Hello,

Sorry to hear you have relapsed

1) ?
2) Daclatasvir works for L31M, ledipasvir does not. ABT-493 is the NS3/4A inhibitor and ABT-530 is the NS5A and it is the current state of the art – but only available via a trial.
3) No, QUEST-1 was salvage of patients like you had failed V-pak (and other DAA regimens) http://www.infohep.org/Treatment-intensification-with-sofosbuvir-permits-cure-after-failure-of-previous-HCV-treatment/page/3014990/

1) http://www.sciencedirect.com/science/article/pii/S0168827813002092

In addition, daclatasvir has been demonstrated to be 2-fold more active against the L31M substitution as compared with ledipasvir [53]

Follow it from there if you like.

2) Because Dasabuvir is a weak NS5B inhibitor compared to Sofosbuvir. Sofosbuvir mono-therapy produces about 70% SVR which is pretty incredible. Sofosbuvir + V-pak + Riba would almost certainly work, and as noted before was the salvage regimen used by Abbvie in QUEST-1

3) No I meant ABT-493. http://www.worldhepatitisalliance.org/latest-news/infohep/3059959/abt-493-abt-530-cures-most-hepatitis-c-patients-across-genotypes-surveyor-studies

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.

Your L31M provides resistance to the NS5A in Viekira (Ombitasvir) leaving you with only the Paritaprevir (NS3/4A) and Dasabuvir (NS5 to do the job. Dasbuvir is significantly inferior to Sofosbuvir and clearly not up to the task in you.

You should be easy to retreat and could retreat now with Viekira + Sofosbuvir (that’s what we use) but Vosevii would be equivalent if you can get it.

http://www.aidsmap.com/Treatment-intensification-with-sofosbuvir-permits-cure-after-failure-of-previous-HCV-treatment/page/3014995/

If you fail Vosevii you will probably be incurable unless you could get Maviret and add Sofosbuvir and Ribavirin. So it’s probably best to take your consultant’s advice on this one.

The retreatment success rate with Vosevii is “only” 96%. Nobody wants to be in the 4% but 1 in 25 patients will be, regardless of what they want. While Ribavirin might not add much not taking it and then relapsing again would leave you wondering… what if?