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 NRTIs^a

Agent	Interacting Drug^a	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
^aClinically 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 NNRTIs^a

Agent	Interacting Drug^a	Result
Etravirine^4,5,7,20,21	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
Rilpivirine^5,6,20,22	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
Efavirenz^8,20,23	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
Nevirapine^20,24	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
Delavirdine^20,25	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
^aClinically 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

Table 3-4 summarizes clinically significant drug-drug interactions for the four PIs recommended for use by most published HIV treatment guidelines: atazanavir, darunavir, lopinavir, and fosamprenavir (the latter is the pro-form of the bioactive amprenavir).¹⁰
Although other PIs (saquinavir and indinavir) may be used in specific situations for treatment-experienced patients whose HIV exhibits multiclass resistance to ARVs, these agents incur significant toxicities and drug interactions, and their unfavorable pharmacokinetics require more frequent daily dosing. Therefore, they should only be used in consultation with an experienced HIV provider, and we do not elaborate further on drug interactions involving these agents.

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