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 13th
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
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.
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 (Cmin) 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
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
should be apparent by that point. The study will continue through 48 weeks.
At week 12 all participants maintained HIV viral load below 50
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
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 (Ctrough), 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.
the investigators concluded, indicate that the brief inductive effect of
efavirenz on rilpivirine metabolism "may not be clinically relevant in
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.