Hep B Blog

Category Archives: Hepatitis Delta (HDV)

Drug Update: Replicor Researchers Talk to HBF About Potential New Hep B and D Treatment

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 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.

Spotlight on Hepatitis Delta: Renewed Scientific Interest Paves the Way for New Data and Treatments

 

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.

References:

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.

Hepatitis B and Delta Coinfection: A Public Health Crisis in Mongolia

 

Mongolia is one of the world’s most sparsely populated countries yet is home to the highest infection rates of hepatitis B and delta coinfection worldwide1. The World Health Organization (WHO) estimates that about 5-10% of the nearly 300 million global hepatitis B patients are co-infected with hepatitis delta. Hepatitis delta is the most severe form of viral hepatitis, and greatly increases the risk of cirrhosis, scarring of the liver, and liver cancer; with seven out of 10 patients progressing within 10 years 4. In Mongolia, 70% of hepatitis B patients are coinfected with hepatitis delta, and the country is known for having the highest rates of liver cancer on the planet2,3. These statistics are startling and highlight a public health crisis for Mongolia, where most families have at least one family member affected 2.

How are people getting infected?

Historically, healthcare-related exposures are suspected to be the biggest risk for contracting hepatitis in Mongolia. Despite the 1993 national policy was set to regulate the multi-use of single-use syringes in healthcare settings, effective sterilization practices, and medical staff training, proper inspections remain an ongoing issue. Healthcare workers themselves are also at risk, with requirements for hepatitis B vaccination set by the Ministry of Health recently in 20145. Although routine infant vaccination for hepatitis B began in 19916, older populations remain at risk or are susceptible to exposures.

Treatment Access

For a nation so widely affected by liver disease, as of 2015, skilled physicians and liver transplant experts are sparse – with only one reported team performing transplants in Ulaanbaatar, the capital city1. Fibroscan, CT scans, and liver biopsies; routine screening tools for liver disease and liver cancer, have only been introduced in recent years, and are still not routinely used for liver cancer screening as recommended by WHO7. This lack of surveillance leaves most patients to endure late diagnoses. Due to the rural landscape, where nearly 30% of the population lives below the poverty line10 and historically nomadic lifestyle accessing care is a challenge. Access to treatment for hepatitis B is additionally a challenge, and traditional medicines might be utilized. Pegylated interferon, the only current and somewhat effective treatment for hepatitis B and delta coinfection, was registered about 10 years ago in Mongolia and is still not covered by its national healthcare system, making it too expensive for most low and middle-income families8. With the help of partnerships, the government has integrated funding for palliative care for liver cancer patients, with most facilities centralized around the capital city7. With a failing insurance system and little government prioritization for prevention and treatment, many are calling on the World Health Organization (WHO), pharmaceutical companies and NGOs to step in to curb the crisis9.

Hope

Mongolia’s crisis has not been left unaddressed. Over the last 10 years, Mongolia’s government has prioritized combatting hepatitis, developing its first viral hepatitis national strategy in 2010, and focusing on prevention, affordable treatment, and public awareness programs. Admirably, coverage under the national insurance plan for antivirals began in 2016, greatly subsidizing the cost of hepatitis B treatment11. These efforts did not go unnoticed, and in 2018, WHO praised Mongolia’s efforts in moving towards the elimination of hepatitis B and C, recognizing its successes in its national program, “Whole-Liver Mongolia”. Another program, “Hepatitis Free Mongolia”, an initiative of the Flagstaff International Relief Effort (FIRE), Flagstaff Rotary Club, Rotary Club of Ulaanbaatar and the WHO, offers free hepatitis education, screening, vaccination and care for those infected. The project also trains healthcare providers and offers free exams, diagnostic services and patient counseling; a vital service for many who may not be able to access or afford these services otherwise. Since 2011, the project, along with FIRE’s Love the Liver program have tested nearly 9,000 people for hepatitis B, screened 6,000 for liver cancer and performed over 3,000 specialist exams, and, in a country of only 3 million people, has made a meaningful impact. The effort is also unofficially supported by Mongolia’s Ministry of Health, who is continually investing in efforts to curb the burden of hepatitis.

References:

1. “Viral Hepatitis in Mongolia: Situation and Response.” World Health Organization, 2015, iris.wpro.who.int/bitstream/handle/10665.1/13069/9789290617396_eng.pdf.

2. “Hepatitis: A Crisis in Mongolia.” World Health Organization, 2017, www.who.int/westernpacific/news/feature-stories/detail/hepatitis-a-crisis-in-mongolia.

3. Rizzetto, Mario. (2016). The adventure of delta. Liver International. 36. 135-140. 10.1111/liv.13018.

4. Abbas, Z., Abbas, M., Abbas, S., & Shazi, L. (2015). Hepatitis D and hepatocellular carcinoma. World journal of hepatology, 7(5), 777–786.

5. Baatarkhuu, Oidov & Uugantsetseg, G & Munkh-Orshikh, D & Naranzul, N & Badamjav, S & Tserendagva, Dalkh & Amarsanaa, J & Young, Kim. (2017). Viral Hepatitis and Liver Diseases in Mongolia. Euroasian Journal of Hepato-Gastroenterology. 7. 68-72. 10.5005/jp-journals-10018-1215.

6. Davaalkham, Dambadarjaa & Ojima, Toshiyuki & Uehara, Ritei & Watanabe, Makoto & Oki, Izumi & Wiersma, Steven & Nymadawa, Pagbajab & Nakamura, Yosikazu. (2007). Impact of the Universal Hepatitis B Immunization Program in Mongolia: Achievements and Challenges. Journal of epidemiology / Japan Epidemiological Association. 17. 69-75. 10.2188/jea.17.69.

7. Alcorn, Ted. (2011). Mongolia’s struggle with liver cancer. Lancet. 377. 1139-40. 10.1016/S0140-6736(11)60448-0.

8. “Country Programme on Viral Hepatitis Prevention and Control.” World Health Organization, Western Pacific Region, 2015, www.wpro.who.int/mongolia/mediacentre/releases/20160318_viral_hep_prevention_control/en/.

9. Jazag, A., Puntsagdulam, N., & Chinburen, J. (2012). Status quo of chronic liver diseases, including hepatocellular carcinoma, in Mongolia. The Korean journal of internal medicine, 27(2), 121–127. 10. “Poverty in Mongolia.” Asian Development Bank, 2019, www.adb.org/countries/mongolia/poverty.

11. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on a National Strategy for the Elimination of Hepatitis B and C; Strom BL, Buckley GJ, editors. A National Strategy for the Elimination of Hepatitis B and C: Phase Two Report. Washington (DC): National Academies Press (US); 2017 Mar 28. 1, Introduction. Available from: https://www.ncbi.nlm.nih.gov/books/NBK442230

 

Printable Hepatitis Delta Fact Sheets for At-Risk Populations (Available in 5 Languages!)

 

Hepatitis delta is estimated to affect 15-20 million people globally who are also living with hepatitis B. Hepatitis delta’s geographic distribution is not uniform, and does not always follow regions of highest hepatitis B prevalence. Although more recent data is sparse, regions of higher coinfection are thought to be in Mongolia, Eastern Europe (particularly Romania, Russia, Georgia, Turkey), Pakistan, the Middle East and the Amazonian River Basin. The American Association for the Study of Liver Diseases (AASLD) recommends that hepatitis B patients from these areas be tested for hepatitis delta. If you are a community member or community health worker or physician, please utilize our printable fact sheets to help raise awareness about hepatitis B and delta!

Fact sheets are available in 5 languages, including English, Mongolian, Romanian, Russian and Spanish!

English for Patients    English for Providers

Mongolian for Patients   Mongolian for Providers

Romanian for Patients   Romanian for Providers

Russian for Patients   Russian for Providers

Spanish for Patients   Spanish for Providers

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

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.  

Hepatitis B Foundation: Now Part of the NORD Rare Disease Community!

We’re pleased to announce that the Hepatitis B Foundation (HBF) is now a member of NORD, the National Organization for Rare Disorders, representing our program, Hepatitis Delta Connect. NORD is a patient advocacy organization dedicated to individuals with rare diseases and the organizations that serve them. We will join 280 other patient organization members, all committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and patient services.

Although globally, hepatitis delta is estimated to affect 15-20 million people, in the U.S. it is classified as a rare disease, as it is estimated to affect less than 200,000 people. The complicated nature of the virus and limited prioritization contribute to the gap in awareness, resources, testing practices and adequate treatments for hepatitis B and delta coinfection. Joining NORD will help amplify our voice, raise awareness about hepatitis delta in people living with chronic hepatitis B, provider and pharmaceutical communities and contribute to health policy efforts.

Hepatitis Delta Connect has previously been active with NORD through participating in rare disease Twitter chats and presenting a poster at the NORD Rare Action Summit in October 2018. We’re very excited to be a part of the coalition, and to be spreading awareness about hepatitis delta!

For more information about Hepatitis Delta Connect, visit www.hepdconnect.org or email connect@hepdconnect.org.

Hepatitis Delta: Flying Under the Radar in the U.S.

As of 2019, the Centers for Disease Control and Prevention (CDC) requires over 100 diseases, infections and conditions – including hepatitis A, B and C – to be reported by state and local health departments. Physicians who diagnose these conditions, and diagnostic laboratories, are required to report confirmed and/or suspected cases to health departments, who then notify the CDC. This requirement allows the government to monitor disease patterns and track outbreaks to contain the spread of disease and protect the public. While all other forms of viral hepatitis are federally ‘reportable’, hepatitis delta cases are not required to be reported. Hepatitis delta is the most severe form of viral hepatitis, and spreads similarly to hepatitis B; through blood and sexual fluids, making it a public health threat, particularly for the 2.2 million people who already have hepatitis B in the U.S.

Hepatitis delta can only be contracted along with hepatitis B or after someone is already infected with hepatitis B. Acute cases can cause liver damage and even liver failure, and in chronic cases, can accelerate the rate of liver disease progression, as there are no effective treatments available. Although estimated to affect 5-10% of hepatitis B patients, hepatitis delta is severely underdiagnosed, leaving the true disease burden largely unknown in the U.S. and worldwide.

In conjunction with awareness efforts, adding hepatitis delta as a reportable disease could reveal a more accurate prevalence landscape of hepatitis B and delta coinfection and allow for more effective prevention efforts. The CDC asserts that “reporting of cases of infectious diseases and related conditions has been and remains a vital step in controlling and preventing the spread of communicable diseases,1” yet hepatitis delta has still been left out of the list of nationally reportable diseases. While notifying CDC is only voluntary2, 23 states have designated hepatitis delta infections as reportable to local and state health departments, allowing for surveillance of outbreaks, particularly relevant to the current nationwide opioid crisis.

Worchester, Massachusetts, which is currently experiencing a hepatitis A outbreak, also saw one of the worst hepatitis delta outbreaks in the country in the mid 1980’s. The infection was seen among drug users and their sexual partners, sickened 135 people, and killed 15. In those infected with hepatitis B, delta coinfection was present in 54% of drug users and 33% of their sexual partners3
. Interestingly, in Massachusetts, only labs (and not clinicians) are required to report hepatitis delta cases. The reporting requirement allowed the state to be alerted of a spike in cases and respond accordingly – a luxury many other states may not have if neither labs nor clinicians are required to report in their state.

Some states are even scaling back their surveillance; in 2016, New York State removed hepatitis delta from their list of reportable diseases, citing just 21 cases in a two-year period and a health code that asserts a “providers obligation” to “report unusual manifestations of novel strains of hepatitis.”4. Although hepatitis delta is more common outside the U.S., there is evidence to suggest persistent and even growing prevalence. A 2016 prevalence map presented by Eiger BioPharmaceuticals revealed New York City as a “hot-spot” for hepatitis delta cases5. Although more recent prevalence studies are sparse, and often include only small sample sizes, several have noted increases in hepatitis delta coinfection among certain groups. One study in Baltimore, published in 2010, compared blood samples from drug users in the 1980’s to samples obtained from 2005-2006 – and found a 21% increase in hepatitis delta coinfection among people already chronically infected with hepatitis B6. A 2015 study analyzed the blood records of 2,100 hepatitis B positive veterans – nearly 4% were coinfected7. A larger study, analyzing chart records of 500 chronic hepatitis B patients in California found that 8% of patients had a delta coinfection8. Another 2018 publication utilized data from 2011-2016 from the National Health and Nutrition Examination Survey (NHANES) and estimated there to be over 350,000 Americans with past or current hepatitis delta9.

While the true burden of hepatitis delta in the U.S. is debated, one study that analyzed diagnosis codes for over 170 million people showed 10,000 coinfected patients newly diagnosed in 2016 alone4. The American Association for the Study of Liver Diseases (AASLD) recommends delta testing in high-risk groups, but countless journals and leading hepatologists have called for universal testing of hepatitis B patients for hepatitis delta9,10,11  which could reveal thousands of unknown infections. Low awareness, testing, and the lack of inclusion on the notifiable diseases list contribute to the unclear picture of prevalence in the U.S. Inconsistent reporting across states creates holes in data collection and opportunities for missed outbreaks and subsequent treatment and prevention efforts. Adding hepatitis delta to the list of reportable diseases nationally could be the key to understanding who this ‘hidden epidemic’ is affecting, and where, and allow for effective surveillance to prevent future infections.

For more information about Hepatitis Delta Connect or hepatitis delta, visit www.hepdconnect.org or email connect@hepdconnect.org.

References:

1. Centers for Disease Control and Prevention. (1990, June 22). Mandatory Reporting of Infectious Diseases by Clinicians. Morbidity and Mortality Weekly Reports. Retrieved from https://www.cdc.gov/mmwr/preview/mmwrhtml/00001665.htm.

2. Centers for Disease Control and Prevention. (2018). National notifiable diseases surveillance system (NNDS): Data collection and reporting. Retrieved from https://wwwn.cdc.gov/nndss/data-collection.html

3. Lettau, L. A., McCarthy, J. G., Smith, M. H., Hauler, S. C., Morse, L. J., Ukena, T., et al. (1987). Outbreak of severe hepatitis due to delta and hepatitis B viruses in parenteral drug abusers and their contacts. N Engl J Med, 317(20), 1256-1262.

4. The City of New York. (2016). Hepatitis D and E and other suspected infectious viral hepatitides reporting. Retrieved from http://rules.cityofnewyork.us/tags/reportable-diseases.

5. Martins, E and Glenn, J. Prevalence of Hepatitis Delta Virus (HDV) Infection in the United States: Results from an ICD-10 Review. Poster Sa1486 DDW May 2017.

6. Lauren M. Kucirka, Homayoon Farzadegan, Jordan J. Feld, Shruti H. Mehta, Mark Winters, Jeffrey S. Glenn, Gregory D. Kirk, Dorry L. Segev, Kenrad E. Nelson, Morgan Marks, Theo Heller, Elizabeth T. Golub, Prevalence, Correlates, and Viral Dynamics of Hepatitis Delta among Injection Drug Users, The Journal of Infectious Diseases, Volume 202, Issue 6, 15 September 2010, Pages 845–852.

7. Kushner, T., Serper, M., & Kaplan, D. E. (2015). Delta hepatitis within the veterans affairs medical system in the United States: Prevalence, risk factors, and outcomes.

8. Gish, Robert & Yi, Debbie & Kane, Steve & Clark, Margaret & Mangahas, Michael & Baqai, Sumbella & A Winters, Mark & Proudfoot, James & Glenn, Jeffrey. (2013). Coinfection with Hepatitis B and D: Epidemiology, Prevalence and Disease in Patients in Northern California. Journal of gastroenterology and hepatology. 28. 10.1111/jgh.12217

Phase 3 Clinical Trials Opening for Hepatitis Delta Patients

Phase 3 clinical trials have been announced for two drugs, Lonafarnib and Myrcludex (Bulevirtide) for the treatment of hepatitis B and delta coinfection.

Phase 3 studies compare new possible treatments to the current standard treatment, to see if it is more effective and/or safer than the current standard of care. Phase 3 studies are randomized control trials, which means that patients will be assigned to one of several different treatment groups. These studies usually evaluate the new treatment over a long period of time but special designations by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), such as Fast Track, Orphan Drug, Breakthrough Therapy Designations and PRIME eligibility status will speed up this process and bring these drugs to approval more quickly. Because the only currently approved treatment for hepatitis delta is pegylated interferon, which is often less than 30% effective, there is an unmet need for faster development of more treatment options.

Phase 3 clinical trials for Lonafarnib are currently recruiting hepatitis B and delta coinfected patients in the United States. Ninety-two international trial site locations have also been announced and will take place in Belgium, Bulgaria, Canada, France, Germany, Greece, Israel, Italy, Republic of Moldova, New Zealand, Pakistan, Romania, Span, Switzerland, Taiwan, Turkey, United Kingdom and Vietnam. This clinical trial, run by Eiger Biopharmaceuticals, will test the new drug Lonafarnib in combination with other treatments. For more information about the study, visit www.D-LIVRstudy.com or clinicaltrials.gov.

Bulevirtide, made by MYR-GmbH Pharmaceuticals, has also announced that its phase 3 clinical trials will be opening in 2019. Trial site locations have not been announced yet. For more information about this study, visit clinicaltrials.gov.Click here for more information on locating additional clinical trials. If you are considering joining a clinical trial, discussing it with your liver specialist can be helpful in determining if joining a trial may be right for you.

It is very important for hepatitis B and delta patients to be managed by a doctor, preferably a liver specialist, who is familiar with managing hepatitis B and delta coinfection. For assistance in locating a specialist near you, please visit our Physician Directory page. For additional questions, please visit www.hepdconnect.org or email connect@hepdconnect.org.

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