Hepatitis B virus is a DNA virus transmitted by blood, sexual contact, or percutaneous exposures. In the United States, the most common modes of transmission are sexual and parenteral (horizontal transmission). In Asia, where hepatitis B is much more common than in the United States, transmission from mother to child (vertical transmission) is the most common mode. The hepatitis B virus itself is a partially double-stranded DNA virus. It replicates through an RNA intermediate. Hepatitis B is a strongly hepatotrophic virus; however, it can replicate and is present in many extrahepatic tissues including peripheral blood mononuclear cells and lymph nodes.

Download PowerPoint slide showing Modes of Transmission

There are four open reading frames for the hepatitis B virus that encode for four major proteins. The identification of three of these major proteins is utilized in diagnosis and treatment of hepatitis B. These include hepatitis B surface antigen (HBsAg). This is an envelope protein that when present in the blood indicates infection. The infection identified by the presence of HBsAg can be further delineated into infection with the presence of viral replication (HbsAg and HBV-DNA positive) or non-replication (HBsAg and HBV-DNA negative) The hepatitis B core antigen (HBcAg) protein is found in the inner core of the hepatitis B virus. It is not secreted into the serum but is expressed on the hepatocyte surface. It is also located in the nuclei of the hepatocytes. Hepatitis B e antigen (HBeAg) is a secretory form of the hepatitis B core antigen. Its presence indicates active viral replication and increased infectivity. This was the main laboratory determinant used to indicate active viral replication before the development of assays that directly measure the virus (HBV-DNA). The HBV-DNA test has become the most valued method if a patient is infective or in the replicative phase of the infection.

Antibodies to these proteins are developed in response to infection. The main antibodies of clinical interest are the hepatitis B surface antibody (HBsAb) that indicates immunity to hepatitis B and the hepatitis B e antibody (HBeAb) that indicates in most cases cessation of infectivity or non-replication. The presence of the hepatitis B core antibody (HbcAb) is utilized to identify acute infection by measuring the HBcAb-IgM component of the antibody. The presence of only HBcAb-IgG with out IgM indicates only exposure to the hepatitis B infection and does not delineate the activity state (replicative or nonreplicative phase).

Once the patient is infected with hepatitis B, he or she will develop an acute infection. The outcome of hepatitis B, i.e.-chronicity, depends on the immune state of the host. If the hepatitis B is acquired when the immune status of an individual is immature, such as with vertical transmission to a neonate, the chronicity rate ranges around 90%. If the immune status of the individual is strong, i.e. adult, the chronicity rate of hepatitis B drops to less than 10%. The immune status of an individual may be affected by age, various other states such as coinfection with HIV, patients undergoing immunosuppression after organ transplantation or those receiving chemotherapy.

Only 30-to-50% of patients with chronic hepatitis B actually give a past history of acute hepatitis. This is especially true in areas where the mode of transmission is predominantly vertical (perinatal infection). Many patients with chronic hepatitis B are asymptomatic until they progress to decompensated cirrhosis or have extrahepatic manifestations. Extrahepatic manifestations of hepatitis B are mediated through circulating immune complexes. This occurs in approximately 10-to-20% of patients with chronic hepatitis B. The two major extrahepatic complications for chronic hepatitis B are polyarteritis nodosa and glomerular nephropathies. Antiviral therapy may help those with polyarteritis but is unlikely to help most patients with glomerular disease.

Patients with active replicating hepatitis B may tolerate the infection quite well without the development of chronic liver disease (immune tolerance). The lack of liver disease in these patients despite high levels of hepatitis B replication is the hallmark of these individuals. Immune tolerance is believed to be the key reason that Asian patients who have acquired their hepatitis B through horizontal transmission are poor responders to interferon therapy in which its major effect is through augmentation of the immune system. The immune tolerance phase can last up to 10-to-30 years. At that time, there is a very low rate of hepatitis B e antigen (HBeAg) clearance. Afterwards, the hepatitis B e antigen (HBeAg) conversion to hepatitis B e antibody (HBeAb) increases. During this immune clearance phase, spontaneous hepatitis B e antigen (HBeAg) clearance occurs at the annual rate of 10-to-20%. Hepatitis B e antigen (HBeAg) seroconversion is often accompanied by abrupt increases in transaminases. This is believed to be due to the sudden increase in hepatocyte lysis. This is often preceded by an increase in the hepatitis B viral DNA levels. This occurs most often in men.

In some patients, the immune response against the hepatitis B virus is enough to suppress replication but not enough to eradicate the virus. (Eradication is indicated by the appearance of hepatitis B surface antibodies (HbsAb). These patients are identified as hepatitis B surface antigen (HBsAg) positive carriers. This state is also referred to as a non-replicative phase of hepatitis B. In these individuals, the hepatitis B viral DNA in the serum when measured is negative. These patients have normal transaminases (ALT/AST). These patients generally have a good prognosis and are unlikely to develop cirrhosis or hepatocellular carcinoma. In HbsAg positive and HBV-DNA negative in the past who did show progression in the past it is now believed that most of these cases occurred due to the poor sensitivity of hepatitis B virus DNA testing, i.e.-these patients actually had low-level replication of hepatitis B viral DNA that was undetectable by old less sensitive methods.

The squeal of hepatitis B depends on the activity of infection, i.e.-replicative (HBV-DNA positive) or non-replicative (HBV-DNA negative) phase. Chronic carries are not replicating virus (HbsAg positive, HBV-DNA negative) Those who are HBsAg negative, HBeAb antibody positive have an excellent prognosis. Chronic replicative HBeAg positive and HBV-DNA positive patients are at greater risk of dying from liver disease or hepatocellular carcinoma than those with non-replicative (inactive) disease. Five-year survival rates in nonreplicative patients with early histologic changes on liver biopsy are higher (97%) than those patients with active (replicative) hepatitis (85%). Development of cirrhosis in patients with active hepatitis B is associated with a five-year survival rate of only 50%. Active HBV patients who have compensated cirrhosis develop hepatic decompensation over five years in approximately 20%. Compensated cirrhotics will develop hepatocellular carcinoma at a five-year rate of 6-to-15%.

The prognosis in patients who are HBeAg positive is worse and an important factor is making treatment decisions. The incidence of hepatocellular carcinoma is significantly higher in these patients. The e antigen status is an independent predictor after adjusting for other co-variants including coinfection with hepatitis C, alcohol intake, and cigarette smoking in the development of hepatocellular carcinoma. In reality, this represents a prolonged replicative phase of the hepatitis B viral infection with increased duration of necroinflammation. In fact, hepatitis B e antigen (HBeAg) seroconversion represents transition from chronic hepatitis B to an inactive hepatitis B surface antigen carrier state. For these individuals, there is little clinical evidence of hepatitis, and the hepatitis B viral DNA levels are low or nonexistent.

Download PowerPoint slide showing HBV and HCV Characteristics

Hepatitis B Mutations

There is a natural occurring mutant form of hepatitis B that does not produce hepatitis B e antigen (HBeAg). These patients will be HBV-DNA positive. HBeAg and HBeAb will be undetected. This occurs because of the mutation in the precore or core promoter region. These patients are referred to as hepatitis B e antigen (HBeAg) negative chronic hepatitis B patients. It is important to recognize these individuals as they may have a poorer prognosis. The mutation results in a stop codon that blocks the production of hepatitis B e antigen (HBeAg) production. This is a mutation that occurs in patients who already have wild type virus. This can occur at anytime during the active disease process. Thirty-to-forty percent of these patients experience persistently high elevated ALT levels. The rest develop an erratic pattern of ALT elevation with frequent flares. In these patients, the hepatitis B viral DNA levels tend to be very high. Spontaneous remission is very uncommon. The long-term prognosis in these patients is very poor.

Other mutations also occur with the hepatitis B virus, but these are most often secondary to selective pressure during treatment. The most common mutation is referred to as the YMDD mutation. This occurs with selective pressure in those patients being treated with lamivudine.

Genotypes

There are eight known genotypes of the hepatitis B virus. These genotypes, analogous to hepatitis C, occur at different rates in different parts of the world. Currently, data concerning these genotypes is sparse. It appears that specific genotypes may have some relationship to clinical outcome and the response to antiviral therapy. However, testing for these genotypes is not currently recommended.

Evaluating the Patient with Hepatitis B

All patients who are identified to have chronic hepatitis B infection should have a complete evaluation, which should include the testing of the various hepatitis B proteins. This would include most importantly hepatitis B e antigen (HBeAg) and hepatitis B viral DNA levels (HBV-DNA). Other common liver diseases should be ruled out, especially hepatitis C infection. It may also be important to consider testing for anti-HDV. A liver biopsy to grade and stage the liver disease is recommended in most patients who meet the criteria for chronic hepatitis. Patients should also be tested for exposure to hepatitis A and should receive two doses of hepatitis A vaccine if they have not been previously exposed. Patients should be instructed to avoid alcohol.

Screening for Hepatocellular Carcinoma

In patients with chronic hepatitis B, consideration for screening for hepatocellular carcinoma should be given. As of yet, the exact mode of screening is debated. Patients who should be screened include those who are noncirrhotic and those who have cirrhosis. Noncirrhotic patients who are at high risk for hepatocellular carcinoma include Asian males over the age of 40, Asian females over the age of 50, Asians of any age with a family history of hepatocellular carcinoma, and African-Americans or blacks from other countries over the age of 20. Any hepatitis B carrier who has stable, persistent, elevated alpha-fetoprotein should also be considered in a surveillance program. All cirrhotics need to be included for hepatocellular carcinoma screening regardless of other cofactors. The exact method of screening is again debatable. It is generally agreed that alpha-fetoprotein (AFP) measurements should be performed at six-month intervals. The radiologic method of screening can either be with ultrasound at six months or yearly intervals, or yearly triple phase CT or MRI. Hepatocellular carcinoma generally begins as an encapsulated single tumor with a doubling time from 2-to-12 months. For this reason screening earlier, i.e.-every three-to-six months, does not appear to be more effective than screening 6 months and 12 months. AFP in the US population has a high predict negative predictive value.

Treatment of Hepatitis B

Recently, treatment guidelines have been published which should be followed. The main criteria in treatment decision includes the presence or absence of hepatitis B e antigen (HBeAg), threshold levels of hepatitis B viral DNA (HBV-DNA) and the presence or absence of cirrhosis. The goal of therapy should be to eliminate or significantly suppress the hepatitis B viral replication. This ultimately will result in prevention of progression of liver disease to cirrhosis or the further decompensation of the cirrhotic patient and the inhibition of developing hepatocellular carcinoma. Hepatitis B e antigen (HBeAg) seroconversion indicates that antiviral therapy may be stopped and a high likelihood that viral replication will continue to be nonexistent.

Currently, there are three approved treatment modalities in the United States, interferon, lamivudine, and adefovir dipivoxil. Interferon is an injectable medication that has limitations. Lamivudine and Adefovir are oral medications. Lamivudine’s major drawback is the strong likelihood of development of mutation in the hepatitis B virus allowing it to escape the viral suppressive effects of lamivudine. This occurs in up to 66% of patients after four years of therapy. For this reason, Adefovir is becoming the treatment of choice in patients with chronic hepatitis B infection. Interferon offers a benefit of treatment in the fact that it has a 30-to-40% seroconversion rate of hepatitis B e antigen (HBeAg) to hepatitis B e antibody (HBeAb). The durability of this response appears to be 80-to-90% in patients after four-to-eight years of follow-up.

Seroconversion, i.e.-e antigen to e antibody, is preferable to just e antigen loss alone. Furthermore, with oral medications, durability of e antigen seroconversion may be affected by the duration of treatment after e antigen seroconversion. Thus, data supports the continuation of treatment with oral preparations for at least four-to-six months after e antigen seroconversion (lamivudine or adefovir).

Treatment Recommendations

The decision to treat HBV patients is dependant upon e antigen status and positive hepatitis B viral DNA levels. Those patients who are e antigen positive with hepatitis B viral DNA levels greater than 105should be considered for treatment. Patients who have hepatitis B viral DNA levels less than 105 with normal ALT do not need treatment. A liver biopsy may be particularly important in these patients as evidence of significant histological disease may tilt one towards treatment. If it decided upon not to treat these “low virus” patients they should be monitored every 6 to 12 months
In patients with e antigen positivity and hepatitis B viral DNA greater than 105 who have an elevated ALT consideration for interferon might be a first-line option. If the hepatitis B viral DNA is significantly high then oral treatment with Adefovir or lamivudine is preferred. Again, it is important to remember the limitations of the lamivudine with its high incidence of development of resistance. This has made Adefovir recently the more favorable choice.

In e antigen negative, HBV – DNA positive patients (pre-core mutants), one must consider the poorer prognosis. For this reason, the threshold for treatment includes lower hepatitis B viral DNA levels, i.e.-104. Patients who are e antigen negative with hepatitis B viral DNA levels greater than 104are recommended treatment. Again those that have elevated ALT are more likely to respond to interferon, and therefore, interferon may be considered as a first line option. If the ALT is normal, the likelihood of interferon therapy success is less, and a liver biopsy may become very important in consideration if disease is present. Those patients who have less than 104 DNA threshold level do not need treatment and should be monitored every 6-to-12 months. Treatment including monitoring hepatitis B viral DNA levels and ALT levels should be performed every 6 months.

All cirrhotic patients should be treated with viral suppression regardless of the level of DNA. Adefovir is preferred for decompensated cirrhotic patients. Monitoring these patients should occur every 3 months. These patients should be considered for transplantation.

Lamivudine Resistance

Patients who have been treated with lamivudine and have developed resistance to lamivudine present a particular problem. In noncirrhotic patients, the accepted practice is to discontinue the lamivudine and start adefovir. This can often be heralded by a flare in ALT levels. For this reason cirrhotic patients present a particular problem, especially if they are decompensated. Patients who are decompensated cirrhotics who develop lamivudine resistance should have adefovir added without lamivudine withdrawal.

Download PowerPoint slide showing Cumulative Rates of Detection of Lamivudine-resistant M552V/I Mutants

Consideration for Oral Therapy

Withdrawal

Compensated hepatitis B e antigen (HBeAg) positive patients should be treated until hepatitis B e antigen (HBeAg) seroconversion and undetectable hepatitis B viral DNA levels by PCR occur and then treat it for an additional six months before withdrawing therapy. Patients with cirrhosis and/or end stage liver disease should have continuous treatment without withdrawal of oral suppression. These patients are not candidates for interferon.

Other Monitoring Suggestions

Renal function is particularly important in monitoring decompensated patients on adefovir therapy. Dosing adjustments need to be made depending on creatinine clearance. Patients who have creatinine clearance less than 50 but greater than 20 should be given adefovir every 48 hours rather than every 24 hours. Patients with creatinine clearance 10-to-19 should be given 10 mg of adefovir every 72 hours, and hemodialysis patients should be treated with Adefovir 10 mg every 7 days post hemodialysis. Dose adjustments for lamivudine are also important.

Monitoring for a development of resistance is important. Resistance is defined by a greater than one-log10 increase in serum hepatitis B viral DNA level from the patients lowest on treatment level occurring in two sequential occasions. Patients on lamivudine should be monitored every three-to-six months. Patients with Adefovir should be monitored every six months. The development of resistance with lamivudine or Adefovir does not negate the fact of the other medication.

In conclusion, hepatitis B virus represents a significant yet treatable disease in the United States. Worldwide, 350 million people are chronically infected with hepatitis B. In the United States, it is estimated that 1.25 million individuals are infected with 100,000 people being acutely infected each year. The incidence of acute infection hepatitis B has dropped dramatically in the United States secondary to the current vaccination program.

Hepatitis B is treatable with current regimens. The most utilized regimen at this time is Adefovir. Goals of treatment should be seroconversion of hepatitis B e antigen (HBeAg) to hepatitis B e antibody (HBeAb) and/or the lowest possible reduction of hepatitis B viral DNA levels with the hope to eliminate hepatitis B viral DNA from the serum as the ultimate achievement.
Screening for hepatocellular carcinoma is especially important in those patients in the high-risk group and patients who already have the development of cirrhosis. Newer treatments for hepatocellular carcinoma including transplantation are dependent on the early discovery of this cancer.

Suggested Reading

1. Keeffe, E.B. et al. A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States. Clinic Gastroenterology and Heptology 2004; 2:87-106
2. Papatheodoridis G.V. et al. Current Management of Chronic Hepatitis B. Aliment Pharmacol Ther 2004: 19(1):25-37
3. Lok A. SF et al. Chronic Hepatitis B. Hepatology. 2001; 34:1225-1241