Hepatitis B

Hepatitis virus. PHIL

Author: Dr Norah Terrault University of California San Francisco 2008-07-22

Hepatitis B can cause both acute and chronic infection. Worldwide, there are approximately 350-400 million persons infected with chronic hepatitis B. Chronic hepatitis B infection cannot be cured, but it can be controlled. Several treatment options are available for those with chronic infection and treatment can prevent or even reverse the complications of liver disease. A safe and effective vaccine is available to protect individuals from getting hepatitis B.

Hepatitis B virus (HBV) is a small enveloped DNA virus that belongs to the Hepadnaviridae family of viruses. Worldwide, there are approximately 350-400 million persons infected with hepatitis B, but the prevalence of infection varies significantly by country (Figure below shows the percent of the population infected with hepatitis B). In the United States, 1% of the population is infected, whereas in countries such as China, approximately nearly 10% of the population is infected. Hepatitis B can cause both acute and chronic infection. Chronic HBV infection cannot be cured, but it can be controlled. Moreover, HBV infection can be prevented by vaccination.

HOW DOES HEPATITIS B VIRUS CAUSE HEPATITIS?

HBV is a hepatotrophic virus, meaning the virus replicates only within the liver. The virus gains access to the liver through blood. Once in the liver, HBV multiples and new viruses are exported from the liver cells back into the blood circulation. The immune system mounts an attack on the virus replicating in the liver and tries to eliminate the virus. This immune response results in inflammation and liver cell injury, which is termed “hepatitis.” If the immune response against HBV is robust and successful in eliminating the liver cells infected with virus, the person will recover from the infection. This is resolved acute HBV infection. The antibodies made by the individual’s immune system will protect them against future infection with HBV. After recovery from the acute infection, the liver returns to normal (hepatitis resolves) and there are no residual liver effects. In some individuals infected with HBV, however, the immune response is not successful in eliminating the virus. In these persons, the virus will establish a persistent infection in the liver. This is called chronic HBV infection and persons with chronic infection are at risk for liver damage over many years and can develop cirrhosis and liver cancer.

ACUTE HEPATITIS B: FREQUENCY OF ACUTE HBV INFECTION IN THE POPULATION

An estimated 51,000 new HBV infections occurred in 2005 in the U.S [1]. The frequency of new HBV infections (i.e. incidence) has been declining in the U.S. since the 1980s, with 80% fewer infections in 2005 compared to 1990. This decrease is due, in part, to the success of vaccination programs. However, cases of acute hepatitis B are still occurring in all age groups, especially among those engaged in risky behaviors and who have not been vaccinated. The figure below shows the number of new infections of hepatitis B by age group per 100,000 people in the U.S. Males aged 25-44 years had the greatest number of new infections in recent years (Figure below).

HOW IS HBV INFECTION ACQUIRED?

HBV is transmitted from one person to another by contact with infected blood (or items contaminated by blood) or by sexual contact. HBV has been shown to remains infectious on surfaces contaminated with blood or body secretions for at least seven days. Blood, semen, and saliva are infectious, with the highest concentration of HBV in blood and lower levels found in semen and saliva. The infection can also be transmitted from mother to infant, usually at the time of delivery.

In the U.S., most new infections occur in adolescents and adults. The most frequently reported risk factors for infection were sex (multiple sexual partners, men having sex with men) and sharing of needles or drug paraphernalia (“works”) accounting for approximately 50% and 15% of all new cases of infection. Other risk factors for HBV infection include household contact with an infected person, work in the healthcare setting, hemodialysis workers and patients, other contact with contaminated needles as might occur with tattoos or body piercing in certain settings, receipt of contaminated blood or organs, or travel to areas with high prevalence of HBV infection. Blood transfusion is now a rare cause of acute HBV infection since routine screening of blood donors and blood was undertaken.

In other parts of the world where HBV infection is more prevalent in the general population –such as in Southeast Asia, parts of South America, and Africa – HBV is more frequently acquired at birth or in early childhood. The age at which persons become infected with HBV strongly influences the likelihood of recovery from the acute infection and immunity against development of chronic HBV infection.  Individuals exposed to HBV at a young age are much more likely to become a chronic carrier of the virus.

WHAT IS THE USUAL COURSE OF ACUTE HEPATITIS B INFECTION?

The average incubation period is two to three months, with range of a few weeks to six months, depending upon how much virus is transmitted at the time of exposure.

Symptoms and Signs of Acute Hepatitis
The symptoms for acute hepatitis B are not specific, but rather are the same symptoms seen in patients with acute hepatitis of any cause so the diagnosis of acute hepatitis B requires additional testing.

Symptoms can be non-specific and include:

• Fatigue
• Nausea, vomiting, loss of appetite
• Diarrhea, possibly weight loss
• Fever
• Pain in the right upper portion of the abdomen
• Dark urine
• Jaundice (yellowing of skin and eyes): seen only about 30% of persons with acute HBV

Symptoms can be more severe in those who are immune compromised or who have chronic liver disease. Rarely the HBV infection can cause injury to organs other than the liver. Immune responses to the virus and complexes of virus and antibody can precipitate rashes, arthritis (joint pain), and glomerulonephritis (kidney inflammation).

Laboratory Test Abnormalities
The most important laboratory abnormalities identified on blood tests in symptomatic patients are:

• Marked elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), usually 1000-2000 IU/L
• The ALT is usually slightly higher than the AST. These tests reflect the severity of liver inflammation and injury.
• Elevated levels of bilirubin (cause of the jaundice)
• There may also be changes in the tests that reflect liver function including the prothrombin time (a measure of clotting capacity) and albumin (a measure of protein production and destruction

Clinical Course

The time course for acute HBV infection is depicted in the Figure below.  Several antibodies develop during infection reflecting the immune system’s response to different parts of the virus. The viral antigens and antibodies that are detected during acute infection are used to make the diagnosis of acute HBV and to determine whether the infection has resolved or not.

Following acute infection, hepatitis B surface antigen (HBsAg) is detected in the blood at a median 30-60 days after exposure to the virus. The diagnosis of acute HBV infection is based on detection of HBsAg and IgM antibody to hepatitis B core antigen (IgM anti-HBc) at the time of symptoms. The IgM anti-HBc level declines within six months and another form of antibody to hepatitis B core antigen called IgG anti-HBc develops slightly later and persists indefinitely as a marker of past infection. In persons whose immune systems eliminate HBV, an antibody to HBsAg (called anti-HBs) becomes detectable during convalescence and coincides with the disappearance of HBsAg. The presence of anti-HBs indicates recovery from acute infection and immunity from re-infection. Anti-HBs is also the antibody that develops when vaccination is given. If the immune system is unable to eliminate HBV, the HBsAg persists in the blood and anti-HBs is not detectable. These persons have persistent virus and develop chronic hepatitis.

The primary determinant of whether a person with acute infection will recover from the infection or go on to develop chronic hepatitis is age at the time of infection. Newborns exposed to HBV develop chronic infection in over 95% of cases.  In contrast, 30% of children between the ages of one and five years develop chronic infection after exposed to HBV and only 1-5% of healthy adults develop chronic infection after exposure.

Fulminant hepatitis (a severe form of acute HBV associated with liver failure) is rare, occurring in 0.5-1.5% of persons exposed to HBV. Older individuals are at greatest risk of dying if fulminant hepatitis develops [2].  This life-threatening manifestation of acute hepatitis B requires specialized care in a center that has expertise in treatment of liver failure and performing liver transplantation.

MAKING THE DIAGNOSIS OF ACUTE HEPATITIS B

As highlighted, the symptoms for acute hepatitis are not specific to HBV but common to all forms of hepatitis, and therefore specific laboratory tests are needed to confirm the diagnosis of acute HBV infection. The tests used to distinguish acute HBV infection from chronic HBV infection are shown in Table 1.

TREATMENT OF ACUTE HEPATITIS B

The primary treatment of acute hepatitis B is support care. The focus is on alleviating symptoms associated with hepatitis. For most patients this includes:

- Bed rest
- Insuring adequate fluid intake (especially if vomiting and diarrhea present)
- Use of analgesics (pain relievers) in limited amounts for fever and joint pains

Close follow-up with a physician is essential and all medications taken, even over-the-counter products, should be taken with physician approval to minimize any risk of additional harm to the liver.

Antiviral Therapy
There are several safe and effective drugs that reduce HBV viral levels and improve liver tests when given to patients with chronic HBV infection (see below). At the present time, treatment of acute hepatitis B infection with antiviral drugs – such as lamivudine, entecavir, adefovir or telbivudine – is not generally recommended because the vast majority of healthy adults will resolve the infection on their own.

However, it is controversial as to whether treatment of those with severe hepatitis is beneficial.  Few studies of treatment during acute HBV infection have been done. The available data suggest that antiviral therapy does not provide an clinical benefit and its use is not routinely recommended in persons with acute HBV [3]. Nevertheless, antiviral use appears to be safe and many clinicians use it for those patients with more severe acute hepatitis.  Additionally, for those with fulminant hepatitis B, antiviral therapy is given to assist with management of the HBV infection should the patient require a liver transplant.

PREVENTING HBV INFECTION

The most effective means of protecting oneself from acquiring HBV infection is by vaccination. A vaccine for HBV has been available since 1981. In the U.S., the current immunization strategy includes universal vaccination of infants, routine vaccination of previously unvaccinated children and adolescents to age 18, and targeted vaccination of previously unvaccinated adults who are at risk of HBV infection (Table below). While the infant, child and adolescent vaccination programs have been quite successful, HBV vaccination in adults who are at risk is suboptimal.  Of the 51,000 new HBV infections in 2005, approximately 95% occurred in adults. New strategies to identify adults at risk and provide HBV vaccination have been recently recommended by the CDC [4].

In addition to vaccination, other measures to prevent HBV include:

• Using latex condoms when having sex
• Never sharing drugs, syringes, needles, or “works”
• Never sharing personal grooming items that may be contaminated with blood such as razors, toothbrushes, or nail clippers
• Never expose oneself to needles that may have been reused (e.g., tattoo or body piercing, medical care in some countries)
• If pregnant, test to see if you are infected with HBV so that the infant can be given hepatitis B immune globulin and vaccination at birth to prevent infection.

HBV Vaccines

• The two vaccines licensed in the United States are not live vaccines but rather are produced by recombinant DNA technology: Engerix-B (GlaxoSmithKline, Research Triangle Park, North Carolina) and Recombivax-HB (Merck, Whitehouse Station, New Jersey). Each is given in a three-dose series over a six month (up to 12 month) period in adults. The recommended doses and schedule of injections are shown in the Table below.
• Both vaccines are highly immunogenic with 95-100% of healthy adult and 90-95% of health children and adolescents developing a protective level of antibody after completing the three-injection series.
• There is also a combination of HAV and HBV vaccines available (Twinrix; GlaxoSmithKline, Research Triangle Park, North Carolina) for adults. Several combination infant/childhood vaccinations containing HBV vaccine are available including Pediarix (Diphtheria, Pertussis, Tetanus, Polio and HBV) and Comvax (HBV and Hemophilus influenzae type b).
• Factors that have been associated with a lower the response to the vaccine are low birth weight infants, age older than 40 years, male sex, smoking, obesity, and certain medical conditions that include immune deficiency (e.g., HIV infection), kidney failure on dialysis, and cirrhosis.
• Booster shots are currently not recommended. Protective levels of antibody have been documented for up to 10 years. Even when the levels of antibody decline to low (less than 10 mIU/mL) or undetectable levels, nearly all vaccinated persons remain protected against HBV infection. The mechanism for continued vaccine-induced protection is through the preservation of immune cells within the body that are still able to mount an appropriate immune response if exposure to the virus occurs.

Preventing HBV Infection after Exposure

For persons who have been exposed to HBV within the prior two week period, post-exposure prophylaxis should be given to prevent symptomatic infection. Post-exposure prophylaxis consists of two therapies: the HBV vaccine and hepatitis B immunoglobulin (HBIG).

• HBIG is effective in all ages regardless of concurrent medical conditions and is given as an intramuscular injection. HBV vaccine is usually given concomitantly if there is an indication for lifelong protection.
• If given in a timely fashion (within seven days following a needle exposure to HBV or within 14 days of a sexual exposure to HBV), both HBIG and HBV vaccine are highly effective in preventing HBV infection, with less than 5% of persons becoming symptomatic.

Vaccine Safety
The HBV vaccine has an excellent safety record [4]. There are reports of Gillian-Barré syndrome, multiple sclerosis, and other neurological conditions in some recipients of HBV vaccines, but the available data does not support a causal relationship between the vaccine and these neurologic disorders. The most frequent side effects are pain at the injection site, fever, headache, muscle aches, and mild fatigue. An allergic reaction to the vaccine may occur but is extremely rare, estimated to be 1 per 1.1 million doses given.

CHRONIC HBV INFECTION

An estimated 1.25 million Americans have chronic hepatitis B infection. Many individuals living in the U.S. were born in areas of the world where the prevalence of HBV is high and infection with HBV occurred at the time of birth or in early childhood. The prevalence of chronic HBV infection is higher is certain racial-ethnic groups, notably Asian-Americans who have prevalence rates of infection of approximately 10%. For this reason, it is recommended that persons from endemic areas of HBV should be tested for hepatitis B.

Strictly speaking, chronic HBV infection is defined by the presence of HBsAg in the blood for a period of six months or more. In practice, individuals with evidence of liver disease who are HBsAg positive have chronic HBV infection and there is little need to wait for six months to confirm the diagnosis. Additional antigen and antibody tests are used to define the phase of infection in those who are chronically-infected.

Chronic HBV infection is a potentially serious disease that can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma (liver cancer). Individuals with chronic HBV infection, even if they have no symptoms, have a 12 to 300 fold higher risk of developing liver cancer than persons without chronic HBV infection. Because of these serious consequences of chronic infection, it is important to identify those who are infected, so that treatment can be offered to prevent these complications.

SYMPTOMS AND SIGNS OF CHRONIC HEPATITIS B

Most persons with chronic hepatitis B infection are without any symptoms and do not recall any prior history of acute hepatitis.  When symptoms are present – the most common is fatigue – they are not very specific to liver disease and may be overlooked.  In fact, many persons with HBV do not know they have it.  However, if suspected, the infection can be easily diagnosed with blood tests.

Symptoms are more frequent in persons with chronic HBV infection who are experiencing a “flare” of hepatitis or if they have progressed to the phase of cirrhosis and liver failure. In these cases, symptoms may include right upper quadrant pain, jaundice (yellowish discoloration of eyes and skin), nausea, and loss of appetite.  If liver failure develops many additional symptoms can occur including decreased mental alertness, swelling of legs and abdomen, and bleeding complications.

Physical findings are typically absent.  Liver enlargement or tenderness may be seen. Patients with cirrhosis may have skin changes indicative of cirrhosis, an enlarged spleen, swelling of lower legs or abdomen, or jaundice.

INTERPRETATION OF BLOOD TESTS

There are a number of antigen and antibody tests used to assess the phase of infection in persons with chronic HBV.  Additionally, the level of virus in the blood can be measured to give a viral load result.  These tests are essential in determining if and when to treat and are also used during treatment to determine when treatment can be stopped.

1. Serologic Tests (measurement of HBV antigens and antibodies)

• HBsAg: indicates presence of hepatitis B (in both acute and chronic infection)
• HBeAg: indicates phase of infection associated with high level of hepatitis B in the blood
• Anti-HBs (or HBsAb: antibody against HBsAg). When present this indicates resolved infection. In persons with chronic HBV infection, there is an approximately 1% chance per year of developing anti-HBs.
• Anti-HBe (or HBeAb): antibody against HBeAg. When present, this is associated with a lower level of hepatitis B virus in the blood.
• Anti-HBc: indicates prior exposure to hepatitis B (present in acute and chronic HBV and persists for life). There is little role of this test in the follow-up of patients with chronic hepatitis B.

2. Virologic Tests (measurement of viral DNA or viral load)
There are two types of tests used to measure HBV DNA: qualitative and quantitative tests.

• Qualitative HBV DNA test reports results as POSITIVE or NEGATIVE. A positive result indicates there is at least 50 IU/ml of HBV DNA detected (could be much higher).  A negative result indicates there is less than 50 IU/ml of HBV DNA present.
• Quantitative HBV DNA test reports results as the number of viral international units present in a milliliter of blood (IU/ml). There are a number of different assays used and they differ on how sensitive the assay is to detection of low levels of virus but most assays currently used can detect as little as 50 IU/ml.

With improvements made in quantitative tests in the past five years, qualitative tests are less frequently used.

3. Other Specialized Tests Used

• HBV Genotype (subtype of hepatitis B viru). There are 8 genotypes of HBV (labeled A-H) that are identified by examining the genetic make-up of the virus.  HBV genotypes have been associated with different responses to antiviral therapy, so this test may be done if treatment is being considered.

• HBV Resistance Testing: For patients on treatment for chronic hepatitis B, monitoring for resistance to the drugs is necessary. These tests detect certain changes in the virus that are known to be associated with drug resistance. These tests are not FDA-approved but are available in some commercial laboratories. 

NATURAL HISTORY OF CHRONIC HBV INFECTION

Chronic hepatitis B is a dynamic disease with variable levels of hepatitis B virus measurable in the blood, and changing levels of ALT, a marker of liver injury. There are four phases of disease that are recognized (Table below). Not all persons with chronic HBV infection will experience all four of these phases, but determination of phase of infection has important implications for treatment.  Only those who are in the immune clearance (also referred to as HBeAg-positive chronic hepatitis B) or immune reactivation (also referred to as HBeAg-negative chronic hepatitis B) phases are recommended to undergo treatment. These two phases represent the most active phases of the disease, when liver injury occurs and during which time the risk of progression of disease is highest.

Long-term studies of patients with chronic HBV indicate that for patients with HBeAg-positive chronic hepatitis B, the annual risk of progressing to cirrhosis is 5% per year and for patients with HBeAg-negative chronic hepatitis B, the risk if 1-2 % per year (see below). Once cirrhosis develops, there is a 5% risk per year of developing liver failure or liver cancer. While liver cancer is most frequent in patients with chronic hepatitis B and cirrhosis, it can also develop in persons with chronic hepatitis B who do not have cirrhosis. The estimated risk for these latter persons with chronic hepatitis B is estimated to be 0.4% per year and is related to duration of infection, sex and family history.
                                            
           Average Yearly Rate of Progression of Liver Disease in Chronic HBV

Risk factors for the development of cirrhosis are known (Table below) and include host, viral and environment factors.  Of the known factors, alcohol use and obesity are the potentially modifiable factors.  Heavy use of alcohol is to be avoided. Diabetes and obesity are associated with fatty liver and a fatty liver can lead to an additional injury in the liver and accelerate progression to cirrhosis in some patients.  This factor has only recently been recognized as an important contributing cause for cirrhosis in patients with viral hepatitis.  Several viral factors have been associated with increased risk of cirrhosis and these may be partially modifiable with treatment. For example, high HBV DNA levels in the blood have been associated with a higher risk of cirrhosis and treatments resulting achieving a low or undetectable HBV DNA level may reduce this risk.

PREVENTING TRANSMISSION OF HBV TO OTHERS

HBV is spread by blood or sexual contact. 

To protect sexual partners, members of the household, or colleagues at work, the following measures to prevent transmission of HBV are recommended:

• Using latex condoms when having sex; sexual contacts should be vaccinated
• Never sharing personal grooming items that may be contaminated with blood such as razors, toothbrushes, or nail clippers
• Cover open sores, cuts or scratches
• Clean any blood-contaminated surfaces with bleach

The following activities are NOT associated with spread of HBV:

• Sharing of food and utensils
• Kissing, hugging
• Handshakes or casual contact
• Coughing or sneezing

PREVENTING DISEASE COMPLICATIONS

Preventing the complications of chronic infection involves three general aspects:

1. Undergo evaluation to determine stage of disease and establish regular monitoring for complications, including surveillance tests to look for liver cancer.
2. Make healthy lifestyle choices so that additional harm to the liver does not occur. The lifestyle factors of greatest importance are:

a. Avoidance of alcohol
b. Maintenance of ideal body weight to prevent a fatty liver
c. Limiting use of acetaminophen (Tylenol®) to no more than 2000 mg per 24 hours

3. Undergo evaluation to determine whether specific treatment of chronic HBV infection is necessary

INITIAL EVALUATION OF PATIENT WITH CHRONIC HBV INFECTION

The initial evaluation of a patient diagnosed with chronic hepatitis B infection includes the following:

1. History and physical examination

• Determination of how infection was acquired (to estimate duration of infection)
• Alcohol use (as factor that affects HBV disease severity)
• Family history of HBV infection (suggests mother-infant or early childhood exposure to HBV)
• Family history of liver cancer (this is a risk factor for liver cancer)
• Assessment for physical findings of cirrhosis

2. Diagnostic tests

• Alanine aminotransferase (ALT or SGPT) and aspartate aminotransferase (AST or SGOT) = indication of liver inflammation
• Total bilirubin, albumin, prothrombin time = indication of liver function. These will be in normal range unless cirrhosis is present
• Serologic and virologic markers for HBV infection = tests of the virus and antibodies
• Anti-HBe, HBeAg, (e antigen and antibody are used to identify the phase of infection – see Table 4), HBV DNA quantitation
• Anti-HDV (hepatitis D antibody), anti-HCV (hepatitis C antibody)
• Liver biopsy in selected patients
• Surveillance tests for liver cancer in those at risk (see Surveillance for Hepatocellular Carcinoma section below)
• Ultrasound of the liver
• Alpha-fetoprotein

Role of Liver Biopsy
Although a liver biopsy is not essential to make the diagnosis of chronic hepatitis B, the liver biopsy provides the most accurate means of assessing the severity of liver disease. In chronic hepatitis B, the severity of infection is measured by the degree of necroinflammatory activity (grade) and amount of fibrosis or scarring (stage). The grade and stage of disease is often used to determine whether treatment is needed and for how long the treatment needs to be continued. For example, patients with cirrhosis require long-term treatment. It is important to be aware of the imperfect correlation between the liver blood tests and the severity of fibrosis on the biopsy. Patients with normal liver blood tests can have fibrosis and even cirrhosis on biopsy. For this reason, it has been recommended that a liver biopsy be considered in patients with minimally or mildly elevated ALT levels (less than twice the normal limit), in order to determine whether the disease on the biopsy is more severe than the blood levels (ALT) suggest.

TREATMENT OF CHRONIC HBV INFECTION

The goals of treatment are to prevent or delay the complications from chronic HBV infection, including cirrhosis and liver cancer.  Chronic HBV infection cannot be cured, but it can be controlled. By suppressing multiplication of the virus, damage to the liver can be prevented. Reversal of liver inflammation and fibrosis (scarring) can occur with treatment (5).

Who Should be Treated?

There are two essential laboratory tests that are used to determine whether treatment is needed:

• ALT level (usually at least two values, three months apart)
• HBV DNA level

Candidates for treatment are patients with elevated ALT levels and elevated HBV DNA levels. 

Patients that are potential candidates for treatment are further divided into two groups, depending upon whether HBeAg is present or not. The two groups are referred to as HBeAg-positive chronic hepatitis B and HBeAg-negative chronic hepatitis B. The distinction is important because the approach to treatment differs for the two groups. The specific cut-offs to define what is an “elevated” HBV DNA level differs in patients who are HBeAg positive versus HBeAg negative (Figures below). 

For persons who are HBeAg positive and have a HBV DNA level ≥20, 000 IU/ml in the blood, the ALT level determines if treatment is needed. If the ALT level is normal, no treatment is needed. If the ALT level is two-times the normal level or higher, treatment is definitely needed and if the ALT level is above the normal range but only 1-2 times the normal level, than treatment may be needed, but additional testing may be needed to make the decisions. A liver biopsy is used to determine whether treatment is indicated in persons who have elevated HBV DNA levels but whose ALT level is borderline elevated.

For persons who are HBeAg negative and have a HBV DNA level ≥2, 000 IU/ml in the blood, the ALT level determines if treatment is needed. If the ALT level is normal, no treatment is needed. If the ALT level is two-times the normal level or higher, treatment is definitely needed and if the ALT level is above the normal range but only 1-2 times the normal level, than treatment may be needed, but additional testing may be needed to make the decisions. A liver biopsy is used to determine whether treatment is indicated in persons who have elevated HBV DNA levels but whose ALT level is borderline elevated.

Additionally, all patients with cirrhosis, regardless of the ALT level, need to be considered for treatment (Table 6). Patients with cirrhosis and signs of liver dysfunction or failure (called decompensated cirrhosis) need to be referred for consideration of liver transplantation.  

What are the Treatment Options?

There are 6 FDA-approved drugs for the initial treatment of chronic hepatitis B (Table below): interferon alfa-2b, lamivudine, adefovir, entecavir, peginterferon alfa-2a, and telbivudine. Another drug, tenofovir, is under FDA review with expected approval in 2008.

Lamivudine is not considered first-line therapy any longer as the rates of drug resistance developing with prolonged periods of treatment are unacceptably high [3][6].  Telbivudine is non-preferred as first-line therapy by some experts for the same reason [3]. 

For persons with chronic HBV infection who are undergoing treatment for the first time, the current drugs of choice are peginterferon, adefovir, or entecavir.

There are many factors considered in the selection of the specific drug treatment including:

1. Efficacy of the drug: This is how well the drug achieves suppression of viral replication.
2. Duration of treatment. Treatment with peginterferon and interferon is limited to one year.  Treatment with the other medications (lamivudine, adefovir, entecavir, and telbivudine) is for more than one year.
3. Frequency of drug resistance when the drug is used for prolonged periods. Drug resistance does not develop with use of peginterferon and interferon. Oral drugs with a low risk of resistance (e.g., adefovir, entecavir) are preferred to reduce the likelihood of resistance with prolonged therapy.
4. Method of administration. The interferons are given by subcutaneous injection (weekly). Lamivudine, adefovir, entecavir, and telbivudine are pills taken one daily.
5. Side effects. Side effects are more frequent with peginterferon and interferon than with the other medications.
6. Presence of other medical conditions.
7. Presence of cirrhosis.  Peginterferon and interferon are not recommended in patients with cirrhosis.

What is the Usual Duration of Treatment?

The optimal duration of therapy has not been defined. In persons with HBeAg-positive chronic hepatitis B, treatment continues until HBeAg is lost and anti-HBe is gained; then an additional six to 12 months of treatment is given to consolidate the response [3][6].  In patients with HBeAg-negative chronic HBV infection, where relapse after treatment discontinuation is frequent, prolonged periods of treatment are used (typically several years).

What Type of Monitoring is required during Treatment?

Regular monitoring of blood tests and symptoms is needed during treatment. The frequency of visits will vary from doctor to doctor and will be dependent upon whether treatment is with peginterferon or with the other approved drugs for hepatitis B (lamivudine, telbivudine, entecavir, or adefovir). Since peginterferon is associated with more side effects, more frequent monitoring is needed. Usually blood tests are needed every month for the first three months and every one to two months thereafter for patients on peginterferon.  For patients receiving treatment with the other HBV drugs, blood tests are typically obtained every three months.

How Will Treatment Affect My Ability to Work and Play?

Peginterferon is associated with more side effects than the other HBV drugs. Indeed, there are very few, if any, side effects associated with lamivudine, telbivudine, entecavir, or adefovir. Thus, for patients on these medications, there will be not limitations on activities at home or work.  For patients on peginterferon, side effects may limit one’s ability to perform all activities at work and home, although the majority of patients will continue in all their usual activities. The common side effects that may limit activities include fatigue, mood disorders (including depression and anxiety), mild nausea, poor appetite. and mild flu-like symptoms. The severity of these symptoms varies from patient to patient and cannot be predicted prior to treatment. Dose adjustments of the peginterferon can be used to help with symptom management if necessary.

The Importance of Taking Medications as Prescribed

For the treatment to be effective, the drug must be taken as prescribed without missed doses. Missed doses will reduce the likelihood that the treatment will work. This is particularly important for patients taking the medications by mouth (entecavir, adefovir, telbivudine, and lamivudine), because missed doses can result in the HBV becoming resistant to the drug. Once drug resistance develops, the HBV will no longer by treatable with that drug and possibly other similar drugs. To prevent this resistant “super” virus from developing, the medication must be taken as prescribed and without missed doses.

MONITORING THOSE WHO ARE NOT ON TREATMENT

Not all persons with chronic HBV infection require drug therapy. However, all persons with hepatitis B require periodic monitoring to assess for changes in the activity and severity of the liver disease. Persons who do not meet criteria for treatment now, may meet the criteria in the future.

For those with normal liver tests (ALT levels) who do not need treatment, the frequency of monitoring is influenced by the HBV viral load (HBV DNA level) and whether HBeAg is present.

• If HBeAg positive and normal ALT level:

o Check ALT every three to six months
o Check HBeAg every six to twelve months

o If the ALT becomes elevated, additional testing is needed, including a HBV viral load, to determine whether treatment is indicated.

• If HBeAg negative, ALT is normal, and HBV DNA less than 2000 IU/ml:

o Check ALT every one to three months for first year and, if still normal, decrease frequency to every three to six months
o If the ALT becomes elevated, additional testing is needed, including a HBV viral load, to determine whether there has been a change in the phase of disease and whether treatment is indicated.

• If HBeAg negative, ALT is normal and HBV DNA greater than 2000 IU/ml:
• A liver biopsy should be considered to evaluate for presence of significant liver disease. If significant liver disease is seen on the biopsy, treatment is indicated.
• Check ALT every one to three months for first year and, if still normal, decrease frequency to every three to six months
• If the ALT becomes elevated, additional testing is needed, including a HBV viral load, to determine whether there has been a change in the phase of disease and whether treatment is indicated.

MONITORING FOR HEPATOCELLULAR CANCER (Primary Liver Cancer)

Chronic HBV infection is a risk factor for hepatocellular carcinoma (also called hepatoma).  Hepatitis B carriers are up to 100 times more likely to develop hepatoma than persons without chronic HBV infection [7]. Thus performing surveillance tests to look for early signs of cancer is recommended in persons with chronic HBV infection. It is important to detect the cancer early, as several curative treatment options are available for small liver cancers, including ablative therapy, surgical removal of the cancer, or liver transplantation.  If the cancer is large when discovered, the treatment options are much more limited.

The testing should be performed every six months and includes:

• An abdominal ultrasound or CT scan
• A blood test called alpha-fetoprotein

Since the risk for liver cancer increases with the duration of chronic infection, is higher in men than women, and is significantly higher in those with cirrhosis than those without, the following guidelines are used to determine when and on whom to begin surveillance testing [7]:

• Asian-American male patients over the age of 40 years
• Asian-American females over the age of 50 years
• African-born Americans over the age of 20 years
• All patients with a family history of primary liver cancer
  
• All patients with cirrhosis

References

1. Wasley A, Miller J, Finelli L. Surveillance for acute viral hepatitis --- United States, 2005. MMWR Surveillance Summaries 2007;56(SS03):1-24.
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