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Long-acting cabotegravir injection shows promise for HIV prevention
Liz Highleyman, 2017-07-27 10:20:00
A long-acting injectable formulation
of cabotegravir given every 8 weeks produces high enough drugs levels in both
men and women to offer protection against HIV, according to results from the
HPTN 077 study presented this week at the 9th International AIDS Society
Conference on HIV Science (IAS 2017) in Paris. But another injectable prevention
candidate, long-acting rilpivirine, has been abandoned.
The effectiveness of antiretroviral drugs for
HIV pre-exposure prophylaxis (PrEP) is heavily dependent on maintaining good
adherence. Some individuals may find it easier to take PrEP consistently if
they could get an injection every month or two as opposed to taking pills every
day or when they plan to have sex.
Raphael Landovitz of the University
of California at Los Angeles presented the first findings from the HIV
Prevention Trials Network's HPTN 077 study.
This study is looking at the safety, tolerability and acceptability of
long-acting injectable cabotegravir, an experimental integrase inhibitor being
developed by ViiV Healthcare. As a phase 2a trial, it is not designed to
evaluate prevention efficacy. (The conference also heard promising data on long-acting cabotegravir for HIV treatment.)
HPTN 077 is a follow-up to the phase 2a ECLAIR
trial, which tested the safety and acceptability of long-acting cabotegravir
injections in a groups of mostly gay and bisexual men at low risk for HIV. That
study also did not evaluate efficacy.
ECLAIR participants received
three injections of 800mg cabotegravir given in the buttocks every 12 weeks. Interim data presented at last year's Conference
on Retroviruses and Opportunistic Infections showed that cabotegravir was absorbed faster and did not last as long in
the body as expected. And while injection site reactions were more frequent and
prolonged than expected, three-quarters of participants said they would like to
continue taking injectable cabotegravir for PrEP.
Informed by these findings, the on-going HPTN
077 study is evaluating both the same dosing regimen used in ECLAIR and 600mg
cabotegravir shots given every 8 weeks.
This study enrolled 199 HIV-negative participants
at low risk for HIV infection at eight sites in Brazil, Malawi, South Africa
and the United States. The average age was approximately 30 years. Overall,
two-thirds were women. Most US participants were men, while the women were
distributed across the three countries. Six trans men and one trans woman were
included. Just over 40% were black, 27% were white and 24% were Latino or
Participants were randomly assigned in a
3-to-1 ratio to receive cabotegravir or placebo (saline) injections. They first
received cabotegravir pills to ensure safety, as the injectable drug cannot be
removed if side effects occur. Cohort 1 received three 800mg doses of
injectable cabotegravir, given as two 2ml intramuscular injections every 12
weeks. Cohort 2 got five 600mg doses, given as a single 3ml injection. The
second 'loading dose' was given 4 weeks later the first injection, with the
rest given every 8 weeks.
The dosing period lasted 41 weeks. Follow-up was
initially planned to last 52 weeks, but this was extended after results from
ECLAIR showed that a small number of men still had measurable cabotegravir levels a year after their last injection. This
'long tail' could lead to cabotegravir drug resistance if people contract HIV
after stopping PrEP, as explained here.
Overall, 94% of participants
completed the oral phase of the study, 89% received at least one cabotegravir
injection and 75% completed all injections. Men and women had equally high
completion rates. Reasons for stopping the study included clinical adverse
events (about 8%), a change in risk behaviour and becoming pregnant.
Looking at drug
pharmacokinetics (PK), in Cohort 1 cabotegravir levels in plasma usually
remained above the IC90 level, but sometimes fell below the 4 x IC90 threshold
thought to be protective, especially in men. In Cohort 2, plasma cabotegravir
levels were higher overall, with most people staying above the 4 x IC90 level,
and a majority above 8 x IC90.
At week 41, 68% of men in Cohort
1 were above the 4 x IC90 threshold, compared with 89% of men in Cohort 2.
Women achieved high drug levels using either dosing schedule, with 100% and 97%,
respectively, above the 4 x IC90 threshold.
With both dosing schedules,
men saw a steeper drop-off in drug levels after each injection than women.
Cabotegravir levels rose a bit over time, suggesting some accumulation of the
"The 800mg dose did not consistently
meet PK targets, but 600mg did for both males and females," Landovitz said.
experienced injection site reactions, but the "overwhelming majority" of these were
mild to moderate, Landovitz said. Moderate or worse
injection site pain was reported more frequently by people who received
cabotegravir injections compared to saline shots (34 vs 2%). Reactions became
less common over time, falling from nearly 90% after the first injection to 60%
after the fifth injection. Only one participant stopped the study for this
reason, according to Landovitz.
Otherwise, the most common moderate
or worse adverse events were respiratory tract infections (about 25%) and a
decline in kidney function (about 45%), but these were equally common in both
the cabotegravir and placebo arms. More people on cabotegravir reported
headaches (15 vs 2%), but no other adverse events differed significantly
between the two arms.
Although HPTN was not
intended to assess prevention efficacy, Landovitz reported that one participant
experienced HIV seroconversion at 48 weeks after their last injection, at which
time they had an undetectable cabotegravir level.
"Having more options
for HIV prevention is critical, especially those that need not be used on a
daily basis," Landovitz said in a press release issued by FHI360.
"The next step is to evaluate in larger studies whether the dose of
cabotegravir identified will work to prevent HIV infection."
HPTN 083, the first phase 2b/3 trial
to study the efficacy of injectable cabotegravir compared to oral Truvada (tenofovir/emtricitabine) for
PrEP is now underway.