Hepatitis B

Hepatitis B (HBV) is a virus that infects and damages the liver. Because hepatitis B can hide inside the body, many people don’t know they have the virus until they get tested. In the United States, more than 2 million people have the hepatitis B virus (HBV) and each year, 70,000 new cases develop. If you or your parents were born in Southeast Asia, the Pacific Islands, Africa, the Amazon Basin in South America or the Middle East, you may be more likely to have hepatitis B infection. This is because people in these areas have not always received the hepatitis B vaccine. Also, mothers with hepatitis B who were not vaccinated against the virus may have passed it to their child without knowing.

The general word “hepatitis” indicates the presence of inflammation in the liver. Once this inflammation begins, scar tissue (called fibrosis) may form. In 20-30% of patients who carry the hepatitis B virus, this scar tissue leads to cirrhosis and/or liver cancer. Liver transplantation is a possible treatment for some patients. In rare patients, recurrence of the infection in the new liver is a problem.

Symptoms

While some people don’t experience any symptoms from hepatitis B, others may have flu-like symptoms normally associated with a virus including:

  • Feeling tired
  • Loss of appetite
  • Upset stomach and vomiting
  • Fever
  • Pain
Additionally, people with acute hepatitis B may experience more serious symptoms such as:
  • abdominal pain
  • jaundice (yellowish eyes or skin)
  • dark urine
  • long-lasting fatigue
Hepatitis B often leads to cirrhosis—a scarring process where liver cells are replaced or destroyed, and unable to function. Patients with cirrhosis may experience:
  • swollen feet
  • swollen abdomen (ascites)
  • confusion (encephalopathy)
  • progressive memory loss
  • difficulty sleeping during the night and increased sleeping during the day
  • vomiting blood
  • passing blood, or purple or black bowel movements
  • yellow eyes and/or skin
  • flapping of the extended hands (asterixis)
  • muscle loss
Patients with liver cancer often have no direct symptoms related to the cancer but may have:
  • pain
  • liver failure
  • poor appetite

Back to top

Types of Hepatitis B Infection


Chronic Hepatitis B
Patients with active infection have elevated liver enzymes and/or inflammation shown on their liver biopsy (defining true “hepatitis”). The likelihood of activation is proportional to the viral load (the amount of virus in the blood). Active liver disease becomes prone to occur when the viral load is greater than 10,000 copies (2000 iu) per ml. Patients with active hepatitis B are at risk for progressive liver damage resulting in cirrhosis (see below) and are at highest risk for developing liver cancer.

People with active liver disease are most likely to respond and benefit from the drugs pegylated interferon, adefovir, entecavir and telbivudine. The liver disease in patients with active hepatitis B can spontaneously flare and dampen, but overall the disease trajectory tends to result in progressive liver damage. Treatment can usually suppress viral replication and liver inflammation, and allow the liver to recover.

Immunotolerant Phase
Patients are identified as “silent carriers” if they have persistently normal liver enzymes and a normal liver biopsy. In these cases, the immune system shows only a minimal, if any, recognition of the virus in the body.

It is not widely appreciated that hepatitis B virus (HBV) causes little, if any, liver damage (hepatitis). The hepatitis is caused by recognition of HBV by cells within the liver’s immune system. Failure to recognize the presence of HBV in the body implies that the immune system is somehow “tolerant” to the virus. This surprising and common state of selective neglect is good for the host (and the virus!) Without immune recognition, there is no hepatitis or liver damage.

“Carriers” in the inactive phase are not considered candidates for interferon or oral therapies—viral loads are already low or undetectable—but their careful assessment may require a liver biopsy. The preferred management for HBV carriers is to observe for liver enzyme abnormalities, for example, every 6 months, consider undertaking a liver biopsy, and consider therapy if one shows evidence of developing active disease.

Contrary to widespread belief, hepatitis B carriers have a significant risk for liver cancer. In the West this starts at age 30-50. Although the cancer risk is not as high as in those patients with active inflammation or cirrhosis, recent work indicates that one’s viral load is an independent predictor of liver cancer risk.

Hepatitis B carriers have a low likelihood of spontaneous conversion (1% per year) and are not believed to be good candidates for interferon or oral therapies, but may be the best patients for a liver biopsy.

Reactivation of Hepatitis B (conversion from inactive to active hepatitis B):
Each year, 5 - 15% of patients carrying HBV experience reactivation of the virus. Symptoms may or may not occur during a flare. Hence, it is important to monitor a patient’s liver enzymes every 6 months as well as HBV DNA levels in the blood. Flares may lead to further liver damage and cirrhosis. Patients may be candidates for antiviral therapy during a flare.

Resolved Hepatitis B
This refers to people who have had hepatitis B but cleared it. The blood marker of infection is the hepatitis B “surface antigen,” usually written as “HBsAg.” All carriers are HBsAg(+). After clearance of HBV, the HBsAg disappears with the emergence of an antibody that specifically binds and neutralizes the HBsAg. This “hepatitis B surface antibody” is denoted as “HbsAb.” The natural process of generating an antibody is called “seroconversion.” Generation of the HbsAb nearly always indicates immunity against HBV. When an uninfected person is vaccinated, they are injected with the HBsAg (which contains no HBV DNA and is not infectious).

Successful immunization is demonstrated by anti HBs seroconversion—the hepatitis B surface antibody becomes positive. Hepatitis B infection is also characterized by seroconversion to a different viral component, the Core protein. The Core antibody (anti HBc) simply suggests past contact with the hepatitis B virus. Some people are anti Hbc+ without anti HBs and have no detectable HBsAg. Such patients may harbor very low levels of virus and can reactivate HBV if there is a change in the immune system due to other infections, organ transplants or immunosuppressive medications such as Prednisone.

Hepatitis B variants
There are two broad categories of chronic hepatitis B. These are called “early [e] antigen negative (HbeAg-)” and “e antigen positive (HbeAg+).”

Patients who are HBeAg- and have HBV DNA levels of greater than 2,000 IU (10,000 copies) per mL have infection with mutated viruses (often called “HBV pre-core mutants”). A substantial number of these patients are likely to progress to cirrhosis. PEG interferon, entecavir, adefovir and telbivudine are the FDA-approved medications for such patients. The latter three medications, commonly referred to as “oral agents,” usually require lifelong therapy. Interferon may help suppress viral replication in these patients after a short period of therapy (48 weeks). Lamivudine has lost its role as a first line chronic suppressive agent due to very high resistance mutation and relapse rates (if the medication is stopped). Furthermore, Lamivudine can promote cross-resistance to some of the newer oral agents. Patients with mutations or changes in the core sequence or surface antigen sequence have also been identified, but the clinical significance of these changes are not well defined.

Responses to Therapy
The first objective of therapy is to achieve efficient viral suppression (a virological response), inducing a decrease in DNA levels to undetectable using sensitive methods (to less than 50 IU/mL). Subsequent to viral suppression in a patient with the wild type virus (unmutated, HBeAg+), the fall in HBV DNA level can result in conversion from HBeAg (+) to (-), followed by seroconversion from anti-HBe (-) to (+) and a decrease in DNA levels to undetectable by PCR (less than 50 IU/mL). Seroconversion to anti Hbe is a highly desirable treatment endpoint, because it can result in long-term natural suppression of hepatitis B.

For HBeAg negative patients, HBV DNA undetectability is the best outcome that can be expected since the anti-HBe is already positive and there is no HBeAg being produced.

Cirrhosis
This is the scarring process that occurs with ongoing inflammation and is found in 10% to 30% of patients with HBV infection. Cirrhosis occurs more frequently in patients with active inflammation but can also occur in apparently immunotolerant patients as well as apparently inactive carriers. This diagnosis is difficult to determine by physical exam or through early laboratory tests.

All patients with hepatitis B should have a liver biopsy if their liver enzymes are elevated. Treatment based on an elevated DNA and ALT is also a rational approach.

If cirrhosis is present, the risk of liver cancer (one of the most common cancers in the world) is 200 times greater than for those individuals without cirrhosis or liver disease.

Inactive Carriers
These patients have undetectable virus by PCR and normal ALT levels. These patients have a lower risk of liver disease progression.


Back to top

Transmission

Hepatitis B is carried in an infected person’s blood and other body fluids. The virus is contagious and can be transmitted through:

  • Having sex (either heterosexual or homosexual relations);
  • Living with someone who has hepatitis B; (this is an unusual event and does not require changes in household practices other than avoidance of blood exposure, yet still requires all household members to be vaccinated for HBV)
  • From a pregnant woman to her baby (“vertical transmission”);
  • Having a tattoo or body piercing done with dirty tools that were used on someone else;
  • Sharing drug needles;
  • Sharing a toothbrush or razor with an infected person;
  • Traveling to countries where hepatitis B is common;
  • Unscreened blood transfusion or getting pricked with a blood-contaminated needle;
  • Organ transplantation from a hepatitis B-infected person.

Back to top

Vaccination

A vaccine is available for hepatitis B and all household and sexual contacts of a person infected with the hepatitis B virus should be vaccinated. All homosexuals should be vaccinated, as well as patients of Asian origin and healthcare workers. Vaccination only protects uninfected people.

The hepatitis B vaccine should be given to high-risk individuals, as listed below. The vaccination process involves three injections—an initial injection, then injections at one and six months. A booster shot is not usually required. The modern hepatitis B vaccine is produced through genetic engineering and has no risk of transmitting HBV or other viruses such as the AIDS virus.

  • All health care workers
  • Emergency workers, EMT, police and firemen
  • Pregnant women
  • International travelers
  • Military personnel
  • Morticians and embalmers
  • Patients and personnel at mentally handicapped and correctional institutions
  • High-risk ethnic groups (Africans and Asians)
  • Male homosexuals
  • Injection drug users
  • Infants born to HBsAg+ positive mothers(in addition to HBV Immune globulin)
  • Members of households with a known HBsAg positive infected person

Revaccination is rarely indicated. Those individuals with frequent blood exposure or at high risk for sharp exposure should/could be revaccinated at 5-year intervals. The benefit of this is not well defined but certain individuals may be at risk of infection if exposed to a large amount of potentially infected blood, especially patients undergoing hemodialysis.


Back to top

Screening for vaccination or infection

To evaluate patients who are at high risk for hepatitis B infection, the best single screening test is HBcAb (Hepatitis B core antibody). If the results of this test are negative, a person should receive the hepatitis B vaccination. If the results are positive, HBsAg (hepatitis B surface antigen) test should be ordered. A positive HBsAg test indicates an infected patient.

For patients who test positive for HBsAg, the HBV DNA level and liver enzymes and function tests should be ordered. If the liver enzymes results are abnormal, a liver biopsy is usually recommended. The biopsy is a common test in which a very small cylindrical piece of liver is removed and examined. By viewing the tissue under a microscope, your liver specialist can determine the extent of your disease and identify whether cirrhosis (severe scarring of the liver) has occurred.

The following are additional screening guidelines for patients with positive HBsAg:

  • If cirrhosis is present, start bi-annual liver cancer surveillance with ultrasound and alpha-fetoprotein (AFP) level (a blood test).
  • If AFP is elevated over 20 and/or there is a family history of liver cancer, also start bi-annual ultrasound and AFP testing.
If liver biopsy shows no cirrhosis and/or liver enzymes are normal:
  • Seek family history of liver cancer:
    - If yes, start liver cancer screening at age 30 by AFP and ultrasound yearly
    - If no, start liver cancer screening at age 40 by AFP and ultrasound yearly
    - Patients infected with genotype C HBV may warrant earlier screening
  • Liver enzymes should be measured bi-annually in all patients who are HBV infected.

Back to top

Tests for Those With Hepatitis B Infection

All patients who are HBV infected should have:

  • ALT (alanine aminotransferase)—a liver enzyme test that measures the level of ALT in one’s blood. An elevated ALT level is a sign of liver inflammation
  • Liver function tests: Albumin, bilirubin, INR (a coagulation test)
  • Liver biopsy (strong consideration)
  • HBV DNA Quantification
  • HBeAg (hepatitis B e antigen), anti-HBe (Hepatitis B e antibody), anti-HDV (Hepatitis Delta virus antibody) — if HBV acquired as an adult
  • Estimation of Time/Age of acquiring HBV
  • A baseline ultrasound of the liver
Other tests that are strongly suggested include:
  • HBV Core and PreCore mutation analysis
  • HBV Genotype
  • Viral resistance testing in patients on oral therapies if HBV DNA does not decrease by a factor of 10 every 3 months on therapy, or if there is viral breakthrough (rising HBV DNA) while on therapy
Liver disease activity and general treatment recommendations:
  • Active progressive liver disease (Grade > 1 inflammation; Stage II, III, IV fibrosis): Treat
  • Inactive (Grade <1 inflammation, Stage 0-1 fibrosis): Probably will not treat


Back to top

Treatment

PEG Interferon
Interferon is the general name of a drug used to treat hepatitis B and C. This drug, which is administered through an injection under the skin (similar to an insulin shot for diabetes), can even eliminate chronic hepatitis B in a few people. More typically, it can slow the liver disease by reducing the amount of virus in the body. Patients who are most likely to respond to treatment with interferon have the following criteria:

  • Hepatitis B infection for less than four years
  • Positive or negative HBeAg and HBV DNA under 10 million IU (50 million copies) per mL
  • Elevated liver enzymes (best if ALT >100iu/mL)
Patients with the following criteria are not likely to respond to interferon:
  • Long duration of hepatitis B virus
  • Hepatitis B acquired at childbirth
  • HBV DNA negative (the virus is not producing) or very high levels of HBV DNA (>200 pg/mL)
  • Normal liver enzymes
  • Presence of HIV (AIDS) virus
  • Older age
  • Organ transplant recipient
  • HBV DNA undetectable
  • Very high levels of HBV DNA (>100 million IU/mL)
Interferon is usually given at higher doses (five million units per day or 10 million units three times a week) for 16-32 weeks. In patients who are positive for the Delta hepatitis virus or pre-core mutants, Interferon may be given for 1 year or longer.

The side effects of interferon include: soreness at the injection site, slight fever, muscle aches, elevated blood sugar, mood swings, hair loss, nausea, joint aches, headache, decreased blood cell counts including white blood cells (those used to fight infection), platelet count (used for blood clotting) and anemia (a decrease in red blood cells which are used for carrying oxygen). There is no known risk of HIV or AIDS (immunodeficiency disease) from the use of these treatments.

We presume that newer forms of interferon including PEG Intron and PEG-Roferon (alfa-2A) are active against HBV infection, but these drugs are not FDA-approved for this indication.

According to published studies, Interferon decreases or halts replication (the virus reproducing itself) of the hepatitis B virus. After treatment with Interferon, 40% of patients have a fall in liver enzymes and a fall or disappearance of the DNA of the virus. The inflammatory changes seen on liver biopsy improve in most patients with improved liver enzymes. Ten percent of patients clear the virus (convert from surface antigen positive to surface antigen negative) and are considered cured. A long-term follow-up study showed that up to 40% of patients treated with interferon will eventually lose HBsAg and be cured of hepatitis B.

Entecavir and Adefovir
Oral medications such as entecavir or adefovir can be prescribed to suppress HBV infection, however, these medications rarely lead to HBsAg seroconversion (<6% of cases for entecavir, <2% for adefovir).

While these medications can be used with other nucleosides or nucleotides, or with PEG interferon, complete information on the utility or efficacy of combination therapy has not been published. It is suggested that combination therapy may increase the chance of viral clearance and decrease the chance of viral mutations that lead to resistance in patients who have a high risk of developing resistance (lamivudine, adefovir and telbivudine treated patients) or in patients with known resistance.

General Rules:
Use entecavir or adefovir for patients who are treatment candidates unless they fit the PEG interferon guidelines as stated above.



Back to top

Glossary

surface antigen (HBsAg): A positive test indicates a patient is infected with hepatitis B virus and is infectious to others

surface antibody (sAby or anti-HBs): A positive test indicates that a person is usually immune to the hepatitis B virus and does not carry infection

core antibody (cAby or anti-HBc): This test, if positive, means the patient has been exposed to the hepatitis B virus but does not mean immunity or active infection, please refer to the two tests above

e antigen (HBeAg): This is a crude marker of active reproduction (and infectivity) of the virus

e antibody (HBeAby or anti-HBe): This test is used to show low reproduction of the virus; a patient is positive if the e antigen test is negative

Hepatitis B DNA: This is the genetic code for the virus and also a blood test. If the blood test is positive, it indicates that the patient has a very actively reproducing virus in the body. The presence of HBV DNA in the blood is also a marker of infectivity

Hepatitis Delta Antibody (HDVAb): A positive test indicates a patient is infected with the hepatitis D virus and is infectious to others

Hepatitis Delta Antigen (HDVAg): A positive test indicates a patient is infected with the hepatitis D virus and is infectious to others


Back to top

Further Information

The following sources have further information about hepatitis B:


Back to top