A pilot study on the efficacy and pharmacokinetics of a switch from nevirapine with emtricitabine, tenofovir or lamivudine, tenofovir or lamivudine, zidovudine to rilpivirine with emtricitabine, tenofovir in virologically suppressed HIV-1 infected patients.

Rilpivirine (RPV) is a nonnucleoside reverse transcriptase inhibitor (NNRTI)
with in vitro activity against HIV-1. A phase 2b, dose-finding study in
ARV-naïve, HIV-1-infected subjects demonstrated sustained and comparable
efficacy of TMC278 25, 75 and 150mg once daily (qd) over 192 weeks.
Furthermore, 2 large phase 3 studies in ARV-naïve, HIV-1- infected subjects,
ECHO and THRIVE have demonstrated noninferiority of RPV 25 mg qd in combination
with emtricitabine (FTC) and tenofovir (TDF) when it was compared with
efavirenz (EFV) 600 mg qd which is the current standard of care in resource
rich countries (1,2). Furthermore, RPV 25 mg was associated with statistically
significantly lower incidences of grades 2-4 adverse events (AE) related to
study drugs, AE leading to discontinuation, rash, dizziness, and little change
in cholesterol and triglycerides compared to increases with EFV. The only
single tablet regimen currently available for the treatment of HIV is Atripla®
in which efavirenz, FTC and TDF are combined in a 1 pill once a day regimen.
Now that the efficacy and improved tolerability of RPV in comparison with the
current standard of care has been documented, Gilead Sciences has incorporated
RPV, FTC and TDF in a new single tablet regimen (STR) for the treatment of
HIV-1. This STR is called Eviplera® and received EMA approval 30th of November
2011 for the treatment of HIV-1 infected patients with a plasma HIV-RNA load
<100.000 copies/ml. Because of its excellent tolerability and ease of
administration it will make HIV management in future patients easier. For
further information on RPV product characteristics, preclinical or clinical
data, please refer to the latest version of the FTC/RPV/TDF single tablet
regimen SPC.
Currently, there are more than 10 antiretroviral drugs in the Netherlands that
are frequently used for the treatment of HIV. However, all these drugs are
associated with mild to sometimes life-threatening side-effects and because it
is as yet impossible to predict which patient will experience side-effects they
often have to switch drugs at some time during there treatment. A recent study
including 25499 HIV patients from 19 European and North-American cohorts that
started HAART after the year 2002. After 3 years of follow-up 60% had changed
one or more antiviral drugs, mostly for toxicity(3).

Because of its well-documented antiviral activity and broad availability and
reduced costs, nevirapine (NVP) is the most frequently used NNRTI for the
treatment of HIV in resource-limited countries. Also in the Netherlands,
several hundreds of patients start NVP as part of their HAART each year.
However, during the first 6 weeks of NVP therapy 2 well-known
treatment-limiting side effects occur in around 10% of patients (rash and
hepatitis). Hence, in the near future a switch from NVP to RPV will be a valid
option for patients experiencing NVP-related AEs. Because NVP-related AEs often
occur during the first 6 weeks of treatment initiation, the plasma HIV RNA load
will usually not be undetectable at time of a switch from NVP to RPV.
Therefore, it is important to assure therapeutic levels of RPV during the weeks
after the NVP to RPV switch to avoid selection of drug resistance. However, as
a result of NVP mediated CYP3A induction of RPV metabolism, it can be expected
that the RPV Cmin concentrations will be significantly lower for some time
(days to weeks) after the NVP to RPV switch.

This study will evaluate the efficacy and safety of RPV in patients with an
undetectable HIV plasma viral load for >6 months while treated with a NVP
containing HAART regimen when they replace NVP by RPV. In a subset of patients
the impact of NVP CYP 3A4 induction on RPV serum levels will be measured. In
patients on HAART with undetectable HIV RNA it takes on average 4 to 8 weeks
before HIV replication can be documented in plasma after all antivirals are
discontinued(4). Furthermore, when NVP is replaced by RPV, the 2 other
antiretrovirals that the patient is taking are continued or replaced by the
current standard of care. Another recent study measured the pharmacokinetic
consequences of CYP3A4 induction by previous efavirenz exposure which is
another NNRTI frequently used for the treatment of HIV. All of the 49 patients
included in this study remained HIV RNA undetectable 12 weeks after the switch
from efavirenz to RPV despite a mean reduction of RPV serum levels of 50%
during the first 2 weeks after the switch. Therefore, the potentially lower RPV
levels during the first days to weeks after the switch from NVP to RPV while
the CYP3A4 induction is waning are not expected to impact HIV control in
patients with an undetectable HIV plasma viral load at the time of switch.
However, the insight that this study will generate on de RPV metabolism
induction by previous NVP use will be valuable to design future pharmacokinetic
studies and find the correct dosing for future patients that switch from NVP to
RPV at a time that their plasma HIV RNA load is not yet undetectable.

Primary objective:
To evaluate the efficacy of a RPV based HAART in patients that switch from NVP
with FTC, TDF or lamivudine (3TC), TDF or 3TC, zidovudine (ZDV) to RPV/FTC/TDF.

Secondary objectives:
To measure the impact (strength and duration) of NVP CYP 3A4 induction on serum
levels of RPV when patients switch therapy from NVP to RPV.

To evaluate efficacy and safety of RPV at 24 and 48weeks after a switch from
NVP.

Open label single arm intervention study. 50 patients will discontinue NVP on
day 1 and start RPV 25mg in combination with emtricitabine and tenofovir given
as a single combination tablet qd (Eviplera®).

For the PK analysis, Cmin levels of a subset of 20 of these 50 patients will be
compared with mean Cmin levels from the 2 phase III registration trials at 1,
2, 3, 4 and 8 weeks

Switch from NVP (Viramune) with FTC, TDF (Truvada) or 3TC, TDF or 3TC, ZDV to
RPV, FTC, TDF (=Eviplera)

Burden: 3 extra visits for blood sampling (30cc) for all 30 of the 50
patients. 7 extra visits for blood sampling for 20 of the 50 patients.

Risks: Risks associated with the study are the side effects of RPV as observed
in the phase III clinical trials. In these studies RPV was well tolerated and
only 4% discontinued RPV for AE after 96 weeks of treatment (9% in control
arm). No life threatening drug-related AE were observed. We do not anticipate
clinically relevant consequences of the lower RPV serum levels during the first
days to weeks after the switch from NVP to RPV because patients are HIV-RNA
undetectable at the time of switch. Even if all antiretroviral drugs are
discontinued in patients with undetectable HIV-RNA in plasma, it takes on
average 4-8 weeks before HIV replication in plasma reappears. Furthermore, when
NVP is replaced by RPV, the 2 other antiretrovirals that the patient is taking
are continued or replaced by the current standard of care NRTI backbone.

Benefit: Decrease in pill count from 3 to 1 pill per day as RPV will be given
as a single tablet regimen(STR) which incorporates TDF, FTC and RPV in 1 pill.