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Integrase Drug Resistance Revisited: New HIV Drugs at Drug Resistance Workshop
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Barbados. 11pm, after the dinner boat cruise.
Hi from Jules Levin at the 2007 HIV Drug Resistance Workshop, this year on the island of Barbados. Attendees arrived last night at this very nice setting at the Hilton Hotel on the beach. Everyone lingered at the beach on yesterday's arrival day. the ocean was warm and inviting and the opening night buffet was great, I had swordfish and fantastic pork jerky ribs, it was worth breaking my diet for these ribs.
My first glance at the agenda at this year's meeting highlights a number of presentations on new HIV drugs. Merck presents an initial discussion on their new HIV protease inhibitor PL-100 for patients with PI resistance, focusing on preclinical resistance data. There is a discussion of drug resistance & the 2 integrase inhibitors from Gilead & Merck. They appear to be cross-resistant. There was discussion and differences of opinion in the meeting today regarding how quickly resistance can develop to the Gilead & Merck drugs and if there is a difference. In the Merck monotherapy study of 10 days no patient developed drug resistance. In the 11 day Gilead monotherapy study 1 study arm used ritonavir boosting and no patient in this arm developed drug resistance. The Gilead and Merck studies were different: the Gilead study used a regimen of the Gilead integrase + 2 nukes and many patients were very resistant to nukes, so after 3-6 weeks a number of patients experienced viral rebound. In the Merck study patients received a boosted PI + nukes along with the integrase. For the patients with 0 scores on the GSS & PSS they had viral load reductions after 24 weeks of 1.35+ logs but its possible their was residual efficacy from the PIs since GSS & PSS may not be very accurate. Regardless how you look at this it is not possible to know definitively how quickly resistance can develop. Clearly NNRTIs often develop resistance quickly, within 1-2 days. So resistance to integrase develops more slowly but probably more quickly than boosted PIs.
The new PI for patients with PI drug resistance SPI-256 from John Erickson (original PI discoverer at NIH & Abbott) at Sequoia Pharma has entered a phase I study in healthy volunteers and Sequoia presents here on 2 additional PIs targeting multi-drug HIV resistance.
Roche is reporting on R1206, a representative compound of a novel series of NNRTI prodrugs, a "potent inhibitor of wild-type HIV" and broadly active against HIV with NNRTI resistance mutations. Idenix is reporting here on their new NNRTI with in vitro potency against NNRTI resistant HIV. There is data from Tibotec on NNRTI TMC-125 characterizing the drug resistance profile. Racivir is a nuke with activity against HIV with the 3TC/FTC mutation M184V and there is data and discussion scheduled for today's opening session.
Ambilia Biopharma report on novel pyrzolopyridine compounds as a new class of integrase inhibitors which "showed a potentially distinct mechanism of strand-transfer inhibition, which may lead to a different resistance profile". Merck has an ongoing program to develop new and potentially improved second generation integrase inhibitors.
Thats all from me for now as it appears at first glance to be a promising workshop. Historically, the HIV Drug Resistance Workshop has been a key meeting as it previews new information and data that appears later in the year at subsequent meetings including CROI. Now for coffee.
Jules Levin
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