Silicon Investor (SI) -- The First Internet Community

STOCKTALK

We've detected that you're using an ad content blocking browser plug-in or feature. Ads provide a critical source of revenue to the continued operation of Silicon Investor. We ask that you disable ad blocking while on Silicon Investor in the best interests of our community. If you are not using an ad blocker but are still receiving this message, make sure your browser's tracking protection is set to the 'standard' level.

Biotech / Medical : Indications -- HIV -- Ignore unavailable to you. Want to Upgrade?

To: Elroy Jetson who wrote (110)	8/14/2009 5:36:16 PM
From: idos	1 Recommendation Read Replies (2) \| Respond to of 155

I have never seen data to back your statement that elvitegravir has a far higher barrier to resistance than does Isentress. Based on limited data, there appeared to be two distinct genetic pathways of mutations in the HIV-1 integrase gene that led to Isentress resistance - the N155H or Q148K/R/H mutations. As for the current information on elvitegravir resistance, analysis of patients provided evidence for cross-resistance between the first-generation integrase inhibitors. See this abstract of Marinello et. al. from Sep. 2008: HIV-1 integrase (IN) is the molecular target of the newly approved anti-AIDS drug raltegravir (MK-0518, Isentress) while elvitegravir (GS-9137, JTK-303) is in clinical trials. The aims of the present study were (1) to investigate and compare the effects of raltegravir and elvitegravir on the three IN-mediated reactions, 3'-processing (3'-P), strand transfer (ST), and disintegration, (2) to determine the biochemical activities of seven IN mutants (T66I, L74M, E92Q, F121Y, Q148K, S153Y, and N155H) previously selected from drug-resistant patients and isolates, and (3) to determine the resistance profile for raltegravir and elvitegravir in those IN mutants. Our findings demonstrate that both raltegravir and elvitegravir are potent IN inhibitors and are highly selective for the ST reaction of IN. Elvitegravir was more potent than raltegravir, but neither drug could block disintegration. All resistance mutations were at least partially impaired for ST. Q148K was also markedly impaired for 3'-P. Both drugs exhibited a parallel resistance profile, although resistance was generally greater for elvitegravir. Q148K and T66I conferred the highest resistance to both drugs while S153Y conferred relatively greater resistance to elvitegravir than raltegravir. Drug resistance could not be overcome by preincubating the drugs with IN, consistent with the binding of raltegravir and elvitegravir at the IN-DNA interface. Finally, we found an inverse correlation between resistance and catalytic activity of the IN mutants. ncbi.nlm.nih.gov So mutations or genetic codon switches on Q148K and N155H are selected by both drugs. These two mutations are associated with high-level resistance and cross resistance to each integrase inhibitor. Gilead is dosing elvitegravir along with GS 9350 which does not have HIV activity and will boost without concerns over additional resistance caused by ritonavir. And there's the quad combo pill (tenofovir/emtricitabine/elvitegravir/GS9350), which I think, will become in a few years time the new SOC treatment in newly diagnosed HIV patients.