BackgroundDrug-drug interactions are common concerns of both patients with HIV and their health care providers. The issues involved in evaluating drug interactions are complex. Although many questions can be articulated simply (eg, "What antidepressant is least likely to have drug interactions with HIV medications?"), the responses to these questions involve more complex concerns (eg, "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 agents, particularly protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), can cause and be affected by alterations in the activity of the cytochrome P450 enzymes in the liver. These enzymes are responsible for metabolizing many medications. Understanding the relevance of the influence of P450 enzymes 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 HIV medications often have complex drug regimens. The interaction of only 2 drugs is rarely the concern; more often, patients are taking 3 or more medications that could influence interactions. Pharmacokinetic studies that evaluate the clinical significance of drug interactions involving more than 2 medications are less likely to be available.
- The P450 system is not the only influence on medication activity. Other influences include absorption, food-drug interactions, protein binding, altered activation of medications intracellularly, and altered efflux-pump activity.
Information on various drug-drug interactions is available in guidelines and via the Internet (see "Resources" below). Such resources can provide data regarding 2-drug combinations, but rarely consider all the complexities outlined above. What follows, therefore, is a suggested approach to considering drug-drug interactions in the management of HIV-infected patients and making patient-specific decisions. S: SubjectiveA new patient arrives for his clinic intake appointment. The patient receives his medical care from a local infectious-disease physician who has only a handful of HIV-infected patients in her practice. The patient was recently released from the hospital with a discharge diagnosis of pneumonia and Mycobacterium avium complex (MAC). He is not yet taking HIV medications, but is likely to start them in the next several weeks after the establishment of care and adherence support programs. Other problems include hyperlipidemia, erectile dysfunction, diabetes, depression, and herpes. The clinician wants to review the patient's medication list to check for any potential drug-drug interactions. O: ObjectiveReview the patient's pharmacy records for current medications. As requested, the patient has brought in all his medications from home for review. His current medication list includes the following: - Clarithromycin 500 mg twice daily
- Ethambutol 1,000 mg daily
- Rifabutin 300 mg daily
- TMP-SMX (Septra, Bactrim) DS 1 tablet daily
- Lovastatin 20 mg daily
- Metformin 500 mg twice daily
- Bupropion 150 mg daily
- Acyclovir 400 mg twice daily
- Milk thistle (silymarin) (patient takes as needed for energy and liver health)
A: AssessmentStep 1: Identify interactions and classify them as follows: - Definite interactions
- Probable interactions
- Possible interactions
Definite Drug InteractionsA 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 (eg, dosage adjustments). Common definite interactions for HIV patients include: - Certain combinations of HIV agents (eg, boosted PIs, NNRTI + PI combinations)
- Rifamycins and PIs or NNRTIs
- Statins and PIs + NNRTIs
- Erectile dysfunction agents and PIs
- Methadone and PIs
Probable Drug InteractionsA 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 that patient. Examples of probable interactions with HIV-related medications include: - Antidepressants and PIs or NNRTIs
- Oral contraceptives and PIs
- Warfarin and PIs or NNRTIs
- Proton pump inhibitors or H-2 blockers and atazanavir
Possible Drug InteractionsPossible 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 an interaction requires weighing the risks and benefits of the combination and making sound clinical judgments. Examples of possible drug interactions with HIV medications include: - Herbal products and PIs or NNRTIs (except in the case of St. John's wort, for which definite information on interactions is available)
- Antidiabetic medications and PIs or NNRTIs
- Antifungal agents and PIs or NNRTIs (except in the case of voriconazole, for which definite information on interactions is available)
- Antiseizure medications and PIs or NNRTIs
- Antipsychotic agents and PIs or NNRTIs
Memorizing all the potential drug interactions is impossible. It is possible, however, to remember a few commonly used drug combinations with the potential for clinically significant interactions. 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 you to submit all of a patient's current medications and planned additions (eg, lopinavir/ritonavir as part of a new antiretroviral regimen) and receive feedback on potential interactions (see "Resources" below). Finally, consultation with clinical pharmacists can aid in identifying and classifying potential interactions. P: PlanStep 2: The patient described above will start an antiretroviral regimen of lopinavir/ritonavir + zidovudine + lamivudine. The PI may cause problematic drug-drug interactions with some of his other medications. Develop a plan for management when lopinavir/ritonavir is added to this regimen. For this patient, the following definite interactions should be of concern: - Rifabutin and lopinavir/ritonavir
- Lovastatin and lopinavir/ritonavir
Refer to available references for management suggestions. Such references include: Most of these sites include specific dosage adjustments or alternative agents to consider when managing these drug combinations. The following are suggestions for the above interactions: - The rifabutin dosage should be 150 mg every other day with standard lopinavir/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 interactions.
- Lovastatin should be discontinued in this patient when lopinavir/ritonavir is begun. To manage hyperlipidemia, the patient should be switched to safer statins such as pravastatin or low-dose atorvastatin.
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 for life-threatening consequences. Some additional probable or possible interactions should be considered if PIs are begun, including: - Bupropion with lopinavir/ritonavir
- Milk thistle with lopinavir/ritonavir
The Web sites and references listed above include some information about these potential interactions, but no specific management or dosage adjustments are given. This patient should be monitored for increased effects of bupropion and educated about potential interactions with milk thistle. Clinical judgment and decision making with the primary care provider and other subspecialists (eg, psychiatrists) may be required. Consultation with clinical pharmacy services also may assist in evaluating the potential significance of an interaction and developing management strategies. Patient Education- Instruct patients that HIV medications, in particular PIs and NNRTIs, have a high potential for significant drug interactions.
- Tell patients to take all their medicines, including any herbal supplements and over-the-counter remedies, with them to all medical appointments. If they cannot take the actual bottles with them, they should make a list of current prescribed medications, supplements, and over-the-counter 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 over-the-counter 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.
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