FW: [CARE-HepC] NATAP: HCV Protease Drug Resistance

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-----Original Message-----From: CARE-HepC [mailto:CARE-HepC ]On Behalf Of JuLev@...Sent: May 1, 2006 4:59 PMCARE-HepC ; HEPC@...Subject: [CARE-HepC] NATAP: HCV Protease Drug ResistanceNew HCV Drugs- Protease Inhibitors & Polymerase inhibitors and Drug Resistancefrom Jules LevinEASL, May 1, 2006, Vienna, AustriaAt EASL, study results in treatment-naive patients receiving VX-950 showed a median 4.4 log reduction in viral load after 14 days of monotherapy, and -5.5 log when patients received VX-950 + Pegasys. At the end of the month at DDW Vertex will present the results from a 28-day study of the 3-drug combination of Vx-950 + Pegasys + ribavirin. At EASL Schering reported for the first time the results of treatment-naive patients receiving SCH 503034 monotherapy for 14-days & there was a median 1 log reduction in HCV viral load. Schering again reported the 14-day study results in treatment-naives who received SCH 503034 monotherapy & the median viral load reduction was 1.5 log. As I leave Vienna today & return to NYC a very important message is the potential development and risk associated with newly developed HCV protease inhibitors. You should recall 10 years ago the impact of HIV drug resistance, particularly drug resistance associated with HIV protease inhibitors & NNRTIs. Emerging out of the 41st EASL conference in Vienna this year 2006 is a message from regarding HCV protease inhibitors. Early during the meeting Vertex Pharmacueticals reported results from drug resistance research conducted in accordance with the 14-day monotherapy study of their new HCV protease inhibitor VX-950. They used an assay they reported detected drug resistant mutation variants present at about 5% of frequency. They reported single and double drug resistance mutations emerged during therapy and later double mutation changes emerged, and IC50s increased. After VX-950 therapy stopped at the 14-day mark HCV viral load increased and resitance mutations started to not be detected and wild-type virus started to emerge. By the time of 3-7 months later wild-type virus was about 65% for the patient group who had viral "breakthrough" on therapy, about 90% for the patient group who had viral "plateau" on therapy and for the patients who had vira; "continuing decline" on therapy. The presentation by Vertex was called elegant research by a number of researchers & doctors in the audience.These findings suggest that like in HIV, HCV drug resistance is a concern, certainly at this point in time. That until we see longer term clinical study results we need to pay attention to this issue. also during the EASL meeting Vertex reported the results from the small 14-day study which included some patients receiving VX-950 plus Pegasys and after 14-days it appeared that the combination fully suppressed the patients HCV viral load and Vertex reported that after VX-950 was stopped due to study protocol and patients remained on Pegasys/RBV all patients remained with undetectable HCV RNA.So, as with HIV it appears combination therapy in HCV may be crucial to full suppression of HCV. Of note, Schering Plough reported the results of their HCV protease inhibitor 14-day study. They reported only 1 patient had 1 HCV drug mutation. I went to the microphone after the presentation and asked why they only reported this 1 mutation finding after Vertex had such an elegant presentation. The presenter said to me and the entire audience that they used an assay which was not sensitive and the Schering PI SCH 503034 was not potent enough for resistance to emerge. For several days numerous people came up to me to discuss my question & the response and this was a hot topic at the meeting.The important point here is that HCV drug resistance is an important point to be concerned about, that combination therapy appears to be important in suppressing HCV & in preventing cross-resistance to drugs in the same class, and that exposing onself to a new oral antiviral HCV drug until we better understand the impact of drug resistance for HCV drugs can put one at risk for drug resistance unless full suppression is achieved.Jules Levin