An combination of two once-daily oral antiretrovirals –
the next-generation integrase inhibitor cabotegravir (GSK1265744) and the
approved NNRTI rilpivirine (Edurant, also in Eviplera
or Complera) – was as effective as an efavirenz (Sustiva)-based regimen when used as
maintenance therapy to keep viral load suppressed, according to a poster
presented at the recent Conference on
Retroviruses and Opportunistic Infections (CROI 2015) in Seattle.
David Margolis from GlaxoSmithKline and colleagues presented findings
from the phase 2b LATTE (Long-Acting Antiretroviral
Treatment Enabling) trial, which was designed to select the best oral
dose of cabotegravir and to evaluate cabotegravir plus rilpivirine as a simple two-drug
maintenance regimen for people who had already achieved undetectable viral load
using a standard combination antiretroviral regimen. Showing that the two drugs
are effective when taken as once-daily pills was intended to lay the groundwork
for studies of long-acting injectable formulations of both drugs.
LATTE started with a 24-week induction phase
comparing three oral doses of cabotegravir plus two nucleoside/nucleotide
reverse transcriptase inhibitors (NRTIs). After 24 weeks, participants with
stable viral suppression discontinued the NRTIs and substituted rilpivirine. The three-drug
lead-in for initial viral suppression was done because rilpivirine has been
shown not to work as well for people with high baseline viral loads
(>100,000 copes/ml) in some prior studies.
This multicentre trial included 243 participants
starting their first antiretroviral regimen. Almost all were men, about 60%
were white and the median age was about 33 years. (The low number of women was
in part due to a restriction on use of hormonal contraception, since
interactions with cabotegravir were not yet known.) The median baseline CD4 cell
count was about 410 cells/mm3 and 14% had an initial viral load
>100,000 copies/ml. About 5% had hepatitis C co-infection.
Participants in this partially blinded
trial were randomly assigned to start on one of three doses of cabotegravir
(10, 30, or 60mg) or 600mg efavirenz, all once daily, taken with two NRTIs
selected by their provider; about 60% used tenofovir/emtricitabine (Truvada) while the rest used
abacavir/lamivudine (Kivexa or Epzicom). Cabotegravir recipients with
HIV RNA <50 copies/ml at 24 weeks stopped their NRTIs and substituted 25mg
rilpivirine, while those in the efavirenz group stayed on their same regimen.
At 96 weeks, cabotegravir recipients could continue on the same treatment in an
open-label phase while efavirenz recipients finished the study.
The primary endpoint
was viral suppression at 48 weeks, which Margolis reported at last year's CROI. At
24 weeks, 87% of participants in the cabotegravir arm (with little difference
between doses) and 74% in the efavirenz arm had undetectable viral load. At
that point, 160 people taking cabotegravir and 47 taking efavirenz entered the maintenance
phase.
At 48 weeks, 82% of all participants
who started on cabotegravir and 71% of participants taking efavirenz (including
those who discontinued at week 24) had continued viral suppression – not a
statistically significant difference. The higher rate of treatment failure with
efavirenz was driven by more discontinuations due to adverse events, in
particular neuropsychiatric side-effects.
This year the researchers presented
96-week findings. At 96 weeks, 76% of all participants who started on
cabotegravir (all doses combined) had HIV RNA <50 copies/ml in an
intent-to-treat 'snapshot' analysis, as did 63% of those who stayed on
efavirenz plus NRTIs. There were six
cases (3%) of protocol-defined virological failure in the
combined cabotegravir arms and six cases (10%) in the efavirenz arm.
Looking only at participants who entered the maintenance
phase, 86% in the combined cabotegravir arms and 83% in the efavirenz arms
maintained undetectable viral load. Within this group, there were three cases
(2%) of protocol-defined
virological failure in the cabotegravir arms and two cases (4%) in the
efavirenz arm. Two cabotegravir recipients showed evidence of
treatment-emergent drug resistance.
Median CD4 cell gains were similar, 260 cells/mm3 in the combined
cabotegravir arms and 289 cells/mm3 in the efavirenz arm.
Both regimens, and all cabotegravir doses, were
generally safe and well-tolerated; 14% of cabotegravir recipients and
19% of efavirenz recipients reported grade 2 (moderate) or worse adverse
events; in both arms, 4% of these arose during the maintenance phase. 10% of
participants in the cabotegravir arm and 6% in the efavirenz arm experienced
serious adverse events. 4% of cabotegravir recipients withdrew early due to
adverse events compared to 15% in the efavirenz arm; most of these
discontinuations occurred prior to the maintenance phase.
Headache was the only side-effect that was more common in the
cabotegravir arms (3% vs 0%), while neuropsychiatric
symptoms such as dizziness and insomnia were more common in the efavirenz arm.
The 30mg cabotegravir dose was selected for further
development as part of oral HIV treatment.
These results confirm that cabotegravir plus
rilpivirine is an effective maintenance regimen for people who have achieved
undetectable viral load on a standard regimen, supporting evaluation of
long-acting injectable formulations of these drugs. Other recent research has
shown that long-acting injectable cabotegravir remains
at therapeutic levels in the blood with either monthly or
quarterly dosing.
The long-acting injectable formulations of cabotegravir and rilpivirine
are also being studied for pre-exposure prophylaxis, or PrEP. In animal
studies, monthly cabotegravir injections protected
macaque monkeys against infection with an HIV-like
virus delivered via either
rectal or vaginal exposure. Other recent research showed that injectable
cabotegravir may reach
adequate levels in rectal and vaginal tissue to work as PrEP.
However, drug level studies suggest that injectable rilpivirine does not last
as long and may be more
effective at preventing rectal infection than vaginal
infection.