<a href="http://www.jhintl.net/JHI/English/Media/Latest_News/Media_LN_HepatitisCVirus.asp">Johns Hopkins Team Finds "Ancestral" Hepatitis-C Virus at the Root of Evolution in Acute and Chronic Infections</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16518754&query_hl=2&itool=pubmed_DocSum">Hepatitis C virus-specific immune responses and quasi-species variability at baseline are associated with nonresponse to antiviral therapy during advanced hepatitis C</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16413618&query_hl=2&itool=pubmed_DocSum">A target on the move: innate and adaptive immune escape strategies of hepatitis C virus</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16472599&query_hl=2&itool=pubmed_DocSum">Vaccination with protein-transduced dendritic cells elicits a sustained response to hepatitis C viral antigens</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16301660&query_hl=2&itool=pubmed_DocSum">The impairment of CD8 responses limits the selection of escape mutations in acute hepatitis C virus infection</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16286260&query_hl=2&itool=pubmed_DocSum">Clearance of HCV RNA in peripheral blood mononuclear cell as a predictor of response to antiviral therapy in patients with chronic hepatitis C</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16139918&query_hl=2&itool=pubmed_DocSum">Relationship between early HCV kinetics and T-cell reactivity in chronic hepatitis C genotype 1 during peginterferon and ribavirin therapy</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16255761&query_hl=2&itool=pubmed_DocSum">Immune tolerance to hepatitis C virus acquired during engraftment of bone marrow transplant</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16234066&query_hl=2&itool=pubmed_DocSum">Natural killer cells in hepatitis C virus infection: from innate immunity to adaptive immunity</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16175596&query_hl=2&itool=pubmed_DocSum">Intrahepatic CD8+ T-cell failure during chronic hepatitis C virus infection</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16189000&query_hl=2&itool=pubmed_DocSum">Full-breadth analysis of CD8+ T-cell responses in acute hepatitis C virus infection and early therapy</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15913800&query_hl=2&itool=pubmed_DocSum">Helper T cell cytokine response to ribavirin priming before combined treatment with interferon alpha and ribavirin for patients with chronic hepatitis C</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15958073&query_hl=2&itool=pubmed_DocSum">Interferon-gamma is produced by CD8 T cells in response to HLA-A24-restricted hepatitis C virus epitopes after sustained virus loss</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16262527&query_hl=2&itool=pubmed_DocSum">Maintenance of T1 response as induced during PEG-IFNalpha plus ribavirin therapy controls viral replication in genotype-1 patients with chronic hepatitis C</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15720526&query_hl=2&itool=pubmed_DocSum">Intrahepatic and peripheral blood virus-specific cytotoxic T lymphocyte activity is associated with a response to combination IFN-alpha and ribavirin treatment among patients with chronic hepatitis C virus infection</a>
<a href="http://www.onmedica.net/content.asp?c=38767&t=1">HCV immune response being studied</a>
<a href="http://www.natap.org/2005/HCV/022205_05.htm">How Hepatitis C Short-Circuits the Immune System</a>
<a href="http://www.cpmc.org/advanced/liver/news/newsletter/livrev-cooper1005.html">Hepatitis C Virus and the Human Immune System: A Scientist's Canon and Fugue</a>
Thanks for the posts. I've read a few that are applicable to my situation and will be armed with them when I meet with Drs. Moe and Jack. I aready know that Dr. Manny doesn't seem to read this stuff. I would have used the names Larry, Curly and Moe but I did not want to denigrate the reputation of the Three Stooges.
Hey, thanks soooo much for posting all of these...what engrossing reading material to go along with my oatmeal! ha ha! ...on the Levin article re the protease inhibitors...these are still basically conjectures, wouldn't you agree? since there is still such little evidence to make any real conclusions,...yet..
you could still postulate that as long as protease therapy included the pegysus you'd still be okay in terms of wild mutations...vis-a-vis this particular's scientists conjectures?...what do you think TN? or anyone else for that matter...
why I oughta....talking about mutations, I was in a wig shop this morning and I thoughta you...there's one right next to the post office...maybe I can send you a sample? hmmmm, for you???...I'm thinking....stay with a tried and true classic...a James Brown two scoop DA...
hey, thanks so much for your All-Things-Hep-C-Cogitations Guy! I'd be plenty happy to take vertex with just the Peg, hopefully not the riba...but you gotta do what you need to...it's very thoughtful of you to go to so much trouble for us, just copying all those url's makes me tired to think of it...now for my next brain teaser...how to spell Tennessee when I'm fogged... (better then Chattanooga, eh?) don't know you that well, is that where youre from? (I'm pretty nosy) anyway, thanks so much for all that you do for us....
<a href="http://www.natap.org/2006/EASL/EASL_06.htm">New HCV Drugs- Protease Inhibitors & Polymerase inhibitors and Drug Resistance</a>
<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15353484&query_hl=2&itool=pubmed_DocSum">Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity?</a>
<a href="http://www.natap.org/2006/EASL/EASL_10.htm">Further reduction of ribavirin dose in HCV genotype 2/3 patients receiving peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS)</a>
<a href="http://www.hivandhepatitis.com/hep_c/news/2006/050906_b.html">Factors That Predict a Rapid Virological Response at Week 4 and a Sustained Virological Response at Week 24</a>
<a href="http://www.hivandhepatitis.com/2006icr/easl/docs/050206_a.html">WIN-R Study Demonstrates Efficacy of Shorter PegIntron and Ribavirin Regimen in Hepatitis C Patients with Genotype 2 or 3</a>
<a href="http://www.hivandhepatitis.com/2006icr/easl/docs/050206_b.html">Results of Pegasys ACCELERATE and REPEAT Trials</a>
<a href="http://www.hivandhepatitis.com/2006icr/easl/pdf/McHutchnsnV9.pdf">Sustained Virologic Response to PegIntron +/- Ribavirin at 6 Months Reliably Predicts Clearance of HCV at 5-year Follow-up</a> <----- PDF file
<a href="http://www.hivandhepatitis.com/2006icr/easl/docs/050206_d.html">Effect of Pegasys Plus Ribavirin in Genotype 1 and 4
tn: thanks, that's quite a reading list you posted! I'm still stumbling through the immunology review cuteus posted and now getting further behind. The first study discussed in that Johns Hopkins press release seems to be the same <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15939790&dopt=Abstract">Cox et al '05</a> paper I linked below. Their synchronized study of changes in T cell epitopes and HCV mutations seems to get at the heart of that "ducks->frogs" flexibilty of the virus and IMHO is a good reason why vx950 and other structure-based drugs may not be that effective. If generating 1000 billion bad copies a day is enough to confuse an immune system fine tuned by six billion years of evolution it's hard to believe we're going to find something "tangible" to target in the first couple of tries. Still, there's just got to be something fixed in all that change, and the fact that HCV will only reproduce in humans and chimps has to be a clue. My hunch is that the best targets will be the conserved non-translated sequence at the two ends of the HCV genome (particularly the IRES), not the various proteins.
goofy: didn't Miss Manners spell out recommendations for how to, um, recover, from such circumstances?
Most everything is conjecture to one extent or another since the trialing (and therefore data) of HCV protease inhibitors (PI) is in it's infancy - occurring as we speak.
Levin - (a strong advocate for HCV and out in the trenches year-after-year) - is an HIV patient and has a tendency to focus his thoughts/attention in that direction, too. That is what he is doing here - looking to past experiences with HIV PI's and previous HIV drug classes - to which many patients can eventually develop resistance/mutations - and extrapolating that experience over to HCV PI's.
(from the article):
"<i>The important point here is that HCV drug resistance is an important point to be concerned about, that combination therapy appears to be important in suppressing HCV & in preventing cross-resistance to drugs in the same class, and that exposing oneself to a new oral antiviral HCV drug until we better understand the impact of drug resistance for HCV drugs can put one at risk for drug resistance unless full suppression is achieved.</i>"
The thing is, it's been known since day one that none of these PI's are going to end up being mono therapy. They all will eventually be trialed and used in combo with interferon and possibly riba - since these are what are currently successful and available today. And the short trial with VX-950 and interferon touches on that: "<i>...during the EASL meeting Vertex reported the results from the small 14-day study which included some patients receiving VX-950 plus Pegasys and after 14-days it appeared that the combination fully suppressed the patients HCV viral load and Vertex reported that after VX-950 was stopped due to study protocol and patients remained on Pegasys/RBV all patients remained with undetectable HCV RNA.</i>" The goal in PI's in a practical tx'ing sense is similar to riba's - quick and severe viral suppression, working in conjunction with interferon to make sure no mutants escape. The hope is that they will be potent enough to perhaps lessen or eliminate the need for riba, maybe lessen the amount of interferon used and possibly shorten the overall length of tx - all with the hope of higher SVR rates and possible lower sx's. It's asking alot. But the hope and promise are there.
Levin is also concerned (and rightly so) about PI failures becoming resistant from doing tx and not succeeding (paralleling HIV tx'ing once again). But HCV research is proceeding across a broad base of drug avenues - not only PI's. And if resistance occurs against one PI, it may not automatically be the case for a different PI. So there are potential options for patients who fail one (or even more) PI's to have differing combos to attempt - both within the PI class of drugs and outside of it.
Tnhepguy,anyone please-last study in cont. post titled:Hep c Virus and human immune system:A scientists canon&fugue at the bottom they show table1" KIRK2DL Receptor and HLA-C Ligands"...and state that "people most likely to clear acute hep c were homozygous for weakest combination of receptor and ligand-KIRK2DL3 and HLA C1"......in table 1 under Position80 they list Lysine(K) ..can someone examine,explain,extrapolate this table;these findings;the role of lysine(if any) in this???...i have used lysine to control herpes-often w/ mega-dosing-during my tx..i was reassured by 2 docs,but neither really examined or even knew much about lysine..i know sooo much less...thank you
WOW! quite a list of immunologic abstracts to decipher, I am going to have to bookmark for future reading, as soon as I can secure an immunology dictionary to use as reference! Whew! fascinating what I could skim through.
I had no idea Jules Levin was also HIV+, I know he cleared hcv with 18 months of tx. There is so much to read, how do you get the time? tnguy, are you up until the wee hours?
thanks again, you too, willing, you have educated many of us, not only in technical stuff but in reasoning and evaluating what is out there.
I wish I was I was a little more logical and sequential in my thinking, cause maybe then I'd get it...but can you extrapolate 'that much' from HIV PI's to HCV PIs? Admittedly, I don't know that much so I'll pose the question to y'all..Also, is the current HIV protease inhibitor therapy posing that much of a mutation threat? Working in the arts as I do, I know a boatload of guys on HIV protease inhibitor drugs, many taking them for more than 10 years now...I didn't realize there was that much of a tangible threat with these drugs, are we talking more of a latent threat?...I haven't read volumes on this of course, but I have read that their approaches (the PI's) are so very different...excuse my naivete..as you can see, this ain't my field, ha ha! Ready to be enlightened...
I read Jules Levin's comments on the recent Vienna EASL meeting and can't say I understand some of his concerns. Viral variability is an intrinsic challenge in HCV structure-based drug design, but when he writes <em>"exposing onself to a new oral antiviral HCV drug until we better understand the impact of drug resistance for HCV drugs can put one at risk for drug resistance unless full suppression is achieved"</em> he is raising a non-existent threat IMHO. HCV has less structural fidelity than jello. As documented in <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16107835&query_hl=2&itool=pubmed_docsum">DeFrancesco&Migliaccio</a> a single amino acid mutation was sufficient to confer resistance to BILN-2061 which targeted the same NS34A serine protease as VX950 and
VX950 doesn't seem that much better equipped to cope with viral mutation:
<em>"VX-950 interacts covalently with the protease but this does not render it immune to the development of viral resistance17. There is only partial cross-resistance between BILN 2061 and VX-950, possibly reflecting the differences in the interaction of different inhibitor types with the enzyme. In fact, substitutions for aspartate 168 of NS3 confer resistance to BILN 2061 but not to VX-950. Conversely, replacement of alanine 156 yields different outcomes depending on the nature of the mutation. Thus, replacement of alanine 156 with serine confers selective resistance to VX-950 (ref. 17), whereas replacement of the same residue with threonine or valine confers significant cross-resistance to VX-950 and BILN 2061 as well as to structurally different protease inhibitors22,"</em>
Levin's comments seem to raise the threat that encouraging HCV mutation away from a designed drug could lead to the same problems encountered with antibiotic resistance. However, this is not an issue here. We're not losing access to drugs that were prieviously known to work. As JJ put it , "when you've got nothing you've got nothing to lose". Failing vx950 or biln2061 tx doesn't put the patient at greater risk.
as best I can tell, you're quite right in questioning whether HIV PI results extrapolate to HCV. First they target different proteins with different shapes & binding characteristics. The drug companies first went after HCV's NS3-4A protease (biln 2061, vx950) presumably because it is a serine protease, a very well-studied class of enzymes. Even there, the way NS3-4A protein binds its substrate (the molecule it's going to cut) turned out to quite different from other serine proteases.
A probably more significant difference however is that an HCV infection generates a much greater output of virus than an HIV infection - the usual number cited is 10^12, or a 1000 billion, virions a day. This feature coupled with a very error-prone polymerase means the virus constantly tests many slightly different forms for survival fitness. Thus, while finding a PI that blocks HIV reproduction represents s significant win, with HCV there is a considerably greater risk of escape mutations. The different drugs may have different patterns of escape mutants (<a href="http://www.jbc.org/cgi/reprint/279/17/17508">Lin et al '04</a>), but from a practical point of view what matters is the presence of any escape mutants. It's kind of like trying to drive a stake through Dracula's heart while he nonchalantly morphs into new shapes, bats, etc. Somewhere in that 9600 base pairs however, there is a biological invariant to which the virus cannot tolerate change if it is to remain viable (or so I'd like to believe...)
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