Prescribing Contraindications and Cautions for HIV

Published:November 25, 2021DOI:https://doi.org/10.1016/j.nurpra.2021.09.021

      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.”
      National Institute of Allergy and Infectious Diseases
      HIV/AIDS.
      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.
      National Institute of Allergy and Infectious Diseases
      HIV/AIDS.
      National Institute of Allergy and Infectious Diseases
      10 things to know about HIV suppression.
      • Margolis A.M.
      • Heverling H.
      • Pham P.A.
      • Stolbach A.
      A review of the toxicity of HIV medications.
      The goal of ART is “to suppress HIV viral load, restore immune function, prevent HIV transmission, prevent resistance, and improve quality of life.”
      • Margolis A.M.
      • Heverling H.
      • Pham P.A.
      • Stolbach A.
      A review of the toxicity of HIV medications.
      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)
      • Evans-Jones J.G.
      • Cottle L.E.
      • Back D.J.
      • et al.
      Recognition of risk for clinically significant drug interactions among HIV-infected patients receiving antiretroviral therapy.
      ; 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.
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      • Brooks K.M.
      • George J.M.
      • Kumar P.
      Drug interactions in HIV treatment: complementary & alternative medicines and over-the-counter products.
      • Jalloh M.A.
      • Gregory P.J.
      • Hein D.
      • Risoldi Cochrane Z.
      • Rodriguez A.
      Dietary supplement interactions with antiretrovirals: a systematic review.
      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.
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      The mechanism of interaction frequently involves cytochrome (CYP) P450 pathway and, to a lesser extent, a membrane transport protein, P-glycoprotein.
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      A study by Evans et al
      • Evans-Jones J.G.
      • Cottle L.E.
      • Back D.J.
      • et al.
      Recognition of risk for clinically significant drug interactions among HIV-infected patients receiving antiretroviral therapy.
      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”.
      • Evans-Jones J.G.
      • Cottle L.E.
      • Back D.J.
      • et al.
      Recognition of risk for clinically significant drug interactions among HIV-infected patients receiving antiretroviral therapy.
      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.
      • Margolis A.M.
      • Heverling H.
      • Pham P.A.
      • Stolbach A.
      A review of the toxicity of HIV medications.
      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 LiverpoolWebsite: 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 Networkhttps://hivclinic.ca/downloads/DDI%20Booklet%202019_English.pdf
      Johns Hopkins University HIV Clinical Guidelines Programhttps://www.hivguidelines.org/antiretroviral-therapy/ddis/#tab_0
      University of California–San Franciscohttp://hivinsite.ucsf.edu/insite?page=ar-00- 02&post=10&param=8
      Table 2Some Clinically Significant Drug-Drug Interactions With 1 or More Antiretroviral Drugs
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      ,
      University of Liverpool
      Antidepressant treatment selector. Revised March 2021.
      ,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,,,
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.
      ,,
      Johns Hopkins University HIV Clinical Guidelines Program
      ,
      • Sharma M.
      • Walmsley S.L.
      Contraceptive options for HIV-positive women: making evidence-based, patient-centred decisions.
      ,
      DrugsCategories
      Budesonide, fluticasone, triamcinolone,
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      , mometasone, dexamethasone, ciclesonide, betamethasone, methylprednisolone
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      Corticosteroids
      Salmeterol
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,
      Johns Hopkins University HIV Clinical Guidelines Program
      Inhaled beta agonist
      Lovastatin, simvastatin
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,
      Lipid-lowering
      Red yeast rice,Dietary supplement for hyperlipidemia
      Dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,,
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.
      Proton pump inhibitors
      St. John’s wort
      University of Liverpool
      Antidepressant treatment selector. Revised March 2021.
      ,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      Herbal therapy for depression
      Apixaban, rivaroxaban, clopidogrel, ticagrelorAnticoagulants and antiplatelets
      Progestin and estrogen
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      ,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,
      • Sharma M.
      • Walmsley S.L.
      Contraceptive options for HIV-positive women: making evidence-based, patient-centred decisions.
      Hormonal contraceptive therapy
      Itraconazole and ketoconazole
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.
      ,

      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%.
      • Pieper A.A.
      • Treisman G.J.
      Depression, mania, and schizophrenia in HIV-infected patients.
      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.
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      It has been suggested that lack of appropriate treatment for depression may be even more detrimental than medication interactions.
      • Pieper A.A.
      • Treisman G.J.
      Depression, mania, and schizophrenia in HIV-infected patients.
      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.
      University of Liverpool
      Antidepressant treatment selector. Revised March 2021.
      A drug reference may suggest interventions including close monitoring, dose adjustment, or avoidance of co-administration.
      University of Liverpool
      Antidepressant treatment selector. Revised March 2021.
      Two important considerations have been highlighted when selecting an antidepressant for a patient taking ART: adverse effect profile and potential interactions.
      • Pieper A.A.
      • Treisman G.J.
      Depression, mania, and schizophrenia in HIV-infected patients.
      ,
      • Yanofski J.
      • Croarkin P.
      Choosing antidepressants for HIV and AIDS patients: Insights on safety and side effects.
      One important potential interaction involves the herbal therapy St. John’s wort, which is contraindicated with several classes of ART.
      University of Liverpool
      Antidepressant treatment selector. Revised March 2021.
      ,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      This herb may lower the level of an ARV and compromise viral control.
      University of Liverpool
      Antidepressant treatment selector. Revised March 2021.
      ,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      More information regarding DDIs between a variety of antidepressants and ART can also be found within Liverpool HIV prescribing resources (Table 1).
      University of Liverpool
      Antidepressant treatment selector. Revised March 2021.
      In addition, neuropsychiatric adverse effects, including depression, have been linked with some antivirals in the nonnucleoside reverse transcriptase inhibitors (NNRTI) class
      • Treisman G.
      • Soudry O.
      Neuropsychiatric effects of HIV antiviral medications.
      and infrequently with the integrase strand transfer inhibitors (INSTIs).
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      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.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.

      Lipid-Lowering Drugs

      Both ART and HIV can cause metabolic dysfunction, such as dyslipidemia.
      • Pitts C.
      • Anthamatten A.
      Pharmacologic management of human immunodeficiency virus and common chronic conditions.
      • Non L.R.
      • Escota G.V.
      • Powderly W.G.
      HIV and its relationship to insulin resistance and lipid abnormalities.
      • Noubissi E.
      • Katte J.
      • Sobngwi E.
      Diabetes and HIV.
      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,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      due to increased levels of the lipid-lowering drugs and increased risk of myopathy and rhabdomyolysis.

      Epocrates. Version 21.4.2 [Apple iOS application]. Accessed April 27, 2021.

      The dietary supplement red yeast rice should not be coadministered with some ARVs, such as PIs because it contains varying amounts of monacolin K, which is structurally identical to lovastatin.
      • Farkouh A.
      • Baumgärtel C.
      Mini-review: medication safety of red yeast rice products.
      ,
      • Cohen P.A.
      • Avula B.
      • Khan I.A.
      Variability in strength of red yeast rice supplements purchased from mainstream retailers.
      Additionally, atorvastatin and rosuvastatin levels can be increased significantly when combined with boosted PIs, and an increased level of pravastatin has been documented when it is administered with darunavir/ritonavir. Therefore, close monitoring with a lower statin dose should be recommended if these combinations are used.

      Epocrates. Version 21.4.2 [Apple iOS application]. Accessed April 27, 2021.

      ,
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.
      Because pitavastatin and pravastatin involve minimal CYP metabolism, they have been highlighted as having fewer risks of interactions with ART.
      • Pitts C.
      • Anthamatten A.
      Pharmacologic management of human immunodeficiency virus and common chronic conditions.
      ,
      • Feinstein M.J.
      • Hsue P.Y.
      • Benjamin L.A.
      • et al.
      Characteristics, prevention, and management of cardiovascular disease in people living with HIV: a scientific statement from the American Heart Association.

      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.”
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.
      In particular, antitubercular therapies, rifampin and rifapentine, have triggered alert of contraindication with multiple ARVs
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,,

      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.

      ,, because they can cause subtherapeutic HIV drug concentrations.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      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.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      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.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,,

      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.

      , 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.

      Epocrates. Version 21.4.2 [Apple iOS application]. Accessed April 27, 2021.

      ,
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.
      ,

      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.

      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.

      Corticosteroids

      Corticosteroids are prescribed for a variety of conditions, but it is important to consider that steroids, such as budesonide, fluticasone, triamcinolone,
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      ,,
      Johns Hopkins University HIV Clinical Guidelines Program
      mometasone, dexamethasone, ciclesonide, betamethasone, and methylprednisolone
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      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.

      Epocrates. Version 21.4.2 [Apple iOS application]. Accessed April 27, 2021.

      , When an inhaled corticosteroid is needed, beclomethasone may be an option, with no clinically significant interaction expected with a variety of ARV drugs. Meanwhile, if a topical corticosteroid is needed, hydrocortisone may be considered.

      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.
      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].
      ,
      • Sharma M.
      • Walmsley S.L.
      Contraceptive options for HIV-positive women: making evidence-based, patient-centred decisions.
      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.
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      ,
      • Sharma M.
      • Walmsley S.L.
      Contraceptive options for HIV-positive women: making evidence-based, patient-centred decisions.
      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.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      When there are significant interactions between hormonal contraceptives and ARV drugs, an alternative therapy or additional effective contraceptive method is recommended.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      Because hormonal contraceptives containing estrogen and/or progestin are primarily metabolized by CYP isoenzymes
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      ,
      • Sharma M.
      • Walmsley S.L.
      Contraceptive options for HIV-positive women: making evidence-based, patient-centred decisions.
      and many agents of ART are inducers or inhibitors of these enzymes,
      • Sharma M.
      • Walmsley S.L.
      Contraceptive options for HIV-positive women: making evidence-based, patient-centred decisions.
      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.
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      ,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      As a result, an alternative therapy, dose adjustment, or additional backup method may be necessary.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      , 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. 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.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      , 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.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,
      • Sharma M.
      • Walmsley S.L.
      Contraceptive options for HIV-positive women: making evidence-based, patient-centred decisions.
      , 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. Meanwhile, drospirenone-containing contraceptives are contraindicated with ATV/c,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      , due to potential for hyperkalemia.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      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.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      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. Additionally, there are also several small studies supporting safety of levonorgestrel-releasing IUDs.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      A nonhormonal option, the copper IUD, has also been found to be safe and effective.
      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].
      More information about DDIs between hormonal contraceptives and ART can also be found within can be found within resources by the University of Liverpool 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.
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      ,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.
      Many PPIs should not be coadministered with ARV drugs.
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,,
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.
      ,

      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.

      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).
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      ,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      ,
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.

      Anticoagulants and Antiplatelets

      Because cardiovascular disease and thromboembolic disease are more common in PLWH than the general population,
      Panel on Antiretroviral Guidelines for Adults and Adolescents
      Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
      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. In addition, caution should be implemented when initiating dabigatran with some ART, such as P-glycoprotein inhibitors.
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      ,
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.
      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.
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.

      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.
      • Littlewood R.A.
      • Vanable P.A.
      Complementary and alternative medicine use among HIV-positive people: research synthesis and implications for HIV care.
      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.
      • Jalloh M.A.
      • Gregory P.J.
      • Hein D.
      • Risoldi Cochrane Z.
      • Rodriguez A.
      Dietary supplement interactions with antiretrovirals: a systematic review.
      Risks of interaction with ARV drugs have been suggested with kava, cat’s claw, ginseng,
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      evening primrose oil,
      • Jalloh M.A.
      • Gregory P.J.
      • Hein D.
      • Risoldi Cochrane Z.
      • Rodriguez A.
      Dietary supplement interactions with antiretrovirals: a systematic review.
      magnesium, aluminum,
      Canadian HIV and Viral Hepatitis Pharmacists Network
      A management tool for HIV drug-drug interactions.
      calcium carbonate, ferrous fumarate, ginkgo, garlic, milk thistle, zinc sulfate,
      • Jalloh M.A.
      • Gregory P.J.
      • Hein D.
      • Risoldi Cochrane Z.
      • Rodriguez A.
      Dietary supplement interactions with antiretrovirals: a systematic review.
      and multivitamins.
      • Jalloh M.A.
      • Gregory P.J.
      • Hein D.
      • Risoldi Cochrane Z.
      • Rodriguez A.
      Dietary supplement interactions with antiretrovirals: a systematic review.
      , A systematic review by Jalloh et al found that many of these supplement interactions may lead to ARV treatment failure.
      • Jalloh M.A.
      • Gregory P.J.
      • Hein D.
      • Risoldi Cochrane Z.
      • Rodriguez A.
      Dietary supplement interactions with antiretrovirals: a systematic review.
      Meanwhile, evening primrose and cat’s claw can cause increased drug levels of certain ARV drugs and adverse effects
      • Jalloh M.A.
      • Gregory P.J.
      • Hein D.
      • Risoldi Cochrane Z.
      • Rodriguez A.
      Dietary supplement interactions with antiretrovirals: a systematic review.
      ; kava and ginseng may increase hepatotoxicity.
      • Stolbach A.
      • Paziana K.
      • Heverling H.
      • Pham P.
      A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
      Many other potential interactions may not have been identified at this time.
      • Jalloh M.A.
      • Gregory P.J.
      • Hein D.
      • Risoldi Cochrane Z.
      • Rodriguez A.
      Dietary supplement interactions with antiretrovirals: a systematic review.
      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.
      • Jalloh M.A.
      • Gregory P.J.
      • Hein D.
      • Risoldi Cochrane Z.
      • Rodriguez A.
      Dietary supplement interactions with antiretrovirals: a systematic review.
      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.

      References

        • National Institute of Allergy and Infectious Diseases
        HIV/AIDS.
        (Accessed May 5, 2021)
        • National Institute of Allergy and Infectious Diseases
        10 things to know about HIV suppression.
        (Accessed May 5, 2021)
        • Margolis A.M.
        • Heverling H.
        • Pham P.A.
        • Stolbach A.
        A review of the toxicity of HIV medications.
        J Med Toxicol. 2014; 10: 26-39https://doi.org/10.1007/s13181-013-0325-8
        • Evans-Jones J.G.
        • Cottle L.E.
        • Back D.J.
        • et al.
        Recognition of risk for clinically significant drug interactions among HIV-infected patients receiving antiretroviral therapy.
        Clin Infect Dis. 2010; 50: 1419-1421https://doi.org/10.1086/652149
        • Stolbach A.
        • Paziana K.
        • Heverling H.
        • Pham P.
        A review of the toxicity of HIV medications II: interactions with drugs and complementary and alternative medicine products.
        J Med Toxicol. 2015; 11: 326-341https://doi.org/10.1007/s13181-015-0465-0
        • Brooks K.M.
        • George J.M.
        • Kumar P.
        Drug interactions in HIV treatment: complementary & alternative medicines and over-the-counter products.
        Expert Rev Clin Pharmacol. 2017; 10: 59-79https://doi.org/10.1080/17512433.2017.1246180
        • Jalloh M.A.
        • Gregory P.J.
        • Hein D.
        • Risoldi Cochrane Z.
        • Rodriguez A.
        Dietary supplement interactions with antiretrovirals: a systematic review.
        Int J STD AIDS. 2017; 28: 4-15https://doi.org/10.1177/0956462416671087
        • Pieper A.A.
        • Treisman G.J.
        Depression, mania, and schizophrenia in HIV-infected patients.
        (UptoDate. 2021. Accessed May 21, 2021)
        • University of Liverpool
        Antidepressant treatment selector. Revised March 2021.
        (Accessed May 7, 2021)
        • Yanofski J.
        • Croarkin P.
        Choosing antidepressants for HIV and AIDS patients: Insights on safety and side effects.
        Psychiatry (Edgmont). 2008; 5: 61-66
        • Panel on Antiretroviral Guidelines for Adults and Adolescents
        Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services.
        (Updated June 3, 2021. Accessed July 19, 2021)
        • Treisman G.
        • Soudry O.
        Neuropsychiatric effects of HIV antiviral medications.
        Drug Safety. 2016; 39: 945-957
        • Pitts C.
        • Anthamatten A.
        Pharmacologic management of human immunodeficiency virus and common chronic conditions.
        J Nurse Pract. 2020; 16: 167-171
        • Non L.R.
        • Escota G.V.
        • Powderly W.G.
        HIV and its relationship to insulin resistance and lipid abnormalities.
        Transl Res. 2017; 183: 41-56
        • Noubissi E.
        • Katte J.
        • Sobngwi E.
        Diabetes and HIV.
        Curr Diabetes Rep. 2018; 18: 1-8
        • University of Liverpool
        Lipid-lowering treatment selector. Revised December 2019.
        (Accessed May 7, 2021)
      1. Epocrates. Version 21.4.2 [Apple iOS application]. Accessed April 27, 2021.

        • University of Liverpool
        Interactions with protease inhibitors.
        (Revised April 2021. Accessed April 27, 2021)
        • Farkouh A.
        • Baumgärtel C.
        Mini-review: medication safety of red yeast rice products.
        Int J Gen Med. 2019; 12: 167-171https://doi.org/10.2147/IJGM.S202446
        • Cohen P.A.
        • Avula B.
        • Khan I.A.
        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
        • Canadian HIV and Viral Hepatitis Pharmacists Network
        A management tool for HIV drug-drug interactions.
        (Accessed April 27, 2021)
        • Feinstein M.J.
        • Hsue P.Y.
        • Benjamin L.A.
        • et al.
        Characteristics, prevention, and management of cardiovascular disease in people living with HIV: a scientific statement from the American Heart Association.
        Circulation. 2019; 140: e98-e124
      2. 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.

        • University of Liverpool
        Interactions with integrase inhibitors.
        (Revised April 2021. Accessed April 27, 2021)
        • University of Liverpool
        Interactions with entry and attachment inhibitors.
        (Revised April 2021. Accessed April 27, 2021)
        • University of Liverpool
        Interactions with NRTIs. Revised April 2021.
        (Accessed April 27, 2021)
        • University of Liverpool
        Corticosteroid treatment selector.
        (Revised March 2021. Accessed April 27, 2021)
        • Johns Hopkins University HIV Clinical Guidelines Program
        (Updated February 2021. Accessed April 27, 2021)
        • 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].
        Lancet. 2019; 394: 303-313https://doi.org/10.1016/S0140-6736(19)31288-7
        • Sharma M.
        • Walmsley S.L.
        Contraceptive options for HIV-positive women: making evidence-based, patient-centred decisions.
        HIV Med. 2015; 16: 329-336https://doi.org/10.1111/hiv.12221
        • University of Liverpool
        Contraceptive treatment selector.
        (Revised December 2019. Accessed April 27, 2021)
        • University of Liverpool
        Anticoagulant and antiplatelet treatment selector.
        (Revised March 2021. Accessed April 27, 2021)
        • Littlewood R.A.
        • Vanable P.A.
        Complementary and alternative medicine use among HIV-positive people: research synthesis and implications for HIV care.
        AIDS Care. 2008; 20: 1002-1018https://doi.org/10.1080/09540120701767216
        • University of Liverpool
        Prescribing resources.
        (Accessed April 27, 2021)

      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]