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)[1,2,3,4,5]. 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.
Natural History and Phases of Chronic HBV
The phases of chronic HBV infection are not considered permanently static and patients who initially develop the immune tolerant phase usually progress to the immune active phase 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, immunosuppresive therapy, such as a tumor necrosis factor alpha (TNF alapha) blocker, or cancer chemotherapy. 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 or less frequently, with oral nucleoside/nucleotide therapy; these patients typically show clearance of HBsAg, are anti-HBc positive, and most 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, with potent chemotherapy regimens, or immunosuppressive biologic agents, such as rituximab (Rituxan) [7,8].
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[2,5]. 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 [2,9]. Even with the use of current more potent antiviral agents, it is difficult to completely suppress the high levels of HBV DNA found in patients in the immune tolerant phase. Thus, treatment of patients in the immune tolerant phase may incus a signficant risk of developing resistance over time. 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 2009 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 20,000 IU/ml, and normal ALT) should undergo follow-up ALT testing every 3 to 6 months (Figure 3). Subsequent follow-up and testing varies depending on whether ALT levels remain normal, increase to 1 to 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.
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 U/L, AST 178 U/L, positive HBeAg, and HBV DNA 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)[2,5]. Patients with perinatally acquired HBV most often have this transition between the ages of 20 and 50, especially those infected with HBV genotype C, whereas those who acquire HBV in childhood generally have an earlier transition (between the ages of 10 and 15). 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 where HBV gentoypes A and D predominate, 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 to 10% per year. When this occurs, most patients will have undergone transition to the inactive chronic carrier state, characterized by normal ALT levels and HBV levels below 2,000 IU/ml. 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. These patients often have recurrent exacerbations with intermittent increases in hepatic transaminase levels. In addition, a minority of patients who have achieved the inactive phase of HBV can reactivate later, so all patients in the inactive phase should be followed with testing for ALT every 6 to 12 months and those whose ALT levels become elevated, should be tested for HBV DNA.
Approach to Patients in the Immune Active Phase
In general, patients with persistent immune active chronic HBV infection should be considered for 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 2,000 IU/ml. 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 above twice upper limits of normal and HBV DNA greater than 20,000 IU/ml, 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 U/L, positive HBsAg, negative HBeAg, positive anti-HBe, and HBV DNA 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 2,000 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.
Approach to Patients in the Inactive Chronic Carrier Phase
Persons in the inactive hepatitis B phase should undergo follow-up every 6 to 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). Further, many experts would also recommend adding serum alpha fetoprotein (AFP) levels along with ultrasound and considering similar periodic screening for HCC in persons with chronic HBV infection who are from areas where HBV is endemic, primarily males born in Africa who are older than 20; this recommendation, however, is without any cost benefit analysis.
1 Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology. 2007;45:1056-75.PubMed Abstract
2 Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-39. PubMed Abstract
3 Lok AS, McMahon BJ. Chronic hepatitis B: Update 2009. Hepatology. 2009;50:661-97.PubMed Abstract
4 Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, Tobias H. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315-41.PubMed Abstract
5 McMahon BJ. Natural history of chronic hepatitis B. Clin Liver Dis. 2010;14:381-96.PubMed Abstract
6 Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005;5:215-29.PubMed Abstract
7 Perrillo RP. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease. Gastroenterology. 2001;120:1009-22.PubMed Abstract
8 Mastroianni CM, Lichtner M, Citton R, et al. Current trends in management of hepatitis B virus reactivation in the biologic therapy era. World J Gastroenterol. 2011;17:3881-7.PubMed Abstract
9 McMahon BJ, Holck P, Bulkow L, Snowball M. Serologic and clinical outcomes of 1536 Alaska Natives chronically infected with hepatitis B virus. Ann Intern Med 2001;135:759-68. PubMed Abstract
10 Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an pdate. Hepatology. 2011;53:1020-2.PubMed Abstract