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Ward 86 Management Recommendations

Ward 86 Recommendations for the Management of Antiretroviral Drug Interactions

updated July 2017

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

Interactions between antiretroviral (ARV) medications and other drugs are common and can have clinically significant effects. This topic focuses on interactions involving ARV drugs that are most commonly used as part of initial ARV regimens in countries that do not have restricted formularies (see Table), below.(1) The interactions between ARVs and rifampin, rifabutin, or warfarin are each complex enough that they are discussed separately below. A reliable internet source such as HIV InSite's Database of Antiretroviral Drug Interactions or a software program such as Epocrates, Lexi-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--questions about ARV drug interactions can be submitted online or by telephone (800-933-3413).

Boosting Agents: Ritonavir and Cobicistat

Many HIV protease inhibitors (PIs) and the integrase inhibitor elvitegravir require coadministration of a boosting agent that slows liver metabolism of the drug so that higher plasma concentrations, increased drug exposure, and a longer half-life can be achieved over a 24-hour period, permitting less-frequent dosing and lower risk of drug resistance. The two available boosting agents, ritonavir and cobicistat, specifically inhibit cytochrome p450 isoenzyme 3A4 (CYP 3A4) metabolism and result in higher drug exposures and trough concentrations of medications that are metabolized via this route. These agents also can inhibit, to a lesser degree, certain other enzymes that are important in the metabolism or elimination of specific ARVs, including P-glycoprotein (P-gp) and organic cation and anion transporters.

Both agents are available as single drugs and in coformulations. Ritonavir is available in a coformulation with lopinavir (Kaletra). Cobicistat is coformulated with elvitegravir, tenofovir disoproxil fumarate, and emtricitabine (Stribild), with elvitegravir, tenofovir alafenamide, and emtricitabine (Genvoya), with atazanavir (Evotaz), and with darunavir (Prezcobix).

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 less risk of interaction with ritonavir and cobicistat. All other statins should be started at the lowest dosage and titrated upward based on efficacy and adverse effects. Darunavir has unique interactions with pravastatin and rosuvastatin that require these statins to be started at the lowest dosage possible with close monitoring for adverse effects.

  2. Anticonvulsants and benzodiazepines

    Certain agents in these classes are absolutely contraindicated for use with ritonavir or cobicistat because toxic plasma concentrations of the anticonvulsant or benzodiazepine can occur. Levetiracetam, gabapentin, and topiramate are the only anticonvulsants that can be used with ritonavir or cobicistat without the risk of a problematic drug interaction. 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 lower 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

    Ritonavir- or cobicistat-boosted PIs and elvitegravir reduce ethinyl estradiol plasma concentrations, which can result in failure of oral contraceptives; therefore, an alternative or additional contraceptive method or alternative ARV drug is recommended. When oral contraceptives are given with unboosted atazanavir, the dose of oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Boosted PIs and elvitegravir/cobicistat also can cause an increase in norgestimate plasma concentrations that can result in adverse effects (eg, insulin resistance, acne, dyslipidemia, deep venous thrombosis).(2)

  4. Drugs that can cause QT prolongation

    Ritonavir and cobicistat can increase the likelihood of QT prolongation when coadministered with agents that can 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.

  5. Inhaled or nasal corticosteroids

    Concomitant use of fluticasone 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 ritonavir-boosted darunavir.

  6. Rivaroxaban and dabigatran

    Ritonavir and cobicistat can increase plasma concentrations of these direct oral anticoagulants, leading to an increased risk of bleeding. We suggest rivaroxaban be avoided in patients who require ritonavir or cobicistat. Dabigatran may be coadministered with ritonavir but should be used with caution 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. 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 usually is coadministered with a boosting agent to maximize virologic efficacy. Tenofovir disoproxil fumarate (TDF), but not tenofovir alafenamide (TAF), lowers plasma concentrations of atazanavir, so 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, so the combination of unboosted atazanavir and an anti-acid 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 cobicistat 150 mg daily or ritonavir 100 mg daily) if tenofovir 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. 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. 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.

    • 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.

  2. Elvitegravir

    Elvitegravir must be coadministered with a boosting agent to achieve adequate plasma concentrations. Elvitegravir induces CYP 2C9 metabolism. The net effect of elvitegravir plus a boosting agent with other drugs can be difficult to predict.

    • All drug interactions discussed that involve boosting agents apply to the combination of elvitegravir plus either ritonavir or cobicistat (see section above on Boosting Agents).

    • Efavirenz and anticonvulsants (eg, carbamazepine, phenobarbital, and phenytoin) can induce elvitegravir metabolism and should be avoided.

    • Elvitegravir dosing should be separated from antacid dosing by at least 2 hours.

    • Elvitegravir interacts with Warfarin, see below.

  3. Raltegravir

    Raltegravir has few drug-drug interactions.

    • Raltegravir may be taken simultaneously with calcium carbonate antacids, but should not be given with aluminum- or magnesium-containing hydroxide antacids.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

  1. Tenofovir disoproxil fumarate (TDF)

    • TDF has potential nephrotoxicity that may be potentiated when it is coadministered with other nephrotoxic drugs (eg, amphotericin, aminoglycosides).

    • TDF also can cause renal phosphate wasting, which can result in bone demineralization. This effect could possibly 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). Caution is advised with coadministration, particularly in patients with risk factors for osteoporosis.

    • The TDF analog tenofovir alafenamide fumarate (TAF) appears to have less renal and bone toxicity than TDF, but long-term clinical data are lacking.

    • 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 now coformulated in tablets containing emtricitabine (Descovy); rilpivirine and emtricitabine (Odefsey); and elvitegravir, cobicistat, and emtricitabine (Genvoya). 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 positive test results must be documented as allergies 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, below.

  1. Efavirenz

    • This agent can enhance the hepatic metabolism of certain coadministered drugs (eg, amlodipine, voriconazole, alprazolam, amiodarone, clarithromycin, oral contraceptives, 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, available as a single agent and in coformulation with TDF and emtricitabine (Complera) or with TAF and emtricitabine (Odefsey), is dependent on low gastric pH for absorption and should not be coadministered with any antacid drugs of the proton-pump inhibitor class. Rilpivirine can be coadministered with a once-daily H2 receptor antagonist (eg, famotidine) if the antacid is taken 12 hours before or 4 hours after rilpivirine.

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 the international normalized ratio (INR). Patients who take both warfarin and a boosting agent (ie, ritonavir or cobicistat) should have close INR monitoring until the INR has stabilized.

  2. Elvitegravir

    Elvitegravir induces CYP2C9 and can lower warfarin plasma concentrations. However, cobicistat, which often is given with elvitegravir, inhibits CYP3A and increases warfarin plasma concentrations. These competing effects may be difficult to predict, and patients who combine warfarin with elvitegravir require close INR monitoring until the INR has stabilized.

  3. Efavirenz and other NNRTIs can increase warfarin metabolism, thus patients on this combination should have close INR monitoring 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. 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.
  3. Gordon LA, Kumar P, Brooks KM, et al. Antiretroviral boosting agent cobicistat increases the pharmacokinetic exposure and anticoagulant effect of dabigatran in HIV-negative healthy volunteers. Circulation. 2016 Dec 6;134(23):1909-11.

Table. Recommended Regimens for Initiating Antiretroviral Therapy [adapted from Reference #1].

INSTI-Based Regimens
  • Dolutegravir/abacavir/lamivudine* -- ONLY for patients who are HLA-B*5701 negative
  • Dolutegravir plus either tenofovir disoproxil fumarate/emtricitabine* or tenofovir alafenamide/emtricitabine*
  • Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine*
  • Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine*
  • Raltegravir plus either tenofovir disoproxil fumarate/emtricitabine* or tenofovir alafenamide/emtricitabine*
PI-Based Regimens
  • Darunavir/ritonavir plus either tenofovir disoproxil fumarate/emtricitabine* or tenofovir alafenamide/emtricitabine*

* Lamivudine may be substituted for emtricitabine or vice versa.