Purpose of This Resource
Lead author: Joshua R. Sawyer, PharmD, AAHIVP,* with the Medical Care Criteria Committee, updated February 2021
The New York State Department of Health (NYSDOH) AIDS Institute (AI) developed this reference for clinicians who manage the care of patients with HIV to accomplish the following:
- Provide a central source of information on drug-drug interactions involving antiretroviral (ARV) medications.
- Assist healthcare providers in preventing or managing drug-drug interactions that could have a negative or dangerous effect on patient health.
- Balance the risks and benefits of noted drug-drug interactions to identify those that should or must be avoided and those that can be managed to alleviate adverse outcomes.
The NYSDOH AI Medical Care Criteria Committee offers guidance on the interactions between ARV agents and medications commonly used in the management of coexisting conditions seen in healthcare settings, based on a comprehensive review of available clinical trial data.
This guideline supports the NYSDOH Ending the Epidemic Initiative by providing a tool for clinicians to use in safely prescribing antiretroviral therapy (ART). ART initiation is now recommended for all patients diagnosed with HIV to improve the health of the patient, optimize virologic suppression, and reduce transmission of HIV (see NYSDOH AI guideline When to Initiate ART, With Protocol for Rapid Initiation). This reference supports proper management of ART.
Scope: This resource does not provide an exhaustive survey of all possible interactions between ARVs and other medications. The focus is on those interactions most commonly encountered. Several robust free online resources are available to check specific drug-drug interactions, including the following:
- University of Liverpool HIV Drug Interaction Checker
- UCSF HIV InSite Database of Antiretroviral Drug Interactions
- WebMD Drug Interaction Checker
- AIDSinfo Drug-Drug Interactions
- Toronto General Hospital Immunodeficiency Clinic
Consultation with an experienced HIV care provider is also recommended when assistance is needed in choosing an ART regimen for a patient who has multiple comorbidities and may have multiple drug-drug interactions. For help locating an experienced HIV care provider, contact the Clinical Education Initiative at 866-637-2342.
*Clinical Assistant Professor, Department of Pharmacy Practice, University at Buffalo, School of Pharmacy and Pharmaceutical Sciences
Identifying Drug-Drug Interactions
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Individuals with HIV have a greatly increased risk of exposure to polypharmacy, especially as the population ages [Edelman, et al. 2013; Gleason, et al. 2013]. The use of several concomitant medications can have unintended consequences, including increased risk of drug-drug interactions and associated adverse events such as fatigue, nausea, and weight gain or loss. Drug-drug interactions may also decrease virologic control of HIV, increasing the risk of drug resistance and HIV-associated symptoms. Multiple factors may be associated with polypharmacy in patients. Physicians should be mindful of potential drug-drug interactions as a possible mechanism for new symptoms or unexpected medical events [Davies and O’Mahony 2015].
Drug-drug interactions can occur regardless of age or disease state. Any of the following potential risk factors for polypharmacy may signal the need to update a patient’s medication list and evaluate the potential for drug-drug interactions:
- Longstanding illness, chronic conditions, or disability [Walckiers, et al. 2015; Zingmond, et al. 2017].
- Age older than 50 years: Comorbidities commonly seen in an aging population, such as hypertension, chronic obstructive pulmonary disease, and diabetes mellitus, are increasingly prevalent in patients with HIV [Gleason, et al. 2013]. As people age, more diseases develop, which increases the risk of polypharmacy. Further, age-related physiologic changes may alter drug response in older patients [Gujjarlamudi 2016].
- Treatment provided by more than 1 care provider (including specialty providers) and limited communication between providers.
- Filling prescriptions at multiple pharmacies.
- Recent hospitalization: Hospitalization may be the result of adverse reactions caused by drug-drug interactions, or interactions may result during transitions of care or because of medication changes for formulary decisions [Mixon, et al. 2015; Walckiers, et al. 2015].
KEY POINT |
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Beneficial Concomitant Drug Use
Drug-drug interactions are most commonly thought of as having a negative effect on a patient’s quality of life, but beneficial drug-drug interactions may also occur. Beneficial concomitant drug use can work in multiple ways [Trevor, et al. 2015].
Pharmacodynamic synergy: The most common positive outcome of drug-drug interactions is pharmacodynamic synergy, which is the combination of 2 or more drugs in which the shared effect is greater than the effect of either agent used alone.
Examples of this type of interaction include the combined use of antiretroviral (ARV) agents from multiple classes to manage a patient’s HIV infection. Combining agents with multiple mechanisms of action suppresses replication of the virus to a greater extent and for a longer period than use of a single agent and reduces the risk of resistance to any single ARV. The use of multiple pharmaceutical agents to treat 1 medical condition is also beneficial for a number of the comorbidities that people with HIV may develop, including hypertension, diabetes, chronic obstructive pulmonary disease, or some psychological disorders.
Pharmacokinetic boosting: Another positive drug-drug interaction results from use of a potent CYP3A4 enzyme inhibitor to allow higher bioavailability of a second agent. This effect is commonly achieved in HIV therapy through pharmacokinetic boosting with ritonavir and cobicistat. Boosting makes possible once-daily dosing or lower dosing of ARVs, which may decrease adverse events caused by higher or more frequent dosing of the active agent. In turn, adherence may be improved by reduced pill burden. Similarly, use of a potent inhibitor of a drug transporter allows for reduced dosing or frequency of the second active agent. An example is the use of probenecid, an organic anion transporter inhibitor, to decrease the elimination of penicillins, such as penicillin, ampicillin, or nafcillin. This increases the clinical activity and efficacy of these agents. Despite their ability to boost other medications, ritonavir is likely to cause more drug to drug interactions, since it exerts a more broad effect on CYP450 enzymes in addition to CYP3A4.
In the current era of HIV treatment, it is well established that, when used as prescribed, 3-drug antiretroviral therapy (ART) regimens effectively suppress viral load over the long term. Ongoing research attempts to simplify ART regimens in an effort to reduce the number of ARVs that a patient must take long-term, thus reducing any long-term adverse effects or drug-drug interactions [Boswell, et al. 2018; Orkin, et al. 2018; Wandeler, et al. 2018]. However, simplifying a patient’s ART regimen can have unintended or unrecognized consequences. For instance, a switch from a boosted ART regimen that includes ritonavir or cobicistat to an unboosted regimen removes a cytochrome P450 (CYP) isoenzyme inhibitor, which may reduce concentrations of drugs that had previously been boosted, and reduce the therapeutic effects of any such concomitantly administered agents. Similarly, when switching from an unboosted regimen to a boosted regimen, a CYP inhibitor is added, which may increase the therapeutic effects or toxicities of other medications.
As a result, when new adverse events occur, a patient or clinician may attribute them to the new ART regimen, even if they are simply the result of a loss or addition of CYP inhibition. It is important to consider the effect of such simplification strategies on concentrations of all of a patient’s concomitantly administered medications. Doing so may prevent the addition of more medications to manage adverse events that could otherwise have been expected or avoided. For example, if ritonavir-boosted darunavir (which inhibits various CYP enzymes) is replaced with dolutegravir (which is not known to be an inhibitor of CYP enzymes), then a low dose of a psychotropic medication known to be a substrate of any of these enzymes may have to be increased to maintain therapeutic effect.
KEY POINT |
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Risks of Concomitant Drug Use
Combining drugs that have multiple mechanisms of action to achieve a similar therapeutic endpoint introduces the risk of additive adverse events. Although this is not seen when combining ARVs to suppress HIV viral load, it can be seen when combining antihypertensive agents (which may cause hypotension) or antidiabetic drugs (which may lead to additive hypoglycemia). In addition, an additive effect may result from medications with overlapping adverse event profiles. A historic example is the use of zidovudine with other drugs that cause bone marrow suppression, including ribavirin or ganciclovir [Aulitzky, et al. 1988; Sim, et al. 1998].
Potent inhibitors: The use of potent inhibitors of metabolizing enzymes or drug transport proteins, such as protease inhibitors, may also lead to negative clinical outcomes (e.g., toxicities). Pharmacokinetic boosting, which is described as a potential beneficial drug-drug interaction in the section Beneficial Concomitant Drug Use, above, can have adverse outcomes if boosting leads to an undesired increase in the level of a concomitantly administered drug. When patients experience adverse events, they are more likely to discontinue medications. Adverse events also increase the number of patient visits to healthcare providers and may lead to prescription of additional medications to treat the adverse symptoms caused by the original medication, thus perpetuating the cycle of polypharmacy.
Potent inducers: The use of potent inducers of metabolizing enzymes or drug transport proteins, such as efavirenz or nevirapine, also has the potential to result in negative clinical outcomes. By increasing the metabolism or elimination of pharmacotherapeutic agents, reduced concentrations of these drugs are available to exert the expected therapeutic effect. Reducing ARVs to subtherapeutic levels can compromise viral suppression and increase the potential for resistance mutations. When simplifying ART by removing strong inducers of CYP isoenzymes, clinicians should remember that the loss of CYP induction may also affect all concomitant medications that a patient is taking, not just the ARVs.
For example, if efavirenz (which induces various CYP enzymes) is replaced with dolutegravir (which is not known to be an inhibitor of CYP enzymes) in a patient who was previously taking high doses of methadone (which is a substrate of several CYP enzymes), then the dose of methadone may have to be decreased to maintain the same therapeutic effect that was seen while the patient was taking efavirenz, but without precipitating overdose.
Clinical Considerations and Prevention of Medication-Related Adverse Events
Box 1: Medication Review and Prescribing Checklist |
At each clinical visit, ask patients about the following: |
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When prescribing new medications or renewing a prescription, always: |
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In reviewing medications, note all current prescription and over-the-counter medications (i.e., oral, inhalers, eye drops, ear drops, throat lozenges, suppositories, and topical medications), injectable drugs (including biologic agents and vaccines), complementary products (i.e., vitamins, supplements, and herbal products), and social and recreational drug use.
Clinicians can take several additional steps to prevent or alleviate unnecessary adverse events, such as encouraging patients to avoid seeing multiple prescribers, to avoid filling their prescriptions at multiple pharmacies, and to keep each of their healthcare providers informed of treatment decisions made by other specialists [Lehnbom, et al. 2014; Lavan, et al. 2016]. Prescribers are encouraged to work closely with clinical pharmacists and, in settings where this is possible, to consider collaborative drug therapy management agreements with these pharmacists [McBane, et al. 2015].
Healthcare providers can assist patients in structuring detailed medication lists to be readily available in case of emergencies. This list should include the patient’s:
- Medication allergies and intolerances.
- Prescription drugs.
- Pharmacy and contact information.
- Over-the-counter drugs and vitamins.
- Herbal or supplemental products.
With the help of their care providers, patients can update their medication lists at each medical appointment to ensure its accuracy [Rose, et al. 2017]. For each medication listed, the following information should be included [McBane, et al. 2015]:
- Name of medication.
- Appropriate dosing.
- Indication for each medication, including those taken “as needed.”
- How and when each medication should be taken.
- How long each medication will be taken.
- What foods, beverages, or medications to avoid while taking each medication.
- Adverse events a medication may cause.
- Special monitoring a medication may require.
Electronic health records have streamlined the process of prescribing and dispensing medications and may even flag the potential for new therapeutic duplication, adverse drug reactions, or drug-drug interactions. Unfortunately, clinical decision support (CDS) systems, which aim to alert clinicians to therapeutic duplications, inappropriate dosages, or drug-drug interactions, are not without their drawbacks. Busy clinicians who receive more notifications than they can attend to may ignore important alerts [Wright, et al. 2018]. Such “alert fatigue” can potentially compromise patient safety. Efforts to further refine and/or customize the information detailed in these CDS alerts are ongoing. However, clinicians should be aware of the risks associated with alert fatigue when utilizing electronic health records or prescribing systems.
Electronic health records are not a replacement for direct review of a patient’s current medications or other drugs being taken. Care providers using electronic health records are at risk of missing important drug information if they fall victim to alert fatigue [Zahabi, et al. 2015].
The New York Medicaid Electronic Health Records Incentive Program is currently available to support care providers in improving interoperability and patient access to health information.
KEY POINT |
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Medication therapy management (MTM) model: The MTM model was created in collaboration with 11 national pharmacy organizations and offers a useful approach to assessing and managing patient health concerns when disciplines work separately to care for a single patient. Centers for Medicaid and Medicare Services (CMS) must participate in MTM programs, and the goals of these programs are to optimize therapeutic outcomes through improved medication use, to reduce the risk of adverse drug events and drug-drug interactions, and to improve medication adherence. The CMS website provides more information on requirements and services. Core elements of the MTM model include [APhA 2018]:
- Medication therapy review, which is a systematic process of collecting patient-specific information to assess medication therapies in order to identify a prioritized list of medication-related problems and create a plan to resolve them.
- Creation of a personal medication record (PMR) and medication-related action plan to address possible interventions and make appropriate referrals, including documenting these procedures.
- The PMR is a comprehensive record of all of a patient’s medications, including herbal products, over-the-counter products, and dietary supplements, and is intended for patients to use in medication self-management.
- Updated PMRs should be created with any medication change.
- The medication-related action plan is a patient-centric document containing a list of actions that the patient can take to improve his or her self-management and includes only information that is within the pharmacist’s scope of practice or has been agreed on by other relevant members of the healthcare team.
- Pharmacotherapy consults, which incorporate a pharmacist’s expertise for safe, appropriate, and cost-effective use of medications, for patients who have already developed medication-related problems or who are at high risk of developing them.
These strategies have several important benefits, including preventing or managing adverse medication reactions and hypersensitivities. They ensure an adequate diagnosis and indication for each therapy and help determine whether symptoms are caused by a medical condition or are simply effects of a medication the patient is already taking. It also aids in transitions of care, including transitions from primary to specialty care or from ambulatory care to inpatient facilities. Such documents also aid in future treatment decisions and allow for appropriate patient education about drug effects and adherence. They may also reduce polypharmacy and healthcare costs by assuring a patient is not given medication simply to treat adverse drug reactions or manage drug-drug interactions.
Pharmacist care services and comprehensive medication management are also considered integral components of the patient-centered medical home [PCPCC 2012].
KEY POINT |
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Therapeutic drug monitoring (TDM): TDM of drug concentrations from plasma, serum, or blood is used to individualize dosing of narrow therapeutic index drugs, allowing drug concentrations to be maintained within a specific target range. Although measurement of drug concentration at the site of action is not always possible, it is believed that with TDM, the concentration of a drug in intracellular fluids is more closely associated with therapeutic and adverse effects than the dose of a medication. TDM is most commonly performed for medications that have a narrow therapeutic window and significant pharmacokinetic variability. Medications that are dosed based on TDM include immunosuppressant drugs used to prevent organ rejection (e.g., cyclosporine and tacrolimus), anti-seizure medications (e.g., phenytoin and carbamazepine), and mood stabilizers (e.g., lithium and lamotrigine). Certain antibiotics, including vancomycin or aminoglycosides, are also dosed based on TDM.
The use of TDM with dosing of ARVs is not currently recommended in the routine management of most patients with HIV. However, limited prospective data suggest that certain clinical scenarios exist in which TDM may be beneficial, such as suspicion of clinically significant drug-drug interactions that result in reduced plasma concentrations of an ARV, which may reduce viral control, or when such interactions result in increased concentrations of an ARV, thereby increasing the risk of adverse drug effects [AIDSinfo 2015]. The effects may be more pronounced when drug-drug interactions are accompanied by pathophysiologic changes that alter the pharmacokinetics of a drug, including its absorption, distribution, metabolism, or excretion. These changes include, but are not limited to, reduced renal or hepatic function, vomiting or other conditions that reduce absorption, and pregnancy.
Resources
Online and print materials are available to help healthcare professionals and patients with the management of interactions between ARVs and other commonly used medications. Use caution when consulting print resources and/or online resources that are not routinely updated because drug-drug interaction data change consistently with new research, case reports, or approval of new medications by the U.S. Food and Drug Administration.
RESOURCES FOR CARE PROVIDERS |
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RESOURCES FOR PATIENTS |
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References
AIDSinfo. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV: Management of the Treatment-Experienced Patient: Exposure Response Relationship and Therapeutic Drug Monitoring (TDM) for Antiretroviral Agents. 2015 Apr 8. https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/17/therapeutic-drug-monitoring [accessed 2018 Jul 6]
APhA. American Pharmacists Association. Medication Therapy Management Services. 2018 http://www.pharmacist.com/medication-therapy-management-services [accessed 2018 Jul 6]
Aulitzky WE, Tilg H, Niederwieser D, et al. Ganciclovir and hyperimmunoglobulin for treating cytomegalovirus infection in bone marrow transplant recipients. J Infect Dis 1988;158(2):488-489. [PMID: 2841384]
Boswell R, Foisy MM, Hughes CA. Dolutegravir dual therapy as maintenance treatment in HIV-infected patients: A review. Ann Pharmacother 2018;52(7):681-689. [PMID: 29442543]
Davies EA, O’Mahony MS. Adverse drug reactions in special populations – the elderly. Br J Clin Pharmacol 2015;80(4):796-807. [PMID: 25619317]
Edelman EJ, Gordon KS, Glover J, et al. The next therapeutic challenge in HIV: polypharmacy. Drugs Aging 2013;30(8):613-628. [PMID: 23740523]
Gleason LJ, Luque AE, Shah K. Polypharmacy in the HIV-infected older adult population. Clin Interv Aging 2013;8:749-763. [PMID: 23818773]
Gujjarlamudi HB. Polytherapy and drug interactions in elderly. J Midlife Health 2016;7(3):105-107. [PMID: 27721636]
Lavan AH, Gallagher PF, O’Mahony D. Methods to reduce prescribing errors in elderly patients with multimorbidity. Clin Interv Aging 2016;11:857-866. [PMID: 27382268]
Lehnbom EC, Stewart MJ, Manias E, et al. Impact of medication reconciliation and review on clinical outcomes. Ann Pharmacother 2014;48(10):1298-1312. [PMID: 25048794]
McBane SE, Dopp AL, Abe A, et al. Collaborative drug therapy management and comprehensive medication management-2015. Pharmacotherapy 2015;35(4):e39-50. [PMID: 25884536]
Mixon AS, Neal E, Bell S, et al. Care transitions: a leverage point for safe and effective medication use in older adults–a mini-review. Gerontology 2015;61(1):32-40. [PMID: 25277280]
Orkin C, Llibre JM, Gallien S, et al. Nucleoside reverse transcriptase inhibitor-reducing strategies in HIV treatment: assessing the evidence. HIV Med 2018;19(1):18-32. [PMID: 28737291]
PCPCC. The Patient-Centered Medical Home: Integrating Comprehensive Medication Management to Optimize Patient Outcomes: Resource Guide. 2012 Jun. https://www.pcpcc.org/sites/default/files/media/medmanagement.pdf [accessed 2018 Oct 16]
Rose AJ, Fischer SH, Paasche-Orlow MK. Beyond medication reconciliation: The correct medication list. JAMA 2017;317(20):2057-2058. [PMID: 28426844]
Sim SM, Hoggard PG, Sales SD, et al. Effect of ribavirin on zidovudine efficacy and toxicity in vitro: a concentration-dependent interaction. AIDS Res Hum Retroviruses 1998;14(18):1661-1667. [PMID: 9870320]
Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor’s Pharmacology. Chapter 61: Drug Interactions. 2015 https://accesspharmacy.mhmedical.com/content.aspx?bookid=1568§ionid=95705561 [accessed 2018 Oct 16]
Walckiers D, Van der Heyden J, Tafforeau J. Factors associated with excessive polypharmacy in older people. Arch Public Health 2015;73:50. [PMID: 26557365]
Wandeler G, Buzzi M, Anderegg N, et al. Virologic failure and HIV drug resistance on simplified, dolutegravir-based maintenance therapy: Systematic review and meta-analysis. F1000Res 2018;7:1359. [PMID: 30271590]
Wright A, Aaron S, Seger DL, et al. Reduced effectiveness of interruptive drug-drug interaction alerts after conversion to a commercial electronic health record. J Gen Intern Med 2018;33(11):1868-1876. [PMID: 29766382]
Zahabi M, Kaber DB, Swangnetr M. Usability and safety in electronic medical records interface design: A review of recent literature and guideline formulation. Hum Factors 2015;57(5):805-834. [PMID: 25850118]
Zingmond DS, Arfer KB, Gildner JL, et al. The cost of comorbidities in treatment for HIV/AIDS in California. PLoS One 2017;12(12):e0189392. [PMID: 29240798]
Classifications and Mechanisms of Drug-Drug Interactions
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Antiretroviral (ARV) medications themselves, though increasingly safe and effective, may cause adverse events that affect organ systems [Dharan and Cooper 2017; Gallant, et al. 2018]. Tenofovir disoproxil fumarate (TDF) has been shown to reduce bone mineral density and may impair renal function. Tenofovir alafenamide (TAF) does not appear to have a similar effect on bone density or kidney function, and increased bone density and improved renal function have been observed in patients who are switched from TDF to TAF [Chan, et al. 2017; Raffi, et al. 2017]. Controversial and conflicting data suggest a possible association between abacavir and cardiovascular disease [Llibre and Hill 2016]. A convincing pathophysiologic mechanism for this association has not yet been described and is likely to be multifactorial [Alvarez, et al. 2017]. Association should not imply causation, but caution may be warranted when prescribing abacavir to patients with underlying risk factors for cardiovascular disease. Boosted protease inhibitors (PIs) and some non-nucleoside reverse transcriptase inhibitors may exacerbate metabolic disorders by reducing insulin sensitivity or causing lipid abnormalities [Carr, et al. 1998; Noor, et al. 2004; Aberg, et al. 2012]. These inherent adverse events may lead to poor control and the need for additional concurrent medications for management of these metabolic conditions. An unintended consequence of the additional medications is the increased likelihood of drug-drug interactions.
Table 1: Mechanisms of Antiretroviral (ARV) Drug-Drug Interactions, below, shows the influence of specific ARVs on liver enzymes and describes the effect of specific ARVs on these drug transport proteins.
Table 1: Mechanisms of Antiretroviral (ARV) Drug-Drug Interactions [1]* | ||||||
ARV | CYP Substrate | CYP Inhibitor | CYP Inducer | UGT1A1 | Drug Transport Protein |
Other |
Integrase Strand Inhibitors (INSTIs) | ||||||
BIC [2] | 3A4 (minor) | — | — | Substrate | Inhibitor of: MATE1; OCT2 | Chelation |
DTG [3] | 3A4 (minor) | — | — | Substrate | P-gP substrate; inhibitor of MATE2, OCT2 | Chelation |
EVG [4] | 3A4 | — | 2C9 | Substrate | — | Chelation |
RAL [5] | — | — | — | Substrate | — | Chelation |
Pharmacokinetic Boosters | ||||||
COBI [6] | 3A4; 2D6 (minor) |
3A4; 2D6 (minor) |
— | — |
Inhibitor of: |
— |
RTV [7] | 3A4; 2D6 (minor) |
3A4; 2C8; 2C9; 2C19; 2D6 | 1A2; 2B6; 2C9; 2C19 | Inducer | Inhibitor of: P-gP; BCRP; OATP; OCT; MATE1 |
— |
Protease Inhibitors (PIs) | ||||||
ATV [8] | 3A4 |
3A4; |
— | Inhibitor | P-gP substrate, inhibitor, inducer; OATP inhibitor |
GI absorp-tion (pH-dependent) |
DRV [9] | 3A4 | 3A4 | 2C9 | — | P-gP substrate; OATP inhibitor |
— |
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | ||||||
DOR [10] | 3A4; 3A5 | — | — | — | — | — |
EFV [11] | 2B6 (primary); 2A6; 3A4 |
3A4 | 3A4; 2B6 | — | — | — |
ETR [12] | 3A4; 2C9; 2C19 | 2C9; 2C19 | 3A4 | — | P-gP inducer | — |
RPV [13] | 3A4 | — | — | — | — | GI absorp-tion (pH-dependent) |
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | ||||||
ABC [14] | — | — | — | Substrate | — | Alcohol dehydroge-nase substrate |
FTC [15] | — | — | — | — | MATE1 substrate | — |
3TC [16] | — | — | — | — | Substrate of: MATE1/2; OCT2 | — |
TAF [17] | 3A4 (minor) | — | — | — | Substrate of: P-gP; BCRP; OATP | — |
TDF [18] | — | — | — | — | Substrate of: P-gP; OATP; MRP | — |
Entry Inhibitor | ||||||
FTR [19] | 3A4 | — | — | — | Substrate of: P-gP; BCRP Inhibitor of: OATP; BCRP |
— |
MVC [20] | 3A4 | — | — | — | P-gP substrate | — |
*Also see drug package inserts.
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Table 1A: Induction Potential of Ritonavir* and Cobicistat Used as Boosters [Foisy, et al. 2008; Marzolini, et al. 2016; Tseng, et al. 2017] |
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Ritonavir | Cobicistat | |
Cytochrome | ||
CYP1A2 | Moderate inducer | Clinically negligible effect |
CYP2B6 | Moderate inducer | Clinically negligible effect |
CYP2C8 | Moderate inhibitor | Clinically negligible effect |
CYP2C9 | Moderate inducer | Clinically negligible effect |
CYP2C19 | Strong inducer | Clinically negligible effect |
CYP2D6 | Moderate inhibitor | Mild inhibitor |
CYP3A4 | Strong inhibitor | Strong inhibitor |
Transporter | ||
P-gP | Moderate inhibitor | Moderate inhibitor |
UGT | Moderate inducer | Clinically negligible effect |
BCRP | Moderate inhibitor | Moderate inhibitor |
OATP1B1 | Moderate inhibitor | Moderate inhibitor |
OATP1B3 | Moderate inhibitor | Moderate inhibitor |
MATE1 | Moderate inhibitor | Moderate inhibitor |
MATE2-K | Clinically negligible effect | Clinically negligible effect |
OAT1 | Clinically negligible effect | Clinically negligible effect |
OAT3 | Weak inducer | Clinically negligible effect |
OCT2 | Clinically negligible effect | Clinically negligible effect |
Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome P450; IC, inhibitory concentration; MATE, multidrug and toxin extrusion; OAT, organic anion transporter; OATP, organic anion transporting protein; OCT, organic cation transporter; P-gP, P-glycoprotein; UGT, uridine 5′-diphospho-glucuronosyltransferase. *The information above is expected when ritonavir is given at doses used to boost other protease inhibitors. Effects may change at higher doses of ritonavir because this drug has a mixed effect (both induction and inhibition) on several CYP isoenzymes when studied at higher doses. |
Pharmacodynamic Interactions
Pharmacodynamic interactions are drug-drug interactions that involve the direct effects of the interacting drugs and a change in a patient’s response to the drugs [Trevor, et al. 2015]. Pharmacodynamic interactions may involve pharmacologic receptors, and drugs may be agonists or antagonists of other drugs.
- Pure agonists attach to the same binding site receptor as another drug, thus causing the same effect.
- Partial agonists bind to a different receptor site on the same receptor and may cause the same effect as another drug but to a lower intensity.
- Antagonists attach to the same receptor site as another drug, but the effect of this binding opposes the effect seen with another drug.
An example of a pharmacodynamic interaction is the concomitant use of zidovudine with other drugs that cause bone marrow suppression, including ribavirin or ganciclovir.
To minimize pharmacodynamic interactions, identify and address potential additive or antagonistic physiologic effects when treating a patient with more than 1 medication. Adding or removing a pharmacokinetic booster from a patient’s medication regimen may alter the levels of coadministered drugs and affect the efficacy or safety of these drugs.
Pharmacokinetic Interactions
Pharmacokinetic interactions involve the modification of drug absorption, distribution, metabolism, and excretion [Trevor, et al. 2015].
Absorption: Modification of gastric pH will influence the absorption of drugs that require the acidity of the stomach (e.g., the absorption of both rilpivirine and atazanavir are reduced when these drugs are given concomitantly with proton pump inhibitors such as omeprazole [Klein, et al. 2008; Schafer and Short 2012]). Some substances will form insoluble complexes with other drugs in a process known as chelation (e.g., the use of integrase inhibitors such as raltegravir with divalent or trivalent cations such as aluminum and magnesium [Wallace, et al. 2003]). Medications that influence the motility of the gastrointestinal tract may also affect absorption of other drugs.
Distribution: When 2 medications that are heavily protein-bound are given at the same time, competition for protein binding sites leads to an increase in free drug concentrations, which are available to exert therapeutic effects or increase toxicity of the medications. In most cases, a rapid equilibrium is reached between the free and bound drugs, and these drug-drug interactions are rarely clinically significant [Benet and Hoener 2002]. An exception is when a drug has a narrow therapeutic index (e.g., warfarin, digoxin, lithium, and aminoglycoside antibiotics); displacement of such a drug may have a dramatic effect on the level of activity of the agent [Zaccara and Perucca 2014].
Metabolism: The liver is the major site of drug metabolism, which occurs in 2 phases. Medications that alter phase I metabolism affect the oxidation, reduction, or hydrolysis of another medication. This typically involves the cytochrome P450 (CYP) isoenzymes, and drugs are classified as substrates, inducers, or inhibitors of specific enzymes. One of the most commonly described CYP enzymes is 3A4, which is responsible for the metabolism of many commonly used medications. However, other enzymes exist, and many play important roles in interactions related to ARVs. Each enzyme has a specific action: some drugs may be substrates, inhibitors, or inducers of more than 1 enzyme, and may even be substrates of one while inhibiting or inducing others. This creates complex interaction possibilities, and the therapeutic effects of these interactions may be unknown.
A drug is defined as a substrate if a certain enzyme metabolizes it. Rilpivirine and maraviroc are substrates of CYP3A4 [Perry 2010; Deeks 2014d]. Enzyme inducers increase the numbers of specific enzyme subtypes inside the body, thus increasing the metabolism of substrates of that enzyme or reducing the drug’s bioavailability. Examples of strong CYP3A inducers include efavirenz and rifampin [Ogburn, et al. 2010]. Moderate inducers of CYP3A include etravirine [Deeks and Keating 2008]. Some drugs, including nevirapine, autoinduce their own metabolism, causing the lead-in period seen when dosing that drug [Cammett, et al. 2009]. Inhibitors block metabolism of substrate drugs by directly binding to enzymes, increasing the bioavailability of substrate drugs. The most common examples of CYP3A inhibitors are the pharmacokinetic enhancers ritonavir and cobicistat and other PIs [Deeks 2014a; Tseng, et al. 2017].
Drugs that alter phase II metabolism affect glucuronidation, methylation, sulfation, or other forms of conjugation. Careful monitoring for therapeutic efficacy and safety is required in these circumstances. Examples of this type of enzyme include uridine diphosphate glucuronosyltransferase (UGT), which also plays a role in the glucuronidation of some drugs, including integrase strand transfer inhibitors (INSTIs) [Adams, et al. 2012]. Other agents, such as atazanavir, can inhibit UGT enzymes [Gammal, et al. 2016]. The interaction between raltegravir and atazanavir is of limited clinical significance. However, rifampin also induces UGT enzymes, and concomitant administration of rifampin and INSTIs greatly reduces bioavailability of these drugs, often necessitating dose adjustments [Miller, et al. 2017].
Excretion: Renal elimination involves both passive and active processes. Tubular secretion is a drug transport protein-mediated process, and competitive inhibition of tubular secretion is a common mechanism of drug-drug interactions in the kidney. Other drugs are more rapidly eliminated in acidic or alkaline urine, and alterations in the urine pH will influence rate of elimination.
To minimize pharmacokinetic interactions, identify and address a drug’s effect on metabolizing enzymes or drug transport proteins when treating a patient with more than 1 medication [Trevor, et al. 2015]. Consider Table 1: Mechanisms of Antiretroviral (ARV) Drug-Drug Interactions, above, as a helpful starting point, but be aware that the chart is not meant to be a finite resource on the pharmacokinetic effects of the listed ARV agents.
Other Drug-Drug Interactions
Drug-drug interactions may also result from modification of drug transport proteins, which exist throughout the body (e.g., kidney, liver, small intestine, and blood-brain barrier). As their name suggests, these drugs are important in the transfer of a drug or other endogenous substance from one body compartment to another [Ivanyuk, et al. 2017; Yoshida, et al. 2017]. P-glycoprotein (P-gP) is a well-known example of a drug transport protein, and this efflux transporter attempts to keep foreign substances, including some drugs, out of a cell [Lund, et al. 2017]. Inducing P-gP may decrease the amount of drug inside a cell, reducing its therapeutic efficacy. Inhibiting P-gP may increase the amount of drug inside a cell, increasing its efficacy, or leading to adverse events.
Several other drug transport proteins have been discovered, and families of these proteins include multidrug and toxin extrusion, organic cation transporter [Yin, et al. 2016], organic anion transporter, breast cancer resistance protein [Mao and Unadkat 2015], and organic anion transporting polypeptide (OATP) enzymes [Kovacsics, et al. 2017; Yu, et al. 2017]. The clinical significance of these proteins or the influence of drugs on the activity of these proteins is incompletely understood, but this area of pharmacotherapeutic research is rapidly evolving. An example of such an interaction is TDF with diclofenac [Morelle, et al. 2009], which are both substrates of OATP1B3 and compete for renal secretion. This increases the levels of these agents and may increase the risk of tubular toxicity due to prolonged tenofovir availability inside the tubular cells.
References
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Cammett AM, MacGregor TR, Wruck JM, et al. Pharmacokinetic assessment of nevirapine and metabolites in human immunodeficiency virus type 1-infected patients with hepatic fibrosis. Antimicrob Agents Chemother 2009;53(10):4147-4152. [PMID: 19620337]
Carr A, Samaras K, Chisholm DJ, et al. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998;351(9119):1881-1883. [PMID: 9652687]
Chan HL, Fung S, Seto WK, et al. Improved bone and renal safety of switching from tenofovir disoproxil fumarate to tenofovir alafenamide: preliminary results from 2 phase 3 studies in HBeAg-positive and HBeAg-negative patients with chronic hepatitis B (PS-041). International Liver Congress; 2017 Apr 19-23; Amsterdam, The Netherlands. https://www.journal-of-hepatology.eu/article/S0168-8278(17)30312-4/fulltext
Croom KF, Dhillon S, Keam SJ. Atazanavir: a review of its use in the management of HIV-1 infection. Drugs 2009;69(8):1107-1140. [PMID: 19496633]
Deeks ED. Cobicistat: a review of its use as a pharmacokinetic enhancer of atazanavir and darunavir in patients with HIV-1 infection. Drugs 2014a;74(2):195-206. [PMID: 24343782]
Deeks ED. Darunavir: a review of its use in the management of HIV-1 infection. Drugs 2014b;74(1):99-125. [PMID: 24338166]
Deeks ED. Elvitegravir: a review of its use in adults with HIV-1 infection. Drugs 2014c;74(6):687-697. [PMID: 24671908]
Deeks ED. Emtricitabine/rilpivirine/tenofovir disoproxil fumarate single-tablet regimen: a review of its use in HIV infection. Drugs 2014d;74(17):2079-2095. [PMID: 25352394]
Deeks ED. Raltegravir once-daily tablet: A review in HIV-1 infection. Drugs 2017;77(16):1789-1795. [PMID: 29071467]
Deeks ED. Doravirine: First global approval. Drugs 2018;78(15):1643-1650. [PMID: 30341683]
Deeks ED, Keating GM. Etravirine. Drugs 2008;68(16):2357-2372. [PMID: 18973398]
Dharan NJ, Cooper DA. Reducing medical comorbidities associated with long-term HIV infection: beyond optimizing antiretroviral therapy regimens. AIDS 2017;31(18):2547-2549. [PMID: 29120900]
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Foisy MM, Yakiwchuk EM, Hughes CA. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 2008;42(7):1048-59. [PMID: 18577765]
Gallant J, Hsue P, Budd D, et al. Healthcare utilization and direct costs of non-infectious comorbidities in HIV-infected patients in the USA. Curr Med Res Opin 2018;34(1):13-23. [PMID: 28933204]
Gammal RS, Court MH, Haidar CE, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther 2016;99(4):363-369. [PMID: 26417955]
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Kiser JJ, Carten ML, Aquilante CL, et al. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther 2008;83(2):265-272. [PMID: 17597712]
Klein CE, Chiu YL, Cai Y, et al. Effects of acid-reducing agents on the pharmacokinetics of lopinavir/ritonavir and ritonavir-boosted atazanavir. J Clin Pharmacol 2008;48(5):553-562. [PMID: 18440920]
Kohler JJ, Hosseini SH, Green E, et al. Tenofovir renal proximal tubular toxicity is regulated by OAT1 and MRP4 transporters. Lab Invest 2011;91(6):852-858. [PMID: 21403643]
Kovacsics D, Patik I, Ozvegy-Laczka C. The role of organic anion transporting polypeptides in drug absorption, distribution, excretion and drug-drug interactions. Expert Opin Drug Metab Toxicol 2017;13(4):409-424. [PMID: 27783531]
Llibre JM, Hill A. Abacavir and cardiovascular disease: A critical look at the data. Antiviral Res 2016;132:116-121. [PMID: 27260856]
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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]
McCormack PL. Dolutegravir: a review of its use in the management of HIV-1 infection in adolescents and adults. Drugs 2014;74(11):1241-1252. [PMID: 25005775]
Miller MM, Kinney KK, Liedtke MD. Virologic failure of high-dose raltegravir with concomitant rifampin. Infect Dis Clin Pract 2017;25(3):168-170. DOI: 10.1097/IPC.0000000000000490
Morelle J, Labriola L, Lambert M, et al. Tenofovir-related acute kidney injury and proximal tubule dysfunction precipitated by diclofenac: a case of drug-drug interaction. Clin Nephrol 2009;71(5):567-570. [PMID: 19473619]
Muller F, Konig J, Hoier E, et al. Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine. Biochem Pharmacol 2013;86(6):808-815. [PMID: 23876341]
Noor MA, Parker RA, O’Mara E, et al. The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults. AIDS 2004;18(16):2137-2144. [PMID: 15577646]
Ogburn ET, Jones DR, Masters AR, et al. Efavirenz primary and secondary metabolism in vitro and in vivo: identification of novel metabolic pathways and cytochrome P450 2A6 as the principal catalyst of efavirenz 7-hydroxylation. Drug Metab Dispos 2010;38(7):1218-1229. [PMID: 20335270]
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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]
Raffi F, Orkin C, Clarke A, et al. Brief report: Long-term (96-week) efficacy and safety after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in HIV-infected, virologically suppressed adults. J Acquir Immune Defic Syndr 2017;75(2):226-231. [PMID: 28272164]
Reznicek J, Ceckova M, Cerveny L, et al. Emtricitabine is a substrate of MATE1 but not of OCT1, OCT2, P-gp, BCRP or MRP2 transporters. Xenobiotica 2017;47(1):77-85. [PMID: 27052107]
Schafer JJ, Short WR. Rilpivirine, a novel non-nucleoside reverse transcriptase inhibitor for the management of HIV-1 infection: a systematic review. Antivir Ther 2012;17(8):1495-1502. [PMID: 22878339]
Scott LJ, Chan HLY. Tenofovir alafenamide: A review in chronic hepatitis B. Drugs 2017;77(9):1017-1028. [PMID: 28493172]
Taneva E, Crooker K, Park SH, et al. Differential mechanisms of tenofovir and tenofovir disoproxil fumarate cellular transport and implications for topical preexposure prophylaxis. Antimicrob Agents Chemother 2015;60(3):1667-1675. [PMID: 26711762]
Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor’s Pharmacology. Chapter 61: Drug Interactions. 2015 https://accesspharmacy.mhmedical.com/content.aspx?bookid=1568§ionid=95705561 [accessed 2018 Oct 16]
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]
Wallace AW, Victory JM, Amsden GW. Lack of bioequivalence when levofloxacin and calcium-fortified orange juice are coadministered to healthy volunteers. J Clin Pharmacol 2003;43(5):539-544. [PMID: 12751275]
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Yoshida K, Zhao P, Zhang L, et al. In vitro-in vivo extrapolation of metabolism- and transporter-mediated drug-drug interactions–overview of basic prediction methods. J Pharm Sci 2017;106(9):2209-2213. [PMID: 28456729]
Yu J, Zhou Z, Tay-Sontheimer J, et al. Intestinal drug interactions mediated by OATPs: A systematic review of preclinical and clinical findings. J Pharm Sci 2017;106(9):2312-2325. [PMID: 28414144]
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Drug-Drug Interactions by Antiretroviral (ARV) Class
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, reviewed February 2021
RECOMMENDATION |
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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
- 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/drugs/drug-interactions-labeling/drug-interactions-relevant-regulatory-guidance-and-policy-documents [accessed 2019 Jan 9]
Boosted Protease Inhibitors (PIs): ATZ, DRV
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
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) |
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Histamine 2 receptor antagonist (H2RA) |
ATV requires an acidic gastric pH for absorption, and acid-reducing agents interfere with the absorption of ATV. |
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Antacids |
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 |
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Pravastatin |
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Use the lowest effective dose of pravastatin and monitor for adverse events, including myopathy and rhabdomyolysis. |
Atorvastatin |
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Rosuvastatin |
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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 |
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PY2-antagonists |
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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 |
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) |
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. |
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Inhaled, intranasal, and injected corticosteroids |
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:
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Oral prednisone |
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Benzodiazepines |
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Antipsychotics |
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HCV PIs (“-previr” drugs) |
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 |
Boosted PIs inhibit daclatasvir metabolism via CYP3A4. | Decrease daclatasvir dose to 30 mg per day. |
Etravirine (ETR) |
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Sleep medications |
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Non-opioid pain medications |
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Other antiplatelet drugs |
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Antidiabetic drugs |
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Trazodone | May increase trazodone concentrations. | Monitor antidepressant and/or sedative effects. |
Anticonvulsants |
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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 |
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Erectile and sexual dysfunction agents |
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Methadone, buprenorphine (BUP), naloxone (NLX) |
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Immunosuppressants |
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Rifabutin, rifampin |
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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; gender-affirming hormones. |
Table 3: Boosted Darunavir (DRV) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Simvastatin, lovastatin |
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Pravastatin |
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If pravastatin use is necessary, use the lowest effective dose and monitor for signs of toxicity. |
Atorvastatin |
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Rosuvastatin |
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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 |
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Antiplatelet drugs and PY2-antagonists |
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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. |
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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 |
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 |
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Long-acting beta-agonists | Inhibition of CYP3A increases plasma concentrations of these agents. |
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Inhaled and injected corticosteroids |
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:
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Oral prednisone |
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Avoid concomitant use unless risk outweighs benefits, because of increased risk of corticosteroid-related adverse events. |
Benzodiazepines |
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Antipsychotics |
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HCV PIs (“-previr” drugs) |
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 |
Boosted PIs inhibit daclatasvir metabolism via CYP3A4. | Decrease daclatasvir dose to 30 mg per day. |
Sleep medications |
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Non-opioid pain medications |
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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. |
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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 |
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Norethindrone: Consider alternative or additional contraceptive method or alternative ARV agent. |
Erectile and sexual dysfunction agents |
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Methadone, buprenorphine (BUP), naloxone (NLX), and naltrexone |
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Immunosuppressants |
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Rifabutin, rifampin |
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|
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; gender-affirming hormones. |
References
Aquilante CL, Kiser JJ, Anderson PL, et al. Influence of SLCO1B1 polymorphisms on the drug-drug interaction between darunavir/ritonavir and pravastatin. J Clin Pharmacol 2012;52(11):1725-1738. [PMID: 22174437]
Brooks KM, George JM, Kumar P. Drug interactions in HIV treatment: complementary & alternative medicines and over-the-counter products. Expert Rev Clin Pharmacol 2017;10(1):59-79. [PMID: 27715369]
Busti AJ, Bain AM, Hall RG, 2nd, et al. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol 2008;51(6):605-610. [PMID: 18520949]
Chauvin B, Drouot S, Barrail-Tran A, et al. Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors. Clin Pharmacokinet 2013;52(10):815-831. [PMID: 23703578]
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]
Daveluy A, Raignoux C, Miremont-Salame G, et al. Drug interactions between inhaled corticosteroids and enzymatic inhibitors. Eur J Clin Pharmacol 2009;65(7):743-745. [PMID: 19399485]
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]
Falcon RW, Kakuda TN. Drug interactions between HIV protease inhibitors and acid-reducing agents. Clin Pharmacokinet 2008;47(2):75-89. [PMID: 18193914]
Feinstein MJ, Achenbach CJ, Stone NJ, et al. A systematic review of the usefulness of statin therapy in HIV-infected patients. Am J Cardiol 2015;115(12):1760-1766. [PMID: 25907504]
Kakadiya PP, Higginson RT, Fulco PP. Ritonavir-boosted protease inhibitors but not cobicistat appear safe in HIV-positive patients ingesting dabigatran. Antimicrob Agents Chemother 2018;62(2). [PMID: 29133562]
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]
Kellick KA, Bottorff M, Toth PP, et al. A clinician’s guide to statin drug-drug interactions. J Clin Lipidol 2014;8(3 Suppl):S30-46. [PMID: 24793440]
Kis O, Zastre JA, Hoque MT, et al. Role of drug efflux and uptake transporters in atazanavir intestinal permeability and drug-drug interactions. Pharm Res 2013;30(4):1050-1064. [PMID: 23224979]
Kiser JJ, Carten ML, Aquilante CL, et al. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther 2008;83(2):265-272. [PMID: 17597712]
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]
McKeage K, Perry CM, Keam SJ. Darunavir: a review of its use in the management of HIV infection in adults. Drugs 2009;69(4):477-503. [PMID: 19323590]
Orrell C, Felizarta F, Nell A, et al. Pharmacokinetics of etravirine combined with atazanavir/ritonavir and a nucleoside reverse transcriptase inhibitor in antiretroviral treatment-experienced, HIV-1-infected patients. AIDS Res Treat 2015;2015:938628. [PMID: 25664185]
Roden DM, Darbar D, Kannankeril PJ. Antiarrhythmic drugs. In: Willerson JT, Wellens HJ, Cohn JN et al., editors. Cardiovascular medicine. London: Springer London; 2007. 2085-2102.
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;14(9):519-529. [PMID: 23590676]
Samineni D, Desai PB, Sallans L, et al. Steady-state pharmacokinetic interactions of darunavir/ritonavir with lipid-lowering agent rosuvastatin. J Clin Pharmacol 2012;52(6):922-931. [PMID: 21712498]
Soriano V, Labarga P, Fernandez-Montero JV, et al. Drug interactions in HIV-infected patients treated for hepatitis C. Expert Opin Drug Metab Toxicol 2017;13(8):807-816. [PMID: 28689442]
Teng R. Ticagrelor: Pharmacokinetic, pharmacodynamic and pharmacogenetic profile: An update. Clin Pharmacokinet 2015;54(11):1125-1138. [PMID: 26063049]
Vildhede A, Karlgren M, Svedberg EK, et al. Hepatic uptake of atorvastatin: influence of variability in transporter expression on uptake clearance and drug-drug interactions. Drug Metab Dispos 2014;42(7):1210-1218. [PMID: 24799396]
Wang X, Boffito M, Zhang J, et al. Effects of the H2-receptor antagonist famotidine on the pharmacokinetics of atazanavir-ritonavir with or without tenofovir in HIV-infected patients. AIDS Patient Care STDS 2011;25(9):509-515. [PMID: 21770762]
Integrase Strand Transfer Inhibitors (INSTIs): BIC, DTG, Boosted EVG, RAL
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 4: Bictegravir (BIC) Interactions (also see drug package inserts) | ||
Print this table | ||
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 |
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. |
|
Atenolol | Atenolol is eliminated via OCT2 and MATE1, which are inhibited by BIC. Coadministration may increase levels of atenolol |
|
Valproic acid | Coadministration may significantly decrease BIC concentrations. |
|
Cyclosporine | May increase BIC concentrations to a modest degree via P-gP inhibition. | Monitor for BIC-related adverse events. |
Rifabutin, rifampin |
|
|
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; gender-affirming hormones. |
Table 5: Dolutegravir (DTG) Interactions (also see drug package inserts) | ||
Print this table | ||
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. |
|
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 |
|
Iron salts [Song, et al. 2015] |
DTG chelates with cations, forming insoluble compounds that inactivate both drugs. |
|
Atenolol |
|
|
Rifabutin, rifampin |
|
Rifampin: When used concomitantly, dose DTG at 50 mg twice per day instead of 50 mg once per day. |
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; gender-affirming hormones. |
Table 6: Boosted Elvitegravir (EVG) Interactions (also see drug package inserts) | ||
Print this table | ||
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] |
|
|
Warfarin | Could potentially decrease (or more rarely) increase metabolism of warfarin. |
|
Cilostazol, ticagrelor, clopidogrel [Egan, et al. 2014; Tseng, et al. 2017] |
|
|
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. |
|
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] |
|
|
Simvastatin, lovastatin [Perry 2014] |
|
Avoid concomitant use (may increase muscle aches and risk of rhabdomyolysis). |
Pitavastatin [Tseng, et al. 2017] |
|
|
Pravastatin [Tseng, et al. 2017] |
|
|
Atorvastatin [Tseng, et al. 2017] |
|
|
Rosuvastatin |
|
|
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 |
|
|
Long-acting beta-agonists (formoterol, salmeterol, etc.) |
|
|
Inhaled and injected corticosteroids |
Risk of Cushing’s syndrome when coadministered with the following:
|
|
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. |
|
Antipsychotics |
Several of these agents are substrates of CYP3A, and inhibitors of this enzyme may increase their concentrations. |
|
PDE5 inhibitors [Perry 2014] |
|
|
Suvorexant [Kishi, et al. 2015] |
|
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. |
|
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin |
Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system |
|
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. |
|
Immunosuppressants |
|
|
Rifabutin, rifampin |
|
|
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; gender-affirming hormones. |
Table 7: Raltegravir (RAL) Interactions (also see drug package inserts) | ||
Print this table | ||
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. |
|
Anticonvulsants | Coadministration with strong inducers of UGT1A1 (phenytoin, phenobarbital, etc.) may decrease RAL concentrations. | Coadministration with strong inducers of UGT1A1 are not recommended |
Rifabutin, rifampin |
|
|
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; gender-affirming hormones. |
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]
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, updated February 2021
Table 8: Doravirine (DOR) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Strong inducers or inhibitors of CYP3A |
DOR is a substrate of CYP3A, and as such, drugs that affect its metabolism affect its concentrations. |
|
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin | Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system. |
|
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; 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; gender-affirming hormones. |
Table 9: Rilpivirine (RPV) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Proton pump inhibitors (PPIs) [Schafer and Short 2012] |
|
Avoid concomitant use; may decrease RPV absorption. |
Histamine 2 antagonists (H2As) [Schafer and Short 2012] |
|
|
Antacids [Schafer and Short 2012] |
|
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. |
|
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. |
|
Methadone, buprenorphine (BUP) |
|
|
Strong inducers or inhibitors of CYP3A | RPV is a substrate of CYP3A, and as such, drugs that affect its metabolism affect its concentrations. |
|
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; gender-affirming hormones. |
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. |
|
Bupropion |
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 |
|
|
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. |
|
Sleep medications | Zolpidem: Potential for reduced concentrations of zolpidem. |
|
Antipsychotics |
|
|
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin | Coadministration may significantly reduce concentrations of antiretroviral agents through induction of CYP450 system. |
|
Lamotrigine, zonisamide | EFV may reduce efficacy of lamotrigine or zonisamide. | Monitor efficacy; titrate dose slowly as needed. |
Opioid analgesics and tramadol |
|
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Hormonal contraceptives | Decreased concentrations of combined progestins. |
|
Erectile and sexual dysfunction agents |
|
|
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] |
|
|
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. |
|
Rifabutin, rifampin |
|
Rifabutin: If EFV and rifabutin are used concomitantly, increase dose of rifabutin by 50%, especially if rifabutin is dosed 3 times weekly. |
Gender-affirming hormones |
|
|
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) | ||
Print this table | ||
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. |
|
Warfarin | Could potentially increase (or more rarely decrease) metabolism of warfarin. |
|
Antiplatelet drugs [Rathbun and Liedtke 2010; Kakuda, et al. 2011] |
|
|
Statins |
|
|
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. |
|
Antipsychotics |
|
|
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin |
Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system. |
|
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 |
|
Erectile and sexual dysfunction agents |
|
|
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. |
|
Cyclosporine, tacrolimus |
Concentrations may be lower when used with ETR. |
|
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] |
|
|
Dolutegravir (DTG) [Green, et al. 2017] |
|
|
Rifabutin, rifampin |
|
|
Gender-affirming hormones |
|
|
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]
Orrell C, Felizarta F, Nell A, et al. Pharmacokinetics of etravirine combined with atazanavir/ritonavir and a nucleoside reverse transcriptase inhibitor in antiretroviral treatment-experienced, HIV-1-infected patients. AIDS Res Treat 2015;2015:938628. [PMID: 25664185]
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]
Robertson SM, Maldarelli F, Natarajan V, et al. Efavirenz induces CYP2B6-mediated hydroxylation of bupropion in healthy subjects. J Acquir Immune Defic Syndr 2008;49(5):513-519. [PMID: 18989234]
Sanford M. Rilpivirine. Drugs 2012;72(4):525-541. [PMID: 22356290]
Scarsi KK, Darin KM, Nakalema S, et al. Unintended pregnancies observed with combined use of the levonorgestrel contraceptive implant and efavirenz-based antiretroviral therapy: A three-arm pharmacokinetic evaluation over 48 weeks. Clin Infect Dis 2016;62(6):675-682. [PMID: 26646680]
Schafer JJ, Short WR. Rilpivirine, a novel non-nucleoside reverse transcriptase inhibitor for the management of HIV-1 infection: a systematic review. Antivir Ther 2012;17(8):1495-1502. [PMID: 22878339]
Soriano V, Labarga P, Fernandez-Montero JV, et al. Drug interactions in HIV-infected patients treated for hepatitis C. Expert Opin Drug Metab Toxicol 2017;13(8):807-816. [PMID: 28689442]
Welz T, Wyen C, Hensel M. Drug interactions in the treatment of malignancy in HIV-infected patients. Oncol Res Treat 2017;40(3):120-127. [PMID: 28253501]
Yeh WW. Drug-drug interactions with grazoprevir/elbasvir: Practical considerations for the care of HIV/HCV co-infected patients. 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; 2015 May 26-28; Washington, DC. http://www.natap.org/2015/Pharm/Pharm_31.htm
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): ABC, TDF/TAF, 3TC
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 12: Abacavir (ABC) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Ethanol |
ABC is metabolized via alcohol dehydrogenase, and competitive metabolism may increase exposure to ABC. | Use cautiously and monitor for adverse events of ABC. |
Rifabutin, rifampin
|
|
Rifampin: No dose adjustments recommended for concomitant use with 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; gender-affirming hormones. |
Table 13: Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF) Interactions (also see drug package inserts) | ||
Print this table | ||
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. |
|
Sofosbuvir/velpatasvir/ |
|
|
Potent CYP3A4 or P-gP inducers (phenytoin, rifampin, carbamazepine, St. John’s wort, etc.) [Gibson, et al. 2016] |
|
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; gender-affirming hormones. |
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]
Entry Inhibitors (EIs): FTR, MVC
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 14A: Fostemsavir (FTR) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Potent CYP3A4 or P-gP inducers (phenytoin, rifampin, carbamazepine, St. John’s wort, etc.) | Reduces fostemsavir levels due to CYP3A4 induction. | Do not coadminister. |
Antineoplastic agent (mitotane) | Reduces fostemsavir levels due to CYP3A4 induction. | Do not coadminister. |
Androgen receptor inhibitor (enzalutamide) | Reduces fostemsavir levels due to CYP3A4 induction. | Do not coadminister. |
HCV antiviral agents | Increases grazoprevir and voxilaprevir levels. |
|
Hormonal contraceptives | Increases ethinyl estradiol levels. |
|
Statins | Increases rosuvastatin, atorvastatin, fluvastatin, pitavastatin, and simvastatin levels. | Use lowest possible starting dose for statins; monitor for statin-associated adverse events. |
Abbreviations: CYP, cytochrome P450; HCV, hepatitis C virus; P-gP, P-glycoprotein. No significant interactions/no dose adjustments necessary: common oral antibiotics; drugs used as antihypertensive medicines; antidiabetic drugs; acid-reducing agents; polyvalent cations; inhaled and injected corticosteroids; benzodiazepines; sleep medications; non-opioid pain medications; opioid analgesics and tramadol; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; gender-affirming hormones. |
Table 14B: Maraviroc (MVC) Interactions (also see drug package inserts) | ||
Print this table | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Potent CYP3A4 or P-gP inducers (St. John’s wort) | Reduced maraviroc levels due to CYP3A4 induction. | Do not coadminister. |
Abbreviations: CYP, cytochrome P450; P-gP, P-glycoprotein. No significant interactions/no dose adjustments necessary: common oral antibiotics; drugs used as antihypertensive medicines; antidiabetic drugs; acid-reducing agents; polyvalent cations; inhaled and injected corticosteroids; benzodiazepines; sleep medications; non-opioid pain medications; opioid analgesics and tramadol; tobacco and smoking cessation products; alcohol, disulfiram, and acamprosate; methadone, buprenorphine, naloxone, and naltrexone; gender-affirming hormones. |
Drug-Drug Interactions by Common Medication Class
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, reviewed February 2021
The following tables are not meant to serve as a definitive resource on all possible drug-drug interactions between common antiretroviral (ARV) and non-ARV drugs. Instead, they offer a brief introduction to the management of interactions between medications used to treat HIV and comorbidities commonly seen in primary care settings. The tables are organized by common disease state and prioritized by those most commonly seen in primary care. Within each table, the medications are prioritized according to the preference the NYSDOH AI and the U.S. Department of Health and Human Services gives each class of medications in the initial management of HIV. The appropriate management of HIV should be individualized according to patient-specific factors, and not all ARVs may be suitable for all patients.
In the event that an ARV does not have a clinically significant interaction with the class of medications described, it is still listed in the table. If an interaction is theoretical but its significance is unknown, the recommendation to monitor for safety and efficacy is provided. Drugs within a class that may have a significant interaction are described within the table. Other drugs that do not have clinically significant drug-drug interactions with ARVs but were reviewed are described in the footnotes of the individual tables. If a drug does not appear in the table or the footnotes, exercise extra caution when prescribing this medication to patients with HIV or AIDS. The resources provided here might be valuable for clinicians who seek more guidance on drug-drug interactions related to ARV medications.
The informational material found within these tables is based on previously referenced primary, secondary, and tertiary literature, as well as the various publicly available databases described in the Resources section. Further information may be found in the literature, including the U.S. Food and Drug Administration’s reports or manufacturer’s prescribing information (package inserts), which are also available online for each of the listed pharmacologic agents. If healthcare providers are interested in learning more about specific drug-drug interactions or seek further information about the methodology of the research or the mechanisms and management of these interactions, they are encouraged to utilize these resources.
Consultation with an experienced HIV care provider is also recommended when assistance is needed in choosing an antiretroviral therapy regimen for a patient who has multiple comorbidities and may have multiple drug-drug interactions. For help locating an experienced HIV care provider, contact the Clinical Education Initiative at 866-637-2342.
KEY POINT |
|
- Table 15: Common Oral Antibiotics
- Table 16: Drugs Used as Antihypertensive Medicines
- Table 17: Anticoagulants
- Table 18: Antiplatelet Drugs
- Table 19: Statins
- Table 20: Antidiabetic Drugs
- Table 21: Acid-Reducing Agents
- Table 22: Polyvalent Cations
- Table 23: Asthma and Allergy Medications
- Table 24: Long-Acting Beta Agonists
- Table 25: Corticosteroids
- Table 26: Antidepressants
- Table 27: Benzodiazepines
- Table 28: Sleep Medications
- Table 29: Antipsychotics
- Table 30: Anticonvulsants
- Table 31: Non-Opioid Pain Medications
- Table 32: Opioid Analgesics and Tramadol
- Table 33: Hormonal Contraceptives
- Table 34: Erectile and Sexual Dysfunction Agents
- Table 35: Tobacco and Smoking Cessation Products
- Table 36: Alcohol, Disulfiram, and Acamprosate
- Table 37: Methadone, Buprenorphine, Naloxone, and Naltrexone
- Table 38: Immunosuppressants
- Table 39: Rifamycins and Other Anti-Tuberculosis Medications
- Table 40: Gender-Affirming Hormones
Common Oral Antibiotics
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 15: Common Oral Antibiotics | ||
→ Penicillins, cephalosporins, tetracyclines, macrolides, fluoroquinolones, sulfamethoxazole-trimethoprim*, linezolid, dapsone | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions. | No dose adjustments necessary. |
Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; TDF, tenofovir disoproxil fumarate Note: Penicillins and cefalexin are eliminated mainly by organic anion transporters, so may compete with TDF for active tubular excretion, thus increasing concentrations of both drugs. Because of the limited duration of most penicillin regimens, the significance of this interaction is expected to be minimal. *Trimethoprim blocks creatinine secretion and could accentuate the effects of cobicistat, BIC, and DTG. |
Drugs Used as Antihypertensive Agents
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 16: Drugs Used as Antihypertensive Agents | ||
→ Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), beta blockers, direct renin inhibitors, diuretics | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions expected. |
No dose adjustments necessary. |
Dolutegravir (DTG) or bictegravir (BIC) |
|
|
Elvitegravir (EVG), boosted |
|
|
Boosted PIs |
|
|
Efavirenz (EFV) or etravirine (ETR) |
|
|
Abbreviations: INSTIs, integrase strand transfer inhibitors; MATE, multidrug and toxin extrusion; NRTI, nucleoside reverse transcriptase inhibitor; NSAID, non-steroidal anti-inflammatory drug; OCT, organic cation transporter; P-gP, P-glycoprotein; PI, protease inhibitor; PK, pharmacokinetic; RTV, ritonavir; TDF, tenofovir disoproxil fumarate. Note: Although not typically nephrotoxic, ACE inhibitors can, rarely, contribute to renal dysfunction, particularly when combined with high-dose NSAIDs. Clinicians are advised to ask patients who are taking TDF about their use of ACE inhibitors, such as lisinopril, with NSAIDs, such as ibuprofen or naproxen, and to monitor the patient’s renal function. |
Anticoagulants
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 17: Anticoagulants | ||
→ Warfarin, non-VKA oral anticoagulants (NOACs), low molecular weight heparins (LMWHs) | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions expected. | No dose adjustments necessary. |
|
|
|
|
|
|
Abbreviations: COBI, cobicistat; INR, international normalized ratio; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RTV, ritonavir. |
Reference
Kakadiya PP, Higginson RT, Fulco PP. Ritonavir-boosted protease inhibitors but not cobicistat appear safe in HIV-positive patients ingesting dabigatran. Antimicrob Agents Chemother 2018;62(2). [PMID: 29133562]
Antiplatelet Drugs
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 18: Antiplatelet Drugs | ||
→ Adenosine phosphate receptor inhibitors, cilostazol, dipyridamole | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions expected. | No dose adjustments necessary. |
Elvitegravir (EVG), boosted |
|
|
Boosted PIs |
|
|
Efavirenz (EFV) or etravirine (ETR) |
|
|
Abbreviations: ARV, antiretroviral; COBI, cobicistat, CYP, cytochrome P450; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RTV, ritonavir; UGT, uridine diphosphate glucuronosyltransferase. |
Statins
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 19: Statins | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions expected. | No dose adjustments necessary. |
|
|
|
Efavirenz (EFV) or etravirine (ETR) |
|
|
Fostemsavir (FTR) |
|
Use lowest starting dose of all statins; monitor for adverse events. |
Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Note: Ritonavir-boosted PIs and EFV are known to cause metabolic dysfunction, which may increase blood cholesterol levels. |
Antidiabetic Drugs
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 20: Antidiabetic Drugs | ||
→ Metformin, sulfonylureas, thiazolidinediones (TZDs), dipeptidyl peptidase IV (DPP-4) inhibitors, a glucosidase inhibitors, glucagon-like peptide 1 (GLP-1) agonists, sodium glucose cotransporter 2 (SGLT-2) inhibitors | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions expected. | No dose adjustment necessary. |
Dolutegravir (DTG) or bictegravir (BIC) |
|
|
Elvitegravir (EVG), boosted |
|
|
|
|
|
Rilpivirine (RPV) |
|
|
Efavirenz (EFV) or etravirine (ETR) |
|
|
Abbreviations: COBI, cobicistat; CYP, cytochrome P450; GFR, glomerular filtration rate; MATE, multidrug and toxin extrusion; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; TDF, tenofovir disoproxil fumarate. Note: Ritonavir-boosted PIs are known to cause metabolic abnormalities, which may cause increased blood glucose and decreased insulin sensitivity. An increased risk for bone fractures has been reported with canagliflozin, particularly in patients with a history of or who are at high risk of cardiovascular disease; therefore, caution is recommended when coadministering SGLT-2 inhibitors in the long term with TDF due to potential additive bone toxicities. |
Acid-Reducing Agents
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 21: Acid-Reducing Agents | ||
→ Proton pump inhibitors (PPIs) and histamine-2 receptor agonists (H2RAs) | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No clinically significant interactions noted. | No dose adjustments needed. |
Atazanavir (ATV), unboosted | PPIs: Markedly reduce ATV concentration and AUC. |
|
Atazanavir (ATV), boosted | H2RAs: Reduce ATV absorption. |
|
Darunavir (DRV)/ ritonavir (RTV) | No clinically significant interaction noted. |
|
Rilpivirine (RPV) | Significant reduction in plasma concentration of RPV. |
|
Abbreviations: ARV, antiretroviral; AUC, area under the curve; COBI, cobicistat; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PK, pharmacokinetic; RTV, ritonavir; TFV, tenofovir; TDF, tenofovir disoproxil fumarate. Notes:
|
Polyvalent Cations
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 22: Polyvalent Cations | ||
→ Supplements, antacids, and laxatives that contain aluminum, calcium, magnesium, zinc, and iron | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No clinically significant interactions noted. | No dose adjustments needed. |
All INSTIs | These form complexes with cations, resulting in reduced concentrations of both INSTIs and cations. For specific recommendations, see individual INSTIs below. | Any polyvalent cation: If coadministration is necessary, administer at least 2 hours before or at least 6 hours after, and monitor for virologic efficacy. |
Dolutegravir (DTG) | Binds to cations, reducing effect of ARV agent and cations. |
|
Bictegravir (BIC) | Binds to cations, reducing effect of ARV agent and cations |
|
Elvitegravir (EVG), boosted | Binds to cations, reducing effect of ARV agent and cations. |
|
Raltegravir (RAL) | Binds to cations, reducing effect of ARV agent and cations. |
|
Atazanavir (ATV), boosted or unboosted | Antacids containing calcium, magnesium, or aluminum: May reduce absorption. | Antacids or buffered medications: Administer at least 2 hours before or 1 to 2 hours after. |
Rilpivirine (RPV) | Antacids: May reduce absorption. | Antacids: Administer at least 2 hours before or at least 4 hours after. |
Abbreviations: ARV, antiretroviral; INSTI, integrase strand transfer inhibitor; NRTI, nucleoside reverse transcriptase inhibitor. |
Asthma and Allergy Medications
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 23: Asthma and Allergy Medications | ||
→ Albuterol, tiotropium, aclidinium, montelukast, loratadine, cetirizine, diphenhydramine | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustments necessary. |
Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. |
Long-Acting Beta Agonists (LABAs)
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 24: Long-Acting Beta Agonists (LABAs) | ||
→ Salmeterol, formoterol, etc. | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustment necessary. |
Elvitegravir (EVG), boosted | Increased risk of salmeterol-associated cardiovascular events. | Do not coadminister; consider use of alternative ARV agent. |
Boosted PIs | Inhibition of CYP3A4 enzyme increases plasma concentrations of salmeterol. |
|
Rilpivirine (RPV) | Both drugs may theoretically increase QT interval, especially at high doses. |
|
Abbreviations: ARV, antiretroviral; CYP, cytochrome P450; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. |
Inhaled and Injected Corticosteroids
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 25: Inhaled and Injected Corticosteroids | ||
→ Fluticasone, triamcinolone, budesonide, and methyl prednisone | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustment necessary. |
Elvitegravir (EVG), boosted |
Risk of Cushing’s syndrome when coadministered with the following:
|
|
Boosted PIs |
Risk of Cushing’s syndrome when coadministered with the following corticosteroids:
|
|
Rilpivirine (RPV) | Potential decrease in RPV concentration. | Systemic dexamethasone: 1) Contraindicated; consider use of alternative agents. 2) If using more than single dose, do not coadminister. |
Efavirenz (EFV) or etravirine (ETR) | Coadministration may reduce concentrations of corticosteroids. | Systemic dexamethasone: Consider alternative corticosteroid for long-term use; if benefits of use outweigh risks, monitor virologic response. |
Abbreviations: ARV, antiretroviral; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Note: Short-term therapy with oral prednisone or prednisolone is not expected to cause significant drug-drug interactions with ARV agents in most cases; however, increased monitoring may be required if a patient is taking an ARV agent, including a boosted PI, that has adverse effects that are the same as those of prednisone, such as insulin resistance. Particular caution may be necessary in patients predisposed to insulin hypersensitivity. Long-term therapy with oral steroids (>2 weeks) is not recommended unless undertaken with guidance from an experienced HIV care provider. |
Antidepressants
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 26: Antidepressants | ||
→ Including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), trazodone, bupropion, and monoamine oxidase inhibitors (MAOIs) | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustments necessary. |
|
Trazodone: May increase trazodone concentrations. | Trazodone: Monitor antidepressant and/or sedative effects. |
Efavirenz (EFV) or etravirine (ETR) |
|
|
Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. |
Benzodiazepines
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 27: Benzodiazepines | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustments necessary. |
Elvitegravir (EVG), boosted | Boosted ARV agents may increase benzodiazepine concentrations via CYP3A4 inhibition. | Alprazolam, clonazepam, diazepam: 1) Consider alternative benzodiazepine. 2) If used, administer lowest effective dose; monitor closely for adverse effects. |
Boosted PIs |
|
|
Efavirenz (EFV) | Alprazolam, diazepam: Potential for reduced alprazolam and diazepam concentrations. |
|
Etravirine (ETR) | Alprazolam, diazepam: Potential for reduced alprazolam and diazepam concentrations. | Alprazolam: Monitor for benzodiazepine withdrawal. |
Abbreviations: ARV, antiretroviral; CYP, cytochrome P450; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Note: Lorazepam, oxazepam, and temazepam do not interact clinically with and do not require dose adjustments when coadministered with ARV agents. |
Sleep Medications
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 28: Sleep Medications | ||
→ Non-benzodiazepine “Z-drugs,” melatonin, ramelteon, suvorexant | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustment necessary. |
|
|
|
Efavirenz (EFV) or etravirine (ETR) | Zolpidem: Potential for reduced concentrations of zolpidem. |
|
Abbreviations: ARV, antiretroviral; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RTV, ritonavir. |
Antipsychotics
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 29: Antipsychotics* | ||
→ First-generation, second-generation, and atypical | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions expected. | No dose adjustments necessary. |
Elvitegravir (EVG), boosted |
|
|
Ritonavir (RTV) | Olanzapine: May induce CYP1A2, especially in cigarette smokers, which may decrease olanzapine concentrations. | Olanzapine: Monitor for efficacy; titrate slowly as needed. |
Boosted PIs |
|
|
Atazanavir (ATV), unboosted |
Lurasidone: Decreases lurasidone metabolism via CYP3A. |
Lurasidone: Reduce dose by 50%; monitor for adverse effects, including QT prolongation. |
Rilpivirine (RPV) |
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. |
Efavirenz (EFV) |
|
|
Etravirine (ETR) |
|
|
Fostemsavir (FTR) | Fostemsavir may prolong QT. | Use caution when combining fostemsavir with other medications known to prolong QT interval. |
Abbreviations: ARV, antiretroviral; CYP, cytochrome P450; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. *Coadministration of antipsychotic and ARV agents may result in QT prolongation; monitor closely. |
Anticonvulsants
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 30: Anticonvulsants | ||
→ Including phenytoin, phenobarbital, carbamazepine, oxcarbazepine, lamotrigine, valproic acid, gabapentin, topiramate, zonisamide | ||
Class or Drug | Mechanism of Action | Clinical Comments |
Tenofovir disoproxil fumarate (TDF) | Zonisamide: May increase concentration of zonisamide. |
|
Tenofovir alafenamide (TAF) | Coadministration with strong inducers of CYP3A (phenytoin, phenobarbital, etc.) may decrease TAF concentrations. | Coadministration with strong inducers of CYP3A is not recommended because it may reduce concentrations of TAF. |
Other NRTIs | No interactions noted. | No dose adjustments necessary. |
Dolutegravir (DTG) or bictegravir (BIC) |
Coadministration with strong inducers of CYP3A (phenytoin, phenobarbital, etc.) may decrease DTG or BIC concentrations. |
No dose adjustments necessary. |
Raltegravir (RAL) | Coadministration with strong inducers of UGT1A1 (phenytoin, phenobarbital, etc.) may decrease RAL concentrations. | Coadministration with strong inducers of UGT1A1 are not recommended. |
Elvitegravir (EVG), boosted | Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system. | 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. |
Ritonavir (RTV) |
|
|
Boosted PIs |
|
|
NNRTIs | Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Coadministration may significantly reduce concentrations of ARV agents through induction of CYP450 system. | 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 if use cannot be avoided. |
Rilpivirine (RPV) | Gabapentin, topiramate, zonisamide: No significant interactions expected. |
Gabapentin, topiramate, zonisamide: No dose adjustments necessary. |
Efavirenz (EFV) or etravirine (ETR) |
|
|
Fostemsavir (FTR) | Carbamazepine, oxcarbazepine, phenobarbital, phenytoin:Significant reductions in fostemsavir expected. | Coadministration should be avoided due to potential loss of FTR efficacy. |
Abbreviations: ARV, antiretroviral; COBI, cobicistat; CYP, cytochrome P450; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; UGT1A1, uridine diphosphate glucuronosyltransferase 1A1. |
Non-Opioid Pain Medications
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 31: Non-Opioid Pain Medications | ||
→ Triptans, tricyclic antidepressants (TCAs), pregabalin, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions expected. | No dose adjustment necessary. |
Elvitegravir (EVG), boosted |
|
Eletriptan: Do not coadminister; use alternative triptan medication. |
Boosted PIs |
|
|
Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; NSAID, non-steroidal anti-inflammatory drug; PI, protease inhibitor; TDF, tenofovir disoproxil fumarate. Note: Although TDF and NSAIDs (such as ibuprofen, meloxicam, or naproxen) are not absolutely contraindicated, NSAIDs may increase the risk of impaired renal function in patients taking high doses of these drugs, and particularly in patients who are predisposed to renal dysfunction. Clinicians are advised to ask patients about their use of over-the-counter or prescribed NSAIDs and to counsel patients to limit NSAID use to the lowest effective dose. Clinicians should also ask patients who are taking TDF as part of a pre-exposure prophylaxis regimen (PrEP) about their use of NSAIDs. |
Opioid Analgesics and Tramadol
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 32: Opioid Analgesics and Tramadol | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustments required. |
Elvitegravir (EVG), boosted |
|
|
Boosted PIs |
|
|
Efavirenz (EFV) |
|
|
Abbreviations: ARV, antiretroviral; COBI, cobicistat; CYP, cytochrome P450; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RTV, ritonavir. |
Hormonal Contraceptives
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 33: Hormonal Contraceptives | ||
→ Combined oral contraceptives, including ethinyl estradiol, norethindrone, and levonorgestrel | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant drug interactions noted. | No dose adjustments necessary. |
Elvitegravir (EVG), boosted | Drospirenone: Potential for hyperkalemia. |
|
All PIs | Combination has not been studied. | Etonogestrel: No data; consider alternative or additional contraceptive method or alternative ARV agent. |
Atazanavir (ATV), unboosted | Complex drug interaction potential has been described. |
|
Atazanavir (ATV), boosted |
|
|
Darunavir (DRV)/ ritonavir (RTV) | Combination appears to decrease oral norethindrone concentrations. | Norethindrone: Consider alternative or additional contraceptive method or alternative ARV agent. |
DRV/cobicistat (COBI) | Combination has not been studied, but since COBI does not induce glucuronidation, it is expected to increase concentrations of norethindrone. | Norethindrone: Consider alternative contraceptive method or alternative ARV agent. |
Other Boosted PIs | Drospirenone: Potential for hyperkalemia. |
|
Efavirenz (EFV) | Decreased concentrations of combined progestins. |
|
Etravirine (ETR) | Information is based on what is known with EFV drug interactions. |
|
Fostemsavir (FTR) |
|
|
Abbreviations: ARV, antiretroviral; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. |
Erectile and Sexual Dysfunction Agents
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 34: Erectile and Sexual Dysfunction Agents | ||
→ Sildenafil [a], vardenafil, tadalafil [b,c], and alprostadil for men; flibanserin [d] for women | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustment necessary. |
Elvitegravir (EVG), boosted |
|
|
Atazanavir (ATV), unboosted | Avanafil: Increased concentration of avanafil expected (for other oral erectile dysfunction drugs, see above). | Avanafil: Do not exceed 50 mg every 24 hours. |
Boosted PIs |
|
|
Efavirenz (EFV) or etravirine (ETR) |
|
|
Abbreviations: COBI, cobicistat; NRTI, nucleoside reverse transcriptase inhibitor; PDE5, phosphodiesterase type 5; PI, protease inhibitor. Notes:
|
Tobacco and Smoking Cessation Products
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 35: Tobacco and Smoking Cessation Products | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustments necessary. |
Efavirenz (EFV) or etravirine (ETR) |
|
|
Abbreviations: NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. |
Alcohol, Disulfiram, and Acamprosate
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 36: Alcohol, Disulfiram, and Acamprosate | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustments necessary. |
Abacavir (ABC) | Alcohol: Metabolized via same pathway as alcohol. | May increase ABC concentrations; monitor for adverse ABC effects. Does not appear to increase concentrations of alcohol in blood. |
|
All contain alcohol and may potentiate symptoms of consumption of ethanol. | Disulfiram: ARV agents formulated with alcohol will induce same aversive effects as consumption of ethanol. |
Abbreviations: ARV, antiretroviral; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Note: Clinicians are advised to inform patients that alcohol should be consumed with caution while taking a prescription medication and should educate patients about how medications may affect their response to alcohol. Clinicians are advised to caution patients against driving or operating heavy machinery after consuming alcohol. |
Methadone, Buprenorphine, Naloxone, and Naltrexone
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 37: Methadone, Buprenorphine (BUP), Naloxone (NLX), and Naltrexone* | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
BUP, methadone: No significant interactions expected. | No dose adjustments necessary. |
Atazanavir (ATV), unboosted |
|
|
Ritonavir (RTV)-boosted PIs | BUP: May greatly increase BUP concentrations, but clinical significance of this is unknown because dosing of BUP is based on clinical opiate withdrawal scale. | BUP: Monitor for signs of increased opioid toxicity, including sedation, impaired cognition, and respiratory distress. |
Cobicistat (COBI)-boosted PIs |
|
|
RTV-boosted darunavir (DRV), taken twice per day |
|
Methadone: Monitor for signs of opiate withdrawal and increase dose of methadone if necessary. |
Rilpivirine (RPV) |
|
|
Efavirenz (EFV) |
|
|
Etravirine (ETR) |
|
|
*No significant interactions expected between ARVs, naloxone, and naltrexone. Abbreviations: ARV, antiretroviral; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. |
Immunosuppressants
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 38: Immunosuppressants* | ||
Class or Drug | Mechanism of Action | Clinical Comments |
|
No significant interactions noted. | No dose adjustments necessary. |
Bictegravir (BIC) | Cyclosporine: May increase BIC concentrations to a modest degree via P-gP inhibition. |
Monitor for BIC-related adverse events. |
Elvitegravir (EVG), boosted |
|
|
Boosted PIs |
|
|
Efavirenz (EFV) or etravirine (ETR) | Cyclosporine, tacrolimus: Concentrations may be lower when used with EFV or ETR. | Cyclosporine, tacrolimus: 1) Dose adjust cyclosporine and tacrolimus based on efficacy and therapeutic drug monitoring (TDM). 2) Conduct TDM more frequently for 2 weeks when starting or stopping NNRTI therapy. |
Abbreviations: NNRTI, non-nucleoside reverse transcriptase inhibitors; NRTI, nucleoside reverse transcriptase inhibitor; P-gP, P-glycoprotein; PI, protease inhibitor; TDF, tenofovir disoproxil fumarate. *Note: Cyclosporine can cause renal toxicity, which may be increased with coadministration of TDF. Clinicians are advised to monitor for signs of renal dysfunction in patients who are taking these two medications at the same time. |
Rifamycins and Other Anti-Tuberculosis Medications
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, updated February 2021
Table 39: Rifamycins and Other Anti-Tuberculosis Medications | ||
→ Rifampin, rifabutin, rifapentine [a], isoniazid [b], pyrazinamide [b], ethambutol [b], rifaximin [b] | ||
ARV Class and Drugs | Rifabutin Interactions and Recommendations | Rifampin Interactions and Recommendations |
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | ||
Abacavir (ABC) |
|
|
Emtricitabine (FTC) |
|
N/A |
Lamivudine (3TC) |
|
N/A |
Tenofovir alafenamide (TAF) |
|
|
Tenofovir disoproxil fumarate (TDF) |
|
N/A |
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | ||
Doravirine (DOR) |
|
|
Efavirenz (EFV) |
|
|
Etravirine (ETR) |
|
|
Nevirapine (NVP) |
|
|
Rilpivirine (RPV) |
|
|
Protease Inhibitor (PIs) and Boosted PIs | ||
All PIs |
|
|
Integrase Strand Transfer Inhibitors (INSTIs) | ||
Bictegravir (BIC) |
|
|
Dolutegravir (DTG) |
|
|
Elvitegravir (EVG), boosted |
|
|
Raltegravir (RAL) |
|
|
Entry Inhibitor | ||
Fostemsavir (FTR) |
|
|
Abbreviations: ARV, antiretroviral; CYP, cytochrome P450; P-gP, P-glycoprotein. Notes:
|
Gender-Affirming Hormones
Lead author: Joshua R. Sawyer, PharmD, AAHIVP, with the Medical Care Criteria Committee, reviewed February 2021
Table 40: Gender-Affirming Hormones | ||
→ Cyproterone acetate, estradiol, finasteride, goserelin, leuprolide acetate, spironolactone, testosterone | ||
ARV Drug Class or Medication | Mechanism of Action | Clinical Comments |
ARV medications, all |
|
|
Cobicistat (COBI) |
|
|
Doravirine (DOR) |
|
N/A |
Efavirenz (EFV) |
|
|
Etravirine (ETR) |
|
|
INSTIs, non-boosted (dolutegravir, DTG; raltegravir, RAL) |
|
N/A |
NRTIs, non-boosted |
|
N/A |
Rilpivirine (RPV) |
|
N/A |
Ritonavir (RTV) |
|
N/A |
Abbreviations: ARV, antiretroviral; CYP, cytochrome P450; INSTI, integrase strand transfer inhibitor; N/A, not applicable; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. |
References
Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: An Endocrine Society Clinical Practice Guideline. Endocr Pract 2017;23(12):1437. [PMID: 29320642]
Irving A, Lehault WB. Clinical pearls of gender-affirming hormone therapy in transgender patients. Ment Health Clin 2018;7(4):164-167. [PMID: 29955517]
Updates to This Resource
February 2021
Additions, Deletions, and Updates | |||
Table or Section | Changes | ||
Additions | Deletions | Updates | |
Table 1: Mechanisms of ARV Drug-Drug Interactions | FTR, MVC | — | — |
Table 2: Boosted ATV Interactions | RFB, RIF | — | PPIs |
Table 3: DRV Interactions | RFB, RIF | — | — |
Table 4: BIC Interactions | RFB, RIF |
|
|
Table 5: DTG Interactions | RFB, RIF |
Pioglitazone, |
— |
Table 6: Boosted EVG Interactions | RFB, RIF | — | Factor Xa inhibitors, inhaled and injected corticosteroids |
Table 7: RAL Interactions | RFB, RIF | — | — |
Table 10: EFV Interactions |
RFB, RIF, gender-affirming hormones |
— | — |
Table 11: ETR Interactions | RFB, RIF, gender-affirming hormones | — | — |
Table 12: ABC Interactions | RFB, RIF | — | — |
Table 14A: FTR Interactions | New table | — | — |
Table 14B: MVC Interactions | New table | — | — |
Section: ARV Drug-Drug Interactions by Common Medication Class | DOR and FTR added to many tables throughout this section | — | — |
— | Valproic acid | — | |
Abbreviations: ABC, Abacavir; ARV, antiretroviral; ATV, atazanavir; BIC, bictegravir; DOR, doravirine; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine; EVG, elvitegravir; FTR, fostemsavir; MVC, maraviroc; PPI, proton-pump inhibitor; RAL, raltegravir; RFB, rifabutin; RIF, rifampin. |
November 2019
Three new tables added: