PK Switch Efavirenz to Maraviroc in Patients Initially Suppressed on an Efavirenz-containing Regimen
Condition: HIV Infection
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of the study aims is to help determine whether it is safe to change directly from
      efavirenz to maraviroc in patients who are stable on an efavirenz-containing regimen. The
      pharmacokinetics (drug levels) of efavirenz and maraviroc when efavirenz is stopped and
      maraviroc is started will be assessed.

      Both the study patients and the study team will know which treatment is being taken at all
      times in the study.
    

Detailed description: 
      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.
    

Intervention name(s): Maraviroc
Intervention type(s): Drug
Intervention description(s): All patients (previously on an efavirenz-based therapy) will be administered maraviroc at 600mg twice-daily for 2 weeks.
Other intervention name(s): Efavirenz = Sustiva; Maraviroc = Celsentri
Intervention MeSH terms: Efavirenz; Maraviroc
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment