HIV
and Hepatitis.com Coverage of the 14th
Annual Conference on Retroviruses and Opportunistic Infections (14th CROI) February
25 - 28, 2007, Los Angeles, CA
Novel
PI GS-8374 Demonstrates Anti-HIV Activity and Favorable Resistance Profile in
Laboratory Studies
While
antiretroviral agents from novel classes garnered the most attention at the 14th
Conference on Retroviruses and Opportunistic Infections, held this past February
in Los Angeles, new drugs in existing classes are also needed, especially for
treatment-experienced patients with highly resistant HIV.
GS-8374,
being developed by Gilead Sciences, is a novel bis-tetrahydrofuran-based peptidomimetic
HIV protease inhibitor (PI) that incorporates a unique diethyl-phosphonate motif.
Researchers reported data from in vitro laboratory studies of GS-8374's
antiviral activity, resistance profile, and toxicity parameters (including lipid
accumulation and insulin-stimulated glucose uptake), in comparison with approved
PIs.
Results
•
GS-8374
potently inhibited the HIV protease.
•
HIV-1 inhibition
was observed in acutely and chronically infected T-cell lines, primary CD4 lymphocytes,
and macrophages.
•
GS-8374
had a minimal cytotoxic effect on various types of human cells, comparable to
that of darunavir and atazanavir.
•
GS-8374
had a minimal effect on lipid accumulation in human liver cells (comparable to
that of darunavir and atazanavir) and insulin-stimulated glucose uptake in mouse
liver cells (less than other tested PIs).
•
Using the
PhenoSense drug-resistance assay, GS-8374 exhibited a mean EC50 fold change of
6.2 relative to wild-type HIV, compared with mean fold changes of 5.9 for tipranavir
(Aptivus), 29.8 for darunavir, 137 for lopinavir, and 148 for atazanavir.
•
Unlike
lopinavir, atazanavir, and darunavir, exposure of to GS-8374 for 6 months did
not lead to the emergence of specific HIV protease resistance mutations.
Conclusion
"GS-8374, a phosphonate-containing PI, exhibits a favorable in
vitro pharmacology profile with potent antiretroviral activity and low toxicity
that has been consistently observed in multiple assay systems," the researchers
concluded. "The in vitro resistance profile of GS-8374 is superior
to all tested PI[s], including darunavir. Collectively, these results support
further evaluation of this novel PI."
Gilead Sciences, Foster City,
CA; Monogram Biosciences, South San Francisco, CA.
Reference C
Callebaut, K Stray, L Tsai, and others. Profile of GS-8374, a Novel Phosphonate-containing
HIV PI: in vitro Antiretroviral Activity, Toxicity, and Resistance. 14th Conference
on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles,
California. Abstract 491 (poster).
