Efavirenz reduces blood statin concentrations

Taking efavirenz (Sustiva) at the same time as the lipid-lowering statin drugs simvastatin (Zocor), atorvastatin (Lipitor) or pravastatin (Lipostat) results in reduced concentrations of the statin in the blood, according to a study presented in the 1^st July edition of The Journal of Acquired Immune Deficiency Syndromes. Although the statins did not affect efavirenz levels, these findings suggest that patients taking efavirenz may need higher doses of statins in order to lower their blood fat levels.

The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is a powerful anti-HIV drug that is used in combination with other antiretrovirals to control HIV levels in the body. One of its side-effects is to cause an increase in the levels of fats, or lipids, in the blood.

Statins are very effective drugs that can lower blood lipids, particularly cholesterol. They are mostly broken down by an enzyme in the liver called cytochrome P450 3A4 (CYP3A4). As efavirenz is known to be both an inducer and an inhibitor of this enzyme, investigators from the AIDS Clinical Trials Group A5108 Team wished to find out whether efavirenz affected the metabolism of the three most commonly prescribed statins.

“Our data indicate that concomitant use of statins and efavirenz does not alter efavirenz exposure, and therefore presumably does not interfere with antiretroviral activity, but the significant induction of metabolism may require increased dosing of statins to achieve serum lipid concentration goals,” they write.

“Clinicians need to be aware that the activity of these statins may be diminished when used in combination with efavirenz,” they warn.

The investigators assessed the blood levels of efavirenz and statins in 52 HIV-negative volunteers. All of the participants had normal blood lipid levels and none had any underlying illnesses or were taking long-term medication.

The volunteers received the standard daily doses of 40mg simvastatin, 10mg atorvastatin or 40mg pravastatin for four days from days 0 to 3. From day 4, the volunteers took 600mg efavirenz alone for eleven days, before taking both efavirenz and a statin together for four more days.

The investigators measured the levels of the statins in blood samples taken over 24 hours at the end of each four-day statin course. After comparing the levels of the drugs with and without concomitant efavirenz, they found that efavirenz reduced the 24-hour exposure (area under the curve) of the active version of simvastatin by 58% (36.5 to 14.5ng.h/ml; p = 0.003). Similarly, atorvastatin exposure was reduced by 43% (11.2 to 6.6ng.h/ml; p

In contrast, after comparing levels of efavirenz levels before and after the addition of a statin, the investigators found that none of the statins had a significant effect on efavirenz concentrations, although they did not present these data in the paper.

The researchers also compared the levels of low-density lipoprotein (LDL or ‘bad’) cholesterol in the blood, finding that efavirenz diminished the cholesterol-lowering properties of simvastatin from a reduction of 37.0 to 32.0mg/dl (p = 0.048). However, the cholesterol-lowering properties of the other two drugs were not significantly impaired after four days of concomitant dosing.

“The changes in serum LDL cholesterol did not reach steady state after only four doses of statins; thus, these data are only suggestive of a pharmacodynamic consequence of efavirenz induction of statin metabolism,” the investigators explain. “Studies of longer duration are needed to clarify the pharmacodynamic consequences of these drug-drug interactions at steady-state concentrations of all drugs”.

As simvastatin and atorvastatin are metabolised by CYP3A4, the effect of efavirenz on these drugs’ levels was unsurprising. “It was not surprising that efavirenz, an inducer of CYP3A4 metabolism, resulted in decreases in the levels of these two statins,” they write.

“Pravastatin, in contrast, is hydrophilic, and systemic elimination does not use CYP3A4 oxidation to any great extent but rather uses multiple other oxidative and conjugative pathways,” they explain. “The mechanism of how efavirenz reduces concentrations of pravastatin is not known.”

They also acknowledge that the use of efavirenz together with protease inhibitors may have unexpected effects on statin concentrations. “Three-way drug interactions are difficult to predict,” they warn. “Practitioners should err on the side of caution and start statins at a low dose and titrate upward until the goal serum LDL level is achieved without toxicity.”