Deciding when to start treatment

General Discussion
368

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):

  1. 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.

  2. 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.

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369

@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)

  1. 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)

  1. I read that HBV could still be present in some cases even after a liver transplant. Does that mean that the ‘reservoir’ of the virus could actually be located also outside of the liver itself? If yes, have the specialists detected all the organs where it could be ‘hiding’? Or could it be because there is still some viral load flowing through the blood?

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

370

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.

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371

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”:

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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.

373

I do not have HBV but two people who are very dear to me have chronic infections.

374

How have you been able to survive with hepb for over 61 years?

375

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:

  1. Treat the infection as soon as it appears.
  2. Treat the infection only when liver disease develops.

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

376

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

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377

Hi @ThomasTu.

Thanks for the reply. The idea is that I am HBeAg negative, not positive.

They said that with the current European/Romanian guidelines, there’s no chance I could be included in the free treatment program. To be included, either the ALTs values should be at least a but over the top (not necessairly >= 2x), or Fibromax to show A1 and/or F1. Or for HB-DNA to be in the range of hundred of thousands or milions.
Myself, beside for a viral load higher than the limit of 2000 IU/mL (for a HBeAg negative person), I don’t check for any of these.

It’s like they want to see first some liver activity or damage before including me in the free medication plan. Which bothers me a lot…

Thank you again!
– Mihai

378

HI @Mihai_P,

Thomas is right, please do not look at the numbers in the qualitative test (S/Co) as an indicator of trends for HBsAg. No only can these values not be converted to a reliable quantitative value, the change in S/Co over time does not tell us if there is an actually a change in time in quantitative HBsAg.

Your challenge (and frustration) in Romania is one experienced by patients in many other countries: denial of HBV therapy (especially in HBeAg negative infection) until liver disease develops. Guidelines in the EU are only guidelines (not rules) but it may be that in Romania these guidelines are officially adopted for state coverage of antiviral medications. This is the current challenge faced by many countries (especially in Romania where HBV is estimated to be present in 4-5% of the population): it may be too expensive to provide therapy for every patient diagnosed with HBV infection. This is also a function of the cost of the medication which also varies worldwide.

In your situation (HBeAg negative with HBV DNA 7700 IU/mL, 35496 IU/mL HBsAg and ALT normal in the absence of therapy) here are the issues to consider:

  1. There is a chance that you might achieve partial cure (HBV DNA < 2000 IU/mL, normal ALT) where some studies have indicated that the risk of liver cancer is lower. This is not a common occurrence after HBV infection becomes chronic.
  2. It is unclear if suppression of HBV replication under NUC therapy has a better long term prognosis than achieving partial cure but you will almost certainly get excellent HBV suppression if you start taking NUC therapy.
  3. Delaying suppression of HBV (even at the levels you currently you have) will certainly not lower your risk of liver cancer.
  4. Once you do start NUC therapy, aggressive reactivation of HBV infection is possible unless HBsAg loss occurs (which is very unlikely).

So what to do?

  1. Take the prescription from your doctor even though you will have to pay for therapy.
  2. Look for the cheapest generic version of ETV or TDF (both of these are off patent) which you can get either inside or outside of Romania. I am not the expert on this but there have been discussions on this forum about acquiring cheap ETV or TDF.
  3. Decide how you want to proceed.

This decision is a very personal one - we are here to simply give you all the tools possible to decide what to and to also wish you the best moving forward!

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379

Hi @availlant. Thank you very much for your reply and thr “action items” list. I will (or am already) considering them.

Quick question for point 4, regarding the “aggresive reactivation of HBV infection” once I start the NUC treatment. You refer here to a possible rebound IF I stop the treatment, and not while I’m actively taking the meds, correct?

Another question regarding the cheapest variant of the Entecavir meds. Does it really not matter at all what I take? I mean they say that the most expensive one, which is double the price compared to the cheapest one, is ETV Baraclude, from the company that was the first to invent the original medication.
But what they aren’t saying is if Baraclude is also the best out there, with visible advantages or results over the others which bought the patent and developed their own versions of ETV. If they are all the same, i.e. with the same expected outcomes and the same risks of side effects, then I reckon it makes no sense to pay double the price for the same thing, just a different name.

Thank you!

  • Mihai
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380

Dear @Mihai_P,

With ETV and TDF (or TAF) rebound of infection during treatment is EXCEEDINGLY rare. Your NUC therapy will effectively control your infection and you will not experience reactivation while you are taking it.

ETV was indeed discovered in 1995 and developed by Bristol Meyers Squib. It was sold by BMS under the trade name Baraclude. Patents protecting ETV either expired or were invalidated worldwide between 2011 and 2017.

Since then, a wide variety of generic brands have become available in different parts of the world which are identical in efficacy and safety compared to Baraclude. I encourage you to source the cheapest generic ETV available, provided it comes from a reputable generic drug manufacturer.

Best regards,

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381

Hello again @availlant and @ThomasTu,

I’ve been doing a lot of reading and watching in the last week and things are starting to get a better shape in my mind. Some of the YT videos or papers I’ve read are from researchers out here, including you, so I want to thank you for all the hard work you’re putting for the rest of us!

I have however one big confusion after all this time, and for some reason I’m not able to find a concludent answer for it. That is the HBV phase I’m in. With my current values (I will paste them at the end of the message for easier reference), I’m not sure if my HBV is in the Reactivation phase (HBeAg-Negative Immune Reactivation Phase) or not.

I mean it’s clear that my HBV is active and I can’t be considered a patient being in the Inactive Chronic Hepatitis B Phase. However, everywhere I read about the Rectivation phase (for HBeAg negative), it’s said that ALTs are at elevated levels and there is moderate to severe liver damage. While neither of this is true in my case, where I have F0, A0 and normal levels of ALTs.

So how should I interpret all these and, assuming that I’m in the HBeAg-Negative Immune Reactivation Phase, why are my values different from the expected ones?

age: 37 years old (male)
HBsAg: 35496 IU/mL
HB-DNA: 7700 IU/mL
HBeAg: negative

Fibroscan: 4.7 kPa
Fibromax: F0, A0, S0-S1

ALP: 98 U/L
GGT: 60 U/L
TGO/AST: 28 U/L
TGP/ALT: 41 U/L

Thank you!
– Mihai

382

Dear @Mihai_P,

Thanks for your question. 7700 IU/mL is a relatively low/moderate level, but indeed is outside the general consensus of the inactive chronic HBV phase (<2000). There are actually a large proportion of patients who do not fit neatly within the 4/5 defined phases. These are known as “grey zone” patients, and these can make up to about a quarter of people with hep B (Significant histological disease of patients with chronic hepatitis B virus infection in the grey zone - PubMed).

There is current discussion about how best to provide care to grey zone patients and it is not a settled issue yet.

Hope this helps,
Thomas

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383

Hi all,
Couldnt find the comment button on this thread, so just replied to the last post.

So what is the formula to start treatment ?

I found this link, Core Concepts - When to Initiate HBV Treatment - Treatment of HBV - Hepatitis B Online.
And offcourse consult your doctor.

Br,

384

Hello @Opa
I am 63 years old. I have survived HBV this long because I get regularly tested every six months, went on anti-viral treatment when my blood levels went up and live ve a balanced lifestyle of no alcohol, cigarettes, drugs. I try to eat healthily, no fried food fresh as possible. No junk food or l soft drinks, cut out as much sugar as possible, although this sounds boring, I do indulge sometimes.
Try to live a stress free life. Liver doesn’t like stress and exercise.
We do have a section on healthy lifestyle somewhere. I hope I’ve answered your question

385

Hi @ThomasTu and thanks for your reply. This GZ category is interesting and I did not know about it. Do you have more references on articles regarding the proposed care approaches for GZ patients?

Also, is there any known reason for patients in this category to not have to start treatment?

Thank you,
– Mihai

386

Hi @Mihai_P,

Here are a few:

There are a lot of opinions on this, but the essential question has been (as it is with all decision of treatment) “does the patient benefit from a treatment more than the risks associated with it?”. The evidence for either side is still under a lot of discussion, and for many doctors it is about the “art” of medicine and where they are drawing the line on 1) the interpretation of the evidence; 2) their own experiences of the risks and benefits; 3) the context of the patient.

I personally would love there to be more input from the patient and affected communities, and emphasise patient-centred care where their informed choice makes a larger (the largest?) impact on whether they are treated or not. I think that our systems should support this choice as much as it can.

Hope this helps,
Thomas

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I seem to be in a gray area and am intimidated by the fact that once I start treatment I have to continue it for life. I am not great with routines and worry I’ll mess up. At the same time, I’m scared of waiting too long or until after harm has already been done.

I haven’t discussed my results with my doctor yet, but she seemed to indicate that treatment would only be recommended for viral loads over 20,000. Mine is at 7,500 and everything else is in normal range. However, I’m reading in this thread that <2,000 is where you want to be.