New Drugs to cure Hep B?

General Discussion
76

Hi John,

The critical part of sterilizing cure is the removal of all cccDNA in the liver (whether active or latent) so that production of virus can no longer occur. Removal of integrated HBV DNA is also part of the definition of sterilizing cure but is it not the critical feature of this definition since integrated HBV DNA is not capable of producing virus. Of course the challenges with latent cccDNA being a non-drug-able form of cccDNA persisting for a very long time in the liver make sterilizing cure very unlikely to achieve.

The coining of the term “functional cure” is several years old now and in the interim, we now know that the integration of HBV DNA is an event which occurs soon after infection and progressively increases with the duration of infection. We also know that integrated HBV DNA cannot be targeted by any direct acting antiviral and cannot be silenced by the immune mechanisms which can inactivate cccDNA. Importantly, integrated HBV DNA is fully capable of producing HBsAg in the form of HBV subviral particles. As such integrated HBV DNA is a source of a significant proportion of HBsAg and in HBeAg negative infection, provides the bulk of HBsAg.

You are quite correct that the original definition of functional cure did not mention integrated HBV DNA, but we now know that the persistent HBsAg loss in the absence of treatment (which is an important part of functional cure) cannot exist while integrated HBV DNA is present.

Functional cure of HBV infection is highly correlated not only with HBsAg loss during therapy but also with transaminase flares (which signal the removal of infected cells with cccDNA or integrated HBV DNA). Functional cure with approved agents (NUCs and pegIFN) are always associated with transaminase flares during therapy, with stronger flares correlated with higher rates of HBsAg loss and functional cure.

The reality of HBsAg loss (and functional cure) requiring removal of integrated HBV DNA and transaminase flares which signal this event were recently acknowledged at the 2022 AASLD-EASL Endpoints meeting.

All the best…

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77

Thank you for your valuable response, it is very much appreciated.

I agree completely with your comments about CAM. I included a CAM, JNJ-6397, together with a NA, such as TDF, in the Replication Inhibition step toward a functional cure is based on two assumptions:

  1. A typical type II Capsid Assembly Modulator will produce rapid empty capsids without the enclosed pgRNA, and therefore will reduce the production of a mature HBV nucleocapsid with hbvdna that will be recycled to the nucleus to be converted to cccDNA.
  2. During liver cell turnover, a liver cell dies and another liver cell undergoes mitosis. During mitosis of an infected liver cell, some cccDNA may be lost, or the overall cccDNA pool in the liver remains constant.

A Type II CAM will not affect cccDNA directly. The Type I CAM that is supposed to interfere with the Core protein that is required for cccDNA formation has not yet been developed despite efforts by Bayer and subsequently a Chinese pharmaceutical company.

It is my understanding that with mono NA treatment, over time, usually after over 8 years, the cccDNA pool will be significantly reduced due to liver cells turnover. Together with a Type II CAM, Replication inhibition will be stronger as NA and the CAM are aimed at different targets in the Replication process. So a Type II CAM has no direct effect on cccDNA, but I assume, together will a NA, it will speed up the reduction of the cccDNA pool in the liver. I have no clear explanation why the serum HBsAg due to integrated hbdna may also be reduced.

I have read the paper you suggested, but it is way above my level of knowledge and comprehension. I heard of the problems with RNAi with off-target and splice variants. I know very little about ASO. Based on clinical trial results, for the HBsAg Reduction step, I can only suggest NAPs and Bepirovirsen. As Bepirovirsen is very much less potent than NAPs, I am hoping monoclonal HBsAb may help to reduce serum HBsAg further. Mindful of your previous comments regarding monoclonal HBsAb, I understand there is a variety of HBs MAb, there is also HBIG.

For the Immune Stimulation step, I take the clues from your research that HBsAg inhibits Adaptive immune and Innate immune functions, therefore hope the latest vaccines will be able to generate the HBV-specific B and T cells, with or without HBs MAb or HBIG.

I will not be surprised that I am wrong in all the above. I will need to study more about Interferon and its inactivation of cccDNA.

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78

Mine was in thousands 3k around (ALT). Severe jaundice with bilirubin reaching 12 mg/dl !!!

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79

HI Stephen these issues are quite complicated!!
See some additional comments below.

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80

Hi AJK,

Did your flare before or during therapy?

Best regards,

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81

Oh ! No, it was an acute infection. No therapy. We have had a long discussion over it.

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82

AJK right I forgot! Apologies.

Yes this is a seemingly contradiction which can be confusing. There are good flares and bad flares - how to tell which is which?

Transaminase flares that occur during acute HBV or with HBV reactivation are almost always associated with decline in liver function. This is likely due to the spread of viral infection to healthy cells, removing their ability to contribute to normal liver function and the associated immune mediated inflammation of the liver which can also kill healthy hepatocytes.

Transaminase flares which occur during antiviral therapy when viral replication is well suppressed are associated with improvement in liver function and virologic status. This is due to the immune mediated targeting of infected cells by the adaptive immune response (T-cells) which does not affect healthy hepatocytes.

Here is an interesting paper Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection - PubMed which shows that during the natural history of chronic HBV infection, transaminase flares as strong as yours occur with no alteration in liver function - see Figure 2A.

ALT flares during HBeAg positive HBV infection
ALT flares during HBeAg positive HBV infection1920×1080 139 KB

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83

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?

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84

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:

  1. 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).

  2. 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).

  3. 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.

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85

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

86

But in functional cure, Anti Hbs may not present at all

87

Hi AJK,

Here are some additional points to help:

  1. 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).

  2. 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).

  3. 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):

  1. 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.

  2. 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.

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88

Hi AJK,

You are correct that functional cure can be established in the absence of detectable anti-HBs.

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89

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.

90

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.

91

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,

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92

Once again, many thanks for the response and the very valuable information provided.

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93

Thank you @availlant

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94

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 :nauseated_face:

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95

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,

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