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What You Need to Know About the 2022 Liver Meeting and How It Relates to Hepatitis Delta

 

 

 

 

This year, the annual Liver Meeting, hosted by the American Association for the Study of Liver Diseases (AASLD), was held in Washington, D.C. The featured presentations included new innovations in liver transplant surgery, disease modeling (which is a process that uses cells to show how a disease develops and to test possible treatment approaches), and drug development. While an effective, functional cure for hepatitis B virus (HBV) is still 5-10 years away, researchers, scientists, healthcare providers, and people with lived experience all came together and agreed that more needs to be done to reduce the burden of liver diseases and improve health outcomes now. One highlight of the meeting was Dr. Francis Collins, former director of the U.S. National Institutes of Health and special advisor to President Biden, hosting a special session to introduce a national hepatitis C elimination plan for the U.S. Unfortunately, this plan is focused on hepatitis C. As a response, the Hepatitis B Foundation will soon send an advocacy letter pushing for the inclusion of hepatitis B and hepatitis delta in this plan. Make sure you are signed up for our Action Center alerts to stay engaged with hepatitis B advocacy efforts.

Of particular note at this year’s meeting were the presence of many patient advocates and people with lived experience, and an increased focus on hepatitis delta. One important hepatitis delta poster presentation was delivered by Dr. Tatyana Kushner of Mount Sinai Hospital in New York City, entitled “HDV Patient Perspective: The Impact of Disease and Current Unmet Needs.” By including the perspectives of people living with hepatitis delta virus (HDV), this study aimed to empower the patient community. Dr. Kushner and her colleagues collected data on people’s quality of life to identify unmet needs, barriers and gaps in HDV care (including disease management and access-to-care inequities).

The researchers found that a person’s care is affected in two ways: In the care they receive for their clinical diagnosis and their emotional journey after diagnosis. The participants’ experience of care was often negatively impacted by having a delayed HDV diagnosis, and limited access to specialized care and tolerable treatment options. Findings describe that the lack of specific and acceptable treatment options for hepatitis delta left people with little hope, which put an emotional burden on their life post-diagnosis. Due to the gaps in providers’ knowledge of HDV, participants held little trust in their healthcare providers. The study participants also shared that they suffered emotionally due to the stigma attached to their diagnosis.

Dr. Kushner and her colleagues call for an increased effort to educate healthcare providers on hepatitis delta, as their lack of HDV-specific knowledge drives health disparities or differences between groups, where one group is more burdened by a disease than the other. These are driven by unequal opportunities to achieve good health (CDC, 2020). Health disparities are preventable, and educating providers is the first step to overcoming these inequalities. Educating providers on HDV will lead to more rapid identification of the disease, as they will have a better understanding of the signs, symptoms and risk factors for hepatitis delta. Increasing advocacy efforts for point-of-care testing for both HBV and HDV in the U.S. will increase levels of testing and earlier identification of people at risk for the diseases. Timely diagnosis allows for people to be linked to specialty care earlier, ultimately improving health outcomes. Improving community awareness of HDV will combat stigma and likely reduce testing hesitancy, which can improve health outcomes. The researchers call for drug developers to meet the needs of the patient community by developing tolerable and hepatitis delta-specific treatments.

In terms of drug development, researchers presented on antiviral treatments for people living with HDV and discussed preferred outcomes of treatment, based on what they believed to be most helpful to each individual’s physical health. To understand these treatment considerations, it is important to review how HDV functions. Hepatitis delta virus (HDV) uses a person’s RNA (ribonucleic acid) to produce and replicate the virus, so high HDV RNA levels in the blood indicate severe infection, and low or undetectable HDV RNA levels indicate that the virus is not rapidly reproducing (Stephenson-Tsoris & Casey, 2022). A virological response is defined as a long-term period of low-level replication that leads to undetectable HDV RNA levels in the blood six months after stopping treatment, and this indicates viral suppression (Yamashiro et al., 2004). A biochemical response is defined as normalization of alanine aminotransferase (ALT) levels after antiviral treatment (Kim et al., 2022). When liver cells are damaged, they release ALT into the bloodstream, so high levels of ALT indicate that one’s liver is diseased or damaged (MedlinePlus, n.d.). ALT normalization is considered a good indicator that antiviral therapy is working because it means that there is less liver damage, liver disease is less severe, and people living with HBV/HDV are at less risk of harm (Kim et al., 2022).

One study of interest from the meeting was the D-LIVR study by Eiger BioPharmaceuticals, Inc.: Lonafarnib Global Study in Chronic Hepatitis Delta. This study consisted of 400 participants, who were all on treatment for 48 weeks, then followed up with researchers 24 weeks after treatment. In total, 50 participants received pegylated interferon (Peg IFN) treatment for 48 weeks; 125 participants received a combination of Lonafarnib, Ritonavir and Peg IFN; and 175 participants received the oral antiviral therapy Lonafarnib and Ritonavir. There were also 50 people on a placebo treatment. A placebo is a harmless pill that has no effect on a person, and is often used in clinical trials to test the effectiveness of a specific treatment being studied, in this case, Peg IFN, Lonafarnib and Ritonavir (Harvard Health Publishing, 2021). The researchers decided that they wanted to see a decline in HDV RNA (virologic response) and normalization of ALT (biochemical response) at week 48 as their study’s main outcome or proof that the treatment could work. In this study, an acceptable virologic response was defined as a “2log decline of HDV RNA levels,” which means they wanted to see HDV RNA levels decrease by 99% from the original levels that were measured before starting treatment (Wikipedia, n.d.).

Pegylated interferon (Peg IFN) is a protein-based medication that prompts the body to activate its natural immune system (induce innate antiviral response) (Zhang & Urban, 2021; Drugbank, n.d.). For Peg IFN-based treatments, researchers determine that undetectable HDV RNA six months after stopping treatment is desirable. However, researchers emphasize the importance of yearly HDV RNA post-treatment screening to monitor for viral relapses after treatment. For long-term treatment (over 48 weeks), a 99% reduction of HDV RNA concentration levels is an appropriate virologic response for non-interferon-based treatments, but more studies must be done to establish whether a person living with hepatitis delta is actually benefiting from the treatment (this is called clinical benefit). When establishing the clinical benefits for non-interferon-based treatments (or any new treatment), researchers can measure delays in disease progression or improvement of signs and symptoms of the disease, which includes symptom relief, improved functioning and improved survival rates (Lee, n.d).

Based on a variety of extensive studies (not just D-LIVR), the researchers decided to combine virologic and biochemical responses to try to demonstrate the clinical benefit of using ongoing antiviral treatment as a functional cure for hepatitis delta. They concluded that acceptable endpoints for HDV treatment studies include undetectable HDV RNA six months after stopping treatment, the loss of the hepatitis B surface antigen (HBsAg), and ALT normalization in people living with chronic hepatitis delta. This can also be considered a functional cure since there are undetectable levels of HBsAg and HDV RNA in the blood for a sustained period of time, even after finishing treatment (Wong et al., 2022).

While there is still time before we overcome the burden of hepatitis delta, the presentations from The Liver Meeting show us that researchers and scientists are constantly working to improve the lives of people living with hepatitis delta. Development toward a functional cure is progressing, and advocates are incorporating peoples’ lived experiences and perspectives into drug development and education. Collaboration between all these groups is the best way to move forward in the fight against hepatitis delta.

For more information on hepatitis delta, you can visit the Hepatitis Delta Connect website or review this hepatitis delta fact sheet.

References

Centers for Disease Control and Prevention. (2020). Health disparities. Centers for Disease Control and Prevention, Division of Adolescent and School Health, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. https://www.cdc.gov/healthyyouth/disparities/index.htm 

Drugbank. (n.d.). Peginterferon alfa-2a. Drugbank. https://go.drugbank.com/drugs/DB00008

Harvard Health Publishing. (2021, December 13). The power of the placebo effect. Harvard Health Publishing, Harvard Medical School. https://www.health.harvard.edu/mental-health/the-power-of-the-placebo-effect 

Kau, A., Vermehren, J., & Sarrazin, C. (2008). Treatment predictors of a sustained virologic response in hepatitis B and C. Journal of Hepatology, 49(4), 634-651. https://doi.org/10.1016/j.jhep.2008.07.013

Kim, S. H., Cho, E. J., Jang, B. O., Lee, K., Choi, J. K., Choi, G. H., Lee, J. H., Yu, S. J., Kim, Y. J., Lee, Y. B., Yoon, J. H., Kim, J. W., Jeong, S. H., & Jang, E. S. (2022). Comparison of biochemical response during antiviral treatment in patients with chronic hepatitis B infection. Liver International: Official Journal of the International Association for the Study of the Liver, 42(2), 320–329. https://doi.org/10.1111/liv.15086 

Lee, J. (n.d.). Defining Clinical Benefit in Clinical Trials: FDA Perspective [Presentation]. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. https://celiac.org/main/wp-content/uploads/2015/04/great3-07.pdf 

MedlinePlus. (n.d.). ALT blood test. National Library of Medicine (U.S.). [updated August 3, 2022]. https://medlineplus.gov/lab-tests/alt-blood-test/ 

Raman, S. (2022 October 25). Administration eyes national hepatitis C treatment plan. Roll Call: Policy. https://rollcall.com/2022/10/25/administration-eyes-national-hepatitis-c-treatment-plan/ 

Stephenson-Tsoris, S., & Casey, J. L. (2022). Hepatitis delta virus genome RNA synthesis initiates at position 1646 with a nontemplated guanosine. Journal of Virology, 96(4), e0201721. https://doi.org/10.1128/JVI.02017-21 

Wikipedia. (n.d). Log reduction. https://en.wikipedia.org/wiki/Log_reduction

Wong, G. L. H., Gane, E., & Lok, A. S. F. (2022). How to achieve functional cure of HBV: Stopping NUCs, adding interferon or new drug development?. Journal of Hepatology, 76(6), 1249–1262. https://doi.org/10.1016/j.jhep.2021.11.024

Yamashiro, T., Nagayama, K., Enomoto, N., Watanabe, H., Miyagi, T., Nakasone, H., Sakugawa, H., & Watanabe, M. (2004). Quantitation of the level of hepatitis Delta virus RNA in serum, by real-time polymerase chain reaction—and its possible correlation with the clinical stage of liver disease. The Journal of Infectious Diseases, 189(7), 1151–1157. https://doi.org/10.1086/382133

Zhang, Z., & Urban, S. (2021). New insights into HDV persistence: The role of interferon response and implications for upcoming novel therapies. Journal of Hepatology, 74(3), P686-699. https://doi.org/10.1016/j.jhep.2020.11.032

What’s the Difference?: Herbal Remedies and Supplements vs. Western Medicine

What’s the Difference?: Herbal Remedies and Supplements vs. Western Medicine

Around the world, people consider the use of herbal remedies or supplements as a natural treatment for hepatitis B and/or D infection. These natural remedies have historically been advertised to boost the immune system and improve liver health. Herbal remedies or supplements are described as products made from botanicals or plants used to treat diseases and maintain health. They can be produced in a variety of forms including liquid extracts, teas, tablets/capsules, bath salts, oils, and ointments4.

Why do people choose to use herbal remedies?

The use of these products over time has social-cultural influences related to the distrust of and unfamiliarity with western medicine for management of hepatitis B or D infection. While herbal remedies have been used widely across cultures and contexts, patterns of racism, medical mistreatment, and inadequate delivery of care in western medicine have influenced the present state of treatment practices. In response to these barriers to sensitive and effective health care delivery, many groups such as Hmong and African communities often rely on herbal remedies and supplements to treat medical conditions and ease suffering.

Silymarin, milk thistle, and Kampo medicine

The distrust of western medicine has contributed to more widespread use of supplements such as silymarin (milk thistle) and Kampo medicine, as alternatives to manage hepatitis B or D infection. Many people believe that Silymarin can improve liver health through its antioxidant and free radical-fighting properties. Traditional Kampo medicine has been used for over 2,000 years to treat a variety of diseases including hepatitis B. One herbal treatment that is frequently used is bupleurum which many people believe can protect the liver or heal liver damage. Despite possible liver health benefits, neither supplement is a treatment for hepatitis B or D and may sometimes cause further harm to the liver4. It is important to note that there is presently no cure for hepatitis B.

False claims and bad interactions

Additionally, several alternative medicine companies often make false claims and testimonials to convince people to purchase expensive alternative treatments with false promises that are not based on scientific evidence. Herbal remedies and supplements may also interact with certain medications prescribed for those with hepatitis B and D, so it is important to seek the advice of a health care professional before use of any of these products3,4.

Strides in western health care

The long-standing hesitancy to participate in western health care is well-reasoned and firmly rooted in past wrongdoing on the part of often fundamentally racist institutions. While the western health care system remains far from perfect, it is important to remember that many strides continue to be made to correct the misdeeds of the past, and conversations around health equity and the social determinants of health (including racism) are becoming more and more common. Meanwhile, research has found that beliefs and misconceptions around western medicine can delay care and increase morbidity rates of hepatitis B in high-risk communities2.

It is vital for those living with hepatitis B or D to stay informed with scientific knowledge about supplements and herbal treatments to ensure these products are effective and safe in their daily life. The coordination of hepatitis B and D care by providers must do better to support those impacted by the viruses, in a way that is culturally sensitive and not dismissive of the harm that has been inflicted on communities of color and immigrant communities, who are more likely to be affected by hepatitis B and D1.  Health care professionals and other service providers must continually work to improve their cultural humility. In addition, health care institutions practicing western medicine must work harder to ensure care is equitable and safe, and to center the voices, stories, and insights of community members in their work to repair the impacts of structural racism and medical mistreatment that have caused such deep distrust in western medical treatments.

To learn more about effective hepatitis B and D medications, check out our Drug Watch page!

Disclaimer: Herbal products are not U.S. FDA-approved, and the Hepatitis B Foundation cannot endorse the usage of such products that lack regulation and scientific evidence to deem them both effective and safe.

References

  1. El-Serag, H., McGlynn, K. A., Graham, G. N., So, S., Howell, C. D., Fang, T., … & Thiel, T. K. (2010). Achieving health equity to eliminate racial, ethnic, and socioeconomic disparities in HBV-and HCV-associated liver disease. The Journal of Family Practice, 59(4 Suppl), S37.
  2. Mukhtar, N. A., Evon, D. M., Yim, C., Lok, A. S., Lisha, N., Lisker-Melman, M., … & Khalili, M. (2021). Patient knowledge, beliefs and barriers to hepatitis B Care: results of a multicenter, multiethnic patient survey. Digestive diseases and sciences, 66(2), 434-441.
  3. National Center for Complementary and Integrative Health website. Using dietary supplements wisely. (2019). Using dietary supplements wisely. https://www.nccih.nih.gov/health/using-dietary-supplements-wisely.
  4. US Food and Drug Administration. (2017). Information for consumers on using dietary supplements. https://www.fda.gov/food/dietary-supplements/information-consumers-using-dietary-supplements.

Results from Hepatitis Delta Clinical Trials Announced at International Liver Congress 2022

London, UK was the host city for this year’s annual International Liver Congress (ILC), the yearly meeting of the European Association for the Study of the Liver (EASL), which took place from June 22nd-26th. This meeting provides an opportunity for those working to address liver diseases around the world to gather in one location and exchange ideas, present research, and work to advance diagnosis, prevention, treatment, and elimination of these serious conditions. This year’s meeting saw significant attention given to hepatitis delta, as new treatments continue to move through the pipeline and more widespread approval for prescription of current treatments is sought. Below is a quick snapshot of some of the presentations!

The US-based pharmaceutical company Gilead Sciences, Inc. demonstrated with results from a Phase 3 clinical trial that treatment with Hepcludex (bulevirtide), the first medication ever approved for hepatitis delta (HDV), has been shown to achieve significant response in chronic HDV. After 48 weeks, 48% of study participants who received different doses of treatment with Hepcludex achieved virological response (meaning a decline in hepatitis delta viral load, ALT normalization, and a change in liver stiffness), compared to only 2% of those who had not received any treatment. When compared to results from clinical trials after 24 weeks, response rates to HDV only improved, showing the drug to be even more effective over time. Throughout the clinical trials, there have been no adverse events reported that are attributable to this treatment.

Hepcludex has also been found to have a positive impact on the quality of life of individuals living with hepatitis delta, and their overall ability to manage the condition. There were improvements found in health distress, performance of daily activities related to hepatitis, emotional impact of hepatitis, and ability to work. This data reinforces the efficacy and safety of Hepcludex and hopefully strengthens the case for approving the drug in more parts of the world.

“As the most severe form of viral hepatitis, HDV presents a significant disease burden with high healthcare-related costs and until recently, no approved treatment options,” said Heiner Wedemeyer, MD, Director, Clinic for Gastroenterology, Hepatology and Endocrinology at Hannover Medical School, and principal investigator of the study. “These results presented at ILC 2022 not only highlight the important clinical role that bulevirtide has to play as a safe and effective treatment option for chronic HDV, but critically also demonstrate that with prolonged treatment, we can achieve higher response rates so we can better manage this rare, life-threatening disease in more people.”

Presently, Hepcludex has been conditionally approved by the European Commission for prescription in France, Germany, and Austria. It has not yet been approved by the United States Food and Drug Administration (FDA) or in other countries. A Biologics License Application was submitted by Gilead to the FDA in late 2021 for injection of 2mg of Hepcludex to treat adults with HDV and compensated liver disease. Hepcludex had previously been granted Breakthrough Therapy and Orphan Drug designations by the FDA and PRIority MEdicines (PRIME) scheme eligibility by the European Medicines Agency (EMA).

The second company to present their research findings at the ILC was US-based Eiger BioPharmaceuticals, Inc. The two primary hepatitis delta drugs that they have in the pipeline are called lonafarnib and peginterferon lambda. One abstract presentation indicated that peginterferon lambda (lambda) had better antiviral activity and tolerability than peginterferon alfa (the previous version of this drug that has been used as the only somewhat effective, but off-label treatment for hepatitis delta since the early 1980s). Lambda has been shown to block production of new hepatitis delta virus very effectively. Additionally, lambda in combination with lonafarnib was found to lower levels of HDV RNA and decrease its production and release, more effectively than lambda by itself. Patterns in HBV DNA, hepatitis B surface antigen, and ALT were also observed as part of this study. In its Phase 3 D-LIVR study, which is assessing the safety and efficacy of lonafarnib in combination with ritonavir, with and without peginterferon alfa, Eiger has assembled the largest cohort of global participants in an HDV study, and therefore the largest body of data. Results from this study are anticipated by the end of 2022.

The final piece of big hepatitis delta news to come out of the conference was the announcement from Vir Biotechnology Inc. that they are beginning a Phase 2 clinical trial for VIR-2218 in combination with VIR-3434 for the treatment of chronic hepatitis delta. Initial data from this study is anticipated in 2023.

Hepatitis delta is now receiving more attention than ever before and there is only more hope as new treatments are created, investigated, approved, and made available. For a complete overview of hepatitis delta, including basic information, resources, clinical trial opportunities, and a complete list of drugs that are in the pipeline, visit www.hepdconnect.org.

References

https://www.gilead.com/news-and-press/press-room/press-releases/2022/6/treatment-with-hepcludex-bulevirtide-meets-primary-endpoint-and-achieves-significant-response-in-chronic-hepatitis-delta-virus-at-48-weeks

https://www.streetinsider.com/Corporate+News/Vir+Biotechnology+Inc.+%28VIR%29+Announces+New+Clinical+Data+From+its+Broad+Hepatitis+B+Program/20256465.html

https://www.prnewswire.com/news-releases/eiger-biopharmaceuticals-announces-results-from-multiple-presentations-at-the-european-association-for-the-study-of-the-liver-easl-international-liver-congress-2022-301576119.html

Recent Roundtable Discussion Highlights Hepatitis Delta Virus

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 – The Year of Hepatitis Delta

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 connect@hepdconnect.org. We look forward to an exciting year of work on HDV!

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.

 

Eiger BioPharmaceuticals: Developing Two New Hepatitis Delta Treatments

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. 

Image courtesy of Praisaeng, at FreeDigitalPhotos.net.

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.

My Hepatitis B Viral Load is Low (Or Undetectable), Am I Still Infected with Hepatitis Delta?

For people who have been diagnosed with chronic hepatitis B and delta coinfection, a low or undetectable hepatitis B viral load does not usually indicate that they’ve cleared both infections. This is because, in cases of coinfection, hepatitis delta usually becomes the dominant virus, and suppresses hepatitis B, slowing or even stopping its replication entirely. If someone is still positive for the hepatitis B surface antigen (HBsAg), the hepatitis delta virus can still replicate (often with copies in the millions) and cause potential liver damage  1For this reason, the test to measure hepatitis delta activity, the HDV RNA test, is important in disease monitoring and management  2,3. Available since 2013, the HDV RNA test can be acquired internationally through the Centers for Disease Control and Prevention (CDC), and from several labs in the US. 

For those suspected of having acute hepatitis B and delta coinfection, HBsAg testing should follow 6 months after initial diagnosis. If HBsAg is negative (non-reactive), both infections are likely to have cleared. It’s important to remember that people who contract hepatitis B and delta during one exposure are likely to clear both viruses.  If HBsAg is positive (reactive) after 6 months, both infections are likely chronic (life-long). Those who are known to have a chronic hepatitis B infection and then become infected with hepatitis delta later on, they are likely to develop chronic coinfections 

Following diagnosis with hepatitis B, with or without delta coinfection, it is important to have close, household contacts and sexual partners screened, and to follow simple prevention measures and practice safe sex using condoms.  

Both hepatitis B and delta are prevented with the safe and effective hepatitis B vaccine series.  

For more information on hepatitis B and delta coinfection, visit www.hepdconnect.org or contact us at connect@hepdconnect.org 

References: 

  1. Huang, C. R., & Lo, S. J. (2014). Hepatitis D virus infection, replication and cross-talk with the hepatitisB virus. World journal of gastroenterology20(40), 14589–14597. 
  2. YurdaydınC, Tabak F, Idilman R; Viral Hepatitis Guidelines Study Group. Diagnosis, management and treatment of hepatitis delta virus infection: Turkey 2017 Clinical Practice Guidelines. Turk J Gastroenterol 2017; 28(Suppl 2); S84-S89. Available at: https://www.turkjgastroenterol.org/sayilar/304/buyuk/S84-S89.pdf 
  3. Tseng, C. H., & Lai, M. M. Hepatitis delta virus RNA replication.Viruses1(3), 818–831.  

Where Can I Order Hepatitis Delta Testing?

By Sierra Pellechio, BS, CHES, Hepatitis Delta Connect Program Manager

Historically, testing for hepatitis delta has been difficult to access and often not commercially available. With the rise in awareness about hepatitis B and delta coinfection, more tests are beginning to be offered by multiple labs for clinicians in the United States looking to test their patients. Because hepatitis delta can only infect people who also have hepatitis B, the Hepatitis B Foundation’s medical director and leading hepatologist Dr. Robert Gish recommends testing all hepatitis B patients for hepatitis delta. “Screening all hepatitis B patients will allow a better understanding of hepatitis delta prevalence and its impact on outcomes and will identify patients who can be offered treatment within or outside clinical trials.”

The first step in diagnosing an infection is the HDV antibody total (anti-HDV) test. Patients who have recovered from or are currently infected will be positive for the anti-HDV and will present high titers in later stages of acute infection and persist in cases of chronic infection. If the HDV antibody total test is positive, it should be followed by the HDV RNA (PCR) test to confirm an active infection. If this test is negative, a current infection is unlikely.

Testing hepatitis B patients for hepatitis delta is important because when people with hepatitis B are exposed to the hepatitis delta virus, 90% will develop a chronic infection1. Coinfection will alter treatment and management plans, because antivirals effective on hepatitis B do not control hepatitis delta2. While the standard treatment of interferon is less than 30% effective in controlling coinfection, there are new drugs in development. With two of these drugs set to enter phase 3 clinical trials in 2019, it is more important than ever to identify coinfected patients and connect patients into clinical trials.

Until recently, only the anti-HDV test was widely available in the United States. In February 2019, Quest Diagnostics began offering HDV RNA testing, making it easier for patients and their physicians to access this more detailed level of testing. A complete list of labs offering testing is below.

Quest Diagnostics (US)

Tests Offered:

ARUP Laboratories (US) 

Tests Offered:

Cambridge Biomedical (US, Limited States)

Tests Offered:

Mayo Clinic Laboratories (US)

Tests Offered:

Viracor (US)

Tests Offered:

Centers for Disease Control and Prevention (CDC) (US & International)

Tests Offered:

  • HDV Antibody Total
  • HDV RNA
  • Genotyping

Disclaimer: This may not be a comprehensive list of all available labs offering testing.

Please note, if you are a patient in the U.S. and wish to be tested for hepatitis delta, these tests must be ordered through a clinician.

It is very important for coinfected patients to be managed by a liver specialist who is familiar with managing coinfected patients. For assistance in locating a specialist near you, please visit our Physician Directory page. For additional questions, please visit www.hepdconnect.org, email connect@hepdconnect.org, or call our hotline at 215-489-4900.

References:

  1. Hooks, B., Billings, J., & Herrera, J. (2009). Hepatitis D Virus. Practical Gastroenterology.

2. Farci, P., & Anna Niro, G. (2018). Current and Future Management of Chronic Hepatitis D. Gastroenterology & hepatology, 14(6), 342-35

Hepatitis Delta: Coinfection vs. Superinfection

By Sierra Pellechio, Hepatitis Delta Connect Coordinator

Hepatitis delta is an aggressive form of hepatitis that can only exist alongside hepatitis B. This means that all hepatitis B patients are at risk for hepatitis delta, but so are people who have not received the hepatitis B vaccination series.

If contracted, 70-90% of people with chronic hepatitis B will go on to also develop a chronic hepatitis delta infection – called a “superinfection”. Approximately 70% of these cases will progress to cirrhosis (liver scarring), compared to 15-30% of those infected only with the hepatitis B virus.

Due to the likelihood of liver complications, hepatitis B patients should be aware of potential exposures to hepatitis delta. The virus is spread the same way as hepatitis B, through direct blood-to-blood contact and unprotected sex with an infected person. It is important to be aware that blood contact could also occur by exposure to unsafe blood transfusions, unsterile medical or dental equipment, and the sharing of razors or toothbrushes with an infected person due to the possibility of infected blood entering the body.

People who are not infected with hepatitis B may be at risk for “coinfection”, when someone contracts hepatitis B and delta simultaneously during one exposure. In these cases, greater than 90% of adults will clear both infections and develop protective antibodies. While a co-infection generally resolves spontaneously after about 6 months, it can sometimes result in a life-threatening or fatal liver failure.

The good news is that the hepatitis B vaccine series can prevent both viruses in people who are not already infected. Once completed, the vaccine can provide a lifetime of protection!

For more information about hepatitis B/delta coinfection, please visit www.hepdconnect.org or email us at connect@hepdconnect.org.