Purpose of This Resource
Reviewed and updated: John Faragon, PharmD, BCPS, AAHIVP; October 14, 2022
Writing Group: Joseph P. McGowan, MD, FACP, FIDSA; Steven M. Fine, MD, PhD; Samuel T. Merrick, MD; Asa E. Radix, MD, MPH, PhD, FACP, AAHIVS; Rona M. Vail, MD; Christopher J. Hoffmann, MD, MPH; Charles J. Gonzalez, MD
Committee: Medical Care Criteria Committee
Date of original publication: April 25, 2019
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 reported drug-drug interactions to identify those that should or must be avoided and those that can be managed to alleviate adverse effects
The NYSDOH AI Medical Care Criteria Committee offers guidance on the interactions between ARVs 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 HIV transmission (see the NYSDOH AI guideline When to Initiate ART, With Protocol for Rapid Initiation). This resource 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
- WebMD Drug Interaction Checker
- Clinical Info HIV.gov Drug Database
- Toronto General Hospital Immunodeficiency Clinic Drug Interaction Tables
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.
Identifying Drug-Drug Interactions
Reviewed and updated: John Faragon, PharmD, BCPS, AAHIVP, with the Medical Care Criteria Committee; October 14, 2022
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 effects 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 polypharmacy-related risk factors 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 [Zingmond, et al. 2017; Walckiers, et al. 2015]
- Age older than 50 years:
- As people age, more diseases develop, which increases the risk of polypharmacy. Comorbidities commonly seen in an aging population, such as hypertension, chronic obstructive pulmonary disease, and diabetes mellitus, are increasingly prevalent in individuals with HIV [Gleason, et al. 2013].
- Age-related physiologic changes may alter drug responses in older individuals [Gujjarlamudi 2016].
- Treatment provided by more than 1 care provider (including specialists)
- Limited care provider communication
- Prescriptions filled 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].
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 ARVs with multiple mechanisms of action suppresses virus replication to a greater extent and for a longer period than using 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 using 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 effects caused by higher or more frequent dosing of the active agent. In turn, adherence may be improved by reducing pill burden. Similarly, using a potent inhibitor of a drug transporter allows for reduced or less frequent dosing 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 its ability to boost other medications, ritonavir is likely to cause more drug-to-drug interactions because it exerts a broader effect on CYP450 enzymes in addition to CYP3A4.
In the current era of HIV treatment, it is well established that when used as prescribed, antiretroviral therapy (ART) effectively suppresses 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, switching 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 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 effects 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 effects 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.
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 effects. Although this is not seen when combining ARVs to suppress HIV viral load, it can be seen when combining antihypertensive medicines (which may cause hypotension) or antidiabetic medicines (which may lead to additive hypoglycemia). In addition, an additive effect may result from medications with overlapping adverse effect profiles. A historic example is the use of zidovudine with other drugs that cause bone marrow suppression, including ribavirin or ganciclovir [Sim, et al. 1998; Aulitzky, et al. 1988].
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, 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 effects, they are more likely to discontinue medications. Adverse effects 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 an ART regimen 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:
When prescribing new medications or renewing a prescription, always:
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 effects, such as encouraging patients to avoid seeing multiple prescribers, avoid filling their prescriptions at multiple pharmacies, and keep each of their healthcare providers informed of treatment decisions made by other specialists [Lavan, et al. 2016; Lehnbom, et al. 2014]. 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 list 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 effects 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.
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, reduce the risk of adverse drug effects and drug-drug interactions, and improve medication adherence. The CMS website provides more information on requirements and services. Core elements of the MTM model include [American Pharmacists Association 2018]:
- Medication therapy review: 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.
- Personal medication record (PMR) and medication-related action plan: Records created for an individual patient 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: Inclusion of a pharmacist’s expertise for safe, appropriate, and cost-effective use of medications for patients who have already developed or are at high risk of developing medication-related problems.
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 ensuring 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 [Patient-Centered Primary Care Collaborative 2012].
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, tacrolimus), antiseizure medications (e.g., phenytoin, carbamazepine), and mood stabilizers (e.g., lithium, lamotrigine). Certain antibiotics, including vancomycin or aminoglycosides, are also dosed based on TDM.
The use of TDM with ARV dosing 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 [DHHS 2021]. 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.
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.
American Pharmacists Association. Medication Therapy Management Services. 2018 https://www.pharmacist.com/Practice/Patient-Care-Services/Medication-Management [accessed 2021 Jul 19]
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]
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DHHS. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV: Drug-drug interactions: Role of therapeutic drug monitoring in managing drug-drug interactions. 2021 Jun 3. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/overview [accessed 2018 Jul 6]
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]
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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]
Patient-Centered Primary Care Collaborative. 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=514§ionid=41817582 [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]
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Classifications and Mechanisms of Drug-Drug Interactions
Reviewed and updated: John Faragon, PharmD, BCPS, AAHIVP, with the Medical Care Criteria Committee; October 14, 2022
Antiretroviral (ARV) medications themselves, though increasingly safe and effective, may cause adverse effects that affect organ systems [Gallant, et al. 2018; Dharan and Cooper 2017]. 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 [Lampertico, et al. 2020; 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 [Aberg, et al. 2012; Noor, et al. 2004; Carr, et al. 1998]. These inherent adverse effects 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 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.
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.
|Table 1: Mechanisms of Antiretroviral (ARV) Drug-Drug Interactions
Cited references are listed at the bottom of this table; also see drug package inserts.
|ARV||CYP Substrate||CYP Inhibitor||CYP Inducer||UGT1A1||Drug Transport Protein||Other|
|Integrase Strand Inhibitors (INSTIs)|
|3A4 (minor)||—||—||Substrate||Inhibitor of MATE1; OCT2||Chelation|
|3A4 (minor)||—||—||Substrate||P-gP substrate
Inhibitor of MATE2; OCT2
|3A4; 2D6 (minor)||3A4; 2D6 (minor)||—||—||Inhibitor of P-gP; BCRP; OATP; OCT; MATE1||—|
|3A4; 2D6 (minor)||3A4; 2C8; 2C9; 2C19; 2D6||1A2; 2B6; 2C9; 2C19||Inducer||Inhibitor of P-gP; BCRP; OATP; OCT; MATE1||—|
|Protease Inhibitors (PIs)|
|3A4||3A4; 2C8 (minor)||—||Inhibitor||P-gP substrate, inhibitor, inducer
|GI absorption (pH-dependent)|
|Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)|
|2B6 (primary); 2A6; 3A4||3A4||3A4; 2B6||—||—||—|
|3A4; 2C9; 2C19||2C9; 2C19||3A4||—||P-gP inducer||—|
|3A4||—||—||—||—||GI absorption (pH-dependent)|
|Nucleoside Reverse Transcriptase Inhibitors (NRTIs)|
|—||—||—||Substrate||—||Alcohol dehydrogenase substrate|
|—||—||—||—||Substrate of MATE1/2; OCT2||—|
|3A4 (minor)||—||—||—||Substrate of P-gP; BCRP; OATP||—|
|—||—||—||—||Substrate of P-gP; OATP; MRP||—|
|Entry Inhibitors (EIs)|
|3A4||—||—||—||Substrate of P-gP; BCRP
Inhibitor of OATP; BCRP
Drug name abbreviations: 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; BIC, bictegravir; CAB, cabotegravir; COBI, cobicistat; DRV, darunavir; DOR, doravirine; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine; EVG, elvitegravir; FTC, emtricitabine; FTR, fostemsavir; IBA, ibalizumab; MVC, maraviroc; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.
Other abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome P450; GI, gastrointestinal; MATE, multidrug and toxin extrusion; MRP, multidrug resistance protein; OATP, organic anion transporting polypeptide; OCT, organic cation transporter; P-gP, P-glycoprotein; UGT, uridine diphosphate glucuronosyltransferase.
Sources: [DHHS 2021; Tseng, et al. 2017; Marzolini, et al. 2016; Taneva, et al. 2015; Kiser, et al. 2008]; 1. [Markham 2018]; 2. [FDA 2021b]; 3. [McCormack 2014]; 4. [Deeks 2014c; Perry 2014]; 5. [Deeks 2017]; 6. [Deeks 2014a]; 7. [Tseng, et al. 2017; Deeks 2014b; Croom, et al. 2009]; 8. [Croom, et al. 2009]; 9. [Deeks 2014b]; 10. [Deeks 2018; Yee, et al. 2017]; 11. [Ogburn, et al. 2010]; 12. [Deeks and Keating 2008]; 13. [Deeks 2014d]; 14. [Barbarino, et al. 2014]; 15. [Reznicek, et al. 2017]; 16. [Muller, et al. 2013]; 17. [Scott and Chan 2017]; 18. [Kohler, et al. 2011; Kearney, et al. 2004]; 19. [FDA 2020]; 20. [FDA 2021a]; 21. [Perry 2010]
|Table 2: Induction Potential of Ritonavir [a] and Cobicistat Used as Boosters|
|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|
|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; MATE, multidrug and toxin extrusion; OAT, organic anion transporter; OATP, organic anion transporting protein; OCT, organic cation transporter; P-gP, P-glycoprotein; UGT, uridine diphosphate glucuronosyltransferase.
Sources: [Tseng, et al. 2017; Marzolini, et al. 2016; Foisy, et al. 2008]
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 [Schafer and Short 2012; Klein, et al. 2008]). Some substances will form insoluble complexes with other drugs in a process known as chelation (e.g., using 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 heavily protein-bound medications 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, 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 [Deeks 2014d; Perry 2010]. 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, are autoinducers of their own metabolism, causing the lead-in period seen when dosing those drugs [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 [Tseng, et al. 2017; Deeks 2014a].
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 ARVs.
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 effects.
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.
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Drug-Drug Interactions by Antiretroviral Drug Class
Reviewed and updated: John Faragon, PharmD, BCPS, AAHIVP, with the Medical Care Criteria Committee; October 14, 2022
Caveats: Many of the formal interaction studies involving ARVs are carried out in small samples of participants who do not have HIV or other known comorbid conditions. Although the results of such studies may be extrapolated to larger populations of individuals 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, an incomplete correlation often exists between predicted drug-drug interactions and in vivo pharmacokinetics. Significant person-to-person variability also exists 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 coadministered drugs they prescribe. 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 prescribed in primary care, and drug-drug interactions may lead to symptoms attributed to ARVs rather than the physiologic effect of 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.
The following tables are available as individual PDF downloads.
Boosted Protease Inhibitors (PIs)
Integrase Strand Transfer Inhibitors (INSTIs)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Entry Inhibitors (EIs)
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 2021 Jul 19]
Drug-Drug Interactions by Common Medication Class
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 medications. 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 states 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 U.S. Department of Health and Human Services give each class of medications in the initial management of HIV. Appropriate HIV management 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 ARVs.
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 (drug package inserts), which are also available online for each of the listed pharmacologic agents. Healthcare providers are encouraged to utilize these resources if they 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.
Consultation with an experienced HIV care provider is also recommended when assistance is needed in choosing an antiretroviral therapy (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.
The following tables are available as individual PDF downloads.
Guideline Information and Updates
|Intended users||New York State clinicians who prescribe and manage antiretroviral therapy for patients with HIV|
|Last reviewed and updated||John Faragon, PharmD, BCPS, AAHIVP; October 14, 2022|
|Original publication||April 25, 2019|
|Writing group||Joseph P. McGowan, MD, FACP, FIDSA; Steven M. Fine, MD, PhD; Samuel T. Merrick, MD; Asa E. Radix, MD, MPH, PhD, FACP, AAHIVS; Rona M. Vail, MD; Christopher J. Hoffmann, MD, MPH; Charles J. Gonzalez, MD|
|Committee||Medical Care Criteria Committee|
|Developer and funding||New York State Department of Health AIDS Institute (NYSDOH AI)|
|Development||See Guideline Development and Recommendation Ratings, below.|
|October 6, 2022||
John Faragon, PharmD, BCPS, AAHIVP, with the MCCC:
|July 20, 2021||
John Faragon, PharmD, BCPS, AAHIVP, with the MCCC:
|February 26, 2021||
|November 25, 2019||
Added 3 new tables:
|Guideline Development: New York State Department of Health AIDS Institute Clinical Guidelines Program|
|Developer||New York State Department of Health AIDS Institute (NYSDOH AI) Clinical Guidelines Program|
|Funding Source||NYSDOH AI|
Clinical Guidelines Program, Johns Hopkins University School of Medicine, Division of Infectious Diseases. See Program Leadership and Staff.
|Mission||To produce and disseminate evidence-based, state-of-the-art clinical practice guidelines that establish uniform standards of care for practitioners who provide prevention or treatment of HIV, viral hepatitis, other sexually transmitted infections, and substance use disorders for adults throughout New York State in the wide array of settings in which those services are delivered.|
The NYSDOH AI Medical Director invites and appoints committees of clinical and public health experts from throughout NYS to ensure that the guidelines are practical, immediately applicable, and meet the needs of care providers and stakeholders in all major regions of NYS, all relevant clinical practice settings, key NYS agencies, and community service organizations.
|Conflicts of Interest Disclosure and Management||
|Evidence Collection and Review||
|Review and Approval Process||
|Recommendation Ratings Scheme|
|Strength||Quality of Evidence|
|A||Strong||1||Based on published results of at least 1 randomized clinical trial with clinical outcomes or validated laboratory endpoints.|
|B||Moderate||*||Based on either a self-evident conclusion; conclusive, published, in vitro data; or well-established practice that cannot be tested because ethics would preclude a clinical trial.|
|C||Optional||2||Based on published results of at least 1 well-designed, nonrandomized clinical trial or observational cohort study with long-term clinical outcomes.|
|2†||Extrapolated from published results of well-designed studies (including nonrandomized clinical trials) conducted in populations other than those specifically addressed by a recommendation. The source(s) of the extrapolated evidence and the rationale for the extrapolation are provided in the guideline text. One example would be results of studies conducted predominantly in a subpopulation (e.g., one gender) that the committee determines to be generalizable to the population under consideration in the guideline.|
|3||Based on committee expert opinion, with rationale provided in the guideline text.|