Hep C Discussion Forum

Canuck · Guru

RE: Cirrhosis in HepC_Mallani

Tig · Admin

I had to take Neupogen shots twice a week for most of the 7 months I was on treatment. My WBC’s dropped so low I had to go into home isolation over the fear I could catch anything. My immune system failed. The combination of the three drugs I was on, made me so sick and weak. I describe it in my Bio, and remember most of it like it was yesterday. I’m so happy they don’t use those treatment drugs anymore.

Canuck · Guru

The old treatments could reak such havoc on cells and bodies. And there can be dear penalties paid for being cirrhotic as well. Similar to other things that have been given for low RBC and low hgbs's. (Procrit), this stuff (on the other hand) addresses low platelets, like (Promacta or "eltabopag") does - this (Mulpleta or "lusutrombopag") are drugs we hope we never have to have, but, for those of us who might be deficient in platelets it is just another way to get you some in sufficient quantity, handy for surgery and such - nice to know these options are out there. smile C.

Platelets - FDA approves Mulpleta for thrombocytopenia in adults with chronic liver disease

Canuck · Guru

Cirrhosis and High Meld scores - "Emricasan" drug being proven to help improve function/reduce meld scores.

Published in Gastroenterology

Journal Scan / Research · July 19, 2018

Emricasan Improves Liver Function in Patients With Cirrhosis

Clinical Gastroenterology and Hepatology

TAKE-HOME MESSAGE

· An open-label trial of patients with cirrhosis was conducted to evaluate the efficacy of emricasan, a pan-caspase inhibitor. The 3 months of treatment with emricasan improved liver function and reduced MELD scores, Child-Pugh scores, INR, and total bilirubin compared with placebo in patients with MELD scores >15. Emricasan was well-tolerated, with no difference in adverse events compared with placebo. The effects of emricasan were maintained or increased after 6 months of treatment.

· Emricasan appears to be safe and effective for patients with cirrhosis with high MELD scores. Further longitudinal studies will be needed to confirm these findings.

Abstract

BACKGROUND & AIMS

Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH).

METHODS

We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (n=42) or emricasan (25 mg, n=44), twice daily for 3 months; subjects then received open-label emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3.

RESULTS

Seventy-four patients completed the 3-month study period (40 given emricasan and 34 given placebo); 69 patients received open-label emricasan for 3 months afterward. At the 3-month timepoint, emricasan significantly reduced mean MELD (P=.003) and Child-Pugh (P=.003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between emricasan and placebo groups in mean MELD (P=.466) or Child-Pugh (P=.124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P=.02) and caspase 3/7 (P<.001), but not cleaved CK-18 (P=.092), decreased significantly at 3 months in the emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment.

CONCLUSIONS

In a randomized trial of patients with cirrhosis, we found 3 months treatment with emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores >15.

______________________________________________________________________

Emricasan, a Caspase Inhibitor, for Treatment of Subjects With ...

https://clinicaltrials.gov/ct2/show/NCT03205345

Jul 2, 2017 - This is a multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of emricasan in improving ...

Emricasan, a potent pan-caspase inhibitor ... - Conatus Pharmaceuticals

https://www.conatuspharma.com/assets/001/5079.pdf

Introduction: Emricasan (IDN-6556, PF-03491390) is a potent irreversible pan-caspase inhibitor with the ability to rapidly reduce elevated levels of serum ALT,.

Emricasan - Wikipedia

https://en.wikipedia.org/wiki/Emricasan

Emricasan (IDN-6556, PF-03491390) is a drug originally invented in 1998 by Idun Pharmaceuticals, which was acquired by Pfizer in 2005 and acquired by ...

Paul B · Senior Member

Great thread !!!

Tig · Admin

Found this article released by the Journal of Clinical Gastroenterology. It indicates the incidence of cirrhosis is greater than previously believed. Also mentions the number of people unaware of it being quite high. Hopefully reports like this will encourage HCV treatment upon diagnosis and not fibrosis stage.

http://www.hivandhepatitis.com/hcv-disease-progression/hcv-fibrosis-cirrhosis-steatosis/5043-liver-cirrhosis-more-common-than-previously-believed-linked-to-hepatitis-c-alcohol

Groupergetter · Guru

RE: Cirrhosis in HepC_Mallaniar

Tig · Admin

RE: Cirrhosis in HepC_Mallani

Rubye · Senior Member

There's no acetaminophen in them. The doctor specifies no tylenol or aspirin.

RUDY · Member

The Acetaminophen in those pain drug will kill quick lights out fast...FACT

Rubye · Senior Member

Duane, I hope you are doing well. I can definitely empathize with the difficulty of coming to a decision on whether or not to transplant. Sometimes it seems like people rush into it without having looked at all the issues so I think it is very intelligent and reasonable to weigh out the good and the bad and the unknown. The main reason I have chosen not to is my age - almost 68. However, you are still young.

-- Edited by Rubye on Saturday 9th of May 2015 07:21:47 PM

Tig · Admin

Hey Duane,

Don't you worry about hijacking anything! I established this thread to discuss the topic of cirrhosis and I think you qualify Brother. So all is fine with me, post away!

I'm glad to hear you've received some good news. Congrats on the ablation! I know you have a lot ahead of you and your ability to handle each problem with confidence and the strength necessary to succeed is more than admirable. Much respect dude... Keep it up!

It's good to know that you have a team of trusted physicians too. It's nice to know you don't have to second guess your care. Your concern regarding the cessation of narcotics is a valid one. It's very wise to consider it ahead of time. I suggest you discuss that well ahead of time with your team so you have a plan in place. No surprises....

Always here for you old friend! Prayers up and always...

Tig

Dzdayscomin · Senior Member

I didn't mean to hijack Tigs thread here, but thank you all for your kind words.....if it's ok I'll just say where things are at.

On March 6th I had my 3 month labs and MRI, the ablation has been determined a great success, although there is still that one spot about .9cm that has remained unchanged, along with some dysplastic nodules that remain, my MELD is now 27 or 28 ? as for some reason I've been told i only get 2 additional exception points each evaluation. ...even though I believe the Milan critera says you are supposed to get 3.

Although i have limited liver volume, what is left I'm told is functioning extremely well, my glucose continues to rise and its currently 162, I have much neuropathic pain in my feet, but we have chosen to try and ride it out to transplant, rather than start the whole diabetes regimine, as a low blood sugar event and the rest of the control meds put in place to deal with diabetes are a greater risk to my compromised situation then a "just over the threshold" blood sugar situation.

Then there is the Rheumatologist. ...again in this situation we are not going to do much.....maybe some prednisone injections in my shoulders? but no paqunil or biologics....as we have decided that unless the intervention is curative and preventing joint damage, we will stick with the current pain management program until after transplant realizing that we will have to deal with the withdrawl at that time.

I cannot express how good it feels to have a GP that understands the challenges that someone with ESLD facing transplant deals with, and realizes that there will be a period of time where we will have to deal with withdrawl from a narcotic that is allowing me to work, live, eat etc....and will then be there after the transplant to work thru the problems.....I know this doctor has been sent as a gift from God to walk with me, comfort me and then help heal the damage we did to make it this far and finish the race.

Thanks for listening....... hope everyone else doing well.

Duane

RudiRoo · Senior Member

Hi Duane,

You may already be familiar with Karen Hoyt, but your post reminded me of a recent one of hers entitled: "I don't want a liver transplant".

Here's the link, (I think I'm allow to post it??) http://www.ihelpc.com/i-dont-want-a-liver-transplant/

She is running your road now, and you two may have much to offer each other.

I think of you often. If you get a sudden sense of sunshine it's me, sending you tropical thoughts. Close your eyes and imagine the Caribbean trade winds carrying soothing, scented breezes and healing. Lots and lots of healing.

Hugs,

Rudi

Tig · Admin

Hey D,

I'm in complete agreement with John. It has to be a trying time and the continual changes have to wear heavily on you and your family. But I know you've got a strong circle of support around you and whatever you decide as a family will be the right choice. You're no dummy, you know more than most people here about ESLD. Trust in yourself and your strengths, they will be your guide. Good luck...

Tig

Gator Man · Senior Member

Hi Duane,

I don't think anyone on the forum believes you are whining, so no need to apologize.

As you said, it's a huge decision and one that most of us have been lucky enough to avoid. I haven't run your road, but I've been in the parking lot. I had a few general discussions with my doctor about ESLD and transplants. If you were in the Atlanta region, the waiting period for a liver transplant tends to be very short, so there is not a whole lot of time to think about it.

It is a decision that could be made for you if your next MRI shows a progression of HCC. Lets hope that will not be the case. If I were faced with this dilemma, I probably would agree with Malcolm, particularly if the underlying liver disease had not substantially diminished my quality of life (QOL). The concern is do you progress so far down the road with ESLD before a transplant that you can never adequately recover a decent QOL afterwords. A tough choice, but I would view a transplant as my last option if I thought I could maintain acceptable health for some reasonable period of time without surgery.

There may not be any "correct" answers, but I hope you have peace with whatever decision you, in consultation with your family and doctors, make in the end. The one thing that I will add is that I am of the firm belief that regardless of your current doubts, you would be a "quality patient" for a transplant if you decide to go ahead with surgery.

We're in your corner Duane and wish you the best things going forward. Take care my friend.

Dzdayscomin · Senior Member

Thank You Mallani,

I keep getting told that Cirrhosis is not reversible, yet I read there is some signs of that actually happening...who do I believe?

It's a huge decision to transplant as either way you have risks...I think I need to head back down to the transplant center and meet with some folks that have undergone this procedure, so that I can talk to a real person that has experienced all the things that I have, and things I'm about too.......when I 1st found out about all this I knew it was yrs away...now that it is months away I am getting a bit more jittery about it, and am feeling desperate for more information and reinforcements to make the right decision.....it's like people that have back surgery...most think that their pain is going to go away, and most realize afterwards that it's a trade off, and in most cases pain still exists, and the success of pain relief is tied to the quality of the patient..... so if you have a back ache all the time and some whacko takes the knife to you telling you it'll help, however in many cases the patient quickly comes to realization of what REAL back pain is and longs for just the back ache...well that is my situation with ESLD I'm told it's (Transplant) the only way, and it likely is, as my labs and scans support it along with the cancer.

But I'm alive, and other than my current liver related problems I never get colds or the flu or any of that crud....so somehow I have to prepare myself for this journey, or convince my self that I can live with these problems..... because I could just make them or others that are worse going through the transplant process...in a short way of saying it I ask myself "am I a quality patient for this procedure"

Nobody has the answer, they all walk around it...I suppose it's so that they can say "well it was your decision" if thigs don't work out.

Anyway sorry about the whining if anybody on this forum has run my road let me know your thoughts.

Duane

mallani · Guru

Hi Duane,

You've presumably a Grade 4 using my classification. The MELD score was initially proposed to assess the likelihood of death within 3 months for end-stage liver disease. It has since been adopted to give a predictive tool. It uses the serum bilirubin, creatinine and INR in a mathematical formula. After SVR, in your case, there may be considerable improvement in these values and your MELD score may drop, but the degree of improvement in liver function after SVR is highly variable. The risk of developing another HCC is undoubtedly decreased.

The problems of diabetes and joint pain is related to the extra-hepatic manifestations of HCV. These may improve in time, but may remain, even if you have a transplant.

Obviously your doctor is the only one who can give you advice. I would try to avoid a transplant and hope my liver can recover enough. Obviously your next MRI will have to be clear.

I did not make it clear that cirrhotic patients may develop HCC at any time, so they may develop at any Stage. 6 monthly imaging is vital for all cirrhotics, even the Grade 1's.

Good luck buddy. I hope things improve for you and the MRI is clear.

Dzdayscomin · Senior Member

Ahh,finally a thread that i feel is written just for me...of course I'm sure that there are many just like me, but i am wondering , if i don't develop more HCC after my March 6th MRI, should I hold off on transplant? As of that scheduled 3 month scan I will have a MELD of 27 due to exception points via Milan criterea , and will put me at or near top of the list for our region by Sept. with a MELD of 31, if there is the possibility of reversal ..... to me that would be the best to avoid the risks of transplant and dealing with rejection the rest of my life.....or do ESLD stage 4 class C patients have no chance in the reversal arena?

Or is it just a given that the HCC will reocurr and that is why you get the points?....keep in mind when the Milan Critera was written few people were eradicating the HCV, so if you had cirhosiss and HCV your liver was still under attack, now with SVR attainment does it change the likely hood that HCC is dramatically reduced and reversal is possible.

The other question is what will I feel like post transplant?I thought I would feel much better and less fatigued attaining SVR but that has not materialized and in fact I have severe joint pain, diabetes, etc, etc, will any of that be corrected with transplant?

Thanks, Duane

Tig · Admin

Hello Forum Members,

After Malcolm "Mallani" wrote this article, we felt it best to close the original post to preserve it's

place and position in the forum index. It will allow future searches on this subject to be located

and referenced without the need of locating it through subsequent posts. With that thought in mind,

I wanted to repost his article in a companion thread so comments and questions could be left by

all interested members. It's too valuable to not allow discussion on the subject.

As a member of this forum and having the good fortune to be a part of the Admin team here, I have

come to depend on his knowledge, compassion and friendship. He is one of our most valued

members and I know everyone here has benefitted from his education and concern for their

wellbeing. With that said, I will repost his article and invite your commentary on the subject.

Thanks for the hard work and dedication Malcolm!

Tig

************************************************************************************************

Mallani (Malcolm)

Moderator

Date: Mar 1 00:41 2015

Cirrhosis in HepC. Do we need a better Grading system?

Permalink Closed

Hi all,

I've been meaning to do a post on this for some time, and was even going to send it to a Journal, but couldn't be bothered with all the Bibliography, rewriting, references etc. I've been through that before.

Cirrhosis ( from the Greek- 'yellow condition') has long been regarded as the end stage of a variety of conditions, and was thought to be irreversible. It's not a good name as yellow condition refers to jaundice, a late manifestation. Cirrhosis from HepC is now the leading reason for liver transplants. As we are seeing more and more SVR's from the new DAA's, there is much talk about reversal of cirrhosis.

The true histological diagnosis should mean bridging fibrosis, haphazard fibrous bands (of varying thickness) and the presence of regenerative nodules . Using the METAVIR scoring system, this is called F4.

Most patients with chronic HepC will develop cirrhosis eventually, although this may take anything from 20-50 years. We've discussed conditions likely to promote progression to cirrhosis- drinking alcohol, coinfection with HIV/HBV, Genotype 3, fatty liver, iron disorders etc. Cirrhosis should be suspected in any patient who has had HepC for a long time, particularly those with a high VL and high ALT levels. High ALT levels (>200) are usually associated with increased inflammation and piecemeal necrosis, which translates into increased fibrosis.

DIAGNOSIS: The long-taught feature of cirrhosis is a scarred liver containing regenerative nodules. We obviously can't pull our liver out and look at it, so liver biopsy is the 'gold standard' for diagnosis, but even this has some errors. Cirrhosis can be suspected from clinical symptoms, and physical examination can confirm this when a hard, nodular liver can be palpated, or when there is ascites, oesophageal varices or hepatic encephalopathy. All of these only occur in the later stages of cirrhosis. Blood tests such as bilirubin, liver enzymes, albumin, Prothrombin time (or INR), platelet count may all raise the suspicion of cirrhosis. Imaging with Ultrasound, CT or MRI may also show features typical of cirrhosis, but again these may not appear in early stages. So we try a variety of Biochemical markers- some of these are APRI, AST/ALT ratio, FIB-4, FibroSure (FibroTest) and ActiTest. All have a varying degree of success in the diagnosis. Fibroscan (Transient Elasticity) using an Ultrasound beam or MRI gradient is one of the latest tools. The accuracy in diagnosing cirrhosis is about 90%. The severity of cirrhosis was proposed using the Child-Turcotte-Pugh score. In cases that may need a transplant, the MELD score was used.

GRADING of CIRRHOSIS: A diagnosis of cirrhosis will be frightening to many, particularly after researching the internet. To date, the only accepted Grading system is Compensated or Decompensated cirrhosis. Clinicians disagree about whether oesophageal varices should be considered 'Decompensated'. A system was proposed:

Grade A: Compensated

Grade B: Beginning to decompensate

Grade C: Decompensated- End Stage.

As usual, there is disagreement about what Grade B means. I propose a better system:

Stage 1: No symptoms, no significant clinical findings, biochemical parameters well within normal limits ( apart from liver enzymes), normal oesophagus and stomach.

Stage 2: May have symptoms (eg fatigue), may have liver and /or spleen enlargement, may have some changes on imaging, some biochemical parameters may be abnormal, may have changes of portal hypertensive gastropathy in the stomach.

Stage 3: Usually have symptoms, obvious liver/spleen enlargement, changes noted on imaging, some abnormal blood parameters (platelets, bilirubin, albumin etc), oesophageal and/or gastric varices.

Stage 4: Symptomatic, obvious clinical signs ,obvious changes on imaging, abnormal blood parameters, with any/all of the following: jaundice, varices (bleeding or not), ascites, hepatic encephalopathy.

Obviously this covers a wide range of patients. When I read 'x' number of cirrhotics are included in a Clinical Trial,it means little as I'm sure most are preselected and are Stages 1 or 2.

DISCUSSION: Cirrhosis is progressive, and eventually we'll progress to a lower stage. Patients could remain at Stage 1 for up to 10 years- others progress more quickly and some of these factors are unknown. Most of us will be Stages 1 or 2 at presentation. Some members are told they have 'mild' or 'early' cirrhosis and this should mean Stage 1. Any system such as this has some blurring of the boundaries. The importance in knowing where you stand is in the expectations post-SVR. If I was Stage 1, I would expect a high likelihood of cirrhosis reversal to F3 or even F2. Stages 2 and 3 have progressively less likelihood. In most cases, SVR removes the cause for liver inflammation/ fibrosis, so progression of cirrhosis should be halted. SVR also causes a reduction in portal vein pressure, so varices often disappear.

This is also important in followup for HCC. As long as there is a high turnover of liver cells, there is an increased risk of HCC. Cirrhotics form nodules that often outstrip their blood supply, leading to necrosis, resorption and regeneration. In time, as fibrosis is resorbed , many post-SVR HepC cirrhotics will revert to F3 and lower, so HCC will not be as much of a worry.

If you haven't been fully assessed and don't want to know if you're cirrhotic, I understand. It does make a difference regarding treatment decisions and followup. Hopefully, cirrhosis from HepC will eventually disappear, and transplants will not be required. Cheers.

* This is basically about cirrhosis from Hepc. It can be applied to other causes of cirrhosis. Treating HBV or AIDs, stopping drinking and dietary changes etc., can help stop progression in other cases.

Hep C Discussion Forum

Emricasan Improves Liver Function in Patients With Cirrhosis

TAKE-HOME MESSAGE

Abstract

BACKGROUND & AIMS

METHODS

RESULTS

CONCLUSIONS

Emricasan, a Caspase Inhibitor, for Treatment of Subjects With ...

Emricasan, a potent pan-caspase inhibitor ... - Conatus Pharmaceuticals

Emricasan - Wikipedia

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