Hepatitis D

Hepatitis D, also known as “delta hepatitis,” is a liver infection caused by the Hepatitis D virus (HDV) (previously called the Delta agent) ¹. Hepatitis D is uncommon in the United States. Hepatitis D virus (HDV) is a defective ribonucleic acid (RNA) virus that requires hepatitis B virus (HBV) for its replication ². In other words, hepatitis D only occurs among people who are infected with the Hepatitis B virus because hepatitis D virus (HDV) is an incomplete virus (also known as a “satellite virus”) that requires the helper function of hepatitis B virus (HBV) to replicate ³. In this way, hepatitis D is a double infection. You can protect yourself from hepatitis D by protecting yourself from hepatitis B by getting the hepatitis B vaccine.

Hepatitis D virus (HDV) can be an acute, short-term, infection or a long-term, chronic infection. Hepatitis D is transmitted through percutaneous (i.e., puncture through the skin) or mucosal contact with infectious blood or other body fluids of an infected person and can be acquired either as a coinfection with hepatitis B virus (HBV) or as superinfection in people with hepatitis B virus (HBV) infection. Hepatitis B virus/hepatitis D virus coinfection occurs when a person simultaneously becomes infected with both hepatitis B virus and hepatitis D virus, whereas hepatitis D virus superinfection occurs when a person who is already chronically infected with hepatitis B virus acquires hepatitis D virus. Although acute hepatitis B virus/hepatitis D virus coinfections can resolve, hepatitis D virus superinfection can lead to rapid progression of the already present hepatitis B virus infection, resulting in liver cirrhosis and liver failure. These outcomes occur within 5–10 years in 70%–80% and within 1–2 years in 15% of people with chronic hepatitis B virus/hepatitis D virus infection ⁴.

Hepatitis D virus is not spread through food or water, sharing eating utensils, breastfeeding, hugging, kissing, hand holding, coughing, or sneezing. And there is no vaccine for Hepatitis D, but it can be prevented in persons who are not already hepatitis B virus (HBV)-infected by Hepatitis B vaccination.

Hepatitis D virus (HDV) infection key facts ⁵:

The hepatitis D virus can cause an acute or chronic infection, or both.
Hepatitis D infection cannot occur in the absence of hepatitis B virus. The hepatitis D virus is unusual because it can only infect you when you also have a hepatitis B virus infection. The coinfection or superinfection of hepatitis D virus (HDV) with hepatitis B virus (HBV) causes a more severe disease than hepatitis B virus (HBV) monoinfection and have a high risk to develop liver cirrhosis and liver cancer (hepatocellular carcinoma) within a few years ⁶.
Vertical transmission from mother to child is rare.
Approximately 15 million people across the world are chronically coinfected with Hepatitis D virus (HDV) and hepatitis B virus (HBV).
Currently there is no effective antiviral treatment for hepatitis D.
A vaccine against hepatitis B is the only method to prevent hepatitis D virus infection. Hepatitis D infection can be prevented by hepatitis B immunization.

Hepatitis D virus geographical distribution

It is estimated that globally, 5% of HBsAg (Hepatitis B surface antigen) positive people are coinfected with hepatitis D virus (HDV) and the distribution is worldwide ⁶. High-prevalence areas include the Mediterranean, Middle East, Pakistan, Central and Northern Asia, Japan, Taiwan, Greenland and parts of Africa (mainly the horn of Africa and West Africa), the Amazon Basin and certain areas of the Pacific. Prevalence is low in North America and Northern Europe, South Africa, and Eastern Asia.

What is acute hepatitis D?

Acute hepatitis D is a short-term infection. The symptoms of acute hepatitis D are the same as the symptoms of any type of hepatitis and are often more severe ⁷. Sometimes your body is able to fight off the infection and the virus goes away.

What is chronic hepatitis D?

Chronic hepatitis D is a long-lasting infection. Chronic hepatitis D occurs when your body is not able to fight off the virus and the virus does not go away. People who have chronic hepatitis B and D develop complications more often and more quickly than people who have chronic hepatitis B alone ⁸.

What is the likelihood that hepatitis D virus infection will become chronic?

The likelihood of progression to chronic hepatitis D virus infection depends on whether the initial infection occurred by hepatitis B virus/hepatitis D virus coinfection or hepatitis D virus superinfection. Of immunocompetent adults, more than 95% clear both hepatitis B virus and hepatitis D virus infections when they are acquired at the same time. On the other hand, hepatitis D virus becomes chronic in more than 80% of people with hepatitis D virus superinfection ⁹.

What health outcomes are associated with chronic hepatitis D virus infection?

Chronic hepatitis D virus generally causes a more aggressive and rapid progression of liver disease than chronic hepatitis B virus infection alone. This is especially evident in patients infected with genotype hepatitis D virus-3, which is common in the Amazon Basin ¹⁰. Of people with chronic hepatitis D virus superinfection, cirrhosis and liver failure occur within 5–10 years in 70%–80% and within 1–2 years in 15% ¹¹. Comparatively, the mean age of onset of cirrhosis for people who acquire chronic hepatitis B in childhood is 40 years ¹².

What is the difference between hepatitis B virus/hepatitis D virus coinfection and hepatitis D virus superinfection?

Hepatitis D and hepatitis B infections may occur together as a coinfection or a superinfection. People can only become infected with hepatitis D when they also have hepatitis B.

Hepatitis B virus/hepatitis D virus coinfection

A hepatitis B virus and hepatitis D virus coinfection occurs when you get both hepatitis D and hepatitis B infections at the same time. Coinfections usually cause acute, or short-term, hepatitis D and B infections. Coinfections may cause severe acute hepatitis.

In most cases, people are able to recover from and fight off the acute hepatitis D and B infections and the viruses go away. However, in less than 5 percent of people with a coinfection, both infections become chronic and do not go away ¹³.

Hepatitis B virus/hepatitis D virus superinfection

A hepatitis B virus and hepatitis D virus superinfection occurs if you already have chronic hepatitis B and then become infected with hepatitis D. When you get a superinfection, you may have severe acute hepatitis symptoms ⁷.

Up to 90 percent of people with a superinfection are not able to fight off the hepatitis D virus, and develop chronic hepatitis D ⁸. As a result, these people will have both chronic hepatitis D and chronic hepatitis B.

Is a hepatitis D vaccine available?

No vaccine for hepatitis D is currently available. The hepatitis B vaccine can prevent hepatitis D by preventing hepatitis B.

How common is hepatitis D in the United States?

Hepatitis D virus infection is uncommon in the United States, where most cases occur among people who migrate or travel to the United States from countries with high hepatitis D virus endemicity. Because hepatitis D is not a nationally notifiable condition, the actual number of hepatitis D cases in the United States is unknown ¹⁴.

Hepatitis D transmission

The routes of hepatitis D virus (HDV) transmission are the same as for hepatitis B virus (HBV):

Hepatitis D virus (HDV) is transmitted through activities that involve percutaneous (i.e., puncture through the skin) or mucosal contact with infectious blood and various body fluids, as well as through saliva, menstrual, vaginal, and seminal fluids, including:

Sex with an infected partner
Injection drug use that involves sharing needles, syringes, or drug-preparation equipment
Contact with blood or open sores of an infected person
Needle sticks or sharp instrument exposures
Sharing items such as razors or toothbrushes with an infected person
Birth to an infected mother (rare)

Sexual transmission of hepatitis D may occur, particularly in unvaccinated men who have sex with men and heterosexual persons with multiple sex partners or contact with sex workers.

The hepatitis D virus rarely spreads from mother to child during birth.

You can’t get hepatitis D from:

being coughed on or sneezed on by an infected person
drinking water or eating food
hugging an infected person
shaking hands or holding hands with an infected person
sharing spoons, forks, and other eating utensils
sitting next to an infected person

Vaccination against hepatitis B virus (HBV) prevents hepatitis D virus (HDV) coinfection, and hence expansion of childhood hepatitis B virus (HBV) immunization programmes has resulted in a decline in hepatitis D incidence worldwide. However, in some settings, the increase of hepatitis D prevalence has been observed in people who inject drugs, or as a result of migration from areas where hepatitis D virus (HDV) is endemic.

Who is at risk hepatitis D virus (HDV) infection?

Chronic hepatitis B virus (HBV) carriers are at risk for infection with hepatitis D virus (HDV).

People who are not immune to hepatitis B virus (HBV) (either by natural disease or immunization with the hepatitis B vaccine) are at risk of infection with hepatitis B virus (HBV) which puts them at risk of hepatitis D virus (HDV) infection.

The following populations are at increased risk for becoming infected with hepatitis D virus:

People chronically infected with hepatitis B virus (HBV)
Infants born to mothers infected with hepatitis D virus
Sex partners of persons infected with hepatitis D virus
Men who have sex with men
People who inject drugs
Household contacts of people with hepatitis D virus infection
Health care and public safety workers at risk for occupational exposure to blood or blood-contaminated body fluids
Hemodialysis patients

How can I protect myself from hepatitis D infection?

If you do not have hepatitis B, you can prevent hepatitis D infection by taking steps to prevent hepatitis B infection, such as getting the hepatitis B vaccine. If you do not get hepatitis B, you cannot get hepatitis D.

If you already have hepatitis B, you can take steps to prevent hepatitis D infection by:

not sharing drug needles or other drug materials
wearing gloves if you have to touch another person’s blood or open sores
not sharing personal items such as toothbrushes, razors, or nail clippers

How can I prevent spreading hepatitis D to others?

If you have hepatitis D, follow the steps above to avoid spreading the infection. Your sex partners should get a hepatitis B test and, if they aren’t infected, get the hepatitis B vaccine. Preventing hepatitis B will also prevent hepatitis D.

You can protect others from getting infected by telling your doctor, dentist, and other health care professionals that you have hepatitis D. Don’t donate blood or blood products, semen, organs, or tissue.

What causes Hepatitis D?

Hepatitis D infection is caused by the hepatitis D virus ¹⁵. Hepatitis D virus (HDV) is a defective ribonucleic acid (RNA) virus that requires hepatitis B virus (HBV) for its replication ². In other words, hepatitis D only occurs among people who are infected with the Hepatitis B virus because hepatitis D virus (HDV) is an incomplete virus (also known as a “satellite virus”) that requires the helper function of hepatitis B virus (HBV) to replicate ³. In this way, hepatitis D is a double infection. You can protect yourself from hepatitis D by protecting yourself from hepatitis B by getting the hepatitis B vaccine.

The hepatitis D virus spreads through contact with an infected person’s blood or other body fluids. Contact can occur by:

sharing drug needles or other drug materials with an infected person
having unprotected sex with an infected person
getting an accidental stick with a needle that was used on an infected person

The hepatitis D virus rarely spreads from mother to child during birth. Perinatal transmission (transmission of a hepatitis D virus from mother to baby during the perinatal period, the period immediately before and after birth) is uncommon. Risk factors include blood transfusions and intravenous drug use ¹⁶.

Hepatitis D replicates independently within liver cells (hepatocytes) but requires hepatitis B surface antigen (HBsAg) for propagation. While the mechanism by which hepatitis D virus induces liver damage is not entirely known, liver cell death occurs is thought to be due to direct cytotoxic effects of hepatitis D virus or a host-mediated immune response ¹⁷, ¹⁸. The spectrum of damage can range from no symptoms to fulminant liver failure. Hepatitis D virus superinfection tends to have a more rapid course and increases the risk of hepatocellular carcinoma ¹⁹. The degree of injury depends on various factors including hepatitis D virus genotype, host immune response and hepatitis B virus genotype.

In individuals who are susceptible to hepatitis B virus, co-infection with both viruses results in an acute hepatitis B and D infection. Clinically, co-infection resembles classic acute hepatitis B, except that a biphasic course of two peaks of serum alanine aminotransferase (ALT) may be seen several weeks apart. This is because hepatitis B virus infection must be established first during the acute coinfection before hepatitis D virus starts to spread. More severe cases than acute hepatitis B virus mono-infection may be seen in some cases with an increased risk for liver failure. Most patients recover during the acute coinfection with hepatitis B virus and hepatitis D virus, and only about 5% of the patients go on to develop chronic infection (defined as persistence of infection beyond 6 months) ²⁰.

In individuals who are chronic carriers of hepatitis B virus antigen (HBsAg), a full-blown superinfection can occur which may present as severe acute hepatitis or exacerbation of preexisting chronic hepatitis B. In patients with chronic hepatitis B virus infection, acute hepatitis D virus infection may be mistaken for a hepatitis B virus flare. In those with hitherto undiagnosed hepatitis B infection, clinical presentation and initial investigations may be mistaken for acute hepatitis B virus infection if hepatitis D virus superinfection is not entertained as a diagnostic possibility. The clinical course during a superinfection is often more severe than hepatitis B virus/hepatitis D virus coinfection. As the presence of HBsAg allows for continuous viral replication, 90% of these individuals progress to chronic hepatitis D. Chronic hepatitis D virus infection causes more severe morbidity and complications (progressive fibrosis, cirrhosis, hepatocellular carcinoma, and hepatic decompensation) than chronic hepatitis B virus infection ²¹.

In cases of triple infection with hepatitis B virus, hepatitis C virus (HCV) and hepatitis D virus, either hepatitis D virus or hepatitis C virus will dominate the other viruses depending on the geographic region, host immune factors, activity, and genotype of the hepatitis D virus involved ¹⁵.

Hepatitis D virus genotypes

Eight different hepatitis D virus genotypes can be found across the globe, all of which share the same transmission routes and risk groups ²².

Hepatitis D virus genotype 1 circulates mainly in North America, Europe, the Middle East, and North Africa ²³. When associated with acute hepatitis D, it has a fulminant course. Once chronic, it can exacerbate previously existing hepatitis B virus disease. It can rapidly progress towards liver cirrhosis but can also have an indolent course.
Hepatitis D virus genotypes 2 and 4 can be found in East Asia. Contrary to genotype 1, it is less frequently associated with fulminant liver disease and progression of chronic liver disease ²⁴.
Hepatitis D virus genotype 3 is found exclusively in the Amazon Basin in South America and tends to cause severe acute hepatitis which can progress to liver failure ²⁵.
Hepatitis D virus genotypes 5, 6, 7, and 8 are found in West and Central Africa.

Hepatitis D symptoms

Hepatitis D virus causes infection and clinical illness only in hepatitis B virus (HBV)-infected people. The signs and symptoms of acute hepatitis D virus infection are indistinguishable from those of other types of acute viral hepatitis infections. These include:

Fever
Fatigue
Loss of appetite
Nausea
Vomiting
Abdominal pain
Dark urine
Clay-colored bowel movements
Joint pain
Jaundice (yellowish tint to the whites of the eyes and skin)
Even fulminant hepatitis

These signs and symptoms typically appear 3–7 weeks after initial infection ⁹. But recovery is usually complete and development of fulminant hepatitis is infrequent and chronic hepatitis D is rare (less than 5% of acute hepatitis).

In a superinfection, hepatitis D virus can infect a person already chronically infected with hepatitis B virus (HBV). The superinfection of hepatitis D virus on chronic hepatitis B accelerates progression to a more severe disease in all ages and in 70‒90% of persons. Hepatitis D virus superinfection accelerates progression to cirrhosis almost a decade earlier than hepatitis B virus (HBV) mono-infected persons. Patients with hepatitis D virus induced cirrhosis are at an increased risk of hepatocellular carcinoma (liver cancer); however, the mechanism in which hepatitis D virus causes more severe hepatitis and a faster progression of fibrosis than hepatitis B virus (HBV) alone remains unclear.

Acute Hepatitis D

Acute hepatitis D (simultaneous infection with hepatitis B virus and hepatitis D virus) is a short-term infection. The symptoms of acute hepatitis D are the same as the symptoms of any type of hepatitis and are often more severe ⁷. Sometimes your body is able to fight off the infection and the virus goes away. Development of chronic hepatitis D is rare (less than 5% of acute hepatitis).

Hepatitis D signs and symptoms may include:

Abdominal pain
Dark urine
Fever
Joint pain
Loss of appetite
Nausea and vomiting
Weakness and fatigue
Yellowing of your skin and the whites of your eyes (jaundice)

Superinfection: Hepatitis D virus (HDV) can infect a person already chronically infected with hepatitis B virus. The superinfection of hepatitis D virus (HDV) on chronic hepatitis B accelerates progression to a more severe disease in all ages and in 70‒90% of persons. Hepatitis D virus (HDV) superinfection accelerates progression to cirrhosis almost a decade earlier than hepatitis B virus monoinfected persons, although hepatitis D virus (HDV) suppresses hepatitis B virus replication. The mechanism in which hepatitis D virus (HDV) causes more severe hepatitis and a faster progression of fibrosis than hepatitis B virus alone remains unclear.

Chronic Hepatitis D

Do people who are coinfected with hepatitis B virus/hepatitis D virus have different symptoms than those who have hepatitis D virus superinfection?

Acute hepatitis occurs in hepatitis B virus and hepatitis D virus coinfected people, and their symptoms may follow a biphasic course. Symptoms of hepatitis B virus and hepatitis D virus coinfection can range from mild to severe (fulminant hepatitis), but for most people, coinfection is self-limited: less than 5% of coinfected people go on to develop chronic infections ²². Regardless, acute liver failure is more common among people with hepatitis B virus and hepatitis D virus coinfection than among those infected with hepatitis B virus alone ²⁶.

Hepatitis D virus superinfection accelerates the progression of chronic hepatitis B virus in 70%–90% of people, regardless of age ²². Although hepatitis D virus suppresses the replication of hepatitis B virus, cirrhosis occurs up to a decade earlier in hepatitis D virus-superinfected persons compared with those infected with hepatitis B virus alone ²². The mechanisms by which hepatitis D virus accelerates progression and more severe disease are not clear.

Hepatitis D complications

Hepatitis D complications may include:

Chronic active hepatitis
Acute liver failure

Acute hepatitis D complications

In rare cases, acute hepatitis D can lead to acute liver failure, a condition in which the liver fails suddenly. Although acute liver failure is uncommon, hepatitis D and B infections are more likely to lead to acute liver failure than hepatitis B infection alone ²⁷.

Chronic hepatitis D complications

Chronic hepatitis D may lead to cirrhosis, liver failure, and liver cancer. People who have chronic hepatitis B and D are more likely to develop these complications than people who have chronic hepatitis B alone ⁸. Early diagnosis and treatment of chronic hepatitis B and D can lower your chances of developing serious health problems.

Cirrhosis: Cirrhosis is a condition in which the liver slowly breaks down and is unable to work normally. Scar tissue replaces healthy liver tissue, partly blocking the flow of blood through the liver. In the early stages of cirrhosis, the liver continues to work. As cirrhosis gets worse, the liver begins to fail.
Liver failure also called end-stage liver disease, liver failure progresses over months or years. With end-stage liver disease, the liver can no longer perform important functions or replace damaged cells.
Liver cancer: Having chronic hepatitis B and chronic hepatitis D increases your chance of developing liver cancer. Your doctor may suggest blood tests and an ultrasound or other type of imaging test to check for liver cancer. Finding cancer at an early stage improves the chance of curing the cancer.

How do doctors diagnose hepatitis D?

Doctors diagnose hepatitis D based on your medical history, a physical exam, and blood tests. If you have hepatitis D, your doctor may perform tests to check your liver. Because cases of hepatitis D are not clinically distinguishable from other types of acute viral hepatitis, diagnosis can be confirmed only by testing for the presence of antibodies against hepatitis D virus and/or hepatitis D virus RNA. Hepatitis D virus infection should be considered in any person with a positive hepatitis B surface antigen (HBsAg) who has severe symptoms of hepatitis or acute exacerbations.

Medical history

Your doctor will ask about your symptoms and about factors that may make you more likely to get hepatitis D.

Physical exam

During a physical exam, your doctor will examine you and look for signs of liver damage, such as yellowing skin or belly pain:

changes in skin color
swelling in your lower legs, feet, or ankles
tenderness or swelling in your abdomen

What tests do doctors use to diagnose hepatitis D?

Your doctor may order one or more blood tests to diagnose hepatitis D. A health care professional will take a blood sample from you and send the sample to a lab.

Blood test

Your doctor may order one or more blood tests to diagnose hepatitis D or its complications. A health care professional will take a blood sample from you and send the sample to a lab.

Hepatitis D virus (HDV) infection is diagnosed by high titers of Immunoglobulin G (IgG) and Immunoglobulin M (IgM) anti-hepatitis D virus (HDV), and confirmed by detection of hepatitis D virus (HDV) RNA in serum.

However, hepatitis D virus (HDV) diagnostics are not widely available and there is no standardization for hepatitis D virus (HDV) RNA assays, which are used for monitoring response to antiviral therapy.

Additional tests

If you have chronic hepatitis D and hepatitis B, you could have liver damage. Your doctor may recommend tests to find out whether you have liver damage or how much liver damage you have—or to rule out other causes of liver disease. These tests may include:

Blood tests. Blood tests can detect signs of the hepatitis B virus in your body and tell your doctor whether it’s acute or chronic. A simple blood test can also determine if you’re immune to the condition.
Elastography, a special ultrasound that measures the stiffness of your liver and can show the amount of liver damage.
Liver biopsy, in which a doctor uses a needle to take a small piece of tissue from your liver. A pathologist will examine the tissue under a microscope to look for signs of damage or disease.

Doctors typically use liver biopsy only if other tests don’t provide enough information about the liver damage or disease. Talk with your doctor about which tests are best for you.

Hepatitis D Treatment

There is no specific treatment for acute or chronic hepatitis D virus (HDV) infection and optimal treatment is not known. Persistent hepatitis D virus (HDV) replication is the most important predictor of mortality and the need for antiviral therapy. Although; it is not FDA-approved for chronic hepatitis D, interferon alpha (IFN alpha) has been shown to be beneficial in most clinical trials ²⁸. Pegylated interferon alpha (Peginterferon Alfa-2a) is recommended to be the preferred agent as per expert guidelines. Doses of 1.5 ug/kg of peginterferon alfa-2b and 180 ug of peginterferon alfa-2a have been used successfully. Current recommendations from an Italian workshop include the use of pegylated interferon alpha for 48 to 72 weeks ²⁹. Pegylated interferon alpha has shown some efficacy, but the sustained virologic response rate (a measure of viral clearance) is low (25%) ³⁰. Treatment is administered once weekly for at least one year ³¹. The goal of treatment is to suppress hepatitis D virus replication which is shown by the inability to detect hepatitis D virus RNA in serum and hepatitis D virus antigen (HDVAg) in the liver. Treatment end-points include normalization of alanine aminotransferase (ALT) and inflammation on liver biopsy. When the disease progresses to cirrhosis, liver transplantation is the only viable option.

Pegylated interferon alpha treatment is associated with significant side effects and should not be given to patients with decompensated cirrhosis, active psychiatric conditions and autoimmune diseases.

New therapeutic agents and strategies are needed, and new therapies are being evaluated ³⁰. Novel drugs, such as prenylation inhibitor or hepatitis B virus entry inhibitors, have shown early promise.

The entry inhibitor bulevirtide also known as BLV (Hepcludex) was approved for conditional marketing in Europe in 2020 ⁶. FDA approval is pending. BLV (Hepcludex) in combination with (off-label) Pegylated interferon alpha (Peginterferon Alfa-2a) for 48 weeks or as monotherapy for a longer duration may allow sustained virological responses in a substantial proportion of patients. For the many hepatitis D virus patients who cannot be treated with Pegylated interferon alpha for different reasons, administration of BLV monotherapy may be a promising ‘suppressive’ strategy. However, the current data indicate that the approved low dose (2 mg subcutaneous daily injection) is suboptimal and the optimal duration of high-dose therapy and its long-term safety profile is currently investigated (MYR301 trial). Studies on the safety in patients with decompensated cirrhosis are required and a more convenient mode of administration or less frequent administrations would be desirable ⁶.

Eating, diet, and nutrition for hepatitis D

If you have hepatitis D, you should eat a balanced, healthy diet. Talk with your doctor about healthy eating. You should also avoid alcohol because it can cause more liver damage.

How do doctors treat the complications of hepatitis D?

If chronic hepatitis D leads to cirrhosis, you should see a doctor who specializes in liver diseases. Doctors can treat health problems related to cirrhosis with medicines, surgery, and other medical procedures. If you have cirrhosis, you have a greater chance of developing liver cancer. Your doctor may order an ultrasound or other type of imaging test to check for liver cancer every 6 months.

If acute hepatitis D leads to acute liver failure, or if chronic hepatitis D leads to liver failure or liver cancer, you may need a liver transplant.

Hepatitis D prognosis

People with an acute hepatitis D virus infection most often get better over 2 to 3 weeks. Liver enzyme levels return to normal within 16 weeks.

About 1 in 10 of those who are infected with hepatitis D virus may develop long-term (chronic) liver inflammation (hepatitis).

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Hepatitis D

What is Hepatitis D