Are we with chronic hepatitis B producing antibodies against HBsAg?
Before starting treatment, my HBsAg levels were at 25000 - which was the higher limit of the lab I was tested in (real value was likely higher). HBV DNA was 5.2 LogIU/mL / 5.9 LogCopy/mL.
I also had minimal HBsAb levels, somewhere around 0.69 (treated as “no antibodies”).
Around a month after starting the TAF therapy my HBsAg levels were around 26000 (different laboratory, was able to detect higher values than the previous one). HBV DNA went into “undetectable” (defined as <10 IU/ml) after around 3 months of TAF therapy.
Fast forward around 1.5 years of therapy - my HBsAg level was constantly dropping with every checkup. The lowest value I had was around 10000.
I’m also unfortunate enough to have a blood cancer - SMZL (diagnosed just before I’ve started HVB antiviral) - and was treated with Rituximab in May 2022. Rituximab kills mature B cells, so I’m unable to produce antibodies for the next 12 months after treatment or so.
Now, I had a checkup in August - my HBsAg levels rebound from around 10000 to over 28000. HBV DNA level is still “undetectable”.
Why such a big HBsAg rebound? Are such jumps normal, after dropping trend for ~1.5 yr? I’m strictly following 1-aniviral-pill a day in the morning since I’ve started taking TAF - with a reminder in my mobile phone, pill box reminder and my wife reminding 
Or, perhaps - we with chronic HBV constantly produce antibodies against HBsAg, but they are so overwhelmed by circulating HBsAg - that the antibodies are outnumbered and can’t clear the infection? This would explain my HBsAg rebound - no new antibodies, nothing in my blood to attach to circulating HBsAg?
Any hints appreciated!
Dear Mantana,
Your last notion is the correct one.
Everyone with chronic HBV infection makes antibodies to HBsAg and HBeAg. Unfortunately, the term “seroconversion” is used a lot to describe the appearance of free antibodies to these antigens during the natural history of or during treatment of chronic HBV infection. This gives the impression that the appearance of these antibodies drives the loss of these antigens. This is not the case.
In the case of HBsAg, the large amounts of this antigen actually turn over very rapidly in your body (within days) by processes we don’t understand yet but which are not driven by antibody production.
For HBeAg and HBsAg, antibodies are rapidly consumed by interactions with these large excesses of antigen and never seen using standard assays (which can only see free antibodies). The presence of these antibodies can be seen by special assays that look for immunocomplexes of antigen and antibody. Using these tests we can see antibody production in all patients.
HBeAg seroconversion results from unmasking of anti-HBeAg antibodies becuase of the loss of production of HBeAg (or in more rare cases the presence of certain HBeAg mutations). Similarly, anti-HBsAg antibodies appear once levels of subviral particles (not virus) are very very low low in the circulation (usually less than 1 IU/mL HBsAg).
The reduction of HBsAg during your TAF therapy is very unlikely to have been impacted by antibodies to HBsAg but rather by silencing of the minor source of subviral particles (cccDNA) by stimulating innate immunity. The ability of medicines like ETV, TDF and TAF to stimulate innate immunity is not well known in the field but is actually one of the oldest described functions for these compounds.
Rituximab interferes with innate immunity and your course of rituximab likely worked against the control of cccDNA established by TAF, allowing increased production of viral proteins, leading to increased levels of HBsAg (from subviral particles) without a detectable increase in the production of virus. This is because the production of subviral particles occurs by a mechanism completely distinct from the production of virus.
In your case, the appearance of blood cancer during your therapy for HBV is a certainly an unfortunate complication but the rituximab you received was undoubtedly an important and necessary therapy for you.
The decline in HBsAg during your TAF therapy is obviously a good thing but the rebound of HBsAg does not mean something is wrong with the control of HBV infection that TAF is providing. The effects of rituximab do not last forever so you may start to see HBsAg declining again in subsequent testing.
Hope this helps.
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