Like other protease inhibitors, atazanavir (Reyataz) is metabolised through the cytochrome P450 system, and is a specific inhibitor of the CYP3A4 enzyme. This means that it may interact with a wide variety of drugs also metabolised through this pathway. These include ritonavir (Norvir), explaining why low-dose ritonavir raises levels of amprenavir, allowing a reduction in the number of capsules that need to be taken.

Many other drugs using the CYP3A4 enzyme should not be given with atazanavir, as their levels may be increased in the body. These include:

• Astemizole.
• Bepridil.
• Cisapride.
• Ergotamine tartrate (Cafergot / Migril).
• Flecainide acetate (Tambocor).
• Fluticasone propionate (Flixotide).
• Halofantrine.
• Hypericin (St John’s wort).
• Lovastatin.
• Lumefantrine.
• Midazolam (Hypnovel).
• Pimozide (Orap).
• Propafenone (Arythmol).
• Quinidine (Kinidin Durules).
• Rifampicin (Rifadin / Rimactane).
• Simvastatin (Zocor).
• Terfenadine.
• Triazolam.
• Voriconazole (Vfend).

Atazanavir also inhibits P-glycoprotein and the multidrug resistance-associated protein, which pump foreign substances, including some drugs, out of cells. This could explain the observation that the blood disorders caused by many anti-cancer drugs are more severe in patients taking protease inhibitors.

Atazanavir should not be taken with indinavir (Crixivan), since both drugs can cause elevated bilirubin levels. Although it has not been tested in human trials, taking both drugs together is expected to increase drug levels and the risk of this side-effect occurring.

Recently, there has been considerable concern over the possible interaction between atazanavir and drugs to treat acid reflux disease and related symptoms. Studies have shown that taking atazanavir with proton-pump inhibitors such as omeprazole (Losec) and esomeprazole (Nexium) or H₂ receptor blockers such as ranitidine (Zantac) and cimetidine (Dyspamet / Tagamet) could result in lowered blood atazanavir concentrations in HIV-negative patients. This was not affected by increasing atazanavir concentrations or by ritonavir boosting. This is believed to be due to reduced absorption because of reduced stomach acidity and could result in treatment failure. As many of these drugs are available without prescription, patients should discuss their use with their doctor before starting to take acid-reducing agents.

Atazanavir’s manufacturer, Bristol-Myers Squibb recommends that atazanavir and H₂ receptor blockers are taken twelve hours apart from atazanavir, and that proton-pump inhibitors are not taken with atazanavir until further research has been carried out. It issued a ‘Dear Healthcare Provider’ letter in the United States and the European Union warning doctors and patients not to combine atazanavir with omeprazole (Losec) in December 2004.

However, this warning has been called into question by a study carried out in HIV-positive patients, which failed to show reduced atazanavir levels when combined with low-dose ritonavir^[1]. Proton-pump inhibitors have also been shown to have no significant effect on the outcomes of antiretroviral therapy containing ritonavir-boosted atazanavir^[2]. The study investigators claim that the effects of omeprazole may be less important in patients with HIV due to reduced stomach acid levels, or that differences in study design and variability in drug levels have led to confusion over the relationship between these drugs^[3][4]. Larger studies are required to resolve this debate.

Because the buffer in the original version of ddI (didanosine, Videx) reduces peak levels of atazanavir, although it is recommended that atazanavir be taken two hours before or one hour after ddI.

Atazanavir slows the clearance of saquinavir (Invirase), resulting in elevated levels of saquinavir^[5]. A double-boosted protease inhibitor regimen of atazanavir, saquinavir and ritonavir results in elevated levels of saquinavir and ritonavir and may be useful in salvage therapy^[6][7][8].

When atazanavir is dosed with efavirenz (Sustiva), atazanavir levels are reduced by around 70%. Adding low-dose ritonavir counteracts this effect in HIV-negative volunteers, but a small study has found that this may not be the case in people with HIV^[9][10][11]. A similar effect of nevirapine has also been seen in a small study. Both drugs are CYP3A4 inducers, which means that they speed up metabolism of other drugs metabolised by the same route^[12].

Combining atazanavir with tenofovir (Viread) may put a patient at risk of treatment failure, since tenofovir can reduce atazanavir levels by up to 40%^[13][14]. Atazanavir can also increase the likelihood of tenofovir-associated adverse events, including kidney disorders. Doctors should consider boosting atazanavir levels with ritonavir, if atazanavir and tenofovir must be used together, although studies have shown that this is not always successful in restoring atazanavir levels^[15][16].

Some drugs require dose adjustments when taken with atazanavir. The following drugs need to be taken at lower doses:

• Clarithromycin (Klaricid / Klaricid EC): the dose should be halved.
• Diltiazem (Tildiem / Angiozem / Optil): the dose should be halved.
• Rifabutin (Mycobutin): the dose should be reduced by up to 75% (150mg every day or three times a week) when atazanavir is dosed at 400mg once daily^[17].

Atazanavir has been observed to increase levels of the hormonal contraceptives ethinylestradiol and norethindrone. No guidance is available at present on appropriate dose reductions or interactions with other contraceptives. There have also been at least three case reports of elevated levels of buprenorphine, which is used to treat opiate addiction, in patients taking atazanavir^[18]. A dose reduction may be necessary. In contrast, no dose adjustment of methadone (Methadose) is needed^[19].