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EACS 2011: Switching from Efavirenz to Rilpivirine Single Tablet Regimen Is Safe and Effective

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People with undetectable viral load who switched from the efavirenz/tenofovir/emtricitabine Atripla single tablet regimen to the new rilpivirine/tenofovir/emtricitabine Eviplera coformulation (marketed as Complera in the U.S.) maintained full viral suppression, researchers reported at the 13th European AIDS Conference (EACS 2011) last week in Belgrade.

Regimens that contain a complete multi-class antiretroviral regimen in a single pill maximize convenience for patients. The three-in-one Atripla tablet is highly popular, but some people taking efavirenz experience central nervous system side effects such as dizziness and unusual dreams; efavirenz is also not recommended for women during the first trimester or pregnancy.

Cal Cohen from the Community Research Initiative in Boston and colleagues conducted a study to evaluate the safety and effectiveness of switching from Atripla to Eviplera for people with well-controlled HIV.

A pair of Phase 3 studies -- ECHO and THRIVE -- that compared the drugs head-to-head found that rilpivirine was non-inferior to efavirenz in effectiveness, but caused fewer adverse events including skin rash and central nervous system symptoms. The present study test whether levels of rilpivirine would remain high enough to maintain viral suppression when the drugs are used sequentially.

This was a potential concern because an earlier pharmacokinetic study of healthy volunteers showed that switching from efavirenz reduced minimum plasma concentration (Cmin) of rilpivirine by up to 25% for about 4 weeks. This occurred due to efavirenz induction of the CYP3A enzyme in the liver, leading to faster rilpivirine processing and lower levels in the body.

This open-label study enrolled 50 HIV positive adults with stable undetectable HIV viral load (< 50 copies/mL) for at least 8 weeks on coformulated efavirenz/tenofovir/emtricitabine who wanted to change their regimen due to efavirenz intolerance. All of them switched to the rilpivirine/tenofovir/emtricitabine single tablet regimen.

Most participants (92%) were men, 80% were white, and the median age was 39 years. They had been taking efavirenz/tenofovir/emtricitabine for a median of 2.5 years and had well-preserved immune function, with a median CD4 T-cell count of 653 cells/mm3.

After 1 enrolled participant dropped out before receiving the new drug, 49 people were included in the analysis. The researchers measured HIV viral load and pharmacokinetic parameters at weeks 1, 2, 4, 6, 8, and 12. They also looked at safety and tolerability.

The primary endpoint, reported at the EACS meeting, was viral suppression 12 weeks after the switch; Cohen noted that any potential drug-drug interactions should be apparent by that point. The study will continue through 48 weeks.

Results

  • At week 12 all participants maintained HIV viral load below 50 copies/mL.
  • Looking at pharmacokinetics, the mean rilpivirine trough concentration (Ctrough), or lowest drug level between doses, was 52 ng/mL 2 weeks after the switch.
  • Ctrough rose to 66-84 ng/mL between weeks 4 and 12.
  • These levels compared favorably with trough concentrations of about 50-80 ng/mL seen in ECHO and THRIVE participants who did not use prior efavirenz.
  • Most participants achieved target effective levels of rilpivirine shortly after 2 weeks.
  • None had rilpivirine below measurable levels (<1 ng/mL) at any point.
  • About half still had measurable efavirenz in their blood 4 weeks after switching drugs; efavirenz concentrations reached zero around 8 weeks after discontinuation.
  • Rilpivirine/tenofovir/emtricitabinewas well tolerated:
    • There were no treatment discontinuations due to adverse events;
    • There were 2 moderate (Grade 2) drug-related adverse events, fatigue and increased bilirubin;
    • No severe side effects were reported.
  • Rilpivirine was associated with a small increase in serum creatinine (from 0.97 mg/dL at baseline to 1.09 mg/dL at week 12); Cohen said this was attributable to the drug's effect on a transporter involved in renal tubular secretion, not kidney damage.

These findings, the investigators concluded, indicate that the brief inductive effect of efavirenz on rilpivirine metabolism "may not be clinically relevant in suppressed patients".

Cohen said there was no reason to expect that these findings would differ for women. Since black patients tend to have higher efavirenz levels on average, he suggested they may have an "even longer cushion" of effectiveness after switching to rilpivirine.

Investigator affiliations: Community Research Initiative, Boston, MA; Anthony Mills MD Inc., Los Angeles, CA; Orlando Immunology Center, Orlando, FL; Capital Medical Associates, Washington, DC; Central Texas Clinical Research, Austin, TX; Gilead Sciences, Inc., Foster City, CA.

10/18/11

Reference

C Cohen, A Mills, E DeJesus, et al. Switching from Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate (EFV/FTC/TDF) Single Tablet Regimen (STR) to Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate (FTC/RPV/TDF) STR in Virologically Suppressed, HIV-1 Infected Subjects. 13th European AIDS Conference (EACS 2011). Belgrade, October 12-15, 2011. Abstract LBPS10/4.