Drug Interactions in Patients with HIV Infection

Drug Interactions in Patients with HIV Infection
Christopher H. Parsons
Michael S. Boger
INTRODUCTION
  • The number of antiretroviral agents (ARVs) approved for treatment of HIV continues to expand, offering patients more effective, tolerable, and convenient options. As a result of this and other advances in HIV management, the life span of patients living with HIV has increased, approaching an age comparable to patients afflicted with other chronic diseases.1
  • Interactions between ARVs and other drugs used to treat comorbid illnesses have become increasingly important for patients and health care providers.
  • Psychiatric illness, diabetes, hypertension, hyperlipidemia, and bacterial and other infections are frequently encountered among HIV patients. Drugs used to treat these conditions may interact with ARVs by utilizing the same hepatic metabolism pathway.
  • Other drugs may influence ARV pharmacokinetics through their effects on gastrointestinal absorption, protein binding, and renal filtration or excretion.
  • ARVs share toxicities with many other drugs, a portion of which are listed in Table 3-1.
  • Drug interactions are often complex and should be considered carefully when choosing an ARV regimen for HIV patients. Potential interactions should be discussed with an experienced HIV provider in consultation with a pharmacist. However, the growing number of HIV patients with comorbid chronic conditions who interact with primary care physicians necessitates that all providers achieve some level of familiarity with drug interactions.
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
  • Table 3-2 summarizes clinically significant drug-drug interactions for nucleoside reverse transcriptase inhibitors (NRTIs). These agents have minimal drug interactions because they are not metabolized by the hepatic cytochrome P450 (CYP450) enzyme system, and are eliminated via renal excretion.
  • Tenofovir reduces atazanavir levels through induction of CYP3A4; therefore, these drugs should only be coadministered in the presence of ritonavir “boosting” (see section on Protease Inhibitors below for more details).
  • The combination of zidovudine and stavudine is contraindicated due to their mutual antagonism and competitive inhibition of intracellular stavudine phosphorylation, resulting in reduced stavudine levels.
  • Because the chewable tablet and solution forms of didanosine are manufactured as a buffer, administration with agents dependent on gastric acid for absorption, including atazanavir and azole antifungals, may reduce their bioavailability. Administration of tenofovir with enteric-coated didanosine may also lead to significant elevations in didanosine levels.
    Table 3-1 Major Toxicities of Common Drugs Used to Manage HIV Infection

    Bone Marrow Suppression

    Renal Toxicity

    Liver Toxicity

    Zidovudine

    Tenofovir

    NRTI

    Co-trimoxazole

    Indinavir

    NNRTI

    Dapsone

    Acyclovir

    Protease inhibitors

    Ganciclovir

    Amphotericin

    Macrolides

    Pyrimethamine

    Aminoglycosides

    Fluconazole

    Sulfadiazine

    Itraconazole

    Flucytosine

    Ketaconazole

    Amphotericin

    Voriconazole

    Interferon alpha

    Rifampin

    Ribavirin

    Rifabutin

    Linezolid

    Valproic acid

    β-lactam agents

    Valproic acid

    HIV, human immunodeficiency virus; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor.

  • The combination of didanosine and allopurinol is not recommended due to potential for didanosine toxicity.2
NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
  • Nonnucleoside reverse transcriptase inhibitors (NNRTIs) interact with a number of ARVs and other drugs, as illustrated in Table 3-3, due largely to their influence on hepatic metabolism. All five agents are substrates of CYP3A4, with efavirenz, etravirine, nevirapine, and rilpivirine inducing CYP3A4 activity, and delavirdine inhibiting CYP3A4 activity. Etravirine also inhibits activity of CYP2C19.3
  • Rosuvastatin, atorvastatin, and pravastatin are the preferred HMG-CoA reductase inhibitors for use with NNRTIs because they incur fewer drug interactions, although myopathies and rhabdomyolysis may be more likely when these medications are used with NNRTIs.
  • Anticonvulsants, including carbamazepine, phenobarbital, and phenytoin, induce CYP450 and reduce NNRTI levels, particularly for etravirine.4
  • Clarithromycin should not be used with NNRTIs.5
  • Rifabutin (in lieu of rifampin) is preferred for the treatment of mycobacterial infections arising in patients receiving NNRTIs.
  • Proton pump inhibitors (PPIs) significantly reduce rilpivirine concentrations and should be avoided. H2 blockers and antacids may be coadministered with rilpivirine if taken at sufficient intervals before or after rilpivirine dosing.3,6
  • Etravirine has demonstrated utility in ARV-experienced patients, but providers should be aware of significant drug interactions, several of which are noted above. Some protease inhibitors (PIs) can be coadministered with etravirine in the presence of ritonavir to minimize CYP3A4-induced reductions in PI levels.5,7
    Table 3-2 Clinically Significant Interactions with NRTIsa

    Agent

    Interacting Druga

    Result

    Tenofovir (TDF)20

    Atazanavir

    ↓ atazanavir levels, ↑ tenofovir levels—atazanavir should be boosted with ritonavir

    Didanosine

    ↑ didanosine levels—reduce didanosine dose to 250 mg a day

    Probenecid

    inhibits tubular secretion of tenofovir—contraindicated

    Abacavir (ABC)

    Methadone

    ↓ methadone levels—monitor for signs of withdrawal

    Zidovudine (ZDV)20

    Stavudine

    antagonistic—contraindicated

    Ganciclovir

    ↑ zidovudine levels—avoid combination if possible

    Ribavirin

    In vitro antagonism of zidovudine—contraindicated

    Emtricitabine (FTC)

    No significant interactions reported

    Lamivudine (3TC)

    Chlorpropamide

    ↓ chlorpropamide levels—consider alternative agents

    Didanosine (ddI)20

    Atazanavir

    ↓ atazanavir absorption (with buffered didanosine formulations)—administer at different times

    Tenofovir

    ↑ didanosine levels—reduce didanosine dose to 250 mg

    Ganciclovir, indinavir, itraconazole (capsule), ketoconazole, fluoroquinolones

    ↓ levels of these agents Indinavir may ↓ bioavailability of didanosine

    Lopinavir/ritonavir

    ↓ lopinavir/ritonavir absorption—administer at different times

    Ribavirin

    ↑ risk of mitochondrial toxicity—contraindicated

    a Clinically significant interactions with commonly used agents are included—additional interactions are reported in the literature.NRTI, nonnucleoside reverse transcriptase inhibitor; TDF, tenovofir; ABC, abacavir; ZDV, zidovudine; FTC, emtricitabine; 3TC, lamivudine; ddI, didanosine

    Table 3-3 Clinically Significant Interactions with NNRTIsa

    Agent

    Interacting Druga

    Result

    Etravirine4,5,7,20,21

    Other ARVs

    Fosamprenavir

    ↑ amprenavir levels—contraindicated

    Tipranavir

    ↓ etravirine levels—contraindicated

    Atazanavir

    ↓ atazanavir levels, ↑ etravirine levels—contraindicated

    Maraviroc

    ↓ maraviroc levels—increase maraviroc to 600 mg b.i.d. unless etravirine given with maraviroc + ritonavir-boosted PI comparable to darunavir, where maraviroc dose should be reduced to 150 mg b.i.d.

    Antibiotics

    Rifampin, rifapentine

    ↓ etravirine levels—contraindicated

    Rifabutin

    ↓ etravirine levels, ↓ rifabutin levels—dose rifabutin at 300 mg daily if administered with unboosted PI, but avoid combination if used with ritonavir boosted PI

    Antifungals

    Ketoconazole, itraconazole

    Use with caution: ↓etravirine and antifungal levels

    Voriconazole

    ↑ etravirine and voriconazole levels—monitor voriconazole levels

    Fluconazole

    ↑ etravirine levels—use with caution

    Others

    Immunosuppressants3

    ↓ immunosuppressant levels—monitor closely

    Warfarin

    ↑ INR—monitor INR closely

    Antiarrhythmics4

    May ↓ antiarrhythmic levels—monitor closely

    Digoxin

    ↑ digoxin levels—monitor digoxin levels and for signs of digoxin toxicity

    Anticonvulsants: phenytoin, carbamazepine, phenobarbital

    ↓ etravirine levels—contraindicated

    Rilpivirine5,6,20,22

    Dexamethasone

    ↓ rilpivirine levels—contraindicated

    Phenytoin

    ↓ rilpivirine levels—contraindicated

    Carbamazepine

    ↓ rilpivirine levels—contraindicated

    PPIs: omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole

    ↓ rilpivirine levels—contraindicated

    Rifamycins: rifampin, rifabutin, rifapentine

    ↓ rilpivirine levels—contraindicated

    St. John’s wort

    ↓ rilpivirine levels—contraindicated

    H2-receptor antagonists: famotidine, ranitidine, cimetidine, nizatidine

    ↓ rilpivirine levels—administer 12 hours before or 4 hours after rilpivirine dose

    Antacids

    ↓ rilpivirine levels—administer 2 hours before or 4 hours after rilpivirine dose

    Methadone

    ↓ methadone levels—monitor for opiate withdrawal

    Azoles: voriconazole, ketoconazole, itraconazole, posaconazole, fluconazole

    ↑ rilpivirine levels, ↓ azole levels—monitor closely

    Efavirenz8,20,23

    Other ARVs

    NNRTI: etravirine, nevirapine, rilpivirine

    ↓ efavirenz/NNRTI levels and ↑ NNRTI toxicity—contraindicated

    Atazanavir/ritonavir

    ↓ atazanavir levels—increase atazanavir to 400 mg with 100 mg ritonavir

    Lopinavir/ritonavir

    ↓ lopinavir levels—consider increase lopinavir/ritonavir to 600/150 mg twice daily

    Fosamprenavir/ritonavir

    ↓ amprenavir levels—total of 300 mg of ritonavir recommended per day

    Antibiotics

    Rifampicin, rifampin

    ↓ efavirenz levels—avoid combination if possible. In patients ≥50 kg, increase efavirenz dose to 800 mg once daily

    Rifabutin

    ↓ rifabutin levels—increase rifabutin dose by 50%

    Voriconazole

    ↓ voriconazole levels, ↑ efavirenz levels—increase voriconazole to 400 mg every 12 hours and decrease efavirenz to 300 mg once a day

    Posaconazole

    ↓ posaconazole levels—contraindicated

    Itraconazole, ketoconazole

    ↓ azole levels—avoid combination if possible

    Clarithromycin

    ↓ clarithromycin levels—avoid combination if possible

    Others

    St. John’s wort

    ↓ efavirenz levels—contraindicated

    Ergot derivatives

    ↑ ergot toxicity—contraindicated

    Benzodiazepines: triazolam, midazolam

    ↑ benzodiazepine toxicity—contraindicated

    Immunosuppressives: sirolimus, tacrolimus, cyclosporin

    ↓ levels of immunosuppressive agents—avoid combination if possible

    Methadone

    ↓ methadone levels—monitor for opiate withdrawal

    HMG-CoA reductase inhibitors: atorvastatin, simvastatin, pravastatin

    ↓ HMG-CoA reductase inhibitors levels—monitor cholesterol levels

    Oral contraceptives

    ↓ ethinyl estradiol levels—use alternative method of contraception

    Carbamazepine

    ↓ efavirenz/carbamazepine levels—use with caution

    Nevirapine20,24

    Atazanavir/ritonavir

    ↓ atazanavir, ↑ nevirapine—contraindicated

    Oral contraceptives

    ↓ ethinyl estradiol levels—use alternative method of contraception

    Fluconazole

    ↑ nevirapine levels—monitor for side effects, use with caution

    Fosamprenavir

    ↓ amprenavir levels, ↑ nevirapine levels—do not coadminister unless fosamprenavir is used with ritonavir at 700/100 mg b.i.d.

    Lopinavir/ritonavir

    ↓ lopinavir levels—increase lopinavir/ritonavir to 600/150 mg twice daily

    Methadone

    ↓ methadone levels—monitor for opiate withdrawal

    Rifabutin

    ↑ rifabutin levels—monitor for signs of toxicity and use with caution

    Rifampin

    ↓ nevirapine levels—consider alternative agent for HIV

    Delavirdine20,25

    Certain benzodiazpines,2 ergot derivatives, pimozide

    ↑ levels of these agents with possible toxicity—contraindicated

    Rifampin, rifabutin

    ↓ delavirdine levels—contraindicated

    Antacids

    ↓ delavirdine levels—separate by at least 1 hour

    Trazodone, certain antiarrhythmics,2 warfarin, clarithromycin, certain HMG-CoA reductase inhibitors,4 methadone

    ↑ levels of all of these—use cautiously

    a Clinically significant interactions are included—other interactions have been studied and reported in the literature.ARVs, antiretroviral agents; PI, protease inhibitor; INR, international normalized ratio; NNRTI, nonnucleoside reverse transcriptase inhibitor; HMG-CoA, hydroxymethylglutaryl-CoA.

  • Use of nevirapine or efavirenz may lead to failure of oral contraceptives, and alternative methods of contraception should be offered to women of childbearing age receiving these agents. Of note, efavirenz is contraindicated during pregnancy due to its demonstrated teratogenicity in animal studies.
  • The dose of lopinavir/ritonavir should be increased in the presence of nevirapine or efavirenz, and we do not recommend using these agents together given increased toxicities.
  • Atazanavir should be administered at a higher dose (400 mg) and boosted with ritonavir when coadministered with efavirenz for treatment-naïve patients, and we recommend avoiding this combination in ARV-experienced patients.8
  • The combination of atazanavir and nevirapine is contraindicated, and fosamprenavir requires dose adjustment when used with nevirapine.9
PROTEASE INHIBITORS
Jun 22, 2016 | Posted by in INFECTIOUS DISEASE | Comments Off on Drug Interactions in Patients with HIV Infection

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