Dr Freeman, I have been wondering about the potential for patients who do not achieve SVR to stay on current generation DAAs until newer more effective regimens come along.
It is certainly possible. With Hep B and HIV - where long term treatment is normal we do see resistance emerge in some patients.
Entecavir monotherapy (one drug only) seems to work happily for years, unlike lamivudine where resistance happens faster.
Lesson 1 - better drugs work better for longer
Lesson 2 - montherapy requires only a mono mutation and then we have a "Houston I think we have a problem" RAV (Resistance Associated Variant)
With HIV monotherapy saw more rapid development of resistance. This almost certainly relates to the fact that HIV is based on single stranded RNA, which is genetically unstable, but HBV is based on double stranded DNA which is inherently much more genetically stable.
Lesson 3 - with RNA viruses mutations happen faster, so monotherapy is a relatively bad idea
With HIV the appearance of resistance is less rapid if we get really good viral supression ie if it ain't duplicating, it ain't mutating (actually I expect the weaker mutants probably get a free ride piggy back off the more fit virus because a virus, during duplication, is really just a sea of chemical floating around in proximity, so has no way to tell if (say) this NS5B came from Arthur or Martha)
Lesson 4 - in patients who rapidly become UND there is very little opportunity for mutations and breakthrough
With drugs like tenofovir (at least in the current TDF form) there are long term issues (bones and kidneys) and for drugs in general there are virtually none with no unwanted side effects. Sofosbuvir has not been used long term in people so we really don't know what the long term impacts might be.
Lesson 5 - as soon as you depart markedly from the trials you are into the area of human experimentation with you as the participant.
Viekira pac is the combination of an NS3/4A, NS5A and weaker than Sofosbuvir NS5B and needs both a booster (that inhibits metabolism of one bit) and Ribavirin to work in GT1a, but even though it might be viewed as 4 weaker drugs mixed into a chemical soup, the overall results are as good as Harvoni.
HAART (Highly Active Anti Retroviral Therapy) for HIV uses combinations of 3 or 4 drugs and the evidence is that doing this is capable of supressing HIV more or less indefinitely.
Lesson 6 - 1+1 might equal 2 but 1+1+1 > 3 and the experience with HIV is that 3-4 drugs is better than 2 so you probably don't just want to do Sofosbuvir+Daclatasvir (which is the rational economy option), but should also be looking at either an NS3/4 or something experimental like chlorcyclizine to get a 3rd agent working for you
DAAs only get out of Phase 2 at the end of 2011, so there has only be 4 years or scale use, and really it's more like 3.
Lesson 7 - if you can wait for retreatment it's not a bad option. There will always be better drugs around the corner and other people can be the guinea pigs. If you can't wait - F4, psychological then I would be chasing 3D (3 drug treatment) or failing that Sof+Vel which is the best 2D regimen available now. Zepatier + Sof, V-pac + Sof look good if you can get the branded stuff on insurance and then add Sof generic, but I would still be going for cure.
And as a last thought, I do know of a couple of patients doing long term DAAs because they were so sick when they started they don't want to risk stopping. So wait if that's reasonable, go hard on retreatment if it's not, buy yes you can go long term.