To treat or not to treat?

[Sergey]

Hi everyone!

I have HCV and beginning compensated cirrhosis (no ascites, fibroscan 18, platelets 200, ALB 45 g/l, INR 1.1, total bilirubin around 20, MELD 8-9). Probably infected in 1977 (big surgery with blood transfusions), diagnosed with cirrhosis in 2005, 1b, high viral load, Peg/Rib 48 weeks in 2005-2006 - relapse.

What do you think about HCV-treatment with DAAs (like Harvoni), taking into account recent controversial news about possibility of development of HCC shortly after treatment?

It seems to me that data from AASLD-2016 abstracts about HCC risks after DAA-treatment for cirrhotics looks like a bit contradictory.

Some results seem as "not worse than no treatment" - for example, abstract 19 - http://onlinelibrary.wiley.com/doi/10.1002/hep.28796/full#hep28796-sec-0073
http://natap.org/2016/AASLD/AASLD_59.htm

"These results indicate that in cirrhotic patients the incidence of HCC during the first 6-9 months following initiation of DAAs therapy is not different from that expected in untreated patients according to historical controls. However, the atypical HCC pattern seen in about half of the cases deserves better understanding."

However, people without SVR12 have 8.4% of HCC - it is high.
 
Some results seem as "pessimistic" -
abstract 1324, http://onlinelibrary.wiley.com/doi/10.1002/hep.28799/full#hep28799-sec-0589
"Unusually High HCC Rates Among Patients With HCV Cirrhosis After Treatment With Direct Acting Antivirals"

"We observed high rate of new HCC development in about 10% with another 7% developing suspicious lesions within 6 mo of completing HCV therapy with DAA. This is much higher than historical annual HCC rate of 2-4% in patients with HCV cirrhosis."

abstract 1325, http://onlinelibrary.wiley.com/doi/10.1002/hep.28799/full#hep28799-sec-0593
"High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis C associated cirrhosis"

"The detected HCC incidence (7.4% in the first year) was higher than the previously reported for regimens containing interferon (1.2-1.4%) in cirrhotic patients achieving SVR. This increased incidence suggests an important role of the immmune system in the control of malignant cells. Nevertheless, these results should be confirmed in larger studies, specifically addressing patients with significant fibrosis. "

Also, abstracts 1340 - http://onlinelibrary.wiley.com/doi/10.1002/hep.28799/full#hep28799-sec-0653, 896 - http://onlinelibrary.wiley.com/doi/10.1002/hep.28798/full#hep28798-sec-0643.

And, some results seem "optimistic" - not worse than after interferon-ribavirin treatment, for example abstract 1938 - http://onlinelibrary.wiley.com/doi/10.1002/hep.28800/full#hep28800-sec-1151

It seems, nobody knows real situation with such risks at current moment... Of course, I may be wrong, but, as a result of conflicting evidence, DAAs-only treatment may seems as "possibly carcinogenic", regarding to liver cancer risk for cirrhotics (it sounds quite scary, really).

As a result, probably, cirrhotic patients becoming as some sort of "guinea pigs" regarding to such quite serious risk. And, the question arises - is it justified to undergo potential possibility of 10% HCC risk after treatment for asymptomatic people with early cirrhosis, whose do not have a serious risk of decompensation in a near future?

What is my options?

1. Treatment

Of course, interferon-free treatment usually is much better tolerated. But, is it justified to add interferon (or peginterferon) to DAA-schema like sof-dac or sof-led (Harvoni) for "anticancer effect"? Maybe, half-dose of interferon, not full dose?

2. Waiting

If it is correct that DAA treatment do not reduce HCC risk (compared to "no treatment"), then, it seems, main reason for treatment with beginning cirrhosis - is attempt of preventing decompensation. Treatment with generics is available now, and, hope, it will be available in future. My liver function is quite stable during 11 years despite HCV, and in case of worsening of liver function (for example, if albumin or platelets goes low, bilirubin or INR goes high, if MELD will become 11-12), hope, treatment with generics may be initiated at any moment. Also, I am not sure that main and sole cause of cirrhosis in my case is HCV, instead of of other causes - for example, some excessive alcohol consumption or consumption of some prescribed hepatotoxic medications etc. before diagnosis.  Alcohol consumption was ceased after HCV diagnosis, hence, if it is correct that alcohol is a main cause of liver damage in my case - there are chances that cirrhosis will not progress further, even with HCV. If it will not progress further, then, it seems, there are no many reasons to be like "guinea pig" regarding to a bit unknown HCC risk of DAA treatment.

What do you think about it?

[gnatcatcher]

Welcome, Sergey. You ask wise and difficult questions. Since I am not a doctor, what I can provide are some thoughts based on my experience.

Like you, I had big surgery with transfusions (1971), which is the only risk factor for HCV in my life. I had not had any alcoholic beverage since 1999 (and before that, I drank only extremely small amounts at social occasions, because I didn't like the taste), yet over the decades my fibrosis progressed to cirrhosis. If you don't get rid of the HCV, just abstaining from alcohol is highly unlikely to be enough to keep the cirrhosis from getting worse.

I just had my most recent ultrasound three days ago. More than thirteen months after the end of Harvoni treatment, there is no sign of any tumors. My fibroscan score has gone down significantly. So, I am in the vast majority who have not gotten HCC soon after treatment.

Is there any medicine that doesn't have a huge downside for at least a few people? I had major allergic reactions to two very common medicines. Deciding to take a new medicine is always a gamble. Deciding not to get treated is also a gamble. In the case of HCV, not getting treated is a large gamble.

My hepatologist did say that HCC, caught early, is very easy to treat. Having an ultrasound every six months is an easy way to catch any tumors early, so that they probably can be surgically removed with clean margins. (In 2003 I had a different cancer removed with clean margins, which meant I didn't need any chemo or radiation.)

Please know that, whatever you decide, you are welcome to be part of this forum community. We're here for each other, because we've faced the fears and stigma.

Gnatty

[Karin]

I feel so stupid sometimes when I am on these forums  Could you please explain what your post was saying Sergy??? In lay mans terms Thx

[Karin]

I feel so stupid sometimes when I am on these forums  Could you please explain what your post was saying Sergy??? In lay mans terms Thx

[BillT]

Hi Karin,
            Don't ever feel stupid.Some of this can get really deep but don't ever be afraid to ask a question if you have one.That's what we're here for.Here's a link that will explain it better.

http://www.hcplive.com/conference-coverage/easl-2016/alarm-over-cancer-recurrence-after-daa-treatment

[Karin]

Thanks BillT much easier read  So sounds like the problem is with patients that already had liver CANCER?? Not patients with liver damage?

[BillT]

Pretty much Karin.It seems be be more prevalent in people that have had HCC and have cirrhosis.One thing to keep in mind is that these drugs are new so there's still a lot to be learned about long term effects and such.I'm glad that helped explain it a little better.

[Karin]

Thx Again BillT

[Sergey]

Hi Gnatty, thank you!

Probably, I will wait for new data about such issue, it is difficult decision for me at current moment... Without HCV treatment, with MELD < 11 my probability of being alive after 10 years looks like 80%. It is not very good, but it is not very bad too. Average probability of survival after HCC diagnosis is worse than 80% after 10 years. I had read that only half cases of HCC are resectable. Unfortunately, many cases requires liver transplantation or even non-curable. Of course, regular liver cancer screening significantly increases survival, but resectability also depends on many things - location of tumor, size, quantity of tumors...

[Sergey]

Hi, BillT!

To be precise, this article (http://www.hcplive.com/conference-coverage/easl-2016/alarm-over-cancer-recurrence-after-daa-treatment) tells about liver cancer "recurrence", not about occurence of new HCC.

We have two slightly different questions:

1. Risks of liver cancer recurrence (for people, who previosly had liver cancer)
2. Risks of liver cancer occurrence, "new HCC" (for people, who previously did not have liver cancer)

My questions are about possibility of increased risks of liver cancer occurence ("new HCC"),  since I did not had a liver cancer.

[Sergey]

Hi, Karin!

No need to feel "stupid" or something like that! It is just some specific medical terms. In simple words, some controversial new medical data suggests possibility of increased liver cancer risks after HCV treatment with Harvoni-like drugs for people with cirrhosis, who did not had liver cancer in the past. And, I trying to understand - whether treatment in my current situation is better than disease or not.

[gnatcatcher]

... Without HCV treatment, with MELD < 11 my probability of being alive after 10 years looks like 80%. It is not very good, but it is not very bad too. Average probability of survival after HCC diagnosis is worse than 80% after 10 years. I had read that only half cases of HCC are resectable. Unfortunately, many cases requires liver transplantation or even non-curable. Of course, regular liver cancer screening significantly increases survival, but resectability also depends on many things - location of tumor, size, quantity of tumors...

Sergey, thanks for this information. To treat now or to wait is indeed a very difficult decision. Best wishes, and may you experience peace when you do decide.

Gnatty

[Sergey]

Gnatty, thank you! Best wishes to you too.

[Lynn K]

Hi Sergey

My understand is the incidence of HCC for those of us with hep c and cirrhosis are about 20% every year. However with cure that risk is reduced significantly not to he level of someone who never had cirrhosis though.

We will need to be monitored every 6 months with abdominal ultrasound an AFP testing likely for the rest of our lives for early signs of HCC so that it can be caught early hopefully allowing for a timely liver transplant.

Keeping the liver we were born with is the best option but if we cannot there is hope.

My platelet count is about 120 it has risen a little post treatment. I was dx with cirrhosis in Jan 2008 with a liver biopsy (my 4th I think) I have some edema and ascities and had enlarged blood vessels in my throat called esophageal varicies that I had have banded to prevent a possible life threatening bleed.

My MELD is about 7 not sure why yours is so high is your Bilirubin elevated? My lady Fibroscan was 27 my ALT was a little elevated but on my last blood week at 1.5 years post is almost in normal range I think it was 8.

Time you have very little choice to treat or not once you have cirrhosis you have a aerolitos medical condition which will only get worse over time. Plus with having cirrhosis we are that much more difficult to cure.

I hope you are being followed by a hepatologist associated with a liver transplant center as they are best equipped to advise and follow patients like ourselves with ESLD (end stage liver disease)

Anyway best of luck to you

[Gaj]

AASLD 2016 Abstract #19 - "Incidence and pattern of “de novo” hepatocellular carcinoma in HCV patients treated with oral DAAs"

edit: link and info regarding this latest study already provided in opening post.

[Lynn K]

Had trouble finding that one but ran across this

http://www.onclive.com/conference-coverage/aasld-2016/daa-therapy-does-not-increase-hcc-risk-in-hcv-patients

DAAs Not Associated With Increased HCC Risk in HCV Patients Monday, Nov 14, 2016

[Lynn K]

AASLD 2016 Abstract #19 - "Incidence and pattern of “de novo” hepatocellular carcinoma in HCV patients treated with oral DAAs"

edit: link and info regarding this latest study already provided in opening post.

Ok found it but bottom line of that abstract was:

"These results indicate that in cirrhotic patients the incidence of HCC during the first 6-9 months following initiation of DAAs therapy is not different from that expected in untreated patients according to historical controls. However, the atypical HCC pattern seen in about half of the cases deserves better understanding."

So basically for those who were already at risk of HCC because of cirrhosis the risk was still bout the same 6 months post per this study which to me isn't all that surprising the risk does not go away immediately or completely for those with cirrhosis post cure. And the other study I posted suggests there is no link

[Sergey]

Hi, Lynn!

My understand is the incidence of HCC for those of us with hep c and cirrhosis are about 20% every year.

I guess, HCC risk as 20% in a year for HCV-cirrhotics without previous history of HCC looks like awful lot, it is overestimated. 2-4% in a year is real, for example from study https://www.ncbi.nlm.nih.gov/pubmed/16729298. And yes, cure with interferon-ribavirin reduces HCC risk, from 2-4% to 1-1.4% in a year. But there is an uncertainty about HCC risks after interferon-free cure with DAAs. Some studies show that there is no additional risk compared to no-treatment (as cited #19 abstract, http://natap.org/2016/AASLD/AASLD_59.htm ), but some studies show increased up to 10% risks (as #1324 abstract, for example). And, it seems, nobody know real situation at this moment , because results of studies after DAA treatment are contradictory. This picture from another "pessimistic" study (http://www.journal-of-hepatology.eu/article/S0168-8278(16)30271-9/fulltext) may illustrate possible problem:



Your cirrhosis was very advanced - you had ascites and banded varices. Probably, it was on the edge of decompensation. Prognosis of decompensated cirrhosis without transplantation usually is poor - hence, treatment in such situations seems well-justified, for preventing of decompensation. I glad to see that treatment works in your case!
My cirrhosis looks not so advanced - no ascites, no varices, normal platelets and albumin. Rapid decompensation seems unlikely in a near year or two (if I will not get HCC). And, is it justified to undergo potential possibility of increased HCC risk after DAA-treatment in such situation? I am not sure... Bilirubin is my problem, yes. MELD is 8-9 due to bilirubin around 20. Last 2016 lab report show MELD 8, it was MELD 9 in 2007. There is possibility that such bilirubin is from some other relatively benign cause (for example, from possible Gilbert syndrome or cholecistitis or something like that). I planning to tell with hepatologist about bilirubin, it seems, it is better try to differentiate causes of such bilirubin. Otherwise, it may lead to overestimated MELD score.  Yes, I followed by a qualified hepatologist, but my cirrhosis looks not so advanced for including in a transplant waiting list.

Best wishes and good luck to you!

[Lynn K]

I do remember reading that 20% somewhere but it has been a while and I could be misremembering it.

I really do not believe curing our hep c puts us at increased risk of HCC there are studies on both sides of the issue.

What I do know is cirrhosis is a serious disease and puts us at the top of the list to have treatment for a reason.

Of course the choice is up to you and your doctor. I treated back when I was F1 with interferon mono therapy 3 shots a week of interferon and no other meds as even ribavirin was not being used at that time.

I wasted to rid myself of the virus before it could cause me further harm but was not successful treating two more times with interferon and now ribavirin then later with that combo and an experimental drug. But it all for nothing as I did not respond at all to treatment. In Jan 08 I was diagnosed with cirrhosis later that year Telaprevir was approved but my doctor would not treat me with it as it probably would not have worked and could cause me to decompensate but even with that I sought out a second opinion to see if they would agree to treat me so I went to UW medical center in Seattle but they also said not a good idea as it would be too dangerous for me.

So there I was having liver cirrhosis with no treatment available and waiting to decompensate for the next 6 years. I treated with Sovaldi and Olysio for 12 weeks when they were first approved and became not detected on treatment but at 12 weeks post in September 2014 I was found to have relapsed. I was later approved in Nov 2014 for Harvoni for 24 weeks and discussed with my doctor about adding ribavirin just in case I needed the extra kick to cure me.

I am not 1 year 6 months post treatment and was not detected at the one year post treatment mark so I am cured.

But even with all the drugs I have taken over the years in my fight against I did not grow an eye in the middle of my forehead or any other weirdness just kidding.

I really think you should treat before anything happens and as I said I think the risk of post treatment HCC especially for those who never had HCC before is over rated you are at higher risk of HCC by not treating than by treating IMHO

I did everything I could to cure my hep c.

Ball is in your court do with it what you want

Just to add the reason to see a hepatologist associated with a transplant center is a quality of care issue not to be placed on the list. I am not and never have been on the list. Your MELD has to be at least 12 to 15 to be on the list and most people who undergo transplant have MELD scores about 35 depending on which transplant region the live in. I hear for example it takes quite a while in California.

Yes maybe I was on the edge of decompensation but that could have still been years away or weeks or months hard to say. And my MELD has never been higher than 8.

The same could be said for you also weeks months or years no way to know.

Best of luck to you what ever you eventually decide

[Lynn K]

Found this about HCC risk

The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%, depending on etiology (it is highest in individuals with HCV infection)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338949/

Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma

[BillT]

 Sergey,That should have said "have had HCC OR have cirrhosis".Sorry about that.

[Sergey]

BillT, no problem, no need to apologize!

[Sergey]

The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%, depending on etiology (it is highest in individuals with HCV infection)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338949/

Yes, they get data from article https://www.ncbi.nlm.nih.gov/pubmed/15508101 (reference 1 in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338949/). More detailed,

"Hepatitis C virus (HCV) infection is associated with the highest HCC incidence in persons with cirrhosis, occurring twice as commonly in Japan than in the West (5-year cumulative incidence, 30% and 17%, respectively),"

Hence, 30/5 = 6% per year in Japan and 17/5 = 3.4% per year in the West. Like that.

[Sergey]

Lynn, your story and treatment history are impressive!

I was treated only with peg-rib in 2005-2006, shortly after being diagnosed with HCV and cirrhosis, and relapsed. I was lucky do not have possible serious negative consequences of peg-rib treatment too. Also, there was a chance to undergo treatment with telaprevir, but my hepatologist was not very enthusiastic about it. Taking into account my unfavorable IL28b TT/TG and other predictors, probability of SVR was around 40%, and mortality for cirrhotics was around several percents for telaprevir-based therapy. It was unclear - whether benefits of treatment outweigh possible harm or not, and I decided do not undergo such treatment (despite guidelines, which suggested that I need this treatment as soon as possible).

Of course, cirrhotics are in top priority for treatment, according to guidelines. But these drugs are relatively new and not well studied yet. We are like "guinea pigs" at some degree... Interferon was studied during decades, but DAA-only regimens are revolutionary new type of treatment. To be "guinea pig" or not to be "guinea pig" is a difficult decision for me. If decompensation will seems imminent in next several years, then, of course, treatment will seems well-justified for me. But, in a stable fully compensated state with 80% of 10-year survival... I don't know, I will think. Hope, some additional information about such issue with post-treatment HCC-risks will become available in a next several months. Otherwise, my precious generic drugs may start to expire

Thank you for your advices!

[Mugwump]

I decided to treat with cirrhosis for different reasons. There were times when my mental facilities were starting to go because of ongoing elevated levels of bilirubin. I began to feel like I had a permanent hang over. I was getting physically weak with extremely long periods where it felt like I had the flu.

This is the problem with cirrhosis it progresses differently in some people and can become very debilitating for a long period of time. Whereas other people succumb quickly.

My major concern other than HCC has been the increased probability of a GI bleed and sudden death from the weakening effects on the vascular system of the liver and especially the portal vein to the spleen. I was just starting to have the cirrhosis effect my level of platelets but the ultrasounds were showing the portal hypertension typical of advancing cirrhosis.

I could not wait much longer for safer treatments so for me the possible long term effects of treating in the late stage were worth the risks.

We must remember that those with cirrhosis were the hardest to achieve svr for a good reason. Our systems cannot respond and heal as well because of the degradation of liver functions. In my case I did not originally respond well to ribaviron in 2004 and the dosage had to be reduced as I almost was hospitalized with low blood counts.

I have know far too many who have died from this disease, two who died of liver cancer, one who took his own life and one who had a transplant and then the infection took his new liver. On top of this a few others, one who married someone who also had HCV and they both died of complications from the disease.

The chance for a cure for me far outweighed the risk of HCC post treatment, especially as I slowly became almost a shut in and began to lose hope of seeing my grandchildren grow.

[Lynn K]

The chance for a cure for me far outweighed the risk of HCC post treatment, especially as I slowly became almost a shut in and began to lose hope of seeing my grandchildren grow.

Amen Eric amen

[Sergey]

Hi, Eric!

Yes, if platelets goes low, and ultrasound looks like advanced cirrhosis, and there are various symptoms - it looks like serious arguments for treatment. It is very good that treatment worked in your case, and I hope you will be fine after treatment!

I do not have noticeable symptoms, platelets usually in range 170-230, and had planned to start treatment in october or november in this year. But, after emerging of new information about possible post-treatment HCC risks I decided to defer treatment (at least on several months) and wait for some new data about such issue.

Yes, HCV may lead to death, I know infected people who died from cirrhosis too... Almost all of them had quite advanced cirrhosis at the time of diagnosis. I dont know people who had F2 or F3 at the time of HCV diagnosis, maintain healthy lifestyle (no alcohol, no overweight), and after that died from complications of cirrhosis. Probably, it also depends on length of observation and treatment history.

On another relatively old big HCV-internet forum, I remember only one case of HCC without treatment since 2003, no cases after treatment with interferon. But, there are three cases in two years, after interferon-free treatment (two were transplanted, one resected - and situation after resection seems still not completely settled). It may looks like noticeable contrast between "interferon era" and "interferon-free era" (or may be just coincidence)... AFP rose in two of these three cases in 3 months after treatment - it looks suspicious regarding to link with treatment.

I hope that data from "pessimistic" studies about increased HCC post-treatment risks are biased or incorrect or incomplete. Otherwise, if I correctly understand, potentially, in a worst case scenario, situation with these risks "in worldwide scale" may turn into nightmare. One famous HCC researcher, prof. Jordi Bruix said, that if data about increased HCC risks will be confirmed, then some risk/benefit decision-making policy might be implemented (http://www.hepbcppa.org/wp-content/uploads/2016/09/HepBC-September16.pdf).

[Gaj]

To provide some perspective on the studies claimed as 'optimistic' or 'pessimistic' in the opening post:

'Optimistic'

- two studies consisting of 1,206 & 3,075 patients.

'Pessimistic'

- Two studies of 54 & 58 patients.

- One study where only 191 of 484 patients completed follow up.

- Plus one study from Japan, a country which already has twice the incidence of HCC per untreated patient population compared with the rest of the world. In this study 22 of the 69 patients had prior HCCs.

The levels of statistical confidence that could be applied to the results of these studies would seem to considerably favour the 'optimistic' ones.

Something else to keep in mind is that due to a lack of reliable treatment until very recently those with HCV are mostly an aging population that has now had this virus for 10 more years than they did in the mid 2000s. You would expect to see continuing higher incidence of cirrhosis and HCC in such a population. Treatment and SVR is the way to potentially short circuit that process.

[Sergey]

Compared to interferon-ribavirin treatment, I dont feel that study with 3075 patients is "optimistic"... It looks like "not worse than no treatment". They concluded in abstract - "These results indicate that in cirrhotic patients the incidence of HCC during the first 6-9 months following initiation of DAAs therapy is not different from that expected in untreated patients according to historical controls." Also, they reported about unusual aggressive HCC pattern and 8.4% HCC in patients without SVR12. 8.4% is very high, these two findings not seem as "optimistic".

"Optimistic" study ("not worse than interferon") with 1206 patients is not "real-life-only" study. They included participants of Phase 3 trials. And, possibly, these participants may were selected by Big Pharma drug producers, with the aim to make their new drugs look better. For example, one guy, who was treated by Vikeira Pak in clinical trial had said that past history of any oncological disease was an "exclusion criteria" in his trial. Of course, in a real life many HCV-infected patients had past history of oncological diseases. Probably, Big Pharma may select people with favorable characteristics for their trials.

About "pessimistic" Japan study with 69 participants - yes, 22 patients had prior HCCs, but it was reported 5 new HCCs.Hence, 69-22 = 47 without prior HCC. 5 / 47 = 10% - in is higher than 6% per year in untreated people in Japan (let alone 1-1.4% per year after interferon-ribavirin).

For me, it is difficult to draw final conclusion about this issue with available controversial data at current moment. These trials are vary significantly by many things - inclusion/exclusion criterias, age of participants, race, previous treatment history etc. In fact, we have several small independent trials, which show unexpectedly high posttreatment HCC rate. There was no such thing with interferon-ribavirin treatment. Something is going on there, and I feel that we need to be very cautious. There are many questions without answers - probably, time will tell...

[andrew j]

Yes - but you're sitting on F4 / compensated cirrhosis! All sorts of things can go wrong!!
You've been lucky so far, and you seem to be in reasonable health - but if complications do develop, or something else goes wrong, you won't necessarily be able to reverse the condition you find yourself in.
Try to stand back from this a bit, and don't over-think it!
The vast majority of people in your situation have treated, and are now doing well.
You know?!

There are two posts on the homepage you might be interested in:
'Treating Hepatitis C When You Have Cirrhosis' (June 17, 2016), and
'Curing Hep C Lowers Liver Cancer Risk, But May Increase Severity of Cases' (posted in the last couple of days - Nov. 23).
... Maybe that's the middle-ground you're looking for?

[Sergey]

I dont feel that all sort of thing may go wrong... Mainly, only two bad things may occur - decompensation or HCC. Decompensation from fully compensated beginning cirrhosis, usually, looks like relatively slow process, it may require years. If liver function will become worse (actually, it is stable from time of diagnosis, during 11 years), probably, it will be an opportunity to start treatment, for preventing decompensation. Because of this, at present moment, I don't feel strong desire "to play with fire" regarding to not well studied HCC risks. If some sort of unusual aggressive HCC after treatment will occur, it may require urgent transplantation, for example. It may be very difficult situation.

Of course, majority of people do not have significant problems after treatment. But, for example, possible 10% HCC per year (hope, these data are incorrect) seem unacceptably high for me. Thank you for links, I don't know, really... Maybe, coin flip will help to make decision (just joking). Probably, I will wait for more confident and conclusive data. Since April 2016, new controversial publications occur every several months.

[gnatcatcher]

Waiting for inner clarity makes sense to me, Sergey. No one on this forum thread has walked in exactly the same shoes as you. From my experience with a different major diagnosis twenty years ago, I had an image of standing in front of two closed doors, each of which hid a horrible future outcome for a certain percentage of patients, and it was up to me to choose to open one of the two doors. You'll know inside yourself when it is time to decide. Here's hoping that you can feel, despite our limited ability to help, that we are all wishing you the best possible outcome.

Gnatty

[Sergey]

Yes, Gnatty, thank you. I feel like that - a bit tough choice between two alternatives. Appearance of DAA generics brought relief to many HCV-infected people, modern treatment is much more available now and often may be initiated in any moment. I see, this forum is very helpful and there are many kind people in this forum. Mutual support, advices and sharing of "real-life" experience and opinions in forum are really helpful.

[Sergey]

Study from EASL-2016 - http://www.natap.org/2016/EASL/EASL_76.htm, more than 1000 had cirrhosis. 6.6% HCC in first year after treatment initiation and 1.9% in second year.

Comment from prof. Bruix:

"Interestingly, a French cohort that has been prospectively followed for several years described that the HCC incidence after DAA decreases after 12 months of successful therapy. However, the incidence during the first year in the study was around 6%, which is clearly in excess of the incidence that was predicted in the same cohort (1.9%) when DAA were not available. Hence, it may be that what has been observed is an unexpected increase after treatment, while later on, the risk would have returned to baseline. The description of the incidence within the 6-12 months prior to DAA would have allowed a clearer understanding of these results. "

I guess, if we want to see only relatively big studies, having >400 patients with cirrhosis, for confidence in statistics, then, average results, probably, tends to "worse than after interferon, but not worse than no treatment". Possibly, with additional risks in first 1-1.5 year after treatment initiation, due to reported 6.6% HCC in one study and unusual aggressive HCC pattern in another study. It is just a guess...

[Mugwump]

If it turns out that there is an increased risk of HCC by quickly healing the liver then a rational explanation of why this happens could very well be the natural production of several interferon types in the liver when under attack by HCV.

It would be very scary if HCV itself actually promotes the production of agents that can keep the victim alive. We know that it messes with the immune system, exactly how over the course of infection is not well studied.

So just perhaps there are other agents that can be used temporarily to wean the liver off being infected with HCV if this is the case. As I have theorized in other threads HCV might indeed hold secrets that could lead to other drugs that can treat other diseases.

All the best in what ever you decide regarding treatment Sergey!

Here is one of the reasons why I decided not to wait.
Seeing the smile on my wifes face when she held her first granddaughter, a strapping 8lb 10 oz grand child!
I truly hope all here are as blessed as I feel today!
Eric

[andrew j]

I am, as it happens, thank you, Eric!

Hey - congrats on the new arrival!

What a CUTE baby!

[gnatcatcher]

Grandpa Mugwump, congratulations!

[Sergey]

Eric, congratulations! Beautiful baby!!!

[Philadelphia]

Congrats Eric!!

[Lynn K]

Congrats Grandpa Eric!

[Sergey]

It would be very scary if HCV itself actually promotes the production of agents that can keep the victim alive.

Yes, it may be scary... Some studies show that DAA treatment may downregulate our innate interferons:

"Further explanations are that major mechanisms for regeneration are stimulated by curing inflammation, and the changed immunologic environment compared to treatment with IFN-containing treatments leading to growth of precancerous lesions or of small malignant cell clones [9]. Interferon is an immune modulator with anti-proliferative properties. With IFN-free treatments, it has been shown that the rapid disappearance of HCV leads to reconstitution of innate immunity [10] and downregulation of type II and III IFNs, their receptors, and interferon stimulated genes [[11], [12]]. The lack of interferon activation may allow growth of malignant cells. Another factor involved may be miR-122, which plays a central role in suppressing viral replication and controlling hepatocarcinogenesis [[13], [14], [15], [16]]. miR-122 concentrations decrease on IFN-free DAA therapy, in serum levels [17]." (http://www.journal-of-hepatology.eu/article/S0168-8278(16)30271-9/fulltext)

Prof Bruix said:

"A relevant aspect to investigate in this situation is what could be the mechanism for an increased cancer emergence (primary or metastatic) after DAA therapy. The most likely one is the immune distortion due to the rapid viral load reduction that abruptly changes the inflammatory profile of the infected liver and of the entire human body, too. A sudden immune surveillance impairment may allow existing preclinical cancer clones to grow and become clinically detectable. The extent of such cancer emergence will not be homogeneous, as some patients may have few subclinical clones just within the liver, while others may have a more extensive spread as it is known that the metastatic process is very complex. If such immune impairment is real, the concern about unexpected neoplastic events should go beyond the liver cancer problem."

Hence, if I correctly understand, potentially, in a worst case scenario, increased probability of other types of cancer may be possible. It may require big long-term trials for determining or refuting of such things and seems not well studied at current moment...

It is interesting, are interferon-containing regimens with inhibitors (for example, peg+sof+rib) safe than DAA-only regimens, regarding to HCC risks or not?.. If yes, then, possibly, some addition of interferon to DAAs may protect IFN-eligible cirrhotics from cancer risks (just a guess)...

As I have theorized in other threads HCV might indeed hold secrets that could lead to other drugs that can treat other diseases.

Interestingly, some researches about modified flu virus are already underway - https://www.sciencedaily.com/releases/2016/04/160414114151.htm

"Further modifications will also be made to enable the virus to trigger the body's immune system, which will attack any cancer cells that have not been infected by the virus."

[Mugwump]

Thank you Sergey for the leg work on this. I have a history of pre cancerous melanoma on my face, call it "fly fisher's" nose syndrome or whatever. Here is hoping my liver is still beat up enough to keep producing the goodies that keep this problem at bay!

Either way I sure as hell do not want HCV back.

The problem with working with HCV is that the encapsulation of the rna is the key to how it works and changing the encapsulation to change the virus neutered state the way that is necessary with other inoculation agents is turning out to be a dead end with HCV. So creating agents with HCV might just be impossible. However the study of exactly what the viral rna sequence does to MAPK and other proto proteins during an infection could very well lead to some interesting findings that might just hold the key to curing other diseases.

Interestingly there are other slightly more complex pathogens that can do strange things. For instance there are primitive agents in cat urine and feces that effect rat behaviour to the extent that rats become easier to predate for the cats!

So I see no reason why HCV may not have properties that defend the zombie host against competing diseases and are symbiotic in equally diabolical ways that Toxoplasma gondii is! 

Stay healthy and let us hope that this puzzle can be solved very soon. I am sure there are greater minds working on it as we speak.

Cheer
Eric

[dragonslayer]

Here's an article I just saw that reports on the Alberti study.

http://www.hepatitiscentral.com/news/previously-unforeseen-risk-tarnishes-hep-c-wonder-drugs/?eml=hepcen257#comments_area

Recapping a couple of the major points:

"The incidence rates of liver cancer were no different in those who
received direct-acting antiviral therapy and those who did not receive
the therapy."

What it did say is that in previously undetected hepatic carcinoma, the tumors can be more aggressive:

 "Alberti and his colleagues hypothesized that when viral replication is
halted, dramatic changes in the immunologic and molecular
microenvironment occur in the liver, which impact tumor suppression
mechanisms. This change allows or promotes the growth of previously
undetected liver cancer cells."

which seems to be consistent with whats been reported in other studies.

More info on that study:
http://www.onclive.com/conference-coverage/aasld-2016/daa-therapy-does-not-increase-hcc-risk-in-hcv-patients

[Mugwump]

Further to the extra-hepatic manifestations of HCV. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659909/
Clearly it is know that HCV does effect the moderation of thyroid functions.
And that treatment with Peg Interferon can exacerbate thyroid dysfunction.
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1413-86702011000400013

But what if the insidious nature of HCV was such that it caused mild anti-thyroid responses early on during infection? It is possible that this simple change would disrupt the normal TSH cycles of individuals in a mild fashion and over stimulate the thyroid gland of infected individuals. These changes would go completely undetected and would have slight effects on the human personality because of a slightly increased production of thyroid hormone. Later as the victim ages the thyroid degrades and then the long term effect of anti-thyroid hormones is, as in Graves disease a deficiency of thyroid function in advanced thyroid disease and hence hypothyroidism.

My problem for very many years perhaps all the way back to my late teens and early twenties was mild ongoing symptoms of hyperthyroidism. Not enough of an effect to be on the level of clinical autoimmune thyroid disease but certainly enough to have a qualified endocrinologist diagnose me with Graves disease in 1990.

This leads to the serious question of why this imbalance can occur and why could it be that HCV might benefit from the individual being mildly hyperthyroid for long periods of time?

At times in my life I had what I call Superman Syndrome. Physically I could work for long periods and eat like a horse where other normal individuals would need greater rest periods. So I was a workhorse.

The down side of this aspect of being slightly hyperthyroid all the time is that your mind races and you are far too prone to be a risk taker because your thinking processes are also accelerated along with the physical metabolism.

What possible advantage would HCV gain from this aspect of the infection?

For one it would make the individual more prone to engage in activities where blood might spill.

My personality to others, always seemed to me that others thought I was spoiling for a fight! Even though I was a bit of a rational "peacenik" especially during my formative years when I could have gone into the military

What I am theorizing here is that HCV has also developed mechanisms to effect the hosts in ways that would make the disease spread and be favorable to the dispersion of the virus in situations especially where humans were prone to tribal conflicts.

So in conclusion if HCV has logically evolved along with human conflict to take evolutionary advantage of our propensities for blood sports just perhaps if we eradicate the disease this might help moderate our penchant for war in the very long term.

A long shot at best but very much worth studying as it becomes possible to eradicate HCV from the general populace. The insidious extra-hepatic manifestations of HCV are huge and rob us much in our lives, much of which goes unnoticed even by the victims.

Cheers
Eric

[Mugwump]

Sorry about the long edited last post on this thread.

The reason why I am keenly interested in the extra-hepatic manifestations of HCV are easily explained by the whole premise of this train of thought;

One must consider that it took HCV thousands of years to evolve and that the prevalent mode of transmission of HCV is direct blood to blood contact amongst humans.

So my supposition is that it has evolved to take advantage of human conflict where direct blood to blood contact can occur more readily. Then with the advent of of blood transfusions before the knowledge of serum hepatitis was know, HCV was given an evolutionary boost to the point where it seemed to become a sudden epidemic. Whereas without this sudden evolutionary boost HCV most likely would have never become anywhere near as wide spread amongst diverse populations.

A simple hypothesis based on how HCV may have evolved and only then become wide spread starting in the middle to late 20th century. If this is the case HCV has most likely been with us since we first started killing each other on mass. The other suppositions of the virus coming from sexual contact with other primates and animals is a very flawed and silly hypothesis. The same nonsense was claimed with HIV and discredited. However this stupid hypothesis is still believed by some which is extremely unfortunate. 

In my case the extra-hepatic manifestations were very long term and seem to have taken hold early on in the infection and worsen only very slowly over very many years.

Interestingly it may very well be that a natural response to some diseases is to boost thyroid stimulation with a temporary upsurge of thyroid antibodies. However the way in which HCV does this is much more insidious and long term, some studies have shown that over 50% of hcv rna serum positive individuals also have elevated levels thyroid antibodies to some extent which seems to vary over time.

How HCV has messed with us as species over time is a very interesting and extremely diverse topic IMO.

Cheers
Eric

[Sergey]

Here's an article I just saw that reports on the Alberti study.

http://www.hepatitiscentral.com/news/previously-unforeseen-risk-tarnishes-hep-c-wonder-drugs/?eml=hepcen257#comments_area

Yes, there are many articles in media about Dr. Alberti's study (abstract 19 on AASLD)...

Recently, recommendation of PRAC (European Pharmacovigilance Risk Assessment Committee) was published:

"The PRAC also reviewed the available data on liver cancer (hepatocellular carcinoma) in patients treated with direct-acting antivirals and concluded that further studies should be carried out before firm conclusions can be drawn. The Committee will continuously review any other new data as they become available."
(http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Direct-acting_antivirals_indicated_for_treatment_of_hepatitis_C_(interferon-free)/human_referral_prac_000057.jsp&mid=WC0b01ac05805c516f)

[Sergey]

So I see no reason why HCV may not have properties that defend the zombie host against competing diseases and are symbiotic in equally diabolical ways that Toxoplasma gondii is! 

Yes, and recent messages about possibility of HBV reactivation and Herpes virus reactivation after DAAs treatment may suggests this.

[Sergey]

My problem for very many years perhaps all the way back to my late teens and early twenties was mild ongoing symptoms of hyperthyroidism.

It is interesting, Graves's disease, usually, is quite rare among men. Women have much higher probability to have it. It looks as difficult question - whether HCV is able to promote human's risky behaviour for further spreading of HCV infection or not. We cannot exclude such possibility...

Of course, it will be very beneficial "to eradicate HCV from population". But we need cheap and safe well-studied drugs for this aim... Currently, it seems, we have "not well studied" drugs. Possibly, as a result of big "worldwide eradication" plan, tens of millions of HCV infected people may become "guinea pigs" on not well studied drugs... In my understanding, it may be controversial...

[Mugwump]

It is interesting, Graves's disease, usually, is quite rare among men. Women have much higher probability to have it. It looks as difficult question - whether HCV is able to promote human's risky behaviour for further spreading of HCV infection or not. We cannot exclude such possibility...

Of course, it will be very beneficial "to eradicate HCV from population". But we need cheap and safe well-studied drugs for this aim... Currently, it seems, we have "not well studied" drugs. Possibly, as a result of big "worldwide eradication" plan, tens of millions of HCV infected people may become "guinea pigs" on not well studied drugs... In my understanding, it may be controversial...

This and many other reasons is why treating the disease early on even before any signs of liver damage is the best solution. If we are onto something here then the development of symbiotic processes with the disease if stopped early on before the onset of all these extra hepatic manifestations should have very little risk for the individual.

This is why the current insurance problems are terrible! They think only in the short term cost factor instead of what the long term costs of waiting till the person has pronounced liver damage and the possibility of developing HCC and the other deadly consequences of cirrhosis.

Two of the people who I have know who had HCV and died from the complications of cirrhosis had GI bleeds from weakening of the portal vein, another two died of HCC and a fifth died of weakening of the cardio vascular system. All died short of 60 years of age and cost millions in total health care dollars not to mention the pain and suffering of their families and lost income over their lives because of this disease.

So it only seems sensible socially to treat very early on with this disease. The moment that the diagnosis of a chronic infection is reached as soon as a positive viral load is discovered before the disease can develop prolonged extra hepatic manifestations. For one this shortens the treatment duration and costs for two over time this approach will reduce the possibility of new strains of DAA resistant strains appearing in the wild and most importantly it is the only way to possibly eradicate this disease for good.

Stay healthy Sergey and I truly hope that you do not progress past F4!

All the best
Eric   

[Pete]

Hi everyone - Some of you likely know a bit of my HCV experience, to others this may be a new story.

I've been reviewing this post for awhile now and have been wanting the chime in, but my histology is long and I up end rambling on (riba) when I attempt to reply here.  I'll try to highlight milestones to keep it brief.

HCV 1a
F4 - Compensated Cirrhosis Child Pugh A
Failed Harvoni July 2015
HCC confirmed March 2016
Currently treating with VP/Riba

Dec 2014 - Treatment naive at this point. Complex liver cyst (3.4 cm) discovered during CAT scan.  Blood test for tumor markers are negative for HCC

April 2015 - Start 12 weeks Harvoni

June 2015 - End treatment, undetected for virus. 

July 2015 - Harvoni treatment failed, virus alive and well. Follow up CAT scan shows lesion is now reduced in size 50%.

Early 2016 - New scan reports lesion has increased in size to 4.0cm. Rejected for Abbvie trial due to increase in size of liver lesion. 

March 2016 - Liver Surgery / resection upper left lobe and RF ablation of newly discovered smaller lesion 8mm. Pathology report confirms HCC.

Turns out I'm in the 15% that does not respond to AFP testing, nothing shows up.  Also negative were Cancer Antigen 19-9 (VMMC) and Carcinoembryonic Antigen Level tumor markers.   My doctors were pretty certain I did not have HCC until surgery confirmed the contrary.  Which is really a drag, as I've no way to monitor HCC with a simple blood test.

June 2016 - Begin 24 weeks Viekira Pak/Ribavirin

Sept 2016 - MRI indicates area in surgical bed "suspicious" of HCC but not confirmed, recommends another scan in 60 days.

I have to tell ya, I was pretty convinced things were going down hill fast at this point. 6 months post surgery and the cancer appeared to be back... I became very depressed, slept alot, didn't eat much, and basically withdrew from everyone.

I read something about high dose curcumin supplementation having stopped the advance of HCC and reducing tumor size to almost nothing in one clinical trial (in 1 patient)  Apparently curcumin is not well absorbed, so high doses are needed for any chance to have an anti-cancer effect.  I figured I had nothing to loose, so I gave it a shot.

Oct 2016 - Started supplementing Curcumin working up to 7.5 grams/day taken with olive oil for 5 weeks.  Stopped one week prior to follow up MRI.

Nov 2016 - MRI results indicate all areas of liver previously of concern are now  stable, no sign of HCC or new lesions. (Praise Jesus!)

Dec 2016 will end VP/Riba (3 more days) Now the waiting begins again.

March 2017 - Next MRI scheduled 

I clearly had HCC prior to any treatment.  Time will tell if duel treatments of DAA's  cause it's return or if it will simply return on it's own terms.  There's now way to tell. I'm simply a statistic now. 

Also, I'm not entirely convinced the 5 weeks of high dose curcumin improved anything (other than my bowel function ) as radiology reports may vary, particularly when terms like "inconclusive for" and "suspicious of" are used in the report.  I will likely continue the curcumin off and on every few months.  If nothing else, placebo effect?

 I'm trying to remain cautiously optimistic going forward. However, I've have not really been able to snap out of my funk.  I'm sleeping more/less normally now, but still somewhat lethargic in many respects.  Maybe the treatment drugs, 24 weeks is a long time. I wonder how long it takes to clear these meds out of you system.  I recall reading somewhere ribavirin can take up to 6 months.  Joy...

Take care,
Pete

[andrew j]

Scary stuff!

Thoughts and prayers, then? ... and hoping that those little b*stards are gone - and stay gone. All of them!

I reckon you're right about that curcumin, Pete.
Some friends gave me some curcumin root a while back (a yellowy / orange root?) - and I used it a few times in cooking.
It's got an interesting taste - and it did feel as if it was doing good work!

I am learning to make curries.
I've always thought that a healthily produced curry is a good thing for the liver.
I use a lot of turmeric!

Best of luck in these uncertain times, eh?
We are with you, and for you (of course)!

Best wishes,
A.

[Luna7]

I read something about high dose curcumin supplementation having stopped the advance of HCC and reducing tumor size to almost nothing in one clinical trial (in 1 patient)  Apparently curcumin is not well absorbed, so high doses are needed for any chance to have an anti-cancer effect.  I figured I had nothing to loose, so I gave it a shot.

Oct 2016 - Started supplementing Curcumin working up to 7.5 grams/day taken with olive oil for 5 weeks.  Stopped one week prior to follow up MRI.

Also, I'm not entirely convinced the 5 weeks of high dose curcumin improved anything (other than my bowel function ) as radiology reports may vary, particularly when terms like "inconclusive for" and "suspicious of" are used in the report.  I will likely continue the curcumin off and on every few months.  If nothing else, placebo effect?

Hi Pete

According to this article, adding black pepper will increase turmeric absorption:
   http://www.turmericforhealth.com/turmeric-benefits/health-benefits-of-black-pepper-and-turmeric

Here's a good recipe to combine the two, called 'golden paste'
 http://www.turmericforhealth.com/turmeric-recipes/how-to-make-turmeric-paste-or-golden-paste

I've had the organic turmeric and peppercorns sitting in my kitchen for a couple months...and it's time to make this recipe!

While you will find some that say curcumin (the substance derived from the turmeric root with the anti-inflammatory properties) is the better choice, I prefer the entire plant (turmeric root) in order to receive whatever benefits might be available in the entire plant, even some elements we might not be aware of yet. And again, the black pepper will increase absorption.

TC,
Luna

[AllShookUp]

Hey Pete

Sounds like you have been on a real bummer of a roller coaster ride. Hopefully it will smooth out for you soon.

From my personal experience, it took about 4 weeks before noticing some relief from the Riba. At 8 weeks much better and at 12 weeks I thought I was back to "normal". Now it is just another distant memory.

In regards to supplements beyond delicious curries (which I love but am too lazy to cook) I found some recent studies about HCC suppression and zinc which sound promising.

This link is from Nov AASLD 20016 - be sure to click the continue to read in green fonts at bottom

 https://hepatitiscnewdrugs.blogspot.com/2016/11/aasld-2016-study-eyed-zinc-for-slowing.html

This next link is a real mind bender

http://airccse.com/caij/papers/3116caij02.pdf

I am going to ask my liver man about zinc when I see him in March for my biannual liver MRI results. Imagine that a small sliver of a currently minted 1 cent coin could suppress HCC.

And while we are talking about metals lets jump up to gold for a possible cure -

http://medicine.missouri.edu/news/20161129-nanotechnology-a-green-approach-to.php

[Pete]

Thanks for the positive energy friends.  Finished my last dose of VP/Riba.  Sure glad to have that checked off the list.

Turmeric - I too receive the turmeric for health newsletter.  Great info. The benefits of this wonderful root seems endless.  While poor absorption is commonly noted, taking with piperine is reportedly one method to increase absorption.  However...

Be careful taking piperine when using certain drugs, including DAA's

Piperine is commonly known for increasing absorption with some substances. What is less known, is that Piperine may reduce bioavailability of other substances.  For example, Ritonavir (contained in viekira pak) is among substaces that may have reduced bioavailability with piperine.  Worthy of note is that every drug contained in VP ends in the suffix "vir".  I posted this link in another topic on this forum, here it is again for anyone who may have missed it. 

See table 2 in the article linked below
http://www.delano.com/blog/?p=70

Although my doctor told me it would be OK to use turmeric, she did not mention anything about piperine precautions.   

Thanks for the links on zinc/HCC.  I was unaware for those studies, really good to know.  I do know that too much zinc is reported to be harmful.  So yet another supplement to be careful with.

If this round of treatment fails, it will likely be the last experiment with DAA's for me.   While my fingers are crossed, I know there are no guarantees. Those of us living with this wicked virus for decades without a cure, are at a higher risk for liver cancer,  particularly if cirrhosis has developed.  It is frightening to think that for some of us, these wonder drugs may end up being our demise.  Now that would indeed suck.   

Sergey, sounds to me you are leaning towards waiting on treatment.  Not a bad call, all things considered.  Whatever you choose to do, you will certainly be well informed. You have obviously done your homework on this subject.  Nice work and great post, very informative.   Good luck and be well.

Be well,
Pete

[Sergey]

Hi Pete!

Hope you will be well after treatment, without HCC and with permanent SVR!
All HCC situations are quite serious... Yes, it seems, you definitely had HCC before first treatment. It is interesting information about circumin and zink. I had read recently, that relatively low body weight (BMI < 23) may reduce probability of HCC after DAA treatment - https://www.ncbi.nlm.nih.gov/pubmed/27694754  Now, I started to reduce body weight using dietary restriction of carbohydrates. Also, some data exist about preventive effect of bloodletting (phlebotomies), mainly from Japanese studies. For example - https://www.ncbi.nlm.nih.gov/pubmed/25743000, https://www.ncbi.nlm.nih.gov/pubmed/17940836/ But, of course, phlebotomy is a serious procedure, with many contraindications and possibility of adverse effects - due to effect on cardiovascular and other systems. It requires strict monitoring of haemoglobin and ferritin. Probably, phlebotomies are contraindicated for many patients with cirrhosis, due to risks of worsening of liver disease. I performed phlebotomies several years ago without significant side effects, by 200 ml every two weeks until ferritin < 20 or haemoglobin < 130. But my cirrhosis is beginning, it may be contraindicated with more advanced cirrhosis.

Really, yes, I tend to some waiting... I already waited during many years without significant problems... Also, consultations with several hepatologists are planned, to hear their opinions.

Good luck and best wishes,
Sergey

[Sergey]

Another relatively big study from AASLD about HCC incidence after DAA treatment with sofosbuvir, possibly sponsored by Gilead - http://natap.org/2016/AASLD/AASLD_140.htm More than 3500 patients with cirrhosis. Looks like "not worse than no treatment, but worse than after interferon-ribavirin". Probably, they excluded people with HCC, diagnosed during treatment - it may reduce HCC incidence.

[Sergey]

This and many other reasons is why treating the disease early on even before any signs of liver damage is the best solution. If we are onto something here then the development of symbiotic processes with the disease if stopped early on before the onset of all these extra hepatic manifestations should have very little risk for the individual.

This is why the current insurance problems are terrible!

Yes, insurance problems are terrible, this is a big problem... It is unethical to restrict access to these drugs. All people in the world should have easy access for modern HCV treatment, regardless of fibrosis stage.

In my understanding, another serious problem - that these drugs are not well studied. We dont know well long-term consequences of treatment. For example, if our innate interferons are downregulated after treatment - potentially, it could lead to increased probability of some other diseases (in worst case scenario, like cancer). If our lipid profile is changed due to treatment - potentially, it could lead to risk of cardiovascular problems. One recent article recommends monitoring of lipid profile after DAA-treatment (and, possibly, correct it, if necessary) - http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163644 From one side, yes, treatment at early stages looks much safer, from the other side it is still experimental at some degree... Just as a guess - for example, some 70 years old patient may have mild fibrosis during 20 years, practically without worsening of fibrosis. It is unlikely that he will die from complications of HCV-induced cirrhosis. But, if treatment will disturb his innate interferons and/or lipid profile - it could potentially lead to serious diseases - and, possibly, its harm may outweigh benefits of HCV treatment for this patient... There is a bit scary article about such issue (maybe, overly "pessimistic" sometimes) - http://www.openhealthnews.com/story/2015-01-18/lack-good-medical-evidence-new-100000-hepatitis-c-drug-treatments

Another problem is that progressing of HCV infection without treatment and extrahepatic manifestations  also seem not well-studied... Many HCV-infected people have history of risky behaviour (intravenous drug use etc.) or history of serious medical problems, which had required blood transfusions. And group with statistically higher prevalence of people with unhealthy lifestyle (intravenous drug use, alcohol, smoking) or with history of serious medical problems - in average, will have an increased probability of various diseases, even without HCV. And some of these various diseases may be named by researchers as "extrahepatic manifestations" of HCV, despite real cause of such diseases may be a risky behaviour, for example... Also, knowledge itself about having HCV may lead to stigma, depression, which may lead to sleep disorders, cognitive disturbancies, brain fog etc. It may be simple psychological issue, instead of real influence of virus. This does not mean that extrahepatic manifestations are not exist at all - really, some serious diseases (for example, like cryoglobulinemic vasculitis with damaging of kidneys) certainly looks as extrahepatic manifestation, they usually improve or disappear after successful HCV treatment. So, all "picture" looks a bit "experimental" for me...

With warm wishes,
Sergey

[Gaj]

Hi Sergey, a couple of points to consider:

1).

"despite real cause of such diseases may be a risky behaviour"

You make many similar statements in other ways in the same paragraph. Please remember that HCV is a virus that is acquired (and progresses) in many different ways, I don't believe making assumptions and 'value' judgements about patients assists the discussion.

2). The AASLD study you referred to http://natap.org/2016/AASLD/AASLD_140.htm seems to arrive at different 'Conclusions' to the ones you make. That's fine, everyone is entitled to their opinion but may I suggest that a more appropriate approach in that situation is to state what their conclusions are and then argue your case for your interpretation of the data.

[Sergey]

Hi Gaj!

1. I feel that issue of quality of evidence about progressing of HCV /extrahepatic manifestations is important for me. If evidence is not strong, this fact may ease some fears and affects treatment decision. In my understanding, many studies show association between various diseases and HCV, but association does not necessarily mean "causative relation". Of course, this does not mean that extrahepatic manifestations do not exist "at all".

the association between hepatitis C infection and premature mortality has not been shown to be causal (i.e., in her words, an “extrahepatic effect”); patients are infected for particular reasons (e.g., risky behaviors or a need for blood transfusions) that, in and of themselves, can result in premature mortality.

- http://www.bmj.com/content/350/bmj.g7809/rr-8

2. Can you clarify your opinion? Do you feel that  "Looks like not worse than no treatment, but worse than after interferon-ribavirin" significantly differs by meaning from study's conclusion "adjustment for these covariates demonstrates no increased risk of incident liver cancer associated with SOF treatment vs no treatment"?

[Gaj]

1. My point was not about whether EHMs exist or not. It was that you appear to be blaming the patient repeatedly via some form of moral judgement about their behaviour. That you were able to quote someone in BMJ with the same attitude does not really surprise me that much.

2. For clarity: In my opinion your conclusion does not accurately reflect the paper's conclusions. At no point do they state "worse than outcome after interferon/ribavirin" or anything that resembles that.

Again, I would request that when you link to data please don't include your own editorialised views in quotation marks so that they can be mistaken for a quote from the paper. That may be misleading to readers.

[Sergey]

Hmm.... Moral judgement? Gaj, I don't understand your point of view about this question. Where is the "moral judgement"?

Today, most people become infected with the Hepatitis C virus by sharing needles or other equipment to inject drugs. Before 1992, when widespread screening of the blood supply began in the United States, Hepatitis C was also commonly spread through blood transfusions and organ transplants.

(https://www.cdc.gov/hepatitis/hcv/cfaq.htm#cFAQ31)

For me, it is not a "moral judgement" or something like that, it is a fact. Big randomly selected group of HCV-infected people will have higher percent of patients with history of intravenous drug usage (risky behaviour), higher percent of patients, that had transfusions of contaminated blood many years ago - than average in population (because intravenous drug usage and transfusions of contaminated blood are significant mechanisms of HCV transmission). Arguments about issue of quality of evidence about extrahepatic manifestations are based on these facts.

In my opinion your conclusion does not accurately reflect the paper's conclusions. At no point do they state "worse than outcome after interferon/ribavirin" or anything that resembles that.

Yes, because they did not compare results of their study with HCC rate after interferon-ribavirin, they compared results only with "no treatment". For clarity, such comparison in my post is based on known HCC rate after successful interferon-ribavirin treatment (1-1.4%), compared to known HCC rate without treatment (2-4%, up to 6%). Hence, probably, it should looks as two fold decreasing of HCC rate after treatment, to be "not worse than after interferon-ribavirin". In their study, before adjustment, HCC rate after SOF-containing treatment was worse than "no treatment", after adjustment it looks not worse than "no treatment", but it does not look as two-fold decreasing:

[Mugwump]

What we are forgetting to take into consideration here is that the numbers of warehoused patients with advanced liver damage suddenly being cured is going to increase the numbers who go on to develop HCC and the other nasty consequences of having HCV eating away at the liver.

This is why the insurance mantra of waiting till someone has advanced liver disease before using a DAA has to be dismissed for what it is. Penny wise, pound foolish. This approach to treatment actually increases the treatment duration needed and will increase the numbers that go on to develop HCC. Perhaps some are actually betting Trump and the conservative right wing nut jobs will completely scrap everything and they will be able to go back to denying coverage to those with diseases again!

But for now until we know how this all works out it seems to me that most who have HCV should get treated asap because you cannot know what is going to happen in the next few years to any degree of certainty. Regarding both future treatment availability or how HCV will effect you in the long term.

In my case it took over ten years to advance from f2-3 to f4 compensated. BUT it only took < 2 years for the level of compensation to swing down to a level where my bilirubin spiked and I began having symptoms of advancing hepatic encephalopathy from the levels of toxins that my impaired liver was putting into my system. Curing HCV has changed this aspect of cirrhosis and was the most important consideration for me.

[andrew j]

Absolutely, Eric.

[kimlav]

The biggest and greatest thing about being cured is that my blood is no longer toxic to others!!  Good lord, it is a no brainer in this day and age to get treatment! I did Harvoni for 8 weeks and ok, I gained 10 lbs., so what - very few side effects - still have the 10 lbs. - my blood isn't toxic to others any longer. AND my liver will recover. Treat Sergei!

[Kdog91711]

Hi,
I'm new to this whole message board thing but I felt I would be remiss not to share my experiences since I too was scared and overwhelmed by all the info that as of late has been evolving so quickly. My quick history: diagnosed with Hep C geno 1a about 15 years ago at age 32. Had been carrying for at least an additional 7-10 years. I had no daily symptoms and was lucky that my first gastroenterologist had told me at the time that there were some real game changing treatments in development (I.e. Harvoni, etc.) and that since I was stable I would be best advised to not to try interferon based treatment. Fast forward to 2 years ago and the recently approved new treatments. Blood work had me with a viral load around 8 million, biopsy revealed some cirrhosis and stage 3 liver damage. I started ribravin and Veikira pak treatment scared and unsure. Initial side effects were mainly gastro and moodiness. I managed the moodiness and anxiety with a small dose of xanax which helped a lot and kept my anxiety in check enough that I would stay the course. I had a concurrent diagnosis of diverticulitis which made the gastro side effects difficult but I kept it in perspective. A couple months of gastro unease was a small price to pay for being cured. My viral count dropped to the low thousands within a few weeks and was undetectable at the 6 week mark. My AST and ALT dropped like a rock and my liver panel was now in 'normal' range. A real miracle! Now mind you, I am by no means the most healthy eater and I do enjoy a few beers from time to time. I did find that a little bike riding and a change to a somewhat healthy diet did help me to feel better, gave me some energy to counteract the gastro issues I was having. It has now been nearly 2 years since I finished treatment and my liver panel is as normal as any 48 yr old could expect. About 6 months after treatment concluded I did have surgery to deal with the diverticulitis that had become a more serious issue. Whether it was due to the treatment or not is up for debate. My gastro seems to believe that the treatment may have pushed it over the edge but the surgery has mostly remedied it. I'd much rather be hep free with some lingering gastro issues. My advice to anyone in a similar predicament would be to try to get any gastro issues under control as best possible before starting treatment but don't use it as an excuse, just not worth putting off the cure. I've heard harvoni not so brutal on the gastro system, but in actuality it was most likely a side effect from the ribravin. Good luck to all, 2 months of mild discomfort (at worst) was worth it to know I'll be around to see my young son grow up!

[I fightis thetitis]

Hi Sergy,

I appreciate all of your research and input.
The DAA and HCC connection in cirrhotics has been my concern as well since I started tx 11/2015.
I began to develop abdominal pain in my upper right quadrant 1 month into tx that went away from 2/16 - 9/16. Then at the 22 week EOT mark the pain re appeared with a vengeance. Could not sleep. I still have it off and on. Oh and I'm a health nut. Make my own Juices, exercise, eat right... yadii..

I educated my GI regarding the latest (worrisome) reports out of Europe and he ordered a new round of tests. Thank God for ipads in the examine room.

 Then, my pain got so bad I went to the ER 10/28/16 1 week before my ultra appt.
Full scan w/labs work up and I received an all clear.
However, my bilirubin went up 6 points and GI wants me to now get scanned every 3 months.. he said ultras S. don't always detect very early stages HCC. They can miss. Huh??? WTF did he just say?

Now, I have seen a couple of folks on this forum who were cirrhotics develop HCC either during, or after DAA treatment. one died. Deb was her username and you can follow her well documented thread.
Her ultra was all clear in 3/2015. She had symptoms of liver disease, itching.. @19 weeks during 24 Harvoni tx she experienced increased abdominal pain. Went in for scan and they found a 2" lesion. Aggressive tumor that appeared within 5 mos beginning tx. in 12/15 she experienced a hematoma on the lesion and it had grown to 5". She passed away in 3/2016 1 year after starting tx. 
She's now a statistic. Coincidence? Maybe. DAA/cirrhotic connection? TBD.

So the debate continues, are those of us with advanced liver disease at a higher risk of HCC after DAA tx? The answer in time, perhaps years away.
 
From my personal experience, I DO believe there is a "not yet understood" DAA-hcc-cirrohsis connection. And once the connection is discovered, I suspect pharma will develop immune booster trials that suppress cancer cells during and after TX for liver diseased patients. 

Hopefully some really smart person is already on that!!

Blessings to all,

Greg

[Sergey]

Hi Greg, thank you. Hope you will be fine, with permanent SVR and without HCC. In my understanding (it may be wrong), ultrasound may not detect very early, very small tumors (1-2 mm in diameter). Having ultrasound scan every 3 months looks as not a bad idea. I see, you expressed some concerns about HCC-DAA connection several months before (!) first publications in medical press (https://forums.hepmag.com/index.php?topic=3765.0).

I had read about another HCC case there - Mauilance (https://forums.hepmag.com/index.php?topic=3563 ) And his tumor is very aggressive... If I correctly understand, it was described by his doctors as "never seen anything grow this fast". In one article (http://www.medscape.com/viewarticle/862041) researcher stated: "What was surprising to us was that we were observing 4 cm lesions after 12 weeks." And another relatively big study (http://natap.org/2016/AASLD/AASLD_59.htm) found unusual aggressive pattern of HCCs, which developed shortly after DAA treatment (many nodules, infiltrative). Hence, potentially, it may be also another problem - if such data will be confirmed, then DAA-only treatment may cause unusual aggressive pattern of HCC, which may be more difficult for treatment, than ordinary HCC. Probably, time will tell...

[Mugwump]

Sergey for all the reasons we have discussed here it seems that studying exactly how HCV changes immune responses could be the key to developing more effective treatments for HCC. 

Firstly, which form(s) of interferons and other agents are created during HCV infection needs to be isolated. The treatments for HCC might change if it is discovered exactly which forms of anti-cancer agents are at work keeping it at bay in some HCV patients. Some are known but it is entirely possible that other forms are created by HCV infected hepatocytes which have yet to be identified.

The protective mechanisms created by the liver are a fascinating field of study, we still have a great deal to learn. And the genetic structure of HCV is a little chemical factory which does all sorts of things that we do not yet completely understand. But it is safe to assume that much of the by products synthesized by the HCV genome is somehow evolutionary advantageous for HCV.

As I have said "what good is a dead host to HCV".  It may very well be that HCV has enhanced or simply taken advantage of the natural protective mechanisms in the liver against competing diseases like HCC and that only in some cases HCC wins the battle.

But to my way of thinking not curing late stage HCV might be the greater risk as the structure of the liver is slowly overwhelmed by the disease and the risk of developing HCC and other nasty problems associated with cirrhosis increases.

[I fightis thetitis]

Today I told GI assistant I need auth for another Ultra in Feb bc Dr mentioned I should do every 3 mos, and my sporadic ab pain is still there.
She called back 10 min later said DR wants me to schedule the Ultra for this Monday..
Told me to fast for at least 10 hours rather than the usual 8.

Reason: Two other F4, Harvoni treated patients tested positive in December 2016 for Lesions.. that could be hcc. Not cool.
One patient was compensated. Both their previous ultras were neg from June.
Same complaint was abdominal pain, low platlets and high bilirubin. She said any patient of his, on or post tx experiencing ab pain will be asked to schedule Ultras immediately.
He attended the recent Liver Meeting in Boston and this is not isolated.
New thread? Polls?
I think Lynn, Gnatty and Eric are symptom free.. Seems like this specific subject is worthy and should be monitored by the forum.

Blessings,

Greg
 

[gnatcatcher]

Greg, I sure hope there's a benign reason for your abdominal pain.

You are correct that I am symptom free. However, it is interesting that all my ultrasounds before treatment, and the ultrasound one and a half months after treatment ended, said my liver had normal echogenicity and echotexture. The two more recent ultrasounds, however, had these statements:
 [Mid-May 2016] "Mildly heterogenous and coarsened in echogenicity."
"IMPRESSION:Mildly coarsened, heterogenous liver consistent with history of hepatitis and cirrhosis."
  [Mid-November 2016] "There is diffusely coarsened echotexture."
"IMPRESSION:1. Coarsened, heterogeneous hepatic echotexture which [sic] consistent with the history of hepatitis and cirrhosis."

These statements need to be taken with a grain of salt, however, as the radiologists in my hospital system routinely cover their derrières. Case in point: this last time, I mentioned to the woman performing my ultrasound that I seemed always to have bowel gas obscuring the tail of my pancreas, and she replied that the radiologists ALWAYS write that. When she was finished, I asked her if she could see the tail of my pancreas, and she replied that she definitely COULD see it. The report, however, said, "The pancreatic tail is obscured by bowel gas."

I agree that the forum should monitor post-tx abdominal pain and findings.

Gnatty

[Gaj]

Hi Greg,

Hoping your u/s is clear on Monday.

I also had abdominal pain just under my right ribs during and after treatment last year. This concerned me greatly due to my prior history of HCCs (both of which occurred prior to treatment). I currently receive 3 monthly CT scans due to that history and my hepatologist who is also a research/teaching professor has run a number of other checks but has been unable to provide a clear explanation for this pain although he has pondered the possibility that it relates to the cirrhotic scarring in my liver much like when we have large scars on other parts of our bodies that pull on the tissues around them as they heal. The pain has abated considerably in the last month or two and is now only a twinge occasionally.

Importantly, from his quick response now and the fact that he has already prescribed 3 monthly u/s you have a good GI there who is proactive and recognises the importance of prompt investigation which is reassuring. While very small lesions can sometimes be difficult to differentiate from other scarring and granulation during u/s it sounds like he is on top of his game and I feel sure he will investigate further if there is anything that raises his suspicions. CT scans can help with that but for liver (chest) they do subject us to a fair amount of radiation so are not usually ordered unless something is spotted that requires further identification or we have an ongoing risk.

This again points to the importance of regular and ongoing checks for those of us with higher levels of fibrosis and particularly cirrhosis post treatment.

[Mugwump]

Today I told GI assistant I need auth for another Ultra in Feb bc Dr mentioned I should do every 3 mos, and my sporadic ab pain is still there.
She called back 10 min later said DR wants me to schedule the Ultra for this Monday..
Told me to fast for at least 10 hours rather than the usual 8.

Reason: Two other F4, Harvoni treated patients tested positive in December 2016 for Lesions.. that could be hcc. Not cool.
One patient was compensated. Both their previous ultras were neg from June.
Same complaint was abdominal pain, low platlets and high bilirubin. She said any patient of his, on or post tx experiencing ab pain will be asked to schedule Ultras immediately.
He attended the recent Liver Meeting in Boston and this is not isolated.
New thread? Polls?
I think Lynn, Gnatty and Eric are symptom free.. Seems like this specific subject is worthy and should be monitored by the forum.

Blessings,

Greg

Greg all the studies done to date on cohorts of post successful interferon treatment individuals are indicating a reduction in HCC rates for those who cleared with the older treatment years ago. What is not taken into account is that those older treatments were far less successful treating individuals who had HCV damage beyond pre cirrhosis levels at the time of treatment. 

What seems to be happening here is as very large numbers of individuals with greater liver damage are being cured for the first time historically thus creating much greater numbers who succumb to HCC post treatment. This would implicate the DAA treatments quite unfairly as being a primary cause of a greater incidence of HCC amongst those who clear the virus.

This is a very good indication that by treating HCV only after waiting for it to progress to a point where there is inflammation and severe liver damage, HCC will become an even greater problem.

All of this could very well become exacerbated by the high cost of DAA treatments causing our health care systems to wait till the last minute to treat HCV. Thus increasing the rates of post treatment HCC in patients with HCV!
........

About the greed factor
Right now if I want to have pcr testing done on my cats for feline immune virus or feline leukemia it costs less than even a common HCV antibody test!

Obviously if the dog and cat diagnostics that require the same level of science that HCV diagnostics were as expensive as human testing then people would not treat their animals.

What I am saying here is that it is blatantly obvious that the pharmaceutical industry is taking us all for a shameless ride with more than just the drugs. They are the ones who sell and hold patents on the kits for HCV testing and have managed to gouge us for a very long time. What they do is play to the fact that humans will pay a great deal more for their essential health care needs if held to ransom!

GRRRRR!!!!!

[Sergey]

Seems like this specific subject is worthy and should be monitored by the forum.

Yes, I agree. I know six self-reported cases of HCC after IFN-free treatment from three internet-forums, five of them were diagnosed not later than 5 months after treatment. And one case of HCC after IFN+DAA treatment.

[gnatcatcher]

Sergey, since the self-reports came from three different forums, are you able to tell whether they came from six different people? That may well be true, but people do sometimes use different screen names on different forums. But, even if the six reports came from only three people (one on all three forums, another on two forums, and the case of HCC after IFN+DAA treatment), this is still definitely something that bears monitoring.

Gnatty

[Sergey]

I am sure that they are six different people. Debula an Mauilance there, Archer on FixHepc and other 3 on russian-spoken forum. But, I saw now, Archer had some liver lesions before treatment (if I correctly understand, without HCC diagnosis before treatment) - hence, really, 5 people, not 6 (if we will exclude people with lesions before treatment).

[gnatcatcher]

Thank you, Sergey. You are very thorough, and your depth of research is a great help to all of us. -Gnatty

[Sergey]

Gnatty, thank you. Sometimes I just collect and share some information, nothing special. Some of such things really may seem scary. Hope I don't scare people with this!)

[dragonslayer]

I like Mugwump's explanation for some of these findings; makes them a little less 'scary'....

[Sergey]

Yes, I hope that this explanation is correct too. But, in one study (http://www.journal-of-hepatology.eu/article/S0168-8278(16)30397-X/fulltext) they feel that selection of people with more advanced disease is unlikely:

"Furthermore, there seems to be no selection bias regarding eligibility to PegIFN treatment, as most affected patients did not have contraindications for this less effective therapy."

Time will tell, further studies are required...

[Sergey]

Relatively new article - "DAAs Rapidly Reduce Inflammation but Increase Serum VEGF Level: A Rationale for Tumor Risk during Anti-HCV Treatment" - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5172554/

[Mugwump]

Yes, I hope that this explanation is correct too. But, in one study (http://www.journal-of-hepatology.eu/article/S0168-8278(16)30397-X/fulltext) they feel that selection of people with more advanced disease is unlikely:

"Furthermore, there seems to be no selection bias regarding eligibility to PegIFN treatment, as most affected patients did not have contraindications for this less effective therapy."

Time will tell, further studies are required...

Indeed Sergey this study does seem to indicate that the rapid replacement of HCV infected hepatocytes does effect the immune system and could very well impair immune surveillance at least in a temporary way. All the more reason to also focus upon studies of exactly how HCV changes our immune system during an active infection.

If other drugs become necessary during DAA treatment to lessen the risks of HCC then this seems a logical way to ascertain what might work.

There is no indication whether or not the cirrhotic people within these studies failed previous treatments with interferon but it is indeed troubling that a 7.4% incidence of HCC post DAA treatment is being reported here.

Studies of how many who have no signs of cirrhosis and yet go on to develop HCC post DAA treatment are just as important because if there is a strong associative factor with the rapid removal of HCV from the human liver and an increased risk of HCC it will show up there as well but perhaps to a much lesser degree.

Touch wood, "the termites" (as Babe Ruth once called them) have not got to me yet! I am more worried about other types of "the termites" that run in my family on both sides.

The really troubling aspect of this possibility is that if that there is a post treatment immune surveillance deficiency, especially for those of us with greater liver damage, it might very well allow other forms of cancer to become more aggressive and overwhelm the persons ability to fight it off.

Hopefully this new turn of events will turn out to not be what exactly is happening! The thought that the removal of HCV being more dangerous than leaving the liver untreated is not one that would be a good out come for any of us. Especially considering that over 60% of those with chronic HCV go on to develop early cirrhosis.

Cheers I hope
Eric 

[dragonslayer]

Hopefully this new turn of events will turn out to not be what exactly is happening! The thought that the removal of HCV being more dangerous than leaving the liver untreated is not one that would be a good out come for any of us. Especially considering that over 60% of those with chronic HCV go on to develop early cirrhosis.

Cheers I hope
Eric

Hi Eric..... Is this really true??  Ive always seen the following to be the number thats been used:

"For every 100 people with chronic HCV infection, between five and 20 people will go on to develop cirrhosis, according to the CDC"

[Mugwump]

Hi Eric..... Is this really true??  Ive always seen the following to be the number thats been used:

"For every 100 people with chronic HCV infection, between five and 20 people will go on to develop cirrhosis, according to the CDC"

I might be off here but the definition of a chronic infection seems to be what differs here. My GI defined it as being an infection that progresses beyond no liver damage. His prediction of the timing which it took for me to go from f2-f3 to f4 was based upon his experience and after treatment with interferon in 2004 he told me that most likely I had 10 years before my infection would go on to f4. He was uncannily accurate.

I am sorry if I got my facts wrong but from what I understand the chances of going from f2-3 to f4 in ones life time if left untreated are about 60%. I should have clarified what I stated to say pre cirrhosis instead of chronic infection. We seem to have precious little data about how many actually go on to naturally clear the virus if the infection shows no signs of creating liver damage stays at a low level and then in consequence is left untreated.

From 1993 when I was first diagnosed until I was first treated in 2004 I hoped beyond hope that there would be a chance I would naturally clear the virus. I was informed that this was not unheard of but not at well studied and no secondary drugs like the ones to moderate aids were in the works. Perhaps there is the possibility in future for other immune stimulating treatments for those who have no liver damage to clear the virus without DAA treatments.

I messed with things like milk thistle and the usual stuff during those years. One interesting one is the known antiviral properties of the Baldhip Rose. But the tea and taste of overripe and thus pungent rose hips is not something which seems to me to be of any real use except maybe to bird physiology

The years of reaching for the snake oil are an unpleasant memory of desperation that I hope soon no one will have to go through! If eventually there is some other form of treatment other than snake oil, for those who are at an earlier stage of infection it would be marvelous.

Cheers
Eric
 

[Gaj]

Chronic HCV is usually defined as those who have not only antibodies but also measurable levels of viral RNA. i.e. Those of us who didn't manage to naturally clear the virus.

The CDC figures refer to within the first 20 years. The WHO has slightly higher estimates.

"Of those with chronic HCV infection, the risk of cirrhosis of the liver is between 15–30% within 20 years."

http://www.who.int/mediacentre/factsheets/fs164/en/

While the rate is variable depending on a large range of risk factors such as alcohol consumption, body mass, age, sex, HCV genotype and even our own genetic makeup the problem is that fibrosis continues to develop and often accelerates past that 20 years so for many of us who have had it for longer the risk becomes progressively higher. Here is one, admittedly fairly small, study that concludes:

"Most HCV patients, if untreated, are expected to develop cirrhosis at about 65 years, irrespective of the age at infection."

https://www.ncbi.nlm.nih.gov/pubmed/17355454

When you start to factor in the reduced incidence of SVR for those with increasing levels of fibrosis and particularly for those with cirrhosis it does suggest that early treatment would be the best option.

[dragonslayer]

"Most HCV patients, if untreated, are expected to develop cirrhosis at about 65 years, irrespective of the age at infection."

Ouch...  Thats a scary finding; wonder how valid this study was.  I had never heard it before.  My last biopsy was in 2013 when I was 64 and scored a stage and grade 0-1 which was consistent with the prior biopsy in 2008 when I was 59 which scored a stage and grade of 0, so extremely slow progression Im glad to say, especially since I think I had been living with it since the early '70s.. But am I really that unusual in that regard?  I had always gone by the 20-25% number the CDC has put out there.   Study results like these start me wondering if my biopsy results were wrong!

[Mugwump]

Ouch...  Thats a scary finding; wonder how valid this study was.  I had never heard it before.  My last biopsy was in 2013 when I was 64 and scored a stage and grade 0-1 which was consistent with the prior biopsy in 2008 when I was 59 which scored a stage and grade of 0, so extremely slow progression Im glad to say, especially since I think I had been living with it since the early '70s.. But am I really that unusual in that regard?  I had always gone by the 20-25% number the CDC has put out there.   Study results like these start me wondering if my biopsy results were wrong!

I will go with what my GI said about his experience dealing with the disease since it was first isolated. His take was that those who show any signs of the disease overcoming the immune system are likely to progress to cirrhosis in their life time.

It is unfortunate that the numbers game is the one played by insurance companies because essentially by denying treatment for those who have no signs of liver damage they are playing dice with human lives.

It turns out that here in Canada there is a yearly check now for three years by HCV RNA for all who clear with treatment. I suspect that the medical community here is pushing for early treatment for all which would be a great thing.

If there are no re-infects that can be explained by a new exposure then hopefully the powers that be will in their infinite wisdom decide to take the route that Australia has taken regarding treatment. But our government is at times like my bowels and tends to move a tad too slow at times!

Cheers
Eric

[I fightis thetitis]

Hi All,

My latest results are in. U Sound clear. No noticeable lesions.
Labs: Platlets down 10 points from 180 to 170, my pre tx #s.
Bilirubin still high at 1.6 which doubled from start of tx on 11/24/15. My Bilirubin jumped 8 points between EOT 12 weeks and EOT 24. Same time as the increased ab pain. Suspicious to me.
All other extensive labs within range.

Since Ab pain still exist and has reffered (spread) to right chest and shoulder, (classic hcc symptoms) & platlets dropped while Bilirubin has risen, I had to confirm with Dr the accuracy of US. Yes they miss..
His advice: BC I have intermitent ab pain, go back to the ER get another US or CT if it gets worse. 
Further, it is possible I could have a lesion in a particular area of either lobe the US tech is missing or can't see. Happens.
Option 2 is alternate imaging (MRI) if pain persist 4 weeks.

Let me say this, I think a lot of us know our bodies well enough that when somethin' ain't right, we can pick up on it. I know I have something causing the pain and Bilirubin jumping 8 points suggest (or confirms) I'm right.
I'm happy that the US is clear but... dang it! I'm in the cracks for the moment.

I also believe that the latest reports from the links above by Sergy regarding Serum VEGF, and Gaj's links should keep the conversation and eye brows raised. 
Severe fibrosis and cirrhotics are possibly linked to a higher initial occurence of HCC 12.5 to 24 MONTHS post tx..
It already appears the evidence is in there is a risk of hcc reoccurrence after DAA-HCV-SVR with advanced LD.   

We need a score board and a separate thread for the advanced fibrosis and cirrhosis folks.

All good things,

Greg

[Sergey]

Greg, I truly hope that your symptoms have a benign cause. Liver is changed due to treatment in many people - after inflammation is gone, fibroscan values may be reduced (and liver stiffness may be improved) etc. But thorough HCC screening seems important in your case.

With warm wishes,
Sergey

[Sergey]

Regarding to question of fibrosis progression with HCV without treatment, in my understanding, this question is not well studied, because, ideally, it requires very long observation, during many decades (due to relatively slow progression rate) - and PCR test was implemented only in 1990s. World-known hepatologists say that "The majority of patients with chronic HCV infection are fortunate not to develop cirrhosis and the need for liver transplantation" (http://www.journal-of-hepatology.eu/article/S0168-8278(13)00598-9/fulltext)

Many studies about progressing rate of untreated HCV have a problem of "selection bias" - as described there:

While a number of studies have assessed the natural history of hepatitis C infections, most of them suffer from a methodologic defect known as selection bias. For example, suppose you work at a liver transplant center and only see patients who are referred there to have such a procedure. If I were to ask you what the natural history of hepatitis C is in your experience, you would say that all of the patients that you see have end-stage disease. On the other hand, if you work at a blood donor facility and I asked you the same question, you would say that all of the hepatitis C positive people that you see are quite healthy (since, if they were not, they would not be donating blood). These examples reflect the different populations who are seen in special centers, but neither is representative of all people infected with hepatitis C.

Most natural history studies employed data collected in centers that treat liver disease, where sicker hepatitis C patients tend to congregate. While data from such studies have suggested that it takes, on average, about 20 years to develop cirrhosis and 30 to develop hepatocellular carcinoma in patients who are infected with hepatitis C (1, 2), that observation is confined to the patients referred to that center who developed cirrhosis or cancer. It is incorrect to assume that all patients who are infected with hepatitis C progress to these end points in two or three decades. In order to calculate the probability that end-stage liver disease will occur, one needs to know the denominator, namely the entire number of people who got infected, in addition to the numerator, namely how many of those people developed end-stage liver disease.

Several research centers actually identified cohorts of people (a cohort is the denominator) when they first got infected and have followed those people for decades. Most of these studies included people who were transfused in the 1970's and, within months afterward, were found to have developed post-transfusion hepatitis C. Decades later, no more than 10% (and usually far fewer) of these infected cohorts had end-stage liver disease (3-10)."

I guess, the study cited by Gaj (https://www.ncbi.nlm.nih.gov/pubmed/17355454), is suffered from "selection bias" too, because this is not cohort study. Best available evidence is possible in cohort studies, because they are free from such selection bias. One of such cohort studies shows 3.8% of cirrhosis with normal weight after 35 years of HCV infection for women, infected in 1978/79 by contaminated immunoglobulin (http://onlinelibrary.wiley.com/doi/10.1002/hep.26644/full). It looks lower than lifetime probability of getting lung cancer for long-term smokers (15%-20%).

Also, probably, another cause of selection bias is possible - because HCV transmission is statistically associated with risky behaviour (like IVDU) - hence, large random group of HCV infected people, in average, may tends to have more alcohol consumption (than group of noninfected people). And excessive alcohol consumption, especially in combination with HCV - may very quickly causes cirrhosis... I was told by a doctor that even without HCV, heavy alcohol consumption may cause cirrhosis within 1-2 years. There is an article about such issue https://www.mja.com.au/journal/2007/187/1/alcohol-and-hepatitis-c , they say that "Clinical practice confirms HCV’s interaction with alcohol, with most patients admitted to hospital with hepatitis C and advanced liver disease having a history of heavy alcohol consumption."

So, I guess, when we read something like "most of HCV infected probably will have cirrhosis at 65" - it may be beneficial to ask a question - "What is about selection bias in this study?" Otherwise, we may just scare yourself, fall in depression, our existence may be "pathologized" etc. even without strong evidence about poor prognosis. Our depression may be beneficial for Big Pharma (because they want to sell their drugs as much as possible) but harmful for us...

[dragonslayer]

Sergey, thanks for your perspective.   The numbers quoted in some of these studies really dont jibe with those quoted by the CDC, and perhaps selection bias is part of the reason why.   

Lets say  100% of HCV patients in hospice are there due to end stage liver disease caused either by cirrhosis or HCC.  Therefore, in that sample,  all HCV patients die from cirrhosis or HCC.

Selection bias.. The sample selection is predetermining the outcome.

[Gaj]

One of such cohort studies shows 3.8% of cirrhosis with normal weight after 35 years of HCV infection for women, infected in 1978/79 by contaminated immunoglobulin

Sergey, while there may have been selection bias in the study I cited, it is also very evident in the example you provide. It would be great if most people with HCV fitted within that cohort which has the low risk factors of being female, normal weight and aware of their infection from a relatively early point so they can make informed desisions about drinking, 'risk taking', diet, etc.

Unfortunately, for too many that is not the case and they are in higher risk groups and/or only become aware of their infection at a later stage in their life when considerable damage may have already occurred.

[Mugwump]

The problem comes down to whether or not one progresses to fibrosis and a pre cirrhotic state IMO. Regardless of whether or not the damage done by infection is exacerbated other factors. Certainly stopping drinking is important and other risk factors such as obesity are a major concern.

However once an infection is shown to be the primary cause of any liver damage whatsoever one cannot know for certain whether or not the immune system will moderate the infection to an extent that it will not progress to cirrhosis.

Even so given the choice I would treat even without liver damage. The reason is that knowing that it is possible to infect others and carrying that sword over my head is too heavy a burden to bear. In my signature you see the reason why. Another real fear for me was getting in a traffic accident and requiring medical procedures in the field which increases the risks to others by exposure to my blood.

The spattering of blood in the eyes is one route of transmission that is hotly debated, but given the rates of infection in emergency response personnel in major cities like Chicago it seems logical that this is one route of possible infection. Not just the obvious possibility of needle sticks from junkies that have syringes in their pockets!

For years I had dental work done before the risks of infection by this disease were well understood or known. I shudder to think that I may have spread this disease BUT it is completely possible that I did.

I had a back-room tattoo done in 1970, I cannot know whether or not I caught the disease or spread the disease in having this done.

Statistics are easy to sway in any argument. This disease is not just about statistics. If left untreated in the general population it will be a curse that many will carry and pass on.

We cannot know how many of our ancestors have died of this disease and were written off as alcoholics or how prevalent the disease was in the general population prior to when it was isolated from other forms of serum hepatitis. Therefore we cannot know how fast this disease will spread in the future. If current theory is correct and the disease has peaked then waiting for its victims to all die off is a cheaper alternative to treatment. (please pardon the cynic in me).

However if the disease only became wide spread post WW11 as is commonly thought then indeed we might see a slow global rise in infection rates instead of a corresponding statistical decline in cases. With infection rates slowing but staying steady with a slow rise in the infection rates instead of a spike in the upward curve.

The other risk of not treating this disease is that it may very well mutate into a form that DAAs will not be able to handle. It is well understood that some strains are more prone resist the immune system, whether or not these strains of the virus existed prior to the peak of infection spread is not known. The age of any one strain of this disease might be a little as 40 years or, if you believe in creationism then they have been here since someone opened Pandora's box!

If the disease did mutate into different genotypes over a short period of less than 50 years then we could very well soon see forms of this disease that are much more deadly than the current ones.

To conclude, yes there are many things that we cannot be certain about with this disease but IMO it is better to not find out!

Eric



 

[andrew j]

Something that might be of interest:

There is a post on the Homepage, dated Jan. 25 (and just under a string of posts on NAFLD):

'Report Raises Concerns About the Safety of Hepatitis C Treatments'.

[Sergey]

Sergey, while there may have been selection bias in the study I cited, it is also very evident in the example you provide. It would be great if most people with HCV fitted within that cohort which has the low risk factors of being female, normal weight and aware of their infection from a relatively early point so they can make informed desisions about drinking, 'risk taking', diet, etc.

Unfortunately, for too many that is not the case and they are in higher risk groups and/or only become aware of their infection at a later stage in their life when considerable damage may have already occurred.

Gaj, yes, I agree. When HCV is diagnosed at cirrhosis stage - then situation is usually much more serious and average prognosis without treatment usually is much worse (especially, with signs of decompensation), than without cirrhosis. Yes, some degree of bias also may be possible in cohort population studies (like in cited study with cohort of women, infected by immunoglobulin, some of them were treated with interferon). And, if we will extrapolate data from such studies to other populations - then it may give some bias too. But, evidence from such cohort studies looks as best available at current moment. Unfortunately, we don't have such evidence for many other groups of patients (for example, for group of overweight men, infected at 50). Hence, for many groups we have only biased evidence (and don't have strong evidence) about HCV progression. Yes, it is better to be aware about positive HCV status as soon as possible, to make informed decisions about body weight, alcohol etc. If I was aware earlier about my HCV, then I definitely had stopped drinking alcohol earlier and, possibly, did not have cirrhosis.

For years I had dental work done before the risks of infection by this disease were well understood or known. I shudder to think that I may have spread this disease BUT it is completely possible that I did.

Eric, yes, I am worried about similar things too... HCV-infected people need to do as much as possible for prevention of infection of others. Also, I feel that some psychological methods may be helpful. We can try to see such things from more wide perspective, for example. We are all interdependent and, sometimes, create some risks for other people... For example, when somebody drive a car,  his car may be a source of danger for others, even unintentionally. The car may just appears in wrong place at wrong time, and somebody may hit such car in traffic accident, and it may create big risks for other people, even without HCV. To avoid such risks, it will be better do not drive cars at all - but many people choose to drive a car.

Also, we can compare chronic tobacco smoking and hep C. It seems, both conditions have similar traits - long-term smoking will cause serious health problem for minority of people - like lung cancer and/or cardiovascular problems (as well as HCV may cause cirrhosis and its complications). In average, in my understanding, "infection" of tobacco smoking seems more harmful for society than HCV - just because it causes much more deaths. HCV causes 20000 deaths (or something like that) every year in USA, smoking causes around 480000 deaths per year. But, interestingly, chronic smokers often much less worrying about his condition, than asymptomatic HCV carriers... I am a former smoker, and, of course, it is better do not smoke at all and achieve SVR, to be sure that we will not infect others and we will not unintentionally involve in smoking others (when they see us with cigarette, for example). But, if treatment may be linked with serious health risks (like HCC) - people may decide to defer it... As other people may choose to drive a car, despite it will create some additional risk from their car on the road for other people... Like that.

The other risk of not treating this disease is that it may very well mutate into a form that DAAs will not be able to handle. It is well understood that some strains are more prone resist the immune system, whether or not these strains of the virus existed prior to the peak of infection spread is not known.

It seems as difficult question... DAA-resistant mutants usually appears after relapses after unsuccessful DAA treatment. Just as guess - it may be possible, that relapsers with such resistant HCV mutants will eventually infect other people - and it may eventually cause wide spreading of Harvoni-resistant 1 genotype in the world, for example... It may be like long-term "cat and mouse" game - powerful DAAs will create strong resistance in relapsers, which will require more powerful DAAs for retreatment, which, in its turn, may create stronger mutants after relapses etc. And yes, we don't know much about such mutants. We cannot exclude that such mutants may be more harmful, than "ordinary virus"... Recent study (http://natap.org/2016/AASLD/AASLD_59.htm) shows 8.4% of HCC per year for relapsers, it is higher than 2-4% without treatment. Also it may be due to some other factors (for example, due to more advanced disease in relapsers) - I don't know...


With warm wishes to all,
Sergey.

[Lynn K]

Hi Sergey i saw a post further up where there was a comment about some of us being without symptoms with my name mentioned.

While I do in general feel fine I would not say I am without symptoms of liver disease just not much noticeable on the surface. I had esophageal varicies diagnosed in 2012 and have a low platelet count plus an enlarged spleen all of which indicate I have portal hypertension. These are not things I am aware of they show up on testing. I have edema and a small amount of ascities. The ascities is the only symptom I notice. Well except for the leg cramps and I have lost most of my body hair and my hair in my head is thinning but not sure if the hair symptom is age related being post menopause or related to liver disease hormal changes. Also I have hundreds of red dots on my body which are probably petechiae and also spider angiomas which are related to my cirrhosis.   

So while I do feel more or less fine I wouldn't go so far as to say I am without symptoms.

About hep c deaths found this from the CDC

https://www.cdc.gov/media/releases/2016/p0504-hepc-mortality.html

Hepatitis C Kills More Americans than Any Other Infectious Disease
New CDC studies underscore urgency of hepatitis C testing and treatment, especially for baby boomers

Deaths associated with hepatitis C reached an all-time high of 19,659 in 2014, according to new surveillance data released today by the Centers for Disease Control and Prevention (CDC).

A second CDC study, published online today in Clinical Infectious Diseases, shows that annual hepatitis C-related mortality in 2013 surpassed the total combined number of deaths from 60 other infectious diseases reported to CDC, including HIV, pneumococcal disease, and tuberculosis. Further, both studies use data from death certificates, which often underreport hepatitis C, so there likely were even more hepatitis C-related deaths than these numbers suggest.

[Sergey]

Hi, Lynn, yes, your cirrhosis is relatively advanced, some symptoms often present in such stage... Hope your situation will be improved with time.

My point about hep C deaths is that we can compare hep C with "infectious disease of tobacco smoking" - and realize that tobacco smoking causes much more deaths - "Cigarette smoking causes more than 480,000 deaths each year in the United States. This is nearly one in five deaths." - https://www.cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/effects_cig_smoking/index.htm
It may bring some psychological relief for HCV carriers - otherwise, they may start to feel stigma, depression etc. - as carriers of "most deadly infection". It works in my case.)

[Sergey]

Two relatively new articles about possible DAA-HCC connection:

"High Rates of Hepatocellular Carcinoma After Hepatitis C Treatment" - http://www.managedhealthcareconnect.com/content/high-rates-hepatocellular-carcinoma-after-hepatitis-c-treatment

"The impact of direct antiviral agents on the development and recurrence of hepatocellular carcinoma " - http://onlinelibrary.wiley.com/doi/10.1111/liv.13321/full

Recently, several studies have described a potential unexpected incidence of hepatocellular carcinoma in treated patients, both in those without a prior history of cancer and those who have been successfully treated and were disease-free for different periods of time. Furthermore, the emergence of cancer is also characterized by a more aggressive and faster progression to advanced stages, making treatment impossible. Thus, a careful risk-benefit analysis must be made when considering antiviral treatment with the new agents in patients with hepatitis C virus.

[I fightis thetitis]

Sergy,

These links seem to confirm that conflicting information is still all we've got.
Although your links seem more legitimate then the article/blog that is posted on the homepage here on hepmag, which is more optimistic and maybe sponsored.

It also seems if we were to poll our forum friends here who are 1. hep c cirrohtics, 2. SVR free via DAA tx, the hcc connection numbers seem favorable so far. However, there clearly is, and there should be a concern that DAA tx still poses uncertain risk.

I for one have just been prescribed a battery of new test bc my ab pain remains, which intensified exactly at 24 week eot that coincided with a sudden spike in
bilirubin.
He ordered: a nuclear liver spleen scan, endoscopy, colonoscopy, fibroscan, 2 separate blood coagulation test, fecal test.
He had frank words regarding 2 patients that were recently diagnosed with the most aggressive hcc he has ever seen. Spread fast. Also said he has other cirrotics that appear to be doing well.

His advise was not to read to many articles as the jury is still out. And, to monitor me close bc it appears that those who get hcc after DAA are dealing with a "very aggressive" type.
Small dose Interferon trials should be considered for cirrotics.

Best to everyone!

Greg

[Lynn K]

So the bottom line for your first link to the Reuters article stated

In any case, the number of events is small, and the data are not enough to support the hypothesis that the risk is directly related to the drugs.”

They only had 66 patients of who 6 developed HCC within 6 months post treatment that is not a very large sample to draw conclusions from as they themselves state at the endocrine the article.

There is also much data supporting an over all reduction of risk for HCC and decompensation post cure.

So certainly the jury is not only out but not yet convened on the possibility of increased odds for HCC post cure.

But if that is what you are going with and are determined to delay I truly hope that works out for you.

[I fightis thetitis]

MELD SCORES slightly off topic..
For Lynn, Eric or anyone who may know or has research info..

My labs before tx 10/2015, Meld score 6.
5 mos post tx labs 10/2016 Meld scored jumped to 8 where it now has remained.

The virus had been und since 1/2016.
So theoretically, since the source of my inflammation AND what was causing cirrhosis has been eliminated, it seems logical to think my meld score would stay the same, or go down if possible, not up.   
What say you??