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Highlighting the Relationship between Hepatitis B and Liver Cancer

Highlighting the Relationship between hepatitis B and Liver Cancer

October marks Liver Cancer Awareness Month, an initiative highlighting this significant, but under-prioritized public health concern. Unfortunately, people living with hepatitis B have greater risk of developing liver cancer, and this risk is even higher for people born in countries where hepatitis B is more prevalent (Department of Health and Human Services [HHS], 2014; Chayanupatkul et al., 2017). Because of this, the Hepatitis B Foundation (HBF) conducted a study among foreign-born communities in the U.S. who are heavily impacted by the hepatitis B virus (HBV) to assess awareness levels about the connection between HBV and liver cancer. HBF used the perspectives and ideas expressed during these focus groups to create culturally and linguistically tailored, community-focused awareness and educational materials, so that everyone has continuous access to user-friendly HBV and liver cancer information.

From April to September 2021, the HBF conducted focus groups with people from the Micronesian, Chinese, Hmong, Nigerian, Ghanaian, Vietnamese, Korean, Somali, Ethiopian, Filipino, Haitian, and Francophone West African communities. A total of 15 virtual focus groups took place, with 101 individuals providing their thoughts about what hepatitis B and liver cancer are, and insights into appropriate strategies to educate their greater communities on the connection between these two conditions. The resulting communications campaign aims to improve the public’s knowledge about the link between HBV and liver cancer, reduce hepatitis B- and liver cancer-related myths and misconceptions, and promote hepatitis B and liver cancer screening and early detection among Asian and Pacific Islander (API) and African and Caribbean immigrant communities. The ideas and experiences voiced by focus group participants also contributed to the development of informational liver cancer materials for community health educators to integrate into existing education programs for immigrant communities.

Summary of focus group findings:

All focus groups emphasized the need for educational materials to highlight the relationship between hepatitis B and liver cancer. Interestingly, people were more aware of liver cancer and its serious health consequences than they were of hepatitis B and how it is a leading cause of liver cancer. Many people had personal experience with liver cancer, having known family members, friends or other community members who have died from the disease. With this, participants believed that people will be more likely to practice healthy behaviors, like vaccination and routine screening, when they know that HBV can lead to liver cancer and know what behaviors can reduce their risk of liver cancer and death. When people learn about the benefits of vaccination (like full protection against HBV and reducing the risk of transmitting the virus to loved ones), and screening (keeping your liver healthy), and are provided with resources and tools to manage their health, they are empowered and are more likely to make healthy choices to reduce their risk of severe health outcomes.

When educating people about the connection between the two diseases, it is also important to address the widespread misconceptions about both hepatitis B and liver cancer, which contribute to shame and stigma surrounding each condition. Many focus group participants revealed that their communities believe that HBV is related exclusively to sexual promiscuity, injection drug use and poor hygiene, all of which lead to stigma against people living with hepatitis B (PLHB), who are believed to be “immoral” or “dirty.” These stigmatizing beliefs cause PLHB to become reluctant to seek care and treatment for the virus, and can discourage screening in the greater community because people do not want to be shamed by or isolated from their social circles. Additionally, participants discussed how their communities believe that liver cancer is only associated with alcohol and are unaware of the causal relationship between HBV and liver cancer. According to focus group participants, educational materials should include some information about how hepatitis B is transmitted and how it can lead to liver cancer if left untreated and unmanaged. One way to do this is by including the personal testimonials of PLHB and liver cancer in educational materials, who show the audience how they stay healthy and maintain a good quality of life while living with these diseases. As people see how one’s quality of life does not diminish, and learn from the stories of people living with hepatitis B or liver cancer, they may become more understanding of the diseases and supportive of their own community members who are living with them.

Focus group participants were also asked to identify communication strategies that would be acceptable for their community groups. As for in-person communication, educational sessions should take place in settings where people feel safe, including community-based organizations, religious spaces, and healthcare offices. These sessions, as emphasized by participants, should be facilitated by trusted messengers, like patient navigators, doctors, and faith leaders, or other people who have a shared culture with the audience. Demonstrating cultural respect during face-to-face communication is also of utmost importance. Certain communities emphasized that it is especially important to have gender-specific messengers when discussing topics like sexual transmission of hepatitis B (Taylor et al., 2013; Cudjoe et al., 2021). 

Educational campaigns should also be strategic when discussing community-specific risk, as it is important to discuss each community’s risk without placing blame on a specific group. Despite the fact that countries in the Asian-Pacific and sub-Saharan African regions have endemic levels of HBV and the highest global incidence rates of liver cancer (Zamor et al., 2017), many focus groups explained that their communities consider HBV and liver cancer to be Western diseases, since the conditions are often not discussed in home countries, and are therefore unaware of both the severity of the diseases and their personal risk. Focus group participants agreed that informational material can group highly impacted communities together when presenting prevalence rates and risk factors, so as to reduce shame associated with HBV and liver cancer of one group while increasing audience awareness of their risk (Parvanta & Bass, 2018). 

Experiences of Community Focus Group Facilitators

Community participation and leadership was of utmost importance in this project. Two focus group facilitators recounted their experiences of recruiting and conducting focus groups with their communities. The first was the leader of the Cantonese focus group.

Despite being nervous about how it would turn out, one facilitator spent time thinking about the project. They chose to conduct the focus group in Chinese (Cantonese), the “native language of the participants,” and hoped that communicating in Cantonese would increase participant engagement, especially when discussing their “lived experience of the disease.” 

“Prior to convening the Zoom meeting, I had provided a one-on-one orientation to each participant about the theme of the focus group and expectations. As a result, everyone was ready and able to fully participate, and speak openly at the meeting. It was a fruitful discussion among the five participants. Everyone brought up their perspectives and insights about stigma and health education strategies to the community. They had expressed a sense of fear and emotional distress when they were made aware of the relationship between hepatitis B and liver cancer. They raised lots of questions on hepatitis B transmission, testing and vaccination, and liver cancer and treatment, and were very interested to learn more about necessary lifestyle changes if they contracted chronic hepatitis B. 

At the end participants had requested a follow-up session to learn more about HBV and liver cancer.  They will be excited to know about the release of the newly developed Chinese-language educational materials on both diseases, which came together because of their contributions. I would suggest Hepatitis B Foundation and UC Davis to host an in-person workshop to present  the new education materials.  That would be a meaningful outreach and education to the local Chinese and Asian communities.”

Another facilitator shared their thoughts and insights regarding the focus group they conducted with their African immigrant community. They felt that being a facilitator for this study was an “enlightening experience,” especially as they uncovered their community’s healthcare awareness as it relates to hepatitis B and liver cancer. They continued to share:

“Running the focus group gave me valuable insights into the knowledge gaps and misconceptions surrounding HBV within the African immigrant population. Through open and honest discussions, we uncovered specific areas where education and awareness initiatives can have a significant impact. Many participants needed to understand the transmission, prevention, and available resources related to these diseases. Understanding these nuances is crucial in tailoring our educational materials effectively.

Regarding the study findings, it was evident that there is a pressing need for culturally sensitive educational resources. The unique challenges African immigrants face, including language barriers and cultural differences, highlight the importance of creating materials that resonate with our community members. Moreover, the findings emphasized the urgency of dispelling myths and stigmas associated with HBV and fostering a supportive environment for affected individuals and their families.

As for the materials produced for the campaign, I am genuinely impressed with the effort and attention to detail put into their creation. The content is informative and culturally relevant, making it relatable to our community. Using images, culturally familiar scenarios, and visuals ensures that these materials will significantly raise awareness about HBV in my community.

When disseminated effectively, these materials will empower African immigrants with the knowledge they need to protect themselves and their loved ones. By addressing the specific concerns and questions raised during our focus group sessions, these resources have the potential to bridge the information gap and promote proactive healthcare practices within our community.”

Conclusion

The overall goals of these materials are to facilitate improved hepatitis B and liver cancer awareness, increase testing and prevention behaviors, and reduce misconceptions about the two diseases to ultimately reduce HBV- and liver cancer-related death. Thanks to the insights and recommendations from the focus group participants, educational hepatitis B and liver cancer materials were created in a culturally sensitive and linguistically appropriate manner for a number of communities in the U.S. who are greatly impacted by the two diseases. To reach a broad audience, the materials will be available on multiple communication platforms and in multiple languages. This first part of the community-informed educational campaign can be found on the HBF’s Liver Cancer Connect website now. All materials will be fully uploaded and available to the public for further community education starting in February of 2024. Translated materials and messages tailored for audio and video formats will also be uploaded on a rolling basis. 

References

Chayanupatkul, M., Omino, R., Mittal, S., Kramer, J. R., Richardson, P., Thrift, A. P., El-Serag, H. B., & Kanwal, F. (2017). Hepatocellular carcinoma in the absence of cirrhosis in patients with chronic hepatitis B virus infection. Journal of Hepatology, 66(2), 355-362. https://doi.org/10.1016/j.jhep.2016.09.013

Cudjoe, J., Gallo, J.J., Sharps, P., Budhathoki, C., Roter, D., & Han, H-R. (2021). The role of sources and types of health information in shaping health literacy in cervical cancer screening among African immigrant women: A mixed-methods study. Health Literacy Research and Practice, 5(2), e96-e108. doi: 10.3928/24748307-20210322-01

Department of Health and Human Services. (2014). Action plan for the prevention, care, & treatment of viral hepatitis. Department of Health and Human Services.

Hong, Y.A., Juon, H.S., & Chou, W.Y.S. (2021). Social media apps used by immigrants in the United States: Challenges and opportunities for public health research and practice. mHealth, 7, 52. doi: 10.21037/mhealth-20-133

Hong, Y.A., Yee, S., Bagchi, P., Juon, H.S., Kim, S.C., & Le, D. (2022). Social media-based intervention to promote HBV screening and liver cancer prevention among Korean Americans: Results of a pilot study. Digital Health, 8, 20552076221076257. https://doi.org/10.1177/20552076221076257 

Joo, J.Y. (2014). Effectiveness of culturally tailored diabetes interventions for Asian immigrants to the United States: A systematic review. The Diabetes Educator, 40(5), 605-615. DOI: 10.1177/0145721714534994

Parvanta, C., & Bass, S. (2018). Health communication: Strategies and skills for a new era: strategies and skills for a new era. Jones & Bartlett Learning, LLC.

Porteny, T., Alegria, M., del Cueto, P., Fuentes, L., Lapatin Markle, S., NeMoyer, A., & Perez, G.K. (2020). Barriers and strategies for implementing community-based interventions with minority elders: Positive minds-strong bodies. Implementation Science Communications, 1, 41. doi: 10.1186/s43058-020-00034-4

Taylor, V.M., Bastani, R., Burke, N., Talbot, J., Sos, C., Liu, Q., Jackson, J.C., & Yasui, Y. (2013). Evaluation of a hepatitis B lay health worker intervention for Cambodian Americans. Journal of Community Health, 38(3), 546-553. doi: 10.1007/s10900-012-9649-6

Zamor, P. J., deLemos, A. S., & Russo, M. W. (2017). Viral hepatitis and hepatocellular carcinoma: Etiology and management. Journal of Gastrointestinal Oncology, 8(2), 229–242. https://doi.org/10.21037/jgo.2017.03.14

Podcast Recap: How Clinical Trials Work in the United States

 

 

 

 

 

 

 

 

 

 

 

 

 

In a recent B Heppy episode on clinical trials, Dr. Yasmin Ibrahim, Public Health Program Director at the Hepatitis B Foundation, discussed the process of how clinical trials work and the importance of clinical research in moving forward public health programs and interventions. 

What is a Clinical Trial? 

A clinical trial (also called clinical research) is the process for approving new medications or devices for a known health condition or disease. When people hear the term clinical trial, they may hink immediately that participants of that trial are at risk. What most don’t know is that before a medication or medical device is tested on human beings, it must go through a very rigorous process with approval from regulatory authorities and agencies. This is why clinical trials go through phases of approval and safety checks in the research process. We have outlined the phases of clinical trials below to help provide an understanding of the process.  

Pre-clinical or lab studies: Before the drug can be tested on human beings, it is thoroughly researched on living cells and then animals with similar biological makeup, to assess its efficacy (benefits) and safety. 

Clinical Phase I: Researchers test a new drug or treatment on a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify any side effects. 

Clinical Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety. 

Clinical Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely. 

Clinical Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug’s effect in many different populations and determine any side effects associated with long-term use of the product or drug. 

All new treatments must go through clinical trials before being approved for use by the United States Food and Drug Administration (FDA), European Medicine Agency (EMA) or any other local regulatory authorities depending on the country.   

Advancing and Sustaining Public Health through Research 

Clinical trials are important because they are the safest way to develop and discover new treatments that work to cure diseases or improve the health and quality of life of patients. Because clinical trials have very strict safety regulations, they also tell us if a treatment is safe for people to use.  

Eligibility Criteria for Participation in Clinical Trials  

Eligibility criteria for clinical trials depends on the type of research being conducted. If a vaccine is being tested, then most participants are healthy to assess the response of the vaccine on the body’s immune system and the ability to produce protective antibodies. In some clinical trials that focus on certain populations or multiple conditions, the criteria may be more specific (e.g., testing the HBV treatments on people living with hepatitis B and diabetes). Study design and objectives determine participant eligibility and criteria. 

Diversity and Inclusivity in Clinical Trials 

Historically, clinical trials have neglected participation from minority populations and under-served communities. For example, sub-Saharan Africa has one of the highest burdens of hepatitis B globally, but clinical trials for hepatitis B are inadequate in those areas. The people who need access to clinical research the most are often denied access to these opportunities due to geographical barriers, lack of political will, regulatory issues, and other logistical challenges. It is important to ensure that all people who are directly impacted by hepatitis B should have access to participating in clinical trials and affording innovative therapies to improve their quality of life. There are steps that pharmaceutical and biotech companies, medical researchers, and public health organizations can take to diversify participation in clinical research. This involves including local patient-centered organizations and patient advocates in the clinical trial participation recruiting process. Partnering with a community is a helpful strategy to build trust with the community and engage people in research. Communication is integral to ensuring that participants fully understand the extent of their participation and the goals behind the research. Participants are encouraged to ask questions from the recruiters before agreeing to participate in the research.  

Find Clinical Trials for Hepatitis B here: https://www.hepb.org/treatment-and-management/clinical-trials/ 

Questions to Ask Providers and Researchers about Clinical Trial Participation: https://www.hepb.org/treatment-and-management/clinical-trials/ask-a-doctor/ 

To listen to the full episode on our podcast, B Heppy, click here. https://bheppy.buzzsprout.com/1729790/13443280 

 

Podcast Recap: Current Treatments in Development for Hepatitis B with Dr. John Tavis

 

 

 

 

 

 

 

 

 

 

 

 

In a recent B Heppy episode, Dr. John Tavis, a molecular microbiologist at St. Louis University School of Medicine, shared updates on curative therapies for hepatitis B along with insights on how treatments for hepatitis B are researched and approved for use. 

Hepatitis B is a virus that can cause serious liver disease such as liver cancer or liver failure if undiagnosed, unmanaged or without proper intervention and treatment. While there is no cure for hepatitis B at this time, there are treatment options available to manage the virus. Research to find an optimal and functional cure for hepatitis B is ongoing and clinical trials have been very successful in advancing research pertaining to the cure.  

In some experimental studies conducted around the globe, 30% to 40% of patients have achieved functional cure. In smaller studies, approximately 50% of patients have obtained functional cure. However, research on the cure and the progression of these clinical interventions are still ongoing. While the future looks promising for a functional cure for hepatitis B, existing treatments should not be undermined or overlooked as they provide effective protection from serious liver disease such as cirrhosis or liver cancer.  

There are key terms that are important to understand related to drug development and the hepatitis B space. Below we describe complete, functional and partial cure definitions according to researchers.  

Complete, Functional, and Partial Cure 

Complete Cure: Elimination of all traces of hepatitis B including loss of surface antigen and HBV DNA. 

Functional Cure: the loss of hepatitis B surface antigen and undetectable HBV DNA levels, although trace amounts of HBV DNA may persist in the liver.  

Partial Cure: A stable suppression of the virus with undetectable HBV DNA levels. 

The progress on the cure: 

Current progress and research indicate that a combination of drugs will provide the best outcome as it is not likely that only one drug will achieve a functional cure for hepatitis B at this time. There are different types of drugs that are being studied and each treatment focus on a different aspect of the lifecycle of the virus to prevent replication and growth.  

Some of the current options being studied for hepatitis B treatment include: 

Antisense RNA and SiRNA: These drugs work by suppressing and destroying the viral messenger RNA, which is crucial to make proteins and replicate HBV DNA. Current drugs that use this mechanism to target the virus include Bepirovirsen. Clinical trials have shown effective reduction in HBV DNA and viral proteins.  

Suppressing and destroying the viral RNA (destroys proteins—RNA makes proteins,  

CAMs (capsid assembly modifiers): These drugs work by disrupting the formation of capsids. Capsids provide a protective space for the genetic material of the virus to make sure it is able to transfer to the host cell without any complications. By disrupting the formation of the capsids, the virus is unable to replicate itself as the genetic material gets destroyed during the process.  

NAPs (Nucleic Acid Polymers): These drugs work by blocking secretion of the viral surface antigen outside of the cells so the virus is unable to spread to other cells. In the process, the surface antigen drops in the bloodstream and the immune system is alerted to attack the virus.  

Nucleotide Analogues: These drugs are the first-line treatments for hepatitis B. Antiviral treatments like entecavir and tenofovir are incredibly effective in suppressing HBV viremia and preventing progression of the virus from becoming cancerous. Although they are not considered functional cure, these drugs have low toxicity and are effective in treating people living with hepatitis B.  

 

To stay updated on developments in hepatitis B research, check out our Drug Watch page: https://www.hepb.org/treatment-and-management/drug-watch-2/ 

To listen to the full episode on our podcast, B Heppy, click here. https://bheppy.buzzsprout.com/1729790/13238616-current-treatments-in-development-for-hepatitis-b 

If You Have Hepatitis B, Donating Your Blood May Change the Face of Hepatitis B Testing.

The Hepatitis B Foundation has partnered with Plasma Services Group to educate people living with Hepatitis B about the critical need for blood donation. This is not like the local blood drives you always hear about. Instead, Plasma Services Group focuses on specialty plasma collection which supports the making of diagnostic tests used in labs around the world. The demand for HBV testing grows every year, but access to those tests is not assured. As you know, only 25% of people in the U.S. and 10% of people worldwide with Hepatitis B have been diagnosed. With your help, we can reduce those real-life barriers to Hepatitis B testing and improve lives. Follow the link.

How do I donate?

Donating your blood to Plasma Services Group is easy. After you complete this form, they will reach out to you if you are a good candidate for blood donation. If chosen, they will send a phlebotomist to your home to complete the blood-draw.  PSG compensates participants financially as a thank you for the trust, time and efforts associated with donation. This program is only available to U.S. residents who are preferably in the Northeast. You must be 18 years of age or older and weight 110 pounds or more. You must be living with chronic Hepatitis B, which means you have had Hepatitis B for over 6 months.

Why this is important to the future of Hepatitis B?

As you may know, access to good healthcare isn’t always easy. By creating new blood tests, we can help diagnose Hepatitis B more reliably which helps more people get into care and manage their hepatitis B. Your blood donation could directly impact the detection, care and quality of life for millions of people living with hepatitis B who have not been diagnosed yet, as well as those who are managing their care on a daily basis.

Despite the large population of people living with hepatitis B, it is hard for companies that source biological raw materials to recruit donors. Most people are unaware of the large amount of blood plasmas that are essential to manufacture test kits. Rarer subtypes that are prevalent in Africa and Asia, where the need for detection is the highest and growing the fastest, are even harder to find in N. America. By becoming a regular donor to Plasma Services Group, you are filling a vital role for the medical diagnostic industry and helping to close the gap between patient and care.

Get started today!

Fill out this form and Plasma Services Group will fill you in on next steps.

Reactivation with Hepatitis B: Understanding Risk Factors and Prevention Strategies

Understanding the hepatitis B virus and the panel of blood tests needed to determine infection or immunity can be a stressful and challenging task. In simplest terms, “hepatitis” means liver inflammation and the hepatitis B virus can ultimately cause liver inflammation. The liver is an important organ in the human body and responsible for the removal of toxins and regulation of digestion (learn more about the function of the liver here). The hepatitis B virus can infect and disrupt critical functions of the liver in supporting your overall health. 

How the hepatitis B virus works 

In the case of the hepatitis B virus, the host is the liver cell. As the virus makes more copies of itself, the liver may become damaged, and sometimes it is unable to carry out its essential tasks to regulate metabolism, nutrients, and digestion. It is best to prevent hepatitis B infections when we can – and since antibodies are the best defense against the virus, the hepatitis B vaccine can be used to signals the body to make antibodies to fight the virus. The hepatitis B vaccine provides lifelong protection from the virus. However, this is only possible before infection with the virus. If somebody is already infected with the virus, antiviral therapy is used to control the virus and prevent liver damage – antiviral medications disrupt the life cycle of the virus by disabling viral receptors from binding to liver cells. 

Blood test panel to diagnose hepatitis B: 

The only way to tell someone’s hepatitis B status is through a panel of blood tests – the tests are all done at one time, and only one small tube of blood is needed. These tests are not included in routine testing, so it is important to ask your doctor to test you for hepatitis B or try to find a free screening event near you (http://www.hepbunited.org/). The panel consists of the following tests to determine your hepatitis B status: 

  1. HBsAg: 
    • This tests for the hepatitis B surface antigen in someone’s blood. The surface antigen is the protein that surrounds the virus and protects it from attack by the host. A positive surface antigen test indicates that the virus is present in the body. A “positive” or “reactive” result for HBsAg indicates that someone is infected with hepatitis B and can transmit the virus to others.  
  1. HBsAb 
    • This tests for the hepatitis B surface antibody in someone’s blood. The surface antibodies are produced by the immune system and can fight off the virus by attaching to the surface antigen protein. This test can detect the presence of these antibodies. Ideally this test will be ordered quantitatively (numerically). A “positive” surface antibody test (meaning numbers reading >10 IU/mL) means that a person has protection against the hepatitis B virus (either by vaccine or from a past exposure).  
  1. HBcAb (total) 
    • This is known as the hepatitis B core antibody test. The core antibody is produced by the immune system after infection with the virus. This test indicates an existing or past infection of the hepatitis B virus.  

 

To learn more about interpreting your test results, click here. 

Important things to know about Hepatitis B Core Antibody (HBcAb) 

Someone who has markers of past infection, particularly hepatitis B core antibody, can be at risk for hepatitis B reactivation. Reactivation can be triggered by immunosuppressive therapies and cause significant life-threatening challenges. If you test HBcAb+, please talk to your doctor about what that means, and make sure you notify all future health care providers. 

How is reactivation with HBV defined? 

Reactivation is defined as the sudden increase or reappearance of HBV (hepatitis B virus) DNA. When the virus invades the cell, it forms a covalently closed circular DNA (cccDNA) in the nucleus of infected cells referred to as hepatocytes. Because cccDNA is resistant to antiviral treatments, it is never removed from the cells. Therefore, even after recovery from a past infection, the cccDNA is present and may reactivate. It is not clearly understood why this may happen, but certain factors may increase the risk for reactivation.  

To learn more about the core, click here. 

What puts one at risk for reactivation? 

  1. Virologic factors such as high baseline HBV DNA, hepatitis B envelope antigen positivity (HBeAg), and chronic hepatitis B infection that persists for more than 6 months.
    • Detectable HBV DNA levels and detectable levels of HBsAG can increase the risk for HBRr (reactivation) 
    • Testing positive for HBeAg also increases the risk for reactivation 
  2. Co-infection with other viruses such as hepatitis C or hepatitis Delta 
  3. Older age 
  4. Male sex 
  5. Cirrhosis 
  6. An underlying condition requiring immunosuppressive therapies (rheumatoid arthritis, lymphoma, or solid tumors) 
    • Certain medications can increase the likelihood of reactivation by more than 10%.  
    • B-cell depleting agents such as rituximab, ofatumumab, doxorubicin, epirubicin, moderate or high-dose corticosteroid therapy lasting more than 4 weeks. 

How to prevent reactivation of hepatitis B 

Hepatitis B reactivation is a serious condition that can lead to health complications, Reactivation is avoidable if at-risk individuals are identified through screening. Current guidelines recommend that individuals at the highest risk (those receiving B-cell depleting therapies and cytotoxic regimens) should receive antiviral therapies as prophylaxis before beginning immunosuppressive therapy. These antiviral therapies should also be continued well beyond stopping the immunosuppressive therapies. Be sure to talk to your doctor to be sure you are not at risk for reactivation.  

References 

Hepatitis b virus reactivation: Risk factors and current management strategies.

Reactivation of hepatitis B virus: A review of Clinical Guidelines.

https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/cld.883

https://www.hepb.org/prevention-and-diagnosis/diagnosis/understanding-your-test-results/

GlaxoSmithKline Recruiting for B-Together Hep B Clinical Trials

The company GlaxoSmithKline (GSK) is launching a new clinical trial, called B-Together, that will investigate how two study drugs might work together to treat chronic hepatitis B (CHB). Researchers are hoping to find new potential treatments that could be more effective than those that are currently available and could lead to positive results that last long after the treatment ends. Participants in this trial could play a role in shaping science and changing the landscape of CHB treatment around the world, and will have an opportunity to learn more about the disease itself.

The two drugs that will be investigated in this trial are GSK3228836 and pegylated interferon, also known as Pegasys. In a previous Phase 2 trial, people living with CHB received GSK3228836 for 4 weeks. The Phase 2b B-Together trial will test longer treatment with GSK3228836, followed by Pegasys, to see what effects this may have on viral antigens (such as HBsAg) in the body. 

About the Study Drugs

GSK3228836 is an investigational drug being tested as a potential treatment for CHB, meaning it is not yet approved for this purpose. Current medicines available to treat CHB only stop the virus from multiplying – they do not enable the body to fully clear the infection, so people have to keep taking these medicines. GSK3228836 is designed to stop the virus from producing proteins that may prevent the immune system from fighting the virus. Thus, the study drug may potentially allow the body to gain control over the infection.

The other drug used in this study, Pegasys, is a medicine that is already used on its own by doctors to treat CHB. Pegasys works by enhancing the body’s immune response to viral infections such as hepatitis B.

What Will Happen During This Trial?

During this trial, all participants will receive GSK3228836 followed by Pegasys. After you have finished treatment with GSK3228836, your doctor will check if it is appropriate for you to start treatment with Pegasys. If it is not appropriate, you may not receive Pegasys at all. At the beginning of the trial, you will be assigned by chance to one of two groups. Each group will receive the study drugs for different lengths of time. You will know which group you are in. The B-Together trial lasts about 79 weeks for each participant. This includes a screening period, a study treatment period, and a follow-up period.

Screening Period

At a screening visit, the study doctor will give you a physical examination, ask about your medical history, and conduct medical tests. The screening period may last up to about 6.5 weeks while the study doctor reviews the results of your screening visit to determine if you meet all requirements for participation.

Trial Treatment period

While receiving GSK3228836, you will visit the clinic for either 12 or 24 weeks. For the first two weeks of your treatment with GSK3228836, you will visit twice per week and for the remaining weeks you will visit the clinic once per week.

When you have finished treatment with GSK3228836, your doctor will assess if it is appropriate for you to start treatment with Pegasys. If it is appropriate, then you will then receive treatment  with Pegasys once a week for up to 24 weeks.

In some countries, it will be possible for you to self-inject Pegasys at home after discussion and training from your study doctor. This could reduce the number of times you have to visit the clinic.

Other study activities will vary from visit to visit and may include:

  •         Discussions about your health and medications you may take outside the trial
  •         Measurement of vital signs (i.e. blood pressure, pulse, weight)
  •         Collection of blood or urine samples
  •         Physical examination
  •         Questionnaires about your health and well-being

Follow-Up Period

During the 24-week follow-up period, you will not receive injections of study treatment, but you will complete other study visit activities as scheduled. There are eight visits scheduled in the follow up period. Your study participation will end about 72 weeks after your first dose of the trial drug.

Who Can Participate?

You may be eligible to participate in this trial if you are at least 18 years old, have been living with documented CHB for at least six months, and have also been receiving stable nucleos(t)ide treatment (not telbivudine) with no changes for at least six months prior to screening and no planned changes for the duration of the study. There are other eligibility requirements that the study doctor will review with you. Individuals who have a current co-infection with or past history of hepatitis C virus, HIV or hepatitis D virus are not eligible to participate in this trial. 

Where Is This Trial Taking Place?

This trial is ongoing in the UK, Spain, Russia, Poland, Italy, Korea, Japan, China, the US, Canada, and South Africa.

You can play a role in shaping your own health and the science of tomorrow! To learn more about this trial and check your eligibility to participate, visit https://clinicaltrials.gov/ct2/show/NCT04676724

Eighth Annual Hep B United Summit a Success!

Hep B United is very pleased to report that the eighth annual (and first virtual) Hep B United Summit was a great success! With over 200 attendees from around the US, the summit brought together partners – both new and familiar – to discuss and collaborate on the successes and challenges of the past year, and strategies to move forward toward the elimination of hepatitis B.  

The theme of this year’s summit was “Standing Up for Hepatitis B: Creative Collaborations to Amplify Awareness, Access, and Equity.” The event included many exciting sessions on topics such as progress toward a hepatitis B cure; strategies for providing hepatitis B services in the time of COVID-19; federal updates on hepatitis B; methods for incorporating hepatitis B into viral hepatitis elimination planning efforts at state and local levels; the path to universal adult hepatitis B vaccination; expansion of hepatitis B outreach in non-traditional settings, such as pharmacies, harm reduction centers, and correctional facilities; the pandemic of structural racism and how to bridge gaps in healthcare; and elevating the patient voice to move elimination efforts forward. The event included a poster session with over 20 submissions from presenters around the country, ranging from medical students to organizational partners, and covering a diverse and comprehensive array of topics related to hepatitis B. 

The virtual platform offered a dynamic and engaging experience, with opportunities for networking, game participation, social media involvement, and learning. The Summit concluded with an award ceremony in which nine Hepatitis B Champions and a Federal Champion were honored for their efforts and dedication to hepatitis B advocacy, awareness, prevention, and elimination efforts over the past year. 

 As in previous years, the Summit provided an opportunity for colleagues to gather and to exchange innovative and creative ideas that will help to advance hepatitis B elimination and elevate hepatitis B as an issue deserving of widespread national attention. Recordings of the Summit are available on Hep B United’s YouTube channel – check them out today!

Announcing the New Current Patient Opportunities Page on the HBF Website

A new page has been created on the Hepatitis B Foundation’s website that contains a compilation of various opportunities available for people living with hepatitis B. These opportunities can be for clinical trials, other types of research, or toolkits with information and resources for those living with hepatitis B and their loved ones and community members. All of these postings are produced or organized by entities external to HBF, but all are related to improved quality of life and liver health. The first two of these opportunities are listed below.

New Tool from CME Outfitters

A new HBV Patient Education Hub has been compiled by continuing medical education company CME Outfitters. The hub includes a great deal of valuable information, such as an overview of hepatitis B, a list of questions to ask your healthcare provider, a patient guide, information about hepatitis B co-infection, doctors’ advice on what to expect from treatment, and many other resources. All information is in an engaging and accessible format. Check it out today!

New Study Opportunity Available for People Living with Itching (Cholestatic Pruritus) Due to Liver Disease or Injury

A new paid opportunity has become available for those experiencing itching caused by hepatitis B, hepatitis C, drug-induced liver injury, auto-immune hepatitis, or primary sclerosing cholangitis (PSC). If you live in Canada or the US and have this condition, you may be eligible to participate in an interview to help researchers better understand your lived experience. The new research study is seeking participants ages 12-80 living in the US and Canada who are living with this itch. This is an opportunity to be involved in research and help advance scientific understanding! Contact the research coordinator for more information and to check if you are eligible. 

Please note that this study does not include treatment and pruritus must be at an intensity level of 4 on a scale of 1-10 for at least the past 8 weeks in order to participate. Patients cannot be pregnant or breastfeeding or have a diagnosis of primary biliary cholangitis. 

We are very excited to unveil this new section of our website and hope it will be a useful resource for many going forward! Please check back often, as more opportunities will be posted as they arise.

New Hepatitis Delta Treatment Approved by European Commission

New Drug Approved for Treatment of Hepatitis Delta in Europe

A new drug to treat hepatitis delta has now been approved by the European Commission! The drug is called bulevirtide and will be marketed under the brand name Hepcludex. It was previously known at Myrcludex B. This approval follows a quarter century of research and development and is the first drug specifically for hepatitis delta approved in Europe. Due to the high prevalence of the hepatitis delta virus in Russia and the former Soviet Union, it has been approved for use there since the end of 2019, under the name Myrcludex. The European Medicines Agency recommended the drug for approval by the Commission at the end of May 2020 (German Center for Infection Research, 2020).

How Does It Work?

Hepcludex, developed by university researchers in Heidelberg, Germany, works as an entry inhibitor – that is, it prevents hepatitis delta virus (HDV) cells, and the hepatitis B virus (HBV) cells upon which HDV depends, from entering healthy liver cells. Both HDV and HBV cells are able to replicate and thrive exclusively in the liver because they need the bile acid transporter NTCP in order to do so. This transporter is the avenue through which HDV is received into the liver cell. Hepcludex works by blocking this reception process, so that the virus does not continue to infect healthy liver cells (German Center for Infection Research, 2020). The currently infected cells either die or are destroyed by the immune system.

How Have People Responded?

Hepcludex is an injectable medication given daily for 48 weeks. In phase I and II clinical trials, people seemed to respond well to this treatment. It seems that just a small amount of Hepcludex is needed, which is good news because it means that the normal processes of the bile salt transporter (NTCP – the receptor of the hepatitis delta virus) will not be widely disrupted (German Center for Infection Research, 2020). MYR Pharmaceuticals GmbH, which now has the license for Hepcludex, is currently in the process of running further phase II and larger phase III trials, in order to continue to determine long-term effects. Hepcludex has also been tested in combination therapy with PEG Interferon, which is administered weekly also via injection (Highleyman, 2019).

Does it also work for Hep B?

Right now, Hepcludex has been tested and works to treat people with hepatitis delta. Since hepatitis delta becomes the dominant virus in those co-infected with hepatitis B and hepatitis delta, clearing hep delta will not necessarily clear hep B as well. However, the curative properties of this drug for those only affected with hep B are being investigated, both alone and in combination with PEG interferon, and there was a loss of surface antigen (HbsAg) noted in 20% of clinical trial participants who were given this combination (Highleyman, 2019).

What does this mean for patients?

Research thus far indicates that Hepcludex can be more effective than interferon alone, the existing hepatitis delta treatment, which is usually not curative and has challenging side effects (Smith, 2020). Hepcludex is now available for prescription in Europe, although pricing schemes remain unclear. For updated information on pricing and availability, check with your doctor or visit the MYR Pharmaceuticals website here.

Clinical trials will continue to take place for this and other drugs. Researchers and pharmaceutical companies might experience difficulty in recruiting patients for hepatitis delta clinical trials because of a lack of awareness and testing – many people living with hepatitis delta worldwide remain undiagnosed. It is important for people at risk for hepatitis delta to be tested and linked to care if found to be infected. If you have hepatitis delta and are interested in participating in a clinical trial, you can search for one near you. To find a doctor to talk to about getting tested for hepatitis delta if you are living with hep B, click here. Hepatitis delta can often be managed and treated, and you are not alone! The most important first step is to know your status.

What does this mean for providers?

The exact number of people living with hepatitis delta around the world is unknown and estimates range anywhere from 20-70 million. Most of these individuals remain undiagnosed due in large part to a lack of testing and diagnostics. Stephan Urban, one of the researchers leading the effort in the development of Hepcludex has said that, in the United States, fewer than 5% of those tested for hepatitis B are also tested for hepatitis delta (Smith, 2020). It is true that in much of the world diagnostic tools remain unaffordable and so Dr. Urban and his team are developing a much less expensive and rapid test. If the capacity exists, however, testing is crucial for the management of this most severe form of viral hepatitis and all of the subsequent liver conditions that can develop from it. Additionally, as with all infectious diseases, vaccination of ALL people to prevent hepatitis B is critical. Click here for more information on hepatitis delta in general and here for questions and concerns.

References

German Center for Infection Research. (2020, August 5). First drug for hepatitis D has been approved by European Commission. EurekAlert! https://www.eurekalert.org/pub_releases/2020-08/gcfi-fdf080520.php

Highleyman, L. (2019, December 16). Combination therapies show promise against hepatitis D. Retrieved August 31, 2020, from https://www.worldhepatitisalliance.org/latest-news/infohep/3548132/combination-therapies-show-promise-against-hepatitis-d

Smith, J. (2020, August 20). Is Hepatitis D Healthcare Being Overlooked? LabioTech https://www.labiotech.eu/medical/hepatitis-d-ema-approval/

Hepatitis B Research Review: May

This month, researchers at Jilin University in Changchun, China have discovered an anti-HBV role of the HIV-1 host restriction factor SERINC5. At Seoul National University in South Korea, HBV researchers have elucidated a mechanism by which HBV hijacks host transcription regulation. Researchers from the Paul Ehrlich Institute in Langen, Germany have demonstrated that HBV DNA can be sensed by the cGAS/STING pathway, but is not in the context of natural hepatocyte infection.  

  • SERINC5 Inhibits the Secretion of Complete and Genome-Free Hepatitis B Virions Through Interfering with the Glycosylation of the HBV Envelope – Frontiers in Microbiology

This paper from Jilin University in Changchun, China reveals the protein serine incorporator 5 (SERINC5) as a host restriction factor for HBV virion secretion. The SERINC family of proteins facilitate lipid biosynthesis and transport in mammalian cells. SERINC5 was recently shown to restrict the replication of HIV-1 and other retroviruses by incorporating into the membrane of budding virions and preventing their entry into target cells. Additionally, the HIV-1 protein NEF as well as the structurally unrelated murine leukemia virus (MLV) protein glycogag have been shown to down-regulate SERINC5 expression on cell surfaces. In this paper, the role of SERINC5 in HBV replication was examined. SERINC5 was found to inhibit HBV virion secretion but not affect intracellular core particle-associated DNA or RNA. Furthermore, the group found that SERINC5 decreased the glycosylation levels of the HBV surface antigens (HBsAg) LHB, MHB, and SHB (large, medium, and small). In order to determine the possible role of SERINC proteins in HBV replication, SERINC proteins 1, 3, and 5, were each transfected into cells alongside an HBV expression vector using Lipofectamine 2000. Transfection of SERINC plasmids was performed in a dose-responsive manner and was confirmed using Western blot. Transfected cell supernatants were then analyzed using an ELISA for HBsAg. Cells transfected with SERINC5 showed a reduction of HBsAg in the supernatant with increasing amounts of SERINC5. Extracellular HBsAg levels in cells transfected with SERINC1 or SERINC3 were unaffected. Furthermore, compared to cells transfected with a control vector, cells transfected with SERINC5 had less HBV virion DNA in the supernatant as measured by qPCR following immunoprecipitation with an anti-HBsAg antibody. Those cells transfected with SERINC1 or SERINC3 showed no change in extracellular HBV virion DNA compared to the control. Interestingly, intracellular levels of HBV DNA and HBV RNA as measured by Southern blot and Northern blot respectively, showed no change between cells transfected with the control vector or any of the SERINC proteins. Additionally, siRNA knockdown of SERINC5 in HepG2 cells concomitantly transfected with an HBV expression vector yielded increased secretion of HBsAg as measured by ELISA and HBV viron DNA as measured by qPCR following immunoprecipitation with an anti-HBsAg antibody. Next, in order to understand the mechanism of SERINC5-mediated HBV secretion inhibition, flag-tagged LHB, MHB, or SHB were transfected into HepG2 cells alongside either a plasmid expressing HA-tagged SERINC5 or a control vector. Interestingly, the glycosylated forms of all three HBsAg proteins were reduced in cells co-transfected with SERINC5 as measured by Western blot. The group then found that SERINC5 colocalizes with LHB in the Golgi apparatus. This was accomplished by co-transfecting HepG2 cells with LHB fused to enhanced cyan fluorescent protein (LHB-ECFP) alongside HA-tagged SERINC5. Cells were then subjected to immunofluorescence dual staining with an antibody against HA as well as an antibody against GM130, a resident protein of the Golgi. These three signals overlapped, implying that SERINC5 interacts with LHB in the Golgi. This finding was further validated by co-immunoprecipitation experiments showing the interaction of SERINC5 with LHB, MHB, and SHB. The group also found, using mutagenesis studies that the fourth to sixth domains of SERINC5 are required for inhibition of HBV secretion. These domains are different than those involved in HIV-1 inhibition, and the group has concluded that SERINC5 inhibits HBV by a completely different mechanism than it does HIV-1. While SERINC5 inhibits HIV-1 by inducing conformational changes on the viral envelope, it inhibits HBV secretion by preventing glycosylation of HBsAg. This publication demonstrates that SERINC5 is a potential anti-HBV host factor. Stimulation of SERINC5 may be a possible treatment for chronic HBV and SERINC5 may prove useful as a diagnostic marker if it is found to correlate with HBV viral load and chronicity.

  • Viral hijacking of the TENT4–ZCCHC14 complex protects viral RNAs via mixed tailing – Nature Structural & Molecular Biology

This paper from Seoul National University in South Korea identifies the TENT4-ZCCHC14 complex as a host factor which protects viral messenger RNA (mRNA) transcripts from degradation. Terminal nucleotidyltransferases (TENTs) are noncanonical poly(A) polymerases. These enzymes add many adenine residues as well as occasional non-adenosine residues to the 3′ end of mRNA molecules. TENT4A and TENT4B (also known as PAPD7 and PAPD5) extend mRNA poly(A) tails with the occasional non-adenosine residue which is typically a guanosine. The results are mRNAs bearing “mixed tails”. Deadenylases are enzymes which trim poly(A) tails to initiate mRNA degradation. The carbon catabolite repression 4–negative on TATA-less (CCR4-NOT or CNOT) complex is the main cytoplasmic deadenylase complex. CNOT trims mRNA poly(A) tails, but its activity is hindered when it encounters a guanosine reside. Therefore, mixed tails protect mRNAs from being targeted for degradation. Interestingly, the inhibitor of HBV called DHQ-1 was recently found to interact with TENT4A and TENT4B. The protein called zinc finger CCHC domain-containing protein 14 (ZCCHC14) was previously found to be an essential host factor for HBV surface antigen production in a genome-wide CRISPR screen. This publication demonstrates that ZCCHC14 recognizes a pentaloop motif in the HBV post-transcriptional regulatory element (PRE) of HBV mRNAs and in turn recruits TENT4A or TENT4B which provide the mRNAs with a protective mixed tail. Additionally, it was demonstrated that viral mRNAs of the human cytomegalovirus (HCMV) contain a similar pentaloop motif and also receive protective mixed tails. This group used a method which they developed previously called TAIL-seq. This method allows for sequencing of 3′ tails on mRNAs as well as identification of the transcript. First, total RNA is extracted from cells. Ribosomal RNA (rRNA) is removed using an rRNA depletion kit in which ssDNA probes are specifically bound to rRNA which are then digested by RNase H. Next, a biotinylated adaptor sequence is ligated to the 3′ end of RNAs. A low concentration of RNase T1 is then used to partially digest the transcripts. Next, the RNAs are pulled down, using streptavidin, phosphorylated, and gel purified to obtain fragments which are 500-1000 nucleotides in length. This size fractionation step removes small non-coding RNAs such as tRNA, snRNA, snoRNA, and miRNA. Next, a second adaptor sequence is added to the 5′ end of the mRNAs. Finally, the mRNAs are subjected to next generation sequencing (NGS) on an Illumina HiSeq 2500 platform. Two reads are obtained for each mRNA, one from the 3′ adaptor and one from the 5′ adaptor. Sequence information derived from these reads reveals the specific composition of mRNA poly(A) tails. In this publication, TAIL-seq was employed to investigate viral mRNA tailing. HepG2.2.15 cells which express the HBV genome, as well as human foreskin fibroblasts (HEF) infected with HCMV were subjected to TAIL-seq. mRNA 3′ tails of both viruses were found to be guanylated significantly more than cellular mRNAs. Additionally, viral mRNA 3′ tails were longer than cellular ones, indicating slower net deadenylation. To check the mechanism of viral mixed tailing, the noncanonical poly(A) polymerases TENT4A and TENT4B were knocked down using siRNA. TAIL-seq showed a significant reduction of viral mRNA 3′ tail guanylation in TENT4-knockdown cells. Additionally, the half-lives of HBV mRNAs were shown to decrease in TENT4-knockdown HepG2.2.15 cells as measured by RT-qPCR at intervals following the addition of the transcription blocker actinomycin D. In order to determine how HBV mRNAs recruit TENT4A and TENT4B, formaldehyde-based crosslinking and immunoprecipitation sequencing (fCLIP-seq) was employed on HepG2.2.15 cells. fCLIP-seq reveals what RNA sequences proteins bind to. In fCLIP-seq, formaldehyde is used to crosslink RNA-protein interactions. RNA-protein complexes are then “pulled down” using an antibody and run on a gel. The protein may then be degraded using proteinase K and RNA molecules may be sequenced. RNA sequencing reads from fCLIP-seq of the HBV genome were enriched in lysates pulled down using antibodies against TENT4A or TENT4B compared to input cell lysate and that pulled down using normal mouse IgG. Importantly, the greatest enrichment occurred specifically in the PRE region of HBV mRNAs. The group goes on to show that the sterile alpha motif (SAM) of ZCCHC14 binds to the stem loop  region of the PRE and recruits TENT4 proteins. This publication demonstrates that both HBV and HCMV have taken advantage of host mRNA transcription regulation to prolong transcript half-life. ZCCHC14, TENT4A, and TENT4B may be possible host targets for HBV or HCMV antiviral treatments.

 
  • Hepatitis B Virus DNA is a Substrate for the cGAS/STING Pathway but is not Sensed in Infected Hepatocytes – Viruses   This paper from the Paul Ehrlich Institute in Langen, Germany shows that HBV DNA is sensed by cGAS, but not in natural HBV infection of hepatocytes. Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS), is a pattern recognition receptor (PRR) that senses cytoplasmic double-stranded DNA (dsDNA). In response to dsDNA binding, cGAS catalyzes the production of 2’3′-cGAMP, a cyclic dinucleotide (CDN) which activates stimulator of interferon genes (STING) by direct binding. Once activated, STING signaling results in the activation of transcription factors promoting the production of type I interferons (IFN-I) and proinflammatory cytokines including tumor necrosis factor alpha (TNFα). IFN-I production and secretion lead to the activation of numerous IFN-stimulated genes (ISGs) which induce a robust antiviral state in the cell. The cGAS/STING pathway is a key component of innate immunity, protecting cells from bacterial and viral infections. How viruses interact with host innate immune sensors such as cGAS is important for understanding their pathogenesis. While the innate immune mechanisms activated by HBV infection remain disputed, HBV is largely considered to be a stealth virus in that it bypasses host innate immunity. Some groups have postulated that the HBV X protein (HBx) or HBV polymerase may inhibit innate immune responses. In this publication it is demonstrated that HBV RNAs are not immunostimulatory, however HBV DNA does elicit an innate immune response mediated by the cGAS/STING pathway. In order to test the immunostimmulatory potential of HBV nucleic acids, they were transfected at multiple concentrations into monocyte-derived dendritic cells (MDDCs) generated from primary human peripheral blood mononuclear cells (PBMCs). Following transfection, mRNA of the gene ISG54 was measured by RT-qPCR. ISG54 was selected as the read-out for innate immune signaling because it is a direct target of the transcription factor IRF3 which is activated downstream of both RIG-I (RNA-sensing) and cGAS/STING (DNA-sensing) pathways. HBV nucleic acids were extracted from HBV virions and quantified prior to transfection. Some groups of nucleic acids were subjected to either DNase or RNase digestion, leaving only HBV RNA or DNA respectively. Total HBV nucleic acids stimulated ISG54 transcription in a dose-dependent manner. Similarly, HBV DNA also stimulated ISG54 transcription. However, transfection of HBV RNA alone did not activate ISG54 transcription, implying that only HBV DNA elicits an innate immune response. In order to test which specific innate immune pathway senses HBV DNA, the human monocytic leukemia cell line THP-1 was used. CRISPR/Cas9 genome editing was used in THP-1 cells to knockout (KO) cGAS, STING, or mitochondrial antiviral-signaling protein (MAVS), which is a key node downstream of the RNA-sensing RIG-I-like receptor (RLR) protein family. Transfection with HBV nucleic acids caused a high level of ISG54 transcription in wild type (WT) and MAVS KO cells which was abrogated when HBV nucleic acids were treated with DNase prior to transfection. However, HBV nucleic acids caused no measurable ISG54 transcription in either cGAS KO or STING KO cells. Next, the group wanted to determine if HBV activates the cGAS/STING pathway in its natural infection of hepatocytes. The levels of cGAS, STING, and other PRRs in a panel of cells were determined using RT-qPCR. The hepatocellular carcinoma cell line HepG2 as well as primary human hepatocytes (PHH) were shown to express less cGAS and STING than Kupffer cells, MDDCs, THP-1 cells, or monocyte derived macrophages (MDMs). Next, HepG2 cells expressing the human sodium taurocholate cotransporting polypeptide used for HBV cell entry (HepG2-hNTCP) and PHHs were transfected with HBV nucleic acids. Both hepatocyte types showed a dose-responsive increase in ISG54 transcription when transfected. Finally, HepG2-hNTCP cells and PHHs were infected with HBV and HBV RNA and ISG54 mRNA were quantified by RT-qPCR. Although both cell types were efficiently infected, they showed no induction of ISG54 across several days. These results indicate that although hepatocytes are capable of sensing transfected HBV genomic DNA via cGAS, they are not able to do so in the context of a natural infection. One possible explanation for the failure of hepatocytes to sense HBV nucleic acids is that they are shielded by the viral nucleocapsid upon infection and during the formation of replication intermediates. Another possibility is that the level of HBV nucleic acids in a natural infection is too low to activate cGAS/ STING, given that these proteins are sparse in hepatocytes. This publication demonstrated for the first time that HBV RNAs are not immunostimulatory, while HBV DNAs activate the cGAS/STING pathway. This finding shows that it may be possible to utilize the cGAS/STING pathway in order to eradicate chronic HBV infection. Perhaps small molecules which destabilize HBV nucleocapsids may be used to expose the DNA of intracellular HBV virions, leading to the activation of the cGAS/STING pathway and an innate antiviral response.

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.