Discussion

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Classification and Phases of Chronic HBV Infection

From a conceptual standpoint, chronic hepatitis B virus (HBV) infection can be classified into three phases (or types of immune responses): immune tolerant, immune active, and inactive chronic carrier state (Figure 1) [1-5]. These distinct phases of chronic infection correspond with characteristic serologic patterns and correlate with the patient's immune response to HBV. In addition, the initial immune response and subsequent initial phase of chronic infection generally depends on the age at which the patient acquired HBV, with immune tolerant phase usually following vertical perinatal acquisition, immune active phase following horizontal acquisition after birth in early childhood, and inactive chronic carrier state following the transition from the immune active phase (either naturally or as a result of HBV therapy) (Figure 2). In addition, the initial immune response and subsequent phase of infection may depend on the HBV genotype. Although most adults with acute HBV infection generate an effective immune response and have complete resolution of the HBV infection, a small proportion will develop chronic infection and enter an immune active phase. The phases of chronic HBV infection are not considered permanently static and patients who initially develop the immune tolerant phase usually progress to immune active and then on to the inactive chronic carrier state (Figure 2). Progression in the reverse direction, such as from the inactive to the immune active phase (manifested as a flare of HBV disease activity), can develop either spontaneously, after initiating interferon therapy for HBV, after withdrawal of HBV therapy, or after withdrawal of corticosteroid or cancer chemotherapy [5]. In addition to the three stages of chronic HBV infection discussed, some chronically-infected patients will resolve their HBV infection, either naturally or occasionally following interferon-based therapy; these patients typically show clearance of HBsAg, are anti-HBc positive, and usually develop anti-HBs (along with anti-HBc). In some patients with resolved HBV, reactivation of HBV infection may develop if they become severely immunosuppressed, as can occur following receipt of chemotherapy, immunosuppressant medications used for transplantation, or with high-dose corticosteroids [6].

Immune Tolerant Chronic HBV Infection

The patient in this case has chronic HBV infection in the immune tolerant phase. We know her mother had chronic HBV and likely infected her at birth. At the time of the patient's birth in the early 1980's, she was presumably neither screened for HBsAg nor given hepatitis B immune globulin (HBIG) and hepatitis B vaccine at birth. Although the CDC recommended this approach at the time, it was not widely practiced in the United States. Although the immune response to HBV remains incompletely understood, exposure to HBV antigens and high levels of HBV DNA very early in life presumably leads to a suboptimal immune response, resulting in “immune tolerance.” Patients with immune tolerant chronic infection usually have acquired HBV perinatally or in early childhood, as often seen in Asia and the South Pacific Islands [2,4]. Laboratory studies characteristically show normal hepatic transaminase levels, presence of HBeAg, and high serum HBV DNA levels. Patients with immune tolerant chronic infection usually remain in this phase for a few decades, until they experience an up-regulation in the immune response and transition to the immune active phase.

Approach to Patients in the Immune Tolerant Phase

Regarding the approach to patients with immune-tolerant chronic infection, treatment of HBV in this phase has poor efficacy [2]. In general, patients with chronic HBV infection respond best to therapy if they have an active immune response to HBV infection, as manifested by pretreatment alanine aminotransferase (ALT) levels greater than twice the upper limit of normal (ULN) and evidence of active hepatitis on liver biopsy. The updated 2004 American Association for the Study of Liver Disease (AASLD) practice guidelines recommend that patients with immune tolerant chronic HBV (HBeAg positive, HBV DNA levels greater than 105 copies/ml, and normal ALT) should undergo follow-up ALT testing every 3-6 months (Figure 3)[2]. Subsequent follow-up and testing varies depending on whether ALT levels remain normal, increase to 1-2 times the ULN, or increase to greater than twice the ULN normal. In addition, these guidelines also recommend considering screening for hepatocellular carcinoma in relevant populations. In a separate set of recommendations published in 2004, a panel of hepatologists suggested that liver biopsy might be indicated for patients with immune tolerant HBV and normal serum ALT to help identify a subset of patients with significant inflammation or fibrosis who may benefit from treatment [3].

Patient Follow-Up

The patient is scheduled for twice yearly appointments, but is temporarily lost to follow-up. When she returns 4 years later, at age 27, she has no complaints, but laboratory studies show an ALT of 250 IU/ml, AST 178 IU/ml, positive HBeAg, and HBV DNA 3.5 X 107 copies/ml (7 million IU/ml). Her physical examination and the remainder of her liver function tests are normal, including prothrombin time.

Immune Active Chronic HBV Infection

At this point in the patient's history, she has transitioned to the immune active phase of chronic HBV infection; this phase is often also referred to as the immune clearance phase. As seen in this case, most patients in the immune tolerant phase eventually mount an enhanced immune response to HBV infection and transition to the immune active phase (Figure 2) [2,4]. Patients with perinatally acquired HBV most often have this transition between the ages of 20 and 40, whereas those who acquire HBV in childhood generally have an earlier transition (between the ages of 10 and 15) [2]. Patients can also develop immune active chronic HBV without an immune tolerant phase as when infection occurs in childhood or adolescence, a pattern frequently seen in sub-Saharan Africa and some Mediterranean countries, or when infection is acquired as an adult, as seen more frequently in industrialized countries. The immune active phase is characterized by high levels of HBV DNA, elevated aminotransferase levels, and active liver disease on biopsy. Patients in this phase may have either positive or negative HBeAg. Most who do have positive HBeAg in this phase eventually spontaneously clear HBeAg and seroconvert from a negative anti-HBe test to a positive anti-HBe test, with a seroconversion rate of 8-10% per year [7]. When this occurs, the patient is considered to have undergone transition to the inactive chronic carrier state. Some patients, however, can remain in the immune active phase for years and experience progressive liver fibrosis that can lead to cirrhosis and an increased risk of hepatocellular carcinoma [7]. These patients often have recurrent exacerbations with intermittent increases in hepatic transaminase levels [4].

Approach to Patients in the Immune Active Phase

In general, patients with persistent immune active chronic HBV infection should receive HBV therapy to prevent progressive liver fibrosis (Figure 4). Treatment of chronic HBV infection is discussed in detail in a separate case on this site. The AASLD practice guidelines for the management of hepatitis B infection recommend waiting for 6 months after diagnosis a patient with compensated chronic immune active hepatitis B infection, then doing a liver biopsy to assess the hepatic pathology (if the HBV DNA is greater than 105 copies/ml) [2]. If only mild hepatitis is present, antiviral therapy is less likely to be effective, and treatment can be deferred. If moderate to severe hepatitis is present and portal fibrosis or worse is found, antiviral treatment should be initiated. Because of increased response rates to antiviral therapy among patients with elevated ALT, some providers may opt to initiate treatment immediately and follow for HBeAg seroconversion.

Continuation of Patient's History

The patient is scheduled to return for follow-up in 6 months. She returns at that time and physically looks well and feels fine. Her laboratory studies show a serum ALT of 18, positive HBsAg, negative HBeAg, positive anti-HBe, and HBV DNA 5.2 X 103 copies/ml (1040 IU/ml).

Inactive Chronic Carrier Chronic HBV Infection

At this point, the patient has undergone spontaneous HBeAg seroconversion, her liver disease in now inactive, and she has transitioned to the inactive chronic carrier phase, formerly called the “asymptomatic chronic HBsAg carrier” state. The transition to the inactive chronic carrier state is typically accompanied by a change from anti-HBe negative to positive, normalization of ALT and AST, improvement in liver histology, and a decrease of serum HBV DNA to less than 105 copies/ml (20,000 IU/ml). Approximately 80% of patients in the inactive chronic carrier phase will remain anti-HBe positive and HBeAg negative, and about 20% will undergo a “HBeAg reversion” and again become HBeAg-positive. Over and above that risk, patients may develop HBeAg-negative (precore mutant) chronic hepatitis B, estimated to occur in 10 to 40% of such patients.

Approach to Patients in the Inactive Chronic Carrier Phase

Persons in the inactive hepatitis B phase should undergo follow-up every 6-12 months with serum ALT measurement (Figure 5). In addition, since these persons are still at risk for the development of hepatocellular carcinoma (HCC), most experts would recommend periodic screening for HCC using serum alpha fetoprotein (AFP) levels and liver ultrasound in persons with chronic HBV infection who are at a higher risk for developing HCC (males older than 45 years of age, presence of cirrhosis, or family history of HCC) [2]. In addition, many experts would also recommend considering similar periodic screening for HCC in persons with chronic HBV infection who are from areas where HBV is endemic [2].

[Back to Question | See References]

CME Credit | CNE Credit | Back to Top

Adapted from Lok AS, Heathcote EJ, Hoofnagle JH. Management of Hepatitis B 2000, Summary of a Workshop. Gastroenterology 2001;120:1828-53.
Figure 1
Abbreviations: HBV = hepatitis B virus

Figure 2
Abbreviations: HBV = hepatitis B virus; ALT = alanine aminotransferase; HCC = hepatocellular carcinoma

Adapted from Lok ASF, McMahon BJ, American Association for the Study of Liver Disease Practice Guideline: Chronic Hepatitis B Update of Recommendations. Hepatology 2004:39:857-61.
Figure 3
Abbreviations: HBV = hepatitis B virus; ALT = alanine aminotransferase; HCC = hepatocellular carcinoma

Individuals with HBV DNA levels greater than 105 copies/ml, elevated ALT, HBeAg negative, and anti-HBeAg positive represent persons with chronic hepatitis B infection with precore or core promoter mutant virus. In contrast, HBeAg-positive individuals who are and observed for 3 to 6 months and then develop anti-HBe positive antibody (spontaneous HBeAg seroconvrsion) generally have normalization of ALT levels along with a decrease of the HBV DNA levels to less than 105 copies/ml. Adapted from Lok ASF, McMahon BJ, American Association for the Study of Liver Disease Practice Guideline: Chronic Hepatitis B Update of Recommendations. Hepatology 2004:39:857-61.
Figure 4
Abbreviations: HBV = hepatitis B virus; ALT = alanine aminotransferase; HCC = hepatocellular carcinoma

Adapted from Lok ASF, McMahon BJ, American Association for the Study of Liver Disease Practice Guideline: Chronic Hepatitis B Update of Recommendations. Hepatology 2004:39:857-61.
Figure 5


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	Question \| Discussion \| References \| CME Credit \| CNE Credit Discussion Classification and Phases of Chronic HBV Infection From a conceptual standpoint, chronic hepatitis B virus (HBV) infection can be classified into three phases (or types of immune responses): immune tolerant, immune active, and inactive chronic carrier state (Figure 1) [1-5]. These distinct phases of chronic infection correspond with characteristic serologic patterns and correlate with the patient's immune response to HBV. In addition, the initial immune response and subsequent initial phase of chronic infection generally depends on the age at which the patient acquired HBV, with immune tolerant phase usually following vertical perinatal acquisition, immune active phase following horizontal acquisition after birth in early childhood, and inactive chronic carrier state following the transition from the immune active phase (either naturally or as a result of HBV therapy) (Figure 2). In addition, the initial immune response and subsequent phase of infection may depend on the HBV genotype. Although most adults with acute HBV infection generate an effective immune response and have complete resolution of the HBV infection, a small proportion will develop chronic infection and enter an immune active phase. The phases of chronic HBV infection are not considered permanently static and patients who initially develop the immune tolerant phase usually progress to immune active and then on to the inactive chronic carrier state (Figure 2). Progression in the reverse direction, such as from the inactive to the immune active phase (manifested as a flare of HBV disease activity), can develop either spontaneously, after initiating interferon therapy for HBV, after withdrawal of HBV therapy, or after withdrawal of corticosteroid or cancer chemotherapy [5]. In addition to the three stages of chronic HBV infection discussed, some chronically-infected patients will resolve their HBV infection, either naturally or occasionally following interferon-based therapy; these patients typically show clearance of HBsAg, are anti-HBc positive, and usually develop anti-HBs (along with anti-HBc). In some patients with resolved HBV, reactivation of HBV infection may develop if they become severely immunosuppressed, as can occur following receipt of chemotherapy, immunosuppressant medications used for transplantation, or with high-dose corticosteroids [6]. Immune Tolerant Chronic HBV Infection The patient in this case has chronic HBV infection in the immune tolerant phase. We know her mother had chronic HBV and likely infected her at birth. At the time of the patient's birth in the early 1980's, she was presumably neither screened for HBsAg nor given hepatitis B immune globulin (HBIG) and hepatitis B vaccine at birth. Although the CDC recommended this approach at the time, it was not widely practiced in the United States. Although the immune response to HBV remains incompletely understood, exposure to HBV antigens and high levels of HBV DNA very early in life presumably leads to a suboptimal immune response, resulting in “immune tolerance.” Patients with immune tolerant chronic infection usually have acquired HBV perinatally or in early childhood, as often seen in Asia and the South Pacific Islands [2,4]. Laboratory studies characteristically show normal hepatic transaminase levels, presence of HBeAg, and high serum HBV DNA levels. Patients with immune tolerant chronic infection usually remain in this phase for a few decades, until they experience an up-regulation in the immune response and transition to the immune active phase. Approach to Patients in the Immune Tolerant Phase Regarding the approach to patients with immune-tolerant chronic infection, treatment of HBV in this phase has poor efficacy [2]. In general, patients with chronic HBV infection respond best to therapy if they have an active immune response to HBV infection, as manifested by pretreatment alanine aminotransferase (ALT) levels greater than twice the upper limit of normal (ULN) and evidence of active hepatitis on liver biopsy. The updated 2004 American Association for the Study of Liver Disease (AASLD) practice guidelines recommend that patients with immune tolerant chronic HBV (HBeAg positive, HBV DNA levels greater than 105 copies/ml, and normal ALT) should undergo follow-up ALT testing every 3-6 months (Figure 3)[2]. Subsequent follow-up and testing varies depending on whether ALT levels remain normal, increase to 1-2 times the ULN, or increase to greater than twice the ULN normal. In addition, these guidelines also recommend considering screening for hepatocellular carcinoma in relevant populations. In a separate set of recommendations published in 2004, a panel of hepatologists suggested that liver biopsy might be indicated for patients with immune tolerant HBV and normal serum ALT to help identify a subset of patients with significant inflammation or fibrosis who may benefit from treatment [3]. Patient Follow-Up The patient is scheduled for twice yearly appointments, but is temporarily lost to follow-up. When she returns 4 years later, at age 27, she has no complaints, but laboratory studies show an ALT of 250 IU/ml, AST 178 IU/ml, positive HBeAg, and HBV DNA 3.5 X 107 copies/ml (7 million IU/ml). Her physical examination and the remainder of her liver function tests are normal, including prothrombin time. Immune Active Chronic HBV Infection At this point in the patient's history, she has transitioned to the immune active phase of chronic HBV infection; this phase is often also referred to as the immune clearance phase. As seen in this case, most patients in the immune tolerant phase eventually mount an enhanced immune response to HBV infection and transition to the immune active phase (Figure 2) [2,4]. Patients with perinatally acquired HBV most often have this transition between the ages of 20 and 40, whereas those who acquire HBV in childhood generally have an earlier transition (between the ages of 10 and 15) [2]. Patients can also develop immune active chronic HBV without an immune tolerant phase as when infection occurs in childhood or adolescence, a pattern frequently seen in sub-Saharan Africa and some Mediterranean countries, or when infection is acquired as an adult, as seen more frequently in industrialized countries. The immune active phase is characterized by high levels of HBV DNA, elevated aminotransferase levels, and active liver disease on biopsy. Patients in this phase may have either positive or negative HBeAg. Most who do have positive HBeAg in this phase eventually spontaneously clear HBeAg and seroconvert from a negative anti-HBe test to a positive anti-HBe test, with a seroconversion rate of 8-10% per year [7]. When this occurs, the patient is considered to have undergone transition to the inactive chronic carrier state. Some patients, however, can remain in the immune active phase for years and experience progressive liver fibrosis that can lead to cirrhosis and an increased risk of hepatocellular carcinoma [7]. These patients often have recurrent exacerbations with intermittent increases in hepatic transaminase levels [4]. Approach to Patients in the Immune Active Phase In general, patients with persistent immune active chronic HBV infection should receive HBV therapy to prevent progressive liver fibrosis (Figure 4). Treatment of chronic HBV infection is discussed in detail in a separate case on this site. The AASLD practice guidelines for the management of hepatitis B infection recommend waiting for 6 months after diagnosis a patient with compensated chronic immune active hepatitis B infection, then doing a liver biopsy to assess the hepatic pathology (if the HBV DNA is greater than 105 copies/ml) [2]. If only mild hepatitis is present, antiviral therapy is less likely to be effective, and treatment can be deferred. If moderate to severe hepatitis is present and portal fibrosis or worse is found, antiviral treatment should be initiated. Because of increased response rates to antiviral therapy among patients with elevated ALT, some providers may opt to initiate treatment immediately and follow for HBeAg seroconversion. Continuation of Patient's History The patient is scheduled to return for follow-up in 6 months. She returns at that time and physically looks well and feels fine. Her laboratory studies show a serum ALT of 18, positive HBsAg, negative HBeAg, positive anti-HBe, and HBV DNA 5.2 X 103 copies/ml (1040 IU/ml). Inactive Chronic Carrier Chronic HBV Infection At this point, the patient has undergone spontaneous HBeAg seroconversion, her liver disease in now inactive, and she has transitioned to the inactive chronic carrier phase, formerly called the “asymptomatic chronic HBsAg carrier” state. The transition to the inactive chronic carrier state is typically accompanied by a change from anti-HBe negative to positive, normalization of ALT and AST, improvement in liver histology, and a decrease of serum HBV DNA to less than 105 copies/ml (20,000 IU/ml). Approximately 80% of patients in the inactive chronic carrier phase will remain anti-HBe positive and HBeAg negative, and about 20% will undergo a “HBeAg reversion” and again become HBeAg-positive. Over and above that risk, patients may develop HBeAg-negative (precore mutant) chronic hepatitis B, estimated to occur in 10 to 40% of such patients. Approach to Patients in the Inactive Chronic Carrier Phase Persons in the inactive hepatitis B phase should undergo follow-up every 6-12 months with serum ALT measurement (Figure 5). In addition, since these persons are still at risk for the development of hepatocellular carcinoma (HCC), most experts would recommend periodic screening for HCC using serum alpha fetoprotein (AFP) levels and liver ultrasound in persons with chronic HBV infection who are at a higher risk for developing HCC (males older than 45 years of age, presence of cirrhosis, or family history of HCC) [2]. In addition, many experts would also recommend considering similar periodic screening for HCC in persons with chronic HBV infection who are from areas where HBV is endemic [2]. [Back to Question \| See References] CME Credit \| CNE Credit \| Back to Top	Adapted from Lok AS, Heathcote EJ, Hoofnagle JH. Management of Hepatitis B 2000, Summary of a Workshop. Gastroenterology 2001;120:1828-53. Figure 1 Abbreviations: HBV = hepatitis B virus Figure 2 Abbreviations: HBV = hepatitis B virus; ALT = alanine aminotransferase; HCC = hepatocellular carcinoma Adapted from Lok ASF, McMahon BJ, American Association for the Study of Liver Disease Practice Guideline: Chronic Hepatitis B Update of Recommendations. Hepatology 2004:39:857-61. Figure 3 Abbreviations: HBV = hepatitis B virus; ALT = alanine aminotransferase; HCC = hepatocellular carcinoma Individuals with HBV DNA levels greater than 105 copies/ml, elevated ALT, HBeAg negative, and anti-HBeAg positive represent persons with chronic hepatitis B infection with precore or core promoter mutant virus. In contrast, HBeAg-positive individuals who are and observed for 3 to 6 months and then develop anti-HBe positive antibody (spontaneous HBeAg seroconvrsion) generally have normalization of ALT levels along with a decrease of the HBV DNA levels to less than 105 copies/ml. Adapted from Lok ASF, McMahon BJ, American Association for the Study of Liver Disease Practice Guideline: Chronic Hepatitis B Update of Recommendations. Hepatology 2004:39:857-61. Figure 4 Abbreviations: HBV = hepatitis B virus; ALT = alanine aminotransferase; HCC = hepatocellular carcinoma Adapted from Lok ASF, McMahon BJ, American Association for the Study of Liver Disease Practice Guideline: Chronic Hepatitis B Update of Recommendations. Hepatology 2004:39:857-61. Figure 5
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