Hep B Blog

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About Hepatitis B, HBV

Hepatitis B Transmission for Those Newly Diagnosed

Being diagnosed with hepatitis B can be a confusing experience and may leave you with many questions. Understanding your diagnosis is essential for your health, and understanding how hepatitis B is transmitted can help prevent transmission to others. 

How is it Spread? 

Hepatitis B is transmitted through direct contact with infected blood. This can happen through direct blood-to-blood contact, unprotected sex, unsterile needles, and unsterile medical or dental equipment. Globally, hepatitis B is most commonly spread from an infected mother to her baby due to the blood exchange during childbirth. It can also be transmitted inadvertently by the sharing of personal items such as razors, toothbrushes, nail clippers, body jewelry, and other personal items that have small amounts of blood on them.

Hepatitis B is not transmitted casually by sneezing or coughing, shaking hands, hugging or sharing or preparing a meal.  In fact, hepatitis B is not contracted during most of life’s daily activities. You don’t need to separate cups, utensils, or dishes. You can eat a meal with or prepared by someone with hep B. Hugging, or even kissing won’t cause infection unless there are bleeding gums or open sores during the exchange. As an infection that is spread through the blood, standard precautions such as covering all wounds tightly, practicing safe sex (using a condom), and cleaning up all blood spills with gloves and a solution of one part bleach to nine parts water will protect against transmission. The best tool we have to prevent transmission is the hepatitis B vaccine!

Most of those who are newly infected have no notable symptoms. This is why it is important to encourage family members and sexual partners to get tested if you test positive. Often, it remains undetected until it is caught in routine blood work, blood donation, or later in life after there is liver inflammation or disease progression. 

Dealing with a Possible Exposure:

One important factor for those that may have been exposed is the timing. There is a 4-6 week window period between an exposure to hepatitis B and when the virus shows up in the blood (positive HBsAg test result).  If you go for immediate testing, please understand that you will need to be re-tested 9 weeks later to confirm whether or not you have been infected. It is essential to practice safe sex and follow general precautions until everyone is sure of their status –both the known and potentially infected.

You may still be in a waiting period trying to determine if you are acutely or chronically infected. It is possible that you have not had symptoms with your hepatitis B. It’s also very likely you are unsure  as to when you were infected. Not knowing the details of your infection can be stressful and confusing, but the most important thing to do now is to educate yourself so that you can take the proper steps to protect your liver and prevent transmission. 

Preventing Future Transmission: 

  1. Always cover open wounds. Keep cuts, bug bites – anything that bleeds or oozes – covered with a bandage. It’s also a good idea to carry a spare bandage.  
  2. Be sure to practice safe sex (use a condom) until you are sure your partner has completed their hepatitis B vaccine series. Be aware that multiple sex partners and non-monogamous relationships can expose you to the potential of more health risks and even the possibility of a co-infection, so it is best to use a condom. Co-infections are when someone has more than one serious chronic condition (like HBV and HCV , HBV and HIV or HBV and HDV).  Co-infections are complicated health conditions that you want to avoid. Therefore, practice safe sex by using a latex or polyurethane condom if you have multiple partners.
  3. Keep personal items personal.  Everyday items that are sharp may contain small amounts of blood. This includes things like razors, nail clippers, files, toothbrushes and other personal items where microscopic droplets of blood are possible. This is good practice for everyone in the house. Simple changes in daily habits keep everyone safe!

If a person has been tested and their results show that they are not already vaccinated or have not recovered from a past infection, then they should start the series as soon as possible. This includes sexual partners and close household contacts and family members. The HBV vaccine is a safe and effective 2 or 3-shot series.  

If you wish to confirm protection, the timing of the antibody titre test should be 4-8 weeks following the last shot of the series. If titers are equal to or above 10 mIU/mL, then there is protection for life.  If someone has been previously vaccinated a titer test may show that their titers have waned and dipped below the desired reading. There is no reason to panic, as a booster shot can be administered and then a repeated titer test 1-2 months later can ensure adequate immunity. Once you know you have generated adequate titers, there is no need for concern of transmission!

When recovering from an acute infection, if your follow up blood test results read: HBsAg negative, HBcAb positive and HBsAb positive then you have resolved your HBV infection and are no longer infectious to others and you are no longer at risk for infection by the HBV virus again.

However if your follow up blood tests show that you are chronically infected or your infection status is not clear, you will want to take the precautionary steps to prevent transmitting your HBV infection to others. You will also need to talk to your doctor to be sure you have the appropriate blood work to determine your HBV status and whether or not you are chronically infected.

Please be sure to talk to your doctor if you are unsure, and don’t forget to get copies of all of your lab results!

 

Hepatitis B Research

Hepatitis B Research Review: March

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.

Summary: This month, researchers at Fudan University in Shanghai, China have identified activation of the cGAS/STING pathway by extracellular DNA as a mediator of radiation-induced liver disease. At the Pennsylvania State University College of Medicine in Hershey, PA, HBV researchers have elucidated the role of the host kinase protein CDK2 in phosphorylating the HBV core protein, leading to new cccDNA formation. Researchers from the University of Charlottesville in Virginia have characterized the “apoptotic metabolite secretome”, a select group of molecules released from cells undergoing apoptosis. 

 DNA sensing and associated type 1 interferon signaling contributes to progression of radiation-induced liver injury – Cellular & Molecular Immunology

This paper from Fudan University in Shanghai, China reveals the role of the cGAS/STING pathway in radiation-induced liver disease (RILD). Either radiation therapy (RT) or accidental exposure to ionizing radiation may cause RILD. RT is used to treat various cancers, including hepatocellular carcinoma (HCC). The dose of radiation used when treating HCC and gastrointestinal malignancies is limited by the risk of RILD as the liver is a highly radiosensitive organ. RILD is associated with a high mortality in patients with HCC and typically occurs within four months of receiving RT. RILD is characterized by hepatic injury due to the deposition of fibrin into the central veins and sinusoids of the liver. While the exact mechanism of RILD development is not well understood, it has been shown that hepatic nonparenchymal cells (NPCs) such as Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells play an important role. NPCs are cells in the liver that are not hepatocytes; they consist of immune cells, endothelial cells, pericytes, and other cell types. The cGAS/STING pathway is a component of the innate immune system in cells responsible for sensing double-stranded DNA (dsDNA) in the cytoplasm and subsequently initiating the expression and secretion of type 1 interferons (IFN-I). This publication identifies the cGAS/STING-mediated production of IFN-I by NPCs as a key mediator of RILD. The authors propose that RT induces massive hepatocyte apoptosis, resulting in a large amount of ectopic dsDNA which is then taken up by liver NPCs, resulting in the activation of cGAS and subsequently STING. In order to determine this, the group exposed wild-type (WT), cGAS knockout, and STING knockout mice to 30Gy of radiation. While livers of WT mice subjected to radiation showed increased steatosis (retention of lipids), mice lacking either cGAS or STING showed less at 48 hours as measured by histological staining. The knockout mice also showed reduced apoptosis in liver tissue at 48 hours as measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay of histological sections. Additionally, histological staining of mouse liver tissues six weeks after radiation showed that the knockout mice had less veno-occlusive inflammation, an indicator of RILD. Next, the group showed that hepatocytes extracted from mice 24 hours following irradiation secrete much more dsDNA in vitro than NPCs extracted from the same liver. Furthermore, levels of cGAS, STING, IFN-α, IFN-β, and TLR9 mRNA transcripts were found to increase dramatically in liver NPCs but not in hepatocytes following radiation as measured by RT-qPCR. Additionally, expression levels of cGAS/STING-related genes TBK1, IRF3, ISG15, JAK1, TYK2, AKT1, AGBL5, TRIM32, RSAD2, and TTL4 were all increased in liver NPCs but not in hepatocytes following radiation. The group then showed that DNase treatment of mice during and after RT prevented increased expression levels of cGAS, STING, IFN-α, and IFN-β mRNAs. This result indicates that extracellular DNA is a trigger for RT-induced IFN-I secretion. Finally, the group showed that knockout of the IFNα and IFNβ receptors in mice reduced the amount of liver steatosis and apoptosis caused by RT. Additionally, blockade of IFN-I signaling with an interferon alpha and beta receptor subunit 1 (IFNAR1)-specific antibody did not negatively affect the tumor-reducing properties of RT in a mouse HCC model. This paper indicates that cGAS/STING-signaling in liver NPCs is a major cause of RILD. Extracellular DNA from hepatocytes killed during RT is taken up by NPCs where it activates cGAS/STING signaling to produce IFN-I. This finding could help scientists and clinicians devise ways to prevent RILD in patients undergoing RT for HCC or other cancers. Perhaps short-term immune modulators may be used in tandem with RT to prevent an excessive response of the innate immune system. 

Role of Hepatitis B Virus Capsid Phosphorylation in Nucleocapsid Disassembly and Covalently Closed Circular DNA Formation – PLOS Pathogens

This paper from Dr. Jianming Hu’s laboratory at the Pennsylvania State University College of Medicine in Hershey, PA outlines the role of phosphorylation of the HBV core protein (HBc) in the HBV life cycle. HBV has a relaxed circular (RC) DNA genome which it delivers to the nucleus of hepatocytes. In the nucleus, the RC DNA is converted into covalently closed circular (CCC) DNA which is the viral transcriptional template for all HBV mRNA species including pregenomic RNA (pgRNA). Along with the viral reverse transcriptase (RT), pgRNA is packaged by HBc into newly formed nucleocapsids (NC) where it is reverse-transcribed to form RC DNA resulting in mature NCs. Mature NCs may either be enveloped and secreted as infectious virions or uncoat within the cell and further contribute to CCC DNA formation. Because CCC DNA is the reservoir of HBV in infected hepatocytes, its eradication is highly sought after and is required to achieve a true cure for the virus. This publication reports a model wherein HBc phosphorylation by the host protein cyclin-dependent kinase 2 (CDK2) facilitates the uncoating of newly formed NCs and their subsequent formation of CCC DNA. Previously, this group has found that CDK2 is a host kinase which is incorporated into HBV NCs. CDK2 is a highly conserved kinase (phosphorylating protein) which is essential during the G1, S, and G2 phases of the cell cycle.  First, the group identified two S-P (serine-proline) motifs on the globular N-terminal domain (NTD) of HBc, S44 and S49 which are potential CDK2 substrates that are on the interior surface of assembled NCs. In order to mimic constitutive phosphorylation or to block phosphorylation of the serine residues, they were mutated to glutamic acid residues (N2E) or alanine residues (N2A) respectively. The phospho-mimetic mutant N2E showed decreased levels of pgRNA packaging into NCs as measured by native agarose gel electrophoresis (NAGE) and Southern blot following transfection of the constructs into HepG2 cells. After release from NCs into the nucleus, the RC DNA HBV genome takes the form of protein free (PF) RC DNA lacking the RT protein, prior to forming CCC DNA. The phospho-mimetic N2E mutant yielded more PF-RC DNA and CCC DNA than wild type (WT) HBV and conversely, the phospho-null N2A mutant yielded less of both species than WT HBV. These results show that while NCs phosphorylated at both S44 and S49 are less efficient at packaging pgRNA, they are more likely to uncoat and release their genomes into the nucleus. Next, PhoenixBio (PXB) primary human hepatocytes harvested from human-liver chimeric mice were infected with HBV and treated with two CDK2 small molecule inhibitors. PF DNA was then extracted from the cells and analyzed via Southern blot. Both CDK2 inhibitors dramatically reduced the level of CCC DNA formation as compared to the mock control. This result indicates that CDK2 activity within NCs modulates their stability causing them to uncoat and deliver their genomes to the nucleus as opposed to being exported as virions. This publication sheds light on the exact stages of HBc phosphorylation and how they affect CCC DNA formation. This work is important because understanding the molecular mechanisms of CCC DNA formation will help in the development HBV antivirals. Small molecules which interfere with specific stages of HBc phosphorylation and dephosphorylation may prove efficacious in preventing CCC DNA formation in individuals chronically infected with HBV.            

 ​Metabolites released from apoptotic cells act as tissue messengers – Nature

This paper from the University of Charlottesville in Virginia investigates the “apoptotic metabolite secretome” and its effect on neighboring cells. Apoptosis is a highly regulated form of programmed cell death (PCD) which accounts for approximately 90% of homeostatic cell turnover. Metabolites are small molecules that are the intermediates or end products of metabolism. Here, a panel of conserved apoptotic metabolites was identified in the supernatants of apoptotic cells using advanced spectroscopy techniques (spectroscopy-based metabolomics). Six metabolites were found to be secreted across a variety of cell types in response to various apoptosis inducers. These six metabolites are: adenosine monophosphate (AMP), guanosine 5′-monophosphate (GMP), creatine, spermidine, glycerol-3-phosphate (G3P), and adenosine triphosphate (ATP). These metabolites were all found in the supernatants of Jurkat cells (acute T cell leukemia) following exposure to UV irradiation as well as following treatment with anti-Fas antibody. These metabolites were also released from primary mouse bone-marrow-derived macrophages (BMDMs) treated with anthrax and primary mouse thymocytes treated with anti-Fas antibody. Additionally, lung and colon cancer cell lines A549 and HCT116 released four of these metabolites (ATP, spermadine, G3P, and creatine) when subjected to the BH3-mimetic ABT-737 (induces mitochondrial outer membrane permeabilization) as measured using commercial kits. Secretion of these metabolites was prevented by pretreatment of cells with the pan-caspase inhibitor zVAD, indicating apoptosis as the mechanism of release. The metabolites alanine, pyruvate, and creatinine were retained within apoptotic cells, showing that metabolite release was organized and not due to nonspecific rupture of apoptotic bodies. Because only specific metabolites were released during apoptosis, the group hypothesized that the opening of plasma membrane channels may determine the apoptotic secretome. Pannexin 1 (PANX1) is a membrane channel activated by caspase 3 and 7 cleavage during apoptosis. Previously, this group has demonstrated that PANX1 activation is responsible for the secretion of ATP and UTP from apoptotic cells, which function as “find me” signals to recruit phagocytes to perform efferocytosis. In order to determine the role of PANX1 activation in the apoptotic secretome, prior to UV irradiation, PANX1 was inhibited in Jurkat cells using two methods: pharmacological inhibition with the drugs trovafloxacin (Trovan) or spironolactone and generation of a cell line bearing a dominant-negative PANX1 mutation at the caspase cleavage site. Jurkat cells with inhibited or nonfunctional PANX1 showed less secretion of 25 metabolites released from UV-treated Jurkat cells as measured by spectroscopy-based metabolomics. Spermidine, GMP, AMP, and G3P were all secreted dependent upon PANX1 activation. Next, to test whether metabolic activity within the dying cell affects its secretome, the group chose to focus on the release of spermidine. Spermidine released from apoptotic cells naturally reduces local inflammation and counteracts autoimmunity. Interestingly, while spermidine was heavily secreted from apoptotic cells, its precursor molecule putrescine was not released at all. As the starting product of spermidine synthesis is arginine, the isotope carbon-13 (13C)-containing argenine was administered to Jurkat cells one minute prior to UV irradiation. Apoptotic cells showed 40% and 25% more incorporation of 13C label into putrescine and spermidine respectively than live cells at one hour post-UV. This indicates that in addition to the caspase-dependent opening of membrane channels, apoptotic cells also maintain or even upregulate certain metabolic pathways to contribute to the apoptotic secretome. Next, in order to test the effect of the apoptotic secretome on neighboring cells, supernatant from apoptotic Jurkat cells was administered to LR73 cells (phagocytic, Chinese hamster ovary). RNA-sequencing analysis of the LR73 cells after four hours in the apoptotic supernatant revealed altered transcription of programs linked to cytoskeletal rearrangements, inflammation, wound healing or tissue repair, antiapoptotic functions, metabolism and the regulation of cell size within the phagocyte. Finally, the group used two concoctions of PANX1-dependent metabolites to treat mouse models of inflammatory arthritis and lung-transplant rejection. Treatment with the metabolite mixtures resulted in significantly reduced inflammation and better clinical outcomes in both inflammatory disease models. This publication shows that apoptotic cells affect their microenvironment by secreting anti-inflammatory metabolites. It also demonstrates that apoptosis may be harnessed to ameliorate inflammatory diseases. Once fully elucidated, other forms of PCD may also prove useful in treating other diseases such as cancer and viral infections.  

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.

Living with Hepatitis B

Hep B and COVID-19: Resources for Individuals and Healthcare Workers

Amidst the global challenges we are facing, the Hepatitis B Foundation remains a resource for our community and our partners. COVID-19 is a rapidly developing situation, and information about it’s impact on those living with liver diseases such as hepatitis B is still emerging. During this time, it is important to be prepared for all situations, including limited access to necessities. Below, we have provided several tips and tools to help you protect yourself and stay healthy. 

Preparing for Quarantine or Self-Isolation

To prevent transmission of the virus, countries around the world are instating protocols requiring individuals to stay home and to practice social distancing as much as possible. If you are currently on hepatitis B medication, it is important to make sure that you have enough medication for an extended period of time. Call your doctor and ask them to write a 90-day prescription for your treatment if they have not done so. The American Association on the Study of Liver Diseases (AASLD) reports that many insurance companies are waiving refill limits on prescriptions, so you can request additional medication at any time. As skipping a day of treatment may cause the virus to flare and increase the risk of liver damage, it is essential to speak with your healthcare provider about long-term medication access.

If you had a doctor’s appointment scheduled during this time period, see if your doctor’s office is scheduling telehealth appointments or holding virtual meetings with their clients instead. Some services for those living with hepatitis B, such as ultrasounds or even blood work, may be delayed until further notice unless there is a cause for concern. You may want to consider scheduling a virtual meeting to discuss your situation and address any questions you may have about recent test results or concerning symptoms. Most telehealth services should be accessible directly from your phone if you do not have access to a computer. 

It is also important to continue protecting the health of your liver.  Consider stocking up on canned vegetables and fruits instead of items that may be unhealthy.  Be sure to read the nutrition labels, as some canned goods can have high sodium and sugar contents. If you have the means, you can also purchase fresh fruits and vegetables, and freeze them to use over the upcoming weeks. Physical activity – both indoor and outdoor – is encouraged during this time as well! Practice social distancing for outdoor activities, and get creative for indoor workouts. 

Protecting Yourself During the Pandemic:

Many individuals are wondering how those living with hepatitis B can protect themselves from COVID-19. Current recommendations are to practice social distancing and to wash your hands frequently with soap and water. Be sure to scrub your hands for at least 20 seconds! If soap and water are not available, a hand sanitizer that contains 60% or more alcohol will also kill the virus. 

Dr. Robert Gish, Medical Director for the Hepatitis B Foundation, says, “If you’re living with chronic hepatitis B or C without cirrhosis, you should be following the standard precautions for the coronavirus infection. The coronavirus does affect liver inflammation and liver enzymes and can also cause liver dysfunction, so individuals living with cirrhosis will be at higher risk for liver disease progression and decompensation.” Dr. Gish also recommends that individuals living with cirrhosis take special precautions, such as increased monitoring of liver enzymes. If you develop COVID-19, Dr. Gish recommends close monitoring of both liver enzymes and liver function. The Centers for Disease Control and Prevention (CDC) also recommends that those with serious chronic conditions self-isolate with or without an official stay-at-home order. 

Resources for Providers and Healthcare Workers:

Resources for Those Living with Hepatitis B

About COVID-19: 

COVID-19 is a respiratory illness caused by a new coronavirus that was discovered in 2019. While most people who become infected experience a mild reaction, COVID-19 can develop into a serious illness in individuals with underlying illnesses and chronic conditions. Precautions should be taken to prevent transmission and keep you, your family, and your community safe.

 

Stay up-to-date with the most recent information. 

HBV, Liver, Liver Health, Living with Hepatitis B

I had a Liver Transplant Because of Hep B: Here’s What You Should Know

April is Donate Life Month in the United States. Donate Life Month is primarily known as a time to acknowledge those who have saved the lives of others by donating an organ, but it is also a chance to highlight the incredible journeys of those who have required organ transplants. 

Two years ago, Peter V. had a seven-hour emergency liver transplant after a chronic hepatitis B infection led to rapid liver failure. Peter sat down with us and shared an in-depth look into why he needed a liver transplant and how it changed his life. 

  1. Why did you need a liver transplant? 

I had acute liver failure.  About 1 and ½ years before my liver failure, I was taken off the hepatitis B medication (Viread) by my gastroenterologist and to maintain blood work monitoring about every 6 months.  From the span of June of 2017 to January of 2018 immediately before my liver failed, my hepatitis B DNA went from 1,000 IU/L to 169 million IU/L and my ALT went from 24 IU/L to 4,419 IU/L.  By this time, my liver had completely been destroyed through cirrhosis. Without the hepatitis B medication, the virus can flare up at any time and reaction to it once this happens could be too late as in my case.

2. What did a liver transplant mean to you previously? Did you realize how serious the procedure was? 

I never thought about a liver transplant, or any transplant for that matter. I never thought I would need one. Before, life with hepatitis B was normal and routine. Hepatitis B was simply part of my life; I took my medications and had no side effects from them, so the liver transplant was a surprise to me. 

I didn’t understand how serious a transplant was. My condition deteriorated rapidly when my liver began to fail. I couldn’t even do basic functions like unlocking my phone. It got to the point where my situation was so severe that I was in and out of consciousness; I didn’t even know that they were taking me into surgery. Upon recovery, when my cognitive function came back, my wife informed me that my situation had been extremely critical. 

3. What kind of treatment and follow-up did the transplant involve? 

I was bed-ridden and unconscious for over two weeks after the transplant. I needed physical therapy to regain my strength –  to sit up or to get out of bed. For two weeks, I had therapy three or four times a day to regain my ability to speak and cognitive thinking. 

Blood work is also a big part of follow-up. In the beginning, I had to have my blood taken daily before it lessened to once a week, then once every two weeks, and eventually to once a month. All of the blood tests are to make sure that your body does not reject the new organ. I’m on anti-rejection medications, but there is always the risk that your body can reject it. About a year ago, my ALT number rose to high levels, which raised immediate concern. My post-transplant team took a sample of my liver and found that my body was rejecting the new liver. They increased my anti-rejection medications and my body was able to adapt. 

I also developed diabetes after my transplant and had to be placed on insulin, however, I was able to stop taking it by changing my diet and monitoring my blood sugar through my eating habits. 

4. How has the liver transplant changed your life? Are you still able to carry out daily activities the same way you did previously?

I don’t drink alcohol at all anymore and I take much better care of my body. Before my transplant, I didn’t take hepatitis B seriously. I was still drinking alcohol and wasn’t eating a healthy diet. The transplant made me realize how serious hepatitis B could be if you don’t take care of your liver. 

The anti-rejection pills suppress my immune system, which means I have to be very careful about what I eat and how it is prepared. Eating out at restaurants is a risk because you have to trust that the restaurants are properly cleaning their food and that it is cooked properly.  Because of the immunosuppressants, improperly cleaned food can be dangerous. One time I developed a fever and had to be hospitalized because of cross-contamination between foods at a restaurant. You really have to be aware of what you are eating. 

The reminders for COVID-19 to wash your hands thoroughly and not touch your face have been my life since the transplant. Eventually, these actions become a habit. I am still able to work and do physical activities like yard work and exercise, but it is not as vigorous as before. I still get fatigued throughout the day, but it doesn’t stop me from living my day-to-day life. 

I don’t know how I would do this without support. I don’t know how I would do this by myself. I still do physical therapy to regain my strength and my family helps while I go through this journey. Family support is key. I also have a post-transplant team that will help monitor my health for at least 3 years after my transplant.

Most importantly, my family support has been abundant and going through an experience like this makes me much more appreciative of the love and care from having family support that should not be taken for granted. Now, the time spent together regardless of the activities are much more precious.

5. Is there anything that you wish you could have changed about your experience? 

I wish I didn’t have to go through the transplant. I wish I knew more about how serious hepatitis B was. I still drank alcohol and ate the same foods that I ate before my diagnosis. I neglected my liver health. I wasn’t serious about it before the transplant; hepatitis B was invisible to me. It shouldn’t have taken a liver transplant for me to become aware of it. 

6. What have you learned since your journey? Do you have any advice for those living with hepatitis B who think that a liver transplant is the best, or only, option for them?

I don’t think that a liver transplant is an “option”. For me, it was life-or-death. Because I was in critical condition, I was able to get it immediately. For others, getting a transplant is a long and difficult journey. 

A liver transplant is not going to get rid of chronic hepatitis B. You will still live with it. Hepatitis B is still a part of my life every day. The difference is that I now have an understanding of what it can do to my liver. 

Having chronic hepatitis B is not life-ending. It’s not even life-changing as long as you take your medication and take care of your liver. I put my friends and family through a scary experience. If you have chronic hepatitis B, take your medications and keep your liver healthy. Take your diagnosis seriously. 

About Liver Transplants for Those Living with Hepatitis B:

A liver transplant is a very serious surgery that removes a diseased or injured liver and replaces it with a healthy one. People living with hepatitis B can need a liver transplant if their liver begins to fail. This typically occurs if the infection is not being monitored properly, or if significant liver damage has been occurring. Regular monitoring by a knowledgeable provider, a healthy lifestyle, and taking medications, if needed, as prescribed, can help prevent the need for a liver transplant.

 Thank you, Peter, for providing a look into your experience! 

Hepatitis B Research, Hepatitis B Treatment

Clinical Trials Finder – Find A Clinical Trial Near You!

 

The Hepatitis B Foundation is thrilled to announce the addition of a new clinical trials search tool to our website! People around the world can now easily search for clinical trial opportunities on the Hepatitis B Foundation website. Created by Antidote – a company that designs technologies to link patients with scientific opportunities – the new tool filters through all of the trials listed in the U.S. National Library of Medicine’s database of private and publicly funded studies. Searching for clinical trials can be time-consuming and confusing to navigate, but this resource eases the process by finding the best trials for you based upon a series of questions.

You can now search for hepatitis B, hepatitis D and liver cancer clinical trials with a few simple clicks! Clinical trials are a series of research phases that a new drug must go through in order to be approved for widespread use. They are an essential to proving that a treatment is safe and effective for the larger population. Generally, these trials take 10-15 years to go from the laboratory to the public, but delays in finding or retaining enough volunteers can extend the process. 

Diverse participation in clinical trials is needed to make sure that a treatment is effective for all groups. Research diversity matters greatly for several reasons. Studies have shown that different races and ethnicities may respond differently to a certain medication. In addition, researchers need to examine the impact of the medication on the populations that will eventually use them. According to data from the U.S. Food and Drug Administration (US FDA), individuals from Africa and Asia or of African and Asian descent consistently remain underrepresented in clinical trials; these populations are also disproportionately impacted by hepatitis B.  If these groups are underrepresented in trials for hepatitis B treatments, new drugs may not be as effective in these communities, or there may be side effects that researchers were not aware of. 

How Our Clinical Trials Finder Works 

 Using our Clinical Trial Finder takes just a few minutes. After clicking the ‘search’ button, the user will answer a series of questions of general demographic and health questions to determine what trials are near you and you fit the criteria for. You will be able to view the available trials at any point while answering questions, but answering all of the questions will give you the best results. You will also have the option to leave your email to receive personalized trial alerts for new trials that you are eligible for in your area! The new tool is designed to match those who wish to join a clinical trial to the best option for them; it is not designed to benefit any company.

 Benefits of Participating in Clinical Trials

While participating in clinical trials helps drug developers, it can also provide major benefits to the participant as well! Blood work, treatments, and monitoring – which can be expensive –  are often provided for free to those who are eligible for the duration of their participation in the study. Volunteers can also potentially benefit from the latest medical advancements and developments! 

Help Improve the Future of Clinical Trials 

You can also help improve the future of drug development and clinical trials by taking our patient engagement survey! The survey, which takes approximately 20-25 minutes to complete, will be made available for use by the US FDA and drug development researchers to help clinical trial development for future hepatitis B therapies. All survey responses are anonymous.  

 

Hepatitis B Research

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. 

 Summary: This month, researchers in Beijing, China have reported that a therapeutic vaccine composed of polylactic acid microparticles loaded with HBV surface antigen and the mouse STING agonist DMXAA showed efficacy in clearing HBV infection in a mouse model. Researchers from Wuhan, China have reported that SOX2, a transcription factor important for cell proliferation is also a host restriction factor for HBV infection. Also, researchers from the University of Boulder in conjunction with Dr. James Chen’s lab in Dallas have reported the synthesis of two potent cGAS inhibitors.

The incorporation of cationic property and immunopotentiator in poly (lactic acid) microparticles promoted the immune response against chronic hepatitis B – Journal of Controlled Release

This paper from the Chinese Academy of Sciences in Beijing, introduces a microparticle vaccine which may be used to treat chronic HBV infection (CHB). The 1μm diameter microparticle is made from polylactic acid (PLA), which is a biodegradable polymer typically synthesized from plant starch. The microparticle also contains didodecyldimethylammonium bromide (DDAB) which is a double-chain cationic surfactant. This group has previously shown that DDAB may be used as a carrier for the HBV surface protein (HBsAg). DDAB also gives the microparticle a positive charge, which accelerates its phagocytosis into antigen-presenting cells (APCs) and facilitates its escape from lysosomal degradation once in the cell. Additionally, the group loaded microparticles with the mouse STING agonist  5,6-dimethylxanthenone-4-acetic acid (DMXAA). The microparticles were refereed to as DDAB-PLA (DP) and DDAB-PLA-DMXAA (DP-D) respectively. Both types of microparticle were saturated with HBV surface antigen (HBsAg). The microparticles were first tested on mouse bone marrow dendritic cells (BMDCs). Administration of microparticles caused less than a 20% reduction of cell viability in these cultures. BMDCs treated with DP-D microparticles had at least ten-fold more expression of IRF-7 and IFN-β mRNA as measured by RT-qPCR than those treated with HBsAg or DP microparticles alone. Surprisingly, the DP-D microparticle-treated cells also had about twice the expression of these genes compared to the positive control HBsAg + DMXAA, which contained ten times more DMXAA than the microparticles. This indicates that the DP-D microparticles induced the STING pathway with high efficiency due to their bioavailability. Next, the group found that DP-D microparticles induced the highest level of chemokine expression (measured via RT-qPCR) and immune cell recruitment (measured via flow cytometry) at the site of injection in inoculated mice compared with HBsAg alone, HBsAg with aluminum salts (traditional vaccine adjuvant), and DP microparticles. This result shows that the DP-D microparticles induced both an innate immune response and an adaptive immune response in mice. Further, the group showed that BMDCs treated with DP-D microparticles had a high level of maturation, expressing CD40, CD86, and MHCII molecules on their surface as measured by flow cytometry. Finally, the group administered the HBsAg-primed microparticles to mice infected with recombinant HBV (rAAV-1.3HBV virus, serotype ayw). Mice treated with both types of microparticles showed a higher cytokine response as well as a higher titer of anti-HBsAg antibody as measured by ELISA. Mice treated with the DP-D microparticles had the most profound immune cell activation and  fastest clearance of serum HBsAg. The microparticle vaccine introduced in this publication is promising because it is highly efficient in delivering antigen to immune cells. The microparticles are unique in that they contain a small molecule STING agonist inside. This design is clever because this vaccine stimulates the innate immune system by activating STING and the adaptive immune system by displaying HBsAg to APCs. This promotes HBV clearance in a multifaceted approach: immune cells produce cytokines through the STING pathway, T cells recognize and destroy infected cells, and B cells secrete anti-HBsAg antibodies to neutralize newly formed viruses. This publication highlights the versatility of biodegradable microparticle technology in designing unique approaches to combat infection. Micro- and nanoparticle delivery systems represent a promising avenue for future drugs to combat HBV and other viruses.

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation – Viruses
This paper from Wuhan University in China identifies the protein sex determining region Y box 2 (SOX2) as a host factor that restricts HBV replication. SOX2 is a transcription factor critical for cell proliferation and the tumorigenecity of solid tumors. In 2006, expression of SOX2 along with three other transcription factors was shown to convert somatic cells into induced pluripotent stem cells. Overexpression of SOX2 indicates poor prognosis in patients undergoing resection of HCC. In HCC cells, SOX2 has also been found to induce the expression of programmed death ligand-1 (PD-L1), leading to the tumor’s evasion of the host immune system. Previously, it has been demonstrated that HBV infection induces increased expression of SOX2 in hepatocytes. This study demonstrates that SOX2 inhibits HBV replication by binding to the Enhancer II (EnhII) and Core Promoter (Cp) regions of the HBV genome. By binding to the EnhII/Cp region, SOX2 disrupts the transcription of the mRNA species precore, core, polymerase, and pgRNA. This reduction of mRNA transcription results in reduced levels of core-associated DNA, HBV surface antigen (HBsAg), and HBV e antigen (HBeAg). To learn this, the group co-transfected both HepG2 and Huh7 cells with a fixed concentration of  HBV 1.3-mer plasmid DNA alongside variable concentrations of Flag-tagged SOX2 in pcDNA3.1 plasmid DNA. Cells transfected with higher concentrations of SOX2 plasmid DNA showed reduced levels of HBV mRNAs (3.5, 2.4, and 2.1 kb) via Northern blotting. SOX2-transfected cells also showed reduced levels of HBV core-associated DNA via qPCR as well as reduced levels of both HBsAg and HBeAg via ELISA. Next, in order to learn  if SOX2 interacts directly with an HBV promoter, a dual-luciferase reporter assay was implemented. Here, four vectors were used, each containing one of the HBV enhancer and/or promoter sequences (preS1, preS2, EnhⅡ/Cp, and EnhⅠ/Xp) upstream of a firefly luciferase reporter. Each of these firefly luciferase reporter vectors were co-transfected into HepG2 cells alongside variable concentrations of SOX2 plasmid DNA. A plasmid encoding Renilla luciferase was also included at a constant concentration in each transfection as a control for transfection efficiency. While firefly luciferase has an emission of 625 nm (red), Renilla luciferase has an emission of 525 nm (green). Therefore, levels of red fluorescence were used to measure the activity of the HBV enhancer/promoter sequences and levels of green fluorescence were utilized as a control for transfection efficiency. Co-transfection with SOX2 significantly diminished the luciferase activity of the EnhII/Cp reporter only and in a dose-responsive manner, indicating its interaction with that region of the HBV genome. Further, using HBV-producing HepAD38 cells, chromatin immunoprecipitation coupled with quantitative PCR (ChIP-qPCR) was used to isolate SOX2 protein and then determine what DNA sequence it was bound to. The EnhII/Cp sequence was found to be highly enriched on SOX2 protein. In order to determine which part of the SOX2 protein is required for binding to the EnhII/Cp region, truncated forms of SOX2 were generated in the pcDNA3.1 plasmid. Using the assays described above, it was found that only SOX2 mutants lacking the high mobility group (HMG) domain were unable to bind to the EnhII/Cp region and suppress HBV products. Interestingly, it was found that SOX2 mutants lacking the transcription activation (TA) domain were still able to bind to the EnhII/Cp region. Further, it was demonstrated by Western blot of subcellular fractions and immunofluorescence that SOX2 mutants lacking the HMG domain were unable to enter the nucleus. Finally, studies were performed in an in vivo BALB/c mouse model. Mice were given a hydrodynamic injection of an adeno-associated viral vector conferring HBV (pAAV-HBV1.3) alongside pcDNA3.1 plasmid DNA conferring SOX, SOX2 lacking HMG domain ( SOXΔHMG), or empty vector. Levels of HBsAG and HBeAg in the blood at days two and four were reduced only in mice given the full length SOX2 plasmid. Additionally, mice given the full length SOX2 plasmid had a reduction of 3.5kb HBV mRNA in liver tissues as measured by qPCR and a lower abundance of HBV core antigen (HBcAg) in liver tissues as measured by immunohistochemical staining. This study shows that SOX2 protein, previously shown to be upregulated by HBV, plays an anti-HBV role in the liver. SOX2 is therefore a new host restriction factor of HBV replication. SOX2 may be one protein which contributes to HBV-induced hepatocarcinogenesis, given its role in promoting the transcription of genes involved in cell proliferation. In the future, SOX2 may be utilized for its anti-HBV activity or targeted for the treatment of HCC.

 Discovery of Small Molecule Cyclic GMP-AMP Synthase Inhibitors – The Journal of Organic Chemistry

This paper from the University of Colorado Boulder introduces the development of novel small molecule inhibitors of the protein cyclic GMP-AMP synthase (cGAS). This publication is in conjunction with Dr. James Chen’s laboratory at the University of Texas Southwestern Medical Center in Dallas, Texas. Dr. Chen’s lab discovered cGAS in 2012. cGAS is a cytosolic, double-stranded DNA (dsDNA)-sensing protein. It belongs to the nucleotidyltransferase family of enzymes which transfer nucleoside monophosphates, the substituents of nucleic acids. When cGAS recognizes dsDNA, it synthesizes the cyclic dinucleotide cyclic GMP-AMP (cGAMP). cGAMP acts as a second messenger and activates the stimulator of interferon genes protein (STING). Once activated, STING triggers TBK1- and IKK-mediated activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). In the nucleus, IRF3 and NF-kB induce the expression of type I interferons and other inflammatory cytokines. cGAS is essential for detecting foreign pathogens which contain dsDNA and triggering an innate immune response to clear them. However, excessive or dysfunctional cGAS activity may lead to chronic inflammation and/or autoimmunity. Pharmacologic inhibition of cGAS may provide treatments for diseases including Aicardi-Goutiés syndrome (AGS), lupus erythematosus, and cancer. Current small molecule inhibitors of cGAS are limited by poor specificity and/or cellular activity. In this study, a high throughput virtual screen (HTVS) was utilized to screen about 1.75 million drug-like compounds for activity against the dimer-forming and DNA-binding faces of mouse cGAS (mcGAS). mcGAS was utilized for the in silico screen because the human cGAS (hcGAS)-DNA complex was only recently published. From this virtual screen, ten compounds were further investigated, leading to the selection of one lead compound. This lead was further optimized for greater potency through chemical modifications resulting in the analogues CU-32 and CU-76. The IC50 of both compounds is below 1µM. To test these compounds’ selectivity for cGAS, human monocyte cells THP-1 were either transfected with  interferon-stimulatory DNA (ISD) or infected with Sendai virus (SeV). ISD is a 45-basepair DNA known to activate cGAS, while SeV is a single-stranded RNA (ssRNA) virus known to activate the RIG-I-MAVS pathway; both stimuli are known to result in IRF3 activation and dimerization. Following treatment with both compounds, Western blot of the cells was conducted probing for the formation of IRF3 dimers. In ISD-treated cells, CU-32 and CU-76 inhibited the formation of IRF3 dimers in a dose responsive manner. Neither compound had any effect on IRF3 dimer formation in SeV-infected cells. This result indicates that these inhibitors are selective to cGAS. Using in silico molecular docking studies, the group speculates that these compounds disrupt the interface of the cGAS dimer, allosterically inhibiting dimerization. The discovery of novel cGAS inhibitors is exciting and important for multiple reasons. These compounds, if made commercially available will allow for improved experimentation investigating the cGAS/STING pathway. If these compounds or their derivatives are found to be safe and effective in humans, they may be promising candidates for the treatment of autoimmune disorders or cancer.

 

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.

 

Hepatitis B Diagnosis & Monitoring, Hepatitis B Prevention

New Resource: Guide To Hepatitis B Management for Primary Care Providers

The Hepatitis B Primary Care Workgroup has released a new resource that helps primary care providers prevent, diagnose, and manage hepatitis B! Hepatitis B experts from diverse health disciplines have contributed to making this comprehensive guide, which is available to download for free on the University of Washington’s website. 

Hepatitis B is a complex condition that typically is managed by a liver specialist (hepatologist). However, many people in the U.S. and other parts of the world do not have access to a hepatologist. Many primary care doctors do not feel comfortable or know how to properly care for someone living with hepatitis B. This leaves a large gap in managing and treating the infection. Hepatitis B Management: Guidance for the Primary Care Provider helps to close this gap by giving all providers the tools to understand the virus and how to manage it.

Dr. Amy Tang, Director of Immigrant Health at NorthEast Medical Services and one of the hepatitis B experts involved in creating the guide, answered a few questions about why this resource is so important: 

 

Why was a guide on hepatitis B management needed? What gaps will this help fill? 

 

Primary care providers are recommended to screen and vaccinate for hepatitis B in at-risk individuals.  However, when an individual tests positive for hepatitis B, they are typically referred to a specialist for care.  Because the majority of persons with chronic hepatitis B in the United States are foreign-born with limited English proficiency and often face both linguistic and access barriers to specialists, referral and retention in specialty care for chronic hepatitis B can often lead to lost follow-up.  Chronic hepatitis B management involves visits at least every 6 months for lab monitoring as well as routine ultrasounds for liver cancer surveillance for patients who fulfill high-risk criteria for liver cancer including Asian and African men over 40 years of age and Asian women over 50 years of age.  Because primary care is already performing routine blood tests and cancer screening for a variety of other chronic diseases such as diabetes, hypertension, and breast, cervical, and colon cancers respectively, we believe that empowering primary care providers with a simple to use hepatitis B algorithm would promote increased access and retention in care for persons with chronic hepatitis B.

 

How does this tool work towards the elimination of hepatitis B? 

 

The National Academies of Science, Engineering, and Medicine report for viral hepatitis elimination by 2030 recommends that primary care providers work closely with hepatitis B specialists and their organizations, e.g., the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (IDSA), to increase primary care capacity for HBV screening, vaccination, monitoring, and treatment. Thus the National Taskforce on Hepatitis B in collaboration with ECHO Institute and San Francisco Hep B Free—Bay Area hosted a meeting at the 2018 AASLD Annual Liver Meeting in San Francisco to convene a workgroup of hepatitis B specialists in hepatology, infectious disease, public health, primary care, and pharmacy, as well as representatives from American College of Physicians (ACP) and American Academy of Family Physicians (AAFP) to discuss how we can increase primary care capacity for not only hepatitis B screening and vaccination, but also management and treatment.

Currently, the majority of hepatitis B care is managed by specialists.  AASLD puts forth guidelines and guidance for hepatitis B every couple of years, however, the guidelines can be lengthy, difficult to access, or intimidating for busy primary care providers to utilize. We polled over 100 primary care providers across the country through the National Association of Community Health Centers’ network of providers and found that primary care providers were interested in managing hepatitis B but felt like they did not have the tools and resources at their fingertips to do it manage it confidently.  They reported using web-based references like Up-to-Date for easily accessible guidance on conditions they were less familiar with. Thus, we wanted to create an easy to use document that would be easily accessible and free online. We teamed up with University of Washington’s Hepatitis B Online to host our Hepatitis B Guidance for Primary Care Providers as a means to widely disseminate our recommendations and work towards the elimination of hepatitis B in the United States and globally.

 

How and when should primary care providers use this? 

 

Primary care providers should use this hepatitis B guidance document when they decide to screen a patient for hepatitis B as the document guides them through how to properly screen for hepatitis B in asymptomatic individuals, how to interpret their lab results and provide appropriate counseling, and for patients who screen positive for hepatitis B, how to perform their initial evaluation, monitoring, treatment, and liver cancer surveillance.  We also have a dedicated section on perinatal management of women screened for hepatitis B that clearly illustrates the simple steps that can be taken by the primary care provider to prevent transmission of hepatitis B from mother to child. 

The guide includes detailed information on the following topics:

  • Chronic Hepatitis B Testing and Management Algorithm
  • Interpretation of hepatitis B test results
  • Tests to run on a hepatitis B surface antigen positive (HBsAg +) individual and how to counsel them
  • Monitoring and management of the HBsAg + individual 
  • Managing pregnant women who are HBsAg + 
  • Monitoring for liver cancer

The guide is part of Hepatitis B Online – a free suite of materials for providers that supplies information on all topics related to hepatitis B such as when a person should begin treatment and liver cancer screenings. The website also includes prescribing information for approved hepatitis B treatments, and clinical calculators to aid in interpreting predictors of liver damage such as the AST to Platelet Ratio Index (APRI) and fibrosis score. 

 To access and download the new tool, click here! 

Hepatitis B Diagnosis & Monitoring, Hepatitis B Prevention

New Resource: Guide To Hepatitis B Management for Primary Care Providers

The Hepatitis B Primary Care Workgroup has released a new resource that helps primary care providers prevent, diagnose, and manage hepatitis B! Hepatitis B experts from diverse health disciplines have contributed to making this comprehensive guide, which is available to download for free on the University of Washington’s website. 

Hepatitis B is a complex condition that typically is managed by a liver specialist (hepatologist). However, many people in the U.S. and other parts of the world do not have access to a hepatologist. Many primary care doctors do not feel comfor table or know how to properly care for someone living with hepatitis B. This leaves a large gap in managing and treating the infection. Hepatitis B Management: Guidance for the Primary Care Provider helps to close this gap by giving all providers the tools to understand the virus and how to manage it.

Dr. Amy Tang, Director of Immigrant Health at NorthEast Medical Services and one of the hepatitis B experts involved in creating the guide, answered a few questions about why this resource is so important: 

Why was a guide on hepatitis B management needed? What gaps will this help fill? 

Primary care providers are recommended to screen and vaccinate for hepatitis B in at-risk individuals.  However, when an individual tests positive for hepatitis B, they are typically referred to a specialist for care.  Because the majority of persons with chronic hepatitis B in the United States are foreign-born with limited English proficiency and often face both linguistic and access barriers to specialists, referral and retention in specialty care for chronic hepatitis B can often lead to lost follow-up.  Chronic hepatitis B management involves visits at least every 6 months for lab monitoring as well as routine ultrasounds for liver cancer surveillance for patients who fulfill high-risk criteria for liver cancer including Asian and African men over 40 years of age and Asian women over 50 years of age.  Because primary care is already performing routine blood tests and cancer screening for a variety of other chronic diseases such as diabetes, hypertension, and breast, cervical, and colon cancers respectively, we believe that empowering primary care providers with a simple to use hepatitis B algorithm would promote increased access and retention in care for persons with chronic hepatitis B.

How does this tool work towards the elimination of hepatitis B? 

The National Academies of Science, Engineering, and Medicine report for viral hepatitis elimination by 2030 recommends that primary care providers work closely with hepatitis B specialists and their organizations, e.g., the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (IDSA), to increase primary care capacity for HBV screening, vaccination, monitoring, and treatment. Thus the National Taskforce on Hepatitis B in collaboration with ECHO Institute and San Francisco Hep B Free—Bay Area hosted a meeting at the 2018 AASLD Annual Liver Meeting in San Francisco to convene a workgroup of hepatitis B specialists in hepatology, infectious disease, public health, primary care, and pharmacy, as well as representatives from American College of Physicians (ACP) and American Academy of Family Physicians (AAFP) to discuss how we can increase primary care capacity for not only hepatitis B screening and vaccination, but also management and treatment.

Currently, the majority of hepatitis B care is managed by specialists.  AASLD puts forth guidelines and guidance for hepatitis B every couple of years, however the guidelines can be lengthy, difficult to access, or intimidating for busy primary care providers to utilize. We polled over 100 primary care providers across the country through the National Association of Community Health Centers’ network of providers and found that primary care providers were interested in managing hepatitis B but felt like they did not have the tools and resources at their fingertips to do it manage it confidently.  They reported using web-based references like Up-to-Date for easily accessible guidance on conditions they were less familiar with. Thus, we wanted to create an easy to use document that would be easily accessible and free online. We teamed up with University of Washington’s Hepatitis B Online to host our Hepatitis B Guidance for Primary Care Providers as a means to widely disseminate our recommendations and work towards the elimination of hepatitis B in the United States and globally.

How and when should primary care providers use this? 

Primary care providers should use this hepatitis B guidance document when they decide to screen a patient for hepatitis B as the document guides them through how to properly screen for hepatitis B in asymptomatic individuals, how to interpret their lab results and provide appropriate counseling, and for patients who screen positive for hepatitis B, how to perform their initial evaluation, monitoring, treatment, and liver cancer surveillance.  We also have a dedicated section on perinatal management of women screened for hepatitis B that clearly illustrates the simple steps that can be taken by the primary care provider to prevent transmission of hepatitis B from mother to child. 

The guide includes detailed information on the following topics: 

  • Chronic Hepatitis B Testing and Management Algorithm
  • Interpretation of hepatitis B test results
  • Tests to run on a hepatitis B surface antigen positive (HBsAg +) individual and how to counsel them
  • Monitoring and management of the HBsAg + individual 
  • Managing pregnant women who are HBsAg + 
  • Monitoring for liver cancer

The guide is part of Hepatitis B Online – a free suite of materials for providers that supplies information on all topics related to hepatitis B such as when a person should begin treatment and liver cancer screenings. The website also includes prescribing information for approved hepatitis B treatments, and clinical calculators to aid in interpreting predictors of liver damage such as the AST to Platelet Ratio Index (APRI) and fibrosis score. 

 To access and download the new tool, click here! 

Hepatitis B Advocacy, Hepatitis B Treatment, Living with Hepatitis B

Copay Accumulators – What They Are and What They Mean For Your Prescriptions

In January of 2020, the Centers for Medicare and Medicaid Services (CMS)  proposed a new rule that could increase the out-of-pocket costs for people who take prescription medication for hepatitis B in the U.S. The proposed rule states that health insurance companies would be able to collect patient coinsurance through pharmaceutical manufacturer financial assistance. However, the insurance companies will be allowed to disregard any coinsurance paid with copay assistance when calculating how much the patient has paid toward their deductible and annual out-of-pocket (OOP) limit. 

This proposal – titled 2021 Notice of Benefit and Payment Parameters – reverses a recent ruling that would have required health insurance companies to count the value of manufacturer copay assistance toward an enrollee’s annual deductible and OOP limit in most circumstances1.  This rule acknowledged that manufacturer copay assistance helps lessen the financial burden of medications for patients. In the US, prescription drugs can be extremely costly, making manufacturer’s copay assistance programs necessary for many patients.  For example, brand name treatments are often expensive in order to help pharmaceutical companies earn back the costs of the research and time spent making the medication. Sometimes, the brand name treatments are the only ones that are available, like Vemlidy, or the only version that a person can take. A reversal of the rule would mean that hepatitis B patients and those living with other chronic illnesses may have to pay a larger amount of out-of-pocket costs for their medications. 

To understand the significance of this change, we first need to understand what a copay accumulator is. 

What is a Copay Accumulator Program and How Does It Work?  

A copay accumulator – or accumulator adjustment program – is a strategy used by insurance companies and Pharmacy Benefits Managers (PBMs) that stop manufacturer copay assistance coupons from counting towards two things: 1) the deductible and 2) the maximum out-of-pocket spending. What does this mean? 

Previously, a person could receive financial assistance from companies that make a drug, and that would count towards their deductible and/or out-of-pocket costs, depending upon the insurance plan. Pharmaceutical companies often provide financial assistance (such as a co-pay card) to help underinsured individuals afford expensive medications. This means that the person paying for the drug would end up saving money, often thousands of dollars. 

Why Is This an Issue? 

As the AIDS Institute explains it, “ … the trend in health insurance benefit design is to shift more of the cost of health care to patients through high deductibles and coinsurance rates …In order to afford the medicine they need, patients increasingly rely on manufacturer copay assistance.” With copay accumulators, the individuals who need assistance the most will be unable to receive it, and will end up paying more for their treatments. 

Below is an example of a copay accumulator program from the Patient Access Network (PAN)  Foundation: 

 

 

 

 

As shown in the above image, with a copay accumulator program – meaning her manufacturer’s assistance is no longer counted toward her out-of-pocket limit- the consumer ends up paying more, while the insurance company is able to reduce the amount they are paying. 

Copay accumulator programs are making life-saving treatments increasingly inaccessible. Research shows that the more out-of-pocket costs a person has to pay, the more likely they are to abandon their medication. Once on a hepatitis B medication, stopping suddenly or only taking it once in a while can cause flares and lead to an even higher risk of liver damage. 

In the United States, many of those who are living with hepatitis B come from underserved populations with limited access to healthcare. Oftentimes, cultural differences and language barriers can make it difficult to access and utilize the services they need. Now, copay accumulators are making the navigation process even more complex and placing a higher cost burden on patients. 

 1 The rule required insurance companies to count manufacturer copay assistance toward a patient’s deductible and OOP limit for all brand name drugs for which there is no generic alternative and in cases where the patient gained access to the brand name drug through an insurance plan’s appeals or exceptions process.

Baruch S. Blumberg Institute