The first resistance data on the follow-on integrase inhibitor to dolutegravir, a Long Acting Parenteral (LAP) formulation of S/GSK1265744, was included as an oral presentation at the workshop.1
Although GSK744 is being developed in an oral formulation, most attention has been focused on a long acting injection with potential indication for both treatment and prevention with rilpivirine, which also has both oral and long acting formulations.
Pharmacokinetic results last year reported that plasma concentrations of GSK744-LAP remained above the IC90 for at least three months following a single intramuscular or subcutaneous injection at doses of 200 mg or higher.2 The potential for use as PrEP was shown by impressive results earlier this year that generated full protection in a macaque study following multiple rectal exposure.3
Previous in vitro studies also supported a resistance profile that retains sensitivity to raltegravir and elvitegravir associated mutations.4
At the workshop new data were presented showing that, as with raltegravir, GSK744 effectively inhibits HIV integration and reduces LTR-circles without impacting levels of viral DNA. No further mutations emerged when GSK744 was passaged for 56 days with raltegravir-associated single site directed mutations E92Q or N155H. However, further mutations developed with the Q148H/K/R pathway although the associated reduced fold change (FC) sensitivity (FC 5.6 with Q148R and FC 5.1 with Q148R) could be overcome by higher dosing.
The resistance profile for GSK-744 appears similar to dolutegravir, rather than being a compound that could salvage dolutegravir resistance. This should inform the approach both to future studies and to proposed integrase sequencing.
Current studies with GSK-744 include an ongoing safety study with rilpivirine LA in HIV negative volunteers and an induction/maintenance study (starting with GSK-744 plus two RTIs and switching to GSK-744 plus rilpivirine maintenance) in treatment naive patients.5,6
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