Hepatitis B

Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus. It is a major global health problem. It can cause chronic infection and puts people at high risk of death from cirrhosis and liver cancer.

A vaccine against hepatitis B has been available since 1982. The vaccine is 95% effective in preventing infection and the development of chronic disease and liver cancer due to hepatitis B.

Transmission

The hepatitis B virus can survive outside the body for at least 7 days. During this time, the virus can still cause infection if it enters the body of a person who is not protected by the vaccine. The incubation period of the hepatitis B virus is 75 days on average, but can vary from 30 to 180 days. The virus may be detected within 30 to 60 days after infection and can persist and develop into chronic hepatitis B.

In highly endemic areas, hepatitis B is most commonly spread from mother to child at birth (perinatal transmission), or through horizontal transmission (exposure to infected blood), especially from an infected child to an uninfected child during the first 5 years of life. The development of chronic infection is very common in infants infected from their mothers or before the age of 5 years.

Hepatitis B is also spread by percutaneous or mucosal exposure to infected blood and various body fluids, as well as through saliva, menstrual, vaginal, and seminal fluids. Sexual transmission of hepatitis B may occur, particularly in unvaccinated men who have sex with men and heterosexual persons with multiple sex partners or contact with sex workers. Infection in adulthood leads to chronic hepatitis in less than 5% of cases. Transmission of the virus may also occur through the reuse of needles and syringes either in health-care settings or among persons who inject drugs. In addition, infection can occur during medical, surgical and dental procedures, through tattooing, or through the use of razors and similar objects that are contaminated with infected blood.

Symptoms

Most people do not experience any symptoms during the acute infection phase. However, some people have acute illness with symptoms that last several weeks, including yellowing of the skin and eyes (jaundice), dark urine, extreme fatigue, nausea, vomiting and abdominal pain. A small subset of persons with acute hepatitis can develop acute liver failure which can lead to death.

In some people, the hepatitis B virus can also cause a chronic liver infection that can later develop into cirrhosis of the liver or liver cancer. Symptoms may include:

  • Weakness
  • Fatigue
  • Loss of appetite
  • Weight loss
  • Breast enlargement in men
  • A rash on the palms
  • Difficulty with blood clotting
  • Spider-like blood vessels on the skin

Decreased absorption of vitamins A and D can cause impaired vision at night and thinning of bones (osteoporosis). Patients with liver cirrhosis also are at risk of infections because the liver plays an important role in the immune system.

Advanced cirrhosis of the liver due to hepatitis B

In patients with advanced cirrhosis, the liver begins to fail. This is life-threatening condition.

Several complications occur in advanced cirrhosis:

  • Confusion and even coma (encephalopathy) results from the inability of the liver to detoxify certain toxic substances.
  • Increased pressure in the blood vessels of the liver (portal hypertension) causes fluid to build up in the abdominal cavity (ascites) and may result in engorged veins in the swallowing tube (esophageal varices) that tear easily and may cause massive bleeding.
  • Portal hypertension can also cause kidney failure or an enlarged spleen resulting in a decrease of blood cells and the development of anemia, increased risk of infection and bleeding.
  • In advanced cirrhosis, liver failure also results in decreased production of clotting factors. This causes abnormalities in blood clotting and sometimes spontaneous bleeding.
  • Patients with advanced cirrhosis often develop jaundice because the damaged liver is unable to eliminate a yellow compound, called bilirubin.

Diagnosis

It is not possible, on clinical grounds, to differentiate hepatitis B from hepatitis caused by other viral agents and, hence, laboratory confirmation of the diagnosis is essential. A number of blood tests are available to diagnose and monitor people with hepatitis B. They can be used to distinguish acute and chronic infections.

Laboratory diagnosis of hepatitis B infection focuses on the detection of the hepatitis B surface antigen HBsAg. WHO recommends that all blood donations be tested for hepatitis B to ensure blood safety and avoid accidental transmission to people who receive blood products.

  • Acute HBV infection is characterized by the presence of HBsAg and immunoglobulin M (IgM) antibody to the core antigen, HBcAg. During the initial phase of infection, patients are also seropositive for hepatitis B e antigen (HBeAg). HBeAg is usually a marker of high levels of replication of the virus. The presence of HBeAg indicates that the blood and body fluids of the infected individual are highly contagious.
  • Chronic infection is characterized by the persistence of HBsAg for at least 6 months (with or without concurrent HBeAg). Persistence of HBsAg is the principal marker of risk for developing chronic liver disease and liver cancer (hepatocellular carcinoma) later in life.

Treatment

There is no specific treatment for acute hepatitis B. Therefore, care is aimed at maintaining comfort and adequate nutritional balance, including replacement of fluids lost from vomiting and diarrhoea.

Chronic hepatitis B infection can be treated with drugs, including oral antiviral agents. Treatment can slow the progression of cirrhosis, reduce incidence of liver cancer and improve long term survival.

WHO recommends the use of oral treatments – tenofovir or entecavir, because these are the most potent drugs to suppress hepatitis B virus. They rarely lead to drug resistance as compared with other drugs, are simple to take (1 pill a day), and have few side effects so require only limited monitoring.

In most people, however, the treatment does not cure hepatitis B infection, but only suppresses the replication of the virus. Therefore, most people who start hepatitis B treatment must continue it for life.

Treatment using interferon injections may be considered in some people in certain high-income settings, as this may shorten treatment duration, but its use is less feasible in low-resource settings due to high cost and significant adverse effects requiring careful monitoring.

There is still limited access to diagnosis and treatment of hepatitis B in many resource-constrained settings, and many people are diagnosed only when they already have advanced liver disease. Liver cancer progresses rapidly, and since treatment options are limited, the outcome is in general poor. In low-income settings, most people with liver cancer die within months of diagnosis. In high-income countries, surgery and chemotherapy can prolong life for up to a few years. Liver transplantation is sometimes used in people with cirrhosis in high income countries, with varying success.

Medications can reduce the number of viruses in the body and may be able to eliminate the virus from the bloodstream. Logically, this should lead to them having a low rate of progression to cirrhosis (<1% per year), although large, long-term studies have not been done. Even in people who clear the virus from their blood, low numbers of viruses still live in the liver and other cells. Thus, the medications do not cure the disease, but they can prevent or delay complications and symptoms. People who have a good response to treatment can still transmit the virus. Doctors follow blood tests that measure viral load and liver function and they may recommend liver biopsies to evaluate if the medications are working.

The medications in current use for chronic hepatitis B include the interferons and nucleoside/nucleotide analogues. New agents are being developed although they are still under investigation and considered experimental. There are no accepted guidelines that tell how every patient should be treated. As a result, treatment is individualized.

Interferon

Interferon-alpha has been used to treat hepatitis B for more than 20 years. Interferon-alpha is a naturally occurring protein that is made in the body by white blood cells to combat viral infections. In addition to its direct anti-viral effects, interferon works against the hepatitis B virus by stimulating the body’s immune system to clear the virus. Compared to older interferon alpha agents, pegylated interferon alpha, marketed as Pegasys or Pegintron, has a more convenient dosing schedule, may be slightly more effective and suppresses the virus for a longer period of time. Pegylated interferon alpha is given once a week for 48 weeks.

  • A significant reduction in the viral load or elimination of detectable viral DNA from the blood occurs in 25%-37% of people during treatment.
  • Blood tests for liver functions normalize in approximately 23%-39% people treated with interferon or pegylated interferon.
  • People who have significant abnormalities in liver function before therapy are more likely to respond to treatment.
  • Those who have normal liver blood tests before treatment are less likely to respond to interferon therapy.
  • Liver biopsy results show improvement in about one-third of patients.

Only 27% to 34% of people who have Hepatitis B e-antigen (HBeAg) in their blood will be able to eliminate HBeAg and produce antibodies against the HBe antigen after treatment with interferon. Relapse may occur after treatment is stopped.

Sustained response (undetectable viral load in the blood, normal liver function tests) occurs in approximately 15% to 30% of patients after the drug is stopped. Although this is not a cure (some virus still lives in the liver and elsewhere), people with sustained response are at low risk for complications of liver disease. If the responder’s immune system is compromised, for example through the use of steroids or acquiring HIV, the disease can recur. Periodic monitoring of blood tests can help confirm that the response continues to be sustained.

Interferon side effects

Interferon causes several side effects including:

  • fatigue, generalized muscle aches, fever, chills and loss of appetite. These flu-like symptoms occur in approximately 80% of treated patients;
  • mood swings, depression, anxiety and other neuropsychiatric effects may occur; and
  • thyroid gland abnormalities resulting inhypothyroidism (too little thyroid hormone);
  • significant suppression of thebone marrow and production of blood cells;
  • infection;
  • or hair loss may occur.

The side effects may be severe enough that the patient is unable to continue treatment. During treatment, the normal immune response to the virus is stimulated and may cause worsening inflammation in the liver. This is normally a good sign showing that the interferon is working, but more extreme responses may in rare cases cause liver failure. Thus, physicians will monitor blood tests closely during therapy. People with unstable liver disease due to cirrhosis usually should not take interferon because of the increased risk of liver failure.

Nucleoside/nucleotide analogues

Nucleoside/nucleotide analogues (NAs) are man-made chemicals that mimic the nucleosides and nucleotides that are used for making DNA. When the virus tries to use the analogues to make its own DNA, it is unable to make the DNA and, therefore, cannot reproduce. Examples of these agents include adefovir (Hepsera), entecavir (Baraclude), lamivudine (Epivir-HBV, Heptovir, Heptodin), telbivudine (Tyzeka) and tenofovir (Viread).

Unfortunately, the hepatitis B virus may become resistant to NAs over time (see below). Adefovir may be effective against strains of virus that have become resistant to lamivudine and may be added to lamivudine when resistance appears. Simply switching from one NA to another is not recommended because this leads to virus strains that are resistant to multiple medications.

Currently, the optimal duration of treatment with nucleoside/nucleotide analogues is uncertain. people with HBeAg may be treated until six months after the HBeAg disappears from the blood and is replaced by antibodies (anti-HBe), if this occurs. In people without HBeAg, the endpoints are less clear. Some experts advocate treating until the viral load (viral DNA) is undetectable and the surface antigen (HbsAg) has been cleared from the blood. Others suggest continuing medications for prolonged periods to suppress the virus. All of these strategies are hampered by the risk of the virus becoming resistant to the medications. Patients who discontinue treatment with NAs should be monitored carefully for recurrent hepatitis, which may be severe.

Is there a preferred treatment for chronic hepatitis B?

There are no clear guidelines to recommend which agent to use first in treating chronic hepatitis B, as there are multiple options. Interferon is given for a defined period of time and may have a more prolonged response after the medication is discontinued than NAs. However, interferon is given as an injection, and side effects often are troublesome. NAs are given as a pill and have few side effects, but the duration of treatment is unclear, and prolonged therapy (years) may be required. NAs may be preferred in patients with unstable disease and cirrhosis because they are thought to be less likely to cause serious flares of hepatitis with more severe liver disease.

Prevention

The hepatitis B vaccine is the mainstay of hepatitis B prevention. WHO recommends that all infants receive the hepatitis B vaccine as soon as possible after birth, preferably within 24 hours. The birth dose should be followed by 2 or 3 doses to complete the primary series. In most cases, 1 of the following 2 options is considered appropriate:

  • a 3-dose schedule of hepatitis B vaccine, with the first dose (monovalent) being given at birth and the second and third (monovalent or combined vaccine) given at the same time as the first and third doses of diphtheria, pertussis (whooping cough), and tetanus – (DTP) vaccine; or
  • a 4-dose schedule, where a monovalent birth dose is followed by three monovalent or combined vaccine doses, usually given with other routine infant vaccines.

The complete vaccine series induces protective antibody levels in more than 95% of infants, children and young adults. Protection lasts at least 20 years and is probably lifelong. Thus, WHO does not recommend booster vaccination for persons who have completed the 3 dose vaccination schedule.

All children and adolescents younger than 18 years-old and not previously vaccinated should receive the vaccine if they live in countries where there is low or intermediate endemicity. In those settings it is possible that more people in high-risk groups may acquire the infection and they should also be vaccinated. They include:

  • people who frequently require blood or blood products, dialysis patients, recipients of solid organ transplantations
  • people interned in prisons
  • persons who inject drugs
  • household and sexual contacts of people with chronic HBV infection
  • people with multiple sexual partners
  • health-care workers and others who may be exposed to blood and blood products through their work
  • travellers who have not completed their hepatitis B vaccination series, who should be offered the vaccine before leaving for endemic areas

The vaccine has an excellent record of safety and effectiveness. Since 1982, over 1 billion doses of hepatitis B vaccine have been used worldwide. In many countries where between 8–15% of children used to become chronically infected with the hepatitis B virus, vaccination has reduced the rate of chronic infection to less than 1% among immunized children.

As of 2014, 184 Member States vaccinate infants against hepatitis B as part of their vaccination schedules and 82% of children in these states received the hepatitis B vaccine. This is a major increase compared with 31 countries in 1992, the year that the World Health Assembly passed a resolution to recommend global vaccination against hepatitis B. Furthermore, as of 2014, 96 Member States have introduced the hepatitis B birth dose vaccine.

In addition, implementing of blood safety strategies, including quality-assured screening of all donated blood and blood components used for transfusion, can prevent transmission of HBV. Safe injection practices, eliminating unnecessary and unsafe injections, can be effective strategies to protect against HBV transmission. Furthermore, safer sex practices, including minimizing the number of partners and using barrier protective measures (condoms), also protect against transmission.