Do you mean to say flare in acute infection is bad? Doesn’t this indicate T cell response killing infected cells ? If not so how do acute HepB recover!!
And I have been reading about nomenclature associated with HepB cure like Functional, sterilizing cure etc. What do we name it when a person recovers from acute infection?
Dear AJK,
Good questions. For the second, resolution of acute HBV infection is classically referred to as resolved HBV infection but it is really identical to functional cure (latent cccDNA remains in the liver in a persistently inactivated state).
Regarding good vs bad flares:
Many people resolve their acute HBV infection asymptomatically. In this case resolution comes from early and efficient control of HBV infection by innate immunity (cccDNA silencing) and adaptive immunity (T-cell function). In this case flares are always good but typically never observed because these individuals never have symptoms of liver dysfunction (like the paper I referred to above).
The innate immune response also has the ability to clear infection from the liver but this occurs by the stimulation of natural killer (NK) cell function in the liver. These cells are like T-cells in they can kill infected cells but differ from T-cells in they are triggered by inflammation and can act without specifically recognizing antigens on infected hepatocytes. Thus NK cells can indiscriminately target healthy hepatocytes as well in the presence of liver inflammation (see Natural killer cell specificity for viral infections | Nature Immunology).
Even though your flare was a component of the resolution of your acute infection, this flare was a “bad” flare because your liver function was also impacted. This is likely because the flare was caused both by T-cells and NK cells (responding to the liver inflammation which almost certainly present).
Bad flares are always accompanied by reduced liver function and most times symptoms like severe fatigue and jaundice. These flares require medical supervision and sometimes early intervention with antiviral treatment in acute HBV infection. In acute HBV infection, these flares are typically intense but short lived as most people that get HBV infection successfully self-resolve it. In chronic HBV infection, bad flares are seen with viral breakthrough during antiviral therapy or reactivation of HBV infection from an inactive state.
Good flares are not accompanied by reduced liver function and are likely purely T-cell mediated and are always accompanied by improved virologic status.
So your “bad” flare was also “good” because it was short-lived.
Best regards.
I don’t understand this. ALT resides in hepatocytes, when excess of these cells are broken , it appears in serum. So basically when T cells kill the infected cells, that is required for removal of infection, it will release in serum! Wether healthy or infected hepatocytes, ALT is present in all!
I have read literature that icteric acute HepB has more chances to recover than non icteric infection.
I also wonder how do asymptomatic cases recover…why no rise in ALT/ flare as T cell response will kill hepatocytes causing to release it
But in functional cure, Anti Hbs may not present at all
Hi AJK,
Here are some additional points to help:
The production of virus and HBsAg can be suppressed non-cytolytically (without hepatocyte death) by the innate immune response via inactivation of cccDNA. So in acute infection this is one way to resolve infection without a flare, provided that there is very little integrated HBV DNA present (which can still produce HBsAg but not virus).
Acute HBV can resolve asymptotically but this does not mean that there was no flare present. Just that it was not observed. This issue persists throughout the clinical literature for NUCs (as I have exemplified by the surveillance study in my previous post).
You are right that ALT is present in all hepatocytes. So how to explain the good flare (with no liver dysfunction) and the bad flare (liver dysfunction)?
The following are important to understand to resolve point (3):
While HBV infected hepatocytes contain ALT, infection alters their metabolic function. For instance, the production of subviral particles hijacks the HDL pathway. Numerous other metabolic alterations of HBV infected hepatocytes have been described in the literature. Thus HBV infected hepatocytes likely do not contribute to the reservoir of normal liver function.
T-cells will target only infected cells while NK cells will target any hepatocyte in a pro-inflammatory environment, including healthy cells.
So in a bad flare, NK cell activity will indiscriminately kill hepatocytes, leading to reduciton of HBV infected hepatocytes but also reduced liver function. T-cell activity will only target infected hepatocytes, not impacting liver function.
Flares can be a combination of NK and T-cell function.
Hope this helps.
Hi AJK,
You are correct that functional cure can be established in the absence of detectable anti-HBs.
I am making things complicated for myself!
Just to avoid all confusion, pls let me know about my immune status…(results of tests you already know) whether T cell immunity is induced and I am now immune to the virus …good/bad flare and NK cell concept giving me jitters !
I had icteric acute HepB with very high bilirubin/ALT and AST. INR and PT were almost normal.
Didn’t take anti viral therapy.
Why do we insist on good and bad…I think it’s always good…it indicates that immune system is getting rid of infected hepatocytes. Just that extent of it varies…higher ALT flare will naturally indicate more of hepatocytes are infected and are being killed. This will hamper hepatic functions as well.
Hi AJK,
Yes its complicated and I am working through the answers not only for you but for other community members who may follow this thread.
Bad transaminase flares are where infected and healthy hepatocytes are killed.
Good transaminase flares are where only infected hepatocytes are killed.
Its important for individuals undergoing treatment to understand the difference between these kinds of flares as some individuals who start antiviral therapy will experience transaminase flares and they need to understand these are typically a good sign rather than worry about damage to the liver. Bad flares are very rare during ETV and TDF / TAF therapy.
In your case the nature of your original fare is irrelevant to understanding your long term outcome since you have had a very good self resolution to your acute infection. This means both innate and adaptive immunity will continue to maintain excellent control of infection in your liver.
Your flare is of course a part of the reason for resolution during during acute resolution but it was still “bad” in that you had jaundice (and strongly elevated bilirubin). A patient who developed a flare like this during treatment or with HBV reactivation would require medical supervision. In your case, the flare was short lived as your body’s immune system gained control of the infection fairly quickly (which is why you did not need antiviral therapy). Any hepatocytes killed during this flare have long been replaced with new hepatocytes. Just because you have had a “bad” flare does not mean that there should any concern for long lasting damage to the liver.
Hope this helps,
Once again, many thanks for the response and the very valuable information provided.
Dear @availlant
One more query, what if I seriously fall ill like get typhoid or dengue or COVID or like that …will that affect my HepB specific immunity? Or it is just chemotherapy, use of steroids, or other immunosuppressive therapies.
I recently caught viral fever 
Dear AJK,
There is not any case literature that I am aware of for increased HBV reaction following these kinds of infection (including SARS CoV-2). However there are case reports of HBV reactivation following aggressive steroid therapy used to treat acute respiratory distress syndrome which very infrequently accompanies SARS CoV-2 infection.
I would not be concerned about this.
Best regards,
Means no need to worry in infections or diseases excluding obviously HIV… I am not talking about treatment part …just wondering if I fall sick of any diseases or infection, would it affect HepB immunity…
Hi AJK,
If this has happened it is very rare and I have not seen any case reports.
Your immune system can handle mutliple infections with no issue. This is something that happens every year during flu season with a variety of respiratory viral infections.
How about “old drugs to cure Hep B”?
Nitazoxanide - a pilot clinical trial:
Theoretical mechanism:
A recent/ongoing clinical trial:
Hi Mantana,
Indeed this drug has been investigated for many years for HBV infection.
This drug appears to destabilize or inactivate cccDNA. Unfortunately it does not target the production of HBsAg from integrated HBV DNA so its impact on functional cure is not expected to be significant (HBV subviral particles produced from integrared HBV DNA are a sunstantial fraction of HBsAg).
Earlier trials with 500mg nitoxanide yielded strong declines in HBV DNA but little affect on HBsAg (similar to NUCs).
Although the latest trial is fully recruited as of 2021 and uses higher doses (600 and 900mg twice daily) I have not seen any data presented from this trial.
Best regards,
The pilot trial also does not contain too many details. And it’s all being run by the same company (producing nitazoxanide). They did run many clinical trials against nitazoxanide (against other viral diseases, including HCV) - in many (most?) of them they didn’t publish the final results.
So indeed it would be too good to be true if it turned out to be curative when added to a NUC therapy! Let’s see when the trial ends in a few months.
About this:
Unfortunately it does not target the production of HBsAg from integrated HBV DNA
Hepatocyte lifetime is estimated to be 6-12 months. Does integrated HBV DNA disappear when the hepatocyte ends its life, or does it continue to “live” in new hepatocytes crated during mitosis?
Hi Mantana,
This rate of hepatocyte turnover is not universal in the liver. Latent cccDNA can remain in the liver and still reactivate decades later. This is why HBsAg must be eliminated as it allows host innate immunity to continually suppress cccDNA reactivation.
Integrated HBV DNA is efficiently maintained during mitosis. It can only be removed by killing those hepatocytes. This is why direct acting antiviral approaches will not be enough to achieve high rates of functional cure.
Best regards,