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RVR and Liver fibrosis
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RVR and Liver fibrosis


Who can tell me why the study data shows those people who achieve RVR have the greatest chance of SVR regardless of liver damage..?

Does this mean that liver damage is something that potentially restricts the chance of achieving RVR but then becomes less of a negative influence on SVR once one achieves RVR..?

What exactly is the role of liver damage relative to killing the virus outright..?

BlackJack
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1768199_tn?1323621536
RVR or an undetectable viral load at 4 weeks indicates how well the triple therapy and your immune system is killing and clearing the HCV.  The liver has no function in immune response to infection.  

Sherry
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163305_tn?1333672171
To clarify one point,( sorry, I'm in a picky mood this morning), but RVR indicates how well your immune system is clearing HCV whether you are doing triple therapy or SOC.
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Avatar_f_tn
I am not sure if this response is pertinent to your question but, according to the principal investigator of my study, the earlier one attains undetectable status in the course of a treatment, the longer one ordinarily stays undetectable throughout the course of treatment and thus the higher the chance that one will stay undetectable post treatment. For example, if you are undetectable at two weeks following the start of dosing and are treating for 24 weeks, that means you are pounding away at the few virons per that are left for a full 22 weeks and that ought to increase your likelihood of being truly virus free as revealed at 24 weeks after you have stopped taking any medication vs. say becoming UND at 12 weeks during the dosing period.
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1941083_tn?1323880345
Not doing Triple... geno 2 on P/R

I understand perfectly what RVR means.... but my question is HOW does liver damage relate to overall chances of SVR once you achieve RVR..?

The study data in relation to SVR once RVR is achieved does not suggest that the percentages are affected by any other factor.

Once one achieves RVR then 90% go onto SVR ( Geno 2 ) so that suggests that only 10% are affected by other factors which cause failure so then if one were considering shortening Tx why would liver damage be a consideration if the damge factor is now reduced dramatically by achieving RVR...?
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446474_tn?1404424777
"why would liver damage be a consideration if the damge factor is now reduced dramatically by achieving RVR...? "

When the liver is stage 3 and especially stage 4, the chances of RVR and SRV are very much reduced. There are many factors that affect the odds of achieving SVR. Race, degree of fibrosis, diabetes, weight, IL28,etc.etc. but the degree of fibrosis has the most profound affect of them all. This is why cirrhotics have such low rates of SVR using only interferon and ribavirin.

The confusion in the reasoning above is that most cirrhotics that treat with only inrtferon and ribavirin never respond to treatment, so they never achieve RVR and many don't achieve EVR either, so they can't ever SVR. And the more damaged the cirrhotic's liver is the less the odds of SRV. When a patient develops decompenstated cirrhosis in fact, the the odds of cure is so low the risk is higher than the benefit.

hector
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1941083_tn?1323880345


Cheers.... appreciate your reply.

So... does this then answer my theorisation that if one achieves RVR as indeed I have with a Bx that reported metavir F3 fibrosis... I could indeed discount the liver damage now being such a potential threat to reducing odds of SVR if considering to opt for shortened Tx of 16 weeks...?

I've had people comment that ' Oh with your liver damage I wouldn't consider shortening'... but in fact does RVR effectively rule out the liver damage..?

I'll just reiterate that I'm going to do the full 24 weeks.... but I like to know and I'm trying to get to the bottom of exactly what factors one should really consider for shortening Tx as a geno 2.... because the only way one can truly qualify for shortened Tx is to achieve RVR.

Does the RVR mean the goal posts have moved in respect of the other influencing factors that at the beginning are the overall influence on SVR...?

BlackJack

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Avatar_m_tn
From this particular trial it was concluded that RVR was a strong predictor of success..as well as "low fibrosis score"

http://www.ncbi.nlm.nih.gov/pubmed/20170514

Short versus standard treatment with pegylated interferon alfa-2A plus ribavirin in patients with hepatitis C virus genotype 2 or 3: the cleo trial.

Rapid virological response, low baseline HCV RNA levels, elevated alanine aminotransferase levels and low fibrosis score, were the strongest covariates associated with SVR, independent of HCV genotype. No baseline characteristic was associated with relapse.
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Avatar_f_tn
I think it is safe to say that RVR is a better predictor than fibrosis of SVR in your case scenario.  However, it ain't over til the fat lady sings (6 months post treatment).  
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1941083_tn?1323880345

Cheers for link to the cleo trial data... one I hadn't seen.

I note this one is even shorter at 12 weeks

It really is a tough decision ... one only wants to do 'enough' to kill the virus and not bombard the immune system if it's not necessary.

If only there were a way to attain the SVR in real-time and know as soon as the beast is dead... I wonder if those very clever molecular biologists will come up with a test that does exactly that at some point...? I think so.

For now it's crystal ball still... and going with one's gut instinct.and as much info as possible.

I have to take into account that the vast majority of Genotypes are 1's and therefore always gonna be doing 48 weeks P/R and with triple possibly 24 weeks minumum.... but 16 or even 12 is simply not a consideration so any opinion about such shorter Tx for geno 2/3's  by anyone who is not a 2/3 will most probably be heavily biased.

As I stated my decision is already made to go the distance.... no sx whatsoever .... but it's interesting to investigate what a really informed decision involves.... knowing of someone who simply felt like crap and was sick of feeling that way and opted for EOT at 17 weeks with RVR...

Appreciate your input
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1669790_tn?1333666195
Althought the sensitivity of the PCR's, TMA's, etc. have improved recently, as I see it, the limiting factor is the inability of detecting live virus at the lowest level.  It would be wonderful if a test existed that could verify that not a single viron was alive within us, and therefore trt could end at any week once the confirmation of no live virus was given.  Until then we're stuck with the current level of detection and are guided by years of trial research data resulting in the developed protocols.  I feel fortunate in some ways that I'm treating now and not 10 years ago with some of the advancements in the detection and trt of HCV.  I'm sure in another 10 years, someone will be saying the same thing.
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148588_tn?1415247401
In regards your queston on the other thread about WBC and neuts, mine barely budged out of normal range and I chose to quit after 23 shots and 22 weeks of riba. Geno 3e 8.5 yrs SVR. My gastro considered me quite daring as he had wanted me to do 48 - but then again I had to bring a copy of the 2002 NIH consensus report to him to read. I knew another 3e who had to quit after 16 weeks due to drops in both reds and whites that epo and neup couldn't remedy and she was still UND 6 months post-tx. Sorry, no RVR data - baseline, 12, and 24 was all my gastro did. I fought to get a 6 week (who knew back then about 2 and 4) but my GP's office was new to PCRs and skrewed up the samples three different ways and by that time it was time for 12, so I had nothing to go on except a 12 week UND.
As for why people with more advanced damage are more likely to relapse after going UND on tx, I've heard a lot of different theories but don't recall reading any definite proof. But hey, low B12 levels post-tx, so I may have forgotten. Like flcyclist said, "Answer hazy, ask again in 10 years.".
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Avatar_m_tn
As I stated my decision is already made to go the distance.... no sx whatsoever ....
------------------------------------------------------------------------------------------------
Good decision....and best of luck..
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Avatar_m_tn
http://www.hivandhepatitis.com/hep_c/news/2010/040910_a.html

"Savino Bruno and colleagues from Italy conducted a study to assess the safety and efficacy of pegylated interferon alfa-2a (Pegasys) plus ribavirin in people with advanced fibrosis enrolled in 3 international randomized clinical trials.

The analysis included data from 341 chronic hepatitis C patients with hard-to-treat HCV genotypes 1 or 4 patients (99 of whom had bridging fibrosis or cirrhosis) and 1547 patients with genotype 2 or 3 (380 of whom had advanced fibrosis or cirrhosis). Genotype 1 or 4 patients were treated 48 weeks, while those with genotypes 2 or 3 were treated for either 16 or 24 weeks.

The researchers looked at early virological response after starting treatment and sustained virological response (SVR), defined as continued undetectable HCV RNA viral load 24 weeks after completion of therapy.

Results

SVR rates progressively decreased as degree of liver damage increased:

Genotype 1 or 4 patients:

60% SVR without advanced fibrosis;
51% SVR with bridging fibrosis;
33% SVR with cirrhosis (P = 0.0028 for trend).

Genotype 2 or 3 treated for 24 weeks:

76% SVR without advanced fibrosis;
61% SVR with bridging fibrosis;
57% SVR with cirrhosis (P < 0.0001 for trend).
Regardless of genotype, participants without advanced fibrosis were more likely to experience early response to treatment.
Earlier treatment response was associated with higher SVR rates and lower relapse rates during post-treatment follow-up.
Patients with similar responses during the first 12 weeks of treatment had similar SVR and relapse rates, regardless of degree of fibrosis/cirrhosis.
Based on these findings, the study authors concluded, "Compared with patients with less severe disease, SVR rates are significantly lower in patients with advanced fibrosis."

However, they added, "irrespective of genotype and degree of fibrosis, the time to become hepatitis C virus (HCV) RNA undetectable was the strongest predictor of SVR.""
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1669790_tn?1333666195
To add on to Dave's information above from the same study, those that were EVR:    http://onlinelibrary.wiley.com/doi/10.1002/hep.23340/full

"Overall SVR rates were considerably higher in genotype 2 or 3–infected patients who achieved an RVR than among those who achieved a complete EVR (Fig. 2B). The positive predictive value of an RVR in genotype 2 or 3 patients treated for 24 weeks was:
87.1% in those without advanced fibrosis,
81.7% in those with advanced fibrosis, and
78.8% in those with cirrhosis."
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1941083_tn?1323880345
Thanks people............. that's the kinda study data I wanted to see.

I think it definitely shows that once RVR is achieved then baseline factors ... especially the level of fibrosis.... no longer have as much influence on SVR.

As such if I were having to make an informed choice right now whether to do shorter Tx I wouldn't put level of fibrosis as a major consideration.

I think the only real consideration for shorter Tx as a geno 2/3 who achieves RVR is whether or not you can handle the therapy.

It's a lucky back door escape for those who don't tolerate Tx well but still offers a very good chance of SVR regardless of other baseline factors because RVR has been achieved.

I think any concern regarding long term damage from the use of P/R is difficult to calculate in the absense of any studies showing a point at which saturation of the drug could likely cause long term damage and as such it's not a viable consideration for justifying shortening of Tx.

Naturally.... this is just my opinion

Thanks again for the input

BlackJack
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1941083_tn?1323880345

Looking thru the Wiley library I found this very definative large study  ( ACCELERATE ) specifically looking at Geno 2/3's who can receive 16 weeks of Tx.

http://onlinelibrary.wiley.com/doi/10.1002/hep.23531/full

Anyone who wants to know hard data on the likely outcome of shortening their Tx as a geno 2/3 ... and has the ability to digest statistical analysis... should give this a look.

I've read thru the whole thing a couple of times.... and now I only have one unanswered question.

Why would the study only include those with ELEVATED ALT....?

I presume elevated is higher than normal range...?

Mine has been between 30 at base and 22 now which is all within normal and so I find it difficult to know if I can fit myself into a comparison with this study.

This was also the same for the Cleo trial.... anyone know why a prerequisite for such studies is elevated alanine aminotransferase...?
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1941083_tn?1323880345

Ooops back again.....

Does perhaps an elevated ALT mean an elevated 'Ratio' between AST and ALT...?

In the ACCELERATE study the data quotes ALT ratio % in 2 groups > 3 and equal to or <3

If anyone can clear that up it would be appreciated
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Avatar_m_tn
http://www.hepatitis-central.com/hcv/labs/altast.html

"Aspartate Aminotransferase (AST)

1. AST is a cytoplasmic enzyme in liver, muscle, RBC's and other locations

2. Released from damaged cells; serum levels peak 24-36 hr after injury and normalize at 3-6 days if injury isn't ongoing

3. Highest elevations occur in viral hepatitis and hepatotoxicity (10-20 times the upper reference limit)

4. Mild-to-moderate (3-10 fold) elevations occur in chronic hepatitis, active cirrhosis, chronic passive congestion, drug-induced injury, metastatic tumor, biliary disease and a number of other conditions.

5. Cardiac and skeletal muscle injury will also produce substantial AST elevations.

Alanine Aminotransferase (ALT)

1. More specific for the liver than AST, but also present in kidney and muscle

2. Used to confirm that AST elevations are of liver origin (e.g., elevation of both AST and ALT strongly suggest hepatocellular injury)

3. The time course of ALT elevations in liver disease is shown below; AST would show a similar overall time course (though the ratio of the AST and ALT varies with disease and from patient to patient, as described in the next section)

AST/ALT Ratio

1. Viral hepatitis, mononucleosis, and acute hepatotoxicity typically show elevations in ALT that are equal to or greater than AST elevations (AST/ALT less than or equal to 1.0)

2. ALT is elevated to a lesser degree than AST in alcoholic liver disease and cirrhosis, passive congestion, bile duct obstruction, or metastatic tumor to the liver (AST/ALT greater than 1.0)

3. These are rules of thumb--substantial minorities of patients deviate from them, making the AST/ALT ratio of limited usefulness in the diagnosis of individual patients (though it may be helpful in suggesting the next appropriate step in the workup)"
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1941083_tn?1323880345

Thanks for that....

Just want to share this conclusion from ACCELERATE which really supports the exclusion of those people with advanced fibrosis for shortened 16 week Tx due to the 27% relapse rate.

It summarises nicely.

"The current analysis has shown that several subgroups of patients with an RVR have an acceptable risk:benefit ratio for contemplation of abbreviated therapy in addition to those that have a low baseline serum HCV RNA level. Given that advanced fibrosis was a stronger predictor of relapse in patients with RVR after 16 weeks of treatment (relapse rate of 27%), it is reasonable to exclude all such patients from abbreviated treatment.

Rather than reducing the treatment duration in patients who experience adverse events that must be managed by dose reductions, physicians should encourage continued treatment for the full 24-week duration to maximize the probability of SVR.

Overall, this analysis shows that for patients infected with HCV genotype 2 or 3 and who achieve an RVR at week 4, the standard 24-week treatment duration produces significantly higher SVR rates than an abbreviated 16-week regimen. Shortening the treatment duration should be considered only in patients with a low baseline HCV RNA level and without bridging fibrosis/cirrhosis who achieve an RVR. The difference in SVR rates is attributable to a significantly higher rate of virological relapse in patients treated with the abbreviated regimen"


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Avatar_m_tn
Personally I would complete the 24 week treatment unless I was unable medically to continue. Having to do treatment more then once if not necassary is something I would want to avoid. If I was cirrhotic or close to it I would feel even more motivated to complete the full 24.

The good thing about treating with SOC is that you can treat again if it doesn't work without resistance issues.

Good luck to you with whatever you decide and I hope you SVR
-Dave
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179856_tn?1333550962
Agrees with Dave but is from the old school so I always figure why take chances at failure if you don't have to - get all the odds you can on your side. See, old school SOC tx'er who never wanted to have to do tx again and luckily does not :)
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