There are 3 target sequences with good drugs that block them in HCV. NS3/4A, NS5A and NS5B. In HIV we started with AZT and resistance was rapid. Adding ddI or ddC improved things and now the standard of care is 3 or 4 drugs targeting 3 or 4 different bits of that unstable RNA virus.
V-pak is already targeting NS3/4A, NS5A and NS5B +/- the non specific effect of Ribavirin for GT1a. The observations from QUEST-1, C-SWIFT and trials of SOF+DCV + either Asunaprevir or Simpeprevir show better results with a 3 target strategy in line with logical expectations. More targets mean resistance requires resistance to all drugs on the same RNA sequence. The chances of a single replication cycle generating a RAV are about 1:1000 to 1:10,000. Let’s say 1:1000. So to get 2 RAVs in the one sequence the chances are 1:1000 x 1:1000 – one in a million. Three RAVS – 1 in a billion. So more targets (as a strategy) works better than stronger drugs. Nothing wrong with stronger drugs, it’s just that extra drugs raise the bar to resistance more.
The combination of ABT-493, ABT-530 and Sofosbuvir would provide best in class inhibition of the 3 targets. I don’t know if anyone is actually doing it, and the who would be Abbvie for salvage of people who failed the 2 drug combination (just as QUEST-1 was salvage for V-pak failures – mostly).
In GT1 SOF+LDV and SOF+DCV are just about strong enough that RBV provides limited benefit. A modest 2% improvement in SVR rate on a 12 week treatment for a GT1 past treatment failure. RBV will probably always provide a slight benefit (it’s a different mechanism, so different target0, but that benefit may be so small it’s not worthwhile, for example the V-pak -RBV used for GT1b. The results would almost certainly be slightly better +RBV but 98% is viewed as good enough to skip it.
The problem, as you have discovered, is that even 98% means that 2 out of every 100 people will fail to SVR.
