Drug-drug interactions are common concerns of patients with HIV and their health care providers. The issues involved in evaluating drug interactions are complex. Although many questions can be articulated simply (e.g., "What antidepressant is least likely to have drug interactions with antiretroviral medications?"), the responses to these questions involve more complex concerns (e.g., "In choosing an antidepressant for my patient with HIV, I must consider efficacy, adverse effects, and tolerability as well as drug interactions.").
This complexity is increased because antiretroviral (ARV) agents, particularly protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), the pharmacokinetic booster cobicistat, and the CCR5 antagonist maraviroc, can cause or be affected by alterations in the activity of the cytochrome (CYP) P450 enzyme system in the liver, as well as by other mechanisms of drug metabolism. Interactions between an ARV and another drug (whether another ARV or a different type of medication) may result in an increase or a decrease in the serum levels of either the ARV or the interacting drug, potentially changing the effectiveness or the toxicity risk of substrate drugs. Understanding drug-drug interactions is challenging because of several factors, including the following:
- Different drugs affect different P450 enzymes.
- Some medications have dosage-related responses that influence their effects on P450 enzymes.
- Formal pharmacokinetic studies on drug combinations are limited.
- Even when pharmacokinetic data exist for specific drug combinations, the clinical significance of any changes in pharmacokinetic parameters may not be clear.
- Patients taking ARVs often have complex drug regimens. Patients typically are taking three or more medications that could influence interactions. Pharmacokinetic studies that evaluate the clinical significance of drug interactions involving more than two medications are less likely to be available.
- Other metabolic pathways of medications such as P-glycoprotein (P-gp) and UDP-glucuronosyltransferase (UGT)-1A1, can be altered by drug interactions. The integrase inhibitors dolutegravir and raltegravir, for example, are metabolized by UGT-1A1.
- Some drug interactions involve effects on absorption or drug availability rather than metabolism. For example, the PI atazanavir and the NNRTI rilpivirine require gastric acidity for absorption; integrase inhibitor activity is impaired by polyvalent cations (e.g., iron, aluminum, calcium, and magnesium, and antacids, laxatives, supplements, and other preparations that contain them).
- Other influences on medication activity include food-drug interactions, protein binding, and altered intercellular activation of medications.
Information on various drug-drug interactions is available in guidelines and via the Internet (see "Resources," below). Such resources can provide data regarding two-drug combinations, but rarely consider all the complexities outlined above. What follows, therefore, is a suggested approach to considering drug-drug interactions in managing HIV-infected patients and making patient-specific decisions, illustrated by a case study.
A new patient arrives for a clinic intake appointment. The patient receives medical care from a local infectious disease physician who treats only a handful of HIV-infected patients. The patient was recently released from hospital with a discharge diagnosis of pneumonia and Mycobacterium avium complex (MAC). The patient is not yet taking ARVs, but needs to start ART promptly, along with an adherence support program. The patient has other medical problems, including hyperlipidemia, erectile dysfunction, diabetes, depression, gastroesophageal reflux disease (GERD), and herpes. The clinician wants to review the patient's medication list to check for any potential drug-drug interactions.
Review the patient's pharmacy records for current medications, and ask about use of over-the-counter (OTC), herbal or natural products, and dietary supplements. As requested, the patient has brought in all medications from home for review. The current medication list includes the following:
- Clarithromycin 500 mg BID
- Ethambutol 1,000 mg QD
- Rifabutin 300 mg QD
- Trimethoprim-sulfamethoxazole (TMP-SMX) (Septra, Bactrim) double-strength, 1 tablet QD
- Lovastatin 20 mg QD
- Metformin 500 mg BID
- Bupropion 150 mg QD
- Acyclovir 400 mg BID
- Omeprazole 20 mg QD (patient buys OTC for heartburn)
- Milk thistle (silymarin) (patient takes as needed for energy and liver health)
Step 1: Identify interactions and classify them as follows:
- Definite interactions
- Probable interactions
- Possible interactions
Definite Drug Interactions
A drug interaction is definite if a high level of evidence is available regarding the drug combination, the clinical significance of the interaction is well understood, and consensus exists regarding the management strategy (e.g., whether dosage adjustments are required, or concurrent use is contraindicated). Common definite interactions for HIV patients include the following:
- Certain combinations of HIV agents (e.g., certain PIs or integrase inhibitors with NNRTIs, maraviroc with PIs or NNRTIs, tenofovir with atazanavir)
- Rifamycins and PIs, NNRTIs, cobicistat, or maraviroc
- Statins with PIs or cobicistat
- Erectile dysfunction agents and PIs or cobicistat
- Methadone and certain PIs or NNRTIs
- Fluticasone and PIs or cobicistat
Probable Drug Interactions
A drug interaction is probable if the limited available evidence suggests that an interaction may occur, even if the clinical outcome or significance may not be clearly established. Effective management of a probable interaction is based on assessment and clinical judgment about the risks and benefits of a particular combination for each patient. Examples of probable interactions with HIV-related medications include the following:
- Antidepressants and PIs or NNRTIs
- Oral contraceptives and PIs or cobicistat
- Warfarin and PIs, NNRTIs, or cobicistat
- Proton pump inhibitors (PPIs) or H-2 blockers and atazanavir or rilpivirine
- Polyvalent cations (e.g., calcium, iron, cation-containing antacids) and integrase inhibitors
- Certain antifungal agents and PIs, NNRTIs, or cobicistat (except in the case of voriconazole, for which definite information on interactions is available)
- Certain antiepileptic medications and PIs, NNRTIs, or cobicistat
Possible Drug Interactions
Possible drug interactions may be difficult to distinguish from probable drug interactions, but in these cases, only theoretical evidence is available. The proper management of such interactions requires weighing the risks and benefits of the combination and making sound clinical judgments. Examples of possible drug interactions with HIV medications include the following:
- Herbal products and PIs, NNRTIs, or cobicistat (except in the case of St. John's wort, for which definite information on interactions is available)
- Antidiabetic medications and PIs or NNRTIs
- Antipsychotic agents and PIs, NNRTIs, or cobicistat
Memorizing all the potential drug interactions is impossible. It is possible, however, to remember a few commonly encountered drug combinations that have the potential for clinically significant interactions. It is also important to recognize that PIs (particularly ritonavir), NNRTIs, and cobicistat very commonly interact with other medications. The above examples of definite, probable, and possible interactions are reasonable "red flag" drug combinations that can be recalled easily. In addition, certain Internet resources allow providers to submit all of a patient's current medications and planned additions (e.g., atazanavir/ritonavir as part of a new ARV regimen) and receive information on potential interactions (see "Resources," below). Finally, consultation with clinical pharmacists can aid in identifying and classifying potential interactions.
Step 2: The patient described above will start an ARV regimen of atazanavir/ritonavir + tenofovir + emtricitabine. The PI may cause problematic drug-drug interactions with some of the patient's preexisting medications, and tenofovir interacts with atazanavir. Develop a plan for management when these ARVs are added. For this patient, the following definite interactions should be of concern:
- Rifabutin and atazanavir/ritonavir
- Lovastatin and atazanavir/ritonavir
- Tenofovir and atazanavir
- Clarithromycin and atazanavir/ritonavir
Refer to available references for management suggestions. Such references include the following:
- U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, relevant tables
- HIV InSite Database of Antiretroviral Drug Interactions
- University of Liverpool HIV Drug Interaction Charts
- Clinical Care Options
Most of these resources include specific dosage adjustments or alternative agents to consider when managing these drug combinations. The suggestions for this patient are as follows:
- Rifabutin levels are increased by atazanavir/ritonavir. The rifabutin dosage should be decreased to 150 mg daily with standard atazanavir/ritonavir dosing. Alternatively, discuss with the patient's primary care provider whether rifabutin is important to the current MAC regimen or whether the patient could be treated adequately with just clarithromycin + ethambutol to avoid the above-cited interactions.
- Lovastatin levels are increased substantially by atazanavir/ritonavir; concurrent use with a PI can lead to potentially fatal rhabdomyolysis. Lovastatin should be discontinued when atazanavir/ritonavir is initiated. To manage hyperlipidemia, the patient should be switched to a statin whose metabolism is less affected by these PIs, such as pravastatin or low-dose atorvastatin (simvastatin, also is contraindicated for use by patients who take a PI).
- Tenofovir can decrease plasma concentrations of unboosted atazanavir, but can be administered safely with ritonavir-boosted atazanavir.
- Clarithromycin levels are increased by atazanavir/ritonavir; concurrent use can lead to QTc prolongation. If clarithromycin is co-administered with atazanavir/ritonavir, its dosage should be reduced by 50%.
Although this patient's current medication list does not contain an erectile dysfunction agent, the patient should be educated about the definite interactions and dosage adjustments recommended for patients using those agents with PIs. Some patients may obtain erectile dysfunction agents outside the care of their physician and, if unaware of the interactions and suggested dosage adjustments, may be at risk of life-threatening consequences.
The following probable or possible interactions should be considered if PIs are begun, including:
- Omeprazole with atazanavir/ritonavir
- Bupropion with atazanavir/ritonavir
- Milk thistle with atazanavir/ritonavir
The web-based resources and other references listed above include some information about these potential interactions. The following are suggestions:
- Omeprazole: PPIs and H2-blockers decrease serum levels of atazanavir, even when boosted with ritonavir, but the clinical significance of this interaction has not been demonstrated. In general, it may be best to avoid concomitant use of these acid-blocking medications with atazanavir by either discontinuing the GERD medication or switching to another ARV. Unboosted atazanavir should not be used with PPIs. For patients without evidence of ARV resistance in whom coadministration of these medications is judged unavoidable, atazanavir/ritonavir may be used, but doses of omeprazole should not exceed 20 mg and must be taken at least 12 hours prior to taking atazanavir/ritonavir. Note that tenofovir also can lower atazanavir levels, so increasing atazanavir to 400 mg/day with ritonavir 100 mg/day could be considered.
- Bupropion and milk thistle: Specific management or dosage adjustments based on data are not available. This patient should be monitored for increased or decreased effects of bupropion and educated about potential interactions with milk thistle. Clinical judgment and decision making with the primary care provider and other specialists (e.g., psychiatrists) may be required.
Consultation with clinical pharmacy services may assist in evaluating the potential significance of drug interactions and developing management strategies.
- Instruct patients that HIV medications, in particular PIs, NNRTIs, cobicistat, and maraviroc, have a high potential for significant drug interactions.
- Tell patients to bring all their medicines, including any herbal, nutritional, and dietary supplements and OTC remedies, with them to all medical appointments. If they cannot bring the actual containers with them, they should bring a list of current prescribed medications, supplements, and OTC medications.
- Patients should have their primary care provider or pharmacist review any newly prescribed medications along with their current list of medicines. This is especially important if another physician prescribes a new medication.
- Patients should not "borrow" medications from friends or family. Assure patients that if they have a problem that needs medical treatment, their primary care provider will discuss it and choose the safest treatments for them.
- Tell patients that, if they are considering buying a new nutritional or herbal supplement or an OTC product, they should consult their pharmacist or primary care provider about interactions with drugs on their current medication list.
- Not all drug interactions are cause for alarm. Some drug combinations are safe for certain people, but less safe for others. Warn patients not to stop taking any medicines without the advice of their primary care provider.
- HIV InSite Database of Antiretroviral Drug Interactions (hivinsite.ucsf.edu/interactions)
- University of Liverpool HIV Drug Interaction Charts (www.hiv-druginteractions.org/)
- Clinical Care Options (www.clinicaloptions.com/HIV.aspx)
- Dickinson L, Khoo, S, Back D. Pharmacokinetics and drug-drug interactions of antiretrovirals: an update. Antiviral Res. 2010 Jan;85(1):176-89.
- Liedtke MD, Lockhart SM, Rathbun RC. Anticonvulsant and antiretroviral interactions. Ann Pharmacother. 2004 Mar;38(3):482-9.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Accessed December 1, 2013.
- Piscitelli SC, Gallicano KD. Interactions among drugs for HIV and opportunistic infections. N Engl J Med. 2001 Mar 29;344(13):984-96.
- Rainey PM. HIV drug interactions: the good, the bad, and the other. Ther Drug Monit. 2002 Feb;24(1):26-31.
- Sheehan NL, Kelly DV, Tseng AL, et al. Evaluation of HIV drug interaction web sites. Ann Pharmacother. 2003 Nov;37(11):1577-86.
- Soodalter J, Sousa M, Boffito M. Drug-drug interactions involving new antiretroviral drugs and drug classes. Curr Opin Infect Dis. 2009 Feb;22(1):18-27.