maybe I missed something in that reading, but their findings indicated this: "...these T-cell responses were focused on much fewer peptides than in HCV-recovered patients and did not differ from responses detected in unexposed individuals." Did I misintrepret when reading that the non exposed individuals had an undistinguishable response from the sexual partners of HCV infected response? I am not sure how this plays into your ongoing concerns. Which section should I focus on?
This is a very good thread...the kind we all love to read! It's been awhile since we have generated such a thought provoking group of issues, and data. I think we all need to visit the board more often! Keeps the old gray matter crackling away.
One note I forgot to mention - I was diagnosed with Type 2 diabetes August '03. My glucose is currently under control w/oral anti-diabetic meds, I understand the issues with Tx and obesity/glucose intolorance. I just didn't feel I had the luxury of time to postpone treatment while I trimmed down.
I had a 1.89 log drop, so decided to continue for 72 wks at the original doses. had a 5 and 12 wk post tx, negative PCR. Of course there is still a 17% relapse rate until hte 6 mo negative, so I will let you know next week, how well that protocol worked for me.
hey bill your gettin good info here, hope you go for it.
now old man willing-
i have not commented in such a long time i had to ask for my password. Did you ever do a post PCR? I am doing a 18 month post PCR this friday...doc wouldn't let me do 12 monther...anyway i have not seen any pink dragons on the stool next to me so i am feeling pretty good about it. so fess up dude...are SVR or what??
You are what is known as a classic slow responder. Traditional tx protocol states that you have only a small chance of SVR at this point, however, this assumes that you follow the standard protocol.
PLEASE DO NOT DO THIS. If you are tolerating tx this well and have this much response you have two choices. Stay on this dosage and see if you eventually clear, and then extend tx for at least 36 weeks after the 1st undetectable test.
The other alternative would be to change tx right now. Either increase the dosage of Peg, or switch to daily Infergen. THis would be my preference.
Do not let them take you off of tx. The first chance is your best and from all signs, if you attack this thing aggressively, you should be able to beat it.
I am not a Dr, just an HCV sufferer who has been down this road and did not have anybody to tell me these things. Thus I have become a nonresponder and have gone through 3 rounds of tx so far, and am getting ready to start a fourth. YOU DO NOT WANT TO GO DOWN THIS ROAD.
Call Dr Ben Cecil in Louisville. He will point you in the right direction. His phone number can be found on his web site which is www.hepatitisdoctor.com.
Best to you and good luck. Let me know if I can answer any other questions.
DD: things are good. I get the occasional wave of joint aches and low energy but then it blows over. Anytime I’m tempted to complain I just think back to tx and smile instead - I’ll probably stay grateful about the end of tx to the end of my days! Hope all is well with you and your post-tx aggravations are settling down.
I must admit I was skeptical about your low-level infection concerns, but it does look like evidence is accumulating for infection that differs from the expected pattern (detectable virus-specific T-cells + ABs + virus). However, as with cuteus, it wasn’t clear to me whether the observed T-cell response was to an actual HCV protein or could have been a response to a similar peptide from another virus. Anyway, it’s all very interesting - given that HCV only replicates in us and chimps, which share around 99% of our genes, HCV does seems like the ultimate intimate enemy – it knows *exactly* where we live
Bill : below some data from a recent study (<a href=”http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15871137&query_hl=18”>Shenoy, et al 2005</a>) which might give you some ammo to argue with if your Dr. suggests stopping. The authors critique a study by Drusano and others that argues for a flat 32 weeks of tx beyond undetectable. The patients all had to drop out early for the reasons shown, nevertheless, all got to SVR They had low initial VL and undetectable by 12 going for them and you’ve got a very low baseline VL.
<TABLE border ALIGN="center" rules="all" cellpadding="8">
<TR><TD align="left" valign="bottom">Age, years<SUP> </SUP><BR>
(HCV genotype)</TD><TD align="center" valign="bottom">Treatment</TD><TD align="center" valign="bottom">Initial<SUP> </SUP><BR>
viral load,<SUP> </SUP><BR>
million IU/mL</TD><TD align="center" valign="bottom">Duration<SUP> </SUP><BR>
of therapy,<SUP> </SUP><BR>
weeks</TD><TD align="center" valign="bottom">Adverse effects<SUP> </SUP><BR>
necessitating dose adjustment</TD></TR>
<TR><TD align="left" valign="top">39 (1a)</TD><TD align="left" valign="top">1.5 <IMG SRC="/ucp-entities/mu.gif" BORDER="0" ALT="μ" ALIGN="BASELINE">g/kg/week of pegylated IFN + 1200 mg daily of ribavirin</TD><TD align="center" valign="top">0.2</TD><TD align="center" valign="top">10</TD><TD align="left" valign="top">Psychosis: cessation of treatment</TD></TR>
<TR><TD align="left" valign="top">52 (1a)</TD><TD align="left" valign="top">1.25 <IMG SRC="/ucp-entities/mu.gif" BORDER="0" ALT="μ" ALIGN="BASELINE">g/kg/week of pegylated IFN + 1400 mg daily of ribavirin</TD><TD align="center" valign="top">0.3</TD><TD align="center" valign="top">22</TD><TD align="left" valign="top">Increase in ALT and AST levels: intermittent cessation and eventual complete cessation of treatment</TD></TR>
<TR><TD align="left" valign="top">46 (1a)</TD><TD align="left" valign="top">1.5 <IMG SRC="/ucp-entities/mu.gif" BORDER="0" ALT="μ" ALIGN="BASELINE">g/kg/week of pegylated IFN + 1400 mg daily of ribavirin</TD><TD align="center" valign="top">0.7</TD><TD align="center" valign="top">30</TD><TD align="left" valign="top">Psychosis: cessation of treatment</TD></TR>
<TR><TD align="left" valign="top">56 (1a)</TD><TD align="left" valign="top">1 <IMG SRC="/ucp-entities/mu.gif" BORDER="0" ALT="μ" ALIGN="BASELINE">g/kg/week of pegylated IFN + 1000 mg daily of ribavirin</TD><TD align="center" valign="top">1.9</TD><TD align="center" valign="top">24</TD><TD align="left" valign="top">Anemia: ribavirin reduced to 800 mg qd from 1000 mg qd, weeks 5<IMG SRC="/ucp-entities/ndash.gif" BORDER="0" ALT="–" ALIGN="BASELINE">19; depression and fatigue: cessation of treatment</TD></TR>
<TR><TD align="left" valign="top">47 (1b)</TD><TD align="left" valign="top">1.5 <IMG SRC="/ucp-entities/mu.gif" BORDER="0" ALT="μ" ALIGN="BASELINE">g/kg/week of pegylated IFN + 1200 mg daily of ribavirin</TD><TD align="center" valign="top">1.3</TD><TD align="center" valign="top">17</TD><TD align="left" valign="top">Neutropenia: dose of pegylated IFN reduced and discontinued for 3 weeks, recurrence of neutropenia on rechallenge</TD></TR>
<u>Bill1954</u> - don't get hung up on not hitting the the 2-log mark. For someone with the amount over liver damage that you have (Stage 3-4) it's not all that unusual for viral clearance to take longer. As others have already stated, the important thing in this regard is that you are showing to be a responder now. You didn't state what Grade number (i.e. 1,2,3 or 4) of inflammation your biopsy showed. A higher level of inflammation can be a sign of possible progression and therfore and even harder nut-to-crack when it comes to viral clearance. I would not advise dropping your current tx, since you are continuing to respond with it. What you may want to do is ask to have your riba dosage upped from from 1,200 to 1,400, at least until your PCR shows clear. And whether or not they go along with that you should get a PCR done every 4 weeks (i.e. - week 16, week 20, etc) until you do show clear. As long as your viral level continues it's downward trend, there is no need nor call for you to end your current type of therapy. Talk to your doctor about the possibility of extending your tx, both for the opportunity to try for SVR as well as the chance for halting or reversing of histological progression. Those really are the keys right now.
<u>willing</u> - thanks for posting the shenoy info. I went looking for it online and found the Journal of Infectious Diseases wanting me to subscribe to be able to view it. Do you have it somewhere else? If not, can you summarize what they did and any conclusions?
You pose an excellent question...and I say the answer is to go with the typical, large scale data indicators rather than considering anecdotal, extraordinary sorts of cases. It's great if someone has to terminate tx early, and happens to somehow obtain the SVR, but as we all know from large studies, this is the rare exception to the rule.
It does a disservice to
patients for researchers to suggest short time
frames for GT-1 patients may be sufficient. It creates a very false sense of security and undercuts the enormous amount of work necessary to obtaining the SVR for most typical type 1's.
As far as the viral persistence issues contradicting any of the current protocols, my opinion is that viral persistence, if it truly is a fact, is something different altogether from blood/liver HCV infection, as we are dealing with it. In other words, the rules of eradication are still fully in effect, and SVR is still SVR as far as we can analyze it....since there are almost no relapsers beyond a certain time point (about 2 years). What this implies is that the viral persistence is either something 'benign' and incapable of re-igniting the old infection, or it is just an 'illusion' of sorts, consisting of non-replicating fragments of HCV proteins, or possibly some
other form of 'compartmentalized' ongoing infection, which does not equate to the original blood/liver virus.
This issue is still VERY hazy, and controversial, and I for one, believe that there IS something to it (if you have read my contemplations on familial 'occult' transmission, without causing typical HCV blood infection), but what that something consists of, is the big question! We must still look at the quest for SVR, and viral 'eradication' as a concrete reality, and very achievable, regardless of what this other viral 'hangover' matter amounts to. I say this because the SVR's are still happening, at an ever increasing rate, and seem to mitigate the deadly end stage ramifications of the disease.
Maybe the next major step in understanding and treating HCV will involve this 'viral persistence after SVR' issue, and will address what it means to our
health, and possibly new therapies to get at this viral invader as well. It cnn't be doing us much good, so I assume it will be best to find a way to eradicate it as well.
I hope the above comments make some sense....and were communicated clearly and
as intended. In other words, I think we are being cured...to a point. The next step, is curing the leftovers!
I wish to state what southernboy said in a different way, just to emphasize the point. "Traditional tx protocol states that you have only a small chance of SVR at this point, however, this assumes that you follow the standard protocol." So, taking the meds at the dosage/frequency/duration you currently are, the numbers do not encourage staying the course. Options are to quit treatment, modify treatment, or stick with current treatment.
A couple of things... You are a biological responder, that is, your liver enzymes have normalized or nearly so. You are having a virilogical response, just not as great a response as one might hope for.
Please take special note of revenire____'s post about improving the condition of the liver with interferon. Since you are indeed a responder there is every reason to believe that you are helping your liver with treatment. Now, given your age, genotype, and degree of liver damage, you may wish to pursue more aggressive treatment, but you will need to weigh that option carefully.
Discontinuing treatment doesn't seem to be indicated.
a good year 1954..the relative importance of attitude vs probability is a pretty interesting topic. The available data is pretty compelling - ignoring it doesn't seem very wise. I'd suggest keeping up the strong attitude but adjusting expectations to match the evidence: at stage 3/4 tx is worth doing even if success is unlikely, unlikely never means impossible, and 1.7 rounds out to 2. You might want to look at <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12939591&dopt=Abstract">Davis, et al,2003</a>, which is probably the main pillar of the 12-week rule, and similar more recent studies so you're prepared for any "it's not worth continuing" arguments from your Dr. and/or ins. co.
True, you missed the 2-Log drop, but you are very close. To me this indicates a slight increase in dosing, and an extension of tx for sure, to at least 72 weeks. FIRST, you must get fully undetected as quickly as possible. You must be negative by 24 weeks, and the closer to 12 the better. Increasing the dosage and/or frequency of shots may help achieve this rapid move to undetected. Bear in mind that if you can get undetected before 24 weeks, you need to keep the dosing at that level for the duration of tx, throughout the extended period, and MUST keep the Riba. at maximum levels as long as possible. Procrit allowed me to make it to week 72 on high Peg dosing and maximum Riba.
This is your best shot...first tx round, and nearing undetected. You ARE a responder, just a slower one (as I also was). Time to be aggressive, determined, and to work very assertively with your doctor to accomplish the short term goal (rapid undetected), and the long term goal (SVR, by extending tx, and keeping full dosing to the end). This is still DOABLE, so please don't feel defeated at this point, by any means. You just need more horsepower, and a longer course. You may be able to get negative by week 18 or so, with a slight increase in dosing.....so get with your doctor, and work out a plan.
I differ from some of the above comments regarding the statistics!!!! Sure you MAY still have a chance by doing the same thing....and hoping....but statistics do not lie, in this case. It is well proven that slower responses, lead to MUCH lower SVR rates...and that just means your ODDS of winning get lower if you continue at the same rate. If you can get undetected quickly, with a modification in tx, the ODDS will move back to your favor, and with an extension of TX will be back up in the 60% to 80% range, if you can keep full dose to 72 weeks, and remain undetected throughout the rest of tx. The big KEY is undetected as far before 24 weeks as possible. PUT the odds on YOUR side! Good Luck!!!!
Shenoy To the EditorWe read with great interest the model described by Drusano and Preston  regarding the prediction of a sustained viral response (SVR) in patients infected with chronic hepatitis C virus (HCV) genotype 1 who were treated with pegylated interferon and ribavirin. We feel that the clearance duration (CD), although important, is overemphasized in their article. Other factors that strongly predict SVRincluding the baseline viral load before the start of treatment (<2 million IU/mL)  and a 2-log reduction in viral load by week 12 (early viral response [EVR]) [3, 4]are not emphasized in the study discussion. We would like to share the experience from our center regarding 5 patients with HCV genotype 1 who were treated with combination therapy (shown in table 1).
Four of 5 patients had HCV genotype 1a, had low viral loads before the start of treatment, and were treated with pegylated interferon and ribavirin for a treatment duration of 1030 weeks. All patients had undetectable HCV RNA loads at week 12. In each of the patients, the treatment was discontinued because of severe adverse effects, including psychosis, transaminitis, fatigue, depression, and neutropenia. All 4 patients successfully attained an SVR, as evidenced by an undetectable HCV RNA load as measured by polymerase chain reaction (PCR) 6 months after the discontinuation of treatment. As per the model described by Drusano and Preston, they would have needed a CD of 32 weeks to attain an 80% probability of an SVR. However, on the basis of our experience with the patients described above, there are patients with HCV genotype 1 who will respond to shorter courses of treatmentthe entire duration of therapy being shorter than the 32 weeks of CD cutoff proposed. This case series indicates that there may be a small proportion of patients with HCV genotype 1 who attain an SVR with a treatment duration shorter than the currently recommended 48 weeks. The factors that indicate a favorable response to treatment identified in previous trials are low baseline viral load, EVR, and the dose of ribavirin . In Drusano and Preston' own work, a low baseline viral load was more strongly associated with SVR than was CD (their table 2) . A recent study showed that the magnitude of the 24-h viral response after a single-dose interferon sensitivity test might be of value in predicting the outcome of combination therapy . In patients with HCV genotype 1, there might be other factors predicting SVR in combination with CDfor example, low baseline viral load, ethnicity, degree of liver disease, and subtype 1a infectionwhich need to be studied.
Analysis of 3 large trials of hepatitis C treatment  showed that 79% of patients could continue treatment for >80% of the time. Most of the remainder reduced or discontinued therapy because of adverse effects. The adherence rates outside clinical-trial settings are likely to be lower. Prolonging the course of treatment past the current standard of 48 weeks will likely result in a longer duration of adverse effects and lower adherence rates.
The above-described data demonstrate that there is variability in the duration of treatment needed by patients with HCV genotype 1 for the HCV RNA load to remain undetectable and to maintain SVR. Continuing treatment for a CD of 32 weeks could substantially increase costs and likely lower adherence rates because of adverse effects. We agree with Drusano and Preston that further studies are needed that examine a longer duration of therapy before the model can be validated. The costs and benefits of frequent RNA PCR testing will need to be studied. Factors that predict SVR with a shorter CD, such as low initial viral load and subtype 1a infection, need to be studied further, primarily because of the toxicities associated with combination therapy.
and reply To the EditorI would like to thank Shenoy et al.  for their commentary on our recent article . I agree that baseline viral load and early response are associated with the probability of a sustained viral response (SVR). The earlier work mentioned by Shenoy et al.  was cited in our article.
What is important is that hepatitis C virus (HCV) genotype 1 infections have a much lower response rate than HCV nongenotype 1 infections, even when the variables pointed out by Shenoy et al. are accounted for. The question raised is whether the duration of therapy would affect the SVR; given the seminal study of Poynard et al. , it is our contention this is a reasonable hypothesis to address. Examination of a large database, with model building in 1 group (771 patients) and model validation in another group, which was not used for model building (298 patients), demonstrated positive and negative predictive values, as well as a sensitivity and specificity, all of which exceeded 91% in the validation step. This clearly does not prove the point and, as was stated in our article, merely points out the need for further investigation in this area. A prospective, randomized trial would be required to prove the hypothesis, as we stated.
In the published model, once the duration of negativity was entered into the model, the backward elimination procedure took one of the factors cited by Shenoy et al. (baseline viral load) out of the model. The database did not allow us to calculate the early viral response (EVR). The deletion of baseline viral load is understandable, because this factor drives an earlier time to negativity and, with a fixed duration of therapy (48 weeks in the trial), this leads to a longer duration of negativity. Certainly, starting off with a lower baseline viral load (or having a good early decline, but we could not examine this) would lead to an earlier time to negativity and longer durations of negativity.
Furthermore, I believe that Shenoy et al. have misinterpreted the entry in table 2 of our article . If one looks at the second column of table 2, under "Virologic" variables, all of the probabilities are approximately equal (all <9 × 10-7). The third column is the McFadden's 2, which is considerably larger for clearance duration. I believe that this is the source of the confusion. This number is the logistic regression analogue of the r2 value of linear regressionthe amount of variance explained by the variable. In this case, higher is better for McFadden's 2. Clearance duration was most explanatory of the variance in attaining the defined outcome, SVR. It is then not surprising that baseline viral load was removed from the final model in the backward elimination procedure.
The point of our article was not to denigrate the effect of baseline viral load or to ignore it (or EVR, had we been able to examine it). Rather, it was a hypothesis-generating article indicating that an exploration of the duration of treatment for patients infected with HCV genotype 1 might be fruitful in raising the probability of attaining a SVR. Clearly, such a strategy would need to balance the possible benefits with the risks of extra toxicity and the possibility of poor adherence to the regimen after a certain point. Extending the duration of treatment from 24 to 48 weeks  also made it necessary to explicitly balance the risk versus benefit, but it was clearly shown to be beneficial, on balance. Only when a randomized trial is performed to examine the hypothesis generated by our analysis can we explicitly make a risk-benefit judgment for patients infected with HCV genotype 1. EVR and baseline viral load may play a role in that judgment.
Hey, great to see you on the forum again. It has been awhile. I also am not on very frequently anymore. How are you doing post-tx?? Everything going smoothly I hope?
I will link an interesting article from the Gastroenterology Forum, re: HCV and familial member cellular t-cell antibody responses. These people are also NEGATIVE for typical HCV antibody testing, and do NOT have acute or chronic HCV.
The article outlines studies that are finding strange cellular patterns in familial and sexual contacts.....along the lines of my ongoing concerns and observations! What do you make of it? See the section titled Transmission of HCV....
Good to see you on the board again!!! Best Wishes.
Thanks for taking the time to post all of the above. These are the type of issues that have everyday applicability in patient tx, yet are not backed, funded and studied to any kind of degree that could make an impact upon current tx protocol. As a result - and lacking the knowledge and experience that come from good research results that build upon past discoveries - too many doctors fall back into the easy-chair of 'standard approach/one-size-fits-all' treatment. And again the patient suffers the consequenses.
I think that in general (as opposed to anecdotal), CD (clearance duration) plays a crucial role. One need look no further than this fact of tx: at some point patitents become serum clear, yet these patients need a certain (average) amount of time to become histologically clear (if I dare say such a thing in light of the 'persistance' arguments currently taking place). That is, the virus has been overcome to the point where SVR is 6 months away in time, if these patients were to stop tx at that exact moment. Therefore, CD is what is needed to 'clear-out-the-crumbs' (COTC), so to speak. Well, based upon all of the early studies, standard COTC time for geno 1's has been (at least) 36 weeks for all of those serum clear by week #12. For all those not clear at week #12 but clear before week #24, COTC time is no less than 24 weeks. Problem is, as far as SVR results go, all of these patients have been lumped together. So, holding for just this one variable (CD), this begs questions such as: in these prior studies, what is the SVR rate for those who cleared at week #2 and were therefore negative for the next 46 weeks of tx? How about for those who cleared at week #4 and were negative for the next 44?. And so forth and so on up the line.
If we could chart the above, I don't think it would be a surprise to watch an inverse relationship develop as the week # of clearance increases against declining SVR odds. This seems to me what Drusano's model proposes.
So, is this general model over-ridden by anecdotal evidence that some geno 1's have the ability to SVR with less than 36 (or 32) weeks of CD? I don't believe so. These patients are by no means representative of the overall geno 1 tx and study/trial population, and appear to be a very-much 'cherry-picked' group.
The real question, in my mind, is how can you take any of this information (the Dursano model as well as the anecdotal patients) and apply them to any particual tx situation? What criteria should a patient beginning tx today - and having only week #12, week #24 and week #48 PCR's in front of them - use when confronted with the ugly fact that they might not be clear at #12? And what about other negative predictors (histology, VL, age, etc) that they may bring to the tx-table - and how to account for them?
When patients have 'invested' themselves into tx, and find out along the way that they have passed the week #12 mark with VL remaining and are therefore considered a 'slow-responders', which way should they 'bet' (assuming they are given that option by their caregivers) - that they will be more like the general HCV population - and therefore in need of a more 'typical' CD timeframe? Or that they will be more like the anecdotals?
cuteus : my bad - I flubbed the html - here it is again <a html="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15871137&query_hl=24">Shenoy</a> and a reply by <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15871138&query_hl=24">Drusano</a>. 10 weeks does seem kind of a light sentence doesn't it? of course there is the minor inconvenience of becoming psychotic - but I'd have had to think twice about it if someone had given me that choice. BTW, of the various comments on this thread I think yours seems the most encouraging to Bill. Good luck with your test and I think you're being a bit pessimistic about the 17% still to jump.
Ken - good to hear from you! Keeping a lookout for pink dragons on the next stool sounds pretty good - stay well. I'm going to wait till next Feb to test. Part of it is curiosity - can I tell whether I've relapsed? (my guess is no)- but most of it is plain fear. Being alive is just so damm good compared to tx I don't like to even drive near that clinic - you never know who might jump out and grab you.
tn - I'll try to post the whole text in the next message. It's basically anectodal(5 patient) evidence against the Drusano model that suggests length of treatment may not be the most important predictor of succes. Drusano's reply doesn't really take issue with this. Both sides agree more data is needed. (remember one of my main gripes with the Drusano paper was that not one of their patients had done more than 48 weeks).
Maybe CD needs to be proportional to the initial time to clearance. In other words, maybe looking at CD as a fixed value is misleading (36 weeks after initial clearance, 44 weeks after, etc. )
just maybe for type 1's, the CD needs to be a multiple of the initial time to clearance. So if a 4 week undetected patient needs another 20 weeks to SVR, then maybe a 12 week undetected patient needs three times that, or 60 weeks CD. And the true 24 week undetected patient would need 120 weeks to assure SVR. Maybe using these time frames would move the SVR rate closer to 100%???? I know it sounds radical, but I think it has more to do with 'half-life' viral decay issues.....so increasing the weeks to initial clearance multiplies the necessary CD period.
Of course we won't get studies testing this theory out, because the costs, and side effects might prove prohibitive...but it just might be closer to the real answer. CD may be MOST important of all, but it is not being calculated correctly currently. I think Dr. Ben Cecil is probably closer to reality with his theories.
all these researchers seem to suggest that early PCRs, maybe within the 1st wk of tx, can give a good indication of a positive antiviral response.
I have seen so many of us low VLs not achieving clearance by wk 12, that I must question the focus of assigning so much value to the initial VL as a predictor.
It looks as if many factors must be considered conjunctively when predicting svr in the general population.
To mind comes Daryl, who did 7 months of tx, with many weeks at reduced doses, and achieved SVR. They are now collecting samples and testing to see what factors contributed to his SVR with such dismal dosing. Genetics looks as a future must do test, if a better protocol is to be built.
THANKS willing, DD and Tnguy for that invaluable discussion.
5 cases certainly are not much to go on. I assume the reason these 4 Drs chose to write their article is that their day-to-day experience in treating HCV patients did not square with Drusano's hypothesis regarding the importance oF CD. In the absence of a reliable database, the intuition of Drs who specialize in HCV treatment and thus accumulate daily experience in who SVRs and who doesn't is important, even if irritatingly subjective. However, I also think data like that reported recently by <a href="http://www.hivandhepatitis.com/2005icr/ddw2005/docs/hcv_052305_b.html">Reddy et al</a> tend to support their argument. The 90 patients lucky enough to show undetectable by week 4 had an 83% chance of SVR with a CD of at least 44 weeks whereas the 133 still showing virus at week 12 only had a 26% chance with a CD of less than 36 weeks. The CD difference between these two groups can't be more than 22 weeks and is more likely to be around 14 weeks whereas their chances of SVR differ by a huge 57%. None of the extended tx studies I've seen come close to suggesting you can boost your SVR chances by 57%, even by doing 72 weeks and thus extending your CD by 24. To me this argues pretty strongly that EVR has to be a more important predictor of SVR than CD. CD is one of the few predictive factors under a patient's control, and there's a natural tendency to squeeze it for all it's worth. Hopefully, Drusano will finally get data to measure exactly how much it's worth.
Definatly makes sense and you communicated very clearly. I always cringe when I see a G1 with any factors that lessen your odds of SVR stop tx at 48 weeks even if it's just being overweight and of coarse including any liver damage. While G1's have a SVR rate of less than 50% this includes everyone in the studies and all doing the same duration of tx. I beleive if they adjusted the recommended duration for individual cases the SVR would be better. I think some people just want to be off tx so bad they do what the doc says and as we know some docs just tx in a box. It's easy to just go with what your doc says because most of us have been brought up with the notion docs know best and all about all illnesses. We know better. LL
will you please, pretty please take a look at Ina's post in:
As Promised....AST and ALT results - BronxRican007 05/16/2005
and give your thoughts on her question to me? the technical stuff that only you guys can express with some clarity. She will be back tonight and I was hoping any or all of you could have something for her by then.
so if willing is correct in his theory and achieving that EVR is most crucial for a high SVR shot, how should those that are not lucky enough, identified as slower to react to tx by comparing to the faster group, suppose to ensure clearance way before wk 12? mega doses seems to be the only way, at least the first few months.
I think Daryl did have EVR before his doses were lowered and eventually stopped.
There are a few studies out there collecting samples from SVRs, either from tx or from spotaneous clearance, and comparing them with non infected and chronically infected samples. That should be an interesting article to read, but I don't expect it out too soon, as the person who told me about it had her blood drawn only a year ago.
I wish that more researchers asking similar questions to ours, could get the funding and subjects to pursue more answers! This is part of the waiting game, a different level of it.
I agree on the megadoses to achieve EVR at week 4 for most normal type 1 responders, the only hitch that I feel is a problem, is reducing the dose after gaining initial clearance. I personally believe that what ever dose it takes to get you to EVR needs to be the dose for the remainder of tx, or the CD period. Most doctors would not concur with my opinion, I realize, but that is what I believe is precisely the reason for so many relapsers. They need strong enough doses to achieve EVR, or early, early, EVR, AND they need the SAME viral decay curve for the remainder of tx (CD period), in order to achieve high probability SVR. Once you change the 'horsepower' on the interferon and/or Ribavirin, all bets are off regarding SVR.
Some people are very fortunate, in that they only need standard doses to achieve 4 week EVR. Their systems are apparently very sensitive to interferon. Most of us would need much higher doses to hit the 4 week EVR. Maybe if you use high enough dosing to get the 4 week response, then you may need only an additional 20 weeks or so to get the SVR, if you maintain the full dose. That might be an interesting trial approach. More interferon, less total duration. Maybe less overall toxic effects!!!
I have to confess I don't spend as much time on pubmed watching the changing hcv landscape as I used to, but it doesn't look like high daily high dose ifn gets you much further than the standard regime (<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15543591&query_hl=15">Tsubota, et al 2005</a>). Bumping your riba dosage in the second half of tx(<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15660393&query_hl=25">Lindahl, et al 2005</a>) may be more effective, if you're willing to risk the sx (that's what I ended up doing, against my Drs recommendation, maybe it did some good?). I know this comes off as fatalistic, but at least as far the ifn is concerned, I tend to believe it's either going to work for you or it isn't, and if it doesn't there's not much to be done. The ifn we inject is the same ifn, minus peg, that our bodies produce naturally, whose function is to kick our bodies into viral-intruder alert mode. If you're chronically infected, your strains of HCV were able to get past this defense mechanism and take up residence. During combo tx we're hoping that raising the ifn level, and sounding the same intruder-alert alarm bell that much louder, will succeed in doing what it had failed to do years ago. However, there's pretty strong evidence that in many cases HCV can just navigate around the increased security - one of the best reviews is <a href="http://mvlab-fudan.cn/xxyd/%E5%8F%82%E8%80%83%E6%96%87%E7%8C%AE/yxbdxjz(doctor)/%E7%97%85%E6%AF%92%E4%B8%8E%E7%BB%86%E8%83%9E%E5%87%8B%E4%BA%A104/287.pdf">Pavio and Lai,2003</a>, also <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15782389&query_hl=2">Gremion and Cerny, 2005</a>: it gets into B and T cells, shuts down signalling and generally thumbs its nose at the ifn-generated response. The impact of all this for prospective tx'ers is that, on the basis of the biology, it makes more sense to jump into the pool for a couple of months and see if you're one of the lucky EVRs than it does to risk damage by trying to compensate by taking more of it (of course this only applies to those for whom tx is optional). By and large it looks like if ifn is going to work for you it's going to work early on and if it doesn't there's probably not much to be gained by insisting.
Thanks again, willing; I'll take a look for those '03 abstracts, and verify info w/the lab. If your memory is correct, my indicated dose would be 1500 mg +. The doc was was considering 1600 to 1800 mg, and adjust as necesary. He also apparently feels comfortable allowing the to HGB to fall to 9.0 before initiating any epoetin. (Although he readily admits I may not feel as comfortable as he does!)
Just a quick post to thank you for the thought-provoking information you have brought to this thread. I am currently agressivly working with my doctor; he wants to confer with colleagues this weekend, but is currently leaning toward an increase in riba doseage. I didn't want you to think your efforts were going unheeded, indeed they are fascinating. Of particular interest is the intermingling of hard science with philosophy. I guess it is almost inevetible, eh? I'll post with our Tx decision as it becomes available, thanks, Bill
Bill - if you can find the aasld 03 abstracts around anywhere there was a german study that had worked on determining optimal riba dosage and had a mg/kg recommendation which was more well-tuned than the standard 1000/1200 rx. As I recall it was 6.25mg/lb so 1200 was suboptimal for anyone over 192 - but my memory is pretty sketchy. Also, I recall another board member, BobK, had issues with the quant reliability of bDNA based tests. Since there's a lot riding on this one you may want to repeat with a TMA and/or check the OC-curve stats reported by your lab.
willing - if this is the abstract you mentioned above, (E. Herrmann et al), you got one hell of a memory. 13.75 mg/kg = 6.25 mg/lb. Its not to terribly long, so I'll try to paste it in...
54th Annual Meeting of the American Association
for the Study of Liver Diseases
October 24 - 28, 2003, Boston, MA
Ribavirin Dosage Significantly Affects Virological Response Rates in HCV Patients Treated with Interferon/Ribavirin
The influence of absolute dose and dose in mg per kg body weight of ribavirin on sustained virologic response (SVR) in interferon-based combination treatment of chronic hepatitis C as well as the influence of dose reduction is still controversial.
In this study, investigators address this problem by reanalyzing data of 343 previously untreated patients with chronic hepatitis C from a multicenter trial who were treated with Pegasys (interferon alfa-2a) plus ribavirin and amantadine or interferon alfa-2a plus ribavirin (Berg et al, Hepatology 2003, 37, 1359-1367) and completed therapy.
The researchers used a multivariate approach to account for correlations of the dose of ribavirin with body weight and body mass index (BMI) and known predictor variables from this data set which are low baseline HCV RNA, high platelet counts, high pretreatment ALT, and low
the 12-week rule supplanted the older, "undetectable by 24" rule, as the standard of care simply because the (slow...) accumulation of data showed that if you didn't have at least a 2-log drop by week 12 your odds of SVR were negligible. There's nothing fair about tx success, it's essentially random, and, as in gambling or investing, it makes sense to stop pouring good money after bad once you realize the odds are not in your favor. For those at stage 3 and above, fibrosis reversal is probably a more important goal than SVR and for those whose results are close to the cutoff it makes sense to round towards the hopeful side, but a stage 2 or less with a log 1 drop at 12 who chooses to continue tx should understand that they're placing a very unlikely bet.
Whether insurance companies and government health plans should finance such an unlikely bet is a separate issue. As an aging Santa Cruz ex-hippy I'm much happier seeing the $50,000 cost of tx go to someone with a 5% chance of success than to ins. co. share holders, but from the point of view of a government bureaucrat who has to allocate that money either for tx or to pay for some other treatment with a better cost/benefit ratio I'd have to side with denying tx (and trying to negotiate better prices with Roche/Schering).
The Shenoy authors' main criticism of the Drusano model seems to be that "CD, although important, is overemphasized ". The two extended-tx papers from last Oct's AASLD (Sanchez-Tapia and Berg) certainly suggest that more than 48 weeks may be optimal for slow responders but I think it's a stretch to say that benefit is now well established. In Teravic, the extended-tx 1s ended up with only a 44% SVR rate, which is lower than 1s on the standard 48-week regime and 1000/1200 riba can expect. How much of the alleged benefit of extended tx is simply compensation for inadequate dosage during the first 48? Also, TERAVIC saw a reduction from 61% at end of tx to 32% at 6 months in who stayed undetectable amomg the 48-week cohort. That's a 50% relapse rate, which is pretty far out of line with what has been reported everywhere else and what we see on this board. The <a href="http://www.hcvadvocate.org/news/reports/AASLD_2004/Posters_AASLD_2004.htm#B75">Berg</a> study, though also flawed by low riba, reported a more credible 23% relapse with a statistically significant 27% to 19% split between the 48 and 72 weeks groups. A recent <a href="http://www.projectsinknowledge.com/Init/G/1710/#4">CME review</a> breaks this split down by VL at 12 and finds, surprise, surprise, that it's exactly those with a definite but sluggish response that account for the split (but note, from the initial Berg abstact, that they're applying this splitting to a toatl group of 72 relapsers, so the numbers are getting a bit scarce). Does the AASLD 04 Berg /Teravic data suggest you can cut your relapse odds if you were detectable at 12 ? yes, though it'll be nice to get better proof. However, IMHO, it's hard to see how it invalidates Shenoy's point that CD is secondary to EVR as a determinant of SVR.
I will toss in my very brief summary of the above conversation along with my opinion: EVR is great. 12 weeks is good, even if only 2 log drop, and still remaining virus, but clear by 12 is better. Clear by 4 weeks is the Mercedes of EVR's.
But even though the above stuff matters a lot, the biggest factor is just BEING ABLE to clear the virus. If it takes 24 weeks to clear, so be it....the real issue is this: Just how long must one stay on the tx AFTER clearing, in order to maximize the odds of success. I think the answer varies according to WHEN you clear, and may be more a 'geometric progression' than an 'adding on' of a specific number of weeks. What do we know about this extended CD period at this point???? VERY LITTLE. Because the protocols have been very limited, conservative, and 'additive' in their approach, rather than using multiples as an approach to CD. You must imagine that if a patient can clear the virus, even if it takes 22 weeks, 26 weeks, even 30 weeks, that they are responding, albeit very slowly, and may well be capable of fully eradicating if the same amount of tx dosages are continued for a very prolonged period of time. That could mean two years or more of CD in some cases. What information do we have about this approach??? Almost none, due to above stated reasons....but there is beginning to be more and more anecdotal support for this sort of approach.
My stance is: if you are a responder, no matter how slow, and you get undetected, then there IS a way to achieve SVR....it just may take a long, long time, and be a very difficult time.
There are almost no answers, because there are almost no studies.
Time to clearance dictates what lies ahead. What we have seen to date is: finishing out the typical 48, for most patients.
This tells us nothing at all about ideal CD, for the various clearance periods.
I believe SVR is the ultimate pre-tx goal, no matter what level histology is brought to the table. If the virus can be eliminated, out goes the source of the ongoing damage. If in the attempt to reach SVR it turns out that those odds appear very unlikely, then the decision must be made about whether or not to continue on maintenance tx to try and halt or reverse damage. This decision is where Stage level of damge becomes most important.
If the discussion above is whether or not CD is of greater importance vis-a-via SVR than EVR, then there really is no question - EVR wins hands-down. Early viral kenetics (i.e. - rapid viral response (RVR)) has shown to have a very strong correlation to overall SVR success. But CD still has a place and a role - one that just doesn't happen to be as well defined as EVR (or RVR) at this point in time.
But I think the real importance here is to leave the purely thoeretical world and to try and determine how to apply any of this information in real-world tx-situations - the kind that occur on an every-day basis today.
In my example above, our 'typical' geno-1 SR patient has not been given the option of a week 4 PCR (as was the case in Teravic), had a 2-log drop by week 12 and has cleared somewhere between weeks 12 and 24 (let's also add that the patient has been taking 1,200 mg. of riba and is given the opportunity of Neupogen and Procrit). If this patient has the option on doing extended treatment (X-tx), how best might they look to studies such as Teravic to be of any use in their particular circumstances?
Realizing that there is no exact apples-to-apples comparison between the Teravic subjects and himself, yet also seeing the inherent value of the information there, should our patient say, "In Teravic, the patients did 72 weeks at 800 mg. of riba and obtained an SVR rate-gain of 16% over those who only did 48 (44% vs. 28%). How much more might I gain by being on 1,200 mg. for a full 72 weeks? And how do I account for the fact that in Teravic SR patients are categorized as anyone not clear beyond week 4, yet I cleared anywhere from 8 - 20 weeks beyond that point in my tx? If I look to Reddy (a study with patients on 1,000 - 1,200 of riba) I see that those in my shoes (2-log drop by week 12 and clearance by week 24) have a 48 week SVR shot of 26% (which is maddeningly similar to the Teravic group at 28% - who were on only 800 mg. of riba). Do I therefore assume that even at a dosage of 1,200 mg., the best I can hope for by doing 72 is the Teravic equivalent of 44%? Or should I assume that the increased riba-dosage will up those odds? Should I also assume that if Neupogen and Procrit were offered in these studies the SVR rates would have been even higher (especially given that 36% of the 72 week Teravic group dropped out), and therefore that might apply to me as well? ".
These are the type of questions/decisions facing patients and their doctors today. Sadly, there are little-to-no studies to be pointed to that say, "This is my situation exactly. Now I know preciesley what I will do!" And also, in the above example we are only holding for this single variable - SR/EVR. Patients present themselves with so many other charateristics (positive and negative) that need to be taken into account in all tx decision-making.
When discussing tx and odds, you and I have something very similar in common: back in the early 90's we were both (*** bad-pun alert***) 'willing' to try for SVR on odds that (at least I was told at the time) were 15-20%, at best. Looking back with hindsight, they were more in the '10% at best' category. So today here we are, with the 'luxury' of discussing whether or not 44% odds (and in all probability even higher) for SR geno-1 patients is an "unlikely bet".
The 12 week 'cut-off' date has been (long) established and is etched in research/tx stone. How reasonable is it to throw 'slow responders' (SR) to the wolves and say that "since we don't have the data/study info that we would like to, you particular class of patients have such low odds according to our 'standard' (i.e. - 48 week) studies that we can no longer justify treating you as such" (with insurance companies wielding the final blow by falling in line, too)? And should we not therefore then extend that 'low odds' logic of lack-of-tx-success to patients with Stage 3, Stage 4, cirrhosis, ESLD, too? Do we now create two (or more) classes of tx-able and non-tx-able groups - before they even get the chance to try? (this last question seems very favorable to insurers, would would undoubtedly pay for only those patients with the highest SVR odds). If we begin holding to these kind of standards, shouldn't we then apply them to the slowest EVR's too, and therefore consider their odds 'too low' when compared to the 'average' EVR? Just what chances are 'too low' for a patient - any patient - when considering tx?
In 'standard' Hep C tx, there is a 'tyranny of the 12 week EVR' (and thus a 'tyranny of the 48 week tx'). Other than some early researchers deciding that they liked the number 12 (perhaps because it's been used so often in the past in other study situations?), and insurers eventually tagging along, what makes 12 weeks the 'golden ring'? Why not make the EVR cut-off date 10 weeks? or 8 weeks? or extend it to 14 weeks? or beyond? - and see the resulting differing SVR figures.
And, should CD need to be a 100% equivalent gain for every week beyond EVR for it to be of use and benefit to those patients classified as SR's? What if SR patients and their doctors find the diminishing returns from extending to be a more-than-acceptable shot at SVR (along with all of the histological and other biological benefits that can ensue from it)?
In the most practical sense, it comes down to this: what can patients do with the things that are presented to them today in the challenge to attain the ultimate goal of tx - SVR? They must take with them whatever set of factors/variables they present to their doctor and try to ensure that they will be given the best chance at achieving that goal. In the vast majority of tx practiced by the medical community today, EVR (or not) is only determined at week #12, leaving the patient and the doctor with a near instantaneous decision to make - do we continue from here? If the patient is a SR, what are the options then? Quite often the patient is told to continue on until the week #24 PCR. And should they be clear at that point, just where do they stand? They do know that they have lower odds of SVR than EVR's, yet they also have invested a full 24 weeks into tx and have ultimately reached the level of serum viral clearance. Should they just accept the low-odds numbers given from the 48 week studies and go only for that length of time? Or should they roll the dice and hope that serum clearance will eventually equal histological clearance and will eventually equal SVR - by tacking on some extra time beyond 48?
With one-half years worth of tx under their belt, knowing that they have reached the point of PCR clearance, knowing that if they stop tx failure will be imminent, and given the chance to increase (even if only marginally) their odds of attaining SVR (along the other benefits of tx) - what should they tell their doctor when presented with the option to extend?
I had been assuming you were aware of the TeraVIC-4 study:
<a href="http://www.natap.org/2004/EASL/easl_06.htm">18 Months Therapy (Pegasys+Ribavirin): study found relapse rate reduced by 70%; viral response rate in genotype 1 increased by 50%</a>
(from the study):
<i>Sustained virologic response rates at the end of follow-up (6 months after stopping Pegasys/ribavirin treatment) were significantly higher in patients who were treated for a longer duration with combination therapy (45% vs 32%, p=0.0144).
In patients who were HCV RNAnegative at week 4, sustained viral responses were achieved in 79% of patients treated for a total of 24 weeks and 64% of patients treated for atotal of 48 weeks. The higher response rate of 79% reflects inclusion of patients with genotypes 2 and 3.
In patients who were HCV RNA positive at week 4, there was a significant difference in the maintenance of viral response rates during followup. In those treated for a total of 48 weeks, the viral response rate declined from 61% at completion of treatment to 32% at the end of followup. In contrast, the viral response rate declined from 52% at completion of treatment to 45% at the end of followup in those who received a total of 72 weeks of treatment.
Extended treatment was beneficial in patients with HCV genotype 1. Sustained viral response rates of 28% and44% were achieved in these patients after treatment for a total of48 and 72 weeks, respectively.
Sustained viral response rates were also consistently higher in patients treated for 72 weeks when the data are grouped by baseline viral load. For patients with high baseline viral load (>800,00 IU/mL) sustained viral response rates were 30% after 48 weeks vs 37% after 72 weeks of therapy.
For patients with low viral load (<800,000 IU/mL), sustained viral response rates were 34% after 48 weeks therapy vs 52% after 72 weeks therapy.</i>"
And these results were obtained with only 800 mg of riba.
tn : it is interesting to look back; fundamental understanding of the virus doesn't really seem to have progressed that much, yet with 3 simple-minded improvements (more ifn in circulation; longer tx; an auxiliary anti-viral) the improvements in therapy have been dramatic. I guess it underscores the point that you don't have to wait for advances in the science to make progress on the clinical side (and wouldn't it be great if we used the data we have, etc, etc.). I think that comment by Baker is looking at the same Lindahl study I linked above. Drs have been pretty cautious with the riba dosage up to now, maybe this will start changing?
dd: tailoring tx duration on the basis of some inverse relation to VL makes all kinds of sense compared to picking arbitray X-week mileposts. For every sluggish responder who may benefit from more than 48 there's probably an EVR who can do less. Trouble is the darn things disappear off the radar screen so early on...
However, I really disagree with the viewpoint that with enough time and ifn you can force success. Reviews like Lai's above provide pretty strong support for the observation that in many cases the virus will persist regardless of the ifn-generated response and patients only risk damage by continuing.
I agree with your comments, but let me clarify what I was referring to by advocating long CD for SOME slow responders. I meant that only for those who DO eventually clear the virus, by highly sensitive PCR, like <5 IU. If that happens somewhere around 20 to 30 weeks (and who knows, even if it happens slightly later) then the VL is continuing to decrease, but MUCH more slowly than in the normal responder. These are the cases that have not been adequately addressed by doing the extra long CD periods, other than in a few studies...where we are seeing a higher SVR % for those that do 72 weeks rather than 48. Who knows, maybe with 2 years of CD, the 28 week or so responder (clear on ultra quant PCR) might start seeing the SVR light go on.
I do not think we can say it won't work, because it has been very rarely attempted. I think Ben Cecil has run some patients for 2 yrs. plus after clearing. My doctor just took a patient that I know, out to 2 years after initial clearance. Again, I meant ONLY for those who DO clear, and show a continuous downward trend throughout initial tx period, until clear.
Another tactic would of course be to increase the inf. and riba, and hope to avoid the need for a super lengthy CD. You could assess whether that strategy was working in the slow responder by bumping up the dosages as soon as it is determined that a SLOW response is taking place. Maybe by 12 weeks, with some research and statistical analysis, we could tell who needed the 'boost' and then observe using PCR tests every 2 to 4 weeks to see if the response curve was steepening substantially.
Again, I am not guaranteeing that either method would be extremely effective in gaining SVR %, but until they try these approaches, on a larger, more structured scale, we will not find out.
Best wishes for a great holiday! This has been the best Memorial weekend for me in decades!!!!
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