combination of antiretroviral drugs in long-acting nanosuspension formulations
achieved adequate blood levels and appeared safe in HIV-negative study
volunteers, offering the potential for a maintenance or PrEP option that could
be taken once a month, researchers reported on Wednesday at the 7th International AIDS Society Conference
on HIV Pathogenesis, Treatment and Prevention in Kuala Lumpur.
While modern antiretroviral therapy is highly
safe and effective, agents that could be administered less frequently could
improve convenience for people with HIV. A long-acting option could prove
especially attractive for maintenance therapy once viral load is suppressed, or
prophylaxis (PrEP) in HIV-negative people.
William Spreen from GlaxoSmithKline
and colleagues evaluated the safety and pharmacokinetics of a nanosuspension
formulation GSK1265744 an investigational HIV integrase inhibitor similar to
dolutegravir, plus TMC278-LA, a long-acting formulation of Janssen's approved
non-nucleoside reverse transcriptase inhibitor rilpivirine (Edurant). GSK1265744 has
shown good antiviral activity in a ten-day monotherapy study and is now in phase
A nanosuspension refers to tiny
drug crystals suspended in a liquid, enabling it to remain active for longer in the
body. Decreasing particle size increases the total drug surface area, allowing
for a manageable injection volume.
This phase 1 trial enrolled
47 healthy, HIV-negative volunteers, 40 of whom received at least one injection.
Just over half were women, most were white and the mean age was 40 years.
randomly allocated to four treatment cohorts. Due to limited safety data, all
participants received a 14-day
lead-in of 30mg/day oral GSK1265744 to assess its safety and
tolerability. Following a seven-day 'wash-out' period, they then got a single 800mg
'loading dose' via intramuscular (IM) injection. After this they received:
- Cohort 1 – three doses of 200mg GSK1265744 via subcutaneous (SC) injection at
weeks 4, 8 and 12 (no TMC278-LA).
- Cohort 2 – three monthly doses of 200mg GSK1265744 via IM injection at weeks 4, 8 and
12, plus 1200mg TMC278-LA via IM injection at week 8 and 900mg at week 12.
- Cohort 3 – three monthly doses of 400mg GSK1265744 via IM injection at weeks 4, 8 and
12, plus 1200mg TMC278-LA via IM injection at week 8 and 600mg at week 12.
- Cohort 4 – a second 800mg GSK1265744 dose via IM injection at week 12 (no
withdrew prematurely from the study for any reason during the oral lead-in
phase and three did so during the injection phase.
In all dose
cohorts, plasma drug concentrations reached levels expected to be therapeutic
within three days. Levels of both GSK1265744
and rilpivirine between doses remained well above the IC90, or 90% inhibitory
concentration. GSK1265744 reached concentrations that reduced viral load in a previous monotherapy
study of people with HIV.
Both drugs had a
long PK 'tail', meaning concentrations remained high for a prolonged period and
declined slowly. In practice, this would allow for some 'forgiveness' in case
of missed or delayed doses, Spreen explained.
All regimens were
generally safe and well tolerated. One participant discontinued the study
during the oral lead-in phase due
to dizziness, and one stopped during the injection phase due to transient skin
rash. Overall, headache was the most common non-injection-related side-effect.
There were no reported severe (grade 4) side-effects or laboratory
abnormalities and no notable electrocardiogram changes.
reported injection-site reactions such as pain, tenderness, redness or nodules, but these were
mostly mild and no one withdrew for
this reason. Moderate injection-site pain was more common with IM compared with
SC injections, but nodules were more common and somewhat larger with SC administration.
of injectable long-acting nanosuspensions [of GSK1265744 and TMC278] was safe and generally
well tolerated in healthy adults," the researchers concluded.
quarterly dosing regimens achieved clinically relevant plasma concentrations"
of GSK1265744 and TMC278, they continued, adding
that these data support evaluation in longer-term clinical studies.
Spreen noted that a dosing-ranging study is
pending, and researchers plan to look at various strategies involving
oral lead-in or induction therapy with both drugs for up to six months before
proceeding to long-acting injections.