Drug-drug interactions can occur with antiretroviral medications

July 2004

It has been estimated that drug-drug interactions lead to 2.8% of hospitalizations annually in the United States, with more than 245,000 hospitalizations. Antiretroviral therapy is increasingly complicated, and there are now approximately 20 antiretroviral agents that can be used to manage HIV infection. Several new agents have been approved in recent years, including tenofovir (Viread, Gilead Sciences), atazanavir (Reyataz, Bristol-Myers Squibb) and fosamprenavir (Lexiva, GlaxoSmithKline), and each of these has been associated with significant drug interactions.

Drug interactions can be thought of in at least four classes:

• Drug-drug interactions where use of two drugs simultaneously or sequentially results in altered effects of one or both drugs
• Drug-food interactions, in which the presence or absence of food or even a particular kind of food affects drug concentrations or biological activity.
• Drug-chemical interactions in which simultaneous or sequential use impacts one or both agents. A good example of this is a dramatic increase in concentrations of the illicit drug ecstasy when taken in the presence of ritonavir (Norvir, Abbott), which has resulted in deaths.
• Drug-lab test interactions are less common but could occur when a drug or its metabolite cross-reacts with a lab test. An example of this type of interaction is a positive tetrahydrocannabinol assay, which can occur among patients receiving efavirenz (Sustiva, Bristol-Myers Squibb).

Numerous drug interactions have been identified for most all antiretroviral agents, but this article will focus on new interactions that have been identified or those that are commonly encountered in clinical practice. In particular, we will focus on drug-drug interactions.

Drug-drug interactions can be further classified by the mechanism through which the interaction occurs:

• Pharmacokinetic, which involves an interaction through absorption, distribution, metabolism and/or excretion.
• Pharmacodynamic, which can result in synergistic, indifferent or antagonistic antiviral effects
• Pharmaceutic, in which there is some chemical or physical incompatibility that affects activity of one or both drugs in combination

Most of the drug-drug interactions that are recognized with antiretroviral agents are largely pharmacokinetic and involve metabolic interactions through the hepatic cytochrome P450 isoenzyme system. Here, we will discuss many of the common and/or unique interactions encountered with the newer antiretroviral agents, with a focus on those that are clinically relevant. The medications contraindicated for use with newer protease inhibitors (PI) are similar to others in the class and, therefore, will not be discussed.

Absorption interactions

Although less common, absorption interactions have been noted, particularly with didanosine (Videx, Bristol-Myers Squibb), due to buffers that are necessary to increase its absorption. These buffers alter gastric acidity, which can lead to reduced absorption of other drugs that require an acidic environment for absorption, such as indinavir (Crixivan, Merck), delavirdine (Rescriptor, Agouron) and atazanavir. When administered simultaneously, didanosine reduces atazanavir concentrations to 10% to 15% of usual levels, so atazanavir should be given at least two hours before or one hour after didanosine or any antacids are administered. This interaction is not anticipated with the enteric-coated formulation of didanosine (Videx EC), but clinical pharmacokinetics data are lacking. Other agents that decrease gastric acidity, such as proton pump inhibitors and H2-antagonists, can reduce absorption of atazanavir. These agents should be avoided if possible, and in the case of H2-antagonists, be dosed at least 12 hours apart from atazanavir.

Distribution interactions

With antiretroviral agents, distribution interactions primarily occur between PIs and other agents that are highly protein-bound. Most PIs are >95% bound to plasma proteins, with the exception of indinavir, which is only 60% bound. Atazanavir, the newest PI, is 86% bound and amprenavir (Agenerase, GlaxoSmithKline), the active component of fosamprenavir, is 90% bound. Higher free-plasma concentrations of individual agents can occur when combined with other highly protein-bound drugs, such as warfarin, phenytoin, carbamazepine and digoxin, as these agents displace each other from protein-binding sites. Increased free concentrations could be associated with increased drug toxicity, so patients should be monitored carefully when receiving such agents in combination.

Metabolism/elimination interactions

Interactions through the hepatic cytochrome P450 system are the most common kinds of interactions observed with antiretroviral agents. These largely involve PIs and non-nucleoside reverse transcriptase inhibitors (NNRTI). Fosamprenavir, which is a pro-drug, has the same metabolic interactions as its active component, amprenavir. Amprenavir inhibits CYP3A4, so it shares many of the interactions common to other 3A4 inhibitors. In addition, levels of amprenavir can be decreased by about 20% in the presence of ethinyl estradiol and 70% to 90% in the presence of rifampin. Administration of these agents with amprenavir is not recommended. Amprenavir can also cause decreased plasma concentrations of delavirdine and methadone and may lead to an increased methadone requirement when administered to patients receiving methadone maintenance therapy. Interestingly, plasma levels of amprenavir are reduced 25% to 30% in those receiving methadone.

Although not well documented with many PIs that were first marketed, drug interactions with PIs and cardiac medications have been reported in the literature. Atazanavir has the potential for similar interactions, and increased concentrations of atenolol and diltiazem have been reported. Atazanavir can lead to a prolonged PR interval; this is prolonged further in the presence of diltiazem but is not affected by atenolol. Therefore, it is recommended to reduce diltiazem doses 50% when using it in the presence of atazanavir and to consider similar dose reductions for other calcium channel blockers. Use with bepridil is contraindicated, however. Atenolol doses do not require reduction, but patients should be monitored. Concentrations of amiodarone, quinidine and lidocaine can also be increased by atazanavir and other PIs, so monitoring of plasma concentrations of these agents is recommended when they are used with PIs.

Atazanavir can also increase concentrations of clarithromycin (Biaxin, Abbott), increasing the risk of QTc prolongation. Therefore, clarithromycin doses should be reduced 50% in those requiring atazanavir therapy, or alternate agents should be used. This interaction is not anticipated with azithromycin (Zithromax, Pfizer).

Many PIs can also increase plasma concentrations of sildenafil (Viagra, Pfizer), resulting in hypotension, visual changes and priapism. This interaction has not been well documented to date with atazanavir or amprenvir but is likely to occur. Therefore, doses of sildenafil 25 mg every 48 hours with careful monitoring are recommended when used with atazanavir or fosamprenavir. Similar interactions are anticipated with vardenafil (Levitra, Bayer) or tadalafil (Cialis, Lilly ICOS) when used with atazanavir or amprenavir.

PIs can inhibit metabolism of hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors; increased concentrations of the statins have been associated with rhabdomyolysis. For example, amprenavir causes dramatic increases in serum concentrations of atorvastatin (increase in peak serum concentrations >300%, area under the curve about 150%). It is recommended that atazanavir not be used with simvastatin (Zocor, Merck) and lovastatin. Pravastatin (Pravachol, Bristol-Myers Squibb) is generally the preferred agent when a statin must be used with PIs, because it is less likely to have serum levels increased by PIs. A newer HMG-CoA reductase inhibitor, fluvastatin (Lescol, Novartis), has a potential role for use because of fewer drug interactions, but pharmacokinetic data in the presence of PIs are lacking. Because metabolic syndromes associated with highly active antiretroviral therapy are increasingly recognized, studies of HMG-CoA reductase inhibitors with PIs are needed to guide clinical use.

Finally, although not anticipated during clinical development, there is an apparent interaction between tenofovir and didanosine. The mechanism of this interaction is still unclear but results in an increase in plasma concentrations of didanosine. Therefore, patients >60 kg should have the daily didanosine dose reduced from 400 mg daily to 250 mg daily when it is combined with tenofovir.

Other interactions

Other interactions can occur by unknown mechanisms. One example is a recent interaction noted between tenofovir and atazanavir, whereby atazanavir concentrations are decreased when coadministered with tenefovir.

Patients should be monitored carefully for potential adverse events. It is recommended that atazanavir be given as 300 mg daily and boosted with 100 mg of ritonavir daily when administered with tenofovir.

In the clinical setting, a common scenario involves managing multiple drug-drug interactions in one patient. Often, there are a lack of available data to guide the clinician in dosing these agents in combination. There are some data available for combinations of efavirenz, atazanavir and ritonavir. Efavirenz can significantly lower plasma concentrations of atazanavir, but this can be overcome by boosting atazanavir with low doses of ritonavir. Atazanavir is dosed as 300 mg with 100 mg of ritonavir daily with food when used with efavirenz 600 mg daily.

Another common clinical scenario involves dosing didanosine, tenofovir and atazanavir together. Atazanavir’s absorption is reduced in the presence of didanosine (chewable tablets), so atazanavir should be dosed at least one hour before or two hours after didanosine chewable tablets. Alternatively, enteric-coated didanosine could be administered in place of the chewable tablets. Tenofovir increases plasma concentrations of didanosine, so the dose of didanosine for a patient >60 kg is recommended to be reduced to 250 mg daily in those receiving tenofovir. Tenofovir could be given in the regimen at the same time as atazanavir (with food) or at a different time with didanosine chewable tablets (on an empty stomach), or all three agents could be administered together using the enteric-coated formulation of didanosine with a light meal. In any case, the daily dose of atazanavir should be adjusted to 300 mg and boosting doses of ritonavir added (100 mg daily) due to the impact of tenofovir on atazanavir concentrations.

Many classifications of drug interactions pose challenges to the clinician who is managing HIV-positive patients receiving antiretroviral therapy. Newer agents, such as enteric-coated didanosine, tenofovir, atazanavir and fosamprenavir, are significant additions to the antiretroviral armamentarium but also possess some challenging drug interaction features. Careful monitoring of each patient is necessary in managing these interactions and limiting drug-associated toxicities.

For more information:

• NIH. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at: www.aidsinfo.nih.gov/guidelines/adult/AA_032304.html.
• HIV drug interactions calculator. Available at: www.medscape.com/px/hivscheduler?src=search.
• Viread prescribing information, 2003. Gilead Sciences Inc.
• Reyataz prescribing information, 2003. BMS Virology Inc.
• Lexiva prescribing information, 2004. GlaxoSmithKline Inc.
• Videx EC prescribing information, 2003. BMS Virology Inc.
• Pecora Fulco P, Kirian MA. Effect of tenofovir on didanosine absorption in patients with HIV. Ann Pharmacother. 2003;37(9):1325-1328.

• Melissa D. Johnson, PharmD, is an associate in the department of medicine in the division of infectious diseases and international health at Duke University Medical Center, Durham, N.C.