If you have the opportunity, Clinical Care Options has a seminar by Douglas M. Heuman titled "Tailoring Therapy for Advanced Liver Disease". A Metavir Score of 3 indicates bridging fibrosis which is considered advanced liver disease. Of course 4 is cirrhosis. The more fibrosis, the less chance of SVR. Hepatitis C treatment is just not as successful in those with advanced liver disease as it is with those who have lesser damage.
Worth listening to. You certainly don't want to be stage 3 or 4 before treating. You are lowering you chances of SVR.
Good question and one you should also ask your liver specialist (hepatologist), assuming you are seeing one.
In general, Hep C is a very slow moving disease. Some decide to treat at any stage, but some decide to take a Watch and Wait approach. I was infected close to forty years ago and did not treat until around thee years ago when I was around stage 3. Some might have treated earlier but I weighed the risks versus rewards in consulation with my doctors and that is what worked for me. I do also disagree on one point with, "Trinity", above. According to the studies I've read, you have the same chance of being cured regardless of stage unless you are stage 4 which is more difficult. In other words, someone with stage 3 damage has the same chance of being cured as someone with stage 1 damage. Personally, if I were stage 1 -- and especially if I were genotype 1 -- I'd wait for the newer drugs which promise better results with half the exposure to interferon, a drug which can cause problems for many of us, even well after treatment is over. But if you do decide to Watch n' Wait, hook yourself up with a good liver specialist (hepatologist) who can monitor you along the way. In general, GI's simply don't cut it in my book. The exception being if you want to educate yourself to the point where you know more than your doctor, and not sure I want a doc who is asking me what to do :)
when I found out I was stage 3 I felt I had absolutely no other choice but to treat. Waiting until I was stage 4 was just not an option I was willing to consider. WHILE you are still stage 3 the fibrosis can possibly be reversed. Once it becomes cirhhosis it cannot.
Treating while you in earlier stage gives you the best chance to improve the condition of your liver - that way, even if treatment is not successful the first time you perhaps have bought yourself some more time in order to treat again.
Waiting until you are losing even stage 3.......isn't a risk worth taking in my opinion. Once you are cirhhotic, you are. It won't go away. Since nobody knows how quickly the disease is progressing (there is never any guarantee on this) to me it's just a big gamble.
You also know there is a huge amount of information out there which indicates people with less advanced liver damage tend to repond better to HCV treatment. Stage 3 bridging fibrosis is considered advanced.
The study I'm referring to stated that only stage 4 didn't respond as well to treatment. Stage 3 did just as well as stage 1, bridging fibrosis or not. If I remember correctly, some of the earlier studies lumped stage 3 and 4 together, therefore the apparent discrepancy in what you and I have read.
I wish I had the study handy because I've posted it in this forum probably at least a half dozen times, yet the last time I tried to find the study, its link (on the hivandhepatitis ******* web site active if not mistaken) was no longer active. I'll give it another shot at some point, but maybe someone else will remember or find it. That's one problem with just posting links as sometimes they go bad.
"...n the entire population of patients logistic regression showed no statistically significant difference in SVR rates between Stage 0 (44%), Stage 1 (46%), Stage 2 (44%) and Stage 3 (44%)...
And what could have been the reason for the discrepency in the studies you saw:
"...Fibrosis is a predictor of sustained virological response (SVR) in hepatitis C (HCV). The majority of prior studies do not involve enough patients with cirrhosis to truly define the contribution of advanced fibrosis to SVR and nearly all combine Stage 3 and Stage 4 in their analyses..."
Here's the whole kaboodle in case the link every goes bad which I thought it did but apparently not.
HIV and Hepatitis.com Coverage of
Digestive Disease Week 2006 (DDW 2006)
May 20 - 25, 2006, Los Angeles, California
The Effect of Liver Fibrosis and Scirrhosis on Sustianed Virological Response in 4913 patients with hepatitis C: Results from the Win-R Trial
Fibrosis is a predictor of sustained virological response (SVR) in hepatitis C (HCV). The majority of prior studies do not involve enough patients with cirrhosis to truly define the contribution of advanced fibrosis to SVR and nearly all combine Stage 3 and Stage 4 in their analyses.
The primary objective of the study was to analyze the effect of fibrosis on SVR in the Win-R trial of 4913 patients receiving PEG-IFN alfa 2b and ribavirin (RBV: fixed-dose (FD) 800 mg or weight-based (WBD) 800 – 1400mg daily.
Fibrosis stage was obtained on biopsies within 3 years of randomization using the Metavir scoring system by local pathologists. SVR was determined by PCR negativity ( 65kg were included in this analysis (n = 4223). The effect of each individual fibrosis stage on SVR was determined by logistic regression for all patients (n = 4913) regardless of treatment group.
* The distribution of fibrosis score was as follows; Stage 0 = 654; stage 1 = 1460; Stage 2 = 1324; Stage 3 = 975; Stage 4 = 500.
* SVR was no different between WBD (657/1464; 45%) and FD 611/1445; 42%) RBV in patients with stage 0 – 2 fibrosis.
* However SVR in stage 3 to 4 was significantly increased in the WBD group ( 282 / 657; 43%) compared to the FD group ( 242 / 657; 37%); p = 0.02.
* In the entire population of patients logistic regression showed no statistically significant difference in SVR rates between Stage 0 (44%), Stage 1 (46%), Stage 2 (44%) and Stage 3 (44%).
* However all stages were significantly superior to Stage 4 which only had an SVR of 34% (p < 0.0001).
In conclusion, the authors write, “WBD of RBV is important to increase SVR in patients with more advanced stages of liver disease. However, overall only cirrhosis is a negative predictor of SVR when individual fibrosis stage and SVR is evaluated.”
“The cirrhotic patient represents a difficult to treat patient requiring optimal therapy, including weight-based RBV.”
The Win-R trial was supported by Schering-Plough.
N. Afdhal, I. Jacobsen, R. Brown, and others. The effect of liver fibrosis and cirrhosis on SVR in 4913 patients with hepatitis C; Results from the Win-R trial. Abstract 655 (Oral Presentation). Digestive Disease Week 2006 (DDW 2006). May 20-25, 2006. Los Angeles, CA.
Regardless of the "treat or wait" theme of this thread, just wanted to point out that there is info out there saying cirrhotics do have a shot at reversing their fibrosis (hope for those who have recently joined the S4 club--you know who you are).
Stage A cirrhosis CAN be reversed. Google it and you will find many results:
Cirrhosis is the final stage of chronic liver damage of various etiologies. It used to be considered an irreversible lesion, but enormous advances in our understanding of hepatic cellular and molecular biology in the past 2 decades have challenged this view. There is now substantial evidence that cirrhosis can be a reversible process.
Recent progress has made in the control and the reversal of cirrhosis. This is confirmed by the decline in the number of cirrhosis-related death rates in the United States over the last twenty years. Therapies such as interferon and ribavirin for chronic hepatitis C, and Epivir and Hepsera for chronic hepatitis B, have been shown to reverse cirrhosis in its early stages. There have been anecdotal reports of scarring being reversed after treatment in people with autoimmune hepatitis (chapter 14), primary biliary cirrhosis (Chapter 15) and hemochromatosis (chapter 18). Thus, cirrhosis, should no longer be considered as an irreversible condition.
2008 Conference In SF
HCV Treatment – Predictors of Treatment Response
1259. Steatosis, Insulin resistance, Iron overload, Fibrosis and Viral load as negative factors affecting Early (EVR) and Sustained (SVR) Virological Response in patients with Chronic Hepatitis C treated with peginterferon and ribavirin.
E. F. Georgescu; R. Ionescu; G. Florescu; G. Mateescu; L. Vancica
Since the relation between hepatitis C virus infection, insulin resistance and iron overload is not fully understood in genotype 1 HCV-infected patients, our aim was to evaluate the impact of several biochemical (serum ferritin, uric acid, HOMA-IR), histological (fibrosis, necroinflammation, steatosis, and hepatic iron scores) and viral factors (HCV viraemia) on both EVR and SVR in patients with genotype 1 chronic hepatitis C (CHC) treated with peginterferon plus ribavirin.
Patients and Methods:
We evaluated retrospectively 188 naïve CHC patients receiving peginterferon plus ribavirin at standard weight-based doses for 48 weeks (96M/92F; mean age 42.75 ± 0.84; mean weight 69.63±1.11 Kg; mean BMI 24.03±0.4). Genotype 1 HCV was confirmed in all cases by PCR analysis with type-specific primers for identification. Biopsies were assessed for inflammatory activity and fibrosis, as quantified by the modified Knodell histological activity index. Steatosis was categorized by the proportion of hepatocytes per low-power field with fatty changes: >5%, >5–33%, 34–66%, >66%. Biopsies were also assessed for stainable iron using the Brissot scoring system. All subjects were evaluated for metabolic syndrome (MS) using the NCEP-ATPIII criteria while HOMA-IR was estimated before treatment using the formula [fasting glucose (mg/dL) × immunoreactive insulin (µU/mL)]/405. All parameters were introduced in multivariate analysis in order to evaluate their contribution to EVR and SVR.
EVR was achieved in 115/188 pts (61.17%) while SVR occurred in 82/115 (71.3%). After adjusting for sex and age, independent factors that negatively interfered with both EVR and SVR were: fibrosis score (OR: 0.478; 95%CI: 0.140-0.912; P=0.031), steatosis (OR: 0.138; 95%CI: 0.035-0.537; P=0.004), iron score (OR: 0.308; 95%CI: 0.143-0.665; P=0.003), HOMA-IR index (OR: 0.478; 95%CI: 0.266-0.857; P=0.013) and viral load (OR: 0.424; 95%CI: 0.240-0.746; P=0.003). After excluding the patients with MS criteria (n=32), EVR was observed in 102/156 (65.4%) and SVR in 82/102 (80.4%). Factors that independently influenced both EVR and SVR were: fibrosis score (OR: 0.468; 95%CI: 0.295-0.743; P=0.001), steatosis (OR: 0.535; 95%CI: 0.342-0.834; P=0.006), iron score (OR: 0.779; 95%CI: 0.650-0.935; P=0.007) and viral load (OR: 0.784; 95%CI: 0.650-0.945; P=0.011).
Fibrosis, steatosis and iron scores, as well as viral load are independent parameters that can affect both EVR and SVR in genotype 1 CHC patients treated with peginterferon and ribavirin at standard doses for 48 weeks, regardless the presence of MS. If MS is present, high HOMA-IR index can also additionally impair viral response.
Thanks for the study, but only 188 patients were evaluated compared to with the WIN-R study, where 4913 patients were evaluated. It's also unclear from your study if they independently examined SVR at stage 4 (like with WIN-R) or if the more advanced stages were more or less lumped together as per earlier studies. It's unfortunate that the smaller study does not reference the opposing WIN-R results, as is often the case when a study seems to contradict a previous one, but it doesn't so one can only speculate on the "why's" but the two things I mentioned above -- sample size and fibrosis breakdown -- are what come to mind.
First, what a shame that prior non-responders or relapsers were subjected to a study that only treated them for 48 weeks, regardless of viral response. The 22% overall SVR rate is not surprising but one might argue irresponsible on the part of the study engineers.
Moving beyond that, this study as stated is for prior non-responders and relapsers and not for treatment naive's which I believe were what the much larger WIN-R study was comprised of. So again, we have apples to donuts and a much smaller sample size here.
But let's assume for agument's sake that the figures are correct. A seven point differential between let's day F2 and F3. Does this still make the argument that treating NOW is better than to Watch and Wait if you were say an F2? (And let's face it, that's what this is all about, it always is here :) ) Yes, seven points is significant IF one were to treat with the same drugs. But if in fact ones strategy was to wait and treat with better drugs (such as the PIs in trial) then that seven points should be wiped right out with HALF the exposure to interferon, given the promising PI trial results. So, as I see it, the case for selective Watch n' Wait is still quite intact even assuming this study is valid which the much larger WIN-R study suggests it might not be.
But again -- and a bit off track -- I have to wonder what these trial doctors disclosed to these poor patients to get them into this trial. Something wrong here, don't you think?
So is it even worth it to try some of these new treatments? I have stage 4 now. When I found out I was already stage 2 and within a few years I was stage 3. I have tried treatment 3 times with no success. I was planning on discussing new treatments with my doctor in december. I'm not sure if the side effects are worth it.
This was from the AASLD 2008 Annual Meeting. This study shows a diffident difference in the time it takes for advanced fibrosis g2 and g3 to get a SVR
With advanced fibrosis the odds go down for g3 g2 in the below study, with shorter tx times, and SOC tx
Not sure if you could translate this to geno 1.
Just another study that shows something different than the other studies. Just something to think about.
This study spells out what they consider advanced fibrosis, Bridging fibrosis/cirrhosis was defined as metavir 3+4, Knodell 3+4, Ishak 4+5+6 on the pre-treatment liver biopsy.
AASLD 2008 Annual Meeting
Nov 03 8:00 AM - 5:30 PM
Q07. HCV: Treatment
Are there differences in treatment outcomes between HCV genotype 2 and 3 patients with advanced fibrosis treated with peginterferon alfa-2a (40KD) (PEGASYS®) plus ribavirin (COPEGUS®)?
S. Bruno1; S. J. Hadziyannis2; M. L. Shiffman3; D. Messinger4; P. Marcellin5
1. AO Fatebenefratelli e Oftalmico, Milano, Italy.
2. Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece.
3. Virginia Commonwealth University Medical Center, Richmond, VA, USA.
4. Biometrics, IST GmbH, Mannheim, Germany.
5. Hôpital Beaujon, Clichy, France.
Background: It has been previously shown that among patients infected with genotype 2 or 3 HCV treated with pegIFN alfa-2a 180µg/wk plus ribavirin (RBV) 800mg/day, rates of sustained virological response (SVR) are generally higher for G2 and overall 24wks of therapy is better than 16wks. The objective of this retrospective analysis of data from two large international phase III studies, is to extend these analyses to patients with advanced hepatic fibrosis infected with G2/3 treated with pegIFN alfa-2a plus RBV for 16 or 24wks.
Methods: G2/3 patients with advanced fibrosis/cirrhosis included in this analysis were those assigned to 16 or 24wks of treatment with pegIFN alfa-2a 180μg/wk plus RBV 800mg/day. Bridging fibrosis/cirrhosis was defined as metavir 3+4, Knodell 3+4, Ishak 4+5+6 on the pre-treatment liver biopsy. Responses were defined as rapid virological response (RVR;HCV RNA <50IU/mL at wk4), complete early virological response (EVR) (non-RVR but HCV RNA<50IU/mL at wk12), partial EVR (non-RVR with a detectable but ≥2 log drop in HCV RNA at wk12) and non-EVR (<2log drop at wk12). SVR was defined as HCV RNA <50IU/mL after 24wks of untreated follow-up.
Results: Data were available for 380 patients with advanced fibrosis/cirrhosis (G2 16wks=107; G2 24wks=99; G3 16wks=84; G3 24wks=90). Among patients treated for 16wks of therapy, SVR rates were 51% and 44% for G2 and G3 respectively and for 24wks of therapy SVR rates were 66% and 53% respectively. By MLR independent baseline factors predictive of SVR included lower body weight, higher alanine aminotransferase quotient, higher serum albumin level, higher platelet count, lower viral load, G2 infection and assignment to longer treatment duration. Among patients treated for 24wks, rates of RVR were substantially higher among G2 patients (Table). Rates of SVR among patients achieving an RVR and assigned to 24wks of treatment were 77% and 90% for G2 and G3 respectively and rates of SVR among patients achieving a complete EVR were 44% and 34% for G2 and G3 respectively. No patient with slower responses achieved an SVR.
Conclusions: Among patients with advanced fibrosis/cirrhosis treated with pegIFN alfa-2a plus ribavirin, those infected with G2 HCV had higher rates of RVR and SVR compared to patients infected with G3 HCV. For patients achieving an RVR and treated for 24wks, rates of SVR were high for both G2 and G3 (77–90%). For both G2 and G3 patients with advanced fibrosis/cirrhosis abbreviated 16-wk therapy was less effective and should be strongly discouraged in this patient population.
Better one bird in your hand than ten birds in the forest.
There's another proverb that says a bird in your hand can sometimes lay an egg.
Did they lump advanced 3's and 4's together. It looks like that at first glance. If so, then the two studies may be consistent because WIN-R does suggest that stage 4's have a tougher time with SVR.
Did you mean "grade 4" or stage 4? I don't think treatiment decisions revolve around grade. I had grade 4 around five years ago and grade 1 or 2 just before I treated. So it appears that grade can fluctuate a lot while stage tends to keep getting worse.
Doc in Atlanta also said because I have stage 3 fibrosis, not cirrhosis, my chances of SVR were reduced. Additonally, I did not clear at 12 wks so because of the advanced liver damage and not clearing, I was considered an excellent candidate for treatment extention. I can't quote him verbatim, but it was discussed in length and his view is the more fibrosis you have as in stage 3, not cirrhosis, SVR percentage is reduced.
This a response from Dr. D as well:
Hi Dr D,
Thank you very much for taking the time to help people on this forum, like myself.
I am geno 1a, "at least" stage 3 (difficult to say for sure because one core was completely fibrous), white male, age 45, received hep c through a transfusion in 1981. I am on tx currently, 180 Pegasys and 1400 ribavirin - I will take shot #30 tomorrow. Besides liver enzymes, I had no hep c symptoms pre-tx.
The results from this study lead me to believe I should extend my treatment to 88 weeks.
So, am I a late responder or a super late responder? Should I stop treatment or extend treatment? If I extend treatment, how long should I extend? Your opinion would be deeply appreciated, thanks!
by Douglas Dieterich, MD
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Douglas Dieterich, MD
New York - NY
Member since May 2008
, Aug 04, 2008 07:42AM
As long as you get to < 10 and stay there I would generally treat for 48-52 weeks ( a year is what I tell my patients) after they become undetectable. I dont think you have to go to 88 weeks 72 should be plenty, but I would go at least that long because of the slow response and the fibrosis on the liver biopsy. Good luck, that should work and then the fibrosis should reverse some too! DTD
Good luck, that should work and then the fibrosis should reverse some too
Hopefully, treating 72 weeks will give the liver plenty of time to have the fibrosis reverse. I wish I had gotten a biopsy as soon as treatment was over so I could have seen for certain what the situation was. I always intended to but........
I'm pretty well wrapped up on the "Treat now or Watch n' Wait" discussion, masked as something or another this time :) Hopefully people trying to make a decision will read this thread (and the referenced studies) carefully and then do their own independent research including discussing everything with a good hepatologist. And as I mentioned before, fibrosis progression and SVR -- whatever study or doc you believe -- is just one of many factors in coming to a decision.
As to Pearlman's "research", don't do it is all I can say! Absolutely no reason for an elective EOT biopsy. Haven't you put yourself through enough?
If you're really that curious -- and remember what it did to the cat -- why don't you wait a year or so post treatment when the liver may have had time to heal a bit more. And hopefully by then, Fibroscan or other non-evasive tests will be more readily available. Frankly, not even sure if I'd get scanned again if I walked into my doc's office and found a new machine sitting there. What's the point? I've already assumed my liver has healed some, so the result could only disappoint. I'm certainly not going to take any more interferon to heal it some more. LOL.
I do know have any idea which scale my biopsies were done under. I've had 4 of them altogether. I've had bridging fibrosis for the past 7 years. I am now a genotype 1A, but previously was classified as genotype mixed of 1A/1B. I am a 10 X non-SVR treater. I did have some response to the treatments in that my viral load would come down and my LFT's would come down, but I've never cleared. Also, I've had no reversal of fibrosis on my biopsies. There's really not much out there for me right now as far as available treatments. Unless I get fortunate enough to be accepted into another Phase 2 or 3 trial. I have no idea if by the time that these newer drugs are finally FDA approved if I'll even be able to get them. Right now, I have no prescription drug insurance and if I even did, these new drugs are going to be costing such a high price that it's doubtful that many insurance companies will even want to pay for it. My chances at having success at any further Telaprevir treatments is not all that great since I've already been exposed to the Telaprevir..., possible resistance factors there. I don't mean to be negative, but facts are facts. I can just try and stay as healthy as I can and hope and pray that I don't have further progression.
" WHILE you are still stage 3 the fibrosis can possibly be reversed. Once it becomes cirhhosis it cannot."
Actually the HALT C trials have shown that at year 5, SVR, 20% of people who cleared and were stage 4 have reduced fibrosis scores. Some have even gone back to no fibrosis. At Stage 3, 80% of patients have reduced their metavir score of 3 to a tage 2 or less.
The key words that you've said, "who cleared"...., I have never cleared and my biopsies show no improvement either. I've had 4 biopsies since 1994. Last one was in spring of 2007. Not everybody who treats, is fortunate enough to have a reversal in fibrosis, I am proof of that fact. I do not drink, I do not smoke, I don't use illicit drugs, I eat a low fat diet and I exercise..., I've treated 10 times, and yet, I still have had no reversal on my fibrosis score. I can look on the positive side in that I have been able to slow my progression to cirrhosis - but I chalk that up more to prayers by others and myself than I do to my treatments. Susan400
I know how hard you have tried to beat this virus. I am in the same place as you, although I already have cirrhosis and did when diagnosed in 1992. I've treated so many times I have lost count as well as beating up my bone marrow so I can never use interferon again.
I probably should have made myself clearer in my comment about cirrhotics never getting an improvement. I was definitely talking about in people who treated and cleared (and were Stage 4)......20% of them had a reversal of cirrhosis.
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