Antiviral Efficacy and Resistance Profile of R1479 Two posters presented at the 46th ICAAC, held last week in San Francisco, provided data on the experimental HCV polymerase inhibitor R1479, being developed by Roche. Past studies have shown that R1479 is a potent inhibitor of replication of the laboratory-optimized HCV genotype 1b strain Con1 and genotype 1a strain H77 replicons. Because HCV shows a high degree of genetic heterogeneity (variability), emergence of resistance could be facilitated by the presence of minority drug-resistant mutations. I. Najera and colleagues performed a study to determine whether the inhibitory activity of HCV polymerase inhibitors and resistance selection are affected by the intrinsic genetic heterogeneity of the virus. They conducted tests to determine if subgenomic HCV replicons encoding NS5B from HCV isolates from 30 treatment-naive patients would be sensitive to R1479 and 2 non-nucleoside polymerase inhibitors (benzothiadiazine derivative NNI-1 and thiophene-2-carboxylic acid derivative NNI-2). To determine the frequency of mutations associated with resistance to R1479 and the non-nucleoside inhibitors within the HCV quasispecies from treatment-naive patients, clonal sequence analysis was performed on 7 different clinical isolates and a total of 720 individual full-length HCV NS5B sequences were generated. This researchers found that R1479 was a potent inhibitor of HCV replication across 30 different genotype 1a and 1b HCV clinical isolates, and that the R1479-resistance mutations selected in vitro were not observed among 720 NS5B polymerase variants. Mutations conferring resistance to the non-nucleoside inhibitors NNI-1 and to NNI-2 were present as minority species in samples from treatment-naive patients. The researchers
concluded that, "The higher frequency of non-nucleoside inhibitor resistance
mutations as compared to the absence of resistance mutations to the nucleoside
analog R1479 in the HCV quasispecies [from] treatment-naive HCV patients suggests
a potential for faster development of clinically significant resistance for non-nucleosides
NNI-1 and NNI-2 as compared to the nucleoside inhibitor R1479." In the second poster, the same research team from Roche presented further data on resistance to R1479. In this study, they used an HCV subgenomic replicon system to select and characterize HCV variants with reduced susceptibility to R1479 (4'-azido-cytidine) and NM283 (2'-C-methyl-cytidine), and investigated potential cross-resistance with interferon-alfa and ribavirin. Characterization of resistant replicons identified S282T in the NS5B coding region as the mutation conferring resistance to NM283, similar to results obtained with other 2'-methylated nucleoside analogs. Mutations S96T and S96T, in combination with N142T, were associated with low-level resistance to R1479. The researchers concluded that there was no apparent cross-resistance between R1479 and NM283, interferon, or ribavirin. "This data will allow the optimization of new polymerase inhibitors and their use in combination therapy" for hepatitis C, they wrote. Roche Palo Alto LLC, Palo Alto, CA. 10/03/06 References I Najera, S Le Pogam, A Kosaka, and others. R1479 is a Potent Inhibitor of HCV RNA Replication Across Genotype 1a and 1b Clinical Isolates. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract F1-1381. I Najera, S Le Pogam, W Jiang, and others. Resistance Profile for 4'-Azido-Cytidine (R1479), Reveals Lack of Cross Resistance with 2'-C-Methyl-Cytidine, Interferon-Alfa and Ribavirin. 46th ICAAC. San Francisco, CA. September 27-30, 2006. Abstract V-1909.
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