research about hepatitis b

Our team assists with new WHO guidelines for treatment of hepatitis B  --  read more here

News & Events

• News coverage of our programs

Journal Articles on Hepatitis B Research, Vaccination and Public Education

• Emerging Scholars Scientific and Medical Advisors
• Journal articles recommended by our Emerging Scholars Scientific and Medical Advisors
• WHO announces new guidelines for hepatitis B treatment
• Hepatitis B Foundation presents globally recognized liver disease expert with 2024 Baruch S. Blumberg Prize
• Hepatitis B Foundation releases new campaign highlighting the connection between hepatitis B and liv
• Hepatitis B Foundation releases report on first-ever Externally Led Patient-Focused Drug Development meeting for hepatitis B
• People living with hepatitis B should have a voice in new treatment guidelines, advocates say
• Hepatitis B Foundation launches training website with user-friendly courses for everyone interested in hepatitis B and D
• Pennsylvania couple receives Hepatitis B Foundation’s Community Leadership Award
• Hepatitis B Foundation, Blumberg Institute and PABC congratulates John Crowley of Amicus on being named BIO President and CEO
• Hepatitis B Foundation extends its engagement in Africa
• Sen. Steven J. Santarsiero honored at the Pennsylvania Biotechnology Center (PABC)
• Hepatitis B Foundation invites providers and the public to participate in The Liver Meeting, Nov. 10-14, in Boston and online
• Hepatitis B Foundation coordinates 2023 International HBV Meeting, a scientific conference held Sept. 19-23 in Kobe, Japan
• Hep B United Commemorates World Hepatitis Day, July 28
• Gala puts the spotlight on creating family and support for those living with hepatitis B
• Global leader, physician treating people living with hepatitis B takes new role with Hepatitis B Foundation
• Hepatitis B Foundation releases white paper calling health care providers into action following new hepatitis B screening and vaccination recommendations
• New CDC Universal Screening Recommendations will save lives, Hepatitis B Foundation president says
• Hepatitis B Foundation invites everyone to participate in the online silent auction fundraiser.
• Hepatitis B Foundation president responds to Janssen decision on the company’s hepatitis B drug development program
• Globally prominent advocate and physician chosen for Hepatitis B Foundation’s 2023 Community Commitment Award
• Dr. Yasmin Ibrahim appointed to national Patient Engagement Collaborative
• Comprehensive hepatitis B program in Vietnam provides an excellent model for other countries
• Hepatitis B Foundation Announces third series of continuing education program on hepatitis B for health care providers and public health professionals
• Hepatitis B Foundation hails decision by U.S. Public Health Service Corps to accept future applicants living with chronic hepatitis B infection and HIV
• German scientist, inventor of new, first-in-class treatment for hepatitis D, to receive the 2023 Baruch S. Blumberg Prize
• Researchers and people living with hepatitis B meet in Paris at the third Hepatitis B Community Forum
• Hepatitis B Foundation mourns Bill Mason, an accomplished scientist whose discovery led to current treatments for hepatitis B
• Hepatitis B Foundation raises alarm about findings from new federal viral hepatitis surveillance report
• Hepatitis B Foundation strongly supports Congressional letters urging Biden administration to end discriminatory military policy
• Longtime Board Chair honored by his colleagues
• Hepatitis B Foundation creates two Global Community Advisory Boards
• Pa DOH Highlights the Importance of Viral Hepatitis Awareness, Need for Expansion of Syringe Services
• Hepatitis B Foundation, StoryCenter release new #justB stories from people with lived experience
• Pediatric Hepatitis Outbreaks
• Philadelphia City Council recognizes May as Hepatitis Awareness Month
• Hepatitis B Foundation hosts Princeton Workshop on Liver Cancer
• Annual Gala raises a record amount for the local Hepatitis B Foundation
• Hepatitis D Roundtable to Address Unmet Needs of Patients
• DiRx teams up with Hepatitis B Foundation to offer low-cost medications
• Many more U.S. adults to get vaccinated against hepatitis B following move by U.S. Centers for Disease Control and Prevention (CDC)
• Hepatitis B Foundation receives Congressional funding for a Center of Public Health Excellence
• CTC Foundation of Princeton donating $100,000 to Hepatitis B Foundation
• Hepatitis B Foundation senior vice president and board member speak on popular podcast
• Anonymous donor provides record gift for hepatitis B research
• Two hepatitis B medications available free through Hepatitis B Foundation and Rx Outreach partnership
• Canadian scientist chosen for the 2022 Hepatitis B Foundation’s Blumberg Prize
• Landmark vote by CDC’s Advisory Committee on Immunization Practices (ACIP) to recommend universal hepatitis B vaccination
• Hepatitis B Foundation strongly endorses the Liver Illness Visibility, Education and Research (LIVER) Act of 2021
• Dr. Chari A. Cohen becomes President of the Hepatitis B Foundation
• New president announced for the Pennsylvania Biotechnology Center (PABC)
• Major successes on Capitol Hill
• CDC awards a $1.375 million, five-year grant to the Hepatitis B Foundation for expansion of Hep B United, a nationwide coalition
• Hepatitis B Foundation Members Selected to Participate as Consumer Reviewers in the Congressionally Directed Medical Research Program’s Peer Reviewed Medical Research Program for the U.S. Department of Defense
• Hepatitis B Foundation supports launch of new global online forum dedicated to supporting people with hepatitis B, connecting with health experts
• Hepatitis B Foundation launches the first global registry of discrimination against people living with hepatitis B
• Hepatitis B Foundation to hold its annual Crystal Ball Gala on April 30
• Hepatitis B Foundation mourns the passing of John C. Martin, pharmaceutical industry leader
• Chronic hepatitis B is far more prevalent among U.S. residents than previously reported
• All of Us research program
• Hepatitis B Foundation Mourns Loss of Co-Founder Paul Witte, Longtime New Hope Resident
• Hepatitis B Foundation launches continuing education series on hepatitis B for health care providers and public health professionals
• HBF applauds President Biden’s Memorandum denouncing racism, xenophobia, and intolerance against Asian Americans and Pacific Islanders
• Hepatitis B Foundation applauds release of National Hepatitis Strategic Plan
• Bristol Myers Squibb awards grant to Hepatitis B Foundation
• Federal Task Force Recommendation for Hepatitis B Screening Fails to Close Gaps in Diagnosis Rates
• Hepatitis B community leaders convene to address eliminating hepatitis B during COVID-19 pandemic
• Pennsylvania Biotechnology Center’s Kassa named one of The 10 Best COOs of 2020
• Hepatitis B Foundation announces recipient of 2021 Baruch S. Blumberg Prize
• Hepatitis B Foundation co-founders chosen for major new award from the American Association for the Study of Liver Diseases
• Hepatitis B Foundation applauds HHS letter on discrimination against people living with hepatitis B who are pursuing careers in health care
• Hepatitis B Foundation launches new tool to assist people living with hepatitis B in making decisions on health insurance
• Nobel Prize to Hepatitis B Foundation and Blumberg Institute Advisors
• Work begins on a $19 million expansion of the Pennsylvania Biotechnology Center (PABC)
• Hepatitis B Foundation launches B the Voice Story Bank
• Hepatitis B Foundation expresses appreciation for the work of Dr. Ding-Shinn Chen with the announcement of his death
• Hepatitis B Foundation and Hep B United Statement on the Federal Government's Rollback of Critical Health Care Protections
• Hepatitis B Foundation stands in solidarity with black communities, calls for action against institutional racism
• Two Powerful Editorials Published by the Hepatitis B Foundation
• Hepatitis B Foundation Expands Hepatitis B Prevention Policy Initiatives
• HBV Vaccinations Save Lives, Reduce New Infections: National Adult Hepatitis B Vaccination Awareness Day
• Hepatitis B Foundation Hepatitis B Foundation Says “Thank You!” to its 100- Volunteers
• Hepatitis B Foundation Announces Annual Fundraising Event to Go Virtual on April 24
• Hepatitis B Foundation, Baruch S. Blumberg Institute and Pennsylvania Biotechnology Center Announce New Director of Communications and Marketing
• Message from Dr. Timothy Block, Hepatitis B Foundation President
• Hepatitis B Foundation Commends New Rx Outreach Program to Provide Access to Affordable Hepatitis B Medication
• Hepatitis B Foundation Endorses the Liver Illness Visibility, Education, and Research (LIVER) Act of 2019
• Hepatitis B Foundation Announces 2020 Baruch S. Blumberg Prize Winner
• U.S. Falls Short in Reaching 2020 Goals for Hepatitis B
• Hepatitis B Foundation Calls for Increased Resources for Hepatitis B Prevention in Response to CDC 2017 Surveillance Data Report
• Our Voices Made a Difference: CVS Caremark to Cover Vemlidy Prescriptions
• Hepatitis B Foundation Announces 2019 Baruch S. Blumberg Prize Winner
• Hep B United Applauds Bipartisan Legislation to Combat the Opioid Crisis and Opioid Related Infectious Diseases
• Hepatitis B Foundation Endorses the Liver Illness Visibility, Education, and Research (LIVER) Act of 2018
• Hepatitis B Foundation Calls for Universal Screening for Hepatitis B
• Hepatitis B Leaders Call for the Elimination of Hepatitis B
• Hepatitis B Foundation Joins Forces with Grace Meng
• Hepatitis B Foundation Releases New #justB Stories
• Hepatitis B Foundation Strongly Supports the Strategic Plan for Trans‐NIH Research to Cure Hepatitis B
• Hepatitis B Foundation Crystal Ball Gala
• New Two-Dose HBV Vaccine Recommended by ACIP
• Timothy M. Block, PhD, President of Hepatitis B Foundation and its Baruch S. Blumberg Institute, named a 2017 National Academy of Inventors Fellow
• Hepatitis B Foundation Applauds FDA Approval of New Hepatitis B Vaccine
• CDC National Progress Report on Hepatitis Elimination Reveals Rise in Acute HBV Infections and Low Birth Dose Vaccination Rates in the U.S.
• Hepatitis B Foundation Announces Promotion of Chari Cohen, DrPH, MPH, to Vice President, Public Health and Programs
• Hepatitis B Foundation Mourns the Loss of Pioneering Hepatitis B Physician-Scientist Dr. W. Thomas London
• Hepatitis B Foundation's #justB Campaign Gives Voice to Personal Stories During May Hepatitis Awareness Month
• Executive Director Retires After 25 Years of Service
• Hepatitis B Foundation Bets on a Cure at the 2017 Crystal Ball
• Targets to Eliminate Hepatitis B in U.S.
• Fred Beans Family of Dealerships Donates $30,000..
• International Leaders to Its Scientific and Medical Advisory Board
• Hepatitis B Foundation Opposes the American Health Care Act
• Appoints Global Expert Dr. Nat Brown
• Hepatitis B Foundation Launches #justB Storytelling Campaign
• Dr. Richard G. Pestell Joins the Baruch S. Blumberg Institute
• Dr. Bud Tennant Leaves Behind a Distinguished Scientific Legacy
• Be About It
• Nationwide Hepatitis Delta Virus (HDV) Campaign
• Current and Past "B Informed" Newsletters
• Hepatitis B: Is a Cure Possible?
• Calendar of Events
• Witte Lecture
• International HBV Meeting
• Externally Led Patient-Focused Drug Development
• Why World Hepatitis Day is July 28
• NYC Marathon
• Princeton Workshop 2022
• Commentary on the Cure
• Pajama Gala April 24, 2020
• A statement regarding COVID-19 from the Hepatitis B Foundation Scientific and Medical Advisory Board (SMAB) to the hepatitis B community

Here are selected, recent peer-reviewed journal articles and other scholarly publications that were written by Hepatitis B Foundation public health researchers and collaborators.

Mondher T., Jack W., Chari C., Chris M., Helen K., Jake M., Hannah P., Ashley F. S., Robert G. G., Qin N., Hiroshi Y., Markus C., Maurizia B., Florian van B. Qing X., Dee L., Noriyuki H., Urbano S., Maria B., Angelina Villasis K., Yasushi T., Yiwei L., Ao L., Qiaoqiao C., Tetsuro I., Olaf R., Anna P., Gudrun H., Eric K.H. C. & Su W. Experience and impact of stigma in people with chronic hepatitis B: a qualitative study in Asia, Europe, and the United States.  BMC Public Health   24 , Article number:  611 (2024). [ link]

Freeland, C., Lo, W., Kabagambe K., Wang S., Adda D., Graham C., Gish R., Cohen C. Urgent need for lived experience in hepatitis B guideline development. The Lancet Gastroenterology & Hepatology , Volume 0, Issue 0. [link]

Cohen C. Dangerous medicine: the story behind human experiments with hepatitis  Emerging Infectious Diseases   Volume 29, Number 7 - 2023 Jul. [link]

Freeland C, Bruckbauer J, Qureshi A, Huynh K, Rutland M, et al. (2023) Enhancing Hepatitis B Care Competency through Project ECHO: A Program Evaluation. Journal of Digestive Diseases and Hepatology 8: 200. DOI: 10.29011/2574-3511.100200 [link]

C. Freeland, V Sreepathi, R. W. Hass, J. M. Fenkel, J. Torgersen, K. Rothstein, C. Cohen, R.G. Gish. The importance of triple panel testing for hepatitis B and the burden of isolated anti-hepatitis B core antibodies within a community sample. Journal of Virus Eradication , 2023, 100358, ISSN 2055-6640 [link]

Wang, M., Qureshi, A., Johnson, N. Mansalay, A. Muhr A., Abatemarco D., Freeland C. A Health Belief Model Examination of Factors Related to Hepatitis B Screening Among African Immigrants in Philadelphia. Journal of Racial and Ethnic Health Disparities  (2023)  [link]

Freeland C, Kanu F, Mohammed Y, Nwokoro UU, Sandhu H, Ikwe H, et al. (2023) Barriers and facilitators to hepatitis B birth dose vaccination: Perspectives from healthcare providers and pregnant women accessing antenatal care in Nigeria. PLOS Global Public Health 3(6): e0001332. [link]

Huỳnh TB, Tina Nguyễn D, Vũ N, Carroll-Scott A, Wong C, Freeland C, Parvanta C. (2023) Perceived Benefits and Barriers to Implementing Occupational Health Recommendations Among Immigrant-Owned Nail Salons in the Greater Philadelphia Region. Health Promotion Practice Mar 16:15248399231160461. doi: 10.1177/15248399231160461. Epub ahead of print. PMID: 36924273. [link]

Ibrahim Y, Umstead M, Wang S, Cohen C. The Impact of Living With Chronic Hepatitis B on Quality of Life: Implications for Clinical Management. Journal of Patient Experience . 2023;10. doi:10.1177/23743735231211069 [ link ]

Freeland C, Cohen C (2023) The impact of a hepatitis B diagnosis.  Gastrointestinal Nursing  2Feb2023 Volume 21, Issue Sup1 | ISSN (print): 1479-5248 | ISSN (online): 2052-2835 [ link ]

Cohen C, Evans A, Block, TM (2023) Hepatitis Viruses: Hepatitis B and Hepatitis D. In: Kaslow, R.A., Stanberry, L.R., Powers, A.M. (eds) Viral Infections of Humans . Springer, New York, NY. [ link ]

McMahon B, Cohen C, Brown RS, et al. Opportunities to Address Gaps in Early Detection and Improve Outcomes of Liver Cancer [published online ahead of print, 2023 May 5].  JNCI Cancer Spectrum  2023;7(3):pkad034. [ link ]

Ha YP , Sun Y , Wilkinson J , Wang S , Chien L , Wu M , Wang E , Freeland C (2022)  Implementation and outcomes of a remote hepatitis B screening program designed to overcome COVID-19 pandemic-related disruptions to community-based screenings for Asians in Greater Philadelphia: A descriptive study  Health Science Reports     8August2022 https://doi.org/10.1002/hsr2.761 [ link ]

Kheir OO, Freeland C, Abdo AE, Yousif MEM, Altayeb EA, Mekonnen HD (2022) Assessment of hepatitis B knowledge and awareness among the Sudanese population in Khartoum State Pan African Medical Journal   10.11604/pamj.2022.41.217.30390  [link]

Ibrahim Y, Cohen C, Araojo R, Merenda C, Dykstra S, et al (2022) Attitudes towards clinical trial participation among people living with chronic hepatitis B.  J Transl Sci.  2022; 8:1-10. Epub ahead of print. [ link ]

Freeland C, Mendola L, Cheng V, Cohen C, Wallace J (2022) The unvirtuous cycle of discrimination affecting people with hepatitis B: a multi-country qualitative assessment of key-informant perspectives.  Int J Equity in Health. 2022 May 31;21(1):77. [ link ]

Matthews PC, Jack K, Wang S, Abbott J, Bryce K, Cheng B, Ghosh I, Story A, Chen J, Munoz C, Bell J, Riddell S, Goldring A, Goddard C, Moraras K, Cohen C, Brown K, Lazarus JV, Elsharkawy AM (2022) A call for advocacy and patient voice to eliminate hepatitis B virus infection.  Lancet Gastroenterol Hepatol. 2022 Apr;7(4):282-285. [ link ]

Silliman M, Alber M, Gib S, Gee M, Conover S, Chan C, Cohen C, Freeland C, Racho R (2022) Comparing lengths and inclusion of information in storytelling videos: Implications for hepatitis B education.  PEC Innovation.  Online ahead of print. [ link ]

Freeland C, Mendola L, Cheng V, Cohen C, Wallace J (2022) The unvirtuous cycle of discrimination affecting people with hepatitis B: a multi-country qualitative assessment of key-informant perspectives. International Journal for Equity in Health [ link ] 

Huynh TB , Nguyen DT , Vu N , Freeland C (2021) Development of health and safety training for Vietnamese American nail salon owners and workers medRxiv [ link ]

C Freeland, M Kamischke, M Jackson, S Bodor, T Block, C Cohen, et al (2021). Common concerns, barriers to care, and the lived experience of individuals with hepatitis B: a qualitative study.  BMC Public Health [link]

Gish RG, Brosgart C, Lok A, Wong R, Block T, Cohen C, et al (2021) An Updated Assessment of Chronic Hepatitis B Prevalence among Foreign-Born Persons Living in the United States. Hepatology  [ link ]

Wang S, Cohen C, Tang A, Graham C (2021). Hepatitis B Virus Elimination in the U.S.: Time to Dismantle Barriers and Implement Solutions.  Current Hepatology  Solutions  [ link ]

Razavi H, Block, T, Cohen, C, et al (2020).  The case for simplifying and using absolute targets for viral hepatitis elimination goals.  Journal of Viral Hepatitis  [ link ]

Moraras K, Block J, Shiroma N, Cannizzo A, Cohen C (2020). Protecting the Rights of Health Care Students Living With Hepatitis B Under the Americans With Disabilities Act.  Public Health Reports . [ link ]

Tu T, Block JM, Wang S, Cohen C, Douglas MW (2020). The lived experience of chronic hepatitis B: a broader view of its impacts and why we need a cure.  Viruses   [link]  

Freeland C, Bodor S, Perera U, Cohen C Barriers to Hepatitis B Screening and Prevention for African Immigrant Populations in the United States: A Qualitative Study.  Viruses  2020:12(3), 305.  [link]

Alber JM, Cohen C, Racho R, Freeland C, Ghazvini S, Tolentino B, Almeida R, & Silliman M (2020) Exploring the impact of storytelling on storytellers in a hepatitis B health communication context.  Patient Education & Counseling .  [link]

Alber JM, Cohen C, Bleakley A, Ghazvini S, Tolentino B, Almeida R, & Chance BL (2019). Comparing the effects of different story types and speakers in hepatitis B storytelling videos.  Health Promotion Practice . [link]

Alber JM, Cohen C, Nguyen G, Ghazani S, Tolentino B (2018). Exploring communication strategies for promoting hepatitis B prevention among young Asian American adults.  Journal of Health Communication ; 16:1-7. [link]

Freeland C, Cohen C, Collier M (2018). Public health response to hepatitis B exposure: A case study on gaps and opportunities to improve postexposure care.  Infectious Disease in Clinical Practice ; 26(4):185-186. [link]

Cohen, C, Alber, JM, Bleakley, A, Grossman, S, Freeland, C, Alarcon, K, Merchant, R (2018). Social media for hep B awareness: Young adult and community leader perspectives.  Health Promotion Practice . Advanced online publication. [link]

Alter H, Block T, Brown N, Brownstein A, Brosgart C, Chang K-M, Chen P-J, Chisari F, Cohen C, et al. (2018). A Research Agenda for Curing Chronic Hepatitis B Virus Infection.  Hepatology ; 67(3):1127-1131. [link]

Block T, Alter H, Brown N, Brownstein A, Brosgart C, Chang K-M, Chen P-J, Cohen C, et al. (2017). Research priorities for the discovery of a cure for chronic hepatitis B: Report of a workshop.  Antiviral Research ; 150:93-100. [link]

Cohen C, Evans AA, Huang P, London WT, Block J, Chen G (2016). Hepatitis B knowledge among key stakeholders in Haimen City, China: Implications for addressing chronic HBV infection.  Hepatology, Medicine and Policy , 1(4):2-9. [link]

Jorgensen C, Chen S, Carnes CA, Block J, Chen D, Caballero J, Moraras K, Cohen C (2016). “Know Hepatitis B:” A Multilingual Communications campaign Promoting Testing for Hepatitis B Among Asian Americans and Pacific Islanders.  Public Health Reports , 2016 Supplement 2, v131: 35-40. [link]

McMahon B, Block J, Block T, Cohen C, Evans AA, Hosangadi A, London WT, Sherman M, et. al. (2015). Hepatitis-Associated Liver Cancer: Gaps and Opportunities to Improve Care.  JNCI J Natl Cancer Inst , 108(4):1-6. [link]

Gish RD, Cohen CA, Block JM, Brosgart CL, Block TM, Clary R, Le LT, Ninburg MH, Sandt L, Kowdley KV (2015). Data supporting updating estimates of the prevalence of chronic hepatitis B and C in the United States.  Hepatology , 62(5):1339-1341. [link]

Evans AA, Cohen C, Huang P, Qian L, London WT, Block JM, Chen G (2015). Prevention of perinatal hepatitis B transmission in Haimen City, China: Results of a community public health initiative.  Vaccine ; epub ahead of print, pii: S0264-410X(15)00111-5. doi: 10.1016/j.  Vaccine  2015.01.054. [link]

Weerasinghe I, Bannister N, Huang V, Cohen C, Caballero J, Wang S (2015). The role of the patient-centered medical home in addressing hepatitis B perinatal transmission.  AAPI Nexus , 12(1,2): 140-160. [link]

Chen G, Block JM, Evans AA, Huang P, Cohen C (2014). Gateway to Care campaign: a public health initiative to reduce the burden of hepatitis B in Haimen City, China.  BMC Public Health , 14:754-759. [link]

Beckett GA, Block JM, Cohen C, McMahon BJ (2014). The role of primary care physician assistants in managing chronic hepatitis B.  Journal of the American Association of Physician Assistants , 27(3):51-54. [link]

Nguyen GT, Cohen C, Evans A, Bautista R (2014). Broadening the scope for national database sampling: a critical need. American Journal of Public Health , 104(2):e3. [link]

Cohen C, Caballero J, Martin M, Weerasinghe I, Ninde M, Block J (2013). Eradication of Hepatitis B: A Nationwide Community Coalition Approach to Improving Vaccination, Screening, and Linkage to Care.  Journal of Community Health , 38(5):799-804. [link]

Evans AA, London WT, Gish RG, Cohen C, Block WT (2013). Chronic HBV Infection Outside Treatment Guidelines: Is Treatment Needed?  Antiviral Therapy , 18(2):229-235. [link]

Apuzzio J, Block JM, Cullison S, Cohen C, Leong SL, London WT, McHugh JA, Neubauer RL, Perrillo R, Squires R, Tarrant D, McMahon BJ (2012). Chronic Hepatitis B in Pregnancy: A Workshop Consensus Statement on Screening, Evaluation, and Management, Part 1.  The Female Patient , 37(4):22-27.

Apuzzio J, Block JM, Cullison S, Cohen C, Leong SL, London WT, McHugh JA, Neubauer RL, Perrillo R, Squires R, Tarrant D, McMahon BJ (2012). Chronic Hepatitis B in Pregnancy: A Workshop Consensus Statement on Screening, Evaluation, and Management, Part 2.  The Female Patient , 37(5):30-34.

McHugh JA, Cullison S, Apuzzio J, Block JM, Cohen C, Leong SL, London WT, McNellis RJ, Neubauer RL, Perrillo R, Squires R, Tarrant D, McMahon BJ (2011). Chronic hepatitis B infection: A workshop consensus statement and algorithm. Journal of Family Practice , Online Exclusive. 60(9):E1-E8. [link]

Evans AA, Cohen C, London WT (2011). Hepatitis B Virus in the United States.  Annals of Internal Medicine , 155(3):205. [link]

Cohen C, McMahon BJ, Block JM, Brosgart CL, Gish RG, London WT, Block TM (2011). Is chronic hepatitis B being undertreated in the United States?  Journal of Viral Hepatitis , 18:377-383. [link]

Cohen C, Evans  A, London WT, Block J, Conti M, Block T (2008). Underestimation of chronic hepatitis B virus infection in the United States of America.  Journal of Viral Hepatitis , 15(1):12–13. [link]

Jessop A, Cohen C, Burke M, Conti M, Black M  (2004). Hepatitis support groups: Meeting the information and support needs of hepatitis patients.  Journal of Gastroenterology Nursing , 27(4):163-169. [link] 

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Hepatitis B

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In this section:

What is hepatitis B?

How common is hepatitis b, who is more likely to get hepatitis b, should i be screened for hepatitis b, what are the complications of hepatitis b, what are the symptoms of hepatitis b, what causes hepatitis b, how do doctors diagnose hepatitis b, what tests do doctors use to diagnose hepatitis b, how do doctors treat hepatitis b, how do doctors treat the complications of hepatitis b, how can i protect myself from hepatitis b infection, how can i prevent spreading hepatitis b to others, eating, diet, and nutrition for hepatitis b, clinical trials for hepatitis b.

Hepatitis B is a viral infection that causes liver  inflammation and damage. Inflammation is swelling that occurs when tissues of the body become injured or infected. Inflammation can damage organs.

Viruses invade normal cells in your body. Many viruses cause infections that can spread from person to person. The hepatitis B virus spreads through contact with an infected person’s blood, semen, or other body fluids.

You can take steps to protect yourself from hepatitis B , including getting the hepatitis B vaccine. If you have hepatitis B, you can take steps to prevent spreading hepatitis B to others .

The hepatitis B virus can cause an acute or chronic infection.

Acute hepatitis B

Acute hepatitis B is a short-term infection. Some people have symptoms, which may last several weeks. In some cases, symptoms last up to 6 months. Sometimes the body is able to fight off the infection and the virus goes away. If the body isn’t able to fight off the virus, the virus does not go away, and chronic hepatitis B infection occurs.

Most healthy adults and children older than 5 years who have hepatitis B get better and do not develop a chronic hepatitis B infection. 6

Chronic hepatitis B

Chronic hepatitis B is a long-lasting infection. Your chance of developing chronic hepatitis B is greater if you were infected with the virus as a young child. About 90 percent of infants infected with hepatitis B develop a chronic infection. About 25 to 50 percent of children infected between the ages of 1 and 5 years develop chronic infections. However, only about 5 percent of people first infected as adults develop chronic hepatitis B. 6

Hepatitis B worldwide

Hepatitis B infection is more common in some other parts of the world than it is in the United States. Though less than 0.5 percent of the U.S. population has hepatitis B, 2 percent or more of the population is infected in areas such as Africa, Asia, and parts of the Middle East, Eastern Europe, and South America. 7,8,9

Hepatitis B infection has been especially common in some parts of the world, such as sub-Saharan Africa and parts of Asia, where 8 percent or more of the population was infected. 9 In some of these areas, Hepatitis B infection rates are now lower than they were, but infection rates are still higher in these areas than in the United States. 8,9

Hepatitis B in the United States

In the United States, about 862,000 people have chronic hepatitis B. 6 Asian Americans and African Americans have higher rates of chronic hepatitis B than other U.S. racial and ethnic groups. 10 Researchers estimate that about half of the people living with chronic hepatitis B in the United States are Asian Americans and Pacific Islanders . 11 Chronic hepatitis B is also more common among people born in other countries than among those born in the United States. 7

The hepatitis B vaccine has been available since the 1980s and, in 1991, doctors began recommending that children in the United States receive the hepatitis B vaccine. The annual rate of acute hepatitis B infections went down 88.5 percent between 1982 and 2015. 12 In 2017, the annual number of hepatitis B infections rose in some states. 13 Experts think the rise was related to increases in injection drug use. Injection drug use increases the risk of hepatitis B infection.

People are more likely to get hepatitis B if they are born to a mother who has hepatitis B. The virus can spread from mother to child during birth. For this reason, people are more likely to have hepatitis B if they

• were born in a part of the world where 2 percent or more of the population has hepatitis B infection
• were born in the United States, didn’t receive the hepatitis B vaccine as an infant, and have parents who were born in an area where 8 percent or more of the population had hepatitis B infection

People are also more likely to have hepatitis B if they

• are infected with HIV , because hepatitis B and HIV spread in similar ways
• have lived with or had sex with someone who has hepatitis B
• have had more than one sex partner in the last 6 months or have a history of sexually transmitted disease
• are men who have sex with men
• are injection drug users
• work in a profession, such as health care, in which they have contact with blood, needles, or body fluids at work
• live or work in a care facility for people with developmental disabilities
• have diabetes
• have hepatitis C
• have lived in or travel often to parts of the world where hepatitis B is common
• have been on kidney dialysis
• live or work in a prison
• had a blood transfusion or organ transplant before the mid-1980s

In the United States, hepatitis B spreads among adults mainly through contact with infected blood through the skin, such as during injection drug use, and through sexual contact. 12

Screening is testing for a disease in people who have no symptoms. Doctors use blood tests to screen for hepatitis B. Many people who have hepatitis B don’t have symptoms and don’t know they are infected with hepatitis B. Screening tests can help doctors diagnose and treat hepatitis B, which can lower your chances of developing serious health problems.

Your doctor may recommend screening for hepatitis B if you 9,14

• are pregnant
• were born in an area of the world where 2 percent or more of the population has hepatitis B infection, which includes Africa, Asia, and parts of the Middle East, Eastern Europe, and South America
• didn’t receive the hepatitis B vaccine as an infant and have parents who were born in an area where 8 percent or more of the population had hepatitis B infection, which includes sub-Saharan Africa and parts of Asia
• are HIV-positive
• have injected drugs
• are a man who has sex with men
• have lived with or had sex with a person who has hepatitis B
• have an increased chance of infection due to other factors

Hepatitis B may lead to serious complications. Early diagnosis and treatment can lower your chances of getting complications.

Acute hepatitis B complications

In rare cases, acute hepatitis B can lead to acute liver failure , a condition in which the liver fails suddenly. People with acute liver failure may require a liver transplant .

Chronic hepatitis B complications

Chronic hepatitis B can lead to

• cirrhosis , a condition in which scar tissue replaces healthy liver tissue and prevents your liver from working normally. Scar tissue also partly blocks the flow of blood through the liver. As cirrhosis gets worse, the liver begins to fail.
• liver failure, in which your liver is badly damaged and stops working. Liver failure is also called end-stage liver disease. People with liver failure may require a liver transplant.
• liver cancer . Your doctor may suggest blood tests and an ultrasound or another type of imaging test to check for liver cancer. Finding cancer at an early stage improves the chance of curing the cancer.

Reactivated hepatitis B

In people who have ever had hepatitis B, the virus may become active again, or reactivated, later in life. When hepatitis B is reactivated, it may start to damage the liver and cause symptoms. Reactivated hepatitis B can lead to acute liver failure.

People at risk for reactivated hepatitis B include those who

• chemotherapy to treat cancer
• medicines prescribed to treat conditions that involve the immune system, such as inflammatory bowel disease , rheumatoid arthritis , and psoriasis
• medicines prescribed for people receiving an organ transplant or bone marrow transplant
• corticosteroids , if taken for more than a few weeks
• take hepatitis C medicines
• have HIV infection

Doctors may test for current or past hepatitis B infection in people at risk for reactivated hepatitis B.

Many people infected with hepatitis B have no symptoms.

Some people with acute hepatitis B have symptoms 2 to 5 months after they come in contact with the virus. 6 These symptoms may include

• dark yellow urine
• feeling tired
• gray- or clay-colored stools
• loss of appetite
• pain in the abdomen
• yellowish eyes and skin, called jaundice

Infants and children younger than age 5 typically don’t have symptoms of acute hepatitis B. Older children and adults are more likely to have symptoms. 6

If you have chronic hepatitis B, you may not have symptoms until complications develop, which could be decades after you were infected. For this reason, hepatitis B screening is important, even if you have no symptoms.

The hepatitis B virus causes hepatitis B. The hepatitis B virus spreads through contact with an infected person’s blood, semen, or other body fluids. Contact can occur by

• being born to a mother with hepatitis B
• having unprotected sex with an infected person
• sharing drug needles or other drug materials with an infected person
• getting an accidental stick with a needle that was used on an infected person
• being tattooed or pierced with tools that were used on an infected person and weren’t properly sterilized, or cleaned in a way that destroys all viruses and other microbes
• having contact with the blood or open sores of an infected person
• using an infected person’s razor, toothbrush, or nail clippers

You can’t get hepatitis B from

• being coughed on or sneezed on by an infected person
• drinking unclean water or untreated water that has not been boiled
• eating food that is unclean or has not been properly cooked
• hugging an infected person
• shaking hands or holding hands with an infected person
• sharing spoons, forks, and other eating utensils
• sitting next to an infected person

Mothers who have hepatitis B can safely breastfeed their babies. If a baby receives hepatitis B immune globulin (HBIG) and starts receiving the hepatitis B vaccine to prevent hepatitis B infection shortly after birth, hepatitis B is unlikely to spread from mother to child through breastfeeding. 15

Doctors diagnose hepatitis B based on your medical and family history, a physical exam, and blood tests. If you have hepatitis B, your doctor may perform additional tests to check your liver.

Medical and family history

Your doctor will ask about your symptoms and about factors that may make you more likely to get hepatitis B . Your doctor may ask whether you have a family history of hepatitis B or liver cancer. Your doctor may also ask about other factors that could damage your liver, such as drinking alcohol .

Physical exam

During a physical exam, your doctor will check for signs of liver damage such as

• changes in skin color
• swelling in your lower legs, feet, or ankles
• tenderness or swelling in your abdomen

Doctors use blood tests to diagnose hepatitis B. Your doctor may order additional tests to check for liver damage, find out how much liver damage you have, or rule out other causes of liver disease.

Blood tests

Your doctor may order one or more blood tests to diagnose hepatitis B. A health care professional will take a blood sample from you and send the sample to a lab.

Certain blood tests can show whether you are infected with hepatitis B. If you are infected, your doctor may use other blood tests to find out

• whether the infection is acute or chronic
• whether you have an increased chance of liver damage
• whether the virus levels in your body are high or low
• whether you need treatment

If you have chronic hepatitis B, your doctor will recommend testing your blood regularly because chronic hepatitis B can change over time. Even if the infection is not damaging your liver when you are first diagnosed, it may damage your liver in the future. Your doctor will use regular blood tests to check for signs of liver damage, find out if you need treatment, or see how you are responding to treatment.

Blood tests can also show whether you are immune to hepatitis B, meaning you can’t get hepatitis B. You may be immune if you got a vaccine or if you had an acute hepatitis B infection in the past and your body fought off the infection.

Additional tests

If you’ve had chronic hepatitis B a long time, you could have liver damage. Your doctor may recommend additional tests to find out whether you have liver damage, how much liver damage you have, or to rule out other causes of liver disease. These tests may include

• blood tests
• transient elastography, a special ultrasound of your liver
• liver biopsy , in which a doctor uses a needle to take a small piece of tissue from your liver

Doctors typically use liver biopsy only if other tests don’t provide enough information about a person’s liver damage or disease. Talk with your doctor about which tests are best for you.

Doctors typically don’t treat hepatitis B unless it becomes chronic. Doctors may treat chronic hepatitis B with antiviral medicines that attack the virus.

Not everyone with chronic hepatitis B needs treatment. If blood tests show that hepatitis B could be damaging a person’s liver, a doctor may prescribe antiviral medicines to lower the chances of liver damage and complications .

Medicines that you take by mouth include

• entecavir (Baraclude)
• tenofovir alafenamide (Vemlidy)
• tenofovir disoproxil fumarate (Viread)

A medicine that doctors can give as a shot is peginterferon alfa-2a (Pegasys).

The length of treatment varies. Hepatitis B medicines may cause side effects. Talk with your doctor about the side effects of treatment. Tell your doctor before taking any other prescription or over-the-counter medicines.

For safety reasons, you also should talk with your doctor before using dietary supplements , such as vitamins, or any complementary or alternative medicines or medical practices.

If chronic hepatitis B leads to cirrhosis, you should see a doctor who specializes in liver diseases. Doctors can treat the health problems related to cirrhosis with medicines, minor medical procedures, and surgery. If you have cirrhosis, you have an increased chance of liver cancer. Your doctor may order blood tests and an ultrasound or another type of imaging test to check for liver cancer.

If chronic hepatitis B leads to liver failure or liver cancer, you may need a liver transplant.

You can protect yourself from hepatitis B by getting the hepatitis B vaccine . If you have not had the vaccine, you can take steps to reduce your chance of infection.

Hepatitis B vaccine

The hepatitis B vaccine has been available since the 1980s and should be given to newborns, children, and teens in the United States. Adults who are more likely to be infected with hepatitis B or who have chronic liver disease should also get the vaccine. The hepatitis B vaccine is safe for pregnant women.

Doctors most often give the hepatitis B vaccine in three shots over 6 months. You must get all three shots to be fully protected. In some cases, doctors may recommend a different number or timing of vaccine shots.

If you are traveling to countries where hepatitis B is common and you haven’t received the hepatitis B vaccine, talk with your doctor and try to get all the shots before you go. If you don’t have time to get all the shots before you travel, get as many as you can. Even one shot may give you some protection against the virus.

Reduce your chance of infection

You can reduce your chance of hepatitis B infection by

• not sharing drug needles or other drug materials
• wearing gloves if you have to touch another person’s blood or open sores
• making sure your tattoo artist or body piercer uses sterile tools
• not sharing personal items, such as toothbrushes, razors, or nail clippers
• using a latex or polyurethane condom during sex

Prevent infection after contact with the virus

If you think you have been in contact with the hepatitis B virus, see your doctor right away. Doctors typically recommend a dose of the hepatitis B vaccine to prevent infection. In some cases, doctors may also recommend a medicine called hepatitis B immune globulin (HBIG) to help prevent infection. You must get the vaccine dose and, if needed, HBIG shortly after coming into contact with the virus, preferably within 24 hours.

If you have hepatitis B, follow the steps above to avoid spreading the infection . Your sex partners should get a hepatitis B test and, if they aren’t infected, get the hepatitis B vaccine. You can protect others from getting infected by telling your doctor, dentist, and other health care professionals that you have hepatitis B. Don’t donate blood or blood products, semen, organs, or tissue.

Prevent hepatitis B infections in newborns

If you are pregnant and have hepatitis B, talk with your doctor about lowering the risk that the infection will spread to your baby. Your doctor will check your virus levels during pregnancy. If virus levels are high, your doctor may recommend treatment during pregnancy to lower virus levels and reduce the chance that hepatitis B will spread to your baby. Your doctor may refer you to a liver specialist to find out if you need hepatitis B treatment and to check for liver damage.

When it is time to give birth, tell the doctor and staff who deliver your baby that you have hepatitis B. A health care professional should give your baby the hepatitis B vaccine and HBIG right after birth. The vaccine and HBIG will greatly reduce the chance of your baby getting the infection.

If you have hepatitis B, you should eat a balanced, healthy diet. Obesity can increase the chance of nonalcoholic fatty liver disease (NAFLD) , and NAFLD can increase liver damage in people who have hepatitis B. Talk with your doctor about healthy eating and maintaining a healthy weight.

You should also avoid alcohol because it can cause more liver damage.

The NIDDK conducts and supports clinical trials in many diseases and conditions, including liver diseases. The trials look to find new ways to prevent, detect, or treat disease and improve quality of life.

What are clinical trials for hepatitis B?

Clinical trials—and other types of clinical studies —are part of medical research and involve people like you. When you volunteer to take part in a clinical study, you help doctors and researchers learn more about disease and improve health care for people in the future.

Researchers are studying many aspects of hepatitis B, such as

• progression of hepatitis B and long-term outcomes
• new treatments for hepatitis B
• prevention of reactivated or worsening hepatitis B in people receiving cancer treatment

Find out if clinical studies are right for you .

What clinical studies for hepatitis B are looking for participants?

You can view a filtered list of clinical studies on hepatitis B that are federally funded, open, and recruiting at www.ClinicalTrials.gov . You can expand or narrow the list to include clinical studies from industry, universities, and individuals; however, the NIH does not review these studies and cannot ensure they are safe. Always talk with your health care provider before you participate in a clinical study.

How is NIDDK- and NIH-funded research advancing the understanding of hepatitis B?

The NIDDK and the NIH have supported many research projects to learn more about hepatitis B, including the NIDDK’s Hepatitis B Research Network (HBRN) . The HBRN, a network of 28 clinical sites throughout the United States and Canada, studies how hepatitis B affects children and adults and explores new approaches to diagnosis and treatment.

This content is provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Content produced by NIDDK is carefully reviewed by NIDDK scientists and other experts.

The NIDDK would like to thank: Anna Suk-Fong Lok, M.D., University of Michigan

Hepatitis B Information

Summary of 2023 screening and testing recommendations.

• All adults 18 and older at least once in their lifetime using a triple panel test
• Pregnant people during each pregnancy
• People who are at ongoing risk for exposure should be tested periodically
• Anyone who requests HBV testing should be tested

Hepatitis B  is a vaccine-preventable liver infection caused by the hepatitis B virus (HBV). Hepatitis B is spread when blood, semen, or other body fluids from a person infected with the virus enters the body of someone who is not infected. This can happen through sexual contact; sharing needles, syringes, or other drug-injection equipment; or during pregnancy or delivery. Not all people newly infected with HBV have symptoms, but for those that do, symptoms can include fatigue, poor appetite, stomach pain, nausea, and jaundice. For many people, hepatitis B is a short-term illness. For others, it can become a long-term, chronic infection that can lead to serious, even life-threatening health issues like liver disease or liver cancer. Age plays a role in whether hepatitis B will become chronic. The younger a person is when infected with the hepatitis B virus, the greater the chance of developing chronic infection. About 9 in 10 infants who become infected go on to develop life-long, chronic infection. The risk goes down as a child gets older. About one in three children who get infected before age 6 will develop chronic hepatitis B. By contrast, almost all children 6 years and older and adults infected with the hepatitis B virus recover completely and do not develop chronic infection.

The best way to prevent hepatitis B is to get vaccinated. All adults aged 18-59 should receive the vaccine and any adult who requests it may get the vaccine.   All adults 18 years and older should get screened at least once in their lifetime.

• 2023 Screening and Testing Recommendations
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• Hepatitis B

Hepatitis B is a serious liver infection caused by the hepatitis B virus (HBV). For most people, hepatitis B is short term, also called acute, and lasts less than six months. But for others, the infection becomes chronic, meaning it lasts more than six months. Having chronic hepatitis B increases your risk of developing liver failure, liver cancer or cirrhosis — a condition that permanently scars the liver.

Most adults with hepatitis B recover fully, even if their symptoms are severe. Infants and children are more likely to develop a long-lasting hepatitis B infection. This is known as a chronic infection.

A vaccine can prevent hepatitis B, but there's no cure if you have the condition. If you're infected, taking certain precautions can help prevent spreading the virus to others.

Symptoms of acute hepatitis B range from mild to severe. They usually appear about 1 to 4 months after you've been infected, although you could see them as early as two weeks after you're infected. Some people, usually young children, may not have any symptoms.

Hepatitis B signs and symptoms may include:

• Abdominal pain
• Loss of appetite
• Nausea and vomiting
• Weakness and fatigue
• Yellowing of the skin and the whites of the eyes, also called jaundice

When to see a doctor

If you know you've been exposed to hepatitis B, contact your health care provider immediately. A preventive treatment may reduce your risk of infection if you receive the treatment within 24 hours of exposure to the virus.

If you think you have symptoms of hepatitis B, contact your health care provider.

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Hepatitis B infection is caused by the hepatitis B virus (HBV). The virus is passed from person to person through blood, semen or other body fluids. It does not spread by sneezing or coughing.

Common ways that HBV can spread are:

• Sexual contact. You may get hepatitis B if you have unprotected sex with someone who is infected. The virus can pass to you if the person's blood, saliva, semen or vaginal secretions enter your body.
• Sharing of needles. HBV easily spreads through needles and syringes contaminated with infected blood. Sharing IV drug paraphernalia puts you at high risk of hepatitis B.
• Accidental needle sticks. Hepatitis B is a concern for health care workers and anyone else who comes in contact with human blood.
• Mother to child. Pregnant women infected with HBV can pass the virus to their babies during childbirth. However, the newborn can be vaccinated to avoid getting infected in almost all cases. Talk to your provider about being tested for hepatitis B if you are pregnant or want to become pregnant.

Acute vs. chronic hepatitis B

Hepatitis B infection may be short-lived, also called acute. Or it might last a long time, also known as chronic.

• Acute hepatitis B infection lasts less than six months. Your immune system likely can clear acute hepatitis B from your body, and you should recover completely within a few months. Most people who get hepatitis B as adults have an acute infection, but it can lead to chronic infection.
• Chronic hepatitis B infection lasts six months or longer. It lingers because your immune system can't fight off the infection. Chronic hepatitis B infection may last a lifetime, possibly leading to serious illnesses such as cirrhosis and liver cancer. Some people with chronic hepatitis B may have no symptoms at all. Some may have ongoing fatigue and mild symptoms of acute hepatitis.

The younger you are when you get hepatitis B — particularly newborns or children younger than 5 — the higher your risk of the infection becoming chronic. Chronic infection may go undetected for decades until a person becomes seriously ill from liver disease.

Risk factors

Hepatitis B spreads through contact with blood, semen or other body fluids from an infected person. Your risk of hepatitis B infection increases if you:

• Have unprotected sex with multiple sex partners or with someone who's infected with HBV
• Share needles during IV drug use
• Are a man who has sex with other men
• Live with someone who has a chronic HBV infection
• Are an infant born to an infected mother
• Have a job that exposes you to human blood
• Travel to regions with high infection rates of HBV , such as Asia, the Pacific Islands, Africa and Eastern Europe

Complications

Having a chronic HBV infection can lead to serious complications, such as:

• Scarring of the liver (cirrhosis). The inflammation associated with a hepatitis B infection can lead to extensive liver scarring (cirrhosis), which may impair the liver's ability to function.
• Liver cancer. People with chronic hepatitis B infection have an increased risk of liver cancer.
• Liver failure. Acute liver failure is a condition in which the vital functions of the liver shut down. When that occurs, a liver transplant is necessary to stay alive.
• Reactivation of the hepatitis B virus. People with chronic hepatitis B who have suppression of their immune system are prone to reactivation of the hepatitis B virus. This can lead to significant liver damage or even liver failure. This includes people on immunosuppressive medications, such as high-dose corticosteroids or chemotherapy. Before taking these medications, you should be tested for hepatitis B. If you test positive for hepatitis B, you should be seen by a liver specialist (hepatologist) before starting these therapies.
• Other conditions. People with chronic hepatitis B may develop kidney disease or inflammation of blood vessels.

The hepatitis B vaccine is typically given as two injections separated by a month or three or four injections over six months, depending on which vaccine is given. You can't get hepatitis B from the vaccine. The hepatitis B vaccine is recommended by the United States Advisory Committee on Immunization Practices for adults 19 to 59 years of age who do not have a contraindication to the vaccine.

The hepatitis B vaccine is also strongly recommended for:

• Children and adolescents not vaccinated at birth
• Those who work or live in a center for people who are developmentally disabled
• People who live with someone who has hepatitis B
• Health care workers, emergency workers and other people who come into contact with blood
• Anyone who has a sexually transmitted infection, including HIV
• Men who have sex with men
• People who have multiple sexual partners
• Sexual partners of someone who has hepatitis B
• People who inject illegal drugs or share needles and syringes
• People with chronic liver disease
• People with end-stage kidney disease
• Travelers planning to go to an area of the world with a high hepatitis B infection rate

Take precautions to avoid HBV

Other ways to reduce your risk of HBV include:

• Know the HBV status of any sexual partner. Don't engage in unprotected sex unless you're absolutely certain your partner isn't infected with HBV or any other sexually transmitted infection.
• Use a new latex or polyurethane condom every time you have sex if you don't know the health status of your partner. Remember that although condoms can reduce your risk of contracting HBV , they don't eliminate the risk.
• Don't use illegal drugs. If you use illicit drugs, get help to stop. If you can't stop, use a sterile needle each time you inject illicit drugs. Never share needles.
• Be cautious about body piercing and tattooing. If you get a piercing or tattoo, look for a reputable shop. Ask about how the equipment is cleaned. Make sure the employees use sterile needles. If you can't get answers, look for another shop.
• Ask about the hepatitis B vaccine before you travel. If you're traveling to a region where hepatitis B is common, ask your provider about the hepatitis B vaccine in advance. It's usually given in a series of three injections over a six-month period.
• Hepatitis B. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/liver-disease/viral-hepatitis/hepatitis-b. Accessed Aug. 15, 2022.
• Feldman M, et al., eds. Hepatitis B. In: Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 11th ed. Elsevier; 2021. https://www.clinicalkey.com. Accessed Aug. 16, 2022.
• Kellerman RD, et al. Hepatitis A, B, D, and E. In: Conn's Current Therapy 2022. Elsevier; 2022. https://www.clinicalkey.com. Accessed Aug. 16, 2022.
• Lok AS. Hepatitis B virus: Clinical manifestations and natural history. https://www.uptodate.com/contents/search. Accessed Aug. 16, 2022.
• Eng-Kiong T, et al. Epidemiology, transmission, and prevention of hepatitis B virus infection. https://www.uptodate.com/contents/search. Accessed Aug. 16, 2022.
• Picco MF (expert opinion). Mayo Clinic. Aug. 22, 2022.
• Weng MK, et al. Universal hepatitis B vaccination in adults aged 19–59 years: Updated recommendations of the advisory committee on immunization practices — United States, 2022. MMWR [Morbidity and Mortality Weekly Report; Recommendations and Reports; Surveillance Summaries; or Supplements]. 2022; doi:10.15585/mmwr.mm7113a1.

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• Hepatitis: WHO...

Hepatitis: WHO publishes warning over rise in global deaths

• Related content
• Peer review
• Gareth Iacobucci

Urgent action is required to reverse the rising number of global deaths from viral hepatitis, the World Health Organization has warned.

WHO’s 2024 global hepatitis report 1 estimates that 1.3 million people died from viral hepatitis in 2022 compared with 1.1 million in 2019. In 2022, 83% of those deaths were caused by hepatitis B and 17% by hepatitis C.

Despite better tools for diagnosis and treatment and decreasing prices of drugs to treat the disease, testing and treatment coverage rates have stalled, the report said.

WHO said its goal to eliminate the disease by 2030 was still achievable, but only if actions are taken now.

WHO director general Tedros Adhanom Ghebreyesus said, “This report paints a troubling picture: despite progress in preventing hepatitis infections, deaths are rising because far too few people with hepatitis are being diagnosed and treated. WHO is committed to supporting countries to use all the tools at their disposal to save lives and turn this trend around.”

The report, which collected data from 187 countries, estimates that in 2022, 254 million people lived with hepatitis B and 50 million with hepatitis C. The overall incidence of viral hepatitis remains high, although new estimates indicate a slight decrease from 2.5 million new infections in 2019 to 2.2 million in 2022.

WHO said that prevention measures such as immunisation and safer injection practices, along with the expansion of hepatitis C treatment, have likely contributed to reducing the incidence.

Gaps in diagnosis and treatment

Across all regions, only 13% of people with chronic hepatitis B infection had been diagnosed and around 3% (7 million) had received antiviral therapy at the end of 2022. For hepatitis C, 36% had been diagnosed and 20% (12.5 million) had received curative treatment. This is well below global targets to treat 80% of people living with chronic hepatitis B and hepatitis C by 2030, WHO said. But it noted the slight but consistent improvement in diagnosis and treatment coverage since 2019. Specifically, hepatitis B diagnosis increased from 10% to 13% and treatment from 2% to 3%, and hepatitis C diagnosis from 21% to 36% and treatment from 13% to 20%.

The burden of hepatitis varies regionally. The WHO African region bears 63% of new hepatitis B infections, yet only 18% of newborns in the region receive the hepatitis B birth dose vaccination. In the Western Pacific region, which accounts for 47% of hepatitis B deaths, treatment coverage is 23% among people diagnosed, far too low to reduce mortality.

Nearly two thirds of the global burden of hepatitis B and C is concentrated in 10 countries: Bangladesh, China, Ethiopia, India, Indonesia, Nigeria, Pakistan, the Philippines, the Russian Federation, and Vietnam. WHO said achieving universal access to prevention, diagnosis, and treatment in these countries by 2025, alongside intensified efforts in the African region, is essential to get the global response back on track.

Despite affordable generic viral hepatitis drugs being available, many countries are failing to procure them at lower prices and are paying above global benchmarks, even for off-patent drugs or when included in voluntary licensing agreements, WHO said.

Service delivery remains centralised, and only 60% of reporting countries offer free viral hepatitis testing and treatment services in the public sector, WHO added.

The report’s key recommendations for accelerating hepatitis elimination include expanding access to testing and diagnostics and strengthening prevention in primary care. Focus is also required to simplify service delivery, optimise product regulation and supply, and advance research for improved diagnostics and potential cures for hepatitis B, it added.

Current topics in hepatitis B

Affiliation.

• 1 Academic Centre for Travel Medicine and Vaccines, WHO Collaborating Centre for Reference and Research on Viral Diseases, Royal Free Campus, Royal Free and University College Medical School, London NW3 2PF, UK.
• PMID: 11023756
• DOI: 10.1053/jinf.2000.0720

Over two billion people around the world have been infected with hepatitis B virus, of whom over 350 million are chronic carriers. Some 25% of carriers develop progressive liver disease. The annual mortality from hepatitis B infection and its sequelae is 1-2 million people worldwide.The following current topics are reviewed: immunization strategies against hepatitis B and the kinetics and antibody response; the controversy on screening blood donors for anti-core antibodies; mutations of hepatitis B surface antigen, including evidence that not all such mutants are detectable by current laboratory tests and, finally, the introduction of second generation nucleoside analogues for treatment of chronic hepatitis B infection, including treatment of patients with decompensated liver disease and liver transplantation.

Copyright 2000 The British Infection Society.

Publication types

• Antiviral Agents / therapeutic use
• Blood Donors
• Hepatitis B Antibodies / blood
• Hepatitis B Antibodies / immunology
• Hepatitis B Surface Antigens / genetics
• Hepatitis B Vaccines* / immunology
• Hepatitis B* / diagnosis
• Hepatitis B* / immunology
• Hepatitis B* / therapy
• Interferon-alpha / therapeutic use
• Lamivudine / therapeutic use
• Reverse Transcriptase Inhibitors / therapeutic use
• Antiviral Agents
• Hepatitis B Antibodies
• Hepatitis B Surface Antigens
• Hepatitis B Vaccines
• Interferon-alpha
• Reverse Transcriptase Inhibitors

Hepatitis killing thousands daily, WHO warns in new report

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The number of lives lost due to viral hepatitis infections is increasing and already accounts for 3,500 deaths daily, according to a report by the World Health Organization (WHO) released on Tuesday.

The disease is the second leading infectious cause of death globally, with 1.3 million deaths per year, the same as tuberculosis, another top infectious killer, according to the World Health Organization ( WHO ) 2024 Global Hepatitis Report.

“This report paints a troubling picture,” said WHO Director-General Tedros Adhanom Ghebreyesus. “Despite progress globally in preventing hepatitis infections, deaths are rising because far too few people with hepatitis are being diagnosed and treated .”

Swift course correction

Even though better tools for diagnosis and treatment are available and product prices are decreasing, testing and treatment coverage rates have stalled, the UN health agency stated in the report, released at the World Hepatitis Summit.

But, reaching the WHO elimination goal by 2030 should still be achievable, if swift action is taken now, the agency said.

“ WHO is committed to supporting countries to use all the tools at their disposal – at access prices – to save lives and turn this trend around ,” the UN health agency chief said.

Spike in deaths

More than 6,000 people are getting newly infected with viral hepatitis each day, according to the report.

New data from 187 countries show that the estimated number of deaths from viral hepatitis increased from 1.1 million in 2019 to 1.3 million in 2022 . Of these, 83 per cent were caused by hepatitis B and 17 per cent by hepatitis C. 

Updated WHO estimates indicate that 254 million people live with hepatitis B and 50 million with hepatitis C in 2022. Half the burden of chronic hepatitis B and C infections is among people 30 and 54 years old, with 12 per cent among children. Men account for 58 per cent of all cases.

Gaps in diagnosis and treatment 

Across all regions, only 13 per cent of people living with chronic hepatitis B infection had been diagnosed and approximately three per cent, or seven million, had received antiviral therapy at the end of 2022, falling far below global targets to treat 80 per cent of people living with chronic hepatitis B and hepatitis C by 2030.

The burden of viral hepatitis also varies regionally. The WHO African Region bears 63 per cent of new hepatitis B infections, yet despite this burden, only 18 per cent of newborns in the region receive the hepatitis B birth-dose vaccination.

In the western Pacific region, which accounts for 47 per cent of hepatitis B deaths, treatment coverage stands at 23 per cent among people diagnosed, which is far too low to reduce mortality.

In addition, despite the availability of affordable generic viral hepatitis medicines, many countries fail to procure them at these lower prices.

Eradicating the epidemic

The WHO report outlines a series of actions to advance a public health approach to viral hepatitis, designed to accelerate progress towards ending the epidemic by 2030.

They include expanding access to testing and diagnostics , strengthening primary care prevention efforts and shifting from policies to implementation for equitable treatment.

But funding remains a challenge , the agency said, with current levels insufficient to meet the needs.

WHO said this arises from a combination of factors, including limited awareness of cost-saving interventions and tools and competing health priorities.

The new report also highlights strategies for countries to address these inequities and access the tools at the most affordable prices available.

SDG 3: HEALTHIER GLOBAL POPULATION

• Promote mental health and wellbeing and strengthen the prevention and treatment of substance abuse
• Reduce the number of deaths and illnesses from pollution, contamination and tobacco
• Achieve universal health coverage and provide access to affordable, essential vaccines and medicines
• Reduce global maternal mortality rate to less than 70 per 100,000 live births and under-five mortality to at least 25 per 1,000 live births
• End epidemics of AIDS, tuberculosis and malaria and combat hepatitis and other communicable diseases

Sustainable development hinges on ensuring healthy lives and promoting wellbeing at all ages.

• Open access
• Published: 18 April 2024

A care coordination program to support patients with hepatitis B virus at Kaiser Permanente Mid-Atlantic States

• M. Cabell Jonas 1 ,
• Yi-Shin Sheu 1 ,
• Kara Wright 1 ,
• Lauren Peyton 1 ,
• R. Clayton Bishop 1 ,
• Sundeep Basra 1 ,
• Fariha Sarwar 1 ,
• Grace Winn 1 &
• Karen Chesbrough 1  

BMC Health Services Research volume  24 , Article number:  482 ( 2024 ) Cite this article

Metrics details

Eliminating hepatitis B virus (HBV) is a significant worldwide challenge requiring innovative approaches for vaccination, screening, disease management, and the prevention of related conditions. Programs that support patients in accessing needed clinical services can help optimize access to preventive services and treatment resources for hepatitis B.

Here, we outline a coordinator-supported program (HBV Pathway) that connects patients infected with HBV to laboratory testing, imaging, and specialty care for treatment initiation and/or liver cancer surveillance (screening of high-risk patients for liver cancer). This study describes the HBV Pathway steps and reports sociodemographic factors of patients by initiation and completion.

Results showed a 72.5% completion rate (defined as completing all Pathway steps including the final specialty visit) among patients who initiated the Pathway. Differences in completion were observed by age, race, ethnicity, and service area, with higher rates for younger ages, Asian race, non-Hispanic ethnicity, and lower rates for patients within one service area. Of those who completed the specialty visit, 59.5% were referred for hepatocellular carcinoma surveillance.

Conclusions

The HBV Pathway offers dual benefits– care coordination support for patients to promote Pathway completion and a standardized testing and referral program to reduce physician burden. This program provides an easy and reliable process for patients and physicians to obtain updated clinical information and initiate treatment and/or liver cancer screening if needed.

Peer Review reports

Hepatitis B is a vaccine-preventable infection of the liver which impacts > 880,000 people within the United States and 296 million people worldwide [ 1 ]. The hepatitis B virus (HBV) can be transmitted perinatally, through blood-to-blood contact (e.g., shared injection equipment, non-sterile tattooing or piercing, needlestick exposures, sharing of razors and toothbrushes), and through contact with sexual fluids [ 2 , 3 ]. HBV infection can be acute or chronic; age at the time of infection impacts the disease progression, with individuals infected at a younger age more likely to develop chronic HBV (CHB) and individuals infected as adults more likely to develop and recover from acute HBV [ 1 ]. There is currently no cure for CHB, however treatment is available.

The HBV vaccine was made available in the early 1980s, and global vaccination rates have continued to rise [ 4 ]. Within the US, the HBV vaccination series is initiated at birth with > 90% coverage among 1-year-olds [ 5 ]. Individuals born outside of the US in a country with medium-to-high prevalence of HBV (Asian countries, Pacific Islands, most countries in Africa) are at increased risk of HBV infection [ 6 , 7 ]. Most of these individuals contracted HBV perinatally and some may be unaware of their infection or unaware of the ongoing health risks related to CHB [ 8 , 9 , 10 ].

CHB and chronic hepatitis C virus (HCV) infection are major risk factors for developing cirrhosis and/or liver cancer—including hepatocellular carcinoma (HCC) which accounts for 75–85% of liver cancer cases [ 11 , 12 ]. HCC is the 6th leading cause of cancer death in the US, and the 3rd leading cause of cancer deaths worldwide [ 13 , 14 ]. HCC mortality is highly related to the timing of cancer detection and available treatments; patients diagnosed early have more treatment options—including liver transplant—and higher survival rates, while patients diagnosed with advanced HCC have very low survival rates [ 15 , 16 ]. Therefore, once the HBV infection is diagnosed, monitoring viral load, initiating or continuing treatment, and monitoring for associated conditions such as cirrhosis and/or HCC are critical components of comprehensive CHB patient care [ 17 ]. One study showed that, of patients who developed HCC, surveillance was underused in over 80% [ 18 ]. Another study demonstrated that fewer than one-fourth of patients with cirrhosis are completing HCC surveillance [ 19 ].

The World Health Organization has set 2030 as the target year for eliminating HBV, as defined by reducing new infections by 90% and reducing deaths by 65% [ 20 ]. Strategies to eliminate HBV are wide in scope and include, but are not limited to, promoting vaccination, ensuring accurate HBV testing (at the screening and management phases), and managing the disease burden in individuals living with CHB (including ongoing care, treatment as appropriate, and HCC surveillance) [ 21 , 22 ].

Generally, HBV care cascades include a multistep diagnostic testing process, imaging, the option for treatment, and ongoing monitoring, which presents a risk of patient loss to follow up at each step [ 23 , 24 ]. The literature suggests improvements to HBV testing and care cascades, including originating testing in primary care, simplified yet comprehensive laboratory testing, optimized monitoring (such as for liver cancer), and connecting patients more seamlessly with treatment [ 25 , 26 ]. Increasing access to testing, monitoring, and treatment may reduce disparities [ 27 ]. We sought to explore whether a coordinator-supported care cascade, a model used for HCV and HIV care, could close gaps in the HBV care cascade [ 28 , 29 , 30 , 31 ]. Coordinator-supported programs are effective means of closing care gaps in infectious disease care– including testing pathways and ongoing chronic disease management [ 31 , 32 , 33 , 34 ]. Our own organizational experience demonstrated that a coordinator-supported program, implemented for HCV testing, resulted in more patients completing the required multi-step testing process, in less time, compared to a non-coordinator-supported usual care process [ 31 , 33 ]. Our HCV testing program also included tests for HBV and HIV, common co-infections. Additionally, patients within the coordinator-supported HCV program accessed curative medication in less time than the usual care group [ 31 ]. Our successful HCV screening and triage-to-treatment care coordination program served as a model for the HBV Pathway program described here.

In 2018, Kaiser Permanente Mid-Atlantic States (KPMAS) launched a new coordinator-supported program that is responsive to the key strategies identified for HBV elimination. The HBV Pathway program described here focuses on supporting patients infected with HBV— ensuring patients are aware of their health status related to HBV infection and are connected to treatment and ongoing cancer monitoring, as recommended by their physician. This care coordination approach, outlined within, is designed to effectively address the unique clinical needs of patients infected with HBV, as well as provide ongoing support for related conditions.

Study population

Kaiser Permanente Mid-Atlantic States (Kaiser Foundation Health Plan and the Mid-Atlantic Permanente Medical Group; KPMAS) is an integrated care delivery system serving over 825,000 members in the District of Columbia, Maryland, and Virginia. The delivery system is grouped by geography into three service areas. Service area results are blinded and noted as service areas A, B, and C. These service areas are administrative groupings of clinics by general location across the entire region. The service areas differ by the number of Kaiser Permanente insurance enrollees (referred to as members). The HBV Pathway team includes an executive physician sponsor, a director/researcher, and two research nurse coordinators working part time on this program. KPMAS uses the EPIC-based KP HealthConnect electronic medical record.

HBV pathway order

The HBV Pathway is a research nurse coordinator-supported testing program for adults age 18 + with an acute or chronic HBV infection. The program includes a standardized outreach and testing process and streamlined specialty referrals to the gastroenterology or infectious disease departments. All physicians can place the unique HBV Pathway testing order (“REFERRAL GI, HBV PATHWAY, CHART REVIEW”) on any eligible patient. Eligible patients include those new to Kaiser Permanente (newly insured) with an existing diagnosis of CHB who require updated laboratory testing and imaging, patients who have fallen out of care and require updated laboratory testing and imaging, patients who are unclear on their vaccination or infection status, patients considering HBV treatment, and other clinical situations where the physician would like updated HBV laboratory testing and imaging.

HBV pathway laboratory testing and imaging

Physicians place one HBV Pathway order that starts the HBV Pathway for a patient. This order authorizes coordinators to input all standard laboratory tests, imaging exams, and specialty referrals (Fig.  1 ). The order includes authorization for laboratory testing [Hepatitis B Surface Antigen (HBsAg) with reflex to confirmation, Hepatitis B Core Antibody (anti-HBc), Hepatitis B e-antigen (HBeAg), Hepatitis B e-antibody (anti-HBe), Hepatitis B Virus DNA, Hepatitis A IgG, HIV Screen (HIV1 Antigen, HIV 1 & 2 Antibodies), Hepatic Function Panel (ALB, TBILI, DBILI, ALKP, TPROT, ALT, AST), Complete Blood Count no differential, CHEM 7, PT and INR] and right upper quadrant abdominal ultrasound. Patients with laboratory results within the lookback period do not have those laboratory tests repeated. Patients with imaging studies completed within one year do not have imaging repeated. The HBV Pathway order includes patient instructions and coordinator contact information. The coordinators conduct chart review for patients with the HBV Pathway order. In the initial Coordinator Telephone Visit, coordinators explain the HBV Pathway program, order laboratory tests and schedule imaging exams. Outreach to patients at this step includes three patient phone calls, and a patient portal message or letter. If patients are unreachable to place laboratory orders and schedule imaging, the coordinator may also reach out to the physician for support in contacting the patient.

HBV pathway overview

Specialty visit

Once the laboratory tests and imaging orders have been placed, coordinators outreach to patients who miss the imaging appointment date and/or patients who do not complete the laboratory tests. After laboratory tests and imaging are complete, the coordinators call patients to schedule a specialty visit with either the gastroenterology or infectious disease departments. In some service areas, the onsite departmental team supports the scheduling of this visit. Coordinators outreach to patients with an additional three patient phone calls, and patient portal message or letter until the scheduling of this visit is complete. The patient receives reminders of the specialty visit date from the health system, electronically and via text (if patient is opted in). Specialists complete a phone, video, or in-person visit using a standard EMR-based note that includes prompts to update the patient about their clinical status, update the HBV diagnosis within the medical record, discuss HBV treatment, and order HCC surveillance (screening of high-risk patients for liver cancer) for eligible patients. Patients with an HCC surveillance order start a separate HCC surveillance program managed by the same research nurse coordinators (not described in detail here but shown in Fig.  2 ). Patients who miss the specialty appointment are contacted by the departmental team and/or the coordinators to reschedule.

Completed steps for HBV Pathway participants. Shown is each step of the HBV Pathway with the number of participants that completed or did not complete each step and the percentage from each prior completed step. Gray boxes indicate HBV Pathway steps completed by the physician. Blue boxes indicate HBV Pathway steps completed by the research nurse coordinator. Columns on the right show the number of participants from each service area that did not complete each step and the percentage of the service area’s total Did Not Complete Pathway population

Support staff: research nurse coordinators

Throughout the HBV Pathway, two research nurse coordinators provide telephonic care coordination support for patients across the KPMAS region. This includes initial outreach telephone calls to place laboratory and imaging orders, reminder calls to complete laboratory tests and imaging, and, after tests/imaging are complete, follow-up telephone calls to schedule specialty visits. Coordinators conduct a chart review of all patients with the HBV Pathway ordered. During this chart review, coordinators can assess eligibility for the program. Coordinators also review the chart for existing laboratory test results and for imaging completed within one year. When laboratory test results are within the standard lookback period automatically set within the medical record, or if imaging is less than or equal to one year old, the patient can proceed with only completing the remaining tests. Coordinators place all laboratory and imaging exam orders as part of the approved testing protocol.

Coordinators have standard actions for managing laboratory testing results, however coordinators do not communicate HBV testing results to patients. Coordinators refer patients in need of HBV vaccination to primary care. For patients who are excluded at any point during the process, coordinators use standardized text for the patient communication and chart documentation. Completing the specialty visit is considered the final step of the HBV Pathway. However, specialists may refer patients into a companion program supported by the same coordinators for HCC surveillance. This HCC surveillance program is a distinct program, initiated through a separate, unique order. The HCC surveillance program, which continuously screens high-risk patients for liver cancer, includes patients from the HBV Pathway, as well as patients with other liver cancer risk factors (such as cirrhosis due to HCV). These programs were intentionally structured so patients from the HBV Pathway, HCV Pathway, or for other clinical reasons could coalesce into one HCC surveillance program for care (Fig.  1 ).

HBV pathway analysis

Analysis of the HBV Pathway program included adult patients aged 18 years or older whose provider placed a single, uncancelled HBV Pathway order (“REFERRAL GI, HBV PATHWAY, CHART REVIEW”) between March 1, 2018 and July 31, 2022 (Table  1 ). Each step of the program was evaluated to assess completion, and to identify reasons patients did not complete a given program step (Figs.  1 and 2 ).

We examined coordinator actions within the EPIC-based KP HealthConnect electronic health record, including visit reasons and unique smartphrases to assess completion of the Coordinator Chart Review and Coordinator Telephone Visit steps. Next, we examined completion of the HBV diagnostic tests, which include HBsAg with reflex to confirmation, anti-HBc, HBeAg, anti-HBe, hepatitis B virus DNA, hepatitis A IgG, HIV screen (HIV1 antigen, HIV1 & 2 antibodies), hepatic function panel (ALB, TBILI, DBILI, ALKP, TPROT, ALT, AST), complete blood count no differential, CHEM 7, PT, and INR, and right upper quadrant abdominal ultrasound. The completion of the laboratory tests was determined by a record of the laboratory tests being completed within the study timeframe. The completion of imaging was determined by a record of the imaging being completed within the study timeframe or within one year prior to the HBV Pathway order being placed. The completion of a specialty visit was determined by whether the patient completed an office, telephone, or video-based visit with a Gastroenterologist or an Infectious Disease physician. Referral to the HCC surveillance program was assessed using the unique order code: “INITIATE HEPATOCELLULAR CARCINOMA SURVEILLANCE TREAT-TO-TARGET PROTOCOL FOR COORDINATOR SUPPORT” (Fig.  1 ). We used insurance status, review of unique smartphrases, and chart review to identify reasons patients left or were excluded from the HBV Pathway. Patients were classified into categories of reasons for not completing the pathway (Fig.  2 ). Patients could fall into multiple categories but were counted only within the first relevant category. Categories are listed sequentially as a patient moved through the program.

Patient characteristics were compared between the Pathway completion group versus the Pathway non-completion group (with completion defined as completing all steps including the final specialty visit). Chi-squared statistics were used to compare categorical variables such as sex, primary language usage (English/Non-English), patient primary service area, race, and ethnicity. Two-sample t-test was used to assess whether there is a significant age difference between the completion/non-completion groups.

Sociodemographic characteristics of HBV pathway participants

From March 1, 2018 — July 31, 2022, 1,868 patients had an HBV Pathway order placed (Table  1 ). 72.3% ( n  = 1,351) of patients completed the HBV Pathway (as defined by completing a specialty visit), and 27.7% ( n  = 517) did not complete the pathway. Patients who initiated the HBV Pathway were nearly evenly divided by administrative sex (female 49.9%, male 50.1%). Most patients were Black (51.4%; n  = 961) or Asian (38.5%; n  = 720). Most (77.4%; n  = 1,445) were of non-Hispanic ethnicity. The highest percentage of patients who initiated the HBV Pathway were aged 36–45 (27.6%; n  = 516), and listed English as their preferred language (79.8%; n  = 1,488). Most patients primarily received care from service area A (51.6%; n  = 963), followed by service area B (37%; n  = 692), and service area C (11.4%; n  = 213).

Characteristics of patients completing the HBV pathway

Table  1 outlines the characteristics of patients who initiated, completed, and did not complete the HBV Pathway. We saw significant differences in the ratio of Pathway completion to non-completion by age, race, ethnicity, and service area. Results show a small, but statistically significant, difference in the mean age of patients completing the Pathway, with younger patients more commonly completing the Pathway (independent t-test statistic = -2.103, p  = 0.035). We also saw significant differences in the ratio of completion to non-completion by race (Black, Asian, and White, χ2 (2, n  = 1,868) = 7.94, p  = 0.018). Post-hoc analysis of pairwise comparisons between the three groups showed significant differences between the Asian and White groups (χ2 = 6.73, corrected p  = 0.028) with the Asian group showing higher completion rate (75.42%) compared to the White group (63.46%); no significant differences were found between the White and Black, or Black and Asian group pairs. Significant differences were noted by ethnicity (Hispanic, Non-Hispanic, and Unknown, χ2 (2, n  = 1,868) = 24.36, p  < 0.001). Post-hoc analysis of pairwise comparisons between the three groups showed significant differences between Non-Hispanic and Unknown (χ2 = 22.32, corrected p  < 0.001) with Non-Hispanic showing higher completion rate (75.09%) compared to Unknown (62.74%); no significant differences were found between Hispanic and Non-Hispanic, or Hispanic and Unknown group pairs. We saw significant differences in the ratio of Pathway completion to non-completion by service area (χ2 (2, n  = 1,868) = 28.951, two-tailed test p  = 0.000). Post-hoc analysis of pairwise comparisons between the three service area groups showed significant differences between service area A and C (χ2 = 25.46, corrected p  < 0.001) and service area B and C (χ2 = 24.64, corrected p  < 0.05) with service area C showing lower overall completion rate (56.81%) compared to service area A (74.14%) and service area B (74.57%); no significant differences were reported between service area A and B. No significant differences in the ratio of Pathway completion to non-completion were seen by sex or preferred language.

Program performance

The HBV Pathway order was placed for 1,868 patients during the timeframe studied. 1,865 (> 99%) of patients were chart reviewed by the coordinator team and progressed to the telephone visit. 98% ( n  = 1,829) completed the telephone visit and 94% ( n  = 1,763) completed the recommended laboratory tests and imaging exams. 72% ( n  = 1,351) completed a specialty visit with either a gastroenterologist or infectious disease physician, which is considered the final step of the HBV Pathway program (Fig.  1 ). Of the 1,351 who completed a specialty visit, 56% ( n  = 804) were referred for HCC surveillance (43% of total patients who initiated the HBV Pathway). HCC surveillance is a distinct program, accessed by a separate, unique order that can accept patients for a variety of clinically relevant reasons including CHB, cirrhosis due to HCV, and other clinical situations (Fig.  1 ).

During the study timeframe, a total of 517 patients (28%) did not complete the HBV Pathway; completion was defined as completing the specialty visit. Patients were classified only according to the first sequential reason for not completing the Pathway—in total and by service area (Fig.  2 ). The service areas had different distributions of patients who Did Not Complete the Pathway by step (Fig.  2 ); the highest percentage not completing a step occurred at the Specialty Visit. The reasons for patients not completing the Pathway are classified in Table  2 –in total and by service area. The two most common reasons for not completing the HBV Pathway were exclusion due to HBV immunity/disqualifying medical history and patients who did not answer the coordinator outreach (Outreach Unanswered). HBV immunity included patients who had been vaccinated for HBV (HBsAb+) and patients previously infected with recovery (HBsAb+, antiHBc+, HBsAg-). Patients with a disqualifying medical history included those with HCV mistakenly referred to the HBV Pathway, those with HIV who are referred directly to infectious disease, and those with other medical priorities (ex., active cancer). Although these groups were not suitable for continuation through the HBV Pathway, excluding these individuals required coordinator effort through chart review or laboratory testing—and thus the study team wanted to capture and report on these groups (see Discussion for additional commentary).

The HBV Pathway program described here is a care coordination program that supports physicians in obtaining up-to-date laboratory testing and imaging results for patients with HBV infection. Patients who complete the HBV Pathway obtain the necessary laboratory testing and imaging required to manage their disease, are connected with a physician specialist to guide treatment, and if advised by their physician, are connected with an HCC surveillance program for ongoing cancer screening. Within the timeframe examined, 72% of patients who initiated the coordinator-supported HBV Pathway completed the program. The integrity of completing the steps within the program was high—of those patients who did not complete the HBV Pathway, 97% were due to reasons not directly related to care coordinator/care coordination activities (Table  2 ). Although the HBV Pathway program ended at the specialty referral, of the patients who were connected with a specialist for assessment, 59.5% were triaged into ongoing HCC surveillance.

The HBV Pathway is not a screening program. At Kaiser Permanente Mid-Atlantic States, HBV screening is already covered by existing order sets accessible to all physicians, including HBV reflex panel testing, sexually transmitted infection screening, order sets for related infectious diseases (ex. HBV screening is part of the HCV screening pathway), and order sets for pregnant individuals. The HBV Pathway program described here aims to close a different gap in care, specifically helping patients with HBV infections and their physicians remain up-to-date on the patient’s clinical status, including assessment for HBV treatment and/or liver cancer surveillance. A secondary goal was to reduce the burden on physicians for HBV testing, imaging, and clinical visits.

Focusing on currently diagnosed patients offered the opportunity to link these patients to services in a reliable way that optimized physician time. In a usual care process, primary care physicians must order and track all the relevant laboratory tests and imaging, then may chart review to gastroenterology for support in deciding next steps (treatment, surveillance). This is time-consuming and creates opportunities for patients to fall out of care. In contrast to usual care, the HBV Pathway offers a standard process that is supported by dedicated staff. Physicians can order the HBV Pathway for a variety of patients including those new to Kaiser Permanente with a stated history of HBV, patients who are unclear on their vaccination or infection status, patients who were engaged in HBV care but had fallen out of care, patients with CHB who require updated laboratory test and imaging, patients seeking treatment, and others. As a result, coordinators receive patient charts and laboratory results associated with a variety of clinical situations including vaccinated/unvaccinated, acute infection, HBV immunity from prior infection, or chronic infection. The program is equipped to handle this variety of clinical situations. Even for patients who initiate the Pathway but are excluded due to immunity, there is still value in updating their charts to reflect an accurate clinical situation, especially if the chart documentation incorrectly indicated an HBV infection. Through this standard Pathway, the burden on the ordering physician is lifted– as coordinators place the standard laboratory set, imaging, and specialty visit on their behalf. Similar to the HCV Pathway [ 31 , 35 ], the HBV Pathway ensures that patients receive an accurate laboratory testing and imaging workup prior to the specialty visit, which saves specialist time within the visit and limits unnecessary visits (to the laboratory or a physician) for the patient.

A major goal of the HBV Pathway was ensuring patients have the correct laboratory and imaging orders submitted and completed. The chart review step enables coordinators to look for imaging completed within the past year, which saves system resources and avoids unnecessary testing. Our results showed the first three coordinator-led steps of the process (Chart Review, Telephone Visit, Tests Completed) were completed > 95% of the time for eligible patients (Fig.  2 ). Results demonstrate that patients are willing to complete the initial coordinator telephone call (98.1% completed). Patients are also highly compliant with completing the laboratory tests and imaging (96.4% completed) which demonstrates that most patients are willing to expend time and effort on managing care related to an HBV infection. The step with the highest drop-off of patients was the specialty visit (76.6% Completed, 23.4% Did Not Complete). This finding was consistent across service areas, with service area C having the highest percentage of patients not completing this step. The project team has begun to explore whether there were implementation barriers in service area C that the program was unaware of, or other factors that may be relevant to other providers seeking to replicate this program in their own health care delivery setting. The differences seen in service areas regarding completion of the specialty visit was somewhat surprising because the specialty visit is primarily conducted via telephone, which is a more convenient option for the patient. Cost burden should not be an issue, as telephone visits have no co-pay or cost share. This is also the step at which specialists convey the HBV test results and next steps for treatment or ongoing monitoring. Language translators are available, and our results showed no differences in completion by language. There are some operational nuances that may have impacted this result. First, some physician cell phone numbers do not show caller ID from Kaiser Permanente, which could result in a patient declining the call from an unknown number. Second, the coordinators did not send individualized reminders in advance of the specialty visit, since patients already receive health system-driven reminders through the patient portal, phone and/or text (if patient is opted in). As a result of this study finding, coordinators are now sending a welcome letter describing the HBV Pathway program and reinforcing the importance of completing the specialty visit. Coordinators are also sending reminder messages for the specialty visit appointment, which are additive to the health system reminders patients already receive. The differences in completing the Specialty Visit seen by service area may be due to many factors, including patient, physician, and system-level factors, and will be explored further in future work.

As outlined in Table  2 , patients without the need to progress through the HBV Pathway are excluded at the relevant Pathway step. Patients with HBV immunity or disqualifying medical history made up 39% of excluded patients—11% of the total patients who began the HBV Pathway. These patients were notified that they did not require additional testing to confirm their clinical situation and would not continue through the Pathway program. The ordering physician updated the chart accordingly. We chose to report these patients as “Did Not Complete Pathway” versus “Completed Pathway” because they did not progress through the Pathway steps as intended. However, we felt it was valuable to report on this population for two main reasons. First, this group demonstrates the uncertainty that patients may have about an HBV infection and/or vaccination status. Clarifying a CHB diagnosis or vaccination status is valuable to both the patients and the physician. Second, confirming patient immunity, through chart review or laboratory testing, and notifying patients of their status requires coordinator time and effort. Similarly, chart reviewing to identify a disqualifying medical history also requires coordinator time (disqualifying medical history includes diagnoses such as HCV or HIV which are managed through other programs). Given that our program can serve as a model for other institutions seeking to implement similar programs, we felt it was important to report on the total number of patients that engaged with the Pathway and the total amount of coordinator effort involved. 36% of excluded patients began the Pathway program but fell out of touch before completing the specialty visit (Outreach Unanswered). In these cases, coordinators sent three messages and a letter to the patient with contact information if the patient wishes to ever re-engage the care team. Because the Outreach Unanswered group made up > 36% of the total who did not complete the program, providers seeking to implement this program should pay particular attention to the cadence and type of outreach and number of reminders required to maximize patient responses. In several cases, patient circumstances led to removal from the HBV Pathway including patients who declined to participate, died, or lost Kaiser Permanente insurance. Occasionally (2%), patients requested to pursue the testing program later (Patient Temporarily on Hold) to accommodate international travel or other personal circumstances. Interestingly, 6% of the patients excluded were due to physicians placing the HBV Pathway order by mistake. In most cases, these physicians were seeking the HCC surveillance order to initiate liver cancer screening or the hepatitis C virus screening pathway. The coordinators connected these physicians with the HCC program or HCV program directly. The HBV Pathway project team provides ongoing education about the various liver programs within KPMAS through CMEs and direct communication with physician leaders and departments. For 6% of excluded patients (1.6% of total patients) our analysis revealed the coordinators had incomplete follow-up with the patient. This was most often due to administrative errors with the patient tracking dashboards. As a result of this finding, the team has conducted troubleshooting exercises to identify the root causes of errors and has contacted the affected patients to re-engage them in care. We saw differences in the distribution of reasons patients did not complete the HBV Pathway by service area. Because service areas are simply administrative groupings of clinics which are unique to our health system, these differences simply serve to illustrate the variability that others may face within their own implementation of such a program. The project team intends to follow up to explore potential patient, provider and system level barriers that may be contributing to these results.

The patients who initiated, completed, and did not complete the HBV Pathway differed by age, race, ethnicity, and service area. As discussed above, service area C had the highest percentage not completing the program, primarily driven by patients not completing the specialty visit step. This finding may be due to patient, physician, or system level barriers which will be explored further but were beyond the scope of this initial manuscript. Patients who initiated the program had a mean age of 45.90 ± 13.41 years, which is squarely within the age range of individuals with the highest rates of HBV infection in the US [ 36 ]. This result was reassuring as it indicates that our program is reaching the target group of patients with HBV infections. The ratio of Pathway completion to non-completion also differed by race, with significant differences seen between Asian and White patients, with Asian patients having higher completion. Because the rates of CHB are higher among Asian patients [ 37 ], it is reassuring that Asian patients are effectively completing the HBV Pathway program. This higher completion may be due to more awareness of HBV among Asian patients or perceived value of obtaining testing, treatment, and/or liver cancer surveillance. A difference was also seen by ethnicity, with Non-Hispanic individuals showing higher completion rates than Unknown ethnicity—more exploration is required to pinpoint drivers of this difference. It is important to note that no difference was seen between Hispanic and Non-Hispanic patients or between Black and White patients, which provides evidence that no disparities exist for these groups within the HBV Pathway program. We also saw no differences by language—indicating a non-English preferred language confers no disadvantage when it comes to program completion. To avoid creating disparities and encourage equitable completion across all racial groups, coordinators should be aware of the racial differences in completion and openly encourage all patients to disclose potential barriers.

Our program is available to patients across the KPMAS service region, which includes Washington, D.C., Maryland (including greater Baltimore), and Northern Virginia. The HBV Pathway coordinators provide telephone-based care to all patients across the region using a standardized approach. Each service area has clinics that include laboratories, radiology departments, and physician specialists. Although not explored in this specific project, availability of specialty telephone visits is generally similar across service areas. Our analysis found significant differences in the ratio of Pathway completion to non-completion by service area– with the one service area (service area C) showing a lower completion rate (56.81%) compared to service area A (74.14%) and service area B (74.57%). Further analysis showed that most patients in service area C that did not complete the HBV Pathway dropped out at the Specialty Visit step (Fig.  2 ). Interestingly, compared to the other service areas, service area C lost fewer patients at the Coordinator Telephone Visit and the Tests Complete steps. Future research will focus on understanding the characteristics of patients in service area C, and further exploration of other possible barriers (such as cost concerns, time constraints), and further analysis of the specialty visit (assessing no show rates and other barriers to the specialty visit) to determine what is driving this difference. As mentioned above, service areas are administrative groupings of clinics and this data is most helpful in demonstrating the type of variability in completion, by step and reason, providers may encounter when implementing such a program in a large geographic area.

There are some limitations to this work. This project explored patients who initiated, completed, and did not complete the HBV Pathway. Future analysis will focus on comparing the HBV Pathway to usual care in terms of comprehensive HBV testing, triage to specialty care, and liver cancer surveillance initiation. The analysis shown here did not include information on percentage of patients referred for HBV treatment, treatment adherence, or compliance with ongoing laboratory or imaging monitoring. Examining this additional information would offer insight into a complete care cascade.

Future directions will focus on a formal evaluation of the related but distinct coordinator-supported HCC surveillance program, including program description, patient demographics, patient compliance with screening, and outcomes. Because significant differences in completion by service area were found, follow-up work will investigate this in more detail, such as exploring sociodemographic differences between the groups and conducting stakeholder interviews to assess reasons for Pathway non-completion at various steps. Future work will also explore the two largest Did Not Complete Pathway groups (Outreach Unanswered, HBV Immunity/Disqualifying Medical History) in more detail with a purpose to identify ways to reduce the Outreach Unanswered group. In the future, the HBV Pathway program could easily be adapted for other purposes, for example to accommodate universal screening for HBV or offer follow-up testing for newly diagnosed patients [ 38 ]. The HBV Pathway was intentionally modeled after the KPMAS HCV Pathway which was easily expanded to accommodate a much wider age range for screening.

Multiple strategies to improve HBV screening, treatment, and ongoing disease management are required to meet the World Health Organization goal of eliminating HBV by 2030. Within the US, great strides have been made with perinatal vaccination as a key prevention step. Equally focused efforts must be made to ensure patients affected by HBV infection are aware of their health status, can access treatment if indicated, and are reliably monitored for associated diseases such as liver cancer. Care coordination by a coordinator or navigator is a well-established model within the United States and is effective in international settings [ 39 , 40 , 41 , 42 , 43 , 44 ]. Care coordination staff can close gaps in care across the care continuum. The HBV Pathway described here offers a model for linking patients living with HBV into care and ongoing monitoring and serves as one way to close key gaps in HBV care.

This program advances the goals of hepatitis elimination and relieves the burden of care coordination for patients affected by HBV. The HBV Pathway program is streamlined, standardized, scalable, and efficient from a patient and provider perspective. Patient completion of the program is high. The HBV Pathway program described here outlines a standardized, reliable approach for updating the clinical status of patients infected with HBV (acute or chronic) within an integrated health system.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy but are available from the corresponding author on reasonable request.

Abbreviations

Hepatitis B virus

Hepatitis C virus

Hepatocellular carcinoma

Kaiser Permanente Mid-Atlantic States

Hepatitis B surface antigen

Hepatitis B core antibody

Hepatitis B e-antigen

Hepatitis B e-antibody

Total bilirubin

Direct bilirubin

Alkaline phosphatase

Total protein

Alanine transaminase

Aspartate transferase

Prothrombin time

International normalized ratio

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Acknowledgements

The study team would like to acknowledge Mid-Atlantic Permanente Medical Group clinical leadership for their support of the HBV Pathway: Richard McCarthy, MD, Michael Horberg, MD, MAS, FACP, FIDSA, Eric Wollins, MD, Dana Sloane, MD, Dia Copeland, MD, Jacquelyn Redd, MD, and Mettassebia Kanno, MD.

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Conceptualization: MCJ, YS, KW, LP, SB, GW, FS; methodology: MCJ, YS, SB; formal analysis: YS, SB; writing—original draft preparation: MCJ, YS, RCB; writing—review and editing: MCJ, RCB, KW, LP, SB, GW, FS, KC; supervision: MCJ; project administration: KC. All authors have read and agreed to the published version of the manuscript.

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Jonas, M.C., Sheu, YS., Wright, K. et al. A care coordination program to support patients with hepatitis B virus at Kaiser Permanente Mid-Atlantic States. BMC Health Serv Res 24 , 482 (2024). https://doi.org/10.1186/s12913-024-10907-2

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Hepatitis B Virus–Mediated m6A Demethylation Increases Hepatocellular Carcinoma Stemness and Immune Escape

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Yuting Meng , Zheyue Shu , Xueyao Wang , Liang Hong , Baohua Wang , Jingjing Jiang , Kangxin He , Qingyi Cao , Fan Shi , Hai Wang , Lan Gong , Hongyan Diao; Hepatitis B Virus–Mediated m6A Demethylation Increases Hepatocellular Carcinoma Stemness and Immune Escape. Mol Cancer Res 2024; https://doi.org/10.1158/1541-7786.MCR-23-0720

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Hepatitis B viral (HBV) persistent infection plays a significant role in hepatocellular carcinoma (HCC) tumorigenesis. Many studies have revealed the pivotal roles of N6-methyladenosine (m6A) in multiple cancers, while the regulatory mechanism in stemness maintenance of HBV persistent infection-related HCC remains elusive. Here, we demonstrated that the level of m6A modification was downregulated by HBV in HBV-positive HCC, through enhanced stability of ALKBH5 mRNA. More specifically, we also identified that ALKBH5 mRNA was functionally required for the stemness maintenance and self-renewal in the HBV-positive HCC, but dispensable in HBV-negative HCC. Mechanistically, ALKBH5 demethylated the m6A modification in the 3′ untranslated region of the oncogenic gene SNAI2 to prevent the recognition of YTHDF2 therewith stabilize SNAI2 transcripts, contributing to cancer stem cell traits in HBV-positive HCC. Moreover, the expression of SNAI2 reversed the suppression of stemness properties by knocking down ALKBH5. In addition, ALKBH5/SNAI2 axis accelerates tumor immune evasion through activated ligand of immune checkpoint CD155. Our study unveiled that the ALKBH5 induces m6A demethylation of the SNAI2 as a key regulator in HBV-related HCC, and identifies the function of ALKBH5/SNAI2/YTHDF2 axis in promoting the stem-like cells phenotype and immune escape during HBV infection.

HBV promotes HCC stemness maintenance through elevate m6A modification of SNAI2 in an ALKBH5-YTHDF2–dependent manner and increases the expression of the ligand of immune checkpoint CD155.

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Supplementary Figure S4 shows the extended data of "ALKBH5-mediated m6A demethylation in 3’UTR region of SNAI2 mRNA is recognized by YTHDF2"

Supplementary Figure S5 shows the extended data of "SLUG reversed the stemness properties and immune escape induced by ALKBH5"

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Hepatitis b drug pipeline research report 2024.

Dublin, April 18, 2024 (GLOBE NEWSWIRE) -- The "Hepatitis B - Pipeline Insight, 2024" drug pipelines has been added to ResearchAndMarkets.com's offering. The report outlays comprehensive insights of present clinical development scenario and growth prospects across the Hepatitis B market. A detailed picture of the Hepatitis B pipeline landscape is provided, which includes the disease overview and Hepatitis B treatment guidelines.

The assessment part of the report embraces in-depth Hepatitis B commercial assessment and clinical assessment of the Hepatitis B pipeline products from the pre-clinical developmental phase to the marketed phase.

In the report, a detailed description of the drug is proffered including mechanism of action of the drug, clinical studies, NDA approvals (if any), and product development activities comprising the technology, Hepatitis B collaborations, licensing, mergers and acquisition, funding, designations, and other product-related details. Hepatitis B Analytical Perspective

In-depth Hepatitis B Commercial Assessment of products This report provides a comprehensive commercial assessment of therapeutic drugs that have been included, which comprises of collaborations, licensing, and acquisition deal value trends. The report also covers company-company collaborations (licensing/partnering), company-academia collaborations, and acquisition analysis in both graphical and tabulated form in a detailed manner. Hepatitis B Clinical Assessment of products The report comprises of comparative clinical assessment of products by development stage, product type, and route of administration, molecule type, and MOA type across this indication. Key Questions

What are the current options for Hepatitis B treatment?

How many companies are developing therapies for the treatment of Hepatitis B?

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Key Topics Covered: 1. Report Introduction 2. Hepatitis B 2.1. Overview 2.2. History 2.3. Hepatitis B Symptoms 2.4. Causes 2.5. Pathophysiology 2.6. Hepatitis B Diagnosis 2.6.1. Diagnostic Guidelines 3. Hepatitis B Current Treatment Patterns 3.1. Hepatitis B Treatment Guidelines 4. Hepatitis B - Analytical Perspective 4.1. In-depth Commercial Assessment 4.1.1. Hepatitis B companies collaborations, Licensing, Acquisition -Deal Value Trends 4.1.1.1. Assessment Summary 4.1.2. Hepatitis B Collaboration Deals 4.1.2.1. Company-Company Collaborations (Licensing / Partnering) Analysis 4.1.2.2. Company-University Collaborations (Licensing / Partnering) Analysis 4.1.2.3. Hepatitis B Acquisition Analysis 5. Therapeutic Assessment 5.1. Clinical Assessment of Pipeline Drugs 5.1.1. Assessment by Phase of Development 5.1.2. Assessment by Product Type (Mono / Combination) 5.1.3. Assessment by Route of Administration 5.1.4. Assessment by Molecule Type 5.1.5. Assessment by MOA 5.1.6. Assessment by Target 6. Hepatitis B Late Stage Products (Phase-III) 7. Hepatitis B Mid Stage Products (Phase-II) 8. Early Stage Products (Phase-I) 9. Pre-clinical Products and Discovery Stage Products 10. Inactive Products 11. Dormant Products 12. Hepatitis B Discontinued Products 13. Hepatitis B Product Profiles 13.1. Product Description 13.1.1. Product Overview 13.1.2. Mechanism of action 13.2. Research and Development 13.2.1. Clinical Studies 13.3. Product Development Activities 13.3.1. Collaboration 13.3.2. Agreements 13.3.3. Acquisition 13.3.4. Patent Detail 13.4. Tabulated Product Summary 13.4.1. General Description Table Detailed information in the report 14. Hepatitis B Key Companies 15. Hepatitis B Key Products 16. Dormant and Discontinued Products 16.1. Dormant Products 16.2. Discontinued Products 17. Hepatitis B Unmet Needs 18. Hepatitis B Future Perspectives 19. Hepatitis B Analyst Review 20. Appendix For more information about this drug pipelines report visit https://www.researchandmarkets.com/r/3hupnw

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Hepatitis B: The Virus and Disease

T. jake liang.

Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD

Hepatitis B virus (HBV) infects more than 300 million people worldwide and is a common cause of liver disease and liver cancer. HBV, a member of the Hepadnaviridae family, is a small DNA virus with unusual features similar to retroviruses. HBV replicates through an RNA intermediate and can integrate into the host genome. The unique features of the HBV replication cycle confer a distinct ability of the virus to persist in infected cells. Virological and serological assays have been developed for diagnosis of various forms of HBV-associated disease and for treatment of chronic hepatitis B infection. HBV infection leads to a wide spectrum of liver disease ranging from acute (including fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis. Most adults infected with the virus recover, but 5%–10% are unable to clear the virus and become chronically infected. Many chronically infected persons have mild liver disease with little or no long-term morbidity or mortality. Other individuals with chronic HBV infection develop active disease, which can progress to cirrhosis and liver cancer. These patients require careful monitoring and warrant therapeutic intervention. Extrahepatic manifestations of HBV infection are rare but can be difficult to diagnose and manage. The challenges in the area of HBV-associated disease are the lack of knowledge in predicting outcome and progression of HBV infection and an unmet need to understand the molecular, cellular, immunological, and genetic basis of various disease manifestations associated with HBV infection.

The hepatitis B virus (HBV) is a small DNA virus with unusual features similar to retroviruses. 1 , 2 It is a prototype virus of the Hepadnaviridae family. Related viruses are found in woodchucks, ground squirrels, tree squirrels, Peking ducks, and herons. Based on sequence comparison, HBV is classified into eight genotypes, A to H. Each genotype has a distinct geographic distribution. Three types of viral particles are visualized in infectious serum by electron microscopy. Two of the viral particles are smaller spherical structures with a diameter of 20 nm and filaments of variable lengths with a width of 22 nm ( Fig. 1 ). The spheres and filaments are composed of hepatitis B surface antigen (HBsAg) and host-derived lipids without viral nucleic acids and are therefore noninfectious. 3 The infectious HBV virion (Dane particle) has a spherical, double-shelled structure 42 nm in diameter, consisting of a lipid envelope containing HBsAg that surrounds an inner nucleocapsid composed of hepatitis B core antigen (HBcAg) complexed with virally encoded polymerase and the viral DNA genome. The genome of HBV is a partially double-stranded circular DNA of about 3.2 kilobase (kb) pairs. The viral polymerase is covalently attached to the 5′ end of the minus strand. 4

Electron micrograph of circulating forms of HBV particles in the blood is shown at the top and a schematic drawing of Dane particle, the infectious HBV particle, is shown at the bottom with various structural features.

The viral genome encodes four overlapping open reading frames (ORFs: S , C , P , and X ) ( Fig. 2A ). 1 , 2 The S ORF encodes the viral surface envelope proteins, the HBsAg, and can be structurally and functionally divided into the pre-S1, pre-S2, and S regions. The core or C gene has the precore and core regions. Multiple in-frame translation initiation codons are a feature of the S and C genes, which give rise to related but functionally distinct proteins. The C ORF encodes either the viral nucleocapsid HBcAg or hepatitis B e antigen (HBeAg) depending on whether translation is initiated from the core or precore regions, respectively ( Fig. 2B ). The core protein has the intrinsic property to self-assemble into a capsid-like structure and contains a highly basic cluster of amino acids at its C-terminus with RNA-binding activity. 5 The precore ORF codes for a signal peptide that directs the translation product to the endoplasmic reticulum, where the protein is further processed to form the secreted HBeAg. The function of HBeAg remains largely undefined, although it has been implicated as an immune tolerogen, whose function is to promote persistent infection. 6 The polymerase (pol) is a large protein (about 800 amino acids) encoded by the P ORF and is functionally divided into three domains: the terminal protein domain, which is involved in encapsidation and initiation of minus-strand synthesis; the reverse transcriptase (RT) domain, which catalyzes genome synthesis; and the ribonuclease H domain, which degrades pregenomic RNA and facilitates replication. The HBV X ORF encodes a 16.5-kd protein (HBxAg) with multiple functions, including signal transduction, transcriptional activation, DNA repair, and inhibition of protein degradation. 7 – 10 The mechanism of this activity and the biologic function of HBxAg in the viral life-cycle remain largely unknown. However, it is well established that HBxAg is necessary for productive HBV infection in vivo and may contribute to the oncogenic potential of HBV.

The HBV genome. (A) The genomic organization, RNA transcripts and gene products are shown with several key regulatory elements. (B) The transcription start sites of various HBV transcripts and the proteins they encode (see text for details).

Other functionally important elements within the HBV genome include two direct repeats (DR1 and DR2) in the 5′ ends of the plus strand, which are required for strand-specific DNA synthesis during replication. 11 Two enhancer elements, designated as En1 and En2, confer liver-specific expression of viral gene products. 12 A glucocorticoid-responsive element (GRE) sequence within the S domain, 13 a polyadenylation signal within the core gene, and a posttranscriptional regulatory element overlapping En1 and part of HBxAg ORF have also been described. 14

The HBV replication pathway has been studied in great detail and is summarized in Fig. 3 . The initial phase of HBV infection involves the attachment of mature virions to host cell membranes, likely involving the pre-S domain of the surface protein. 15 Various cellular factors have been proposed to be the viral receptors, but only carboxypeptidase D has been shown to play an essential role in viral entry for the duck HBV. 16 Mechanisms of viral disassembly and intracellular transport of the viral genome into the nucleus are not well understood and probably involve modification of the nucleocapsid core protein. 17 After entry of the viral genome into the nucleus, the single-stranded gap region in the viral genome is repaired by the viral pol protein, and the viral DNA is circularized to the covalently closed circular (cccDNA) form. 18 This form of HBV DNA serves as the template for transcription of several species of genomic and sub-genomic RNAs and is the stable component of the replication cycle that is relatively resistant to antiviral action and immune clearance ( Fig. 2B ).

The replication cycle of HBV (see text for details).

The transcripts from the cccDNA are unspliced, polyadenylated, and possess a 5′ cap structure. The 3.5-kb genomic transcripts consist of two species with different 5′ ends: the pregenomic and the precore RNAs. The pregenomic RNA (pgRNA) serves as the template for reverse transcription and the messenger RNA for core and polymerase; the precore RNA directs the translation of the precore gene product. The polymerase translation is initiated at the pol start codon of the pgRNA, probably as a result of a ribosomal scanning mechanism. 19 The large HBsAg (L-HBsAg) protein is translated from the 2.4-kb subgenomic RNA, the middle (M-HBsAg) and small HBsAg (S-HBsAg) proteins from the various forms of 2.1-kb RNAs, and the HBxAg protein from the 0.7-kb RNA.

The S-HBsAg is the major S gene product and the L and M proteins are the minor species. Each surface protein has a glycosylation site in the S domain. Additional modifications of the L and M proteins occur at the pre-S2 domain with an N-linked oligosaccharide and a myristic acid at the amino-terminal glycine residue of the pre-S1 domain. 20 The distribution of the three envelope glycoproteins varies among the types of viral particles, with little or no L and M protein in the 20-nm particles but relatively more L protein in the Dane particles.

Replication of HBV begins with encapsidation of the genome. The packaging signal is a cis -acting element referred to as epsilon, which contains a stem-loop structure. 21 The terminal protein of the pol interacts with the epsilon and in concert with the core protein forms the nucleocapsid. After encapsidation, the pol mediates the reverse transcription of the pgRNA to minus-strand DNA and subsequent positive-strand synthesis. The circular form of the DNA is completed through several complicated steps of strand transfer. 22 The nucleocapsid then interacts with the envelope proteins in the endoplasmic reticulum to assemble into mature virions, which are then secreted into the extra-cellular milieu.

Diagnosis and Serology

HBV infection leads to a wide spectrum of liver disease ranging from acute hepatitis (including fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). 2 The diagnosis of HBV infection and its associated disease is based on a constellation of clinical, biochemical, histological, and serologic findings. A number of viral antigens and their respective antibodies can be detected in serum after infection with HBV, and proper interpretation of the results is essential for the correct diagnosis of the various clinical forms of HBV infection ( Table 1 ).

Hepatitis B Virus Serological and Virological Markers

The typical course of acute hepatitis B is shown in Fig. 4A . HBV DNA followed shortly afterward by HBsAg and HBeAg are the first viral markers detected in serum. 23 HBsAg may be detected as early as 1–2 weeks or as late as 11–12 weeks after exposure, and its persistence is a marker of chronicity. HBeAg correlates with the presence of high levels of HBV replication and infectivity. 24 Within a few weeks of appearance of viral markers, serum alanine and aspartate aminotransferase (ALT, AST) levels begin to rise and jaundice may appear. HBeAg is usually cleared early, at the peak of clinical illness, whereas HBsAg and HBV DNA usually persist in the serum for the duration of clinical symptoms and are cleared with recovery. Antibodies to the HBV proteins arise in different patterns during acute hepatitis B. Antibody to HBcAg (anti-HBc) generally appears shortly before onset of clinical illness, the initial antibody being mostly immunoglobulin M (IgM) class, which then declines in titer as levels of IgG anti-HBc arise. Antibody to HBeAg (anti-HBe) usually appears shortly after clearance of HBeAg, often at the peak of clinical illness. Thus, loss of HBeAg and appearance of anti-HBe is a favorable serological marker during acute hepatitis B, indicating the initiation of recovery. Antibody to HBsAg arises late during infection, usually during recovery or convalescence after clearance of HB-sAg. Anti-HBs persists after recovery, being the antibody associated with immunity against HBV. However, between 10% and 15% of patients who recover from hepatitis B do not develop detectable anti-HBs and have anti-HBc alone as a marker of previous infection. For this reason, anti-HBc testing is the most reliable means of assessing previous infection with HBV, whereas anti-HBs testing is used to assess immunity and response to HBV vaccine. 25

The clinical course and serologic profiles of (A) acute and (B) chronic hepatitis B.

Patients who develop chronic hepatitis B ( Fig. 4B ) have a similar initial pattern of serological markers with appearance of HBV DNA, HBsAg, HBeAg, and anti-HBc. In these persons, however, viral replication persists and HBsAg, HBeAg, and HBV DNA continue to be detectable in serum, often in high titers. The subsequent course of chronic hepatitis B is quite variable. Most persons remain HBsAg-positive for years if not for life and have some degree of chronic liver injury (chronic hepatitis) that can lead to significant fibrosis and cirrhosis. Persons with chronic HBV infection are also at high risk to ultimately develop HCC.

The diagnosis of acute hepatitis B is reliably made by the finding of IgM anti-HBc in serum, particularly in a patient with HBsAg and signs, symptoms, or laboratory features of acute hepatitis. Nevertheless, in some instances, HBsAg is cleared rapidly from the serum, and IgM anti-HBc is the only marker detectable when the patient presents with hepatitis. Testing for anti-HBc (total) and anti-HBs are not useful in diagnosis, and testing for HBeAg and anti-HBe should be reserved for persons who test positive for HBsAg. The finding of HBsAg without IgM anti-HBc suggests the presence of chronic hepatitis B, but this diagnosis generally also rests upon finding of persistence of HBsAg for at least 6 months. 23 , 26 HBV DNA testing can also be helpful in the assessment of level of viral replication and possibly helpful in assessing prognosis and need for antiviral therapy. Assays for HBV DNA level have improved substantially over the years. 27 The current real-time polymerase chain reaction–based assay (TaqMan) has a lower limit of detection of 5–10 HBV DNA copies/mL and can accurately quantify a wide range of levels ( Fig. 5 ). With this degree of sensitivity, HBV DNA can be detected early during the course of infection, arising before the appearance of other serological markers, such as HBsAg or anti-HBc. As a consequence, testing for HBV DNA has emerged as a primary approach in the diagnosis and management of HBV infection. HBV DNA testing has now become routinely used in blood product screening (nucleic acid testing) 28 and monitoring of patients with HBV during treatment. 29 Persistently high levels of HBV DNA following resolution of hepatitis may be indicative of a failure to control the infection and an evolution into chronic infection.

The detection limits and dynamic ranges of assays for HBV DNA.

Acute Hepatitis B

About two-thirds of patients with acute HBV infection have a mild, asymptomatic and subclinical illness that usually goes undetected. 30 Approximately one-third of adults with acute HBV infection develop clinical symptoms and signs of hepatitis, which range fom mild constitutional symptoms of fatigue and nausea, to more marked symptoms and jaundice, and rarely to acute liver failure. The clinical incubation period of acute hepatitis B averages 2–3 months and can range from 1–6 months after exposure, the length of the incubation period correlating, to some extent, with the level of virus exposure. 31 The incubation period is followed by a short preicteric or prodromal period of constitutional symptoms such as fever, fatigue, anorexia, nausea, and body aches. During this phase, serum ALT levels rise and high levels of HBsAg and HBV DNA are detectable. The preicteric phase lasts a few days to as long as a week and is followed by onset of jaundice or dark urine. The icteric phase of hepatitis B lasts for a variable period averaging 1–2 weeks, during which viral levels decrease. In convalescence, jaundice resolves but constitutional symptoms may last for weeks or even months. During this phase, HBsAg is cleared followed by the disappearance of detectable HBV DNA from serum.

Acute liver failure occurs in approximately 1% of patients with acute hepatitis B and jaundice. 32 The onset of fulminant hepatitis is typically marked by the sudden appearance of fever, abdominal pain, vomiting, and jaundice, followed by disorientation, confusion, and coma. HBsAg and HBV DNA levels generally fall rapidly as liver failure develops, and some patients are HBsAg-negative by the time of onset of hepatic coma. Patients with acute liver failure due to hepatitis B require careful management and monitoring and should be referred rapidly to a tertiary medical center with the availability of liver transplantation. 33

Chronic Hepatitis B

Chronic hepatitis B has a variable and dynamic course. Early during infection, HBeAg, HBsAg, and HBV DNA are usually present in high titers, and there are mild to moderate elevations in serum aminotransferase levels ( Fig. 4B ). With time, however, the disease activity can resolve either with persistence of high levels of HBeAg and HBV DNA (the “immune tolerance phase”) or with loss of HBeAg and fall of HBV DNA to low or undetectable levels (“inactive carrier state”). Other patients continue to have chronic hepatitis B, although some lose HBeAg and develop anti-HBe (HBeAg-negative chronic hepatitis B). The course and natural history of hepatitis B are discussed in detail elsewhere in these proceedings. 34

The overall prognosis of patients with chronic hepatitis is directly related to the severity of disease. For those with severe chronic hepatitis and cirrhosis, the 5-year survival rate is about 50%. 35 – 37 Among patients with evidence of chronic hepatitis (elevated ALT and inflammation and/or fibrosis on liver biopsy), many are asymptomatic or have nonspecific symptoms, such as fatigue and mild right upper quadrant discomfort. Patients with more severe disease or cirrhosis may have significant constitutional symptoms, jaundice, and peripheral stigmata of end-stage liver disease including spider angiomata, palmar erythema, splenomegaly, gynecomastia, and fetor hepaticus. Ascites, peripheral edema, encephalopathy, and gastrointestinal bleeding are seen in patients with more advanced cirrhosis. ALT and AST are often elevated but may not correlate well with severity of liver disease. Bilirubin, prothrombin time, and albumin often become abnormal with progressive disease. Decreasing platelet count is often a poor prognostic sign.

Patients with chronic hepatitis may develop acute exacerbations with markedly elevated serum ALT. This scenario is more frequently described in those with HBeAg-negative chronic hepatitis B. 6 To distinguish between acute hepatitis B and chronic hepatitis B with a flare, anti-HBc IgM is a useful marker, as described in the previous section. However anti-HBc of the IgM class can be detected occasionally in patients with chronic hepatitis B with exacerbation. Alpha-fetoprotein (AFP), used as a marker for HCC, is often elevated in parallel with ALT during acute exacerbation. 38 However, it is unlikely to exceed 400 ng/mL. In patients with AFP much greater than this level, development of HCC should be suspected. 39

An estimated one-third of persons with chronic HBV infection will ultimately develop a long-term consequence of the disease, such as cirrhosis, end-stage liver disease, or HCC. The determinants of outcome of chronic hepatitis B appear to be both viral (HBV DNA levels, HBV genotype, some HBV mutation patterns) and host-specific (age, gender, genetic background, immune status).

Extrahepatic Manifestations of Hepatitis B

Extrahepatic manifestations of hepatitis B are present in 1–10% of HBV-infected patients and include serum-sickness–like syndrome, acute necrotizing vasculitis (polyarteritis nodosa), membranous glomerulonephritis, and papular acrodermatitis of childhood (Gianotti-Crosti syndrome). 40 , 41 Although the pathogenesis of these disorders is unclear, immune complex–mediated injury related to high level of HBV antigenemia is thought to be the cause.

The serum-sickness–like syndrome occurs in the setting of acute hepatitis B, often preceding the onset of jaundice. 42 The clinical features are fever, skin rash, and polyarteritis. The symptoms often subside shortly after the onset of jaundice, but can persist throughout the duration of acute hepatitis B. The course of this syndrome often parallels the duration and level of HBV viremia: rapid clearance of the virus leads to rapid resolution of the illness. This disorder resembles experimental serum sickness, in which immune complexes activate the complement pathways leading to complement-mediated injury. Patients with this syndrome have low complement levels and high-level circulating immune complexes containing HBV antigens and complement components.

About 30%–50% of patients with acute necrotizing vasculitis (polyarteritis nodosa) are HBV carriers. 41 , 43 This entity is more commonly seen in patients with recent exposure to HBV. Immune-mediated vascular injury can involve large, medium, and small vessels. Early clinical features are marked constitutional symptoms, high fever, anemia, and leukocytosis. Multisystem involvement is common, including arthritis, renal disease (proteinuria and hematuria), heart disease (pericarditis and congestive heart failure), hypertension, gastrointestinal disease (acute abdominal pain and bleeding), skin involvement (vasculitic lesions), and neurological disorders (mononeuritis multiplex and central nervous system abnormalities). The disease is highly variable and has a mortality rate of 30% within 5 years if not treated.

HBV-associated nephropathy has been described in adults but is more common in children. 44 , 45 Membranous glomerulonephritis is the most common form. Liver disease may be mild or absent in many of these patients. This disorder is frequently observed in countries with high prevalence of HBV infection. About 30%–60% of children with this disorder experience spontaneous remission, especially with HBeAg seroconversion. However, about 30% of adults with this condition can progress to renal failure with as many as 10% requiring dialysis or renal transplant. 46

Papular acrodermatitis (Gianotti-Crosti syndrome) is a distinct skin manifestation of acute HBV infection in childhood. 47 Skin lesions are maculopapular, erythematous, and nonpruritic, and involve the face and extremities. The syndrome lasts about 15–20 days and can either precede or follow the onset of jaundice in acute hepatitis B. Generalized lymphadenopathy and hepatomegaly have been described.

Other immune-mediated hematological disorders, such as essential mixed cryoglobulinemia and aplastic anemia have been described as part of the extrahepatic manifestations of HBV infection, but their association is not as well-defined; therefore, they probably should not be considered etiologically linked to HBV.

Occult or Latent HBV Infection

Other atypical HBV infections include seronegative occult or latent HBV infections. This heterogeneous group consists of patients who are HBsAg-negative who are either seronegative for all HBV markers or positive for anti-HBc and/or anti-HBs. 48 – 52 Many of these patients are positive for HBV DNA by polymerase chain reaction either in the liver or serum or both. Some of these patients have underlying liver disease, suggestive of ongoing hepatocellular injury from persistent HBV infection. Studies in animal models have demonstrated long-term persistence of viral genomes in the serum and/or liver of animals that have biochemical and serologic evidence of viral clearance and recovery from infection. 49 , 53 The important question is whether this observation represents ongoing viral replication and therefore clinically significant infection in terms of liver disease and transmission. Existing evidence supports the notion that it indeed indicates low-level viral replication, capable of transmission. 49 , 54 Studies in liver transplantation revealed transmission of HBV infection to recipients if the donors carried the anti-HBc marker. 55 In addition, reactivation of HBV infection in patients with serologic evidence of recovery undergoing immunosuppression or chemotherapy has been reported. 56 – 59 These observations, together with the immunologic studies described above, provide compelling evidence that one may not be able to completely eliminate HBV infection. Patients with serologic evidence of recovery probably have low-level viral replication that is effectively controlled by an active immune response. The possibility that these occult infections are caused by HBV mutants has been proposed. Although mutations have been reported in various regions of the viral genome, 60 – 63 definitive evidence in support of a pathogenic role of these mutants is lacking. Furthermore, whether liver disease can indeed result from these occult HBV infections is controversial. At present, there are no convincing studies in support of a causal relationship. Therefore, these occult HBV infections, other than the special situations described above, may not be clinically important.

Important Questions and Needs for Future Research

• How does HBV establish productive infection in vivo and what is the host response early during the infection? Despite well-described information on the clinical manifestations and natural history of acute HBV infection, detailed knowledge of the virus-host interaction during this stage remains poorly defined. Advances in this area would offer a better understanding of the pathogenesis of HBV infection and its associated disease.
• What is the immunologic basis of chronic infection and hepatocellular injury? There have been great strides in understanding the virology and immune response of HBV infection, but the molecular mechanisms whereby the host fails to clear the virus and develops chronic infection remain largely unknown. In addition, the adaptive evolution of virus under host immune pressure remains to be elucidated. Finally, the pathogenesis of various extra-hepatic manifestations associated with HBV infection is poorly understood. Further research in these areas is crucial not only in better understanding the natural history and disease progression but also in improving treatment for chronic hepatitis B.
• What is the genetic basis of the diverse clinical manifestations and disease outcomes of HBV infection? With the recent advances in genetic and genomic medicine, there are increasing opportunities to elucidate the genetic basis for variations in expression and susceptibility to HBV-associated diseases. Genome-wide association studies and other genomic technological advances would provide crucial information to identify useful genetic markers for disease outcome, clinical manifestations, and treatment response of HBV-associated disease.

Acknowledgments

Supported by the NIDDK Intramural Research Program, NIH.

Abbreviations

Potential conflict of interest: Nothing to report.