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Potent Antiviral Activity of GSK Integrase S/GSK1349572
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Reported by Jules Levin
EACS Oct 31-Nov 3 2009, Cologne, Germany
ABSTRACT
Objectives: Next generation INIs that provide improvements in dosing and resistance profile are needed. S/GSK1349572 is the only once daily unboosted INI in clinical development; in vitro studies show limited cross-resistance to raltegravir and elvitegravir and the potential for a higher
barrier to resistance. Antiviral activity, safety and exposure-response relationships were investigated in this phase 2a study.
Methods: 35 HIV-infected subjects (INI-naïve) were randomized to doses of 2mg, 10mg, 50mg, or placebo once daily for 10 days. Serial HIV-1 RNA and PK samples were collected. PK parameters were calculated by non-compartmental methods. Relationship between PK (AUCτ, Cmax, and Cτ) and PD measures (changes in HIV-1 RNA) was assessed using various Emax and linear models.
Results: On Day 11, a mean decrease from baseline in plasma HIV-1 RNA of 1.5 to 2.5 log10 copies/mL was observed across the doses tested, which was significant when compared to placebo. Seventy percent of subjects achieved undetectable plasma HIV-1 RNA levels (<50 c/mL) at the 50mg dose. No genotypic/phenotypic resistance to S/GSK1349572 was observed.
INTRODUCTION
In a Phase 2a study of 10-day monotherapy, S/GSK1349572 demonstrated unprecedented
antiviral activity1, including:
- 2.5 log10 decline in HIV RNA after 10-day monotherapy with 50mg dose
- 70% of subjects treated with 50mg had <50 copies/mL at nadir despite receiving no other ARVs
Given that 70% of subjects were below the limit of quantitation (BLQ), the 'true' change from baseline in HIV RNA was constrained by the limitations of the assay. We have thus repeated the analysis with a more sensitive assay in order to more accurately measure the potency of S/GSK1349572.
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