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HCC risk in Hbsag cleared patients
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HCC risk in Hbsag cleared patients

Dear Studyforhope, Steff ! Could you please comment?

Eradication of hepatitis B virus (HBV) is not an
achievable endpoint with the current available anti-HBV
therapeutic regimens. Even the closest outcome to a cure,
hepatitis B surface antigen (HBsAg) seroconversion, is
not associated with HBV eradication, as clearly shown by
the significant risk of HBsAg seroreversion on drug- or
disease-induced immunosuppression. Because HBV is a
covalently closed circular DNA (cccDNA) virus, it is only
marginally affected by long-term nucleotide or nucleoside
analogue (NA) therapy. That HBV can integrate into the
host genome makes eradication of it a dream that will
never come true. To shed some optimism on this issue,
clinicians should be aware that eradication of HBV is
really not necessary to improve patient survival or prevent
progression to cirrhosis or clinical decompensation,
although HBV may play a significant role in the residual
risk of hepatocellular carcinoma (HCC) that patients face
despite successful long-term viral suppression.

http://www.gastroenterologyandhepatology.net/files/2013/10/gh1013_hep1.pdf

Does this mean that even in case of hbsag clearance good chance of HCC still remain and the only advantage of hbsag clearance is that antivirals can be stopped safely? Is there any clear relationship between HCC development and levels of hbsag? I hope I am wrong.
26 Comments Post a Comment
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Avatar_m_tn
Clearance of the surface antigen is associated with a significant risk reduction for HCC. Several studies have shown that. But the risk is still elevated in comparison to the non infected population.
The paragraph in gastroenterology re eradication is quite realistic.

Within the hbsag seroconverted population there will be a great variation in regard to the amount of remnant cccDNA and also the residual cancer risk and the propensity to flare up upon immunosuppressive treatments.
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Avatar_m_tn
Studyforhope thanks for comment! Very disappoining that even hbsag loss elivated HCC risk still remains.

Hepatology. 2010 May;51(5):1531-7. doi: 10.1002/hep.23464.
Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus.
Simonetti J, Bulkow L, McMahon **, Homan C, Snowball M, Negus S, Williams J, Livingston SE.
Author information
Abstract
Some individuals who are chronically infected with hepatitis B virus (HBV) eventually lose hepatitis B surface antigen (HBsAg). Hepatocellular carcinoma (HCC) has been demonstrated to occur in a few patients after loss of HBsAg. Neither factors associated with loss of HBsAg nor the incidence of HCC thereafter have been clearly elucidated. We performed a prospective population-based cohort study in 1,271 Alaska Native persons with chronic HBV infection followed for an average of 19.6 years to determine factors associated with loss of HBsAg and risk of developing HCC thereafter. HBsAg loss occurred in 158 persons for a rate of HBsAg clearance of 0.7%/year. Older age, but not sex, was associated with clearance of HBsAg, and loss of HBsAg was not associated with any particular HBV genotypes (A, B, C, D, and F) found in this population. Participants were followed for an average of 108.9 months after HBsAg loss. Six patients, two with cirrhosis and four without, developed HCC a mean of 7.3 years after HBsAg clearance (range, 2.0-15.5 years). The incidence of HCC after clearance of HBsAg was 36.8 per 100,000 per year (95% CI 13.5-80.0) which was significantly lower than the rate in those who remained HBsAg-positive (195.7 cases per 100,000 person-years of follow-up [95% CI 141.1-264.5; P < 0.001]). After loss of HBsAg, HBV DNA was detected in the sera of 28 (18%) of those who cleared a median of 3.6 years after clearance.
CONCLUSION:
HCC can occur in persons with chronic hepatitis B who have lost HBsAg, even in the absence of cirrhosis. These persons should still be followed with periodic liver ultrasound to detect HCC early.
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Avatar_m_tn
http://www.ncbi.nlm.nih.gov/pubmed/20087968
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Avatar_m_tn
Is it possible to meausre and monitor remnant cccDNA over time after hbsag is cleared? By what means?  
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Avatar_m_tn
CccDNA can be measured in liver biopsy specimens by specialized PCR. In the lowest ranges it's accuracy will be doubtful. It is not available for patient routine samples.
The hbsag itself is a measure of remaining ccccDNA. But once an antibody is present, it will complex and mask small amounts of free hbsag. Thus it's negativity, even with very sensitive assays, does not mean that it is not still produced in small amounts.

Assays could be developed that allow to identify hbsag inside immune complexes. They are not available yet.
For the e antigen, such an assay to detect e ag inside immune complexes was developed and it showed that even in e ag negative patients a large amount was hiding inside immune complexes.

Ulrike protzers Tcells with a modified TCell receptor that has a single chain hbsag B cell epitope specific       attached at the recognition end of of its artificial TCR should be capable to search and clear the liver from remaining hbsag producing cells to a much higher extent than what naturally occurs, leaving almost no HBV infected or integrated hepatocyte behind. This could further reduce the residual HCC risk.
It is unclear if this system will ever reach approval stage. The use of a retro viral vector to introduce the artificial TCR into the patients CTLs will be considered a risky aspect of the technique. Furthermore the practical application will be cumbersome and expensive, preventing commercial entities to engage into an uncertain development. However, its use as a promising cancer treatment might be able to overcome this hurdle. The same can be said of bertolettis engineered CTLs, which use the regular TCR.
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Avatar_m_tn

for hcc prevention i see only this as available today (and in the next 3-5years) and applying to myself:

monitoring nagalase and using gcmaf to make it normal

trying to make hbsag negative by sequential treament nucs and peg add on

prevention of other diseases thru diet/correct lifestyles
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Avatar_m_tn
Do the s and e immuno complexes remain in the blood or are some of them trapped in other organs, such as the kidney?

Stef2011 posted this recently:

Study finds genetics—not drug resistance—is why some patients don't respond to entecavir: While entecavir is recommended as one of the top, first-line treatments for hepatitis B, a small percentage of patients respond slowly to the antiviral.

Researchers have suspected that some people may harbor virus with mutations that are able to "resist" entecavir's ability to halt viral replication. However, a study published in the November 2013 journal Antiviral Therapy, finds that a weak immune system may be the culprit.

Italian researchers analyzed HBV from five people who responded quickly to entecavir and five who responded slowly. They found no entecavir-resistant virus in patients who failed to respond, instead they found a weak immune response that... "might be at odds in rapidly clearing infected cells from the liver."

Source: www.ncbi.nlm.nih.gov/pubmed/24275042

RESULTS:

The few resistance mutations present at T0 were not selected by treatment: no other resistance mutations nor suggestive mutational patterns were selected at T1. Selective pressure analysis indicated that both at T0 and T1 the HBsAg ORF was subjected to a significantly higher pressure in rapid responders, especially in a region rich in CTL epitopes.
CONCLUSIONS:

The results did not provide evidence that a slower response to entecavir is due to the emergence of less sensitive variants. Rather, the lower selective pressure and variability in humoral and CTL epitopes in slow responders suggests that their immune response might be at odds in rapidly clearing infected cells from the liver.

Does this suggest that antiviral can cause immune system to clear infected liver cells?!

Your help in understanding this concept of selective pressure is greatly appreciated.
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Avatar_m_tn
Immune complexes circulate in the blood for some time, have a tendency to attach to capillary walls, like on the loops of kidney glomerular endothelium. This attachment can cause local inflammatory cascade events and is responsible for many of the prodromal and chronic peripheral symptoms of HCV and HBV extra hepatic manifestations.
Eventually, these complexes are all engulfed and processed by macrophages, which tend to process their protein components into both class I and classII pathways for dual presentation on both types of MHC membrane proteins in their respective peptide grooves, where they wait for cd4 and cd8 cognate, that means fitting, t lymphocytes.
Immune complex engulfment provides a higher level danger signal to the macrophage than the endocytosis of pure surface antigen particles.That was the basis for Dr. Wens therapeutic vaccination approach, that she tenaciously pursued for many years. An iron lady indeed....

Regarding the slow response to Entecavir by some patients, without the presence of resistance mutations:

Entecavir by itself can lower the vital load only about 98%, that reflects the reduction in the speed of reverse transcription and replication together, it also has some effect on the so called priming step.

But in clinical practice , we see a much more pronounced reduction , often 10000 fold or more.
If you look at the viral,load curves in the trials, you see a quick drop in the first few weeks followed by a slow, but consistent decline afterwards, often called phase two.
It reflects the fact, that there is a variable, but substantial antiviral effect present simply by the sum of all immune activity, especially certain cytokines, that lower the efficiency of replication, by mechanisms different from the antivirals.
Some of these mechanisms get partially blocked by high virion and antigen loads.

So the answer lies in the fact, that some patients do not provide a high contribution to the antireplicative mechanisms of the antiviral. So it appears as if Entecavir is not fully working, while it does its job, without proper internal support.

The paper also points correctly to the possibility that the existing epitope repertoire is not of an effective nature in certain patients, as expected, hence a lower given dynamics of infected cell clearance.
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Avatar_m_tn
The higher selective pressure as determined by sequencing in rapid responders in regions of epitope richness is simply a reflection of the fact, that an effective mechanism was indeed in place, against which the HBV system of this patient started to respond with evasive mutations...exactly as expected.
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Avatar_m_tn
Many thanks for that.

"It reflects the fact, that there is a variable, but substantial antiviral effect present simply by the sum of all immune activity, especially certain cytokines, that lower the efficiency of replication, by mechanisms different from the antivirals. "

These antiviral effect is always present, even in the absence of antiviral medication? Or are they unlocked or enhanced when a patient starts taking antivirals?

The slower phase 2 reduction is due to what?
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Avatar_m_tn
This antiviral effect is always present, obviously in dramatically different strength, that explains the huge differences in untreated viral loads that we see. But the antiviral might also, by lowering some of the blocking effects of high virion and antigen loads, contribute to a recovery from these immunosuppressive effects.
The best example for the effectiveness unblocking of antigen loads  are the Replicor compounds, that have no direct antiviral replication inhibitory effect, and yet the viral load starts to drop dramatically.

Thus the phase 2 reduction is due to a new equilibrium between production/reinfection rate and removal rate of infected cells, that favors removal for a while, before a stable phase is reached again and the phase 2 ends.

In the beginning it was naively assumed, that the phase 2 will continue indefinitely. So they came to calculate how many month it will take to remove all the infection...

A further effect on phase 2 comes from the slight immunostimulatory effect of adefovir and tenofovir. They stimulate macrophages, it was published by Antonin Holy himself. So that might explain some differences between entecavir and tenofovir.

Paradoxically, in the end, the almost complete removal of the virions from the circulation leads to a reduction of immune stimulation. This is good news for the liver, so that the relentless but nevertheless unsuccessful attacks reduce substantially. This is mainly how the antivirals protect liver health.
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Avatar_m_tn
Hepatology. 2010 May;51(5):1531-7. doi: 10.1002/hep.23464.
Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus.
Simonetti J, Bulkow L, McMahon **, Homan C, Snowball M, Negus S, Williams J,

I understand above article discusses chance of development HCC for patients who naturally cleared hbs antigen, do you think HCC chance is lower for people who cleared hbsag under interferon treatment? or there is no significant difference between natural clearance of chronic hep b and under interferon regime?
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Avatar_m_tn
Natural hbsag seroconversion is the better development, because it indicates a constellation of viral epitopes, TCell responses and other immune factors, that does not need the extra stimulation by external ifn to reduce the infected cell burden.

But HCC development depends on many other factors, leading either to more integration events with genomic disturbances and then chronic inflammation with oxidative stress introducing maturing mutations into the precancerous liver cell, expression intensity of the x gene and more.
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Avatar_m_tn
Many thanks, again. I am still trying to understand all these. I read in a paper by M-L Michel in which she stated:
"A decrease in HBV load seems to precede the detection of HBV-specific T cell responses, both in patients resolving natural infections and in those displaying flare-ups of hepatitis associated with HBeAg seroconversion during chronic infection. Reducing HBV load by antiviral chemotherapy may therefore increase the responsiveness of HBV-specific T cells, which are hypo responsive in cases of persistent HBV or viral antigen stimulation. Indeed, HBV-specific T cells are detectable during the first few months of lamivudine treatment."
She continued: "However, this restoration of T-cell activity is partial and transient and does not lead to an increase in HBeAg seroconversion".

All these agreed with your explanation. However, the reliance on our immune system for a rapid decline in viral load after the start of antiviral treatment, seems to raise doubt, in my mind, about the potency and effectiveness of antivirals. Yet most patients achieve very good viral load suppression. In those slow responders, seen in Entecavir patients, there seem to be a pause in viral load reduction after initial good reduction - can we expect Entecavir to be able to continue to reduce the viral load, even though at a slower pace? Most studies seem to indicate Entecavir can eventually bring down the viral load for most of these slow responders. But what to do, for the few exceptions (they may even see a small rise in hbvdna)?

In an abstract by Marie Buti published in the recent EASL Monothematic Conference, 25 TDD-treated patients with persistently undetectable HBV for 7 years were observed after they stopped TDF. She concluded:
"Increased ALT levels 2 months after TDF suggest delayed immune system activation, apparently not sustained over time, and patients may show different patterns of response to it."

So this seems to pose a dilemma - antivirals may restore T cells response, but the T cells seem to be overwhelm again when viral load is again allowed to increase by stopping the antivirals.

Any comments?
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Avatar_m_tn
To explain the great variety in the antiviral effectiveness of Entecavir in different patients, we have to consider three major areas of influence on overall effectiveness:

1. The combined extra cellular and intracellular pharmacokinetics can be quite variable and influence the actual level of the final processed compound on the HBV polymerase. The effectiveness of phosphorylation in the cytosol is critical in the process of creating the actual inhibitor, but is hard to measure in vivo. The classical pharmacodynamics parameters examine blood and urine and bile , but not the speed of uptake into the hepatocyte and the intracellular processing by enzymes into the final truly inhibiting triphosphate nucleotide analogs, that do the real job.
Thus a particular patients processing capacity might variable contribute to the  available concentration of the replication inhibitor inside the hepatocyte. These concentrations are very important for the efficiency of reducing the polymerase processing speed.

2. Aside from known resistance mutations, the polymerase will contain genotype specific and other patient specific slight structure variations that will influence the actually available reduction in replication processing speed.

3. The ongoing impairment of transcription and replication by cytokine responsive intracellular mechanisms, globally called the "immune effect", depending on the multitude of signals from a partially effective anti HBV immune response....that is leading to chronic inflammation, hence hepatitis...will provide its contribution to the net effect of lowering virion production. Additionally, the lowering of tolererizing virion and antigen load will variable contribute to TCell activities that help to reduce viral productivity.

In combo, we will see substantial variation in the vl curve from patient to patient and a small percentage never makes it to und status. These could try to combo etv and Tdf. And never forget that a liver protective life style will reduce fibrosis progression and HCC risk.
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Avatar_m_tn
In regard to the so called restoration of the TCell response one needs to be aware that a laboratory test to induce TCell replication and possibly some function is a far cry from the needed breath and intensity and quality of a TCell response to effectively limit and control the hepatic infection to a few remnant cells.
Thus the initial discovery by Carlo Ferrari that lamivudine patients restore some measurable TCell function when using his test battery has caused much early  excitement. But it is way less than what is truly needed to control the HBV system in vivo.
Nevertheless, preparing the TCell system by partial restauration using Tdf  for a new start under the whip of interferon is likely a way to get a certain percentage under true permanent control.
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Avatar_f_tn
Glad to see studyforhope again providing hope for hopeless people through his sound scientific knowledge of the subject.
Please folks, we need to develop a way in this community to actually show appreciation to the people that offer the time and skills to others.
May God bless and reward you immensely.
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Avatar_m_tn
How about serum HBsAg and HBVDNA BOTH becoming negative on their own (by the body, not drug-induced) in later stages of life, say in the 50s? I mean HBVDNA already und and HBsAg finally becoming und with age.

They say the liver has regenerative properties so that if the damage is not already substantial at that stage, the liver can return to normal.
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Avatar_m_tn
Very grateful for the explanations.
It is difficult to understand all the variability of the different antiviral treatments.   It seems there is no single magic approach, but one has to throw everything at it, including the kitchen sink, to get a cure.
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Avatar_m_tn
Dear Studyforhope

It is well known that even after reaching hbsag clearance by interferon majority of patients still test positive for HBV DNA and cccDNA inside liver cells. Do you think that extending interferon therapy even after Hbsag clearance is reached can further reduce amount of cccDNA in liver hopefully eliminating it completely? If yes, then to what maximum time can theraphy be extended?  

Always thanks for you kind support!
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Avatar_m_tn
The complete elimination of all cccDNA is an unrealistic goal, unfortunately.Plus, some of yhe viral genomes are already integrated into the chromosomes and do not exist as cccDNA, but are able to ecpress themselves and produce virions. these liver cells with integrations can be eliminated by killing only, not by interferon gamma. Some will contain mutations that will make them invisible to patrolling cd8 cells.

Extending peg ifn therapy beyond hbsag "loss" will further reduce the viral remnants, reducing chances for HCC, but the price will be increasing autoimmunity disorders and all the side effects of ifn therapy.
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Avatar_m_tn
In case of extending INF therapy beyond hbsag loss in serum, what blood tests need to be done to catch autoimmunity disorders on early stage and stop INF?
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Avatar_m_tn
maybe high dose vitamin d and or gcmaf can prevent autoimmunity

the problem is few studies on this with vit d and supposed autoimmune diseases, nothing pegintf plus vit d
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Avatar_m_tn
My current vit d level is 85.44 ng/ml while it was 57 ng/ml one year ago. I am not taking vitamin D.
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Avatar_m_tn
ANA..anti nuclear antibodies... Titer is the usual unspecific test for B cell dominated autoimmunity, as in lupus erythematodes. But there is no test to predict autoimmunity early or specifically. There are so many different manifeststions of autoimmunity, for example thyroid dysfunction, often brought out by ifn therapy. The HCV board has many examples of this.
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Avatar_m_tn
According to this latest study lowering HBV DNA is most significant factor in reducing risk for future HCC developmnet and should be major goal for HBV management.  So antivarls are not that useless as some researchers report?

http://www.alabmed.com/uploadfile/2013/1223/20131223090246322.pdf
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