Replies to post #137312 on Biotech Values

[genisi]

Longer durations are worth trying but personally I feel it won't make a difference with patients relapsing at 12-weeks after achieving a RVR. The trend appears to be set. Using a third agent seems like the best option with nulls but unfortunately drugs outside the nuke class aren't known to have strong resistance profiles.

A safe purine nucleotide (monotherapy/dual nuke) could possibly overcome the shortcomings of the GS-7977/Riba combination.

We know the RVR achieved with GS-7977 means the level of virus were below the limit of detection but it is possible that there were very low viral titers, below the limit of detection of current assays, which haven't necessarily mutated (nukes do have high barrier for mutation), but simply survived and rebounded. In this case, longer treatment period should do better and we both agree that treating nulls for 24 weeks with just GS-7977+Riba would still be worth, considering current alternatives. In case resistance did occur, typically by mutation, another drug that induces a different mutation from that caused by GS-7977, should help because multiple simultaneous stresses on the virus prevent these 'drug escape mutants' by repressing selection of resistant variants, which generally are associated with a significantly impaired replicative fitness anyhow. Since NS3a cleaves NS5a to its active form, combining these two complementary mechanisms should be synergistic even if the NS5a inhibitor has a weaker resistance profile.