Preliminary EASL Coverage

[dointime]

http://www.hcvadvocate.org/news/reports/EASL_2010/Advocate_EASL_2010_Coverage.htm#_Pharmasset_to_Present

[dointime]

I've had a look at 23andme and I will do it if another round of ifn becomes imminent for me.  I didn't know that this was available to Joe Public so it's great that you posted the info.  One of these days the docs should do this routinely for anybody about to embark on tx, just like they will have to test for resistant mutations.  My doc is a virologist and tells me they are way ahead on all this in the HIV field so the groundwork has already been done.  It's just that the virologists and the liverheads don't always communicate.     .

Anyway I'll will wait until my next tx is planned.  I am still entertaining the possibility of an interferon-less tx if they'd only get a move on with the inform-1 trials.  And by that time the 23andme tests might be cheaper.

dointime

[willing]

agreed - particularly frustrating since for the ns3/ns5b combo  it's no longer a matter of safety/efficacy but of  ACCESS.  Please post if you decide to spend the money on the personalized sequencing - I'm surprised no one around here has tried it yet; there may be less expensive options than 23andme. The 3 main il28b publications are cited on their page above.

[dointime]

Whatever them in Vienna think they have proved, I would say to all - do not bank on the relative unfitness of resistant mutations.  Mine certainly weren't unfit, they turned out to be olympic athletes.  I am banking on the NS5b and NS3 drug combo to finally eradicate them - so bring it on guys and make it snappy.

Willing - great info on IL28, thanks.  I struggle to understand this stuff but I for one would find it very useful to know if I were a TT.  My last tx took most of 2 years to get done and over completely so I am not eager to lose another 2 years unless I believe my odds of success are pretty high.  Haven't they tested gamma interferon with TT's yet?  Get on the case and hurry up, why don't they.

dointime      

[willing]

agreed, relative unfitness of mutants resistant to Boce  seems one of the better news items to have come out of Vienna (a number of bigwigs seemed to have gotten stuck there, hope they're enjoying the forced layover..). Resistance profiles for  the two 1st gen NS3 PIs are nearly identical, so all this doubtless applies to Tela. as well. Note that there are significant differences among resistant strains - eg V36M fizzles out much faster than T54S, which underscores the importance of finding out which mutants surfaced in one's individual tx. How this will be used in future tx planning is still uncharted. However, the main point seems to be that even the leaky, 1st gen, PIs are not "use-once" and, in combination with other agents can be applied in a repeat attack.

MrL: there's also a  Pharmasset study on combining NS5b and NS3 drugs which suggests that, for most, resistance will be a short-term problem:
"These in vitro results indicate that combinations of two nucleosides/tides targeting NS5b as well as DAAs targeting different HCV proteins effectively suppress resistant replicons."
Now if they would just start making that combination available to patients...

Dointime:  the IL28 story is pretty interesting and seems to be making a huge splash in the HCV world (note number of Vienna presentations). On a practical level, I think your VL curve will give more information than anything else about ifn-sensitivity, however if you're trying to pin down causes it may be helpful to investigate.  The story, as far as I can tell,  goes something like this. Of the 3 billion nucleotides of DNA, about 64 million are on chromosome 19. SNPs (single nucleotide polymorphisms ) are just points where that DNA varies from person to person (accounting for a lot of the differences among us). About 3K upstream of  a gene called IL28B is a SNP which was found to largely account for why some  SVR on SOC and some don't. The SNP, labeled rs12979860, is  at position chr19:39,738,787. You can get a glimpse of the surrounding DNA via one of the human genome browsers, eg,

http://genome.ucsc.edu/cgi-bin/hgTracks?position=chr19:39738537-39739037&hgsid=156953788&snp130=pack&hgFind.matches=rs12979860,

but that only tells you what Criag Venter's DNA looks like. To find out what your DNA codes at that position check out sites like 23andme:

https://www.23andme.com/health/Hepatitis-C-Treatment-Response/

for about $ 500 they will send you a bag to spit into. Mail them the bag and they send back a report of various SNPs.

Note that they don't test rs12979860 but another nearby SNP rs8099917 which has been found to have  similar effects. This is likely due to pending patent issues (which came up in  a recent anti-pharma thread). Along with those two SNPs three others  rs12980725, rs1188122 and rs8105790 have also been reported to be highly correlated with ifn response (and there's a number of other firms that do personalized sequencing).

What you want to see at that location is a C, not a T. If you have Cs on both of your copies of chromosome 19 your SVR odds on SOC are in the 80% range, dropping to under 30% for a TT (needless to day, that statement oversimplifies). So a minor C to T  molecular arrangement in one lonely base somewhere in a vast ocean of DNA can make a huge impact on how we spend years of our lives - sort of  a "for want of a nail" story...  Of course, there's the obvious question of what do you do with the information. Of the various factors affecting tx outcome this seems to the most powerful but there's not much you can do about it (in fact IR seems to be the only factor under patient control). However, knowing to what extent you can rely on ifn for the next tx can help plan the attack.

BTW - no one yet has a clue why that variation at chr19:39,738,787 does what it does. IL28B turns out to be a gene for another type of interferon (gamma) which will be getting a lot more attention as a result.

[Mr Liver]

" Failed PI tx can't help but strengthen resistant mutations, but it's good to seem them slowly get buried by wild type."

Hi Willing,
Interesting post,thanks, I wanted to mention that there are a few studies going on with novel PIs that haven't displayed the broad cross-resistance seen with bocep and telep. It will be a few years but it will at least offer options to those who relapse with other PIs.

I haven't read anything on this topic but wouldn't you expect to see the same resistance if a relapser went back to bocep or telep ? Wouldn't the same degree of viral resistant strains be expected ?

It was interesting to hear how the wild-type dominates eventually. It served as a reminder for me how the virus competes within its own family.
regards,
ML

[dointime]

Hi Willing,

I'm interested in the INFORM-1 data too - actually in anything that can either do without interferon or improve the interferon response.  

My doc tells me that it could have been my interferon non-response rather than the resistant mutations or riba non-absorbtion that defeated my one and only tx so far.  (For those that don't know, I had 2 breakthroughs.)  I note that the Globeimmune vaccine is having some interaction with 'polymorphisms in the human IL-28 B gene'.  I saw that you wrote about this gene before and I gather it appears to be key to getting an interferon response.  There are also a few other drugs, eg. Alinia, which seem to do little harm and give an edge to the success of tx.  So boosting the interferon response is how I'm thinking about my next tx at the moment.  

Even if those pesky resistant mutations have mostly gone there's still the archived memory, but in any case I'd rather get run over by a bus than do telaprevir again, because of the rash.  I'm just hoping that I can hang on long enough for some kind of more humane tx to become available.

dointime              

[willing]

oops -my bad. I thought it was some new MH widget for disclosing conflicts of interest (as in 'if you follow recommendations in this post I can surely save your wretched soul/liver/life. Now please send  check to..'). Must be the combined assault of the  bootyliscious and belly fat ads - us old farts just can't handle this much skin before coffee...Apologies.

[willing]

thanks! the apple trees are in blossom, the birds are making a racket - must be time for EASL (been thinking about this stuff too long when the year divides into EASL, DDW, AASLD and DART).
The big surprise for me was no announcement from Vertex on final phase III results. They should have final data by now, and I recall seeing an investor's advisory suggesting FDA filing by June - hopefully not  a delay. The Merck note about not filing until end of the year also is not great news ,

Looks like the final SVR data from INFORM-1 should have been released at a poster presentation given yesterday. It'll be interesting to hear whether all the 5/8 in the 1000/900 arm who got to UND with 12 days of tx *without soc* managed to keep it.

Also more good news for the blue-pill brigade from the Merck boceprevir presentation:
"No late relapse was confirmed in the 290 subjects who previously had SVR." and (relatively) good news  for you and susan400, two years after EOT probability of detecting any resistant mutation dropped under 50%. Failed PI tx can't help but strengthen resistant mutations, but it's good to seem them slowly get buried by wild type. Suggests that in the next attack you can still rely on BC/TV to wipe out the majority of virus. BTW what's with the Disclosure Guide? been hiding something..