Hep B Blog

Addressing Hepatitis B in Africa

Conference on Liver Disease in Africa

To discuss the latest advances in addressing viral hepatitis and other liver diseases in Africa,  there will be a virtual Conference on Liver Disease in Africa (COLDA) from September 10th to 12th, 2020. COLDA is organized by Virology Education on behalf of the organizing committee led by Drs. Manal Al-Sayed, Mark Nelson, and Papa Saliou Mbaye. This virtual conference will gather clinicians, patients, other healthcare professionals, and policymakers from African regions, with international experts to support and exchange innovative ideas and knowledge about liver disease. The conference will consist of lectures discussing viral hepatitis infections, hepatitis co-infections, non-viral hepatitis-related infections, non-infectious induced liver disease, hepatocellular carcinoma, and end-stage liver disease. This virtual conference is important for addressing viral hepatitis since fewer than 1 in 10 people in Africa has access to testing and treatment for viral hepatitis. The World Health Organization (WHO) states that viral hepatitis is a bigger threat to Africa than HIV/AIDS, malaria, or tuberculosis with over 1.34 million deaths a year attributed to it.1 Over 60 million people in Africa have hepatitis B which annually accounts for an estimated 68,870 deaths.1 These statistics demonstrate the need for conferences like COLDA to discuss best practices and reduce viral hepatitis in Africa.

Mother-to-Child and Early Childhood Transmission

Hepatitis B is commonly transmitted from mother-to-child and close contact with infected individuals during the first 5 years of life. These modes of infection transmission are preventable with proper birth prophylaxis. There are two types of mother-to-child and early childhood transmission of hepatitis B resulting in chronic infection: vertical and horizontal. Vertical transmission refers to the transmission of hepatitis B from an infected mother to her baby during delivery. Horizontal transmission refers to infection with hepatitis B from direct blood-to-blood contact with an infected individual. Most early childhood transmission cases in sub-Saharan Africa are from horizontal transmission especially during the first 5 years of life from contact with family members or close friends infected with hepatitis B2, though vertical transmission from a hepatitis B infected mother to her baby is also common and completely preventable with birth prophylaxis.

 The best way to prevent the transmission of hepatitis B (HBV) from mother to child is through a “birth-dose”, meaning infants are vaccinated against hepatitis B within 24 hours of birth. However, in the WHO Africa region, only 6% of infants are administered the birth-dose.1 Only three countries in Africa: Cameroon, Rwanda, and Mauritania, have national guidelines addressing mother-to-child transmission of hepatitis B.2 Additionally, healthcare providers do not routinely screen future mothers for hepatitis B which contributes to a higher burden.2 This lack of screening demonstrates the need for universal guidelines to provide information to future mothers about hepatitis B. The World Health Organization recently released updated guidelines for hepatitis B which recommends a universal birth dose for all infants, as soon as possible, preferably within 24 hours followed by an additional 2-3 doses (often fulfilled with the pentavalent vaccine). Additionally, the WHO newly recommends that pregnant women testing positive for a hepatitis B infection (HBsAg positive) with an HBV DNA ≥ 5.3 log10 IU/mL (≥ 200,000 IU/mL) receive tenofovir from the 28th week of pregnancy until at least birth, to prevent mother-to-child transmission of HBV.4 This is in addition to the three-dose hepatitis B vaccination in all infants, including the timely birth dose. The WHO also strongly recommends that in settings in which antenatal (pre-birth) HBV DNA testing is not available, HBeAg testing can be used as an alternative to HBV DNA testing to determine eligibility for tenofovir prophylaxis to prevent mother-to-child transmission of HBV.4 Testing for hepatitis B in early pregnancy, a timely birth-dose, pentavalent vaccination, and administration of antivirals in the last trimester if needed would prevent vertical transmission and in turn, prevent horizontal transmission.

HIV/HBV Co-infection

There is a high burden of HIV/HBV co-infection in African countries because both diseases share similar transmission routes such as mother-to-child, unsafe medical and injection practices, and unscreened blood transfusions.2 Chronic HIV/HBV infection is reported in up to 36% of people who are HIV positive, with the highest prevalence reported in west Africa and southern Africa. The co-infection of HIV and HBV is especially dangerous because it accelerates liver disease such as fibrosis and cirrhosis. In fact, liver-related mortality is twice as high among people with an HIV/ HBV co-infection.2

Nosocomial Transmission

Another common way hepatitis B is transmitted in Africa is through nosocomial transmission or transmission from a hospital setting.3 The World Health Organization estimates 24% of blood donations in lower-income countries are not systematically screened for hepatitis B or hepatitis C. Additionally, countries have inconsistent screening procedures and use non-WHO prequalified test kits. Implementation of screening guidelines would significantly assist in reducing the risk of transmitting hepatitis B.

Barriers

 There are numerous barriers to eliminating hepatitis B in African countries. Screening is costly and often inaccessible, especially in rural areas. Moreover, there is an irregular supply of test kits for screening for healthcare providers.2,3 Lack of public awareness and often provider knowledge also contributes to the higher hepatitis B burden. Research has found that less than 1% of Gambian adults previously knew their status when tested positive for HBsAg.3 Additionally, there are financial constraints when it comes to hepatitis B treatment and care. The World Hepatitis Alliance and the WHO found that 41% of the world’s population live in countries where there is no public funding for hepatitis B treatments.3 This financial barrier prevents people from accessing important screening and vaccination prevention services. A collaborative effort among governments, local health officials, and community members is needed to manage hepatitis B in African countries.

Importance of Conference

Hepatitis B disproportionately affects the WHO Africa Region where 6.1% of the adult population is infected.1 The Conference on Liver Disease in Africa will address problems and discuss potential solutions for this neglected preventable disease. COLDA will help to make eliminating hepatitis B in Africa a reality by engaging the global community to collaborate on public health efforts, develop innovative ideas, and discuss best practices to reduce barriers. We hope to see you there!

Learn more and register for the conference.

 

References:

  1. https://www.who.int/news-room/fact-sheets/detail/hepatitis-b
  2. Spearman, C. W., Afihene, M., Ally, R., Apica, B., Awuku, Y., Cunha, L., Dusheiko, G., Gogela, N., Kassianides, C., Kew, M., Lam, P., Lesi, O., Lohouès-Kouacou, M. J., Mbaye, P. S., Musabeyezu, E., Musau, B., Ojo, O., Rwegasha, J., Scholz, B., Shewaye, A. B., … Gastroenterology and Hepatology Association of sub-Saharan Africa (GHASSA) (2017). Hepatitis B in sub-Saharan Africa: strategies to achieve the 2030 elimination targets. The lancet. Gastroenterology & hepatology, 2(12), 900–909. https://doi.org/10.1016/S2468-1253(17)30295-9
  3. Maud Lemoine, Serge Eholié, Karine Lacombe, Reducing the neglected burden of viral hepatitis in Africa: Strategies for a global approach, Journal of Hepatology, Volume 62, Issue 2, 2015, Pages 469-476, ISSN 0168-8278, https://doi.org/10.1016/j.jhep.2014.10.008
  4. Prevention of mother-to-child transmission of hepatitis B virus: guidelines on antiviral prophylaxis in pregnancy. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO.

Get Vaccinated for Hepatitis B!

 

August marks the start of National Immunization Awareness Month! This month highlights the importance of vaccines for people of all ages. Let’s talk about why you should get vaccinated for hepatitis B.

Understanding Your Status

Before becoming vaccinated for hepatitis B, it is important to understand your status. You can test through a simple triple panel blood test for HBsAg, HBcAb total and HBsAb. This will tell you if you have a current infection, have recovered from a past infection and if you need to be vaccinated. More details about the blood tests can be found here. Many people with hepatitis B do not look or feel sick so it is important to get tested. Learning your status early can help manage your hepatitis B and identify at-risk close contacts (household/family members or sexual partners) who can then be vaccinated and protected against hepatitis B.

 Why You Should Be Vaccinated

The hepatitis B vaccine is the first anti-cancer vaccine because it successfully prevents a hepatitis B infection which is the leading cause of liver cancer worldwide. It’s important for people to receive the vaccine since most people with hepatitis B are not aware they are infected. Hepatitis B is known as a silent infection as many people can live with hepatitis B for years without knowing they are infected. With chronic hepatitis B, when symptoms do finally present, often the infection may have already caused severe liver damage. The hepatitis B vaccine can prevent hepatitis B and also the health consequences that can come from hepatitis B, including the increased risk for cirrhosis, liver failure and liver cancer

It is especially important for future mothers to be tested for hepatitis B and vaccinated if needed. Mothers can easily pass hepatitis B to their infant during childbirth through either vaginal delivery or c-section. The most common mode of transmission of hepatitis B is from mother to child, so administering the vaccine to infants at birth is one of the most effective ways to reduce the number of hepatitis B cases worldwide. Read more about preventing perinatal transmission both in the U.S. and internationally.

In fact, it is very important to vaccinate children, starting with a birth dose, because greater than 90% of acute (short-term infection lasting less than 6 months) cases in infants and up to 50% of infected young children of hepatitis B will progress to chronic (lasting a lifetime) infections while only 5%-10% of adult cases will become chronic. That said, vaccination rates in adults are low and due to the nature of hep B, even those who recover from infection are at risk of reactivation. Left untreated, chronic infections can harm your liver and cause poor health outcomes. That is why the Hepatitis B Foundation calls for universal testing for hepatitis B. Luckily, you can expect to live a long and healthy life when you manage chronic infections of hepatitis B. Learn more about hepatitis B management here.

In the United States, you can get the vaccine through your healthcare provider or health clinics. Ask your doctor if you can get vaccinated today!

Hepatitis B is a preventable virus so why not take steps to become a healthier you!

About the Hepatitis B Vaccine

Hepatitis B can cause long-term serious damage to the liver like cirrhosis, fibrosis, and liver cancer. Fortunately, a safe and effective vaccine exists which can prevent a hepatitis B infection in all persons.

The World Health Organization recommends the vaccine for infants at birth and children up to age 18. Additionally, the WHO recommends high-risk groups become vaccinated for hepatitis B such as:

  • Pregnant women
  • People who frequently require blood to blood products
  • People who inject drugs
  • People in prison
  • Household and sexual contact of people with chronic HBV
  • Healthcare workers with blood to blood contact
  • People with multiple sexual partners
  • Travellers without completion of their vaccine series to endemic areas.

The WHO recommends that infants receive the vaccine within 24 hours of birth followed up with two additional doses. Children up to the age of 18 can also receive this series if they either were not vaccinated for hepatitis B at birth or did not complete the series. The series should be as followed:

  • 1st Dose: Anytime, but for infants, it should be administered at birth
  • 2nd Dose: One month (28 days) after the first dose
  • 3rd Dose: 4 months (16 weeks) after the 1st shot (and at least 2 months after the 2nd shot). Infants should be a minimum of 24 weeks old at the time of the 3rd shot.

Find out more about the vaccine schedule here!

You do not need to restart the hepatitis B vaccine series if you miss any of the shots.

In November 2017, a vaccine was approved by the FDA for use in the U.S. Heplisav-B (Dynavax) is a two-dose vaccine approved for use in adults aged 18 and older. The vaccine is administered as two doses given one month apart.

Ask your doctor about the 2-dose vaccine. You can now find Heplisav-B at more than 1,700 Albertsons Companies’ store pharmacies across the US. For assistance accessing this vaccine, you can contact Heplisav-B’s Access Navigator at 1-844-375-4728. 

For more information on the hepatitis B vaccine, read here.

#ThrowbackWHD: Hep B United Summits, Advocacy Days and World Hepatitis Days Through The Years

 

While we were not able to gather together for our annual Hep B United Summit this World Hepatitis Day to discuss best practices, advocate on Capitol Hill, and innovate ideas together to improve testing,  hep B vaccination and linkage to care and treatment for hep B in our communities, we did have our Virtual Week of Advocacy. Hep B advocates emailed their Congress members to ensure policy priorities include provisions for hepatitis B elimination -specifically supporting funding for a hep B cure and CDC viral hepatitis programs.  You too can advocate for hepatitis B elimination here! The templates make it so easy!

To learn more about past  Hep B United Summits, check out previous summit agendas and presentations here.

Join us today, World Hepatitis Day, for a Twitter Storm all day long sharing  memories, pics and videos  from past Hep B United Summits,  Advocacy Days and  World Hepatitis Day events.  Tag your posts and pics with #ThrowbackWHD, #WorldHepatitisDay, and #HepBUnite. Be sure to tag @HepBUnited and @HepBFoundation on Instagram, Twitter, or Facebook!

292 Million People Worldwide Have Hepatitis B – So Why Do We Feel Alone?

 

Hepatitis B is the global pandemic no one talks about, yet 292 million people worldwide have been infected. In 2015, the World Health Organization estimated that hepatitis B caused 887,000 deaths annually.

Today, 292 million people have chronic hepatitis B1. Despite the availability of an effective vaccine, the number of people living with hepatitis B virus is projected to remain at the current, unacceptably high level for decades and cause 20 million deaths through 2030.

How can this happen? Viral hepatitis infection and death rates far outstrip that of ebola and zika. In fact, you have to combine the death toll from HIV and tuberculosis to find human suffering on par with what viral hepatitis causes around the world each year. How has this pandemic remained so hidden and ignored for so long? There are several factors that have kept hepatitis B off public health’s global radar. It’s a complicated, silent infection, often with few or no symptoms. Those who have it have been silenced by shame and ignorance, and more than two-thirds of those infected with hepatitis B have never been tested and are unaware of their positive status.

And then there’s avoidance by the global healthcare community. The development of a hepatitis B vaccine 40 years ago was thought to signal the death knell of this disease. While new infections have plummeted in North America and Europe, in impoverished countries, the vaccine is often not available or too expensive and infected mothers continue to unknowingly infect their children at birth.

There have been successful hepatitis B immunization campaigns around the world, even in poor, remote areas, but there’s a catch. The Global Vaccine Alliance (Gavi) provides a free hepatitis B pentavalent vaccine which is effective in children starting at 6 weeks of age. To break the mother-to-child infection cycle, a different and more costly hepatitis B vaccine must be administered as-soon-as-possible, within 12 hours of birth. However, this vaccine is often unavailable and out-of-reach financially in rural Africa and Asia, which is why chronic hepatitis B rates remain stubbornly high and are projected to remain unchanged.

To successfully combat hepatitis B, communities need to launch campaigns that combat stigma and teach how to prevent the spread of the disease through education and immunization. They need the resources to test people for hepatitis B and vaccinate those who need it. They also need to teach healthcare providers how to treat patients with liver damage.

Fortunately, we have started to see change. On May 28, 2016, at the United Nations World Health Assembly, 194 countries made a historic commitment to eliminate viral hepatitis by 2030. The Global Health Sector Strategy for Viral Hepatitis pledges to reduce deaths from hepatitis B and C by 65 percent and increase treatment by 80 percent. This action is the greatest global commitment to viral hepatitis ever taken.

On July 28, 2016, a campaign called NOhep, the first global movement to eliminate viral hepatitis, launched on World Hepatitis Day by the World Hepatitis Alliance. This day was chosen to mark the birthday of Baruch S. Blumberg, MD, D.Phil, who won the Nobel Prize in Medicine for the discovery of the hepatitis B virus.

Many of our partners and other organizations around the world are raising awareness to highlight World Hepatitis Day. Here are some of the activities you can support.

WHO – The World Health Organization is celebrating World Hepatitis Day through its theme: Hepatitis-free future with a strong focus on perinatal transmission. Read more about their efforts here. You can register to join their global virtual event, WHO Commemoration of World Hepatitis Day, on July 28th 1pm-3:15pm CEST here.

Hep B United – Yesterday, in anticipation of World Hepatitis Day, Hep B United kicked off a week of action with a call where we heard about the importance of hepatitis B elimination from hepatitis B advocates and representatives Judy Chu and Grace Meng. You can advocate for hepatitis B elimination here.

Hep B United and the Hepatitis B Foundation will have a #ThrowbackWHD twitter storm all day July 28th,  World Hepatitis Day! Partners and hepatitis B advocates are encouraged to share memories from past in-person Hep B United Summits and Advocacy Days.  Share your memories, pics, and videos with the hashtags: #ThrowbackWHD #WorldHepatitisDay and #Hepbunite.

Global Liver Institute – On July 28 at 12:30pm-1pm ET, the Global Liver Institute will host GLI LIVE on the Global Liver Institute’s Facebook page. Dr Chari Cohen will discuss the progress and challenges with eliminating hepatitis B globally, and strategies for commemorating World Hepatitis Day.

DiaSorin hosts Dr. Robert Gish, renowned hepatologist and HBF medical director – July 28th, 12 pm ET. Register now for Laboratory Testing for Viral Hepatitis: What’s new and what has changed?

Hep Free Hawaii – On World Hepatitis Day, July 28th at 12pm HST, Hep Free Hawaii will unveil Hawaii’s first Hepatitis B Elimination Strategy. More information and registration here!

CEVHAP and Burnet Institute – The Coalition to Eradicate Viral Hepatitis in Asian Pacific and the Burnet Institute is hosting a webinar on July 24th at 11am (GMT+5) to discuss access to hepatitis care, the world of hepatitis amidst the COVID-19 pandemic, and literacy on COVID-19 and hepatitis. You can stream it here.

You can be part of this global social justice movement. Take action, speak out, and join the effort to eliminate viral hepatitis by 2030. In anticipation of World Hepatitis Day 2020, NOhep is asking you to urge governments worldwide to uphold their commitment to eliminate hepatitis B. Add your voice to the open letter here.

For more information, visit the NOhep website, the Hepatitis B Foundation website or Hep B United’s website to learn how to lend your voice to this fight and to help address hepatitis and save lives in your community.

 

Reference

  1. Razavi H. (2020). Global Epidemiology of Viral Hepatitis. Gastroenterology clinics of North America, 49(2), 179–189. https://doi.org/10.1016/j.gtc.2020.01.001

Know Your ABCs

What is Hepatitis?

Hepatitis simply means inflammation of the liver which can be caused by infectious diseases, toxins (drugs and alcohol), and autoimmune diseases. The most common forms of viral hepatitis are A, B, C, D, and E. With 5 different types of hepatitis, it can be confusing to know the differences among them all.

The Differences

While all 5 hepatitis viruses can cause liver damage, they vary in modes of transmission, type of infection, prevention, and treatment.

Hepatitis A (HAV) is highly contagious and spread through fecal-oral transmission or consuming contaminated food or water1. This means that if someone is infected with hepatitis A they can transmit it through preparing and serving food and using the same utensils without first thoroughly washing their hands. Symptoms of HAV include jaundice (yellowing of skin and eyes), loss of appetite, nausea, fever, abnormally colored stool and urine, fever, joint pain, and fatigue1. Sometimes these symptoms do not present themselves in an infected person which can be harmful because they can unknowingly spread the virus to other people. Most people who get HAV will feel sick for a short period of time and will recover without any lasting liver damage2. A lot of hepatitis A cases are mild, but in some instances, hepatitis A can cause severe liver damage. Hepatitis A is vaccine preventable and the vaccine is recommended for people living with hepatitis B and C. Read this blog post for a detailed comparison of hepatitis B and hepatitis A!

Hepatitis B (HBV) is transmitted through bodily fluids like blood and semen, by unsterile needles and medical/dental equipment and procedures, or from mother-to-child during delivery1. HBV is considered a “silent epidemic” because most people do not present with symptoms when first infected. This can be harmful to individuals because HBV can cause severe liver damage, including cirrhosis and liver cancer if not properly managed over time3. Hepatitis B can either be an acute or chronic infection meaning some cases last about 6 months while other cases last for a lifetime. In some instances, mostly among people who are infected as babies and young children, acute HBV cases can progress to a chronic infection3. Greater than 90% of babies and up to 50% of young children will develop lifelong infection with hepatitis B if they are infected at a young age.

Hepatitis C (HCV) is similarly transmitted like HBV through bodily fluids, like blood and semen, and by unsterile needles and medical/dental equipment and procedures. Symptoms of HCV are generally similar to HAV’s symptoms of fever, fatigue, jaundice, and abnormal coloring of stool and urine1, though symptoms of HCV usually do not appear until an infected individual has advanced liver disease. Acute infections of hepatitis C can lead to chronic infections which can lead to health complications like cirrhosis and liver cancer1. Read this blog for a detailed comparison of hepatitis B and hepatitis C!

Hepatitis Delta (HDV) infections only occur in persons who are also infected with hepatitis B1,3. Hepatitis Delta is spread through the transfer of bodily fluids from an infected person to a non-infected person. Similar to some other hepatitis viruses, hepatitis Delta can start as an acute infection that can progress to a chronic one. HDV is dependent on the hepatitis B virus to reproduce3. This coinfection is more dangerous than a single infection because it causes rapid damage to the liver which can result in fatal liver failure. Find out more about hepatitis B and hepatitis Delta coinfection here!

Hepatitis E (HEV) is similar to hepatitis A as it is spread by fecal-oral transmission and consumption of contaminated food and water1. It can be transmitted in undercooked pork, game meat and shellfish. HEV is common in developing countries where people don’t always have access to clean water. Symptoms of hepatitis E include fatigue, loss of appetite, stomach pain, jaundice, and nausea. Talk to your doctor if you are a pregnant woman with symptoms as a more severe HEV infection can occur. Many individuals do not show symptoms of hepatitis E infection1. Additionally, most individuals recover from HEV, and it rarely progresses to chronic infection. Read this blog for a detailed comparison of hepatitis B and hepatitis E!

Here is a simple table to further help you understand the differences among hepatitis A, B, C, D, and E.

Prevention

Fortunately, hepatitis viruses are preventable.

Hepatitis A is preventable through a safe and effective vaccine. The Centers for Disease Control and Prevention (CDC) recommend that children be vaccinated for HAV at 12-23 months or at 2-18 years of age for those who have not previously been vaccinated. The vaccine is given as two doses over a 6-month span1. This vaccine is recommended for all people living with hepatitis B & C infections

Hepatitis B is also preventable through a safe and effective vaccine. The vaccine includes 3 doses over a period of 6 months, and in the U.S. there is a 2-dose vaccine that can be completed in 1-month1,3. Read more here, if you would like to know more about the vaccine series schedule.

Hepatitis C does not have a vaccine, however, the best way to prevent HCV is by avoiding risky behaviors like injecting drugs and promoting harm reduction practices. While there is no vaccine, curative treatments are available for HCV1.

Hepatitis Delta does not have a vaccine, but you can prevent it through vaccination for hepatitis B1,3.

Hepatitis E does not have a vaccine available in the United States. However, there has been a vaccine developed and licensed in China1,2.

 

References

  1. https://www.cdc.gov/hepatitis/index.htm
  2. https://www.who.int/news-room/q-a-detail/what-is-hepatitis
  3. https://www.hepb.org/what-is-hepatitis-b/the-abcs-of-viral-hepatitis/

 

Are You At Risk For Hepatitis B

 

An estimated 292 million people worldwide are living with chronic hepatitis B and most are unaware of their status. Many at-risk groups are Asian and African descended. This month, we join our global community to observe World Hepatitis Day on July 28th – a day chosen to commemorate the birthday of Dr. Baruch Blumberg, who won the Nobel Prize for the discovery of the hepatitis B virus  Let’s take action and raise awareness to find the “missing millions”!

Not knowing your hepatitis B status can cause long term damage to your liver, so it is important for you to understand risk factors besides ethnicity. The CDC’s Know Hepatitis B Campaign’s fact sheet, “Hepatitis B – Are You At Risk?” is a great resource for sharing basic information on getting tested for hepatitis B. The fact sheet is available in 14 languages including Burmese, Khmer, French, Somali, Amharic, Hmong, and Swahili, among many others!

 For more information about the Know Hepatitis B Campaign, which is co-branded with Hep B United, visit the campaign website.

So if you think you are at risk –  what are the next steps? The first thing you can do is visit your healthcare provider to see if you should be tested for hepatitis B. 

A simple blood test can check to see if you are infected or at risk for hepatitis B. The hepatitis B panel blood test includes the following tests: 

  1. HBsAg (Hepatitis B surface antigen) – A “positive” or “reactive” HBsAg test result means that the person is infected with hepatitis B. If a person tests “positive,” then further testing is needed to determine if this is a new “acute” infection or a “chronic” hepatitis B infection. A positive HBsAg test result means that you are infected and can spread the hepatitis B virus to others through your blood.
  2. anti-HBs or HBsAb (Hepatitis B surface antibody) – A “positive” or “reactive” anti-HBs (or HBsAb) test result indicates that a person is protected against the hepatitis B virus. This protection can be the result of receiving the hepatitis B vaccine or successfully recovering from a past hepatitis B infection. A positive anti-HBs (or HBsAb) test result means you are “immune” and protected against the hepatitis B virus and cannot be infected. You are not infected and cannot spread hepatitis B to others.
  3. anti-HBc or HBcAb (Hepatitis B core antibody) – A “positive” or “reactive” anti-HBc (or HBcAb) test result indicates a past or current hepatitis B infection. The core antibody does not provide any protection against the hepatitis B virus (unlike the surface antibody described above). This test can only be fully understood by knowing the results of the first two tests (HBsAg and anti-HBs). A positive anti-HBc (or HBcAb) test result requires talking to your health care provider for a complete explanation of your hepatitis B status.

You can see what each test result means in this table!

Ask your doctor if you should be tested today! 

LGBTQ+ Risk Factors and Hepatitis B

As June wraps up Pride Month, it is still important to address LGBTQ+ health and risk factors for hepatitis B. Many resources are available regarding gay and bisexual men’s risk factors for hepatitis B, but information discussing lesbian, bisexual women, and transgender folx for hepatitis B is lacking. 

Gay, bisexual, and men who have sex with men (MSM) have a higher chance of getting hepatitis B. It can be spread through body fluids like semen or blood from an infected person to an uninfected person during unprotected sex. 

A research study found that lesbian, bisexual women, and womxn who have sex with womxn (WSW) had significantly higher rates of hepatitis B than the control group due to risk factors like multiple sexual partners, injection drug use, and sex work1. Additionally, potential mothers need to know their hepatitis B status because it can easily transmit from mother-to-child during childbirth.

Being transgender is not a risk factor for hepatitis B (HBV), but some transgender folx may have a higher risk due to discrimination surrounding their gender identity.  Discrimination in workplaces or health care facilities can lead transgender individuals to engage in risky behaviors like sex work and exposure to unsterile needles which can put some transgender individuals more at risk than others2. While there is insufficient information regarding hepatitis B and transgender folx,  much information exists about hepatitis C (HCV)  and its co-infection with hepatitis B. Since both viruses have similar modes of transmission it is not uncommon for someone to be co-infected with HCV and HBV.  It is important to get tested for HBV because hepatitis C can become a dominant liver disease which leaves HBV levels virtually undetectable and can cause further liver damage if hepatitis B is not addressed3. This is especially true for individuals being treated with hepatitis C curative Direct Acting Antivirals (DAAs), which can lead to hep B reactivation. 

For LGBTQ+ individuals living in the United States and who want to know their hepatitis B status, here is a list of LGBTQ+ friendly healthcare providersIf you identify as LGBTQ+, ask your provider to be tested for hepatitis B today. The great news is that if you are not infected, there is a safe and effective vaccine that can prevent you from getting hepatitis B in the future!

On the other side; healthcare professionals have a duty to provide culturally competent care to LGBTQ+ individuals and encourage hepatitis B testing and vaccinations. The Centers for Disease Control and Prevention (CDC) has recommendations and guidelines for health professionals here.

 

Citations:

  1. Fethers, K., Marks, C., Mindel, A., & Estcourt, C. S. (2000). Sexually transmitted infections and risk behaviours in women who have sex with women. Sexually transmitted infections, 76(5), 345–349. https://doi.org/10.1136/sti.76.5.345
  2. https://hepfree.nyc/hep-c-transgender-health/
  3. https://www.hepb.org/what-is-hepatitis-b/hepatitis-c-co-infection/

Take Pride in Your Health: LGBTQ+ & Hep B

June is Pride Month! As we celebrate our differences and recognize the rights of the LQBTQ+ community, it is important to highlight the health disparities that they face, and ways to overcome such difficulties. To help spread awareness about the impacts of hepatitis B within this group, we‘ve interviewed Thaddeus Pham, Co-Director of Hep Free Hawaii!

 

 

 

 

 

 

Hi Thaddeus! So to start off with, can you tell us a little about who you are, and why this topic is important to you?

Thanks, Michaela! Well, I am currently the Co-Director for Hep Free Hawaii, our statewide coalition dedicated to eliminating hepatitis and related harms on our islands. I am also the Viral Hepatitis Prevention Coordinator for the Hawaii State Department of Health, although most folks in the community have also dubbed me the “Queen of Hepatitis” hahaha. 

This work is important to me personally because I am a cisgender, gay man whose parents were born in Vietnam. As such, my work in public health has always been informed by the intersection of multiple identities, in this case, people who are LGBTQ+ and also foreign-born Asians or Pacific Islanders. That’s why I was so excited you asked me to chat about the impact of hepatitis B on gay and bisexual men. 

As the Queen of Hepatitis, can you explain more about hepatitis B & how it impacts members of the LGBTQ+ community?

Sure thing! First of all, hepatitis B is a highly infectious blood-borne disease that can be transmitted through sex, injection drug use, and from mother-to-child during childbirth. The hepatitis B virus attacks the liver and causes an acute (short-term) or chronic (life-long) infection. If untreated, it can lead to liver disease, liver cancer, and even death. 

In the United States, gay and bisexual men are at high risk for hepatitis B infection, usually through sex. According to the CDC, about 20% of new hepatitis B infections occur among this community. Think about that: 1 out of 5 new cases of hep B is a gay or bisexual man. To my community, I say: get tested!

Good point! What are some additional reasons to get tested for hepatitis B? 

Well, getting tested for hepatitis B is essential for many reasons:

  1. Hepatitis B is called a “silent infection”; there are usually no symptoms until it gets pretty bad (e.g., serious liver damage or even liver cancer). Liver damage can be happening even if you don’t notice any symptoms. Also, the virus can be spread even if you are asymptomatic. Testing is the only way to know for sure that you are not living with hepatitis B. 
  2. Co-infections with hepatitis B can be dangerous. People living with hepatitis C and HIV/AIDS are at higher risk of contracting hepatitis B, and will also suffer more serious complications.  Even a co-infection with hepatitis A, which is short-term, can cause liver damage. Knowing your hepatitis B status can help your healthcare providers treat you properly and lower your risk of liver disease and liver cancer!
  3. Acute infections can have future consequences. About 90% of hepatitis B infections in adults are acute. This means that your body will recover from the virus in 6 months or less. The virus will no longer be in your bloodstream, but it will be “sleeping” in your liver. Even though the hepatitis B virus is not causing any damage and you are not infectious, the infection can be reactivated by certain medications and treatments. That’s why it is important to know that both you and your healthcare provider are 100% sure of your hepatitis B status. 

Wow, so is hepatitis B preventable? 

Hepatitis B can be prevented with a vaccine! If you get tested for hepatitis B and learn that you have no infection and no immunity, you can get the 2-dose hepatitis B vaccine, which protects you in a month, or the 3-dose vaccine, which can offer protection in six months. If possible, get tested first because the vaccine will only protect you if you don’t have the virus yet. Also, remember to get ALL the recommended doses of the vaccine series so you can be fully protected. Finally, if you are unsure of your status, it is important to use a condom. A condom is effective in preventing transmission of hepatitis B as well as other STIs, including HIV.

Great! So, where can someone get tested or vaccinated for hepatitis B? 

Your healthcare provider can provide hepatitis B testing and vaccination services. If you do not have a doctor, federally qualified health centers, community health clinics like Planned Parenthood, and your local health department can test and vaccinate you for hepatitis B. The CDC  lists LGBTQ+-friendly health centers here. The vaccine is covered by most insurance providers, as well as Medicare part B for high-risk groups.

Is there anything I can do to help raise awareness? 

Let’s talk about it! Even though it is just as harmful as HIV, hepatitis B is not as widely discussed among gay and bisexual men. This is scary because the U.S. is seeing an increase in adult acute hepatitis B cases, and studies show that hepatitis B vaccination rates are low amongst gay and bisexual men. 

Talk to your friends, your partners, and your community to know their status, and to take action to protect themselves! The CDC has free resources that can help promote vaccination, as well as information that can help you get the discussion started. 

Thanks Thaddeus! Any final thoughts you would like to share with our readers? 

Thank YOU, Michaela! I really appreciate this opportunity to chat about the impact of viral hepatitis on gay and bisexual men. I think it is important to point out the LGBTQ+ community also encompasses our lesbian and bisexual sisters as well as our transgender and gender nonconforming siblings, who could also benefit from hepatitis vaccinations and care.  

Finally, I can’t help but think about Pride month in the context of the COVID-19 pandemic and Black Lives Matter protests. I am super grateful to work with Hepatitis B Foundation, who has always aligned with one of the core concepts of our hepatitis efforts in Hawaii: public health work is social justice work! 

Hepatitis B Research Review: May

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

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

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

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

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

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

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

 

Does Hepatitis Delta Increase My Risk for Liver Cancer?

 

 

 

 

 

The short answer is, possibly.  Although there is extensive research to support the role of hepatitis delta in accelerating the risk for progression to cirrhosis (liver scarring) compared to hepatitis B infection (1,2) only, strong data directly linking an increase in risk for hepatocellular carcinoma (HCC) is lacking. It is known that coinfection promotes continually progressing inflammation within the liver by inducing a strong immune response within the body; where it essentially attacks itself (3), but the specific role of hepatitis delta in HCC isn’t fully understood. It gets complicated because although cirrhosis is usually present in hepatitis B patients who also have HCC, but scientists have not pinpointed a specific way that the virus may impact cancer development (4). There have been some small studies that have documented a correlation between hepatitis delta and an increase in HCC, but some analysis’s have even called the extent of its involvement in HCC as ‘controversial’ (5). However, other scientific studies may suggest the contrary.

Because hepatitis delta cannot survive without hepatitis B, and doesn’t integrate into the body the same way, it may not be directly responsible for cancer development, but it has been suggested that the interactions between the two viruses may play a role (6). It has also been suggested that hepatitis delta may play a role in genetic changes, DNA damage, immune response and the activation of certain proteins within the body – similarly to hepatitis B and may amplify the overall cancer risk (7,8). One of these theories even suggests that hepatitis delta inactivates a gene responsible for tumor suppression, meaning it may actually promotes tumor development, a process that has been well-documented in HCC cases (9,10).

Regardless of the specific impact or increase in risk for HCC due to the hepatitis delta virus, hepatitis B is known to increase someone’s risk, with 50-60% of all HCC globally attributable to hepatitis B (11). People with hepatitis delta coinfection still need to be closely monitored by a liver specialist, as 70% of people with both viruses will develop cirrhosis within 5-10 years (12). Monitoring may be blood testing and a liver ultrasound to screen for HCC every 6 months. Closer monitoring may be required if cirrhosis is already present, or to monitor response to treatment (interferon).

For more information about hepatitis delta, visit www.hepdconnect.org.

References:

  1. Manesis EK, Vourli G, Dalekos G. Prevalence and clinical course of hepatitis delta infection in Greece: A 13-year prospective study. J Hepatol. 2013;59:949–956.
  2. Coghill S, McNamara J, Woods M, Hajkowicz K. Epidemiology and clinical outcomes of hepatitis delta (D) virus infection in Queensland, Australia. Int J Infect Dis. 2018;74:123–127.
  3. Zhang Z, Filzmayer C, Ni Y. Hepatitis D virus replication is sensed by MDA5 and induces IFN-β/λ responses in hepatocytes. J Hepatol. 2018;69:25–35.
  4. Nault JC. Pathogenesis of hepatocellular carcinoma according to aetiology. Best Pract Res Clin Gastroenterol. 2014;28:937–947.
  5. Puigvehí, M., Moctezuma-Velázquez, C., Villanueva, A., & Llovet, J. M. (2019). The oncogenic role of hepatitis delta virus in hepatocellular carcinoma. JHEP reports: innovation in hepatology, 1(2), 120–130.
  6. Romeo R, Petruzziello A, Pecheur EI, et al. Hepatitis delta virus and hepatocellular carcinoma: an update. Epidemiol Infect. 2018;146(13):1612‐1618.
  7. Majumdar A, Curley SA, Wu X. Hepatic stem cells and transforming growth factor β in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2012;9:530–538.
  8. Mendes M, Pérez-Hernandez D, Vázquez J, Coelho AV, Cunha C. Proteomic changes in HEK-293 cells induced by hepatitis delta virus replication. J Proteomics. 2013;89:24–38.
  9. Chen M, Du D, Zheng W. Small Hepatitis Delta Antigen Selectively Binds to Target mRNA in Hepatic Cells: A Potential Mechanism by Which Hepatitis D Virus Down-Regulates Glutathione S-Transferase P1 and Induces Liver Injury and Hepatocarcinogenesis. Biochem Cell Biol. August 2018.
  10. Villanueva A, Portela A, Sayols S. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. 2015;61:1945–1956.
  11. Hayashi PH, Di Bisceglie AM. The progression of hepatitis B- and C-infections to chronic liver disease and hepatocellular carcinoma: epidemiology and pathogenesis. Med Clin North Am. 2005;89(2):371‐389.
  12. Abbas, Z., Abbas, M., Abbas, S., & Shazi, L. (2015). Hepatitis D and hepatocellular carcinoma. World journal of hepatology, 7(5), 777–786.