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Drug Update: Replicor Researchers Talk to HBF About Potential New Hep B and D Treatment

In October 2019, the Hepatitis B Foundation had the opportunity to speak with Andrew Vaillant, Ph.D., Chief Scientific Officer at Replicor at the annual International HBV Meeting in Melbourne, Australia. Dr. Vaillant gave us an inside look at REP 2139 – their drug candidate developed for the treatment of chronic hepatitis B and HBV/HDV coinfection. REP 2139 is a nucleic acid polymer that removes surface antigen (HBsAg) and as part of combination therapy, has achieved functional cure for chronic HBV (sustained HBsAg loss) and sustained clearance of HDV infection from the blood in early phase II proof of concept clinical trials it has completed to date. REP 2139 is currently in phase II of clinical trials. Below is Dr. Vaillant’s response to a series of questions we posed to him.

1. Replicor’s drug candidate REP 2139 is a nucleic acid polymer (NAP) for the treatment of chronic hepatitis B. Can you explain the mechanism for this drug and how it works?

REP 2139 is a polymer built from the building blocks the body uses to store genetic material in the body (nucleic acids). These building blocks are linked together in a unique pattern to form nucleic acid polymers (or NAPs for short) and in the case of REP 2139, use only naturally occurring nucleic acids and modifications to prevent it being recognized as a foreign molecule. As a result, REP 2139 is very well tolerated and safe in clinical trials.

In HBV infection, the most abundant viral antigen in the blood is the hepatitis B surface antigen (HBsAg) which plays an important role in preventing immune control of HBV. Circulating HBsAg is almost entirely in the form of non-infectious HBV subviral particles (SVP) which are produced independently from viral replication, making this viral antigen difficult to target with approved therapies. REP 2139 naturally enters liver cells (hepatocytes) and blocks the assembly of SVP in any hepatocyte producing SVPs. This mechanism effectively blocks the replenishment of HBsAg in the blood and also reduces HBsAg inside these hepatocytes. The overall antiviral effect of REP 2139 is to allow the body to clear HBsAg in order to reduce or remove the inhibition of immune control caused by this viral antigen.

2. REP 2165 is also mentioned as a drug candidate. Can you explain the difference between REP 2139 and REP 2165.

REP 2165 is a close cousin of REP 2139 being examined for potential use in future therapy with more frequent dosing to improve HBsAg response in selected cases and was proven to be as effective as REP 2139 in this study. More information about REP 2165 can be found under question 6.

3. Can you share the latest results from phase 2 trials? How is REP 2139 administered to patients, and for what duration of time? What kind of side effects can patients expect with REP 2139?

In our latest trials, side effects have been limited to mild effects from pegylated interferon (pegIFN). REP 2139 is currently given in a formulation (REP 2139-Mg) which results in little to no side effects during administration. REP 2139 is currently administered once every week for 48 weeks by intravenous infusion in combination with other antiviral agents. REP 2139-Mg is expected to be as effective with a once weekly injection under the skin (subcutaneous injection) which will be used in future trials.

4. Is REP 2139 equally effective in HBeAg positive and negative patients?

REP 2139 is effective in HBeAg positive and in HBeAg negative patients in multiple genotypes. As REP 2139 targets a host protein involved in SVP formation and not the virus or SVP directly, its antiviral effects are expected to be similar in all HBV genotypes and may also be effective in the presence of other co-infections with HBV such as HCV and HIV.

5. Can REP 2139 be safely used in patients with cirrhosis?

Another of the remarkable features of NAP based therapy is the high rate of flares in liver transaminases during therapy (occurring in almost all participants in the REP 401 study). Patients with these flares had no symptoms or any negative impact on their liver function.

Continually expanding evidence in the field tells us that during treatment of HBV, these flares are signs of elimination of HBV infection from the liver and are not accompanied by changes in liver function. These same features appear to hold true for transaminase flares during NAP therapy and, when occurring in the absence of HBsAg in the blood, are highly correlated with functional cure in our clinical trials. The ability of cirrhotic patients to tolerate these flares will be tested in future trials and we are encouraged by recent results (produced by a different group) with pegIFN in HBV / HDV co-infected patients showing that host mediated transaminase flares may also be well tolerated in cirrhotic patients.

6. Do you anticipate combination therapy will be needed? Will combination therapy include immune modulators like pegylated interferon and/or treatment with antivirals?

Replicor’s latest REP 401 study is the first in the field to feature triple combination therapy: Tenofovir disoproxil fumarate (TDF), pegIFN and either REP 2139-Mg or REP 2165-Mg. REP 2165 is a close cousin of REP 2139 being examined for potential use in future therapy with more frequent dosing to improve HBsAg response in selected cases and was proven to be as effective as REP 2139 in this study. In addition to the excellent control of HBV DNA with TDF exposure, this triple combination therapy for 48 weeks led to meaningful HBsAg decline (greater than a 10-fold reduction from baseline) in 90 % of participants, HBsAg clearance to very low levels similar to HBsAg “negative” in the qualitative test used in the United States (< 0.05 IU/mL) and HBsAg seroconversion (often with very high titers of anti-HBs antibodies) in 60% of participants. After removal of all treatment (including TDF), a 48-week follow-up yielded very encouraging results: 89% had normal liver function, 56% had reduced liver inflammation, 39% had stable virologic control and an additional 39% had functional cure with HBsAg seroconversion. These results illustrate the effectiveness of combining potent HBsAg reduction with immunotherapy but also suggest that direct acting antivirals such as TDF and entecavir may also contribute to establishing functional cure in a combination setting.

7. Surface antigen loss is key to people living with chronic HBV. Do you believe REP 2139 can provide a functional cure for chronic HBV?

In an early clinical study using NAPs alone, HBsAg clearance by itself resulted in virologic control (low level infection with normal liver infection no longer requiring therapy under current guidelines ) or functional cure (complete control of HBV DNA and HBsAg) persisting after removal of all therapy only in a small proportion of patients but stable throughout a 5 year follow-up. Importantly, HBsAg clearance with REP 2139 in a subsequent study led not only to a dramatic improvement in the activity of various immunotherapies (including pegIFN) but to virologic control occurring in a larger proportion of patients after removal of therapy persisting throughout more than 2 years of follow-up. As a result of these early studies, Replicor believes that the best approach to achieving functional cure of HBV infection is to simultaneously combine potent HBsAg reduction using REP 2139 with immunotherapy to restore effective and long-lasting immune control.

8. Which countries do you anticipate phase 3 trials to occur? Do you anticipate trials in the U.S?

Replicor believes that the combination of therapy with NUCs such as TDF and ETV, pegIFN and REP 2139-Mg will be the first available therapy to offer patients a real chance of eliminating the need for therapy and establishing functional control of their HBV infection and normalizing their liver function. Work is ongoing to start a phase II US trial in collaboration with the Aids Clinical Trials Group as soon as possible. We are also planning to assess other immunotherapies, the effectiveness of which we believe will be similarly improved with HBsAg clearance as we have demonstrated for pegIFN.

9. With regard to hepatitis delta, is there a difference in the mechanism for how it works?

REP 2139 is also potently active against HDV infection and is able to rapidly eliminate HDV RNA, normalize liver function and reverse the liver inflammation associated with HBV / HDV co-infection. The completed follow-up results from our long term follow-up study of co-infected participants treated with REP 2139 and pegIFN show complete control of HDV infection at 3.5 years follow-up in the absence of all therapy in a large proportion of patients. In many patients this control of HDV infection was associated with functional cure of HBV and in some patients with virologic control of HBV. This potent effect against HDV infection is assumed to be driven not only from the effect of REP 2139 on SVP (which also forms the envelope of the HDV virus) but on the ability of REP 2139 to interact with different forms of the hepatitis delta antigen protein essential for HDV replication and assembly.

Thank you to Dr. Vaillant for taking the time to talk to us about REP 2139. The results look promising! We look forward to learning more from continuing and new trials with REP 2139, used alone and in combination with antivirals and immune modulators. We know the hepatitis B virus is challenging, but those living with chronic HBV look forward to a day when there are therapies resulting in a durable loss of surface antigen and sustained viral suppression in a reasonable, finite amount of time. 

Love Your Liver This Valentine’s Day

For most people, Valentine’s Day is a day full of love, but for those living with hepatitis B, it can be filled with dread and anticipation. Perhaps you haven’t told your significant other that you have been diagnosed with hepatitis B, or maybe you are spending this year alone because you are scared to begin a relationship. This year, instead of focusing on others, take Valentine’s Day to love yourself – and your liver! 

Taking Care of Your Liver 

Find a Knowledgeable Provider (and be sure to see them regularly!): 

Most people who are diagnosed with hepatitis B lead long, healthy lives. The key is proper care and monitoring by a trained healthcare provider. If you do not yet have a healthcare provider who is regularly monitoring your diagnosis, you can search our physician directory to find one near you. You can also search the World Hepatitis Alliance’s member list to find local resources and organizations who can help you identify a provider in your area.  

It is always a good idea to conduct your own research as well! Look into what your provider specializes in, as some may be more knowledgeable about the infection than others. Ideally, it would be best to regularly see a hepatologist – someone who specializes directly in diseases of the liver. However, due to finances and other constraints, this may not be an option for everyone. Seeing any doctor is extremely important, but if you only have access to a provider who is not as experienced in hepatitis B, make sure that they are performing the correct tests to monitor the health of your liver. At each follow-up appointment, your doctor should: check your liver enzymes (ALT, AST), perform a physical exam of the liver, and any other blood tests they might feel is needed to determine the stage of the infection and the health of the liver. Sometimes, the doctor will also perform an ultrasound of the liver to get a better picture of what is going on. You can find some questions that are important to ask your doctor here. 

Watch What You Consume: 

When people are first diagnosed with hepatitis B, they may feel fine and may not consider making small changes in their daily lives. The truth is that your diet plays a large role in the health of your liver! Everything that enters your body is filtered through your liver. This makes adopting healthy habits essential to keeping the liver in good shape. A standard rule of liver disease is to avoid alcohol – even small amounts – and maintain a steady diet of fruits and vegetables. Foods that are high in fat, salt, and sugar content can lead to weight gain, which puts a strain on your liver. Beware of what you are drinking as well! Drinks like juices and sodas might seem like healthier options, but often contain high amounts of sugar. Diet sodas may lack sugar but have other additives which may have other health implications. Opt for flavored water or seltzer to satisfy a sweet craving instead! If healthier beverage options are not readily available, see if any coffee is available. Studies have shown that drinking coffee can lower one’s risk of developing liver damage and liver cancer – just be sure to watch how much sugar and creamer you put in it! Other diseases of the liver, such as fatty liver, can also increase your risk of liver damage and liver cancer, so it is extremely important to be aware of the risks and what you are consuming. 

Those living with hepatitis B should also be aware of aflatoxins. Aflatoxins – which can cause liver cancer – are natural toxins that are produced by a mold that grows on crops like corn, peanuts, and tree nuts. Aflatoxins are more common in warm, humid parts of the world, such as African countries and areas with tropical climates. Before eating any grains and nuts, check for any signs of mold. If the food appears to be moldy, do not consume it. The World Health Organization also recommends buying grains and nuts as fresh as possible to minimize the risk of aflatoxin exposure. The fresher the food is, the less time it has been in storage, which is where aflatoxins commonly grow. 

Be Mindful of Your Stress Levels: 

Living with hepatitis B can be a big stressor, especially for those who may face stigma and discrimination. Research shows that stress can negatively impact liver health. Take some time to find ways that might relieve your stress, such as meditation, listening to music. Being social can also be a stress reliever for some, so try spending more time with your trusted friends and family members. Exercise is also a great stress reliever and it has the benefit of helping you maintain a healthy weight! 

If you are celebrating Valentine’s Day with your partner or if you are in a new relationship, remember that hepatitis B is preventable and cannot be transmitted casually! Holding hands, kissing, or sharing utensils or food made by someone who is living with hepatitis B will not spread the infection. Hepatitis B is a vaccine-preventable disease so make sure that they have completed their hep B vaccine series. If they are not protected from hepatitis B, be sure to practice safe sex (use a condom) to prevent transmission.

Hepatitis B Research Review – February

Welcome to the Hepatitis B Research Review! This monthly blog shares recent scientific findings with members of Baruch S. Blumberg Institute (BSBI) labs and the hepatitis B (HBV) community. Technical articles concerning HBV, Hepatocellular Carcinoma, and STING protein will be highlighted as well as scientific breakthroughs in cancer, immunology, and virology. For each article, a brief synopsis reporting key points is provided as the BSBI does not enjoy the luxury of a library subscription. The hope is to disseminate relevant articles across our labs and the hep B community. 

This paper from the University of Duisburg-Essen in Germany shows that hepatocytes infected with HBV exhibit innate immune signaling via the pattern precognition receptor (PRR) Toll-Like Receptor 2 (TLR2). The adaptive immune response to HBV infection is well characterized and is broken into phases based on serological testing of antibodies produced against the virus. However, whether HBV infection triggers an innate immune response has remained controversial, with the long-held belief being that HBV evades the innate immune system as a “stealth virus”. Contrary to this view, studies of acute HBV infection in patients have indicated an early, innate immune response to HBV characterized by a natural killer (NK) cell response. Toll-like receptors (TLRs) are a class of membrane-bound receptor proteins which play a key role in innate immunity by recognizing foreign pathogens and activating inflammatory signaling cascades. A previous publication from this group has demonstrated that primary human hepatocytes (PHHs) can be stimulated through the TLR proteins TLR1-9. In this paper, PHHs from human donors were infected with HBV ex vivo. Then, expression of the innate immune cytokines Interleukin 1 Beta (IL1B), Interleukin 6 (IL6), and Tumor Necrosis Factor Alpha (TNFα) were measured by quantitative, reverse-transcription polymerase chain reaction (qRT-PCR). HBV-infected PHHs showed greatly increased expression of these genes at three hours after infection compared to mock-infected and not treated PHHs. Additionally, immunocytochemical staining revealed translocation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) to the nuclei of HBV-infected PHHs, indicating a cytokine response. Next, to characterize the innate immune response caused by HBV infection, a DNA microarray was used. Here, PHHs were either infected with HBV or treated with a known TLR ligand such as Pam3Cys (TLR2 agonist) or poly(I:C) (TLR3 agonist). Then, RNA was extracted from the cells and converted through a complementary DNA (cDNA) intermediate into biotin-labeled anti-sense RNA (aRNA) which was then hybridized to a Human Genome U219 Array Plate. This plate, coated with over 530,000 DNA probes representing over 20,000 human genes served as a scaffold for complementary base-pair binding of the aRNAs derived from the cells. Once bound to the microarray, the biotin-labeled aRNAs were detected by staining with streptavidin phycoerythrin, resulting in a fluorescent signal wherever complementary base-paring occurred. This microarray analysis revealed which specific inflammatory genes were up-regulated in the PHHs by each stimuli. Gene expression signals which were induced by HBV infection were compared with those induced by the TLR agonists. The gene expression profile of HBV-infected PHHs was most similar to that of PHHs treated with the TLR2 agonist Pam3Cys. This data indicates that HBV infection induces a TLR2-like innate immune response. Importantly, no expression of interferon-stimulated genes (ISGs) was detected in the microarray analysis. Finally, PHHs were pre-treated with neutralizing antibodies against TLR2 (nABTLR2) prior to infection with HBV. HBV-mediated induction of IL1B, IL6 and TNF was significantly reduced by nABTLR2 pre-treatment and conversely, HBV replication was increased. In summary, this paper shows that PHHs exhibited an innate immune response to HBV infection via the TLR2 pathway. The group suggests that this response is one of the body’s first steps leading to HBV clearance. Furthermore, in the discussion section the group indicates that the HBV surface antigen (HBsAg) is likely the protein component of HBV which activates TLR2 upon infection. This finding may help in the development of strategies to cure chronic HBV infection.

​This paper from Wuhan University in China reports that HBV infection can increase the expression of Programmed Death Ligand 1 (PD-L1) on the surface of infected hepatocytes, allowing them to escape destruction by the adaptive immune system. PD-L1 is the binding partner of Programmed Death 1 (PD-1), an immune checkpoint protein on the surface of T cells. The expression of PD-L1 on cell surfaces allows for their recognition by circulating T cells as part of the body and not an outside threat. This interaction is important for the prevention of autoimmune disorders in which the immune system attacks healthy cells of the body. However, PD-L1 is commonly over-expressed in a number of cancers and is a hallmark of especially aggressive cancers. PD-L1 expression on cancer cells allows them to neutralize T cells which specifically target them. This is one example of an “immune-escape” strategy exhibited by cancers. Accordingly, PD-L1 and PD-1 are the target of a number of FDA approved immunotherapies for cancer including the PD-L1 inhibitors Tecentriq, Bavencio, and Imfinzi and the PD-1 inhibitors Keytruda, Opdivo, and Libtayo. These drugs are some of the first in their class in that they are not small molecules, but are recombinant, monoclonal antibodies. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor which is mutated or deleted in many human cancers. PTEN is a phosphatase, a protein which dephosphorylates other molecules. This group has previously shown that PTEN plays a role in antiviral innate immunity. Therefore, they wanted to see if PTEN also regulates the adaptive immune response in the context of HBV infection. First, they used immunohistochemical staining of patient liver tissues to compare the levels of PTEN and PDL-1 in patients chronically infected with HBV vs healthy controls. There was a reduced staining of PTEN and a heightened staining of PD-L1 in chronic HBV tissues compared to controls. The group then found a similar correlation using immunofluorescence, qPCR and Western blotting of HepG2 cells vs HepG2.2.15 (HBV-producing) cells. They also transfected HepG2 cells and infected mice via hydrodynamic injection with an HBV-containing vector (pHBV1.3) or an empty vector control (pUC18) and then performed qPCR and/or Western blotting.  In all systems, HBV infection/production induced a reduction of PTEN and an increase in PD-L1 expression. Then, in order to elucidate this phenomenon further, a PTEN-expressing plasmid was transfected into HepG2.2.15 cells, which resulted in a reduction in PD-L1 mRNA and protein. Conversely, PTEN knockdown in HepG2.2.15 cells resulted in a two-fold increase in PD-L1 mRNA and protein expression. These results show that HBV inhibits PTEN expression which in turn causes up-regulation of PD-L1. Next, the group transfected HepG2 and Huh7 cells with a number of constructs conferring individual HBV proteins. They found that HBV X protein (HBx) and HBV polymerase (HBp) reduced PTEN expression more than any other HBV protein components. Next, the group analyzed how HBV production in hepatocytes affected human T cells grown in co-culture. Jurkat T cells were co-cultured with either HepG2 or HepG2.2.15 cells and then analyzed by flow cytometry. Jurkat T cells grown alongside the HBV-producing HepG2.2.15 cells had a higher incidence of apoptosis, a higher expression of PD-1, and less Interleukin-2 (IL-2) secretion than those grown alongside HepG2 cells. This result indicates that HBV-infected hepatocytes suppress local T cell responses by PD-L1/PD-1 signaling. Finally, the group used a mouse model of HBV infection to show that PTEN over-expression promotes HBV clearance in vivo. This paper shows that PD-L1, a highly studied drug target implicated in the immune-escape of cancers is also up-regulated by HBV infection. Furthermore, the HBV proteins responsible for this up-regulation are HBx and HBp. This finding may help in the development of  immunotherapies to treat chronic HBV infection. Perhaps FDA approved PD-L1 or PD-1 inhibitors may be used in conjunction with interferon alpha treatment or HBV antivirals to boost the immune response against HBV-infected hepatocytes.

This paper from National Tsing Hua University in Hsinchu, Taiwan reports the design and testing of nanoparticles which selectively confer immunogene therapy to hepatocellular carcenoma (HCC) cells. Nanoparticles are very small (1-1000nm) particles which have become an attractive novel drug candidate in recent years. The use of nanoparticles as medicine would enable the customizable delivery of DNA, RNA, or protein payloads to cells. The novel nanoparticles presented here deliver both a small interfering RNA (siRNA) against the Programmed Death Ligand 1 (PD-L1) gene as well as a plasmid DNA (pDNA) encoding the cytokine Interleukin 2 (IL-2). The strategy behind the nanoparticles’ design is to both inhibit an immunosuppressive gene (PD-L1) and up-regulate an immunostimmulatory gene (IL-2) in tumor cells. Delivery of such genes to tumor cells would make them more vulnerable to destruction by circulating cytotoxic T cells (CD8+ T cells). This type of approach is needed, because many advanced tumors create an immunosuppressive tumor micro-environment (TME) rendering many cancer treatments ineffective. The nanoparticles presented here are referred to as tumor-targeted lipid dendrimer-calcium phosphate (TT-LDCP) nanoparticles. The nanoparticles consist of a core of calcium phosphate, thymine-capped polyamidomine (PAMAM) dendrimers, siRNA, and pDNA. This core is coated with an inner lipid called DOPA and outer leaflet lipids DOPC, DOTAP, and DSPE-PEG. The nanoparticle is then tagged with SP94 (SFSIIHTPILPL), a polypeptide which selectively binds to HCC cells but not healthy hepatocytes. Dendrimers are repeatedly-branching molecules which exhibit a sphere-like shape. PAMAMs are the most well-characterized class of dendrimers, consisting of branching amide and amine groups. The calcium phosphate and PAMAM dendrimers in the core of the TT-LDCP nanoparticle promote endosomal escape of the nucleic acid payload. Additionally, this group shows that the PAMAM dendrimers in TT-LDCP nanoparticles also activate the STING pathway. The group showed that STING was activated by treating mouse HCC cells HCA-1 with complete nanoparticles or those lacking the dendrimers. Cells treated with complete nanoparticles showed, by Western blot a higher level of both TBK1 and IRF3 phosphorylation than those treated with incomplete nanoparticles. Those cells treated with complete nanoparticles also displayed heightened transcription of the STING-triggered proinflammatory genes Ifnb,Ccl5, and Cxcl10 as measured by qPCR. Furthermore, the group showed that treatment using their nanoparticles of mice bearing orthotopic HCC implants resulted in dendritic cell maturation in those animals, regardless of the identity of the genes delivered. These results indicate that the dendrimers used in the TT-LDCP nanoparticles not only serve for efficient delivery of nucleic acids, but also as adjuvants that stimulate the STING pathway and activate tumor-infiltrating dendritic cells. This publication gives a glimpse into what future therapies for cancer may look like. The nanoparticle designed by this group is unique in that it has multiple functionalities: selectively targeting HCC cells, inhibiting PD-L1 expression, inducing IL-2 expression, and activating the STING pathway. Such a complex design is bound to require fine tuning before it can become a medicine. But a multi-target immunotherapeutic such as this may be exactly what is needed to help the body fight against aggressive, immunosupressive tumors.

Lay Summary: 
This month, the innate immune system was the focus of HBV research. Scientists hope to find how the innate immune system interacts with HBV during viral infection and proliferation. Doing so will shed light on host factors which lead to chronic infection and inform antiviral strategies. Notably, this month a human protein, MX2 was found to have potent anti-HBV activity by preventing cccDNA formation. Also, a microRNA encoded by HBV called HBV-miR-3 was found to activate the human innate immune system to limit HBV replication. This month, a paper studying woodchuck hepatitis virus (WHV) traked activation of the innate immune system as well as he adaptive immune system in an acute infection model. Also this month, concerning hepatocellular carcenoma (HCC), the alternative splicing of mRNA in tumors was found to vary in HCC patients based upon their risk factor (HBV, HCV, or alcohol). Finally, a review was published this month concerning STING, an innate immune protein which is not activated by HBV infection but which may prove a valuable tool for cancer treatment.  

Meet our guest blogger, David Schad, B.Sc., Junior Research Fellow at the Baruch S. Blumberg Institute studying programmed cell death such as apoptosis and necroptosis in the context of hepatitis B infection under the direction of PI Dr. Roshan Thapa. David also mentors high school students from local area schools as part of an after-school program in the new teaching lab at the PA Biotech Center. His passion is learning, teaching and collaborating with others to conduct research to better understand nature.

Hep B Patient Engagement Survey: Help Guide The Future of Hepatitis B Therapies

If you’ve ever wanted to help guide the future of hepatitis B treatments, now is your chance! The Hepatitis B Foundation has created a short survey that is designed to capture a comprehensive view of the patient experience. The survey, which takes approximately 20-25 minutes to complete, will be made available for use by the US Food and Drug Administration (FDA) and drug development researchers to help clinical trial development for future hepatitis B therapies. All survey responses are anonymous.  

All individuals living with chronic hepatitis B are welcome to take this survey! After answering a few standard questions, participants will be asked whether or not they are currently on treatment for hepatitis B. If they are on treatment, the survey will prompt the participant to answer a few questions about their experience with the medication, such as how it makes you feel to take it, 

and what challenges you may face while taking your medication. All participants, regardless of their current treatment status, will have an opportunity to provide feedback on what they hope future medications will look like! 

The patient perspective is essential to creating a treatment that is not only effective but something that those living with hepatitis B would be willing to take. Oftentimes, researchers do not have the opportunity to gather insight into what patients are looking for or how a therapy would impact their lives. This can result in missed dosages of a medication, or avoiding a therapy altogether, rendering the treatment ineffective. This survey is also unique because it seeks to capture the diverse experiences of global patients living with hepatitis B. As we want to ensure that new treatments are as universal as possible, gathering the thoughts of both international and national individuals will ensure that different voices and opinions are captured! 

The survey is the first part of a multistep process to collect information on the patient experience. In the upcoming months, we will carry out focus groups and interviews to have a better understanding of what it is like to live with hepatitis B, its impact on a person’s daily life, and more. The information collected will help to direct our patient-focused drug development meeting – a chance for stakeholders and those living with hepatitis B to meet and discuss the patient perspective –  in June 2020.

The work being done will result in a broader understanding of how individuals are affected by the disease and more informed decisions regarding future hepatitis B therapies. Help guide the future of hepatitis B clinical trials and drug development by taking the survey today! 

Eiger BioPharmaceuticals: Developing Two New Hepatitis Delta Treatments

Eiger is currently working on two new drugs for hepatitis delta; Lonafarnib and Pegylated Interferon Lambda, which are both currently inphase 3 clinical trials. Lonafarnib is a new type of treatment that attempts to control hepatitis delta through a new method: through blocking a key enzyme that is needed for the hepatitis delta virus to replicate. Blocking this enzyme prevents a new virus from being created, which may control and even cure hepatitis delta.

Lambda is being developed as a better tolerated interferon compared to interferon alfa (IFN alfa). Interferons work by stimulating the body’s own immune system to fight the virus. Pegylated interferon alpha, which is the only current treatment for hepatitis delta, is a difficult treatment to tolerate, with many patients experiencing unpleasant side-effects. Lambda utilizes the same method of treatment as IFN alfa, in combination with a new strategy, which stimulates an immune response and targets receptors in the liver, which may reduce side effects and result in improved tolerability.

Below is Eiger Biopharmaceuticals’ response to a series of questions we posed to them. 

Image courtesy of Praisaeng, at FreeDigitalPhotos.net.

1. Lambda is an immunomodulator and Lonafarnib is a prenylation inhibitor. Can you explain in laymen’s terms the mechanism for these drugs and how they work?

Eiger’s wording: Lonafarnib is a well-characterized, first-in-class, orally active inhibitor of an enzyme that is key to a vital process in the life cycle of HDV. Inhibiting this enzyme blocks the ability of HDV to assemble and package viral particles. Currently approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not affect HBsAg, and have no impact on HDV infection.

Lambda is being developed as a better tolerated interferon compared to interferon alfa (IFN alfa). Lambda is a well-characterized, first-in-class, type III interferon (IFN) that stimulates immune responses that are critical for the development of host protection during viral infections. By targeting receptors that are localized in the liver, Lambda treatment may reduce side effects and result in improved tolerability .

Can you share, in simple terms, the basic results of Eiger phase 3 studies for hepatitis delta trials? Are these drugs equally effective in HBeAg positive and negative HBV patients?

The Eiger Phase 2 LOWR program with Lonafarnib has been completed. Over 120 patients were dosed in Phase 2 dose-finding studies to identify combination regimens of lonafarnib (LNF) and ritonavir (RTV) with and without pegylated interferon-alfa (PEG IFN α), with efficacy and tolerability to enable viral load suppression of HDV RNA and ALT normalization at Week 24.

  • Dosing regimens of LNF 50 mg twice daily + RTV 100 mg twice daily with and without PEG IFN-a-2a 180 mcg once weekly were identified with the following reported results:
    • All-oral: Lonafarnib boosted with ritonavir
    •  29% of patients achieved ≥ 2 log decline and ALT normalization
  •  Combination: Lonafarnib boosted with ritonavir + PEG IFN-a-2a
    •  63% of patients achieved ≥ 2 log decline and ALT normalization

These dosing arms are being further studied in the global Phase 3 D-LIVR study. Phase 2 studies have not been stratified by HBeAg status.

The D-LIVR Study, a Phase 3 pivotal trial, is on-going and evaluating the safety and efficacy of lonafarnib treatments in patients chronically infected with Hepatitis Delta Virus (HDV). Topline Week 48 data will be available in 2021.

2. How will Lambda and Lonafarnib be administered to patients?

Lonafarnib capsules are administered orally twice daily by mouth. Lonafarnib is taken in combination with ritonavir, a therapeutic booster that increases the bioavailability of lonafarnib. Ritonavir tablets are administered orally twice daily by mouth.

Pegylated interferon-lambda is administered as a self-administered subcutaneous injection once weekly.

3. Do you anticipate combination therapy will be needed and if so, which combinations do you anticipate?

No form of viral hepatitis has been cured with a single drug. Combinations of treatments with different mechanism of actions have always been required.

Lonafarnib and interferons have different mechanisms of action and have been studied as monotherapies and in combination together as treatments for HDV. While each treatment alone reduces the HDV viral load, combination studies have shown that using these treatments together leads to a synergistic effect and further reduces the HDV viral load.

Recently, the interim end of treatment results of peginterferon lambda (Lambda) and lonafarnib combination study in HDV-infected patients were presented at AASLD 2019. The LIFT study is being conducted within the National Institutes of Health (NIH) at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). LIFT is a Phase 2a open-label study of 26 adult patients with chronic HDV treated with Lambda 180 mcg once weekly in combination with Lonafarnib 50 mg twice daily boosted with ritonavir 100 mg twice daily for 24 weeks. Primary efficacy endpoint is > 2 log HDV RNA decline at end of treatment. At the time of analysis, 19 of 26 patients had reached Week 24. Median HDV RNA decline was 3.4 log IU/mL (IQR: 2.9-4.5, p<0.0001) with 53% (10 of 19) patients achieving below the limit of quantification and 37% (7 of 19) patients achieving undetectable HDV RNA at Week 24. 18 of 19 patients (95%) achieved primary endpoint of > 2 log decline during 24 weeks of therapy. We believe these data are the most encouraging yet in pursuit of HDV cure.

4. What kind of side effects can patients expect with Lambda and Lonafarnib, with or without combination therapy?

The most common side effects of lonafarnib include diarrhea, nausea, fatigue, decreased appetite, vomiting, abdominal pain, and decreased weight. Antacid, antiemetic, and antidiarrheal medications may be used prophylactically to treat these gastrointestinal side effects.

The most common side effects of pegylated interferon-lambda (Lambda) are the expected side effects of interferons. However, these side effects have been demonstrated to be much milder and less severe than what has been previously been shown with pegylated interferon-alfa (alfa). These include musculoskeletal (myalgia, arthralgia, and back pain), flu-like symptoms (chills, pyrexia, and pain) and elevated alanine aminotransferase (ALT) levels.

A combination of these side effects is expected with combination therapy.

5. Are Lambda and Lonafarnib safe for use in people with cirrhosis?

Currently, the safety and efficacy of lonafarnib and pegylated interferon-lambda are being investigated in persons chronically infected with HDV. The clinical trials require study participants meet certain eligibility criteria to be included in these studies. These eligibility criteria may or may not reflect the type of patient who will use these therapies after they receive FDA approval.

Phase 2 and Phase 3 studies both include patients with well-compensated cirrhosis.

6. With a clearance of HDV, would you also anticipate a loss of surface antigen – functional cure for chronic HBV as well? If so, in what percentage of HBeAg and HBeAb patients?

HDV is always found as a co-infection with HBV because HDV requires just a small amount of HBV surface antigen (HBsAg) to complete HDV viron replication. However, an HDV / HBV coinfection leads to much more severe chronic viral hepatitis compared to HBV monoinfection alone. Therefore, it is important to treat HDV, even if HBV is not cured. It is possible to clear HDV RNA without loss of HBsAg.

7. Lambda and Lonafarnib are currently in phase 3 trials for delta. Are you able to provide an approximate timeline for when it will be approved for use in U.S. and Europe?

Eiger BioPharmaceuticals is committed to developing safe and effective therapies for HDV and providing patients with a pathway to gain access to approved therapies as quickly as possible.

The D-LIVR Study is a global study that is evaluating the safety and efficacy of lonafarnib treatment in patients chronically infected with HDV. The D-LIVR Study is recruiting subjects in up to 20 countries in over 100 study sites. The D-LIVR study includes 48 weeks of treatment with two different lonafarnib-based treatment regimens, followed by 24 weeks of follow-up. Primary endpoint is ≥ 2 log decline and ALT normalization at Week 48. Topline data from the Phase 3 D-LIVR study will be available in 2021. For more information about study locations and eligibility, please visit www.clinicaltrials.gov  (NCT03719313).

End of Phase 2 meeting with FDA to discuss Phase 3 development with Lambda monotherapy is planned for Q1 2020.

The Journey to Hepatitis Elimination in Nigeria

Nigeria, with an estimated population of 190 million people, has a Hepatitis B prevalence of 8.1% and Hepatitis C at 1.1%, based on a recent Nigeria HIV/AIDS Indicator and Impact Survey(NAIIS) report. The NAIIS survey was a National house-hold based Survey that assessed the prevalence of HIV and related health indicators including the national prevalence of two additional blood-borne viruses: Hepatitis B virus and Hepatitis C virus. This gives an estimated number of about 19 million Nigerians living with Hepatitis B and or C.

The large population and relatively high prevalence rates of hepatitis B and hepatitis C, suggest that Nigeria should be considered a key country for hepatitis elimination efforts. Nigeria’s population was estimated at over 190 million in 2017, and growing rapidly, with projections suggesting it will surpass the United States to become the third most populous country in the world by 2050

The Journey to Hepatitis Elimination in Nigeria

In 2018, Patient groups and members of the World Hepatitis Alliance under the umbrella of the Civil Society Network on viral hepatitis in Nigeria partnered with the Federal Ministry of Health, and World Health Organization (WHO) to organize the 1st Nigeria Hepatitis Summit in Abuja, FCT. The meeting was the flagship event in the country that brought together 26 states Ministry of health officials, academia, and civil society groups to engage on ways to accelerate hepatitis elimination in the country. The event was supported by Gilead Sciences and Roche Products Limited, with technical support from Clinton Health Access Initiative.

In May 2019 as a follow up to the Summit, the National Viral Hepatitis Control Program, convened the first Review meeting of all Hepatitis Desk officers across Nigeria in Abuja, with the active participation of the civil society groups in the event. The meeting was organized to review the Hepatitis Treatment facilities directory and share best practices among key actors.

In response to high prevalence rates and in alignment with the global effort towards elimination, The Nigerian Ministry of Health developed the National Viral Hepatitis Strategic Plan 2016 to 2020, which maps out actions to put Nigeria on the path of hepatitis elimination. National guidelines for the prevention, care and treatment of viral hepatitis B and C were also developed and published in 2016, which centre on firmly establishing the management of viral hepatitis as part of universal health coverage. Although there is a paucity of data on modes of viral hepatitis transmission within Nigeria, local intelligence suggests that there are some modes of transmission that are particularly relevant, including mother-to-child transmission, healthcare related transmission due to poor infection control and traditional cultural practices, including scarification, female genital mutilation, male circumcision, and uvulectomy.

However, whilst this political will and strategic direction are promising, there remain substantial challenges to the realisation of these plans and the attainment of elimination goals in Nigeria.

Although there have been efforts to work towards universal health coverage in Nigeria, the health system has limited funding, and there is a need for coordination between the levels of government.

Challenges to accessing health care in Nigeria

Although guidelines and strategic direction have been developed to guide Nigeria’s response to viral hepatitis, important barriers remain in place, which must be surmounted to reach elimination targets. These include geographical and financial barriers to accessing testing and treatment and the availability of alternative tests and treatment providers that lack connection with the health system and efficacy for treatment outcomes.

Service barriers to hepatitis care

The allocation of health care resources, including the health care workforce, in Nigeria, is skewed towards secondary and tertiary services, which are predominantly situated in urban areas. Currently, the majority of hepatitis treatment in Nigeria is provided at tertiary level services, which are not easily accessible to large parts of the population.

Financial barriers to hepatitis care

For Nigerians that are able to access health care services, significant financial barriers remain to access testing and treatment for hepatitis. Despite an effort to develop a system of universal health coverage, the majority (approximately 70%) of health spending for health in Nigeria still comes from private expenditure. The majority of this is out-of-pocket spending, with only a small minority of Nigerians (approximately 4-5%) covered by health insurance. Costs of testing and treatment pose significant barriers to accessing viral hepatitis care, as tests, treatments, and vaccines must be paid for privately, and there is often limited availability of supplies.

This barrier of cost in accessing the hepatitis continuum of care is the primary drive towards quackery and unethical practices perpetrated by some organizations and individuals in Nigeria, providing alternative herbal and relatively cheaper treatment options to vulnerable and gullible patients.

The l ack of social and financial risk protection for Nigerians in accessing hepatitis continuum of care leads to high levels of poverty, vulnerability, and inequality in health

Elimination efforts in Nigeria

Clinton Health Access Initiative (CHAI) to date is leading in providing access to affordable treatment for Hepatitis C patients in Lafiya, Nasarawa state, through its partnership with the government. The program provides affordable HCV RNA @ $35 and generic DAAs/month @ $80/month. CHAI through its access program has succeeded in negotiating costs of HCV diagnostics in some health centres across Nigeria, such as Lagos, Abuja, and Kwara, where patients can access affordable HCV RNA tests.

Similarly, Taraba State Government in partnership with Roche Products is providing a Pegasys based HBV treatment program for Tarabans. The Yakubu Gowon Centre in partnership with Taraba state government is also providing affordable diagnostics and treatment on HCV for patients at its treatment locations in Takum local council of Taraba state. The centre recently donated some doses of DAAs for patients.

Birth-dose HBV vaccination: Nigeria has a coverage rate of about 51% birth-dose HBV vaccination rate in the country. Sadly, there are no HBV vaccination programs for at-risk populations such as Men who Have Sex With Men, health care workers, People Who Inject Drugs, Incarcerated Populations. There are no government-funded harm reduction projects for People Who Inject Drugs in Nigeria.

Over 80% of activities of civil society and patient groups in Nigeria are on-demand creation, awareness and testing and linkage to care for patients. In June 2019, Centre for Initiative and Development (CFID) and other civil society organizations in Nigeria received a donation of 120 doses of DAAs at the African Hepatitis Summit in Kampala, Uganda through the African Regional Board Member.

Nigeria and the 2030 target

Unless something drastic is done, Nigeria and most of Africa stands the risk of missing the SDGs Goal 3.3 and the WHO Global Health Sector Strategy on Viral Hepatitis Elimination target for 2030.

Nigeria, with its vast mineral, natural resources, and human capital, has what it takes to eliminate viral hepatitis by 2030. But what it lacks is the strong political will and financial commitment by governments at all levels to finance an elimination strategy!

References:

  1.  1st Nigeria Hepatitis Summit Report, 2019
  2.  World Hepatitis Summit 2015. New data shows relentless rise in hepatitis deaths.
  3. World Health Organization (WHO). Global Hepatitis Report 2017. Geneva: WHO, 2017.
  4.  WHO, 2016.WHO Global Health Sector Strategy for the Elimination of Viral Hepatitis: 2016-2030
  5. NASCP, Nigeria Viral Hepatitis Strategic Plan: 2016-2020
  6.  World Health Organization (WHO). Global Hepatitis Report 2017. Geneva: WHO, 2017:Availableat:apps.who.int/iris/bitstream/handle/10665/255016/9789241565455-eng.pdf;jsessionid=9DECA1FF83BC4A8CAE3BE2649662?sequence=1
  7. Centers for Disease C, Prevention. Progress in hepatitis B prevention through universal infant vaccination – China, 1997–2006. Morbidity and Mortality Weekly Report, 2007;56(18): 441–445

Hepatitis B Research Review

 

 

 

 

Welcome to the Hepatitis B Research Review! This monthly blog shares recent scientific findings with members of Baruch S. Blumberg Institute (BSBI) labs and the hepatitis B (HBV) community. Technical articles concerning HBV, Hepatocellular Carcinoma, and STING protein will be highlighted as well as scientific breakthroughs in cancer, immunology, and virology. For each article, a brief synopsis reporting key points is provided as the BSBI does not enjoy the luxury of a library subscription. The hope is to disseminate relevant articles across our labs and the hep B community. 

Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication Journal of Hepatology

  • This paper from Fudan University in Shanghai, China reports the interferon-induced GTPase MX2 as a host protein which inhibits HBV replication. Interferon alpha (IFN-α) is a type 1 interferon used in a subset of HBV-infected patients to help eradicate the virus. IFN-α treatment results in the activation of hundreds of genes known as interferon-stimulated genes (ISGs). Which ISGs are most important in eliminating HBV infection remain largely unknown. GTPases are a large family of hydrolase enzymes which convert guanosine triphosphate (GTP) to guanosine diphosphate (GDP). GTPases act as molecular switches in an array of cellular process including signal transduction, cell division and differentiation, and protein translocation. The myxovirus resistance (Mx) proteins are highly conserved, dynamin-like, large GTPases. Humans have two MX proteins: MX1 and MX2, both of which are known ISGs. While MX1 is known to have broad-spectrum antiviral activity against RNA viruses, MX2 has only recently been shown to inhibit human immunodeficiency virus 1 (HIV-1), hepatitis C virus (HCV), and hepesviruses. MX2 antiviral activity against HIV-1 and herpesviruses is mediated through MX2 binding to the capsid of invading viruses whereby it likely inhibits the uncoating of viral DNA. In HCV, MX2 was found to interact with non-structural protein 5A (NS5A) thereby inhibiting its localization to the endoplasmic reticulum (ER). MX1 has been reported to inhibit HBV replication by inhibiting nuclear export of viral RNas and/or trapping the HBV core protein indirectly. This study investigates the anti-HBV activity of MX2. First, the group compared the anti-HBV activity of MX2 to four other innate immune restriction factors: HNRNPU, SAMHD1, MOV10 and A3G. They co-transfected these genes along with the HBV genome into HUH-7 cells and then assessed HBV replication via Southern blot. MX2 was found to inhibit HBV replication the most, with 44% of viral DNA compared to the empty vector control. The group then used siRNA, Southern blot, Western blot, fractionation, and mutagenesis studies to elucidate the anti-HBV role of MX2. Overall, they found that MX2 significantly reduces HBV RNA levels and indirectly impairs cccDNA formation. MX2 was found to contribute substantially to the anti-HBV affect of  IFN-α. Both the GTPase activity and oligomerization status of MX2 were found to be important in conferring its anti-HBV affect. In the future, MX2 and its related pathways may be exploited to help prevent the formation of and even eliminate cccDNA in those infected with HBV.

An HBV-encoded miRNA activates innate immunity to restrict HBV replication – Journal of Molecular Cell Biology

    • This paper from the Tianjin Medical University in China explains how an HBV-encoded microRNA (miRNA) activates the innate immune system in humans infected with the virus. miRNAs are short (21-25 nucleotides) sequences of mRNA which are mainly involved in post-transcriptional silencing of genes. miRNAs are produced in plants, animals, bacteria, and viruses. Typically, miRNA acts to silence protein translation from a messenger RNA (mRNA) by binding to the 3′ untranslated region (UTR) of the mRNA. This binding may result in the destabilization or cleavage of the mRNA or inhibit the function of the ribosome during translation. This group has identified an miRNA from the HBV genome called HBV-miR-3 which they have previously reported inhibits HBV replication by targeting the HBV mRNA transcript. In this paper, the group first shows that HBV-miR-3 is produced in an amount proportional to virus infection in vitro. They also show that HBV-miR-3 is secreted from cells in exosomes. Next, using both patient serum samples and in vitro assays, the group found a positive correlation between HBV-miR-3 production and IFN-α signaling pathways. In patient serum, levels of HBV-miR-3 positively correlated with levels of the hepatitis-related parameters alanine aminotransferase (ALT), aspartate transaminase (AST) and type I IFNs (IFN-α and IFN-β). In cell culture, they observed an increased expression of  the IFN-α-induced antiviral effectors OAS-1, MX1, IFIT2 and IFIT3 in the context of HBV-miR-3 production. Further experiments indicated that HBV-miR-3 promotes IFN-α production by suppressing the expression of suppressor of cytokine signaling 5 (SOCS5), allowing for signal transducer and activator of transcription 1 (STAT1) to be activated by phosphorylation. Finally, the group shows that HBV-miR-3 released from infected cells in exosomes  promotes polarization of the M1 macrophage phenotype. M1 or “classically activated” macrophages secrete high levels of pro-inflammatory cytokines and thereby fight pathogenic infections. Taken together, these results show that aside from directly limiting HBV replication, HBV-miR-3 also indirectly limits HBV infection by activating the host innate immune system. The virus may do this in order to adopt host miRNA-mediated antiviral machinery and thereby alleviate pathogenesis so that persistent and latent infection can continue. In the future, levels of HBV-miR-3 may be used as a diagnostic marker for HBV infection and may shed light on novel antiviral approaches.

Innate and adaptive immunity associated with resolution of acute woodchuck hepatitis virus infection in adult woodchucks – PLOS Pathogens

    • This paper from Georgetown University in Washington, DC is a “woodchuck paper”. That is, it is an in vivo study of woodchucks infected with Woodchuck Hepatitis Virus (WHV). WHV infection is used as a model system for HBV infection in humans because WHV is similar to HBV. This type of study is beneficial, especially when studying the immune response to hepadnaviruses, because humans infected with HBV are typically asymptomatic in the early stage of infection and because it is not advisable to obtain liver biopsies from these patients. The woodchuck infection model offers a controlled infection with WHV at a known time-point, which can be monitored by regular blood tests and liver biopsies. When studying the immune response to hepadnaviruses, liver biopsies are necessary because the liver is the site of the infection. About 95% of adults infected with HBV “clear” the virus; that is, their immune system is able to fight off the virus completely, giving them life-long immunity. The other 5% become chronic carriers of HBV and are at a high risk for liver cirrhosis and hepatocellular carcinoma (HCC). However, 95% of infants infected with HBV become chronic carriers. Differences in the immune systems of adults vs infants have been attributed to this drastic difference in chronicity, but what specific components of the immune system are important in staving off chronic infection remain unknown. Overall, the data presented here indicate that there is an early, non-cytolytic control of WHV replication mediated by interferon gamma (IFN-γ) produced mainly by natural killer (NK) cells. This was followed by an adaptive immune response characterized by antibody production, a T-cell response, and cytolytic action of cytotoxic T lymphocytes (CTLs). This adaptive immune response led to both the decline of WHV as well as symptoms of acute hepatitis B (AHB) including sinusoidal and portal inflammation in the liver.

Differential alternative splicing regulation among hepatocellular carcinoma with different risk factors BMC Medical Genomics

    • This paper from the University of Utah School of Medicine in Salt Lake City, Utah uses bioinformatics to examine how different risk factors for hepatocellular carcinoma (HCC) correlate with differential alternative splicing (AS) of tumor mRNAs. After a primary (precursor) mRNA transcript is produced in the nucleus by RNA polymerase, the transcript must “mature” by having regions called “exons” removed in a process called splicing. Splicing results in an mRNA transcript consisting entirely of “introns”. The mRNA is then capped at its 5′ end with a 7-methylguanosine residue and polyadenylated at its 3′ end with about 200 adenylate residues (poly-A tail). This mature mRNA is able to exit the nucleus and be translated into protein by a ribosome. Alternative splicing (AS) describes how one genomic region may code for many different protein variants (isoforms) by differential spicing of the primary mRNA transcript. A common mechanism of AS is “exon skipping”, where exons are included in some mature transcripts but not others. HCC has various risk factors including alchohol consumption and infection with hepatitis B or C viruses (HBV and HCV). This study used data from The Cancer Genome Atlas (TCGA) and  the Genomic Data Commons (GDC) Data portal to analyze 218 patients with primary HCC associated with HBV (n = 95), HCV (n =47), or alcohol (n = 76). They used RNA sequencing (RNA-Seq) data to examine differences in AS between three groups: HBV vs. HCV, HBV vs. alcohol, and HCV vs. alcohol. 143 genes were identified with differential AS across these groups and these genes were found to be mainly involved in immune system, mRNA splicing-major pathway, and nonsense-mediated decay pathways.Of the 143 AS genes identified, eight and one gene were alternatively spliced specific to HBV and HCV respectively. The human leukocyte antigen genes HLA-A and HLA-C had differential AS in HBV-related HCC compared to both HCV- and alchohol-related HCC. HLA ptoteins are part of the major histocompatibility complex (MHC) class 1 surface proteins which present foreign antigens to the immune system. Also, exon 3 of  the gene encoding inositol hexakisphosphate kinase 2 (IP6K2) was skipped more often in HBV-related HCC than in other groups. IP6K2 is known to be involved in cancer metastasis. This study represents the first investigation into how different risk factors of HCC may affect the AS status of specific genes.

The Cytosolic DNA-Sensing cGAS–STING Pathway in Cancer (Review) Cancer Discovery

    • This review from the Memorial Sloan Kettering Cancer Center in New York City covers current understanding of the cGAS-STING pathway in the context of cancer. While it is well known that the cGAS-STING pathway is an evolutionarily-conserved  antiviral signaling platform, how this pathway is involved in tumorigenesis remains unclear. In preneoplastic (early tumor) cells, cGAMP produced in response to DNA damage is exported out of the cell to activate STING in neighboring antigen-presenting cells (APC). This activation results in the release of type 1 interferon (IFN) from the APC, which cross-primes natural-killer and CD8 T-cells to kill the preneoplastic cells. In this context, the cGAS-STING pathway plays a role in tumor surveillance by activating innate immunity to create “hot spots” of inflammation. However, there is also evidence that activation of the cGAS-STING pathway can contribute to tumorigenesis.  In advanced, metastatic tumor cells, chronic activation of STING by chromosomal abnormalities leads to suppressed production of IFN and the upregulation of Nf-kB-driven pro-survival genes. This can drive chronic inflammation of the tumor as well as its metastasis to other locations in the body. Activation of the STING pathway in tumor cells may also allow for their immune evasion by inducing autophagy and upregulating expression of programmed death-ligand 1 (PD-L1). Another interesting finding mentioned in this review is a STING-independent form of cGAS activation which may drive tumorigenesis during cell division. During mitosis, cytoplasmic cGAS may bind to repeat sequences in the centromere regions of chromosomal DNA. Once bound, cGAS may interrupt the repair of sister chromatids by homologous recombination, causing aneuploidy in daughter cells, a hallmark of tumor cells. Of additional interest, mentioned in this review are several recent findings regarding the cGAS-STING pathway, including: cGAS can be activated by extracellular DNA entering the cell in exosomes; cGAS can be activated by “micronuclei” which are small nuclear compartments in the cytoplasm formed by chromosomal instability; cGAS-DNA complexes turn into a liquid phase to produce cGAMP; STING dimers oligomerize to form tetramers when activated; palmitoylation of STING has been proposed to recruit TANK binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3).

Lay Summary: 
This month, the innate immune system was the focus of HBV research. Scientists hope to find how the innate immune system interacts with HBV during viral infection and proliferation. Doing so will shed light on host factors which lead to chronic infection and inform antiviral strategies. Notably, this month a human protein, MX2 was found to have potent anti-HBV activity by preventing cccDNA formation. Also, a microRNA encoded by HBV called HBV-miR-3 was found to activate the human innate immune system to limit HBV replication. This month, a paper studying woodchuck hepatitis virus (WHV) traked activation of the innate immune system as well as he adaptive immune system in an acute infection model. Also this month, concerning hepatocellular carcenoma (HCC), the alternative splicing of mRNA in tumors was found to vary in HCC patients based upon their risk factor (HBV, HCV, or alcohol). Finally, a review was published this month concerning STING, an innate immune protein which is not activated by HBV infection but which may prove a valuable tool for cancer treatment.  

Meet our guest blogger, David Schad, B.Sc., Junior Research Fellow at the Baruch S. Blumberg Institute studying programmed cell death such as apoptosis and necroptosis in the context of hepatitis B infection under the direction of PI Dr. Roshan Thapa. David also mentors high school students from local area schools as part of an after-school program in the new teaching lab at the PA Biotech Center. His passion is learning, teaching and collaborating with others to conduct research to better understand nature.

Help Eliminate Hepatitis in the New year

With a new year right around the corner, now is a great time to reflect upon the past year and plan for the one ahead! 2020 is the start of a new era, but it also means that we have just 10 more years left to reach the World Health Organization’s 2030 goal of eliminating viral hepatitis. Many strides have been made over the years. In order to truly work towards elimination, we need everyone’s help – including yours!

 

  • Take Care of Your Health: The hepatitis B virus and your liver health can change over time, making regular doctors’ appointments essential to staying healthy and preventing liver disease and possibly liver cancer. Take a few hours this January to sit down and schedule your healthcare appointments for the year. Following up with your healthcare provider will allow them to monitor the infection, identify any signs of liver damage, and prescribe treatment early, if needed, to prevent further damage.

 

If you were diagnosed with acute hepatitis B and recovered, there are steps you can take to take care of your health too! You – and your healthcare providers – should be aware of the risk of reactivation, and how to prevent it. Always read the warning labels on over-the-counter medications, and make sure that anyone prescribing medication to you is aware of your past infection.

    • Get involved: Researchers are working hard each day to find a cure for hepatitis B and while they do so, there are many other issues in the hepatitis B community that can be addressed with the help of people like you! If you are in the United States, you can join our advocacy network to be notified of opportunities to take action. If you are located in another country, get involved with the #NOhep campaign, or search for World Hepatitis Alliance members near you to see what activities you can take part in. It’s essential for us to work both within our own country and globally. When we work together, our voices will be heard! 

 

  • Get tested – or encourage others to: Despite being the most common liver disease in the world, just 10% of those infected are aware that they are living with hepatitis B. It is very important that people with hepatitis B are tested – especially because hepatitis B does not have any symptoms. Start small by encouraging your family members and loved ones to get tested or offering to go with a friend to their doctor’s appointment. If you want to help on a larger scale, you can volunteer with local health organizations who are active in the hepatitis community. 

        Perhaps your friends and family have already been tested and      found out that they are not – and have never been – infected. That’s great! Now, it’s time to make sure that they get vaccinated to protect themselves. Remind them to schedule an appointment to receive their vaccine, and check in on them to make sure that they receive all necessary doses. Increasing global vaccination rates – especially in high-risk communities – is essential to meeting the 2030 elimination goals.

  • Put Your Social Media to Good Use: Technology is one of the best and most powerful communication tools that we have. Consider spreading positive, accurate messaging about hepatitis B in the new year to help destigmatize the disease, raise awareness, and combat false information. Start simple by liking, retweeting, and sharing posts by groups that are working hard to educate others!  Be sure to follow reputable organizations so that the information you are receiving and passing on is correct! Join the Hepatitis B Foundation community on Facebook, Twitter, and Instagram for international updates and Hep B United on Facebook, Twitter, and Instagram for hepatitis B information in the United States! 

 

For those of you who may be struggling to cope with your diagnosis or are dealing with stigma and discrimination around your diagnosis, the suggestions above may not be for you. Instead, consider taking 2020 to empower yourself by learning more about hepatitis B and sharing your experiences, even if you are only comfortable sharing anonymously. Remember, you are not alone! Over 292 million individuals are living with hepatitis B and each person has a story to tell. 

The only way to fight stigma and discrimination is to make it known that it is unacceptable. Many of our #justB storytellers have faced the same obstacles that others are currently going through. Take some time in 2020 to watch some of our #justB storytelling videos that share the journeys of brave men and women who have found the strength to speak about their diagnosis and how hepatitis B has impacted their lives or family. Other global storytelling campaigns, such as the World Hepatitis Alliance’s #StigmaStops Campaign, or online support groups can provide support, too. However you decide to contribute to eliminating hepatitis B, your efforts will be appreciated!

Liver Health & The Holidays: How to Stay Healthy with Hep B

The holiday season is here once again! It’s often a time filled with love and happiness, but for those living with chronic illnesses like hepatitis B, this time of year can be uncomfortable and stressful. The most important thing to remember is that your health – physical and mental – should come first. 

Alcohol is usually present at holiday gatherings and can be difficult to avoid. However, it is also extremely damaging to the liver – especially if you are living with a liver disease like hepatitis B. It may be tempting, but avoiding all alcohol, including small amounts, is best for the health of your liver. Focus on the conversation and catching up with your coworkers or friends instead of the drinks!  If you feel pressured, you can carry around a cup of another beverage, such as sparkling water or juice, to bypass any questions about why you are choosing not to drink. 

The holidays are also filled with sugary treats and foods that are high in unhealthy fats. Too many sugary, processed, and fatty foods (and drinks) are harmful and can contribute to liver diseases such as Non-Alcoholic Fatty Liver. When combined with hepatitis B, liver diseases can make your risk of liver damage and liver cancer even greater, so it is extremely important to maintain a balance of healthy foods and exercise. A few treats here and there will not harm you, but moderation is key! Try eating smaller portions of dessert and keep holiday sweets out of your house to avoid temptation. If you were gifted a delicious, but unhealthy snack, share it with friends and family!  

If you are preparing a meal or a dish for your celebrations, make it a healthy one! The American Liver Foundation has a great fact sheet on how to read the nutrition label on food packing. This will help you make better choices while you are food shopping. Try using healthier alternatives to ingredients, such as butter, that may be high in cholesterol or fats, and experiment with using more spices instead of salt to add flavor to the meal. 

Be sure to stay active during the holidays! Exercise is one of the best ways to maintain a healthy weight and reduce the risk of liver cancer. Grab a friend and take a walk or head to the gym. This is a great way to keep your fitness routine, encourage your friends to stay healthy, and catch up with those you haven’t seen in a while! If you don’t want to leave the comfort of your home or if you prefer to work out alone, you can also stay active by following along to exercise videos on Youtube. 

Remember that everything that you consume is filtered through your liver; your liver never gets a break! The lifestyle tips listed above may seem simple, but they have a large, positive impact on your health. Sticking to a regular healthy routine even during the holiday season will make it easier to continue those habits all year long! You can also check out our healthy liver tips to see what other actions can be taken to protect your liver.