Highlights
- •People living with HIV often need treatment for other acute and chronic conditions.
- •Important interactions can occur when drugs are coadministered with antiretrovirals.
- •Interactions may compromise viral control or cause toxicity.
- •Some drug combinations are contraindicated.
- •Clinical resources can help nurse practitioners analyze interactions and make appropriate decisions.
Abstract
Pharmacotherapy may be indicated to treat a variety of conditions for patients living with human immunodeficiency virus. It is important for nurse practitioners (NPs) to be aware of clinically significant interactions involving antiretroviral therapy and other prescribed drugs or over-the-counter products, herbal therapies, and dietary supplements. Drug interactions may result in adverse clinical outcomes by increasing or decreasing drug levels, which subsequently may compromise viral control, enhance risk of toxicity, or have other unintended effects. Various clinical resources are available for NPs to make safer prescribing decisions.
Keywords
American Association of Nurse Practitioners (AANP) members may receive 1.0 continuing education contact hour, approved by AANP, by reading this article and completing the online posttest and evaluation at aanp.inreachce.com.
Introduction
The first acquired immunodeficiency syndrome (AIDS) cases were reported in 1981, and human immunodeficiency virus (HIV)/AIDS has been described as one of “humanity’s deadliest and most persistent epidemics.”
1
However, extraordinary progress has been made, and the emergence of effective antiretroviral therapy (ART) to treat HIV has turned what was once a frequently fatal disease into a manageable chronic condition.1
, 2
, 3
The goal of ART is “to suppress HIV viral load, restore immune function, prevent HIV transmission, prevent resistance, and improve quality of life.”3
Nurse practitioners (NPs) may need to prescribe medication(s) for patients with acute or chronic conditions while they are taking ART for HIV. Although it is important for prescribers to be aware of clinically significant drug–drug interactions (DDIs) involving antiretroviral (ARV) agents and other drugs, it is also important to appropriately treat the other conditions.Antiretroviral drugs have been described as being among the most risky for clinically significant drug interactions (CSDIs)
4
; thus, it is important for clinicians to identify and analyze CSDIs that may occur with ART to promote safe and effective prescribing. Several prescription drugs and over-the-counter (OTC) medications, including vitamins and herbal supplements, can have CSDIs with ARV drugs.5
, 6
, 7
These interactions may lead to drug toxicity or reduction of therapeutic effects of either drug. Further, DDIs can also have a devastating effect on viral control of HIV.5
The mechanism of interaction frequently involves cytochrome (CYP) P450 pathway and, to a lesser extent, a membrane transport protein, P-glycoprotein.5
A study by Evans et al4
examined prescriber awareness of HIV drug interactions and found a low rate of awareness, with only 36% of CSDIs being correctly identified. Some of the most common interactions reported in this study were associated with antidepressants, antibiotics, and “statins”.4
Helpful online resources are available for clinicians to identify potential interactions before prescribing a new medication in the presence of ART. A partial list of references is provided in Table 1. Additionally, a clinician could also consult with a clinical pharmacist or an HIV specialist when necessary.
3
While reviewing drug–drug interactions, prescribers should be aware that not all drug interactions must be avoided. Precautionary interventions such as close monitoring or dose adjustment of either drug may be recommended. However, other serious interactions may provide more absolute warnings, such as “contraindicated,” “should not be co-administered,” “should be avoided,” or “not recommended.” Because DDIs involving ART may pose serious risks, this article outlines and discusses important interactions that may commonly occur in clinical practice (Table 2). Alternative options for consideration and resources for clinicians are also reviewed. It is important to realize that DDI recommendations may change over time as the body of knowledge evolves and new drugs are developed. To get the most updated and accurate interaction information, prescribers should use an evidence-based drug reference immediately before prescribing any drug with ART.Table 1Some Clinical Resources to Identify Interactions With Antiretroviral Therapy
| University of Liverpool | Website: https://www.hiv-druginteractions.org/prescribing-resources Free mobile application: Liverpool HIV iChart |
| National Institutes of Health, Office of AIDS Research |
|
| Canadian HIV and Viral Hepatitis Pharmacists Network | https://hivclinic.ca/downloads/DDI%20Booklet%202019_English.pdf |
| Johns Hopkins University HIV Clinical Guidelines Program | https://www.hivguidelines.org/antiretroviral-therapy/ddis/#tab_0 |
| University of California–San Francisco | http://hivinsite.ucsf.edu/insite?page=ar-00- 02&post=10¶m=8 |
Table 2Some Clinically Significant Drug-Drug Interactions With 1 or More Antiretroviral Drugs
5
,9
,11
,16
,18
,21
,27
,28
,30
,34
| Drugs | Categories |
|---|---|
| Budesonide, fluticasone, triamcinolone, 5 ,27 mometasone, dexamethasone,27 ciclesonide, betamethasone, methylprednisolone11 | Corticosteroids |
| Salmeterol 11 ,28 | Inhaled beta agonist |
| Lovastatin, simvastatin 11 ,16 | Lipid-lowering |
| Red yeast rice 18 ,24 | Dietary supplement for hyperlipidemia |
| Dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole 11 ,18 ,21 | Proton pump inhibitors |
| St. John’s wort 9 ,11 | Herbal therapy for depression |
| Apixaban, rivaroxaban, clopidogrel, ticagrelor 32 | Anticoagulants and antiplatelets |
| Progestin and estrogen 5 ,11 ,30 | Hormonal contraceptive therapy |
| Itraconazole and ketoconazole 21 ,23 University of Liverpool. Interactions with NNRTIs. Revised April 2021; Accessed April 27, 2021, https://liverpool-hiv-hep.s3.amazonaws.com/prescribing_resources/pdfs/000/000/078/original/NNRTIs_2021_Apr%282%29.pdf?1618306570. | Antifungals |
Antidepressants
Depression is a common comorbidity of HIV, with major depression having a greater prevalence in people living with HIV (PLWH) and AIDS than the general population at an estimated 15–40%.
8
DDIs can occur when antidepressants are administered in the presence of ART, but Stolbach et al expounded that this potential effect should not deter treatment of depression because many benefits can also be derived from appropriate treatment, including increased ART adherence.5
It has been suggested that lack of appropriate treatment for depression may be even more detrimental than medication interactions.8
Potential effects of DDIs between ARVs and antidepressants include increased or decreased concentrations of the antidepressant or HIV drug, as well as potential cardiac abnormalities QT and/or PR prolongation.9
A drug reference may suggest interventions including close monitoring, dose adjustment, or avoidance of co-administration.9
Two important considerations have been highlighted when selecting an antidepressant for a patient taking ART: adverse effect profile and potential interactions.8
,10
One important potential interaction involves the herbal therapy St. John’s wort, which is contraindicated with several classes of ART.9
,11
This herb may lower the level of an ARV and compromise viral control.9
,11
More information regarding DDIs between a variety of antidepressants and ART can also be found within Liverpool HIV prescribing resources (Table 1).9
In addition, neuropsychiatric adverse effects, including depression, have been linked with some antivirals in the nonnucleoside reverse transcriptase inhibitors (NNRTI) class12
and infrequently with the integrase strand transfer inhibitors (INSTIs).11
The Panel on Antiretroviral Guidelines for Adults and Adolescents recommended periodic screening for depression and suicidality for patients taking the NNRTI efavirenz and closely monitoring those with a preexisting psychiatric condition who were prescribed an INSTI, due to the potential for depression and suicidality.11
Lipid-Lowering Drugs
Both ART and HIV can cause metabolic dysfunction, such as dyslipidemia.
13
, 14
, 15
HMG-CoA reductase inhibitors are important treatment options for dyslipidemia, which could cause serious CSDIs. For example, lovastatin and simvastatin are contraindicated with several ARVs, including protease inhibitors (PIs) and the boosted INSTI elvitegravir/cobicistat,11
due to increased levels of the lipid-lowering drugs and increased risk of myopathy and rhabdomyolysis.17
The dietary supplement red yeast rice should not be coadministered with some ARVs, such as PIs18
because it contains varying amounts of monacolin K, which is structurally identical to lovastatin.19
,20
Additionally, atorvastatin and rosuvastatin levels can be increased significantly when combined with boosted PIs,16
and an increased level of pravastatin has been documented when it is administered with darunavir/ritonavir.16
Therefore, close monitoring with a lower statin dose should be recommended if these combinations are used.17
,21
Because pitavastatin and pravastatin involve minimal CYP metabolism, they have been highlighted as having fewer risks of interactions with ART.13
,22
Antimicrobials
Antimicrobials may also have CSDIs with ART and trigger a variety of alerts and recommendations, such as “closely monitor,” “adjust dose,” “use an alternative,” “do not coadminister,” and “contraindicated.”
11
,21
In particular, antitubercular therapies, rifampin and rifapentine, have triggered alert of contraindication with multiple ARVs11
,18
,23
,University of Liverpool. Interactions with NNRTIs. Revised April 2021; Accessed April 27, 2021, https://liverpool-hiv-hep.s3.amazonaws.com/prescribing_resources/pdfs/000/000/078/original/NNRTIs_2021_Apr%282%29.pdf?1618306570.
24
,25
because they can cause subtherapeutic HIV drug concentrations.11
Furthermore, if tuberculosis (TB) therapies are required for TB/HIV coinfection, the Panel on Antiretroviral Guidelines for Adults and Adolescents will provide a discussion of ART options to mitigate their interactions.11
In addition, the treatment of hepatitis B or hepatitis C could also cause serious DDI; therefore, prescribers should check for interactions before selecting a treatment regimen.11
,18
,23
, University of Liverpool. Interactions with NNRTIs. Revised April 2021; Accessed April 27, 2021, https://liverpool-hiv-hep.s3.amazonaws.com/prescribing_resources/pdfs/000/000/078/original/NNRTIs_2021_Apr%282%29.pdf?1618306570.
24
,26
ART may compromise the efficacy of antifungal therapy because itraconazole and ketoconazole levels can decrease when they are combined with the NNRTI drugs nevirapine or efavirenz.17
,21
,23
The University of Liverpool notes some antibacterials that are not expected to cause clinically significant interactions with ARVs, including amoxicillin, cefazolin, cefixime, ceftazidime, and ceftriaxone.University of Liverpool. Interactions with NNRTIs. Revised April 2021; Accessed April 27, 2021, https://liverpool-hiv-hep.s3.amazonaws.com/prescribing_resources/pdfs/000/000/078/original/NNRTIs_2021_Apr%282%29.pdf?1618306570.
18
,23
, University of Liverpool. Interactions with NNRTIs. Revised April 2021; Accessed April 27, 2021, https://liverpool-hiv-hep.s3.amazonaws.com/prescribing_resources/pdfs/000/000/078/original/NNRTIs_2021_Apr%282%29.pdf?1618306570.
24
, 25
Corticosteroids
Corticosteroids are prescribed for a variety of conditions, but it is important to consider that steroids, such as budesonide, fluticasone, triamcinolone,
5
,27
,28
mometasone, dexamethasone,27
ciclesonide, betamethasone, and methylprednisolone11
can cause CSDIs. The University of Liverpool drug resource indicates the risks of elevated corticosteroid levels, Cushing’s syndrome, and adrenal suppression when protease inhibitors and the boosters cobicistat and ritonavir are coadministered with a variety of corticosteroids in multiple formulations, such as oral, injected, topical, inhaled, and ophthalmic.17
,27
When an inhaled corticosteroid is needed, beclomethasone may be an option, with no clinically significant interaction expected with a variety of ARV drugs.27
Meanwhile, if a topical corticosteroid is needed, hydrocortisone may be considered.27
Hormonal Contraceptives
Women represent more than half of the 37 million people worldwide currently living with HIV, and the majority of these women are of childbearing age.
29
,Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium
HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial [published correction appears in Lancet. 2019 Jul 27;394(10195):302].
HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial [published correction appears in Lancet. 2019 Jul 27;394(10195):302].
30
When clinicians discuss options for safe and effective contraception with HIV-positive women, it is important to note that estrogen and progestin components can have clinically significant interactions with ART.5
,30
The Panel on Antiretroviral Guidelines for Adults and Adolescents states that all available contraceptive methods can be used by individuals with HIV after potential DDIs have been considered.11
When there are significant interactions between hormonal contraceptives and ARV drugs, an alternative therapy or additional effective contraceptive method is recommended.11
Because hormonal contraceptives containing estrogen and/or progestin are primarily metabolized by CYP isoenzymes5
,30
and many agents of ART are inducers or inhibitors of these enzymes,30
the risk of clinically significant interactions is high. Fluctuations of hormonal contraceptive concentrations may cause various effects, including lowering of contraceptive efficacy or escalation of estrogen- or progestin-related adverse effects.5
,11
As a result, an alternative therapy, dose adjustment, or additional backup method may be necessary.11
,31
For example, many oral, implantable, vaginal ring, and patch formulations of progestins can have serious interactions with efavirenz, an NNRTI, causing a decrease in the level of the progestin and compromised efficacy.31
The boosted PI, atazanavir/ritonavir (ATV/r), may lower ethinyl estradiol (EE) levels; therefore, an oral contraceptive with a minimum EE dose of 35 μg may be needed.11
,31
In contrast, the unboosted PI ATV may increase EE levels, so an oral contraceptive with an EE dose of no more than 30 μg may be recommended.11
,30
,31
Consequently, the product label of the boosted PI, atazanavir/cobicistat (ATV/c), recommended an alternate, reliable, nonhormonal method be considered instead of a hormonal contraceptive.31
Meanwhile, drospirenone-containing contraceptives are contraindicated with ATV/c,11
,31
due to potential for hyperkalemia.11
Of note, the Panel on Antiretroviral Guidelines for Adults and Adolescents suggests that the magnitude of changes in contraceptive drug concentrations are unknown for all forms of contraceptives when given together with ARV drugs, which made the interpretation of the DDI even more challenging.
11
However, 2 forms of contraceptives, medroxyprogesterone depot and levonorgestrel intrauterine device (IUD), have been noted by the University of Liverpool as not expected to have CSDIs with multiple classes of ART.31
Additionally, there are also several small studies supporting safety of levonorgestrel-releasing IUDs.11
A nonhormonal option, the copper IUD, has also been found to be safe and effective.29
More information about DDIs between hormonal contraceptives and ART can also be found within can be found within resources by the University of LiverpoolEvidence for Contraceptive Options and HIV Outcomes (ECHO) Trial Consortium
HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial [published correction appears in Lancet. 2019 Jul 27;394(10195):302].
HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial [published correction appears in Lancet. 2019 Jul 27;394(10195):302].
31
and the National Institutes of Health, Office of AIDS Research (Table 1).Gastrointestinal Drugs
Proton pump inhibitors (PPIs), H2 receptor antagonists (H2RAs), and antacids (such as those containing magnesium, aluminum, or calcium) can have serious interactions with ART, which can lead to poor absorption and compromise viral control.
5
,11
,21
Many PPIs should not be coadministered with ARV drugs.11
,18
,21
,23
, University of Liverpool. Interactions with NNRTIs. Revised April 2021; Accessed April 27, 2021, https://liverpool-hiv-hep.s3.amazonaws.com/prescribing_resources/pdfs/000/000/078/original/NNRTIs_2021_Apr%282%29.pdf?1618306570.
24
Meanwhile, the administration time of H2RAs and antacids may need to be separated as far apart as possible from the ARV therapies to avoid potential prevention of absorption (for example, taking the ARV 2–4 hours before or 10–12 hours after the H2RA may be recommended).5
,11
,21
Anticoagulants and Antiplatelets
Because cardiovascular disease and thromboembolic disease are more common in PLWH than the general population,
11
it is crucial to be cautious when prescribing anticoagulants and antiplatelets. Important CSDIs have been noted when apixaban, rivaroxaban, clopidogrel, and ticagrelor are coadministered with ARV drugs, which can lead to potential toxicity or subtherapeutic effects; thus, coadministration is not recommended.32
In addition, caution should be implemented when initiating dabigatran with some ART, such as P-glycoprotein inhibitors.5
,21
The DDIs between ART and the narrow therapeutic index drug warfarin have been described as complex and difficult to predict; thus, close monitoring with frequent dose adjustments will likely be necessary.5
Complementary and Alternative Medicines, Vitamins, and Dietary Supplements
It was estimated that approximately 60% of individuals infected with HIV use complementary and alternative medicines (CAMs) to treat HIV-related health concerns.
33
These CAMs could result in CSDIs when taken together with ART; therefore, it is important to screen PLWH for use of CAMs to prevent ART failure or adverse effects resulting from a significant interaction.7
Risks of interaction with ARV drugs have been suggested with kava, cat’s claw, ginseng,5
evening primrose oil,7
magnesium, aluminum,21
calcium carbonate, ferrous fumarate, ginkgo, garlic, milk thistle, zinc sulfate,7
and multivitamins.7
,24
A systematic review by Jalloh et al found that many of these supplement interactions may lead to ARV treatment failure.7
Meanwhile, evening primrose and cat’s claw can cause increased drug levels of certain ARV drugs and adverse effects7
; kava and ginseng may increase hepatotoxicity.5
Many other potential interactions may not have been identified at this time.7
Therefore, as a general precaution, it may be safest for patients who are taking ART to avoid dietary supplements, especially when there is a confirmed or suspected interaction and the potential benefit is unproven or unclear in this population.7
The risk of serious clinically significant interactions may be unacceptably high.Conclusion
Clinically significant interactions of ARV drugs with commonly prescribed drugs, as well as OTC drugs, vitamins, supplements, and herbal therapies, can affect patient outcomes. Thus, it is important for clinicians to be aware of potential interactions and use reliable resources to determine next steps, which may include close monitoring, dose adjustment, or choosing another safer drug. Because research is constantly evolving, new drugs are continuously developed, and drug information changes over time, it is prudent to use an updated, evidence-based drug reference to check for interaction before prescribing any drug with ART.
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- Variability in strength of red yeast rice supplements purchased from mainstream retailers.Eur J Prev Cardiol. 2017; 24: 1431-1434https://doi.org/10.1177/2047487317715714
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- (Updated February 2021. Accessed April 27, 2021)
- HIV incidence among women using intramuscular depot medroxyprogesterone acetate, a copper intrauterine device, or a levonorgestrel implant for contraception: a randomised, multicentre, open-label trial [published correction appears in Lancet. 2019 Jul 27;394(10195):302].Lancet. 2019; 394: 303-313https://doi.org/10.1016/S0140-6736(19)31288-7
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Biography
Angelina Anthamatten, DNP, FNP-BC, is an Assistant Professor at Vanderbilt University School of Nursing, Nashville, TN, and can be contacted at [email protected]
Article info
Publication history
Published online: November 25, 2021
Footnotes
In compliance with standard ethical guidelines, the author reports no relationships with business or industry that would pose a conflict of interest.
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© 2021 Elsevier Inc. All rights reserved.
