
EVG/c 
↑ atorvastatin possible 
Titrate statin dose slowly and use the lowest dose possible. 
EVG plus PI/r 
↔ EVG expected 
Refer to Table 19a for dosing recommendations when used with PI/r. 

Lovastatin 
EVG/c EVG plus PI/r 
Significant ↑ lovastatin expected 
Contraindicated. Do not coadminister. 
Pitavastatin
Pravastatin 
EVG/c  No data  No dosage recommendation 
EVG plus PI/r 
↔ EVG expected 
Refer to Table 19a for dosing recommendations when used with PI/r. 

Rosuvastatin  EVG/c 
Rosuvastatin AUC ↑ 38% and C_{max} ↑ 89% 
Titrate statin dose slowly and use the lowest dose possible. 
EVG plus PI/r 
↔ EVG expected 
Refer to Table 19a for dosing recommendations when used with PI/r. 

Simvastatin 
EVG/c EVG plus PI/r 
Significant ↑ simvastatin expected 
Contraindicated. Do not coadminister. 
Immunosuppressants  
Cyclosporine
Everolimus Sirolimus Tacrolimus 
EVG/c EVG plus PI/r 
↑ immunosuppressant possible 
Initiate with an adjusted immunosuppressant dose to account for potential increased concentration and monitor for toxicities. Therapeutic drug monitoring of immunosuppressant is recommended. Consult with specialist as necessary. 
Narcotics/Treatment for Opioid Dependence 

Buprenorphine Sublingual/Buccal/Implant 
EVG/c 
Buprenorphine AUC ↑ 35%, C_{max} ↑ 12%, and C_{min} ↑ 66% Norbuprenorphine AUC ↑ 42%, C_{max} ↑ 24%, and C_{min} ↑ 57% 
No dosage adjustment necessary. Clinical monitoring is recommended. When transferring buprenorphine from transmucosal to implantation, monitor to ensure buprenorphine effect is adequate and not excessive. 
EVG plus PI/r 
↔ EVG expected 
Refer to Table 19a for dosing recommendations when used with PI/r. 

RAL 
No significant effect observed (sublingual) or expected (implant)  No dosage adjustment necessary. 

Methadone 
DTG  No significant effect 
No dosage adjustment necessary. 
EVG/c  No significant effect 
No dosage adjustment necessary.  
EVG plus PI/r  ↓ methadone 
Opioid withdrawal unlikely but may occur. Dosage adjustment of methadone is not usually required. Monitor for opioid withdrawal and increase methadone dose as clinically indicated. 

RAL  No significant effect 
No dosage adjustment necessary. 

Neuroleptics 

Perphenazine Risperidone Thioridazine 
EVG/c 
↑ neuroleptic possible 
Initiate neuroleptic at a low dose. Decrease in neuroleptic dose may be necessary. 
PDE5 Inhibitors 

Avanafil 
EVG/c EVG plus PI/r 
No data  Coadministration is not recommended. 
Sildenafil 
EVG/c 
↑ sildenafil expected 
For treatment of erectile dysfunction:

Tadalafil 
EVG/c EVG plus PI/r 
↑ tadalafil expected 
For treatment of erectile dysfunction:
In patients on EVG/c >7 days:

Vardenafil 
EVG/c EVG plus PI/r 
↑ vardenafil expected 
Start with vardenafil 2.5 mg every 72 hours and monitor for adverse effects of vardenafil. 
Sedative/Hypnotics 

Clonazepam Clorazepate Diazepam Estazolam Flurazepam 
EVG/c EVG plus PI/r 
↑ benzodiazepines possible 
Dose reduction of benzodiazepine may be necessary. Initiate with low dose and clinically monitor. Consider alternative benzodiazepines to diazepam, such as lorazepam, oxazepam, or temazepam. 
Midazolam Triazolam 
DTG  With DTG 25 mg: midazolam AUC ↔  No dosage adjustment necessary. 
EVG/c EVG plus PI/r 
↑ midazolam expected ↑ triazolam expected 
Do not coadminister triazolam or oral midazolam and EVG/c or (EVG plus PI). Parenteral midazolam can be used with caution in a closely monitored setting. Consider dose reduction, especially if more than one dose is administered. 

Suvorexant 
EVG/c EVG plus PI/r 
↑ suvorexant expected 
Coadministration is not recommended. 
Zolpidem 
EVG/c EVG plus PI/r 
↑ zolpidem expected 
Initiate zolpidem at a low dose. Dose reduction may be necessary. 
Miscellaneous Drugs 

Colchicine 
EVG/c EVG plus PI/r 
↑ colchicine expected 
Do not coadminister in patients with hepatic or renal impairment. For treatment of gout flares:

Flibanserin 
EVG/c EVG plus PI/r 
↑ flibanserin expected  Contraindicated. Do not coadminister. 
Metformin 
DTG 
DTG 50 mg once daily plus metformin 500 mg BID:
Metformin AUC ↑ 79%, C_{max} ↑ 66% DTG 50 mg BID plus metformin 500 mg BID: Metformin AUC↑ 2.4 fold, C_{max} ↑ 2 fold 
Limit metformin dose to no more than 1,000 mg per day. When starting/stopping DTG in patient on metformin, dose adjustment of metformin may be necessary to maintain optimal glycemic control and/or minimize GI symptoms. 
Polyvalent Cation Supplements Mg, Al, Fe, Ca, Zn, including multivitamins with minerals Note: Please refer to the Acid Reducers section in this table for recommendations on use with Al, Mg, and Cacontaining antacids. 
All INSTIs 
↓ INSTI possible DTG ↔ when administered with Ca or Fe supplement simultaneously with food 
If coadministration is necessary, give INSTI at least 2 hours before or at least 6 hours after supplements containing polyvalent cations, including but not limited to the following products: cationcontaining laxatives; Fe, Ca, or Mg supplements; and sucralfate. Monitor for virologic efficacy. DTG and supplements containing Ca or Fe can be taken simultaneously with food. Many oral multivitamins also contain varying amounts of polyvalent cations; the extent and significance of chelation is unknown. 
Salmeterol  EVG/c EVG plus PI/r 
↑ salmeterol possible 
Do not coadminister due to potential increased risk of salmeterolassociated cardiovascular events. 
Key to Acronyms: Al = aluminum; ART = antiretroviral therapy; ARV = antiretroviral; ATV/r = atazanavir/ritonavir; AUC = area under the curve; BID = twice daily; Ca = calcium; CaCO3 = calcium carbonate; CCB = calcium channel blocker; C_{max} = maximum plasma concentration; C_{min} = minimum plasma concentration; c or COBI = cobicistat; CrCl = creatinine clearance; CYP = cytochrome P; DTG = dolutegravir; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; Fe = iron; GI = gastrointestinal; INR= international normalized ratio; INSTI = integrase strand transfer inhibitor; Mg = magnesium; PAH = pulmonary arterial hypertension; PI = protease inhibitor; PI/r = ritonavirboosted protease inhibitor; PPI = proton pump inhibitor; RAL = raltegravir; SQV/r = saquanavir/ritonavir; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; Zn = zinc 
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