Nucleic acid polymers (NAPs): targeting subviral particles to achieve HBV functional cure

Disclosure: I am the Chief Scientific Officer of and a shareholder in Replicor Inc.

If you have chronic HBV, should you care about HBsAg?

YES! The hepatitis B surface antigen or HBsAg is by far the most abundant viral protein circulating in your blood (at levels 1000’s of times greater than other viral proteins). HBsAg has the ability to suppress several aspects of your immune system’s ability to control your liver infection. Immune control of HBV infection is a very positive outcome which happens for most people who become infected with HBV. In your case, this circulating HBsAg has now made it difficult for your body to control the infection in your liver without medicine (read more about this here).

I have never heard about subviral particles, why are these so important?

Almost all (more than 99.99%) of the HBsAg in your blood is found in subviral particles. These particles are produced inside infected liver cells by a mechanism that is separate from the process which produces infectious virus. The very large amounts of these subviral particles and the HBsAg they carry are main reason why your HBV infection is chronic. This evolved mechanism of producing “decoy” particles to confound the immune response is also found in many other viral infections but not to the extent found in HBV infection (read more about this here).

Subviral particles have to be removed from your blood to achieve HBsAg loss and to allow your body’s immune response to either recover or to respond productively to immunotherapy. Unfortunately, none of the currently approved treatments for HBV infection (NUCs such as entecavir or tenofovir disoproxil fumarate and or immunotherapy such as pegylated interferon [pegIFN]) interfere with the production of subviral particles and as such, have little impact on your immune system’s ability to control infection. Although these medications work well to control your liver disease, if they are removed, your viral infection will return because the HBsAg-mediated immune suppression remains.

Are there different sources of subviral particles in the liver?

HBV infection establishes two stable sources of HBsAg production. In some liver cells, the genetic template for new viral production is established as a “minichromosome” which behaves like normal chromosomal DNA but is separate from the chromosomes in your cells. In these cells, both infectious virus and subviral particles are produced but the activity of this minichromosome can be controlled by the immune system without their removal. In other liver cells, the genetic template becomes physically inserted into one or more chromosomes. This “integrated HBV DNA” is only able to produce HBsAg so these cells can only produce subviral particles. The extent of HBV DNA integration in the liver gradually increases during the lifetime of HBV infection and this reservoir of subviral particle production can only by removed by immune mediated killing of this cell.

Are there any medications in development which can target subviral particles?

There are several antiviral technologies in development that you may have heard of, including capsid assembly modulators (CAMs), RNA interference (RNAi), antisense oligonucleotides (ASOs) and nucleic acid polymers (NAPs). Of these, only NAPs have been shown to result in the efficient removal of subviral particles in clinical studies of people with chronic HBV infection (read more about this here and here). NAPs are the only drug class which has been able to achieve HBsAg loss during therapy in a majority of patients.

How do nucleic acid polymers work?

Replicor scientists have discovered a protein in hepatocytes which is used in HBV infection to produce subviral particles. This protein is specifically targeted by NAPs, stopping the formation of subviral particles and their release into the blood. In the presence of NAPs, subviral particles are rapidly cleared from the blood by your body, leading to their elimination (read more about this here, here and here).

What about my immune system and “functional cure”?

Functional cure is the term scientists and doctors use to describe completely restored immune control of your chronic HBV infection. This outcome is very similar to the spontaneous control of infection which normally occurs in most people following HBV infection. This is the goal of all current drugs in development for chronic HBV infection: it means someone who is infected no longer has to take medicine – their own immune system effectively controls the infection and allows the liver to heal and functional normally.

For some people, simply clearing HBsAg may be enough to allow their immune system to restore control of their liver infection. However, the longer your chronic HBV infection persists (even while receiving treatment), the more likely your immune system is to become damaged or “put asleep”. As a result, most people will require some form of immunotherapy (while HBsAg is absent) to restore immune function.

How are NAPs being used to achieve functional cure of HBV?

In patients with chronic HBV infection, combination therapy with approved antiviral agents like tenofovir disoproxil fumarate (TDF) and immunotherapy – pegylated interferon alpha 2a (pegIFN) has a very poor activity in the most difficult strain of HBV (genotype D) with 0% of patients achieving functional cure after 48 weeks of therapy. When NAPs are used to clear HBsAg, the functional cure rate in genotype D patients rises to 39%, with an additional 39% of patients with partial cure. This means 78% of patients after receiving 48 weeks of combination therapy with TDF + pegIFN + NAPs no longer need to receive treatment to control their infection. This represents a major breakthrough in the treatment of chronic HBV (read more about this here).

What about HBV co-infection with HDV?

NAPs also directly impact the replication of HDV virus through their interaction with the hepatitis delta antigen, the only HDV viral protein, responsible for replication and assembly of HDV. In a preliminary clinical trial, combination therapy with NAPs and pegIFN was able to eliminate HDV viremia in all patients during therapy with 74% of patients experiencing a “functional cure” of their HDV infection. This means that in the absence of any therapy for at least 3.5 years, no HDV viremia was detected, liver function was normal and liver inflammation and scarring (fibrosis) was regressing. All of these patients also established immune control of their HBV infection (either partial cure or functional cure). Read more about this here, here and here.

What comes next for NAPs?

Replicor’s next trial will use a combination therapy with TDF, immunotherapy and subcutaneously administered REP 2139-Mg (our most advanced NAP drug) in patients with HBV/HDV co-infection to confirm the activity and safety of this treatment in patients with fibrosis and mild cirrhosis. We will compare two different immunotherapies (low dose pegIFN and thymosin alpha 1) to see which one performs better. The results we observe with this combination therapy in HBV / HDV co-infected patients will be applicable to chronic HBV infection in other patients without co-infection or with co-infection with another virus.

What work needs to be completed before NAPs will be available?

REP 2139-Mg is currently in phase IIa trials. Larger phase IIB and phase III trials will be required before regulatory approval can be sought. This process can take anywhere from 3-4 years.

What will NAP treatment look like when it is available?

Therapy will be 48 weeks long. You will take a pill once a day (TDF) and two easy to self-administer injections once each week (immunotherapy and REP 2139-Mg).

Who will benefit from NAP therapy?

NAP-based therapy promises a high rate of functional cure of HBV for the following individuals:

  • Any person with chronic HBV regardless of stage of infection, ethnicity, or strain of HBV
  • Any person regardless of the extent of liver disease.
  • Any person regardless of co-infection (HDV, HIV or HCV).
  • A high rate of functional cure of HDV for those with HDV co-infection.

Thank you very much for posting this. It is great information both in terms of insight into what happens and why it happens with these subviral particles and also in terms of what it seems to be a “realistic hope” for a functional cure.
I have a question though regarding criteria that match initiation of treatment with NAPs. Does it aim to eliminate HbsAg even in patients that are not in treatment with TDF or only in patients in antiviral therapy.
Thank you again


Dear Nipatoho,

The best way to attack HBV infection to maximize the chance to achieve functional cure is a combination of agents that do the following:

  1. Eliminate circulating SVP.
  2. Eliminate viral replication.
  3. Stimulate the immune response.

Now there are many people with chronic HBV infection who do not receive antiviral therapy as current guidelines only recommend starting approved treatments when signs of liver disease appear. However, it is our expectation (and goal) that once a combination therapy regimen is approved that can give high rates of functional cure (such as we have seen with NAPs in phase II trials), access to this combination therapy (which will include medicines such as TDF to eliminate HBV replications) will be allowed in all patients with chronic HBV infection, regardless of the presence of liver disease or not.

Hope this answers your question.


Thanks for your article and detailed information about new development.
Is pegINF also a NAP therapy?

Sorry if question does not make any sense.
I am coinfected with HBV HDV


Dear Suresh786,

PegIFN is short for pegylated interferon. While NAPs target HBV subviral particles, pegIFN stimulates your immune system so that control of your infection will persists after antiviral treatment is withdrawn. NAPs and pegIFN are two separate kinds of medicines that are given in combination in clinical trials.


Thanks. I am currently on pegIFN and TAF.
Wish me good luck thanks


Good luck and let us know how your treatment is going.


Hi Andrew,

I have just read your post and although I gave it my best shot, I am a teacher with the brain of someone who has worked with 5-year-olds all day so I wanted to ask some questions to clarify.

  1. By functional cure, do you mean that these new NAP treatments will give someone with chronic HBV the same categorisation as someone that has recovered from HBV, as in, immune to new infection and unable to transmit the infection to others? Or does it mean to lower viral replication to such a low state that a person loses HBsAg but it remains in their system for life?

  2. The 48-week course of NPAs that is mentioned at the end of this article. Is it a one-and-done course of treatment to last for life, or is this something that is still unknown?

Thank you for taking the time to read this, as a 23-year-old that only received their chronic and inactive diagnosis a month ago, to be reading about the possibility of some type of cure being relatively around-the-corner, makes this whole ordeal much easier for me to manage and it’s thank to the efforts of memebers of the scientific community that such a feat is possible. :heart:


Dear EH1999,

Glad to have the questions and it is a complicated subject, even for us that have been immersed in it for a while!

Firstly if you are an inactive carrier (HBV DNA < 2000 IU/mL and normal ALT), this is a very good outcome from having chronic HBV. When someone reaches this outcome after removal of antiviral therapy, we call this a “partial cure” because some aspect of your immunity has recovered.

Yes functional cure is the same as fully resolved acute chronic HBV infection. Functional cure means that we cannot detect any evidence of the virus in your blood (HBV DNA undetectable) or of viral activity in your liver (HBsAg < 0.05 IU/mL). Individuals with functional cure are not able to transmit the infection to others.

Clinical studies have shown that a large proportion (~39%) of people who receive a 48 week course of NAP-based combination therapy do achieve a functional cure and an additional 39% achieve partial cure. This functional / partial cure has shown to last for at least 5 years in the absence of all therapy (there has been no follow-up longer than this). So yes NAP therapy is expected to be a “one and done” for most people. Additional larger clinical studies will be required to confirm the encouraging results we have seen to date in our clinical studies.

Best regards,


NAPs are currently in which phase of trials and when can we expect to have available for general population.

Hi Andrew,

Thank you so much for taking the time to answer my questions. It is greatly appreciated and thank you for sharing this information on this platform so that it can be easily accessed and discussed by the very people it hopes to help! :heart:


Hi Suresh785,

Cut and paste from my initial posting…


Hi Andrew,

Thank you for the article. I have followed Replicor for a long time and am always very hopeful. In your next clinical trial, you plan to use pegIFN and thymosin alpha 1. PegIFN has potential side effects and Thymosin alpha 1 is very expensive. Have you considered using the latest generation of HBV vaccines or therapeutic vaccines, even HBSag monoclonal antibodies, as your immunomodulator? The subcutaneous version of your NAP seems to have taken a long time to develop, clinical trials were announced and postponed. Is there anything the research communities, pharmaceutical companies, governments or patient community can do to help push development and clinical trials to happen quicker?

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Hi Stephen,

It took a long time to get the scientific / medical community to accept NAPs as a legitimate antiviral technology because of their novel biochemistry and potent antiviral responses. NAPs are now well accepted and we have used our previous trials to date to move the drug product to a formulation which is now easy to self administer via subcutaneous injection (SC). The proof of this was only achieved in our last trial with REP 2139-Mg (published in 2020). As for many other companies, the SARS CoV-2 pandemic has had a negative impact on our ability to initiate new clinical development but we have gone ahead to use SC REP 2139-Mg in compassionate use patients in France with very good results ( so we hope to be in a position to conduct the final phase IIA trial with SC REP 2139 in the very near future. The delay with the clinical development of NAPs is not because of any problems with the drug or with our science but is due to other unrelated issues. We are working as hard as we can to get REP 2139-Mg to patients as soon as possible.

Your question about immunotherapy is good one. There are two important steps in achieving functional cure: 1) clear SVP from the blood and 2) remove HBsAg producing capacity from the liver. With NAPs (1) is easy but (2) is more difficult. In all patients, HBsAg is also produced from integrated HBV DNA (which only efficiently produces HBsAg and SVP), this reservoir of HBsAg production gradually increases throughout HBV infection. Complicating this further is the presence of 1000’s of HBV quasispecies leading to many quasispeceis of HBV DNA integration producing many quasispecies of HBsAg. A final complication is that the only way to remove this reservoir is a broad HBsAg specific T-cell response capable or efficient removal of cells containing integrated HBV DNA.

So lets look at the pros and cons of the various immunotherapies in the context of HBV functional cure:

PegIFN - strong activation of existing pools of HBsAg specific T-cells but mild side effects in HBV.

Thymosin alpha 1 - strong activation of HBsAg specific T-cells with negligible side effects (not approved in many countries)

HBV vaccines - only one strain of HBsAg! poor induction of HBsAg specific T-cells.

Therapeutic HBV vaccines - stimulate T-cells but only to a small spectrum of HBsAg quasispecies because of a single strain of HBsAg antigen

HBsAg monoclonal antibodies: - not effect on T-cell stimulation, only one strain of HBsAg.

This is why you have not seen any combination trials of NAPs with these agents. The good news is that with NAPs we are able to reduce the dose of pegIFN from 180 to 90ug without affecting antiviral response.

Your questions are appreciated!


Thank you for the reply, greatly appreciated. Looking forward to your next clinical trial!

Hi all,

I just want to put in a good word for Andrew’s NAPs.

His studies have achieved the highest level of functional cure that I’ve seen for any HBV therapy so far in Phase I or II clinical trials. Drug discovery/development is high risk, nerve-wracking and expensive, and there is never certainty of success. However, Andrew has pushed this forward through a great deal of adversity over the years. His NAPs have as good a chance as any approach (probably better than almost all) to receive approval and improve therapy for HBV infected people. I wish him and his research the best!



John your comments are very much appreciated.


@availlant hope for a great success future!


when new phase for clinical trials of NAPs start ?

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Hi Suresh,

My suggestion is that you refer to the Replicor website for these kinds of details.

Best regards,