PK Switch Efavirenz to Maraviroc in Patients Initially Suppressed on an Efavirenz-containing Regimen

Maraviroc (MVC) is a CCR5 antagonist that prevents virus entry blocking the binding of R5-tropic HIV to the cell surface CCR5 co-receptor. The MERIT Study compared MVC with EFV, each with a Combivir backbone, as initial therapy. Using a non-inferiority margin of 10% MVC was non-inferior to EFV using the <400 copies/ml viral load cut-off but failed to reach non-inferiority when a <50 copies/ml analysis was used. Since this study was performed a more sensitive tropism assay has become routinely available and a re-analysis of the MERIT results showed that some of the patients with apparent R5-tropic virus actually had non-R5 virus. When these patients were excluded from the analysis, MVC did achieve non-inferiority compared to efavirenz. Of note, a subanalysis in the original MERIT Study of individuals with a baseline viral load below 100,000 copies/ml demonstrated only a small numerical difference between MVC and EFV recipients with 69.6% and 71.6% respectively achieving a viral load less than 50 copies/ml at 48 weeks. Recent data from the MOTIVATE Study (a comparison of maraviroc and placebo with optimised background regimen in treatment-experienced patients) showed geno2pheno (a genotypic algorithm for tropism estimation) to be as accurate as Trofile (a phenotypic assay) at predicting response to maraviroc. In situations where the genotypic and phenotypic test showed discordant results virological response was similar to where both demonstrated concordant R5-tropism.

Importantly MVC has been very well-tolerated in both treatment-naïve and treatment-experienced patients. Overall similar proportions of subjects experienced grade 3/4 adverse events; importantly, malignancy rates were similar in the two arms (4.4% on EFV and 2.8% on MVC). Broadly, individual adverse events occurred at similar frequencies in the two arms although abnormal dreams, dizziness and rash were all less common on MVC. In addition median lipid changes were greater in the EFV arm, correlating with a lower predicted risk of cardiovascular disease for MVC recipients.

Maraviroc is a substrate of the CYP3A4 enzyme; therefore, its metabolism is reduced by pure CYP3A4 inhibitors (most protease inhibitors) and increased by CYP3A4 inducers (such as EFV). Dose adjustments are required when MVC is co-administered with certain protease inhibitors (reduced from 300mg BD to 150mg BD) or EFV (increased from 300mg BD to 600mg BD). When switching from a protease inhibitor (PI), the PI is cleared rapidly such that no interim dose adjustment would be required. EFV, however, is cleared slowly and can remain at detectable concentrations for several days and can continue to induce CYP3A4 for some time after stopping the drug. Therefore, if switching from EFV to MVC, it can be expected that EFV may affect MVC concentrations for a period of time after the switch. The length of time that the inducing effect of EFV will persist for after stopping the drug is unclear. Crucially, the inducing effect of EFV could result in sub-therapeutic MVC concentrations (if MVC is started immediately after efavirenz) during initial therapy. Sub-therapeutic drug concentrations are associated with virological failure and development of resistance. In addition, maintaining an elevated dose of MVC after the induction effect of EFV has worn off could result in adverse events (such as hypotension) hence the fact that, in this study, increased dose will be maintained for a 2 week period only.

In conclusion, while MVC dose adjustments required during co-administration with EFV are clear, the correct dose of MVC when switching from an EFV-containing regimen remains unknown.