TOPIC: DAAs and Liver Cancer Risk

Hi Gaj, thanks for your efforts about clarification of such things. Possibly, some waiting for more confident data may be an appropriate decision for many people with compensated cirrhosis.

I agree with most of your doubts about confidence in study's statistics. Really, group is quite small, and HCC incidence may vary according to disease severity, age... Probably, HCC rate in group of young compensated cirrhotics will be lower than in group of old sub/decompensated cirrhotics. There are many people with child B cirrhosis in group - it is unlikely that such people are interferon eligible. Hence, interferon-treated group, in average, is more helathy than DAA treated group - such difference may affects HCC rate. Five of the nineteen relapsed, probably, is not an issue, because they are "subgroup with HCC" of full cohort. Real SVR rate in full cohort may be much higher.

Another small study - dx.doi.org.sci-hub.cc/10.1016/j.jhep.2016.07.027 - "High incidence of hepatocellular carcinoma following successful interferon-free antiviral therapy for hepatitis C associated cirrhosis" 4 HCC ocurrence per 54 patients - 7.4% rate. 7.4% rate is quite high - 1:13 chance. Nearly 30% of HCC recurrence rate from other studies seems extremely high... From the other side, some studies do not show increased HCC rate - www.natap.org/2016/EASL/EASL_76.htm Results of studies seem contradictory - probably, time will tell...

HeySerg
I am not a doctor but I do know that the virus damages the liver (and the immune system) 24*7 and most people with HCV develop cirrhosis and HCCs.

I have always been given to believe it's the cirrhosis that leads to the HCCs, so if you have cirrhosis and do nothing, chances are the HCC will come.

Looking at the tests (and I'm not a doctor and I'm not very scientific) it seems that it's really not possible to extrapolate that the DAAs cause HCCs in cirrhotics.

Maybe if there were some longitudinal studies some evidence might come to light in a few years. But how could you ethically conduct such a study?

Hi beaches,

of course, patients with cirrhosis have some risk of HCC (several percents per year)... But main question - whether treatment is worse than disease or not... Sofosbuvir was approved in 2013 - and many people was treated with DAAs during 2013-2016 (and earlier, in clinical trials). Hope that retrospective studies are possible to determine HCC risk after DAA treatment.

If i correctly understand, from point of view of current medical evidence this is not correct. "The majority of patients with chronic HCV infection are fortunate not to develop cirrhosis and the need for liver transplantation" (www.journal-of-hepatology.eu/article/S01...(13)00598-9/fulltext ) In some studies, there are such data that only 20% (or something like that) of HCV-infected will develop decompensated cirhhosis and/or HCC during lifetime without treatment. Really, we dont know this percent with 100% certainty - because this requires very long observation (lifetime long), and virus was discovered only several decades ago. Also, there are many contributing factors which affects fibrosis progression - alcohol consumption, body weight...

Serg wrote: Sorry, I may be wrong in interpretation of results of this study - they count HCC incidence by 6 month intervals and sof-peg-rib group may affects results for DAAs-only regimens. Possibly, "rate per 1000" - 36+30 = 66, hence - 6.6% per first year, quite high... Unfortunately, full article is not accessible.

Hi Serg,

This thread was initially mostly a warning about a potential increased risk of HCC recurrence for those who had a previous history of HCC but you seem to be trying to extrapolate that to show that

...You seem to believe there is a significant risk for all cirrhosis patients taking DAAs and using that to justify not commencing treatment. You should remember that when looking at any risks associated with a disease and its treatment we need to ensure we look at the big picture rather than just focussing on one particular aspect to the exclusion of all others.

While HCC rate in the study graph you link is 6.6% for the first 12 months, in the following 12 months it drops to 1.9% (and still falling) and that needs to be compared with the ongoing annual rate without treatment. If you go back and look at Dr James initial post in this thread he says -

So 6.6% dropping to 1.9% may indicate an increased initial risk followed by a rapid decline....or it may just be within the normal spread of statistical data over any period of time.

Then have a look at the graph marked DC below that one which shows a large and continuing decrease in the rates of liver decompensation for this same group of patients. That correlates well with our overall knowledge about how removing the antagonist of cirrhosis results in a reduction in its progression in line with the comments here fixhepc.com/forum/experts-corner/923-daa....html?start=30#20388

As medical research progresses we learn more but there will never be a stage where we know everything. With that in mind we all need to look at our individual situations and take the best medical advice currently available to us and then weigh up whether we treat now or wait. But at some point we do need to make a decision and with that in mind perhaps a reread of the below link may assist?

fixhepc.com/forum/experts-corner/320-why...edications.html#2770

Hi Gaj!

Yes, I am not sure about this too. Drugs are under review by european regulator now, and, hope, we will have some decision and additional information in near future. Personally, I decided to wait, at least several months. Of course, I had read fixhepc.com/forum/experts-corner/320-why...edications.html#2770 - but this posting was written before emerging of data of possibly increased risk of HCC occurence/recurrence shortly after DAA treatment with cirrhosis. If there is an increased possibility (for example, 1:13 chance) of getting HCC in first year after treatment, then decision looks not so obvious for my situation ("well-compensated" cirrhosis during 10 years).

Yes. But if we will focus on question whether benefits of treatment outweigh harm or not, probably, we need to take into account that treatment itself may cause decompensation in some cases, mostly in sub/decompensated cirrhosis. For example, one study (www.natap.org/2015/EASL/EASL_34.htm) show that albumin < 35 or age > 65 in Child B or C cirrhosis are associated with more risks than benefits in terms of liver function, measured by MELD score. This may be a cause of recommending treatment after liver transplantation for some patients, for example. Each case is individual...

P.S. If you feel that discussing of possibility of increased HCC occurence (not only HCC recurrence) after DAA treatment in cirrhotics is some "offtopic" in this thread - please feel free to edit my messages.

My comment was just a lead in to my thoughts and not intended to imply you shouldn't be discussing it in this thread. I have struck out that part.

Are you "well" compensated or decompensated as are those in the last study you are now citing? If the first my comments about reduced risk of decompensation still apply. But the study is looking at patients who are already decompensated and have compromised livers to start with. In that cohort a subgroup with certain criteria such as older than 65 and albumin less than 35 were found to be more likely to see an increase in MELD score under treatment. That is not entirely unexpected in a group who are seriously ill to begin with.....but it is a different argument to HCC occurrence.

Agree, probably, SVR may reduce my risk of decompensation in "long-term" perspective. I am "well"-compensated, probability of "on-treatment" decompensation is not a worry in my case.

If I correctly understand, establishing of reducing of decompensation risk "in average", compared to "no treatment" from DC graph (www.natap.org/2016/EASL/EASL_76.htm) may be difficult, because we do not have "identical" untreated group in this study for comparison. We can see from DC graph about 33 per 1000 rate of decompensation in 0-6 month after treatment initiation, after that - 8 in 6-12 month, 6 and 1...

About possible HCC risks - some people says that it may be possible that interferons (as anticancer agent) may be used in future in treatment regimens together with inhibitors, but it seems quite experimental now for many cases... It is interesting to see HCC risks data for sof-peg-rib therapy, for example.

Interferon is anti lots of things. Anti-cancer and anti-viral being two. Unfortunately it makes people feel sick.

The problem for you Serg, it that it's not the drugs that cure Hep C that cause the problem, which I believe is likely to be real. It's the curing the cell death by curing the Hep C, so now, or at any time in the future, treatment will present this risk, but, the evidence suggests fibrosis is progressive (after all you start at F0) and that only cirrhotics are impacted. You could extrapolate and suggest more cirrhosis == more risk, after all cirrhosis is a line in the sand - under this number and you are not, over and you are. Risk, like fibrosis is likely to be a spectrum.

www.medsci.org/v03p0047.htm

Studies have estimated the 3, 5, and 10-year survival rates of compensated cirrhosis to be 96%, 91%, and 79%, respectively. [51] . The cumulative probability of an episode of clinical decompensation is 5% at 1 year, and increases to 30% at 10 years from the diagnosis of cirrhosis. [51-53] Once decompensated cirrhosis occurs, the 5-year survival rate falls to 50%. [51] The time from HCV infection to cirrhosis is dependent on multiple factors, and cannot be predicted in an individual patient. Virtually all HCV-related HCC occurs among patients with cirrhosis. In a meta-analysis of 21 case-control studies, the risk for HCC was increased 17-fold in HCV-infected patients compared to HCV-negative controls. [54] The results of several retrospective trials show a moderate decrease in the risk of developing HCC among HCV patients treated with interferon. [55-58] This benefit appears to be greater in patients with a sustained viral response rather than non-responders to interferon treatment. [59]

There are no right answers, only informed speculation. My expectation is that the HCC risk post DAA treatment will just be a blip, and that it will drop back to the 3% untreated rate (from the 7%).

One thing that seems to getting missed is that most of that 7% was made up of 21% of people who HAD PREVIOUSLY HAD AN HCC.

James, thank you. Yes, I agree that "There are no right answers, only informed speculation". There is a situation of uncertainty... But possible 7% blip with subsequent 3% rate seems quite high compared to results of HCC risks after SVRs, achieved with interferon-ribavirin treatment (1-1.4%). Is it possible that interferon-ribavirin treatment is more safe in terms of HCC risks? Probably, it may be possible - because we did not hear about increased HCC risks after interferon-induced SVRs. If it is correct, then more safe (than DAAs-only) treatment in terms of HCC risks may be possible.

Is it possible that combinations of interferon-ribavirin with DAAs (for example, sof-peg-rib) are more safe than "DAAs-only regimens" in terms of HCC risks?

Could you please clarify - what is the reason for such conclusion? In a study dx.doi.org.sci-hub.cc/10.1016/j.jhep.2016.07.027 with 7.4% HCC occurence rate "Those with “non-characterized nodules” and a previous diagnosis of HCC were excluded."

Serg - I truly hope you can find solace between hell and the deep blue sea. Statistics are made from either indecision or over a analyzing, may you find your way and then be persistent in it. I always said a decision must be made even if it is wrong, I made it and I'll deal with it.
In good health to you my friend.

Hi Serg,

I was sitting in the room when this was presented:

ilc-congress.eu/high-rate-cancer-recurre...g-antiviral-therapy/

In the Italian study, medical records of 344 HIV-negative patients with HCV related cirrhosis, who did not have active HCC, were analysed. All patients had received treatment with one of the following DAA combinations: sofosbuvir and simeprevir (34%), 3D combination* (22%), sofosbuvir and ribavirin (17%), sofosbuvir and daclatasvir (16%) and sofosbuvir and ledipasvir (10%). Occurrences of HCC were assessed by comparing baseline enhanced-ultrasonography and MRI/CT-scans with those taken during the six month post treatment follow-up.

Sustained virologic response was achieved in 89% of patients at 12 weeks post treatment. At 24 weeks post treatment, active HCC was detected in 7.6% of all patients (n=26) without a history of HCC – deemed to be a ‘standard rate’ by the study authors. However, in the 59 patients who had a previous history of HCC, a ‘high rate’ of 29% (n=17) redeveloped the condition.

Which is not the study you are looking at. The upshot was that in cirrhotics the headline numbers were:

1) 7.6% for all participants (26/344)
2) 29% for those who had previously had an HCC (17/59)
3) 3.1% for participants who had not had an HCC before (26-17=9)/(344-59=285) ie 9/285

All participants were assessed with MRI for current HCC prior to starting, and patients with a past history of HCC were not excluded.

Unfortunately although Interferon may provide some HCC protection when it comes to all cause death patients who have a second round of interferon have a 9.7% mortality rate compared to 6.4% taking placebo so the interferon adds ~ 3.3% mortality, and you still have the HCC risk from the cirrhosis.

www.everydayhealth.com/hepatitis/second-...y-be-fatal-2345.aspx

Sven, thank you. Of course, nobody wants to suffer, and everyone wants to be healthy and happy. My decision is some waiting for additional data now, treatment with cirrhosis looks like "game with high stakes" - thus, I want to be confident about possible risks.
I wish you health and good luck with your treatment!

James, thank you. Yes, probably we spoke about different studies. Some studies show 7% initial risk, some studies show only 3% risk (as cited by you ilc-congress.eu/high-rate-cancer-recurre...g-antiviral-therapy/) for "HCC-naive" patients. Situation seems not well-studied yet...

Regarding to additional 3% mortality risk with interferon, if i correctly understand, this finding was made in Cochrane analysis of HALT-C and EPIC3 trials (www.cochrane.org/CD003617/LIVER_interfer...-chronic-hepatitis-c). But these trials used long-term (during 3 years, for example) "supportive" interferon monotherapy treatment for patients with cirrhosis. Of course, interferon is a serious medication with many side effects, and its long-term (for several years) administration with cirrhosis may cause decompensation and/or additional mortality risk. But, if I correctly understand, this does not mean that "short" courses of interferon (for example, 12-24 weeks) will give similar 3% of additional mortality.

Another question is possible - if we possibly have initial 7% blip of HCC risks after treatment, then, does it mean that treatment with DAAs with cirrhosis looks like some sort of "Russian roulette" game with 1 "HCC-bullet" per 13 empty chambers?

Hey Serg, you have forgotten to add your path details to your signature.