News Stories

Question

Nation's Top Medical Centers Seek Participants for Largest Study Comparing Leading Hepatitis C Treatments Long-term outcome of hepatitis C in children Darbepoetin Alfa improves Ribavirin-related Anemia and Allows for Maintenance of Optimal Ribavirin Dose PEG-Intron Plus Ribavirin for Retreatment of Chronic Hepatitis C Twice a Week Administration of PEG-Intron Plus Ribavirin in Obtaining SVR Among Patients with HCV Genotype 1 Improved Efficacy and Tolerability in Treating Post-Transplant HCV Utilizing an Escalating Regimen of Pegasys and Ribavirin with Hematopoietic Growth Factors

cuteus · Answer

fascinating discussion, I am printing this one and handing it over to my PA to share with DR. Bersntein and get back to me on it.  They don't have the time to read every study and you guys have compiled a collection of links here that might come in handy.

TY both

TnHepGuy_ · Answer

Also meant to ask - when did you do your mono tx? What were your experiences with it?

I did mine back in 1992-93. Had dosage lowered a few months in as a result of the white side of things tanking (no Neupogen back then). One thing I've noticed is that the sx's from the mono were much more intense than the ones I receive now via the peg.


TnHepGuy

TnHepGuy_ · Answer

Thanks for the clarification - and all of your thoughts and input - they are very much apprecitated.

I have that 'temptation' right now - stopping at 48 - since I've had such a good response so far. Given my neg. factors (geno 1, high viral load, failed mono), I was fully prepared to come back somewhere above undetectable and below 2-log. And I have been gathering up all the most relevant studies (not too many - and no exact comparisons) to present to my doc/GIPA to go ex-tx. Now, this 'monkeywrench' has changed my plans ... ahahahha. I should be - and am - very grateful for this turn of events. I just now have more potential paths to choose - though no single one is clearly lit.


TnHepGuy

willing · Answer

yes, as best I can tell Crotty's argument is still pretty controversial, though it's probably going to take a while to settle the argument (how much of the genome do you have to sequence and for how long to detect the alleged riba-induced mutations?) BTW - when I was saying I would opt to exend in the above post I was thinking of my VL tests (undetect at <500 at 12 but probably still >5 given I was still 1000 iu at 9.5). With a <10 before 12, I'd be very tempted to say 48 was good enough.

TnHepGuy_ · Answer

Thanks for the 'mental prep. reminder' - I've been trying to do just that almost since day 1 of combo. I've also been gathering up all the data I can and passing it along to my GIPA - for whatever it's worth, given that she and my GI are strict 48 week'ers.

You're right about that data not being invalidated re: extended tx in the Berg and Teravic studies. The 'pause for thought' I am thinking of is in terms of thier SVR figures. It's a safe bet to assume they would be higher using the 1,000-1,200 mg. amounts.

P.S. - in case you hadn't read <a href="http://jvi.asm.org/cgi/content/full/74/8/3543?view=full&pmid=10729128">this</a> before - thought you may enjoy it. I had been concerned about the possibility of my previous failed mono tx causing viral mutation. I found this particularly facinating:

"<i>...memory of past history... ...is a property of the viral quasispecies as a whole and not of the individual genomes that compose it." "To test whether bottleneck events could eliminate the molecular memory in the quasispecies... ...therefore, bottleneck events eliminated the preference to rescue mutants.</i>"

According to this then, a severe reduction in the viral population (via my mono tx) will cause the virus to select for its original genetic structure upon rebound, and it will delete any possible interferon-resistant mutations that did not exist prior to mono-tx.

Also, another thought that pops into my head re: combo tx and SVR rates - I wonder how much the ability of the immune system to rebound during tx and become a player in viral suppression and elemination plays a role? It can be easy to just think in terms of interferon and ribavirin being the only two factors in viral eradication. But, I wonder how many 'lost' SVR's might be attributed to a low/lack-of immune response?

P.S.S. - What were your stats going into tx? during?

- Given whatever negative predicting factors you may have brought to tx, if you were starting out today, would you have pushed for X-tx?

TnHepGuy

willing · Answer

interesting article, thanks! The notion of memory embedded in the mutant spectrum is kind of spooky - it makes you think of the billions of virions as a single living entity. I got lost in the genetics and need to spend more time on this but I didn't see a connection betweeen the bottleneck event they constructed and selection for the RGD->RED mutation whereas with ifn therapy we are explicitly selecting for ifn-resistance so it seems that trait would be enhanced even if the collective viral memory is otherwise diminished.
As far as the immune-response goes, I believe it's critical, if poorly understood. IFN's job in our genome is to trigger immune-response pathways and of the various mechanisms proposed to explain the efficacy of the riba, stimulation of immune pathways is usually at the top of the list (though Croddy's mutate-to-the-max theory seems to be gaining ground).
My pre-tx load was 723000 copies/268000iu,  AST/ALT were in-range though they had been askew in the past. During tx hemoglobin and neutrophils collapsed as expected but I never got around to needing remediation. I upped my riba from 1.0->1.2 about 3/4 of the way through because I believed Herrman more than my Dr and  was impressed by the impact of that one extra pill..
My main negative predictor is that I had failed prior mono. I  probably would have needed to change Drs to extend. If I were starting out again today I think I'd opt to cut my relapse odds by extending 6 months at half-dose: now that the tradeoff is becoming clearer it seems worthwhile. However I strongly doubt that I will treat again if I do relapse - life isn't all that long after all.

TnHepGuy_ · Answer

On the subject of ribavirin and mutation - these are interesting: Is the Antiviral Effect of Ribavirin in Humans Mediated by Mutagenic Properties? The potentiating effect of ribavirin on interferon in the treatment of hepatitis C: lack of evidence for ribavirin-induced viral mutagenesis. TnHepGuy

willing · Answer

it's funny how one's perspective on  relapse odds changes over time: at 6 months I thought 20-30% was way too high for comfortand by the  time I crawled to the 40s it looked just fine (though that was before TERAVIC).
I believe Scott, Layla, MikeSimon, DoubleDose, BobK and others have set a good precedent for extended tx : make your commitment early on so you can adjust your contdown calendar accordingly.  Several have reported that having their Drs recommend more time just as they thought they were getting to the end was harsh. 
Good point about the Riba dosage but it's hard to see how increasing the dosage to the std. level could invalidate their results on the impact of longer duration. If anything, the impact at std. dosage might be higher. It does mean however that there is  less data on the safety of 72 weeks of 1-1.2g riba, which may be something to ponder. Overall I don't think you can assign an RVR classification from just the 0 and 11.5 tests. As I understand it, eliminating virions from serum is like shooting fish in a barrel, you often see a huge drop in VL in the first 24 hours. The rate at which virions are cleared from infected cells is the actual predictor of ifn's success and this requires a few measurements during weeks 0-4 to estimate the slope over that range.

TnHepGuy_ · Answer

My 11.5 week was my first PCR. My guess that I may be highly sensitive (HS) (ie - no inherent resistance in my strain) and a RVR is just that - pure speculation based upon a geno 1 (me) having a 5-6 log decline over 11.5 weeks and early normalization of LFT's. The logrithmic drop represents a 99+% decline over that time frame. And given that phase II decline has a reduced decay slope, it's possible I fit the RVR definition (though - I'll never know. The 'RVR' thoughts I am having are the ones saying '48 weeks should be enough').

One thing about the Berg and Teravic studies that gives me pause - they used 800 mg. of riba - with 1,000mg.-1,200mg. being the standard now. It is pretty well accepted that a strong, constant dose of riba upfront plays a key role in SVR rates(<a href="http://www.hivandhepatitis.com/2003icr/03_assld/docs/pegasys/102703_g.html">
Ribavirin Dosage Significantly Affects Virological Response Rates in HCV Patients Treated with Interferon/Ribavirin</a>

Brouwer used intron A - and I haven't seen the results broken down by genotype.

Quite often it seems as if I'm driving myself nuts looking for the data points that will fit my situation precisely; knowing full well that they just don't exist.

TnHepGuy

willing · Answer

Did you have any VL tests before week 11.5? There are many definitions of RVR but, as far as I know, they all depend on getting tests up to week week 4. Having gotten to <10 by 11.5 gives you very good prospects even if don't have enough tests to tell whether you responded quickly enough to qualify as a RVR. The percentages from the Davis and Fried studies above are from large-scale clinical trials and are based on the subset that tested undetectable by 12. (BTW, sorry about a typo: that should read 1-258/308=17% for the Davis results - see their Table 1). So at this stage, if you stop at 48, you'd be facing no more than a 25% chance of relapse.
How much you can shrink that by extending is unclear. The differences in relapse for a 6-month extension are on the order of 10 % from Berg( 27->18, per-protocol)and much larger for TERAVIC (48->13). The TERAVIC data is a little suspect in this regard insofar as their SVR rate of only 28% and a whopping relapse rate of 48% are out of line with values reported elsewhere. Ditto, in the study you linked, did not report the difference in relapse rates but reported the SVR improvement as 40->46 for B2(72-week) vs STD. All this only gives limited guidance but suggests that the benefits of extending for only 4 weeks are small wheras doing at least 6 months might halve your relapse odds. Whether you can reduce your dosage during that time is also not clear. The <a href="http://www.medscape.com/viewarticle/466007?">Tarantino</a> study points to a "yes" - but their "consolidation therapy" still involved daily 1.5MU shots on monoIFN. My hunch is that a longer extension at reduced dosage will get you more than a shorter extension at full. Regardless of whether you extend however, it's looking pretty darn good.

TnHepGuy_ · Answer

I was undetectable <10 at week 11.5 - from a pre-tx starting point of 2,400,000.

I'm putting more faith into the idea of high (HS) and low (LS) sensitivities and the related response rates. In the little in the way of studies that are out there - most of the clearest data correlating to HS seems to be on geno 2's and 3's.

My quandry (of the moment) is what assumtions should I make in regards to me potentially being HS and having an RVR? If I am to assume I am a HS geno 1 who has achieved RVR prior to my week 11.5, then <a href="http://www.hivandhepatitis.com/2003icr/03_assld/docs/pegasys/102703_b.html">Zeuzem et al.</a> would suggest I would be up in the 83% SVR range (which would correlate closely with Drusano's model of 80% SVR for 32 weeks and 90% for 36 weeks post clearance - yet his model includes both HS and LS strains).

"<i>Rapid Viral Responders Have Most Promising Results

Rapid viral responders were prospectively defined as patients whose HCV RNA declined by at least 99 per cent during the first month of treatment. The study found that in this sub-group, even the most difficult-to-treat genotype 1 patients could achieve 83% SVR.

A relatively high SVR rate (71%) was obtained even for the rapid responding patients treated with ribavirin for only the first 6 weeks instead of the standard regimen of ribavirin during the whole peginterferon treatment of 48 weeks. These SVR rates are similar to that achieved by genotype 2/3 patients (88%), who traditionally have been easier to treat.

willing · Answer

nothing frustrates a lab-rat more than mediocre analysis of data so painfully acquired! I went down  a very similar path to the one you're treading. A rapid decline followed by enough leveling to boot me out of a clear-cut RVR. After pondering the various conflicting  definitions of RVR I plotted my <a href="http://www.soe.ucsc.edu/~afyfe/vl.gif">vl graph</a> and discussed it with my treating physician (an internist) and a specialist (a hepatologist at the Stanford liver transplant unit). Neither said there was any demonstrated benefit to pushing past 48. This was last summer. In October the <a href="http://www.hcvadvocate.org/news/reports/AASLD_2003-1.html#11">Berg</a> study was released and provided the first large-trial data on the benefits of extended tx on standard combo meds (I hadn't found the earlier <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15030987">Brouwer</a> data useful because it only compared 24 vs 72 weeks and was based on high, non-standard dosages). The Berg data indicated little benefit to extending, tx was grinding, and I finally decided enough was enough. Last month, when the  SVR data from <a href="http://www.natap.org/2004/EASL/easl_06.htm">TERAVIC</a> was reported, the balance definitely tipped towards extended-tx for slowish responders in my opinion. Had  this data been available in Jan. I probably would have done another 6 months at reduced dosage to try and cut my relapse odds down from the 20-30% I was facing.
If I've relapsed, it's  happened by now.  I won't test for at least another year so at this point it's all hindsight, getting my life back is my main concern. I am left with the impression that you really don't want to do anymore of the meds than you need to get to your personal sense of acceptable relapse risk. If you were undetectable on <100iu test before 12 weeks, the <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12939591">Davis</a> peg-intron data puts your relapse odds at 1-258/208=17% and the <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12324553">Fried</a>  pegasys data puts them at 1-221/293=25%.

These binary cutoffs throw away a great deal of information. My 12-week test was only sensitive to <500 iu so I really didn't know which odds applied. What one really wants to do is estimate SVR/relapse odds as a function of the whole VL graph. There are stat techniques for doing this but they haven't been applied to this data( I tried getting the Fried data out of Roche, to no avail). Personally, I wouldn't put too much weight on the Drusano model until it's confirmed on patients that did extended tx.  If A. Neumann is right, and the Jules Levin report on his talk at last Oct's AASLD that you linked above does a nice job of summarizing how amazingly successful his  predictors are, then the reason the SVR rate was so high among those who did 36 weeks after clearing is not due to the duration of their tx but to the fact that they cleared early: these were the patients blessed with  hcv strains that quickly succumbed to the ifn.

TnHepGuy_ · Answer

Thanks for the articles. I hope that someone picks up on this research to look further into interferon resistant sub-strains and the related strategies that can be mustered to counter them.

Rapid viral response (RVR) certainly seems to exhibit a strong correlation to high sensitivity to interferon:

<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14645325">Predicting the therapeutic response in patients with chronic hepatitis C: the role of viral kinetic studies</a>

<a href="http://www.natap.org/2002/AASLD/day21.htm">HCV Viral Kinetics and Early Response Predicting Sustained Response</a>

<a href="http://www.natap.org/2003/AASLD/day3_2.htm">Early Viral Kinetics Prediction of Sustained Viral Response After 1 or 4 Weeks of Peg-Interferon-a-2a (40KD) and Ribavirin Therapy (DITTO-HCV Project)</a>

Would you happen to know of any studies out there related to SVR probabilities for those geno 1's who's viral load drops in excess of 2-logs by week 12? Mine has dropped in the 5-6 log range (started at 2,400,000 - and clear by week 11.5). That seems like a pretty large drop for a geno 1. It's possible I
might also classify as an RVR - defined as a 99% decrease in the first 4 weeks ( i.e. - phase I decline). My logrithmic drop represents a 99+% drop over 11.5 weeks. And given that phase II decline has a reduced decay slope, it could well be that I fit the criteria as an RVR.

I'm currently at week 15 - still trying to decide if I am going to extend or not (based upon negative factors going in of - geno 1, high viral load and previous failed mono tx). If I am to believe the <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14999598)">Drusano statistical model</a>, the odds at week 48 would be 90% (assuming I stay clear the entire way, of course). As a probable RVR who has been 100% compliant (and hopefully will remain so), my odds my actually be somewhat higher.

As of right now, I am leaning to extend somewhere in the 4-12 week range.

Glad to read that you are continuing to improve post-tx.

TnHepGuy

willing · Answer

I haven't been as obsessed with hcv research as I used to be but tn's flurry of interesting articles (thanks!) got me interested again and while following his links I came across the following item by Kumagai et al. There's nothing directly useful here but it does shed some light on the importance of (a) the exact sequence of the strain you're infected with and (b) the importance of mutations in the virus during tx. For 8 patients on combo tx (on a slightly weird protocol) they sequenced part of the viral RNA and compared it with the sequence of gnwvcj, a 1b strain "generally considered IFN-resistant". Lo and behold in 5 of the patients that were clear at week 8 the same mutation had occurred at two positions in the hcv genome, in the part that encodes the virus' polymerase (its "copying machine"). In the the three patients in whom this mutation did not occur viral load did not decrease significantly. Looks like even if we don't get better meds for a while it might be possible to start cutting down the uncertainty about whether combo tx will/is working.

indyjo · Answer

Regarding the IDEAL study.... My hepatologist is involved in this study and I hope I qualify as a participant. It is country wide and the purpose of the study IS to compare peg-intron and pegasys, but also to test lower doses of peg-intron against standard doses. Supposedly the research addresses quality of life issues as well as the efficacy of these medications. It's free to participants and is being conducted by top experts around the country. Can you tell that I'm sold and ready to go!

cghamm · Answer

It's great to see all these "news" stories coming out of Digestive Disease Week. Maybe the Doc's are doing something other than getting drunk-ass lap dances in the French Quarter!

donAlfonso · Answer

Just wanted to respond to those who wrote to me a few days back (thread on "should I continue tx").

Revenire, yes, I agree that this whole business of RVR/EVR is somehow misguided.  Haven't really investigated, but since in America it is always about the money, I would suspect that this system is set up to benefit insurance companies, not patients.  Of course, then you would think that drug industry would benefit more from giving everyone long-term treatment.  Well, haven't really thought this through, maybe you or others have?

Jonihs, thanks for your concern and for mentioning Vioxx.  Again, I am somewhat suspicious whenever new uses for old meds are "discovered", especially in light of recent findings re Neurontin, which drug company reps were paying doctors to prescribe for all kinds of "off-label" uses.  I have tried both Celebrex and Vioxx in the past for joint pain, never found either any more effective than ibuprofen.  I do want to look at those articles about its effect on wbc/platelet counts (an off-label" use), but of course wonder who financed the studies.  Sorry, I've become a real cynic over the past few years.

Anyway, the heck with statistics.  This weekend I felt better than I have in a month.  Go figure, did nothing different, fever went down, let's hope it stays this way.  Maybe just bitching here was the right medicine (sorry, but I'm trying to spare my wife lately).  Sending some positive vibes to all.  Whatever works, carry on.

dA

cuteus · Answer

"IDEAL is sponsored by Schering-Plough Research Institute (SPRI) and is being conducted to respond to questions raised by the hepatitis C medical and patient communities"
I love that statement, how they always "wrap"  things with an attractive ribbon to justify the "real" reason: ours is better than theirs.   
If they really wanted to answer OUR questions, they would test  optimum dosage and length of tx for genotype 1.
 enough BS already.

TY for the links, I printed 3 just in case

Plutonium-kid · Answer

Hello,
The following items have been recently posted to www.hcvadvocate.org
 
*Conference coverage from the DDW Conference being held in New Orleans, LA 
 
Conference coverage for HCV, HIV/HCV Coinfection and Liver Transplantation:
http://www.hcvadvocate.org/news/reports/DDW_2004/TOC_HCV.htm
 
Conference coverage for HBV:
http://www.hcvadvocate.org/news/reports/DDW_2004/TOC%20HBV.htm
 
*HCV Medical Writers' Circle--Attacking the Hepatitis C Virus with New Mechanisms of Action:  Drugs in the Pipeline by Paul Pockros, MD
html:  http://www.hcvadvocate.org/hcsp/articles/Pockros-4.html
pdf:  http://www.hcvadvocate.org/hcsp/hcsp_pdf/Pockros_4.pdf
 
*Weekly News Review:  Week ending May 12, 2004
Html:  http://www.hcvadvocate.org/news/newsRev/2004/NewsRev-48.html
PDF:  http://www.hcvadvocate.org/news/NewsUpdates_pdf/News_Review_2004/NewsRev-48.pdf
 
*Hepatitis C Journal Review:  May 12, 2004
Html:  http://www.hcvadvocate.org/news/newsRev/2004/HJR-1.9.html
pdf:  http://www.hcvadvocate.org/news/NewsUpdates_pdf/News_Review_2004/HJR-1.9.pdf
 
*New Easy C and Basics Fact Sheets:
http://www.hcvadvocate.org/hepatitis/factsheets.asp
 
Thanks!
 
Alan
 
.

TnHepGuy_ · Answer

Switching from PEG-Intron to an Escalating Pegasys Regimen for Recurrent Hepatitis C Post Liver Transplantation May Improve Virological Response and Tolerability Therapy with Peginterferon Alfa Does Not Increase the Risk of Acute Rejection Post Liver Transplantation End of Treatment Response for PEG-IFN + Weight-Based Ribavirin Nonresponders Retreated with Consensus Interferon Plus Ribavirin Interim Results of a Pilot Study of the Combination of Consensus Interferon and Interferon Gamma in HCV Nonresponders to Peginterferon Alfa 2 Plus Ribavirin High Dose Consensus Interferon Induction Therapy Results in Successful Retreatment of Peginterferon Nonresponder HCV Patients

News Stories

You are reading content posted in the Hepatitis C Community