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Long-acting injectable cabotegravir + rilpivirine works well as HIV maintenance therapy
Liz Highleyman, 2016-02-23 20:50:00
A combination of two
long-acting injectable antiretrovirals, cabotegravir and rilpivirine, given
once every 4 or 8 weeks, maintained viral suppression as well as a standard
oral antiretroviral therapy (ART) regimen and appeared safe and well-tolerated,
according to results from the LATTE 2 trial presented at the Conference on
Retroviruses and Opportunistic Infections (CROI 2016) taking place this week in
Long-acting medications could
offer an attractive option for people with HIV facing a lifetime of
antiretroviral treatment. These agents have the advantage of being more
convenient and potentially improving adherence, but the drawback is that a
long-lasting drug cannot be easily removed from the body, so it is especially
important to establish safety in advance.
To this end, the LATTE (Long-Acting
Antiretroviral Treatment Enabling) trial evaluated ViiV Healthcare's experimental integrase
inhibitor cabotegravir (formerly GSK1265744) and Janssen’s NNRTI rilpivirine (Edurant) as a simplified two-drug
oral maintenance regimen for people who had already achieved undetectable viral
load using standard three-drug ART.
At last year’s CROI, David Margolis from ViiV presented 96-week findings showing
that 76% of participants who switched to oral cabotegravir plus rilpivirine
dual therapy maintained viral suppression, compared to 63% of people who stayed
on a three-drug regimen containing efavirenz (Sustiva).
The oral combination was safe and well-tolerated, which
laid the groundwork for testing the long-acting injectable formulations of
cabotegravir and raltegravir in the LATTE 2 trial. Dr Margolis presented 32-week
results from LATTE 2 at this year’s conference.
This phase 2b analysis
included 309 people with HIV who had not previously taken treatment. More than 90%
were men, about 80% were white and the median age was 35 years. At baseline, the
median CD4 cell count was 489 cells/mm3 and nearly one-fifth had a
high viral load >100,000 copies/ml.
Participants in this
open-label study first started a three-drug induction regimen consisting of
30mg once-daily cabotegravir plus abacavir/lamivudine (the drugs in Kivexa or Epzicom).
Those who achieved viral
suppression (<50 copies/ml) during the induction period were randomly
assigned either to receive intramuscular injections of cabotegravir and
rilpivirine every 4 weeks (Q4W) or every 8 weeks (Q8W), or to stay on the same oral
regimen. Previous research showed that injectable
cabotegravir remains at therapeutic levels with either
monthly or quarterly dosing.
The injectable regimen consists of separate
2-3ml injections of cabotegravir and rilpivirine in the buttocks. Dr Margolis
suggested injections in the thigh might be possible to allow
self-administration. He said there is some flexibility in dosing, so people can
get the shots within a week before or after their scheduled date.
Of the 309 initial participants, 286 achieved viral
suppression and were randomised to maintenance therapy. During the maintenance
period, 94% of people who received the injectables every 4 weeks and 95% of
those treated every 8 weeks maintained HIV RNA <50 copies/ml at week 32, as
did 91% of those who stayed on the oral regimen.
The small number of participants – one in the cabotegravir
Q4W arm, five in the Q8W arm, and two in the oral therapy arm – experienced
virological non-response. Two of these (one in the Q8W arm and one in the oral
arm) had protocol-defined virological failure, but neither showed evidence of
integrase inhibitor or NNRTI resistance.
Injectable cabotegravir and rilpivirine were generally
safe and well-tolerated. Serious adverse events occurred in 6% of people who
switched to the long-acting injectables and 5% of those who stayed on the oral
regimen, but these were not considered drug-related.
The most common drug-related side-effect was injection
site reactions, occurring in more than 90% of injection recipients. Out of 4286
total injections, 2282 led to reactions such as pain and swelling. These reactions
were mostly mild or moderate, usually resolved within a week (median duration three
days) and became less common over time, but they led two people to withdraw
from the study.
The most common drug-related adverse events other than
injection reactions were fever, fatigue and flu-like illness, experienced by 19
participants taking the injectable drugs and one person on the oral regimen.
Laboratory abnormalities of grade 3 or higher were seen in 16% of and 14%,
Pharmacokinetic analysis showed that the
long-acting injections maintained cabotegravir levels similar to those seen
with oral therapy in the original LATTE study. Concentrations started low and
then increased, and Dr Margolis said they are working on strategies to increase
early levels. Rilpivirine concentrations rose over time, but he said they
stayed well below the level that might present a risk for heart problems.
Study participants reported a high level of
satisfaction with their treatment – more than 90% receiving the long-acting
injections reported that they were satisfied, compared with about 70% of those
on the oral regimen.
Neither the four-weekly or eight-weekly dosing regimen was
clearly better. LATTE 2 follow-up will continue through week 96 and
researchers plan to further evaluate the long-acting
injectable regimen in larger phase 3 trials.
The long-acting formulations of cabotegravir and
rilpivirine are also being studied for pre-exposure prophylaxis (PrEP) – data
that are also being presented at CROI this week.