Hep B Blog

Category Archives: Hepatitis Delta (HDV)

Hepatitis Delta (HDV)

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

Hepatitis Delta (HDV), Uncategorized

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.

Hepatitis Delta (HDV)

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 (HDV)

What is silymarin (milk thistle), and is it helpful for managing my hepatitis B and D?

 

Silymarin, an herb and extract of milk thistle seeds, is a supplement commonly taken by hepatitis patients across the world, yet its proven benefits remain controversial. It is not a treatment for hepatitis B or D, nor has it been shown to have any effect against fighting the viruses. This herb is believed to have possible benefits on liver health due to its antioxidant and free radical fighting properties, although no studies have found a consistent positive effect on viral load or fibrosis scores 1 .

Silymarin is often taken by patients or suggested by their health care provider during or after interferon treatment ends, presumably with the hope of a protective or anti-inflammatory effect on the liver. But a 2013 study on hepatitis C patients unsuccessfully treated with interferon (the standard treatment for hepatitis B and D coinfection) found no significant difference in silymarin’s ability to lower ALT scores over placebo, a pill with no active drug ingredients 2 . Another 2013 metanalysis reviewed 8 studies which tested silymarin against a placebo and looked for measurable levels of improvement in ALT scores, of which the results were mixed and inconsistent1.

Interestingly, several studies have found improvements in patients’ self-reported patient quality of life after taking silymarin 1 – perhaps due to decreased stress or self-perceived control over their health. However, a 2012 study which randomly assigned patients either silymarin or placebo to measure possible declines in ALT or virus levels, in addition to self-reported quality of life, found little to no improvement in any of these outcomes3 regardless of whether they took milk thistle or a placebo.

As mentioned in our previous blog post, the U.S. National Institutes for Health (NIH) has published a directory of what scientific research has discovered about common herbal supplements. Probably the most popular herbal supplement pitched as a liver remedy is milk thistle, and its extract silymarin. The NIH milk thistle report found, “Previous laboratory studies suggested that milk thistle may benefit the liver by protecting and promoting the growth of liver cells, fighting oxidation (a chemical process that can damage cells), and inhibiting inflammation. However, results from small clinical trials of milk thistle for liver diseases have been mixed, and two rigorously designed studies found no benefit.”

The verdict on silymarin? Due to mixed literature and lack of proven improvements, patients should not rely on silymarin as a treatment for hepatitis B or D, and should discuss any new prescription recommendations with their doctor. Silymarin will not counterbalance damage done by hepatitis B or D viruses. While some studies have found silymarin to be well tolerated with low side-effects6, individual reactions can vary. In the U.S., supplements including silymarin are not regulated by the Food and Drug Administration (FDA), making the true contents of supplements unknown. For these reasons, patients should be cautious about supplements and consider additional ways to improve their overall health. Lifestyle changes including eating a nutritious, balanced diet, avoiding alcohol and cigarettes, and getting regular exercise have been repeatedly proven to have the ability to lower ALT and AST numbers4,5. It is understandable why many patients may turn to herbal supplements for possible health benefits, but without more consistent regulation, and proven clinical benefit, investing in overall healthy lifestyle changes may prove most beneficial.

It is very important for hepatitis B and D patients to be managed by a doctor, preferably 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 or email connect@hepdconnect.org.

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. Polyak, S. J., Ferenci, P., & Pawlotsky, J. M. (2013). Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepatology (Baltimore, Md.), 57(3), 1262-71.

2. Fried, M. W., Navarro, V. J., Afdhal, N., Belle, S. H., Wahed, A. S., Hawke, R. L., Doo, E., Meyers, C. M., Reddy, K. R., Silymarin in NASH and C Hepatitis (SyNCH) Study Group (2012). Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA, 308(3), 274-82.

3. Fried MW, Navarro VJ, Afdhal N, et al. Effect of Silymarin (Milk Thistle) on Liver Disease in Patients with Chronic Hepatitis C Unsuccessfully Treated with Interferon Therapy: A Randomized Controlled Trial. JAMA.2012;308(3):274–282. doi:10.1001/jama.2012.8265

4. Rusu, E., Jinga, M., Enache, G., Rusu, F., Dragomir, A. D., Ancuta, I., Draguţ, R., Parpala, C., Nan, R., Sima, I., Ateia, S., Stoica, V., Cheţa, D. M., Radulian, G. (2013). Effects of lifestyle changes including specific dietary intervention and physical activity in the management of patients with chronic hepatitis C–a randomized trial. Nutrition journal, 12, 119.

5. St George A, Bauman A, Johnston A, Farrell G, Chey T, George J Gastroenterol Hepatol. 2009 Mar; 24(3):399-407.

6. Rambaldi, Andrea & P Jacobs, Bradly & Gluud, Christian. (2007). Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane database of systematic reviews (Online).

Hepatitis Delta (HDV), Living with Hepatitis B

Ask An Expert: Managing Hepatitis Delta During Pregnancy

 

  What is the standard treatment for hepatitis delta and how long is it taken?

 

Although there are no standard guidelines for the treatment of hepatitis delta, pegylated interferon has been shown to be effective for some patients. It is usually administered via weekly injections for 1 year or more and is able to cure roughly 15-40% depending on the length of time that treatment is administered. Although many patients see declines in their hepatitis delta virus levels, most do not maintain long-term control following the conclusion of treatment.

Can pregnant hepatitis delta patients be treated with interferon?

 

Interferon has not been proven to be safe for administration during pregnancy and should not be administered. It may be harmful to the baby.

 

What is the best way to manage a hepatitis delta infection during pregnancy, if interferon cannot be used?

 

A liver specialist may continue to manage the hepatitis B infection during pregnancy through antiviral treatment. The American Association for the Study of Liver Diseases (AASLD) recommends antiviral treatment during the third trimester of pregnancy for women with high hepatitis B viral loads.

How can hepatitis B and delta transmission be prevented to the baby?

 

Because a hepatitis B infection is required for someone to become infected with hepatitis delta, transmission from mother to child can be prevented with the hepatitis B vaccine. Centers for Disease Control and Prevention (CDC) guidelines recommend the first dose within 12 hours of birth, along with and a dose of HBIG (hepatitis B immunoglobulin), followed by the additional 2 vaccine shots; one at 1 month and the final one at 6 months old. The vaccine, along with HBIG and hepatitis B antiviral treatment (if necessary) greatly reduce the risk of transmission to the baby. In resource-limited countries, the World Health Organization (WHO) recommends the first dose of the hepatitis B vaccine within 24 hours of birth, followed by the additional shots on the recommended schedule. Once the vaccination series is completed, the baby should be protected for life against hepatitis B and delta.

If hepatitis delta cannot be treated during pregnancy, do most women have progression of their liver disease during pregnancy?

 

 While some women may see progression of their liver disease, due to the relative short length of pregnancy, most women do not show clinical signs of advancing liver disease.

 

What treatment should follow delivery? 

 

 

Following delivery, the mother may resume interferon treatment as long as she is not breastfeeding. Interferon treatment while breastfeeding could be harmful to the baby. As for all patients, keeping up-to-date on the latest hepatitis delta clinical trials could provide access to new, experimental treatments that may be more effective. For a global list of clinical trials for hepatitis delta, visit the clinicaltrials.gov web page.

It is very important for all pregnant women who are hepatitis B and delta positive 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 or email connect@hepdconnect.org.

Hepatitis Delta (HDV)

Nearly 1 in 4 Romanians with Hepatitis B also Infected with Hepatitis D

 

By Sierra Pellechio, Hepatitis Delta Connect Coordinator

Since the 1990’s most of Eastern Europe has seen a decline in the prevalence of hepatitis D, a dangerous coinfection of hepatitis B, attributed to successful vaccination programs and government prioritization. Romania, which has the highest hepatitis B prevalence in the EU, has not seen such declines of hepatitis D, which affects 23% of its hepatitis B patients. Hepatitis D coinfection is considered hyperendemic to the country, and has some of the highest rates of coinfection globally1. Seventy percent of these 200,000 patients will progress to cirrhosis, often within only 10  years2, and face barriers to receiving effective treatment and management. Although the country enacted a national hepatitis B vaccination program for all newborns in 1995 and a catch-up program for school-age children in 1999, older populations already infected with hepatitis B and inadequately immunized young people represent susceptible groups for coinfection with hepatitis B and disease.1,3. Additionally; lack of hepatitis B vaccination recommendations for high risk groups, low implementation of hepatitis B screening during pregnancy, supply shortages and vaccine hesitancy, have created opportunities for hepatitis B and D transmission. Exposure to infected blood or sexual fluids through blood transfusions or surgeries (before the 1990’s), tattoos, piercings, injection drug use, or sexual contact with an infected person, can expose people already living with hepatitis B to hepatitis D, or expose those who have not received the full hepatitis B vaccine series to both viruses. Control of hepatitis B and D coinfection has also been hindered by the lack of a national registry and surveillance system thus preventing an understanding of the accurate prevalence and public health burden1.

With health expenditure and life expectancy the lowest in the EU, Romania is battling large system-wide failures that have fostered the persistence of hepatitis B and D in its population5.

Dr. Florin Caruntu, of the National Institute of Infectious Diseases in Bucharest, has suggested that there is a general low level of awareness and screening among health care providers in Romania, which has led to late diagnoses and cost many patient lives. For patients who are diagnosed, investigational testing is not covered by the national insurance house, placing a financial burden on patients to pay out of pocket for the additional testing necessary to manage their coinfection. With pegylated interferon injections as the only semi-effective treatment option, even diagnosed patients struggle to effectively control their coinfection and even less are connected to clinical trials. Although there are 7 new drugs in clinical trials, progress has lagged behind patient need for new therapies, many of whom are living with cirrhosis.

Increased government investment in the healthcare system, including medical training and education programs for provider awareness, updated protocols and coverage of investigational testing, would pave the way for increased patient identification and navigation to successful care. As clinical trials continue to progress, it is critical that Romania be a top consideration for clinical trial sites, as patients anxiously await more effective treatment options.

For more information on HDV in Romania, please watch our webinar featuring expert speaker, Dr. Florin Caruntu, of the National Institute of Infectious Diseases in Bucharest, Romania.

For more information about hepatitis B/D coinfection and the Hepatitis Delta Connect program, please visit www.hepdconnect.org or email us at connect@hepdconnect.org. If you are a hepatitis delta patient, and wish to receive information about upcoming clinical trials, please enter your information here. Hepatitis Delta Connect seeks to provide information, resources and support for hepatitis B/D patients and their families through its website, social media, fact sheets, webinars  and hepatitis D liver specialist directory.

1. Hepatitis delta virus infection in Romania: Prevalence and risk factors. (2015). Journal of Gastrointestinal and Liver Diseases, 24(4) doi:10.15403/jgld.2014.1121.244.dtv

2. Noureddin, M., & Gish, R. (2014). Hepatitis delta: Epidemiology, diagnosis and management 36 Years after discovery. Current Gastroenterology Reports, 16(1), 1-8. doi:10.1007/s11894-013-0365-x

3. Ruta, S. M., Matusa, R. F., Sultana, C., Manolescu, L., Kozinetz, C. A., Kline, M. W., & Cernescu, C. (2005). High prevalence of hepatitis B virus markers in Romanian adolescents with human immunodeficiency virus infection. Journal of the International AIDS Society, 7(1), 68-68. doi:10.1186/1758-2652-7-1-68

4. Gheorghe, L., Csiki, I. E., Iacob, S., & Gheorghe, C. (2013). The prevalence and risk factors of hepatitis B virus infection in an adult population in Romania: A nationwide survey. European Journal of Gastroenterology & Hepatology, 25(1), 56.

5. OECD/European Observatory on Health Systems and Policies (2017), Romania: Country Health Profile 2017, State of Health in the EU,OECD Publishing, Paris/European Observatory on Health Systems and Policies, Brussels. http://dx.doi.org/10.1787/9789264283534-en

 

Hepatitis Delta (HDV), Liver Cancer, Uncategorized

Where is Hepatitis D? High Prevalence of Hepatitis B/D Coinfection in Central Africa

By Sierra Pellechio, Hepatitis Delta Connect Coordinator

While hepatitis B is known to be highly endemic to sub-Saharan Africa and is estimated to affect 5-20% of the general population, the burden of hepatitis D, a dangerous coinfection of hepatitis B, has largely been left undescribed. Since the virus’s discovery 40 years ago, Africa has faced structural barriers that have contributed to the ongoing prevalence of the virus in this region. Widespread instability, under-resourced health systems, and poor surveillance have contributed to inadequate research and a lack of understanding about the health burden of hepatitis D on hepatitis B patients, particularly in Central Africa.

New data, however, reveals pockets of hepatitis B/D coinfection in this region, particularly in countries such as Cameroon, Central African Republic and Gabon. In a recently published study of nearly 2,000 hepatitis B infected blood samples from 2010-2016 in Cameroon, 46.7% tested positive for hepatitis D antibodies, a marker of past or current hepatitis D coinfection. Another study of 233 chronic hepatitis B carriers from 2008-2009 found a 17.6% positivity for hepatitis D antibodies. Other small studies from the Central African Republic have revealed 68.2% prevalence in hepatitis B patients, 50% coinfection in liver cancer patients and an 18.8% coinfection in hepatitis B infected pregnant women. Not only are new studies revealing evidence that there are groups at higher risk for hepatitis D, but a 2008 study on 124 community members in Gabon found 66% of them had markers for hepatitis D, proving this virus can also be circulating in the general population. Globally, hepatitis D is thought to affect about 5-10% of hepatitis B patients, making Central Africa an area of extremely high prevalence.

A diagnosis with hepatitis B and D can increase the risk for cirrhosis and liver cancer by nearly three times, and with only one available treatment, the future for coinfected patients if often uncertain. Although hepatitis B and D can be safely prevented by completing the hepatitis B vaccine series, which is available in many countries throughout Africa, the birth dose of the hepatitis B vaccine is often not given within the recommended 24 hours of birth. Lack of awareness, availability, and high cost mean many infants will not begin the vaccine series until 6 weeks of age, creating a window for exposure to hepatitis B. Greater than 95% of babies infected with hepatitis B will go on to develop chronic hepatitis B infections, leaving them susceptible to a future hepatitis D infection. Spread the same way as hepatitis B, through direct contact with infected blood and sexual fluids, hepatitis D can be contracted through unsterile medical and dental equipment and procedures, blood transfusions, shared razors and unprotected sex. Although the severity of disease varies greatly by hepatitis D genotype, coinfection always requires expert management by a knowledgeable liver specialist, which are often difficult to find.

As an increasing number of studies continue to describe the widespread endemicity of hepatitis B/D coinfection and its public health burden, researchers and the Hepatitis Delta International Network are calling on the World Health Organization (WHO) to declare hepatitis D a “threat” in this region in order to promote increased priority and awareness. Addressing hepatitis B/D coinfection prevention and management will be complex and require a multi-pronged approach through methods such as government prioritization, increased funding for health systems, hepatitis B vaccination awareness programs, birth dose prioritization, better sterilization techniques in hospitals, clinics, and barbers, and public awareness of the disease.

For more information about hepatitis B/D coinfection and the Hepatitis Delta Connect program, please visit www.hepdconnect.org or email us at connect@hepdconnect.org. Hepatitis Delta Connect seeks to provide information, resources and support for hepatitis B/D patients and their families through its website, social media, fact sheets, webinars and hepatitis D liver specialist directory.

Hepatitis Delta (HDV), Living with Hepatitis B

Karen and Dave’s Story

One Couple’s Journey through Hepatitis B, Hepatitis D and Liver Cancer

“Dave knew he had hepatitis B for decades, but honestly, no one ever seemed concerned. His liver
enzymes were slightly elevated, so the doctor told him to just watch what he ate and drank. He didn’t
even insist on bi-yearly blood tests!

In 2016, Dave was scheduled for a routine colonoscopy. Because he’d been looking pale and sickly
around that time, I suggested they do a blood test first at his family doctor. His numbers were off the
chart. They sent us back for the colonoscopy and added an endoscopy too. They found four varices
(enlarged veins in the esophagus that can indicate serious liver disease). How did this happen?

This was when I started to get angry. The gastroenterologist called us in to discuss the results. He asked
if Dave knew he had hepatitis B. Dave said yes, knowing his drug use in his teens and early twenties was
likely the source. Dave never felt shame about it at all, and just accepted it as a path he took, and
thankfully came out of. After that conversation, the doctor slammed his chart shut and pushed it across
the desk. He said that Dave’s liver was so badly damaged that there was nothing he could do and to
‘come back in a year’. When we asked about his options for treatment for the varices and his hepatitis B,
he actually told me that no one would treat the varices unless they were bleeding! He also told us that
hepatitis B antivirals would “make things worse”. That didn’t make sense. We asked about a transplant.
He said there was ‘no way’ anyone would give him a new liver. He didn’t even let us know that there
were actual liver clinics for this very purpose. He sent Dave away to die, really.

Many months later, with much perseverance, we made it to Stanford, where he was immediately put on
entecavir to treat his hepatitis B and to hopefully relieve some of his liver damage. That doctor alerted
us that he should also be tested for hepatitis D, a coinfection of hepatitis B. “It won’t be good if you have
it.” He did.

Due to changes in our health insurance, we were sent to continue at the University of California San
Francisco Liver Center…they were our saving grace. They treated the varices right away and put him on
other medications to help his failing systems. His hepatitis B viral load was now undetectable, with
hepatitis D being the biggest concern. Dave tried interferon to treat the hepatitis D, but with no luck. His
only chance was a transplant, but even though he was doing poorly, his test results didn’t qualify him to
get on the transplant list right away. He had lots of ER visits – 210 office visits in 2017 alone. It was a
whirlwind. Dave hadn’t even driven in 2 ½ years. It was an enormous stress on me, too.

Dave developed liver cancer but wasn’t in good enough shape to go through treatment. As he got sicker,
he eventually qualified for two different                  
liver transplant waiting lists. Finally, on
Thanksgiving night 2017, we got the call
that a healthy liver was available, and we
took it.
Caregiving is a very tough road. Especially
when your person also has encephalopathy,
caused by years of liver damage – and Dave
had it really bad. The encephalopathy
caused mood swings, short-term memory
loss, hand tremors, low appetite. He could
be down-right nasty. At that time, we were
doing the 4 ½ hour drive to San Francisco
once or twice a week. It was stressful for
both of us – and he was really unaware of
the stress that was put on me. Between
driving, taking out the garbage, bills, our
construction business…you name it, I did it
all.

The first 3-4 months out of the transplant, people were telling him all that had gone on. Much to my
frustration, he didn’t believe any of it! Now, over 6 months post-transplant, little things are coming back
to him. I showed him about 2 dozen pictures of him during his journey, and he was shocked! He said he
thought he was fooling everyone into thinking he was well.

The hardest part of this journey was seeing Dave so sick at times. I spent a lot of time in my closet
crying. It was hard on our adult girls too, to see their dad so weak and disoriented. I had a lot of support
through our girls though, and my family, which made a world of a difference. My sister is also a retired
nurse, and she accompanied us to most of our visits. She was a helpful adviser, since his medications
always needed tweaking, and we were often on long calls with our care team, health insurance
company, and pharmacies.

The good we took away is his health! He still doesn’t feel it’s real. We went through so much, and are so
grateful to be on the other side.

Things I’ve learned:
• Get on a Facebook forum for liver transplant patients…they are a great resource and a wealth of
information from other patients.
• Take a third person with you to doctor visits and procedures. At times, I was so consumed with
my concern for Dave, it was easy for me to forget some of the things we discussed. My sister
would take notes, and we would review them after.
• Always get a second opinion if you don’t have a good feeling about your doctor. You will all
become a team, and it’s important to have a team you can trust.
• Get on the transplant list at multiple hospitals, their criteria for transplant varies!
• Have willing family members and friends get tested to see if they are donor matches. Usually the
recipient’s insurance will pay for the testing and survey if they are a match. My sister-in-law and
I were both tested but were not a match.
• Ask about organ swap programs. Apparently, my kidneys were in perfect health. My
hepatologist had me apply to the kidney donor program, in hopes that I may be able to donate
my kidney in exchange for a piece of someone’s liver for Dave.
• Dave was put on depression and anxiety medication early in the process. He was initially very
resistant, mostly because of the stigma. His doctors finally convinced him it would be very
helpful for his general mood…it was!
• I had to make several phone calls to his team without his knowing. Encephalopathy really makes
you confused, and in Dave’s case, grumpy. I asked the doctor to push for the depression and
anxiety medications, which she did. Also, he wouldn’t exercise or take short walks before
surgery, which she had asked him to, to better prepare for surgery. I made the phone call, and
at the next visit, she set him up with a Fitbit! It helped that the ‘suggestions’ came from his
doctor and not me!
• After the transplant, I was so surprised he wasn’t more ‘thankful’ …that he wasn’t in awe of
what we had all gone through for HIM! I got angry with him. I made a private call to our new
post-transplant team. She said depression right after is very common. The patient feels
overwhelmed, and sometimes not very thankful. It’s kind of a way to deny they were in trouble,
to deny that they needed help. That fits my man to a tee!
• I would strongly suggest lots of patience after the transplant. I wish our team would have told
me the possible mental-state Dave might be in. Don’t force them to be thankful. Don’t play the
‘remember when’ game, “remember when I drove you to the ER in the middle of the night?
Remember when they told us you had cancer? Remember when I tried to be your donor?”
Because a lot of it he doesn’t remember.
• Take pictures along the way, but don’t show them until at least 6 months out. I showed Dave
pictures right away, and they didn’t resonate. I just showed him them the other night…and he
was floored! He really ‘got it’. He’s been looking at things differently lately: he’s calmer and
more loving.
• I wish I had kept a journal. The ups and downs of this journey were sometimes excruciating, and
Dave wasn’t ‘present’ to understand it. Hire cleaning help if needed. Get family and friends to
take the patient to lesser important appointments. Don’t let household things pile up on you. Fix
the gutter. Repair the screen. Hire a gardener for a few hours. Ask family to set things up for
you. It’s amazing how in two years without Dave to physically help around the house, things
started to go south pretty quickly! Luckily, I dug in and kept up.

Quite the journey for sure. I feel blessed to be on this side of health!”

– Karen

Hepatitis Delta (HDV)

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.

Hepatitis B Diagnosis & Monitoring, Hepatitis B Treatment, Hepatitis Delta (HDV)

What New Treatments Are on the Horizon for Hepatitis B/D Coinfected Patients?

Although there are highly effective treatments available to manage hepatitis B, there are few available treatments for hepatitis D, and none are U.S. Food and Drug Administration (FDA) approved. Hepatitis D is the most severe form of viral hepatitis, and coinfection can accelerate liver damage and cause cirrhosis or liver cancer in as little as 5 years for some patients. Currently there is no approved drug for acute or chronic hepatitis B/D coinfection, but in trials pegylated interferon alpha has shown to be somewhat effective. By stimulating the body’s immune system, around 25-30% of patients are able to suppress their hepatitis D viral load with weekly injections over 48 weeks. Emerging research is showing higher rates of effectiveness with prolonged interferon treatment beyond one year, but it can be difficult for patients to continue due to the physical and mental toll of interferon on the body. Antiviral medications that are proven effective against hepatitis B are sometimes prescribed along with interferon therapy for patients with a high hepatitis B viral load, but these have no effect on hepatitis D. It is urgent that more treatment options be developed for the millions of hepatitis B/D patients that are eagerly awaiting them.

The good news is that with renewed scientific interest, research and funding, eight new drugs are currently in development that offer hope for more treatment options in the coming years. Two drugs have even been granted special designations by the FDA and one by European Medicines Agency (EMA), paving the way for increased resources and funding for development. Due to recent advancements, the future looks hopeful, and within a few years it is likely there will be more treatment options available. Below is a chart that provides more information on these new drugs and their current clinical trial status.

Pegylated Interferon Lambda

Pegylated-interferon-lambda (PEG-IFN-λ) is a well-characterized, late-stage, first in class, type III interferon that stimulates cell-mediated immune responses that are critical for the development of host protection during viral infections. This drug has now been granted “Orphan Drug Designation” by the FDA, fast-tracking the development process.

Myrcludex B

This drug is an “entry inhibitor” that prevents the virus from entering into hepatocytes (liver cells) and has shown activity against the hepatitis B virus. It may also stop the development of a hepatitis D infection. A recent study showed promise for Myrcludex B when combined with PEG-INF in reducing hepatitis D viral levels. It has been granted PRIME Eligibility by the European Medicines Agency, a status that promotes support in development of drugs that serve an unmet medical need.

Ezetimibe

Currently used to lower cholesterol in the blood, Ezetimibe is being studied for effectiveness against hepatitis D. Ezetimibe possesses pharmacophore features to stop NTCP, the receptor required for hepatitis B and hepatitis D hepatocyte entry.

Lonafarnib

This drug works by targeting the protein assembly process, preventing the production of new virus particles. In a current clinical trial, Lonafarnib combined with Ritonavir has shown promise in reducing hepatitis D viral levels, and the FDA has granted it fast-track status since this class of drugs have been developed for the treatment of cancers and have been shown to be safe.

Rep 2139

This compound is known as a “Nucleic acid-based Amphipathic Polymer” (NAP) which prevents the release of hepatitis B surface antigen (HBsAg) from infected liver cells and is being evaluated for hepatitis D virus in combination with pegylated interferon (PEG IFN).

GI-18000

GI-18000 Tarmogen is being studied for its effectiveness in causing a T cell immune response against cells infected with Hepatitis D and thereby improving outcomes. The strategy is to identify molecular targets that distinguish diseased cells from normal cells and activate the immune system to selectively target and eliminate only the diseased cells.

ALN-HDV

This approach is being used for both the hepatitis B and hepatitis D virus to “silence” the viral RNA with compounds that interfere with and cause the destruction of the viral genome (e.g. stop replication of the virus).

As clinical trials progress, sites may open across the world that are enrolling hepatitis D patients. Keep checking here for an up-to-date list of all current clinical trials.

Click here for more information about the phases of the clinical trial process.

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

Baruch S. Blumberg Institute