April 21st and 22nd, 2022 marked the occurrence of a roundtable meeting solely focused on hepatitis delta virus (HDV), which was jointly hosted by the American Liver Foundation and the Hepatitis B Foundation. This was one in a series of events taking place this year to raise the profile of hepatitis delta, a serious coinfection of hepatitis B virus (HBV) that is estimated to affect between 5 and 10% of people who are living with HBV. HDV is more severe than HBV alone, with a 70% chance of developing into cirrhosis or liver cancer if unmanaged, compared to an approximately 25% chance for those living with HBV alone. With approval of the first official treatment for hepatitis delta in Europe in July of 2020, expected approval in the United States later in 2022, and other treatments moving through the clinical trial pipeline, more is happening in the world of hepatitis delta than ever before. Despite the promising treatment landscape, the virus still remains significantly under-diagnosed (making estimation of true prevalence difficult), largely due to lack of awareness, low prioritization compared to other health conditions, and limited advocacy, and big questions persist about treatment equity, including access to knowledgeable providers, clinical trials, and available medications. The purpose of this roundtable was to begin a conversation among a diverse group of stakeholders about some of these issues, to bring attention to HDV and its potential consequences, to identify unmet needs in this area, and to prepare calls to action and next steps to address these needs.
Participants at the roundtable included individuals living with hepatitis delta, caregivers, healthcare providers, public health professionals, and representatives from community-based organizations. The conversation was very generative and really underscored some of the key issues that exist around hepatitis delta, including gaps in awareness and knowledge among medical and high-risk communities and limited access to and availability of HDV screening and care. These factors lead to under-diagnosis and under-surveillance, making the production of accurate data difficult, which in turn complicates advocacy efforts, since compelling data is often a key ingredient for policy change that might make screening, treatment, and linkage to care more available and accessible.
The ultimate planned outcome of this virtual event will be production of a white paper that will highlight key takeaways from the discussion, clearly outline unmet needs and priority issues for people living with HDV, and detail calls to action for stakeholders at every level to meet these needs and overcome some of the significant barriers and challenges that persist in diagnosing, managing, and treating HDV.
Another goal of the meeting was to begin to develop resources that can better support and engage the larger community around HDV awareness and advocacy – a first step toward this goal will be creation and dissemination of a visually appealing infographic, which will provide at-a-glance information about HDV and its estimated prevalence, transmission, prevention, testing, and treatment.
The white paper and infographic are expected to be complete by early summer 2022. The organizers of this roundtable meeting are hopeful that its outcomes will bring hepatitis delta virus more into focus for various stakeholder communities and generate more engagement and energy around this dangerous virus that has long been neglected and is not receiving the attention it deserves.
2022 is shaping up to be a big year for hepatitis delta, the rare but serious virus that can co-infect people who are already living with hepatitis B. As a quick refresher, hepatitis delta is a virus that depends upon the hepatitis B virus in order to survive and replicate – so only those who are already living with hepatitis B can become infected with hepatitis delta. Hepatitis delta virus (HDV) is believed to infect between 5 and 10% of people living with hepatitis B virus (HBV). HDV can occur through either a superinfection or a coinfection. A superinfection occurs when someone who is already living with HBV contracts HDV, in which case there is a very high chance that the individual will develop chronic (lifelong) infections of both HBV and HDV. A coinfection occurs when both HBV and HDV are contracted at the same time – when this happens in adults, both infections tend to clear within six months and there is only a 5% chance that chronic HBV and HDV will occur. Chronic HDV is particularly dangerous because it advances progression to serious liver damage and liver failure much more quickly than HBV alone – 70% of people diagnosed with HDV and HBV will experience serious liver damage within 10 years without intervention, compared to 15-30% of people diagnosed with HBV alone.
So, What’s Happening in the World of Hepatitis Delta?
The past 18 months have been very important for hepatitis delta research and drug development. In July of 2020, the European Medicines Agency approved Hepcludex, the first-ever drug approved for treatment of hepatitis delta, for prescription in France, Austria, and Germany. Hepcludex works by stopping HDV from entering and infecting liver cells (and is known as an entry inhibitor). In 2021, MYR Pharma, the German company that originally developed Hepcludex, was bought by Gilead Sciences, Inc., which is based in the United States, and which has since filed a Biologics Licensing Agreement for approval of Hepcludex by the US Food and Drug Administration, which is expected later this year. At this time, there is not a timeline for when Hepcludex approval will be expanded to more countries and parts of the world. Prior to Hepcludex, the only drug available for hepatitis delta management, which was never officially approved, was called pegylated interferon alpha. This drug, still in use today, is only effective in controlling HDV in about 25% of people living with the virus and has challenging side effects that can negatively impact quality of life.
In addition to Hepcludex, two other promising drugs are in clinical trials, both developed by Eiger BioPharma in the United States. The first of these is called Lonafarnib, which is being evaluated for how well it works to target the protein assembly process, which keeps new viruses from being created (it is known as a prenylation inhibitor). Lonafarnib, in combination with another drug called Ritonavir, is currently in Phase III clinical trials (the phase in which the safety and effectiveness of a drug is compared to that of currently available treatments). These trials are fully enrolled, and data is expected by the end of 2022. Additionally, Eiger is currently enrolling phase III clinical trials for Pegylated Interferon Lambda, which works by stimulating the body’s own immune system to fight the virus. For a full list of drugs under investigation for hepatitis delta, including one from Janssen Research and Development and one from Antios Therapeutics, visit our Drug Watch page.
Are There Other Clinical Trials Happening for Hepatitis Delta?
Yes! There are clinical trials happening worldwide to test many of the drugs listed above and more. You can check out our clinical trials page here. This page includes a detailed description of each clinical trial, along with information about where it is being conducted and how to contact the principal investigator (or person leading the clinical trial). This page also includes a helpful graphic describing the clinical trial process and what it takes for a drug to move from an idea into the real world. It is important to note that not all of the trials listed here are for the purpose of testing a medication – some are observational studies to monitor what are called disease biomarkers, which are physical measures used to monitor the progress of a disease and could include tests of blood or liver function, for example. Clinical trials are currently happening in Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, France, Georgia, Germany, Greece, Israel, Italy, Japan, Mongolia, New Zealand, Pakistan, Republic of Moldova, Romania, Russian Federation, Spain, Sweden, Switzerland, Taiwan, Turkey, Ukraine, the United Kingdom, the United States, and Vietnam.
When Will HDV Drugs and Clinical Trials Be More Accessible in More Parts of the World?
This is unfortunately a difficult question to answer. Even though up to 10% of people who are living with hepatitis B are also living with hepatitis delta, there are not good systems in place to make sure that everyone who is living with HBV or who is at increased risk for HDV is tested and diagnosed, so there are not very accurate numbers about how many people in the world are living with HDV. Indeed, of the nearly 300 million people around the world who are living with hepatitis B alone, only 10% are aware of their diagnosis, so this number is undoubtedly far lower than even 10% for hepatitis delta. Without accurate information about how many people are living with the virus, it is difficult for drug and clinical trial developers to invest resources into studying or pursuing drug development or clinical trials for HDV.
Another problem is the many resources of time, money, and labor that are necessary for developing drugs, and preparing and running clinical trials. The development process for a single drug can take anywhere from 5-15 years and a much larger number of drugs fail to complete this process than succeed. Additionally, there needs to be some degree of existing infrastructure in a particular country in order to both support a clinical trial and ultimately to get a drug approved. Unfortunately, this kind of infrastructure is generally already established and easier to navigate in wealthier countries, so these are the countries in which clinical trials are generally held and in which drug approvals tend to happen first. Public health and clinical infrastructure is slowly developing and becoming more prioritized in different parts of the world and hopefully this trend will continue, but for the time being, the locations of clinical trials and approvals for important treatments point to the much larger issues of lack of access to health and healthcare in much of the world, that in turn stem from deep-seated poverty and inequity. Again, as health equity continues to be a focus of the public eye, these trends will hopefully begin to change, paving the way for greater access to healthcare for hepatitis delta, hepatitis B, and countless other health conditions.
What Is Hep Delta Connect’s Role?
This year, Hep Delta Connect will continue its work to raise the profile of hepatitis delta, both in the United States and around the world. We are committed to building awareness through partnerships with community-based organizations, healthcare providers, and governmental agencies around the world and through dissemination of educational materials and programming. We hope to foster greater engagement of those living with and affected by hepatitis delta globally, more focused advocacy efforts to bring HDV into the spotlight, and increased screening, diagnosis, and management of HDV. We keep our website and social media channels updated regularly with program news and events – make sure to follow us on Facebook, Twitter, and Instagram and check out our website frequently! You are always welcome to connect with us anytime at email@example.com. We look forward to an exciting year of work on HDV!
Hepatitis delta is a liver infection that results from the hepatitis delta virus (also known as HDV) that causes the most severe form of viral hepatitis known to human beings. It is also the smallest virus known to infect humans. Hepatitis delta is unique because it is dependent on the hepatitis B virus (HBV) to infect and reproduce in liver cells, so those already infected with hepatitis B are at a greatly increased risk of developing hepatitis delta.
Since testing for hepatitis delta is not as widespread as it should be (everyone who is diagnosed with hepatitis B should also be tested for hepatitis delta), the exact number of people living with hepatitis delta is unknown. Some reports point to 15-20 million people living with hepatitis delta worldwide, but other studies have estimated that as many as 60-70 million people could be living with hepatitis delta around the world.
Co-Infection with Hepatitis B
Co-infection with hepatitis B and hepatitis delta can cause more serious liver disease than hepatitis B infection alone. This includes faster progression to liver fibrosis (or scarring), higher risk of liver cancer, and earlier onset of cirrhosis or liver failure.
There are two ways in which someone living with hepatitis B can become infected with hepatitis delta. One is through co-infection, which occurs when an individual acquires hepatitis B and hepatitis delta infections at the same time, and the other is through super-infection, which occurs when someone who is already living with hepatitis B acquires hepatitis delta.
A co-infection is less common and will often clear up on its own within six months, but sometimes it can cause very dangerous or fatal liver failure. A superinfection is more common and is the culprit of severe liver disease. As many as 90% of people with a superinfection will develop chronic (life-long) hepatitis B and hepatitis delta infections, 70% of which will progress to cirrhosis. This compares to only 15-20% of chronic hepatitis B infections alone.
Transmission and Prevention
Hepatitis delta can be transmitted in the same ways as hepatitis B, through exposure to infected blood or bodily fluids. This occurs most often through the sharing of hygiene equipment; practices of bodily alterations, such as tattoos, piercings or scarification; unsterile healthcare practices; sharing needles, syringes, or other paraphernalia during injection drug use; or having unprotected sex. Although hepatitis B virus is most commonly transmitted from mothers to their babies during childbirth, it is believed that hepatitis delta transmission through this route is uncommon. Since hepatitis delta cannot be contracted on its own, only people who are already infected with hepatitis B or who are at high risk of contracting both viruses simultaneously can contract hepatitis delta.
A vaccine for hepatitis delta does not exist, but fortunately, the vaccine for hepatitis B protects against hepatitis delta as well! Just as with hepatitis B, family members and sexual partners of people living with hepatitis delta should also receive the hepatitis B vaccine to significantly lower their risk of contracting hepatitis B and hepatitis delta. For those who are already infected with chronic hepatitis B, the best way to protect yourself from hepatitis delta is to practice protected sex (with a condom) and avoid potential blood exposure.
All individuals who have been diagnosed with hepatitis B should also get tested for hepatitis delta. The test is a simple blood test. Hepatitis delta can be managed by a doctor – it is most dangerous when a person does not know they have it, making it that much more important to get tested!
Who is at Risk
If you are living with chronic hepatitis B, you are at risk for hepatitis Delta. Groups at risk for hepatitis delta include:
People chronically infected with hepatitis B are at risk for infection with HDV.
People who are not vaccinated for hepatitis B
People who inject drugs
Indigenous people and people with hepatitis C virus or HIV infection
Recipients of hemodialysis
Men who have sex with men
Commercial sex workers
Individuals from countries or regions where hepatitis delta prevalence is high
Several geographical hotspots have a high prevalence of hepatitis delta infection, including Mongolia, the Republic of Moldova, and countries in Western and Middle Africa.
If you are living with hepatitis B, it is recommended you get tested for hepatitis delta. Please ask your healthcare providers to be tested for hepatitis delta.
The Hepatitis B Foundation has resources for patients living with hepatitis delta.
Drug Watch – Drugs and Medications in Development for Hepatitis Delta
Clinical Trials – Clinical trials are research studies that test new potential treatments for a disease. Talk to your doctor about possible clinical trials that could be helpful to you.
Find a Doctor – Visit our Physician Directory to locate a doctor near you! It now includes a specific search tool to locate doctors that also manage hepatitis delta patients. For additional assistance locating a doctor, email firstname.lastname@example.org.
Providers in the United States can request hepatitis Delta tests from Quest Diagnostics. It is recommended that you first call your local Quest representative to confirm that the location does this specialty testing.
Below is the coding list for hepatitis delta testing as well as quantitative HBsAg and hepatitis B genotyping.
Quest Test Code for HDV Antibody Total—4990 Set up 2 times/week
Quest Test Code for HDV Antibody IgM—35664 Set up 2 times/week
Quest Test Code for HDV RNA Quantitative PCR—37889 Set up 6 times/week
Quest does not currently offer a national test code for hepatitis delta antibody reflex to HDV RNA quantitative, but you can coordinate with the Quest commercial person that covers your account to possibly set up a custom reflex.
The 2020 meeting of the American Association for the Study of Liver Diseases (AASLD) in November offered the opportunity for scientists from industry and academia to present their findings from clinical trials, studying new medications for hepatitis B and D. Two such presentations were given by Eiger BioPharmaceuticals, Inc. who presented their findings about how well their medications peginterferon lambda and lonafarnib work, both independently and in combination, to treat hepatitis delta virus (HDV) and halt liver fibrosis. The results are promising and offer hope for those affected by HDV.
The two medicines under investigation in these studies work in different ways. Lonafarnib works by blocking farnesyl transferase, an enzyme involved in prenylation, the modification of proteins that is necessary for the life cycle of HDV. Peginterferon lambda, on the other hand, triggers immune responses that are crucial for host protection during viral infections. Lambda can also target liver cells accurately, thus reducing the effects of inadvertently targeting central nervous system cells and making it more tolerable to those taking it (Eiger, 2020).
Eiger’s first study examined how well peginterferon lambda and lonafarnib (known as LIFT – Lambda InterFeron combo Therapy) work together to lower levels of HDV RNA, 24 weeks post-treatment (Eiger, 2020). This was a Phase 2 study. Lambda was administered at a dosage of 180 mcg once weekly, in combination with 50 mg of Lonafarnib and 100 mg of ritonavir given twice daily, for 24 weeks. The results of this study found that 77% of the 26 participants saw their HDV RNA levels decline and reach a level that was either undetectable or below the level of quantification. 23% of these participants were able to maintain these levels for 24 weeks after treatment had ended. Both tenofovir and entecavir were started prior to treatment for management of HBV. The observed side effects of this regimen were mild to moderate and included mostly gastrointestinal issues or were related to blood chemistry (Eiger, 2020).
The second study found that peginterferon lambda caused the regression of liver fibrosis after 48 weeks of treatment in people living with hepatitis delta. Two case studies emerged from the completed Phase 2 LIMT (Lambda Interferon MonoTherapy) study (Eiger, 2020). In these studies, a total of 33 participants received either 180 µg or 120 µg of lambda subcutaneous injections weekly for 48 weeks. Results indicated that degrees of liver fibrosis and levels of HDV RNA declined below the level of quantification in some participants, even after 72 weeks in a handful of cases. In some instances, ALT levels decreased as well. Side effects were found to be mild to moderate and fewer than those experienced by participants who had taken peginterferon alpha in the past. Side effects were primarily flu-like in nature (Eiger, 2020).
Therapies for hepatitis B and D will only continue to improve and become more precise and targeted as time goes by. Check out the Hepatitis Delta Connect website for detailed information on HDV, as well as current clinical trials and a drug watch page, both of which are updated regularly. (A brand-new clinical trial has just been added!) For more information about Eiger BioPharmaceuticals, click here.
New Drug Approved for Treatment of Hepatitis Delta in Europe
A new drug to treat hepatitis delta has now been approved by the European Commission! The drug is called bulevirtide and will be marketed under the brand name Hepcludex. It was previously known at Myrcludex B. This approval follows a quarter century of research and development and is the first drug specifically for hepatitis delta approved in Europe. Due to the high prevalence of the hepatitis delta virus in Russia and the former Soviet Union, it has been approved for use there since the end of 2019, under the name Myrcludex. The European Medicines Agency recommended the drug for approval by the Commission at the end of May 2020 (German Center for Infection Research, 2020).
How Does It Work?
Hepcludex, developed by university researchers in Heidelberg, Germany, works as an entry inhibitor – that is, it prevents hepatitis delta virus (HDV) cells, and the hepatitis B virus (HBV) cells upon which HDV depends, from entering healthy liver cells. Both HDV and HBV cells are able to replicate and thrive exclusively in the liver because they need the bile acid transporter NTCP in order to do so. This transporter is the avenue through which HDV is received into the liver cell. Hepcludex works by blocking this reception process, so that the virus does not continue to infect healthy liver cells (German Center for Infection Research, 2020). The currently infected cells either die or are destroyed by the immune system.
How Have People Responded?
Hepcludex is an injectable medication given daily for 48 weeks. In phase I and II clinical trials, people seemed to respond well to this treatment. It seems that just a small amount of Hepcludex is needed, which is good news because it means that the normal processes of the bile salt transporter (NTCP – the receptor of the hepatitis delta virus) will not be widely disrupted (German Center for Infection Research, 2020). MYR Pharmaceuticals GmbH, which now has the license for Hepcludex, is currently in the process of running further phase II and larger phase III trials, in order to continue to determine long-term effects. Hepcludex has also been tested in combination therapy with PEG Interferon, which is administered weekly also via injection (Highleyman, 2019).
Does it also work for Hep B?
Right now, Hepcludex has been tested and works to treat people with hepatitis delta. Since hepatitis delta becomes the dominant virus in those co-infected with hepatitis B and hepatitis delta, clearing hep delta will not necessarily clear hep B as well. However, the curative properties of this drug for those only affected with hep B are being investigated, both alone and in combination with PEG interferon, and there was a loss of surface antigen (HbsAg) noted in 20% of clinical trial participants who were given this combination (Highleyman, 2019).
What does this mean for patients?
Research thus far indicates that Hepcludex can be more effective than interferon alone, the existing hepatitis delta treatment, which is usually not curative and has challenging side effects (Smith, 2020). Hepcludex is now available for prescription in Europe, although pricing schemes remain unclear. For updated information on pricing and availability, check with your doctor or visit the MYR Pharmaceuticals website here.
Clinical trials will continue to take place for this and other drugs. Researchers and pharmaceutical companies might experience difficulty in recruiting patients for hepatitis delta clinical trials because of a lack of awareness and testing – many people living with hepatitis delta worldwide remain undiagnosed. It is important for people at risk for hepatitis delta to be tested and linked to care if found to be infected. If you have hepatitis delta and are interested in participating in a clinical trial, you can search for one near you. To find a doctor to talk to about getting tested for hepatitis delta if you are living with hep B, click here. Hepatitis delta can often be managed and treated, and you are not alone! The most important first step is to know your status.
What does this mean for providers?
The exact number of people living with hepatitis delta around the world is unknown and estimates range anywhere from 20-70 million. Most of these individuals remain undiagnosed due in large part to a lack of testing and diagnostics. Stephan Urban, one of the researchers leading the effort in the development of Hepcludex has said that, in the United States, fewer than 5% of those tested for hepatitis B are also tested for hepatitis delta (Smith, 2020). It is true that in much of the world diagnostic tools remain unaffordable and so Dr. Urban and his team are developing a much less expensive and rapid test. If the capacity exists, however, testing is crucial for the management of this most severe form of viral hepatitis and all of the subsequent liver conditions that can develop from it. Additionally, as with all infectious diseases, vaccination of ALL people to prevent hepatitis B is critical. Click here for more information on hepatitis delta in general and here for questions and concerns.
Highleyman, L. (2019, December 16). Combination therapies show promise against hepatitis D. Retrieved August 31, 2020, from https://www.worldhepatitisalliance.org/latest-news/infohep/3548132/combination-therapies-show-promise-against-hepatitis-d
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.
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.
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.
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).
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.
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.
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.
Nault JC. Pathogenesis of hepatocellular carcinoma according to aetiology. Best Pract Res Clin Gastroenterol. 2014;28:937–947.
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.
Romeo R, Petruzziello A, Pecheur EI, et al. Hepatitis delta virus and hepatocellular carcinoma: an update. Epidemiol Infect. 2018;146(13):1612‐1618.
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.
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.
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.
Villanueva A, Portela A, Sayols S. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. 2015;61:1945–1956.
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.
Abbas, Z., Abbas, M., Abbas, S., & Shazi, L. (2015). Hepatitis D and hepatocellular carcinoma. World journal of hepatology, 7(5), 777–786.
In October 2019, the Hepatitis B Foundation had the opportunity to speak with Andrew Vaillant, Ph.D., Chief Scientific Officer at Replicor at the annual International HBV Meeting in Melbourne, Australia. Dr. Vaillant gave us an inside look at REP 2139 – their drug candidate developed for the treatment of chronic hepatitis B and HBV/HDV coinfection. REP 2139 is a nucleic acid polymer that removes surface antigen (HBsAg) and as part of combination therapy, has achieved functional cure for chronic HBV (sustained HBsAg loss) and sustained clearance of HDV infection from the blood in early phase II proof of concept clinical trials it has completed to date. REP 2139 is currently in phase II of clinical trials. Below is Dr. Vaillant’s response to a series of questions we posed to him.
1. Replicor’s drug candidate REP 2139 is a nucleic acid polymer (NAP) for the treatment of chronic hepatitis B. Can you explain the mechanism for this drug and how it works?
REP 2139 is a polymer built from the building blocks the body uses to store genetic material in the body (nucleic acids). These building blocks are linked together in a unique pattern to form nucleic acid polymers (or NAPs for short) and in the case of REP 2139, use only naturally occurring nucleic acids and modifications to prevent it being recognized as a foreign molecule. As a result, REP 2139 is very well tolerated and safe in clinical trials.
In HBV infection, the most abundant viral antigen in the blood is the hepatitis B surface antigen (HBsAg) which plays an important role in preventing immune control of HBV. Circulating HBsAg is almost entirely in the form of non-infectious HBV subviral particles (SVP) which are produced independently from viral replication, making this viral antigen difficult to target with approved therapies. REP 2139 naturally enters liver cells (hepatocytes) and blocks the assembly of SVP in any hepatocyte producing SVPs. This mechanism effectively blocks the replenishment of HBsAg in the blood and also reduces HBsAg inside these hepatocytes. The overall antiviral effect of REP 2139 is to allow the body to clear HBsAg in order to reduce or remove the inhibition of immune control caused by this viral antigen.
2. REP 2165 is also mentioned as a drug candidate. Can you explain the difference between REP 2139 and REP 2165.
REP 2165 is a close cousin of REP 2139 being examined for potential use in future therapy with more frequent dosing to improve HBsAg response in selected cases and was proven to be as effective as REP 2139 in this study. More information about REP 2165 can be found under question 6.
3. Can you share the latest results from phase 2 trials? How is REP 2139 administered to patients, and for what duration of time? What kind of side effects can patients expect with REP 2139?
In our latest trials, side effects have been limited to mild effects from pegylated interferon (pegIFN). REP 2139 is currently given in a formulation (REP 2139-Mg) which results in little to no side effects during administration. REP 2139 is currently administered once every week for 48 weeks by intravenous infusion in combination with other antiviral agents. REP 2139-Mg is expected to be as effective with a once weekly injection under the skin (subcutaneous injection) which will be used in future trials.
4. Is REP 2139 equally effective in HBeAg positive and negative patients?
REP 2139 is effective in HBeAg positive and in HBeAg negative patients in multiple genotypes. As REP 2139 targets a host protein involved in SVP formation and not the virus or SVP directly, its antiviral effects are expected to be similar in all HBV genotypes and may also be effective in the presence of other co-infections with HBV such as HCV and HIV.
5. Can REP 2139 be safely used in patients with cirrhosis?
Another of the remarkable features of NAP based therapy is the high rate of flares in liver transaminases during therapy (occurring in almost all participants in the REP 401 study). Patients with these flares had no symptoms or any negative impact on their liver function.
Continually expanding evidence in the field tells us that during treatment of HBV, these flares are signs of elimination of HBV infection from the liver and are not accompanied by changes in liver function. These same features appear to hold true for transaminase flares during NAP therapy and, when occurring in the absence of HBsAg in the blood, are highly correlated with functional cure in our clinical trials. The ability of cirrhotic patients to tolerate these flares will be tested in future trials and we are encouraged by recent results (produced by a different group) with pegIFN in HBV / HDV co-infected patients showing that host mediated transaminase flares may also be well tolerated in cirrhotic patients.
6. Do you anticipate combination therapy will be needed? Will combination therapy include immune modulators like pegylated interferon and/or treatment with antivirals?
Replicor’s latest REP 401 study is the first in the field to feature triple combination therapy: Tenofovir disoproxil fumarate (TDF), pegIFN and either REP 2139-Mg or REP 2165-Mg. REP 2165 is a close cousin of REP 2139 being examined for potential use in future therapy with more frequent dosing to improve HBsAg response in selected cases and was proven to be as effective as REP 2139 in this study. In addition to the excellent control of HBV DNA with TDF exposure, this triple combination therapy for 48 weeks led to meaningful HBsAg decline (greater than a 10-fold reduction from baseline) in 90 % of participants, HBsAg clearance to very low levels similar to HBsAg “negative” in the qualitative test used in the United States (< 0.05 IU/mL) and HBsAg seroconversion (often with very high titers of anti-HBs antibodies) in 60% of participants. After removal of all treatment (including TDF), a 48-week follow-up yielded very encouraging results: 89% had normal liver function, 56% had reduced liver inflammation, 39% had stable virologic control and an additional 39% had functional cure with HBsAg seroconversion. These results illustrate the effectiveness of combining potent HBsAg reduction with immunotherapy but also suggest that direct acting antivirals such as TDF and entecavir may also contribute to establishing functional cure in a combination setting.
7. Surface antigen loss is key to people living with chronic HBV. Do you believe REP 2139 can provide a functional cure for chronic HBV?
In an early clinical study using NAPs alone, HBsAg clearance by itself resulted in virologic control (low level infection with normal liver infection no longer requiring therapy under current guidelines ) or functional cure (complete control of HBV DNA and HBsAg) persisting after removal of all therapy only in a small proportion of patients but stable throughout a 5 year follow-up. Importantly, HBsAg clearance with REP 2139 in a subsequent study led not only to a dramatic improvement in the activity of various immunotherapies (including pegIFN) but to virologic control occurring in a larger proportion of patients after removal of therapy persisting throughout more than 2 years of follow-up. As a result of these early studies, Replicor believes that the best approach to achieving functional cure of HBV infection is to simultaneously combine potent HBsAg reduction using REP 2139 with immunotherapy to restore effective and long-lasting immune control.
8. Which countries do you anticipate phase 3 trials to occur? Do you anticipate trials in the U.S?
Replicor believes that the combination of therapy with NUCs such as TDF and ETV, pegIFN and REP 2139-Mg will be the first available therapy to offer patients a real chance of eliminating the need for therapy and establishing functional control of their HBV infection and normalizing their liver function. Work is ongoing to start a phase II US trial in collaboration with the Aids Clinical Trials Group as soon as possible. We are also planning to assess other immunotherapies, the effectiveness of which we believe will be similarly improved with HBsAg clearance as we have demonstrated for pegIFN.
9. With regard to hepatitis delta, is there a difference in the mechanism for how it works?
REP 2139 is also potently active against HDV infection and is able to rapidly eliminate HDV RNA, normalize liver function and reverse the liver inflammation associated with HBV / HDV co-infection. The completed follow-up results from our long term follow-up study of co-infected participants treated with REP 2139 and pegIFN show complete control of HDV infection at 3.5 years follow-up in the absence of all therapy in a large proportion of patients. In many patients this control of HDV infection was associated with functional cure of HBV and in some patients with virologic control of HBV. This potent effect against HDV infection is assumed to be driven not only from the effect of REP 2139 on SVP (which also forms the envelope of the HDV virus) but on the ability of REP 2139 to interact with different forms of the hepatitis delta antigen protein essential for HDV replication and assembly.
Thank you to Dr. Vaillant for taking the time to talk to us about REP 2139. The results look promising! We look forward to learning more from continuing and new trials with REP 2139, used alone and in combination with antivirals and immune modulators. We know the hepatitis B virus is challenging, but those living with chronic HBV look forward to a day when there are therapies resulting in a durable loss of surface antigen and sustained viral suppression in a reasonable, finite amount of time.
Eiger is currently working on two new drugs for hepatitis delta; Lonafarnib and Pegylated Interferon Lambda, which are both currently inphase 3 clinical trials. Lonafarnib is a new type of treatment that attempts to control hepatitis delta through a new method: through blocking a key enzyme that is needed for the hepatitis delta virus to replicate. Blocking this enzyme prevents a new virus from being created, which may control and even cure hepatitis delta.
Lambda is being developed as a better tolerated interferon compared to interferon alfa (IFN alfa). Interferons work by stimulating the body’s own immune system to fight the virus. Pegylated interferon alpha, which is the only current treatment for hepatitis delta, is a difficult treatment to tolerate, with many patients experiencing unpleasant side-effects. Lambda utilizes the same method of treatment as IFN alfa, in combination with a new strategy, which stimulates an immune response and targets receptors in the liver, which may reduce side effects and result in improved tolerability.
Below is Eiger Biopharmaceuticals’ response to a series of questions we posed to them.
1. Lambda is an immunomodulator and Lonafarnib is a prenylation inhibitor. Can you explain in laymen’s terms the mechanism for these drugs and how they work?
Eiger’s wording: Lonafarnib is a well-characterized, first-in-class, orally active inhibitor of an enzyme that is key to a vital process in the life cycle of HDV. Inhibiting this enzyme blocks the ability of HDV to assemble and package viral particles. Currently approved nucleos(t)ide treatments for HBV only suppress HBV DNA, do not affect HBsAg, and have no impact on HDV infection.
Lambda is being developed as a better tolerated interferon compared to interferon alfa (IFN alfa). Lambda is a well-characterized, first-in-class, type III interferon (IFN) that stimulates immune responses that are critical for the development of host protection during viral infections. By targeting receptors that are localized in the liver, Lambda treatment may reduce side effects and result in improved tolerability .
Can you share, in simple terms, the basic results of Eiger phase 3 studies for hepatitis delta trials? Are these drugs equally effective in HBeAg positive and negative HBV patients?
The Eiger Phase 2 LOWR program with Lonafarnib has been completed. Over 120 patients were dosed in Phase 2 dose-finding studies to identify combination regimens of lonafarnib (LNF) and ritonavir (RTV) with and without pegylated interferon-alfa (PEG IFN α), with efficacy and tolerability to enable viral load suppression of HDV RNA and ALT normalization at Week 24.
Dosing regimens of LNF 50 mg twice daily + RTV 100 mg twice daily with and without PEG IFN-a-2a 180 mcg once weekly were identified with the following reported results:
All-oral: Lonafarnib boosted with ritonavir
29% of patients achieved ≥ 2 log decline and ALT normalization
Combination: Lonafarnib boosted with ritonavir + PEG IFN-a-2a
63% of patients achieved ≥ 2 log decline and ALT normalization
These dosing arms are being further studied in the global Phase 3 D-LIVR study. Phase 2 studies have not been stratified by HBeAg status.
The D-LIVR Study, a Phase 3 pivotal trial, is on-going and evaluating the safety and efficacy of lonafarnib treatments in patients chronically infected with Hepatitis Delta Virus (HDV). Topline Week 48 data will be available in 2021.
2. How will Lambda and Lonafarnib be administered to patients?
Lonafarnib capsules are administered orally twice daily by mouth. Lonafarnib is taken in combination with ritonavir, a therapeutic booster that increases the bioavailability of lonafarnib. Ritonavir tablets are administered orally twice daily by mouth.
Pegylated interferon-lambda is administered as a self-administered subcutaneous injection once weekly.
3. Do you anticipate combination therapy will be needed and if so, which combinations do you anticipate?
No form of viral hepatitis has been cured with a single drug. Combinations of treatments with different mechanism of actions have always been required.
Lonafarnib and interferons have different mechanisms of action and have been studied as monotherapies and in combination together as treatments for HDV. While each treatment alone reduces the HDV viral load, combination studies have shown that using these treatments together leads to a synergistic effect and further reduces the HDV viral load.
Recently, the interim end of treatment results of peginterferon lambda (Lambda) and lonafarnib combination study in HDV-infected patients were presented at AASLD 2019. The LIFT study is being conducted within the National Institutes of Health (NIH) at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). LIFT is a Phase 2a open-label study of 26 adult patients with chronic HDV treated with Lambda 180 mcg once weekly in combination with Lonafarnib 50 mg twice daily boosted with ritonavir 100 mg twice daily for 24 weeks. Primary efficacy endpoint is > 2 log HDV RNA decline at end of treatment. At the time of analysis, 19 of 26 patients had reached Week 24. Median HDV RNA decline was 3.4 log IU/mL (IQR: 2.9-4.5, p<0.0001) with 53% (10 of 19) patients achieving below the limit of quantification and 37% (7 of 19) patients achieving undetectable HDV RNA at Week 24. 18 of 19 patients (95%) achieved primary endpoint of > 2 log decline during 24 weeks of therapy. We believe these data are the most encouraging yet in pursuit of HDV cure.
4. What kind of side effects can patients expect with Lambda and Lonafarnib, with or without combination therapy?
The most common side effects of lonafarnib include diarrhea, nausea, fatigue, decreased appetite, vomiting, abdominal pain, and decreased weight. Antacid, antiemetic, and antidiarrheal medications may be used prophylactically to treat these gastrointestinal side effects.
The most common side effects of pegylated interferon-lambda (Lambda) are the expected side effects of interferons. However, these side effects have been demonstrated to be much milder and less severe than what has been previously been shown with pegylated interferon-alfa (alfa). These include musculoskeletal (myalgia, arthralgia, and back pain), flu-like symptoms (chills, pyrexia, and pain) and elevated alanine aminotransferase (ALT) levels.
A combination of these side effects is expected with combination therapy.
5. Are Lambda and Lonafarnib safe for use in people with cirrhosis?
Currently, the safety and efficacy of lonafarnib and pegylated interferon-lambda are being investigated in persons chronically infected with HDV. The clinical trials require study participants meet certain eligibility criteria to be included in these studies. These eligibility criteria may or may not reflect the type of patient who will use these therapies after they receive FDA approval.
Phase 2 and Phase 3 studies both include patients with well-compensated cirrhosis.
6. With a clearance of HDV, would you also anticipate a loss of surface antigen – functional cure for chronic HBV as well? If so, in what percentage of HBeAg and HBeAb patients?
HDV is always found as a co-infection with HBV because HDV requires just a small amount of HBV surface antigen (HBsAg) to complete HDV viron replication. However, an HDV / HBV coinfection leads to much more severe chronic viral hepatitis compared to HBV monoinfection alone. Therefore, it is important to treat HDV, even if HBV is not cured. It is possible to clear HDV RNA without loss of HBsAg.
7. Lambda and Lonafarnib are currently in phase 3 trials for delta. Are you able to provide an approximate timeline for when it will be approved for use in U.S. and Europe?
Eiger BioPharmaceuticals is committed to developing safe and effective therapies for HDV and providing patients with a pathway to gain access to approved therapies as quickly as possible.
The D-LIVR Study is a global study that is evaluating the safety and efficacy of lonafarnib treatment in patients chronically infected with HDV. The D-LIVR Study is recruiting subjects in up to 20 countries in over 100 study sites. The D-LIVR study includes 48 weeks of treatment with two different lonafarnib-based treatment regimens, followed by 24 weeks of follow-up. Primary endpoint is ≥ 2 log decline and ALT normalization at Week 48. Topline data from the Phase 3 D-LIVR study will be available in 2021. For more information about study locations and eligibility, please visit www.clinicaltrials.gov (NCT03719313).
End of Phase 2 meeting with FDA to discuss Phase 3 development with Lambda monotherapy is planned for Q1 2020.
For decades, hepatitis delta, the dangerous coinfection of hepatitis B, was thought to only affect about 5-10% of the estimated 292 million people worldwide with chronic hepatitis B infections. With limited data and funding for research related to this complicated virus, true prevalence data, diagnostic tools and skilled physicians to manage hepatitis B and delta coinfection have remained limited until recent years. Publications in 2019 by Miao, et al., Chen, et al., Shen, et al., are helping to reveal a possibly more accurate picture of the burden of coinfection, conducting meta-analyses comprising data from hundreds of thousands of hepatitis B patients and the general population. While it was previously thought that 15-20 million coinfections existed globally, this new research has suggested there may be between 48-74 million1,2,3. Although these studies analyzed data that classified the presence of hepatitis delta antibodies, which can be present in cases of both past or current infection, there is a strong correlation between their presence and likelihood of an ongoing infection. These new studies may place coinfection at upwards of 10-15% of those with hepatitis B, with some of the hardest hit areas facing coinfection rates greater than 30%, in regions like Central Asia, Eastern Europe, Central Latin America and West and Central Africa1,2,3.
Understanding hepatitis delta is vital to helping to identify coinfected patients, who require altered treatment and management plans, and who may progress to cirrhosis and/or liver cancer in periods as little as 5-10 years. Diagnosis and management for hepatitis delta is still a challenge in much of the world, but in the US, it is becoming easier than ever before, with Quest Diagnostics, a commercial U.S. lab, rolling out a new HDV RNA test, a game-changer for physicians to easily order the test and manage patients. HDV RNA testing was previously available only through the Utah-based lab, ARUP, and Boston’s Cambridge Biomedical, but had to be specialty ordered. As testing continues to become more widely available and affordable, hepatitis B patients can more easily access testing. The more patients who are diagnosed, the more evidence for the urgent need for improved treatments to combat the virus, which is currently poorly controlled by the only available treatment; pegylated interferon.
Luckily, the virus has attracted the attention of nine pharmaceutical companies from around the world, with each working on a different approach to better controlling, or even curing hepatitis delta. Two of these companies, Eiger Biopharmaceuticals (US) and Myr Pharma (Germany) are now in Phase 3 clinical trials, where patients are flocking to enroll in these trials, which present new opportunities to receive treatments that may be more effective in controlling their coinfection. Eiger’s clinical trials will test their new drug, Lonafarnib, in clinical trial arms with and without pegylated interferon and/or ritonavir, with sites open in many countries throughout the world. Myr’s clinical trial will test their new drug, Myrcludex B, in similar triple-treatment combinations. Their clinical trial sites are now open in Russia, and the drug is already being prescribed for “compassionate use” in France. The United States Food and Drug Administration (FDA) has even taken notice; issuing guidance for industry on the development of hepatitis delta drugs for treatment in October 2019. This provides a valuable set of standards and expectations for clinical trials in regard to ethics, trial design, and patient needs.
Hepatitis delta coinfection has also received more attention this year at international hepatology conferences such as at the European Association for the Study of the Liver (EASL)’s International Liver Congress in Vienna, Austria, the International Liver Congress in American Association for the Study of the Liver (AASLD) meeting in Boston, and HEP DART in Hawaii. This year has brought many milestones for hepatitis delta data, diagnostics, and clinical trials. With continued scientific research and interest, Hepatitis Delta Connect hopes to continue to support these milestones and drive awareness efforts.
1. Zhijiang Miao, Shaoshi Zhang, Xumin Ou, Shan Li, Zhongren Ma, Wenshi Wang, Maikel P Peppelenbosch, Jiaye Liu, Qiuwei Pan, Estimating the global prevalence, disease progression and clinical outcome of hepatitis delta virus infection, The Journal of Infectious Diseases, jiz633.
2. Chen H, Shen D, Ji D, et al. Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut 2019;68:512-521.
3. Shen D, Ji D, Chen H, et al. Hepatitis D: not a rare disease anymore: global update for 2017–2018. Gut Published Online First: 09 April 2019.