The experimental HIV integrase inhibitor GSK1265744 demonstrated rapid and potent antiviral
activity and good tolerability for treatment-naive people in the LATTE study,
according to a report at the 14th European
AIDS Conference this week in Brussels.
Integrase inhibitors are among the most well tolerated
antiretroviral medications. GSK1265744 (or GSK744 for short), being developed by GlaxoSmithKline, is
similar to the recently approved dolutegravir. It is being tested both as a
once-daily oral drug and as a long-acting
injectable that may allow for once-monthly administration. A recently
presented analysis of eight studies showed that it is safe with no
notable safety concerns.
David Margolis from GlaxoSmithKline and
colleagues evaluated the safety, tolerability and efficacy of GSK744 in previously
untreated people with HIV.
The phase 2b LATTE trial started with a
24-week induction phase comparing three oral doses of GSK744 plus two
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) to inform
selection of an optimal dose for further development. At week 24, participants
with stable viral suppression discontinued NRTIs and switched to a simplified
dual maintenance regimen of GSK744 plus oral rilpivirine (Edurant).
The primary endpoint of this partially blinded, dose-ranging, multicentre
study is undetectable HIV viral load (<50 copies/ml)
at 48 weeks. Margolis reported interim 24-week findings.
This analysis included 243 treatment-naive participants. Almost all
were men; Margolis explained that the lack of women was in part due to a
restriction on use of hormonal contraception since drug interactions with
GSK744 are not yet known. A majority of participants (about 60%) were white,
about 30% were black and the median age was about 34 years. The median CD4 cell count was approximately 410 cells/mm3 and 16% had high
baseline viral load (>100,000 copies/ml). About 5% were co-infected with
were randomly assigned to receive GSK744 at doses of 10mg, 30mg or 60mg, or 600mg
efavirenz, all once daily. They also started on two investigator-selected
NRTIs, about 60% taking tenofovir/emtricitabine (Truvada) and 40% taking abacavir/lamivudine (Kivexa).
weeks, 87% of participants taking GSK744 achieved undetectable viral load (all
dose arms combined) compared with 74% of those taking efavirenz in a 'snapshot'
analysis. Response was similar with all GSK744 doses (88, 85 and 87%). There
was no significant difference according to NRTI backbone.
load fell rapidly after starting treatment in all GSK744 dose groups. People
taking GSK744 achieved viral suppression significantly sooner than those taking
efavirenz, with 76 vs 24%, respectively, having undetectable HIV RNA by week
CD4 cell gains were similar for GSK744 and efavirenz recipients at week 24 (185
and 159 cells/mm3), though the increase was faster in the GSK744
arms (123 vs 59 cells/mm3 at week 8).
failure rates in the snapshot analysis were 6% with GSK744 (all arms combined)
and 15% with efavirenz. Protocol-defined virological failure – the narrower
criteria used to determine who was eligible for the maintenance phase – was
uncommon, with six total cases: one in each GSK744 dose arm (2% combined) and
three in the efavirenz arm (5%). All these patients underwent genotypic or
phenotypic resistance testing and no integrase, NRTI or NNRTI mutations were
taking GSK744 were about half as likely to withdraw from the study as those
taking efavirenz (12 vs 26%), with no notable differences across GSK744 dose
groups. This was mainly driven by a significantly lower dropout rate due to
adverse events amongst GSK744 recipients (2 vs 11%, respectively).
rates of grade 2 to 4 adverse events were similar, 18% with GSK744 and 16% with
efavirenz. As expected, people taking efavirenz had more neuropsychiatric or
central nervous system side-effects. Headache, usually mild to moderate, was more
common with GSK744 (<3 vs 0%). Six people taking GSK744 had serious adverse events (none considered
drug-related), as did three people taking efavirenz (one deemed drug-related, a
abnormalities occurred with similar frequency amongst GSK744 and efavirenz
recipients overall. However, abnormalities were more common with the highest
GSK744 dose. One-quarter of people in the 60mg group developed ALT liver enzyme
elevations; these were usually mild, but there were two transient grade 4
(severe) elevations in people with pre-existing liver disease. Lipase elevation
occurred in 8% in this arm but there were no cases of pancreatitis.
"Oral [GSK744] administered once daily with
two NRTIs was associated with a good treatment response," the researchers
on these findings the 30mg GSK744 dose was selected. The maintenance phase of
LATTE testing GSK744 plus rilpivirine maintenance therapy is currently
underway. Results from that part of the trial will prepare the way for a phase
2b study of combined long-acting injectable formulations of both drugs, which
may one day be used as monthly maintenance therapy or pre-exposure prophylaxis