Switching from efavirenz to rilpivirine single tablet is safe and effective

People with undetectable viral load who switched from the efavirenz-containing Atripla single tablet regimen to the new rilpivirine-containing Eviplera (Complera in the United States) coformulation maintained full viral suppression, researchers reported at the 13^th European AIDS Conference (EACS) last week in Belgrade.

Regimens that combine a complete multi-class antiretroviral regimen in a single pill maximise convenience for patients. The three-in-one Atripla tablet containing efavirenz/tenofovir/emtricitabine is popular in high-income countries, but some people taking efavirenz experience persistent central nervous system side-effects such as dizziness and unusual dreams. Efavirenz is also not recommended for women trying to become pregnant, or during the first three months of pregnancy, due to the risk that the drug will harm the foetus.

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 the Eviplera tablet containing rilpivirine/tenofovir/emtricitabine in people with well-controlled HIV.

Two 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.

Cohen's team wanted to test if 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 (C_min) of rilpivirine by up to 25% for about four 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 (less than 50 copies/mL) for at least eight 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 cell count of 653 cells/mm³.

After one enrolled participant dropped out before receiving any of 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.

At week 12 all participants maintained HIV viral load below 50 copies/mL.

Rilpivirine/tenofovir/emtricitabine was well tolerated with no treatment discontinuations due to adverse events. There were two moderate (grade 2) drug-related adverse events - fatigue and increased bilirubin - but none more severe.

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), which Cohen explained was attributable to the drug's effect on a transporter involved in renal tubular secretion, not due to kidney damage

Looking at pharmacokinetics, the mean rilpivirine trough concentration (C_trough), or lowest drug level between doses, was 52 ng/mL two weeks after the switch, rising to 66-84 ng/mL between weeks 4 and 12. These levels compared favourably with trough concentrations of about 50-80 ng/mL seen in ECHO and THRIVE, in which rilpivirine was used without prior efavirenz.

Most participants achieved target effective levels of rilpivirine shortly after two weeks. None had rilpivirine below measurable levels (<1 ng/mL) at any point. However, about half still had some measurable efavirenz in their blood four weeks after switching drugs; efavirenz concentrations reached zero around eight weeks after it was discontinued.

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

In response to a question, Cohen said that 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.

Cohen C 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. 13^th European AIDS Conference, LBPS10/4, Belgrade, 2011.