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Management Recommendations > Drug Interactions

Ward 86 Management Recommendations

Ward 86 Recommendations for the Management of Antiretroviral Drug Interactions

updated June 2019

Contributors: Janet Grochowski, PharmD
Parya Saberi, PharmD, MAS
Mark Jacobson, MD
Susa Coffey, MD

Interactions between antiretroviral (ARV) medications and other medications are common and can have clinically significant effects. This topic focuses on interactions involving ARV medications that are most commonly used as part of initial ARV regimens in countries that do not have restricted formularies.(1) The interactions between ARVs and rifamycins, and anticoagulants are each complex enough that they are discussed separately below. A reliable internet resource such as HIV InSite's Database of Antiretroviral Drug Interactions or software programs and applications such as University of Liverpool HIV Drug Interactions, HIV/HCV Drug Therapy Guide, Lexicomp Interact, or Micromedex should be used to check all potential interactions with concomitant medications. Potential drug-drug interactions should be discussed with a clinical pharmacist, if one is available. Another resource is the UCSF Clinician Consultation Center where questions about ARV drug interactions can be submitted online or by telephone (800-933-3413).

Boosting Agents: Ritonavir and Cobicistat

The currently recommended HIV protease inhibitors (PIs) and the integrase inhibitor elvitegravir (EVG) require coadministration of a boosting agent that slows the liver metabolism of the PI or EVG so that higher plasma concentrations, increased drug exposure, and a longer half-life can be achieved, permitting less-frequent dosing and lower risk of drug resistance. The two available boosting agents, ritonavir and cobicistat, inhibit cytochrome P450 isoenzyme 3A4 (CYP3A4) metabolism and result in higher drug exposures (noted by higher area under the curve [AUC]) and trough concentrations of medications that are metabolized via this route compared with when the boosting agents are not used. However, the two boosting agents differ in their effects on CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 and thus have different effects on drugs that are primarily metabolized by these isoenzymes--ritonavir tends to induce these enzymes, whereas cobicistat does not. The boosters also impact glucuronidation in different ways and variously affect levels of drugs that are mainly metabolized via this route. Their effects on drug transporters also are not equivalent, which may be the reason for elevations in serum creatinine levels seen in persons who take cobicistat. Due to these differences, it is important to review comedications before switching boosting agents and to modify dosing as necessary.(2)

Both agents are available as single drugs and in coformulations. Ritonavir is available in a co-formulation with lopinavir (Kaletra). Cobicistat is available in five coformulations: with elvitegravir, tenofovir disoproxil fumarate, and emtricitabine (Stribild); with elvitegravir, tenofovir alafenamide, and emtricitabine (Genvoya); with atazanavir (Evotaz); with darunavir (Prezcobix); and with darunavir, tenofovir alafenamide, and emtricitabine (Symtuza).

The pharmacokinetic boosting action of cobicistat and ritonavir can have clinically significant effects on plasma concentrations of commonly used non-ARV medications that are metabolized via these pathways. The following are among the important interactions:

  1. Statins

    Lovastatin and simvastatin are contraindicated for use with boosting agents. Pitavastatin, due to minimal metabolism by the CYP system, has a lower risk of drug-drug interaction with ritonavir and cobicistat compared with other statins. Atorvastatin and rosuvastatin should be started at low doses and titrated up slowly in patients receiving boosting agents, as should pravastatin if this ARV regimen contains darunavir. The maximum recommended daily dosage of atorvastatin with boosters is 20 mg, though higher dosages may be used if necessary to control LDL levels, as long as the patient is regularly monitored for symptoms of muscle damage and laboratory evidence of serum creatine kinase (CK) elevation. Atorvastatin should be avoided with the atazanavir/cobicistat combination. Rosuvastatin dosage should not exceed 20 mg per day when combined with darunavir boosted with cobicistat or 10 mg per day when combined with lopinavir/ritonavir.

  2. Anticonvulsants and benzodiazepines

    Certain anticonvulsants and benzodiazepines are contraindicated for use with ritonavir or cobicistat due to toxic plasma concentrations. Levetiracetam, gabapentin, and topiramate are anticonvulsants that can be used with ritonavir or cobicistat without the risk of problematic drug interactions. Whereas cobicistat does not appear to have problematic interactions with lamotrigine and valproic acid, ritonavir has the potential to induce hepatic UDP-glucuronosyltransferase metabolism of these two drugs and reduce their plasma concentrations. Hence, monitoring for efficacy and increasing the anticonvulsant dosage may be necessary if lamotrigine or valproic acid is coadministered with ritonavir.

  3. Oral contraceptives

    Boosted darunavir, lopinavir, and elvitegravir reduce plasma concentrations of ethinyl estradiol, which can result in failure of oral contraceptives; therefore, an alternative or additional contraceptive method (or an alternative ARV drug) is recommended. Combination oral contraceptives can be administered with atazanavir. If given with unboosted atazanavir (400 mg daily), the dose of oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. If given with ritonavir-boosted atazanavir, the contraceptive needs to contain at least 30 mcg of ethinyl estradiol, because ritonavir induces glucuronidation of estradiol. There are no data on the effects of cobicistat-boosted atazanavir on ethinyl estradiol. When used in combination with progestogen-containing oral contraceptives, boosted PIs and elvitegravir/cobicistat can cause an increase in norgestimate plasma concentrations that can result in adverse effects (eg, insulin resistance, acne, dyslipidemia, deep venous thrombosis).(3)

  4. Drugs that can cause QT prolongation

    Ritonavir and cobicistat can increase the likelihood of QT prolongation when coadministered with agents that cause QT prolongation (particularly quinidine, haloperidol, amiodarone, mefloquine) or agents that can cause hypokalemia or hypomagnesemia. Monitoring of potassium, magnesium, and EKG results is recommended. Also, for patients receiving dofetilide for arrhythmia control, either bictegravir or dolutegravir can increase the levels of this drug leading to QT prolongation and should be avoided.

  5. Inhaled or nasal corticosteroids

    Concomitant use of budesonide, ciclesonide, fluticasone, and triamcinolone with either boosting agent can lead to elevated plasma corticosteroid concentrations and signs or symptoms of Cushing syndrome. Beclomethasone is the only inhaled or nasal corticosteroid for which there are data demonstrating that it is safe when used with boosting agents. Flunisolide has low risk of drug-drug interactions with ritonavir and cobicistat and is another potential option.(4)

  6. Direct Oral Anticoagulants

    Ritonavir and cobicistat can increase plasma concentrations of direct oral anticoagulants (DOACs), leading to an increased risk of bleeding. Data on these interactions are limited, and we currently avoid apixaban, betrixaban, edoxaban, and rivaroxaban in patients who require ritonavir or cobicistat. Dabigatran may be coadministered with ritonavir but should be avoided with cobicistat, and patients should be monitored for possible increase risk of bleeding.(3) Concurrent administration of dabigatran and either boosting agent is contraindicated in patients whose estimated creatinine clearance is <50 mL/min.

  7. Rifamycins

    Boosting agents interact with rifampin and rifabutin (see section on Treatment of Tuberculosis and Latent Tuberculous Infection) as well as Warfarin, below.

Protease Inhibitors (PIs)

  1. Darunavir

    As noted above, darunavir must be coadministered with ritonavir or cobicistat to be virologically effective, and it has a unique interaction with pravastatin, which requires that the lowest dosage of this statin be given initially.

  2. Atazanavir

    Atazanavir is primarily coadministered with a boosting agent to maximize virologic efficacy. Tenofovir disoproxil fumarate (TDF), but not tenofovir alafenamide (TAF), lowers plasma concentrations of atazanavir; therefore, atazanavir must be given with ritonavir or cobicistat if TDF is part of the ARV regimen. In addition, atazanavir absorption is decreased by high gastric pH; therefore, the combination of unboosted atazanavir and an antacid medication should be avoided. If an alternative ARV is not an option, boosted atazanavir can be administered simultaneously with or 10 hours after an H2 receptor antagonist (not to exceed a dosage equivalent to famotidine 40 mg twice daily in ARV-naive patients or 20 mg twice daily in ARV-experienced patients), or 12 hours apart from a proton-pump inhibitor at a daily dosage comparable to 20 mg of omeprazole. In ARV-experienced patients, atazanavir dosage must be increased to 400 mg daily plus ritonavir 100 mg daily if TDF and an H2 receptor antagonist are given concurrently.

Integrase Inhibitors (INSTIs)

All INSTIs interact with rifampin; elvitegravir also interacts with rifabutin. See section on Treatment of Tuberculosis and Latent Tuberculous Infection.

  1. Bictegravir

    • Aluminum- or magnesium-containing antacids: Bictegravir may be taken in a fasted state 2 hours before an antacid containing aluminum or magnesium.

    • Calcium or iron supplements: Bictegravir can be taken simultaneously with calcium or iron supplements if they are taken together with food. Bictegravir has not been studied with other polyvalent cation supplements.

    • Anticonvulsants: Levetiracetam can be taken with bictegravir. Oxcarbazepine, phenytoin, phenobarbital, and carbamazepine induce bictegravir metabolism and should be avoided.

    • Atazanavir: Atazanavir can increase bictegravir levels and should be avoided in combination.

    • Dofetilide: Bictegravir can increase dofetilide levels and increase the risk of serious and/or life-threatening events. The combination should be avoided.

  2. Dolutegravir

    • Aluminum- or magnesium-containing antacids: Dolutegravir must be taken at least 2 hours before or at least 6 hours after antacids containing aluminum or magnesium.

    • Calcium or iron supplements: Dolutegravir can be taken simultaneously with a calcium or iron supplement if they are taken together with food. If it is taken without food, dolutegravir must be given at least 2 hours before or 6 hours after calcium or iron. Dolutegravir has not been studied with other polyvalent cation supplements.

    • Efavirenz: Efavirenz induces dolutegravir metabolism, and dolutegravir dosing should be increased to 50 mg twice daily to achieve optimal plasma concentrations.

    • Anticonvulsants: Levetiracetam can be given with dolutegravir. Oxcarbazepine, phenytoin, phenobarbital, and carbamazepine induce dolutegravir metabolism and should be avoided.

    • Etravirine: Etravirine can be coadministered with dolutegravir only if the patient is also receiving ritonavir-boosted atazanavir, darunavir, or lopinavir.

    • Metformin: Metformin plasma concentrations can be increased by dolutegravir. In patients on dolutegravir, a low dose of metformin should be initiated and doses >1,000 mg daily should be used with caution.

    • Dofetilide: Dolutegravir can increase dofetilide levels and increase the risk of serious and/or life-threatening events. The combination should be avoided.

  3. Elvitegravir

    Elvitegravir is only available as a combination product with the boosting agent, cobicistat. Elvitegravir induces CYP 2C9 metabolism. The net effect of elvitegravir plus cobicistat with other drugs can be difficult to predict.

    • Aluminum- or magnesium-containing antacids: Elvitegravir dosing should be separated from antacid dosing by at least 2 hours.
    • Cation-containing supplements: These may decrease elvitegravir serum levels. If coadministration is needed, elvitegravir should be taken at least 2 hours before or at least 6 hours after supplements containing polyvalent cations.
    • Elvitegravir interacts with Warfarin, see below.
    • All drug interactions discussed that involve cobicistat apply to the combination of elvitegravir plus cobicistat (see section above on Boosting Agents).

    • Anticonvulsants: Levetiracetam can be given with elvitegravir. Oxcarbazepine, phenytoin, phenobarbital, and carbamazepine induce elvitegravir metabolism and should be avoided.
    • Efavirenz can induce elvitegravir metabolism, and the combination should be avoided.

  4. Raltegravir

    Raltegravir has few drug-drug interactions.

    • Aluminum- or magnesium-containing antacids: Do not coadminister.

    • Calcium-containing antacids: Do not coadminister with raltegravir 1,200 mg once daily (ie, raltegravir HD). No dose adjustment or separation is needed if raltegravir is dosed 400 mg twice daily.

    • Cation-containing supplements: These may decrease raltegravir serum levels. If coadministration is needed, raltegravir should be taken at least 2 hours before or at least 6 hours after supplements containing polyvalent cations.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

  1. Tenofovir disoproxil fumarate (TDF)

    • o TDF has potential nephrotoxicity, which may be potentiated when coadministered with other nephrotoxic drugs (e.g., amphotericin, aminoglycosides).

    • TDF also can cause renal phosphate wasting, which can result in bone demineralization. This effect may be potentiated if TDF is coadministered with other drugs that may contribute to osteoporosis (eg, lithium, medroxyprogesterone acetate, methotrexate, proton pump inhibitors, selective serotonin reuptake inhibitors, corticosteroids, and tamoxifen). We recommend caution if TDF is given concurrently with these drugs, particularly in patients with risk factors for osteoporosis.

    • The TDF analogue tenofovir alafenamide fumarate (TAF) appears to have less renal and bone toxicity than TDF.

    • TDF decreases atazanavir plasma concentrations; atazanavir must be given with a boosting agent if TDF is given concurrently.

  2. Tenofovir alafenamide (TAF)

    TAF is a prodrug of tenofovir with less nephrotoxicity and bone toxicity than TDF. TAF is coformulated in tablets containing emtricitabine (Descovy); rilpivirine and emtricitabine (Odefsey); elvitegravir, cobicistat, and emtricitabine (Genvoya); darunavir, cobicistat, and emtricitabine (Symtuza); and bictegravir and emtricitabine (Biktarvy). TAF has unique interactions with rifamycins that do not occur with TDF; thus, TAF combined with rifamycins is contraindicated (see section on Treatment of Tuberculosis and Latent Tuberculous Infection).

  3. Abacavir, lamivudine, and emtricitabine are not associated with any clinically significant drug interactions. However, abacavir should not be administered until blood testing has verified that the patient is HLA-B*5701 negative. Those who are HLA-B*5701 positive have a significant risk of life-threatening hypersensitivity reactions to abacavir, and abacavir should be documented as an allergy in the patients' medical records.

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

All NNRTIs interact with rifampin and rifabutin (see section on Treatment of Tuberculosis and Latent Tuberculous Infection) as well as Warfarin, see below.

  1. Efavirenz

    • This agent can enhance the hepatic metabolism of certain coadministered drugs (eg, amlodipine, voriconazole, alprazolam, amiodarone, clarithromycin, oral contraceptives, and itraconazole). The interaction with voriconazole is particularly complex. Coadministration lowers plasma concentrations of voriconazole and increases efavirenz plasma concentrations. To compensate for this interaction, it is possible to decrease the dosage of efavirenz to 300 mg Q24H and increase voriconazole to 400 mg Q12H.

  2. Rilpivirine

    • This drug is available as a single agent and in coformulation with TDF and emtricitabine (Complera), with TAF and emtricitabine (Odefsey), and with dolutegravir (Juluca). It is dependent on low gastric pH for absorption and should not be coadministered with proton-pump inhibitors. Rilpivirine can be coadministered with a once-daily H2 receptor antagonist (H2RA) (eg, famotidine) if the H2RA is taken 12 hours before or 4 hours after rilpivirine. Antacids should be taken at least 2 hours before or at least 4 hours after rilpivirine.

  3. Doravirine

    • Doravirine is a CYP3A4 substrate; therefore, its metabolism can be affected by CYP3A4 inducers or inhibitors.

    • Anticonvulsants: Levetiracetam can be given with doravirine. Oxcarbazepine, phenytoin, phenobarbital, and carbamazepine induce doravirine metabolism and should be avoided; also, doravirine cannot be started until 4 weeks after discontinuation of these anticonvulsants.

    • Miscellaneous CYP3A4 inducers (enzalutamide, mitotane, St. John's wort): Coadministration should be avoided; wait 4 weeks after discontinuation of these before starting doravirine.

    • Strong CYP3A4 inhibitors: These will increase doravirine levels. However, there have been no reports of increased rates of adverse events, and coadministration is considered safe.

Rifamycins: Rifampin, Rifabutin, and Rifapentine

See section on Treatment of Tuberculosis and Latent Tuberculous Infection.

Warfarin

  1. Ritonavir and cobicistat

    These boosting agents can interfere with hepatic metabolism of warfarin and increase prothrombin time and the international normalized ratio (INR). Patients who take both warfarin and a boosting agent (ie, ritonavir or cobicistat) should have close monitoring of the INR until the INR has stabilized.

  2. Elvitegravir

    Elvitegravir induces CYP2C9 and cobicistat inhibits CYP3A. These competing effects make it difficult to predict warfarin levels, and close monitoring of the INR is required when starting this combination.

  3. Efavirenz and other NNRTIs can increase warfarin metabolism; thus, patients on this combination should have close monitoring of the INR until the INR is stable.

Direct-Acting Antiviral Agents for Hepatitis C Virus Infection

Direct-acting antiviral agents (DAAs) that target specific steps in the HCV replicative cycle are standard of care for treatment of chronic, active HCV infection in HIV-infected patients in the United States. Many DAAs interact with ARVs in a manner that limits coadministration. Because the field of DAA treatment continues to evolve rapidly, we refer readers to the regularly updated consensus guidelines of the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) for specific recommendations regarding which DAAs can be safely coadministered with which ARVs.

References

  1. U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents -- A Working Group of the Office of AIDS Research Advisory Council (OARAC). What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient.
  2. 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 Jul;71:1755-58.
  3. Tittle V, Bull L, Boffito M, et al. Pharmacokinetic and pharmacodynamics drug interactions between antiretrovirals and oral contraceptives. Clin Pharmacokinet. 2015 Jan;54(1):23-34.
  4. Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management. HIV Med. 2013 Oct;14(9):519-29.
  5. Kumar P, Gordon LA, Brooks KM, et al. Differential influence of the antiretroviral pharmacokinetic enhancers ritonavir and cobicistat on intestinal P-glycoprotein transport and the pharmacokinetic/pharmacodynamic disposition of dabigatran. Antimicrob Agents Chemother. 2017 Oct 24;61(11).