Hi @Mihai_P,
Sorry to hear that what you had hoped was only an acute HBV infection concluded to be chronic. One of the experts will have a response for you as soon as they can. Until then, I just wanted to welcome you to the community. You have found a good place for understanding and support. Feel free to take a look around the forums and you can do some searches with the magnifying glass on the top right of the mainpage.
-Paul
Dear @Mihai_P,
Welcome to the community and thank you for sharing your story. With HBeAg positive status and moderate HBV DNA levels, your condition doesn’t necessarily fit into a textbook “phase” of chronic HBV infection. My understanding is that people over 30 such as yourself can consider treatment, but there is no outright recommendation to treat. This is because we essentially don’t know if treating you now will cause any different clinical outcomes compared to not treating you.
If you were to begin treatment, then the 2 first-line treatments (tenofovir or entecavir) are both highly potent drugs with minimal side-effects.
Hope this helps,
Thomas
Hello @ThomasTu and thanks for your reply!
I understand, but I just need to make one clarification:
In the results I got from the clinic, both in March and in September, the HBeAg 0.395 S/CO is considered negative (Nonreactiv: < 1.00 S/CO, Reactiv: >= 1.00 S/CO). While Anti-HBeAc 0.01 S/CO is considered positive (Nonreactive: >1.00 S/CO, Reactive: =< 1.00 S/CO).
So HBeAg being negative changes what you said in any way, regarding the start of treatment?
Thanks so much!
@PuallyHBV thank you for your kind words!
Ah, thanks for the clarification @Mihai_P, it is a bit confusing!
My understanding is that if there is no evidence of liver inflammation (and you do not have a family history of liver cancer) then current guidelines would not recommend treatment in HBeAg-neg phase (but you can consider it).
This is based on current EASL guidelines, but these are being updated over time given more research in the field.
Thomas
Thank you @ThomasTu. I went to another medic for a second opinion l, and she suggested that I should do a FibroMax blood tests to decide if medication should be started. I’ll do it on Monday and then it will take 4-6 days for the results to come.
Btw, regarding medication: here in Romania where I live they prescribe Entecavir by default, no alternatives. But from what I’m reading on the internet, in other countries Tenofovir is more common. And it seems that for Tenofovir there are two variations. My question is, which is the best antiviral out there?
Thank you!
Great to hear, @Mihai_P.
In answer to your question, essentially tenofovir and entecavir are equivalent in antiviral effect. I’ll refer you to some responses to a similar post:
Cheers,
Thomas
Hi again @ThomasTu @john.tavis @availlant and other experts from the forum.
I repeated the tests yesterday, after one and a half months, and although I didn’t get yet the result for HB-DNA, I did get the other values, and the HBsAg one scares me honestly. Below you can see what I got so far:
| Fosfataza alcalina | 98 U/L | 40 - 150 U/L |
| Gama GT | 60 U/L | 12-64 U/L |
| TGO/AST | 28 U/L | 5- 34 U/L |
| TGP/ALT | 41 U/L | < 55 U/L |
| HBsAc | 0.22 mUI/mL | Nonreactiv: <10.0 mUI/ml / Reactiv: >=10.0 mUI/ml |
The problem is this one:
| HBsAg cantitativ High Reactiv 35496.17 IU/mL |
Last time when I did it, back in September, the value was 3005 S/CO.
I don’t know why they’ve changed the measure unit this time from S/CO to IU/mL and also I don’t know if we 're looking at the same values where only the unit of measurement differs. But I highly doubt that’s the case.
I’m still waiting for the HB-DNA result which I will get on Tuesday/Wednesday next week, but I’m already scared by such a high HBsAg value. Am I right in being scared or isn’t it something to concern me that much?
By the way, as I was telling you last time, I also did a FibroMax which came with F0, A0, S0-S1, N0 and H0. Also the Fibroscan gave a value of 4.7 kPa and since my ALTs values were always normal, they’ve said that probably I don’t need to start with the antiviral treatment.
Until today when I got the new HBsAg value, and they don’t know what to do with me anymore.
I also did a MRI abdominal check and beside a 2.5x2.5 hemangioma, there’s nothing wrong with my liver so far.
I’m grateful for any feedback or insight I might get from you!
Thank you so much!
– Mihai
Dear @Mihai_P,
Your first HBsAg test result (3005 S/Co) is a from a qualitative test which cannot accurately quantify the level of HBsAg present. However, with this ratio of signal to cutoff S/Co the amount of HBsAg present in this first test result is certainly significant.
There is no point in comparing (numerically) this result to your most recent result (35496.17 IU/mL) which is from a quantitative test. However, I don’t think there has been a meaningful change in the level of HBsAg present. It is important to understand the HBsAg levels like this are not uncommon in chronic HBV infection, even under NUC therapy. Also changes in HBsAg do not predict potential progression in liver disease.
The important thing is that your liver function assessments and fiborscan are normal. Please get back to us with your HBV DNA when you get it.
Best regards,
Thank you for the reply and explanations @availlant (and @ThomasTu on the other thread).
This is pretty much in line with what healthcare providers are saying here in Romania where I live, that is: HB-DNA being the true marker of the disease progression and the one saying if medication should be started or not, while the HBsAg quantitative values can be ignored.
The first thing that troubles me regarding this is the medical studies and articles I’ve read, which make a correlation between the level of HBsAg higher than 2000 IU/mL, HBeAg negative, and the high incidence of HCC later down the road (usually after 10-20 years).
Secondly, only with the previously known HB-DNA of 15000 UI/mL and the value of HBsAg of 35496 IU/mL, one healthcare professional I’ve been going to is already recommending starting the Entecavir treatment. While other two healthcare professionals are saying that HBsAg value does not matter, HB-DNA is relatively low and will probably fluctuate between 3000 and 15000 IU/mL, and overall the disease has been there for decades and pretty much is inactive, so treatment is not required, unless I personally decide to start it.
So with these two “sets” of information and decisions, I’m really confused and torn, to say the least. I would really appreciate if you could give me your perspective on these two points from above.
Thank you again!
– Mihai
Dear @Mihai_P,
You are not alone in your confusion. Guidelines in different parts of the world take different approaches:
Liver cancer is caused at least in part by the buildup of insertions of viral DNA in cells of the liver which accumulates over the lifetime of infection. You are right that the risk of liver cancer is elevated in individuals with chronic HBV infection - which is why the approach in (1) makes sense. There is also data to suggest that early initiation of suppressive therapy (ETV / TDF / TAF) lowers the risk of liver cancer.
This is important debate currently in the field.
You may want to consider starting therapy even though you do not have liver disease as the long term safety profile of these medications is excellent. I encourage you to discuss with with your doctor.
Best regards,
Thank you again for your reply @availlant, I really appreciate it.
I’ll definitely discuss this further with my healthcare providers and also come back here with my HB-DNA result when I’ll get it in the coming days.
However, one thing that confuses me is this (based on my limited knowledge and understanding):
HBsAg is a marker of how many of the hepatocytes are infected by the virus, while HB-DNA says how much of the virus is in the blood.
Also, antiviral medicine as Entecavir and Tenofovir are capable of taking down the viral load to low or even undetectable levels.
But antiviral medicine does not (normally) decrease the values of HBsAg.
So if high levels of HBsAg can be a risk of HCC development in the future, how can antivirals be of any help if they can’t take down also the HBsAg values?
I’m sure I’m missing something in my reasoning
Thank you,
– Mihai
Dear @Mihai_P,
Well actually you are on the right path!
HBsAg is almost entirely (> 99.99%) in the form of subviral particles (SVP) which are very similar to the “good” cholesterol (HDL) in your blood. SVP can get recycled through liver cells (like HDL) but have no HBV genetic material and so cannot support the production of virus. SVP play an important role in the prevention of immune control of HBV replication in chronic infection. Importantly, these particles are produced by a pathway completely distinct from that used to make virus inside infected cells. This is in large part why HBsAg is not affected by currently approved oral antiviral drugs which target viral infection also and why therapy is life long with these medications.
HBsAg is produced from two kinds of infected hepatocytes (liver cells):
Hepatocytes which contain the active genetic reservoir of the virus (we have a complicated name for this: cccDNA). These cells produce both infectious virus and subviral particles.
Hepatocytes which contain one or more “broken” copies of the HBV viral genome which has become inserted into the one or more chromosmes. We call this form of HBV genetic material integrated HBV DNA. While these cells are technically “infected”, in its broken form, integrated HBV DNA they contain cannot support the production of virus but can still support the production of SVP. With the progression of chronic HBV infection (to a stage we call HBeAg negative), the shift of production of SVP (and the bulk of HBsAg) occurs mainly to cells with integrated HBV DNA.
We have good data that shows that the level of HBV DNA integration is much higher in cancer cells than in normal cells in the liver. This is because as integration increases over time, more chromosomes, and the genes that they contain, get disrupted by these integration events, leading to cells dividing out of control (cancerous).
HBV DNA integration is a process which begins after the first infection event and progresses over the course of chronic infection. This process of continual HBV DNA integration requires production of new infectious virus and occurs even with low levels of HBV DNA being produced.
Thus while HBsAg is produced from all infected cells in the liver, the level of HBsAg present does not reflect either the number of infected cells nor the proportion of cells with integrated HBV DNA nor how much HBV DNA integration is present is in individual liver cells. HBsAg persistence does indicate an enhanced risk of liver cancer long term but the level of HBsAg present (or even its change over time) does not provide an indication of the risk of developing liver cancer.
Clinicians who understand these features of HBV infection are more likely to understand the importance of early introduction of therapy to suppress viral replication in order to slow down HBV DNA integration as much as possible and lower the long term risk of developing liver cancer as much as possible
Hope this helps.
@availlant Thank you so much for your detailed answer. I’m honest when I say that since March 2023 when I found about my infection, in all the studies and articles I’ve been reading on the subject, I haven’t found anything as close as detailed and well explained. For e.g., most of the papers talk about the cccDNA concept, what it is and why it’s so hard for scientists around the world to find a fix for it. But I did not find absolutely anything about ‘integrated HBV DNA’ and what it means in the context at hand.
What you wrote makes a lot of sense and it’s pretty clear that the sooner I start the treatment the better it might be later down the road. However, I do have a few follow-up questions if I may:
(disclaimer: I’m an IT professional since 2008, and I’ve been coding and dealing with computers since '96, so my mind is one of a programmer which is used with lines of code, debugging, etc., a mindset that might be not proper for this field/context)
Regarding the infected hepatocytes and active viral replication: let’s assume that via a NUC treatment, a patient takes their viral load down to 0 (or undetectable values). Also, the HBeAg seroconversion happened so it is negative. But the same patient has a HBsAg value of ~30,000 IU/mL (so some of the hepatocytes are infected by the integrated HBV DNA and they are actively producing the HB surface antigen SVP).
My question is then: if there is no active viral replication (HB-DNA being 0), and knowing that the liver cells are periodically regenerating, will new cells also be infected (i.e. have their DNA infected with the HBV DNA) or will they be clean? If they will still be infected, I would ask why? What could infect them again? Or is it because the regeneration happens through cell division, and since the ‘source’ cell was infected so is the new one?
“This is in large part why HBsAg is not affected by currently approved oral antiviral drugs which target viral infection”
My question here is why in some studies from around the world it was observed that sometimes (rarely, but still happening) oral antiviral medication also helped patients take down their HBsAg values. And extremely rarely some experienced even an HBsAg seroconversion.
If Entecavir/Tenofovir/others are not affecting SVP such as HBsAg, how come sometimes the values are still decreasing? Or is it just a coincidence and the HBsAg value decrease is caused by something else?
This process of continual HBV DNA integration requires production of new infectious virus and occurs even with low levels of HBV DNA being produced.
But would in this case an antiviral treatment help only by preventing more infection to happen, or could it also help “fixing” the already infected hepatocytes? (this one might be linked to the 1st question)
I hope that my questions make some sense, sorry if not. But I do appreciate any answers I might get for them.
Thank you so much again!
– Mihai
Dear @Mihai_P,
HBV is a very intensely studied virus and HBV infection is also studied by numerous groups worldwide. However, for a layperson, it can be very challenging to navigate where to go. This is why we are here to help individuals like yourself to understand your infection better. So lets get back our ongoing discussion…
Question 1.
It is important to understand thereis no such thing as HBV DNA = 0 but rather that HBV DNA so low that it cannot be detected by the assays that we use. For this situation in a HBV DNA test we use the term “target not detected” . These levels of HBV DNA are so low that liver inflammation can reverse as if there was no virus present and is it very likely that all new infection and HBV DNA integration is halted as well.
Cells in the liver do turnover and there are some good studies (especially from Thomas Tu’s lab) which show that with this effective suppression of HBV replication, a slow gradual erosion of cells containing cccDNA in the liver occurs because cccDNA does not get efficiently sorted into progeny cells when a liver cell divides. However cccDNA is generally maintained as a stable “minichromosome” in non-dividing cells so we measure these declines in cccDNA over years and decades.
Question 2.
You are correct. In general, HBsAg loss (and functional cure) generally occurs in 0.5 - 1 % of patients. There are some studies which have shown higher rates of rapid HBsAg loss on NUC therapy but these have been in special populations where HBV infection has only just become chronic.
There are several issues at play here:
NUCs are actually bifunctional agents which can also stimulate some parts of the immune response (innate immunity) to inactivate cccDNA. So studies where patients have only just recently developed chronic HBV infection (and most of the HBsAg is coming from cccDNA), HBsAg loss rates are higher because of the inactivation of cccDNA.
Individual immune function, is variable from person to person and in some rare cases, small declines in HBsAg or even reduced viral replication is enough to start the process of immunological control. We know very little about how this occurs and as you know this is very rare.
There is a correlation between the levels of HBsAg circulating and the response to approved immunotherapies like pegylated interferon and also the efficacy of some antiviral drugs currently in development. This is becuase the amount of HBsAg present is correlated with reduced functioning of some aspects of immune function (like innate immune response in the liver).
Question 3.
Current antiviral treatment which targets viral replication primarily helps by blocking new infection and preventing HBV DNA integration. “Fixing” already infected hepatocytes is something unlikey to happen (atleast with high efficiency) because of the stability of cccDNA (even thought inefficiently transmitted during cell division) and the ability of cccDNA to exist in a dormant state which can reactivate even decades later. “Fixing” all infected cells including those with integrated HBV DNA is an outcome we call “sterilizing cure”. This is widely regarded to be an unachievable outcome in chronic HBV infection.
Question 4.
A great question. There are several studies demonstrating the existence of an extrahepatic reservoir of HBV infection in white blood cells. This is widely regarded to be a tiny and largely dormant reservoir of infection - however still theoretically a source of HBV reactivation. There are no approved drugs or drugs in development which are focused on this extraheaptic reservoir.
This old study from 1990 shows that “hepatitis B virus appears to replicate in the human spleen, although at a lower level than in the liver”:
Yes @mantana! …we also have this:
https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.1840180406
Evidence of extrahepatic HBV infection found in many tissues.
I confined my comments to the recent publications involving larger cohorts of patients but there are several older articles like this from individual patient studies.
What is interesting is that many of these extrahepatic tissues do not express the NTCP receptor, which has been identified as a receptor which can support HBV viral entry in the liver.
I do not have HBV but two people who are very dear to me have chronic infections.
How have you been able to survive with hepb for over 61 years?
Hi @availlant and thank you for you last reply. Again, a very insightful one!
Unfortunately, after almost a week I return with even more confusion, fear, uncertainty and doubt. Here’s why:
HB-DNA finally came yesterday and it went down from 15500 IU/mL in September to 7700 IU/mL. I also ask them to do with the same blood sample a qualitative HBsAg test, which went down from 3005 S/CO in September to 2500 S/CO now (which is however, quantitatively, 35496 IU/mL).
I went yesterday to my health provider, and they said that with my current values, and normal ALTs, F0, A0, S0-S1, I can not be included in the state HBV treatment plan, and if I really want to start the treatment, I’d have to pay for it myself. And once I’m doing that, I will pretty much have to pay for it myself forever, because most likely once I’m starting it, the viral load will go to undetectable values, which means that if I’ll ever have financial difficulties and need to switch to the hospital to provide me Entecavir, I will have first to stop taking the medication for a while to get the HB-DNA and ALTs levels high again, which might end up with a dangerous rebound.
Based on what you wrote me last time, I’m pretty much convinced that I want to start the antiviral treatment ASAP, but it’s now even harder than before to decide. In the way that now it’s not only a matter of a pill / day for the rest of my life, but also paying a few hundred euros per month for the rest of my life (which now I can perfectly afford, but living in Romania and having a war at our borders, I don’t know what future holds for me and my family).
What “kills” me is that my health provider and the others I’ve been to for a second opinion, are telling me “Mihai, you are ok, your liver is fine for now, so let’s way for six more months and redo the tests then”.
But this is exactly what you said last time:
They seem to prefer going with the latter, which on a 10-20 years perspective, I don’t know if it’s the best path for me to go.
I’m aware that you can’t give me a “do this” absolute answer, however I would appreciate any thoughts and suggestions regarding all this.
Thank you!
– Mihai
Dear @Mihai_P,
Thanks for the update. Some comments:
The number associated with S/CO doesn’t really have any relevance. Think of it as a pass/fail grade: if it is above a certain threshold, you are positive; if not, then you are negative - that’s all. Any numbers associated with this are difficult to say anything about. High HBsAg levels are expected for a chronic infection and do not really provide any information about the actual liver disease.
Yes, this is a difficult position to be in. There are many in the field trying to push for more open treatment options to cover more patients.
Meanwhile, there are aspects in the EASL guidelines for HBV treatment (https://easl.eu/wp-content/uploads/2018/10/HepB-English-report.pdf) that suggest that you should be considered treatment (e.g., Patients with HBeAg-positive chronic HBV infection, defined by persistently normal ALT and high HBV DNA levels, may be treated if they are older than 30 years regardless of the severity of liver histological lesions). I’m not sure if it’s worthwhile talking to your doctor about this?
Thomas