ART Drug-Drug Interactions

ART Drug-Drug Interactions

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:

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].
KEY POINT
  • People with HIV may experience a greater number of comorbid conditions as they age. Treatment of multiple comorbid conditions increases the risk of polypharmacy and associated drug-drug interactions.

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.

KEY POINT
  • When simplifying or changing ART regimens, it is important to identify the potential effects that a loss (or gain) of CYP inhibition may have on every drug (not just ARVs) that an individual is taking.

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:
  • Current medication list, including prescription medications, over-the-counter medications, supplements, and herbal preparation (see discussion below)
  • Any changes in medications or dosages since the last visit or medication review
  • Current medical conditions being treated or that require treatment
  • Previous medical conditions that have been resolved to check for medications that should be discontinued
When prescribing new medications or renewing a prescription, always:
  • Identify the new drug’s potential to cause adverse effects and current or future drug-drug interactions
  • Identify any potential interactions between an existing prescription medication and any new medications on the patient’s list
  • Inform patients about the potential for drug-drug interactions or adverse effects when taking ARVs that interact with commonly available over-the-counter medications, including nasal steroids, mineral supplements, antacids, or proton pump inhibitors

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.

KEY POINT
  • Clinicians utilizing electronic prescribing systems should be aware of the risks associated with “alert fatigue,” including the potential to miss drug-drug interaction alerts.

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].

KEY POINT
  • An accurate and frequently updated medication history helps to prevent errors with prescription, over-the-counter, and supplement and/or herbal medications.

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.

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 clinicians:
For patients:
References

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

Davies EA, O’Mahony MS. Adverse drug reactions in special populations – the elderly. Br J Clin Pharmacol 2015;80(4):796-807. [PMID: 25619317

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

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

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&sectionid=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

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

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

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)
BIC
[1]
3A4 (minor) Substrate Inhibitor of MATE1; OCT2 Chelation
CAB
[2]
Substrate P-gP substrate
OATP1 inhibitor
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 P-gP; BCRP; OATP; OCT; MATE1
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; 2C8 (minor) Inhibitor P-gP substrate, inhibitor, inducer
OATP inhibitor
GI absorption (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 absorption (pH-dependent)
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
ABC
[14]
Substrate Alcohol dehydrogenase 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 Inhibitors (EIs)
FTR
[19]
3A4 Substrate of P-gP; BCRP
Inhibitor of OATP; BCRP
IBA [a]
[20]
MVC
[21]
3A4 P-gP substrate

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.

Note:

  1. Based on the IBA mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected.

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
  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; 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.

Note:

  1. 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.

Sources: [Tseng, et al. 2017; Marzolini, et al. 2016; Foisy, et al. 2008]

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 [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.

References

Aberg JA, Tebas P, Overton ET, et al. Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type 1-infected subjects over 48 weeks. AIDS Res Hum Retroviruses 2012;28(10):1184-1195. [PMID: 22352336

Adams JL, Greener BN, Kashuba AD. Pharmacology of HIV integrase inhibitors. Curr Opin HIV AIDS 2012;7(5):390-400. [PMID: 22789987

Alvarez A, Orden S, Andujar I, et al. Cardiovascular toxicity of abacavir: a clinical controversy in need of a pharmacological explanation. AIDS 2017;31(13):1781-1795. [PMID: 28537935

Barbarino JM, Kroetz DL, Altman RB, et al. PharmGKB summary: abacavir pathway. Pharmacogenet Genomics 2014;24(5):276-282. [PMID: 24625462

Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002;71(3):115-121. [PMID: 11907485

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

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

DHHS. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV: Table 23. Mechanisms of antiretroviral-associated drug interactions. 2021 Jun 3. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/overview?view=full [accessed 2022 Jun 30]

FDA. Rukobia (fostemsavir) extended-release tablets, for oral use. 2020 Jul. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212950s000lbl.pdf [accessed 2020 Nov 25]

FDA. Trogarzo (ibalizumab-uiyk) injection, for intravenous use. 2021a Apr. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761065s011lbl.pdf [accessed 2021 May 28]

FDA. Vocabria (cabotegravir) tablets, for oral use. 2021b Jan. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212887s000lbl.pdf [accessed 2021 Apr 12]

Foisy MM, Yakiwchuk EM, Hughes CA. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 2008;42(7):1048-1059. [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

Ivanyuk A, Livio F, Biollaz J, et al. Renal drug transporters and drug interactions. Clin Pharmacokinet 2017;56(8):825-892. [PMID: 28210973

Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fumarate: clinical pharmacology and pharmacokinetics. Clin Pharmacokinet 2004;43(9):595-612. [PMID: 15217303

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

Lampertico P, Buti M, Fung S, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study. Lancet Gastroenterol Hepatol 2020;5(5):441-453. [PMID: 32087795

Llibre JM, Hill A. Abacavir and cardiovascular disease: A critical look at the data. Antiviral Res 2016;132:116-121. [PMID: 27260856

Lund M, Petersen TS, Dalhoff KP. Clinical implications of P-glycoprotein modulation in drug-drug interactions. Drugs 2017;77(8):859-883. [PMID: 28382570

Mao Q, Unadkat JD. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport–an update. AAPS J 2015;17(1):65-82. [PMID: 25236865

Markham A. Bictegravir: First global approval. Drugs 2018;78(5):601-606. [PMID: 29564777

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. https://doi.org/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

Perry CM. Maraviroc: a review of its use in the management of CCR5-tropic HIV-1 infection. Drugs 2010;70(9):1189-1213. [PMID: 20518583

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] https://pubmed.ncbi.nlm.nih.gov/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=514&sectionid=41817582 [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

Yee KL, Sanchez RI, Auger P, et al. Evaluation of doravirine pharmacokinetics when switching from efavirenz to doravirine in healthy subjects. Antimicrob Agents Chemother 2017;61(2). [PMID: 27872069

Yin J, Duan H, Wang J. Impact of substrate-dependent inhibition on renal organic cation transporters hOCT2 and hMATE1/2-K-mediated drug transport and intracellular accumulation. J Pharmacol Exp Ther 2016;359(3):401-410. [PMID: 27758931

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

Zaccara G, Perucca E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord 2014;16(4):409-431. [PMID: 25515681

Drug-Drug Interactions by Antiretroviral Drug Class

Reviewed and updated: John Faragon, PharmD, BCPS, AAHIVP, with the Medical Care Criteria Committee; October 14, 2022

RECOMMENDATION
  • Clinicians should consult an experienced HIV care provider for assistance in managing drug-drug interactions between antiretroviral (ARV) agents and less common medications. (A3)

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)

Table 3: Boosted Atazanavir (ATV) Interactions

Table 4: Boosted Darunavir (DRV) Interactions

Integrase Strand Transfer Inhibitors (INSTIs)

Table 5: Bictegravir (BIC) Interactions

Table 6: Cabotegravir (CAB) Interactions

Table 7: Dolutegravir (DTG) Interactions

Table 8: Boosted Elvitegravir (EVG) Interactions

Table 9: Raltegravir (RAL) Interactions

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Table 10: Doravirine (DOR) Interactions

Table 11: Rilpivirine (RPV) Interactions

Table 12: Efavirenz (EFV) Interactions

Table 13: Etravirine (ETR) Interactions

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Table 14: Abacavir (ABC) Interactions

Table 15: Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF) Interactions

Table 16: Lamivudine (3TC) and Emtricitabine (FTC) Interactions

Entry Inhibitors (EIs)

Table 17: Fostemsavir (FTR) Interactions

Table 18: Maraviroc (MVC) 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 2021 Jul 19]

Drug-Drug Interactions by Common Medication Class

Reviewed and updated: John Faragon, PharmD, BCPS, AAHIVP, with the Medical Care Criteria Committee; October 14, 2022

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.

KEY POINT
  • Medications used to treat epilepsy, various types of malignancies, and tuberculosis and to prevent graft-versus-host disease following solid organ transplants are known to interact with several ARVs. Because of the serious nature of these conditions and the complexity of their treatment, many details of the specific interactions of these drugs have not been reviewed here. Clinicians should consult with the appropriate specialty service when questions arise pertaining to the management of these conditions.

The following tables are available as individual PDF downloads.

Table 19: Common Oral Antibiotics

Table 20: Drugs Used as Antihypertensive Medicines

Table 21: Anticoagulants

Table 22: Antiplatelet Drugs

Table 23: Statins

Table 24: Antidiabetic Drugs

Table 25: Acid-Reducing Agents

Table 26: Polyvalent Cations

Table 27: Asthma and Allergy Medications

Table 28: Long-Acting Beta Agonists

Table 29: Inhaled and Injected Corticosteroids

Table 30: Antidepressants

Table 31: Benzodiazepines

Table 32: Sleep Medications

Table 33: Antipsychotics

Table 34: Anticonvulsants

Table 35: Nonopioid Pain Medications

Table 36: Opioid Analgesics and Tramadol

Table 37: Hormonal Contraceptives

Table 38: Erectile and Sexual Dysfunction Agents

Table 39: Alpha-Adrenergic Antagonists for Benign Prostatic Hyperplasia

Table 40: Tobacco and Smoking Cessation Products

Table 41: Alcohol, Disulfiram, and Acamprosate

Table 42: Methadone, Buprenorphine, Naloxone, and Naltrexone

Table 43: Immunosuppressants

Table 44: Rifamycins and Other Antituberculosis Medications

Table 45: COVID-19 Therapeutics

Table 46: Mpox Treatments

Table 47: Gender-Affirming Hormones

Guideline Information and Updates

Guideline Information
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.
Updates
October 6, 2022

John Faragon, PharmD, BCPS, AAHIVP, with the MCCC:

  • Added mpox and COVID-19 therapeutics information throughout Drug-Drug Interactions by Antiretroviral Drug Class section
  • Table 3: Boosted ATV Interactions: Added alpha-adrenergic antagonists for benign prostatic hyperplasia; updated anticoagulants, factor Xa inhibitors, PY2-antagonists, antipsychotics, and antidiabetic drugs
  • Table 4: Boosted DRV Interactions: Added pitavastatin, alpha-adrenergic antagonists for benign prostatic hyperplasia, and antipsychotics; updated anticoagulants, factor Xa inhibitors, antiplatelet drugs, PY2-antagonists, and antidiabetic drugs
  • Table 5: BIC Interactions and Table 6: CAB Interactions: Updated antacids
  • Table 8: Boosted EVG Interactions: Added alpha-adrenergic antagonists for benign prostatic hyperplasia, midazolam, and triazolam; updated factor Xa inhibitors, antiplatelet drugs, rosuvastatin, and PDE5 inhibitors
  • Table 13: ETR Interactions: Updated antiplatelet drugs
  • Added new tables to Drug-Drug Interactions by Common Medication Class section: Table 39: Alpha-Adrenergic Antagonists for Benign Prostatic Hyperplasia, Table 45: COVID-19 Therapeutics, and Table 46: Mpox Treatments
July 20, 2021

John Faragon, PharmD, BCPS, AAHIVP, with the MCCC:

  • Table 1: Mechanisms of ARV Drug-Drug Interactions: Added new information on CAB and IBA
  • Table 6: CAB Interactions: Added new table to Drug-Drug Interactions by Antiretroviral Drug Class > INSTIs section
  • Table 11: RPV Interactions: Added new information
  • Updated CAB and RPV information in all tables in Drug-Drug Interactions by Common Medication Class section
  • Updated rifabutin (RFB), rifampin (RIF), and rifapentine information throughout tables in Drug-Drug Interactions by Antiretroviral Drug Class section
  • Table 44: Rifamycins and Other Antituberculosis Medications: Expanded and updated
February 26, 2021
  • Table 1: Mechanisms of ARV Drug-Drug Interactions: Added FTR and MVC
  • Table 3: Boosted ATV Interactions: Added RFB and RIF; updated proton pump inhibitors
  • Table 4: Boosted DRV Interactions: Added RFB and RIF
  • Table 5: BIC Interactions: Added RFB and RIF
  • Table 7: DTG Interactions: Added RFB and RIF; deleted pioglitazone and valproic acid
  • Table 8: Boosted EVG Interactions: Added RFB and RIF; updated factor Xa inhibitors and inhaled and injected steroids
  • Table 9: RAL Interactions: Added RFB and RIF
  • Table 12: EFV Interactions: Added RFB, RIF, and gender-affirming hormones
  • Table 14: ABC Interactions: Added RFB and RIF
  • Table 17: FTR Interactions: New table
  • Table 18: MVC Interactions: New table
  • ARV Drug-Drug Interactions by Common Medication Class: Added DOR and FTR to many tables throughout this section
  • Table 34: Anticonvulsants: Added DTG and BIC interactions; deleted valproic acid
November 25, 2019

Added 3 new tables:

  • Table 2: Induction Potential of Ritonavir and Cobicistat Used as Boosters
  • Table 44: Rifamycins and Other Antituberculosis Medications
  • Table 47: Gender-Affirming Hormones
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
Program Manager

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.
Expert Committees

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.

Committee Structure
  • Leadership: AI-appointed chair, vice chair(s), chair emeritus, clinical specialist(s), JHU Guidelines Program Director, AI Medical Director, AI Clinical Consultant, AVAC community advisor
  • Contributing members
  • Guideline writing groups: Lead author, coauthors if applicable, and all committee leaders
Conflicts of Interest Disclosure and Management
  • Annual disclosure of financial relationships with commercial entities for the 12 months prior and upcoming is required of all individuals who work with the guidelines program, and includes disclosure for partners or spouses and primary professional affiliation.
  • The NYSDOH AI assesses all reported financial relationships to determine the potential for undue influence on guideline recommendations and, when indicated, denies participation in the program or formulates a plan to manage potential conflicts.
  • Disclosures are listed for each committee member.
Evidence Collection and Review
  • Literature search and review strategy is defined by the guideline lead author based on the defined scope of a new guideline or update.
  • A comprehensive literature search and review is conducted for a new guideline or an extensive update using PubMed, other pertinent databases of peer-reviewed literature, and relevant conference abstracts to establish the evidence base for guideline recommendations.
  • A targeted search and review to identify recently published evidence is conducted for guidelines published within the previous 3 years.
  • Title, abstract, and article reviews are performed by the lead author. The JHU editorial team collates evidence and creates and maintains an evidence table for each guideline.
Recommendation Development
  • The lead author drafts recommendations to address the defined scope of the guideline based on available published data.
  • Writing group members review the draft recommendations and evidence and deliberate to revise, refine, and reach consensus on all recommendations.
  • When published data are not available, support for a recommendation may be based on the committee’s expert opinion.
  • The writing group assigns a 2-part rating to each recommendation to indicate the strength of the recommendation and quality of the supporting evidence. The group reviews the evidence, deliberates, and may revise recommendations when required to reach consensus. 
Review and Approval Process
  • Following writing group approval, draft guidelines are reviewed by all contributors, program liaisons, and a volunteer reviewer from the AI Community Advisory Committee.
  • Recommendations must be approved by two-thirds of the full committee. If necessary to achieve consensus, the full committee is invited to deliberate, review the evidence, and revise recommendations when required.
  • Final approval by the committee chair and the NYSDOH AI Medical Director is required for publication.
External Reviewers
  • External peer reviewers recognized for their experience and expertise review guidelines for accuracy, balance, clarity, and practicality and provide feedback.
  • Peer reviewers may include nationally known experts from outside of New York State.
Update Process
  • JHU editorial staff ensure that each guideline is reviewed and determined to be current upon the 3-year anniversary of publication; guidelines that provide clinical recommendations in rapidly changing areas of practice may be reviewed annually. Published literature is surveilled to identify new evidence that may prompt changes to existing recommendations or development of new recommendations.
  • If changes in the standard of care, newly published studies, new drug approval, new drug-related warning, or a public health emergency indicate the need for immediate change to published guidelines, committee leadership will make recommendations and immediate updates.
  • All contributing committee members review and approve substantive changes to, additions to, or deletions of recommendations; JHU editorial staff track, summarize, and publish ongoing guideline changes.
Recommendation Ratings Scheme
Strength Quality of Evidence
Rating Definition Rating Definition
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.