Should Efavirenz Be Dosed Higher When Coadministered with Rifampin?

With this new recommendation, the FDA aims to resolve a decade-long debate on how best to treat HIV/TB-coinfected patients. Efavirenz is metabolized by CYP450 enzymes, which are known to be induced by rifampin. When the two drugs are coadministered, the interaction could lead to suboptimal efavirenz levels, such that patients on efavirenz-containing triple therapy receive effective exposure to only two of the three drugs in their regimen. In a 2008 case study, FDA investigators concluded that the existing evidence on this interaction was inadequate to support a dosing change (J Clin Pharmacol 2008; 48:518), but 3 years later, they have changed their view.

Although the studies cited in the FDA's recommendation support the proposed approach, others do not. Our own work — and at least one additional pharmacokinetic study — have demonstrated that the drug–drug interaction could be in the opposite direction, thus increasing efavirenz exposure (Antivir Ther 2011; 16:527, Eur J Clin Pharmacol 2011; e-pub ahead of print). If this is the case, a non-individualized weight-based dosage increase could result in toxicity, possibly without any added efficacy benefit. Several studies indicate that efavirenz pharmacokinetics are influenced by CYP450 G516T and possibly other single nucleotide polymorphisms, rather than by rifampin alone. Perhaps more important, numerous studies show that patients receiving concurrent rifampin and efavirenz achieve virologic suppression even with standard efavirenz dosing (AIDS 2005; 19:1481, J Antimicrob Chemother 2006; 58:1299, Clin Infect Dis 2011; 53:716). Taken collectively, these data suggest that the rifampin–efavirenz interaction may not be consistent in all populations and that increasing the dose of efavirenz may not improve clinical outcomes.