Key points

Introduction

Chronic hepatitis B virus (HBV) infection is a leading global cause of chronic liver disease with the potential to result in cirrhosis, liver failure, and/or hepatocellular carcinoma (HCC) in as many as 15% to 40% of patients. It is estimated that 2 billion people worldwide have been infected with HBV, 350 to 400 million of whom are chronically infected. Despite the availability of an effective and safe vaccine, 50 million new cases continue to be diagnosed annually with the largest burden of incident cases due to mother-to-child transmission (MTCT). In the United States, previously reported estimates of chronic HBV infection have recently been modified to 2.2 million when accounting for foreign-born individuals from regions with high endemic rates of seropositivity.

Chronic hepatitis B infection in the female population has implications not just for the individual but for her children as well. This article discusses the natural history of hepatitis B and how it plays an important role in HBV transmission, current strategies and new strategies to control HBV and reduce transmission, and the updated guidelines for the management of HBV.

Exposure and infection in hepatitis B is age dependent. Infection in the very young, particularly in infancy, results in high rates of chronic HBV infection. Conversely, infection in the adult population is associated with relatively low rates of chronic infection. Although exposure to hepatitis B in adults may result in an acute syndrome, viral clearance is more common ( Fig. 1 ).

Risk of chronic infection.

( Adapted from McMahon BJ, Alward WL, Hall DB, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151:599–603; with permission.)

Chronic hepatitis B progresses through 4 distinct phases as described in Table 1 . First, the host acquires immune tolerance. The second phase is characterized by immune activity/clearance. In the third phase the host enters into an inactive carrier state. Finally, the fourth phase is characterized by reactivation/HBeAg chronic hepatitis B. Phase duration is variable, and fluctuation between phases is frequent. Therefore, determining the true natural history of HBV in an individual patient is rather challenging. Correctly determining the phase of infection in which that patient lies is critical in optimizing management.

Introduction

Chronic hepatitis B virus (HBV) infection is a leading global cause of chronic liver disease with the potential to result in cirrhosis, liver failure, and/or hepatocellular carcinoma (HCC) in as many as 15% to 40% of patients. It is estimated that 2 billion people worldwide have been infected with HBV, 350 to 400 million of whom are chronically infected. Despite the availability of an effective and safe vaccine, 50 million new cases continue to be diagnosed annually with the largest burden of incident cases due to mother-to-child transmission (MTCT). In the United States, previously reported estimates of chronic HBV infection have recently been modified to 2.2 million when accounting for foreign-born individuals from regions with high endemic rates of seropositivity.

Chronic hepatitis B infection in the female population has implications not just for the individual but for her children as well. This article discusses the natural history of hepatitis B and how it plays an important role in HBV transmission, current strategies and new strategies to control HBV and reduce transmission, and the updated guidelines for the management of HBV.

Exposure and infection in hepatitis B is age dependent. Infection in the very young, particularly in infancy, results in high rates of chronic HBV infection. Conversely, infection in the adult population is associated with relatively low rates of chronic infection. Although exposure to hepatitis B in adults may result in an acute syndrome, viral clearance is more common ( Fig. 1 ).

Risk of chronic infection.

( Adapted from McMahon BJ, Alward WL, Hall DB, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151:599–603; with permission.)

Chronic hepatitis B progresses through 4 distinct phases as described in Table 1 . First, the host acquires immune tolerance. The second phase is characterized by immune activity/clearance. In the third phase the host enters into an inactive carrier state. Finally, the fourth phase is characterized by reactivation/HBeAg chronic hepatitis B. Phase duration is variable, and fluctuation between phases is frequent. Therefore, determining the true natural history of HBV in an individual patient is rather challenging. Correctly determining the phase of infection in which that patient lies is critical in optimizing management.

Immune-tolerant phase

In the earliest phase of a perinatally infected individual, immune tolerance is the norm with little immune response raised by the host against the virus. Thus, very high virus levels are typical, whereas little inflammation is found on liver biopsy and ALT is persistently normal. The probability of hepatitis B e antigen (HBeAg) loss and seroconversion, which are immune-related events, is low.

The viral mechanism of the immune-tolerant state has not been fully elucidated. HBV-specific T-cell hyporesponsiveness causing energy, deletion, and expansion of regulatory T cells may all be contributing to the immune-tolerance phase. Vertical transmission leading to fetal infection is postulated to occur by transplacental maternal HBeAg induction of T-cell intolerance to HBV core antigen and HBeAg in the neonate. As neonates do not have immunoglobulin M (IgM) antibodies to hepatitis B core antigen (HBcAg), a primary response cannot be mounted.

The utilization of an appropriate cutoff for normal alanine transaminase (ALT) values is important as it can affect treatment decisions. It is known that age, body mass index, and metabolic factors all impact ALT levels. Lai and colleagues evaluated liver biopsies in patients with Chronic hepatitis B (CHB) with normal ALT values (≤40 IU/L at the institutional laboratory) as well as patients with elevated values. In those with persistently normal ALT levels, 34% had grade 2 to 4 inflammation and 18% had stage 2 to 4 fibrosis. Patients in this cohort tended to be of an older age, highlighting that even with normal ALT values a liver biopsy may be useful in older patients with long-standing disease. In a large retrospective analysis of 6835 healthy blood donors, Prati and colleagues reported that the normal limit of ALT should be 30 IU/mL for men and 19 IU/mL for women: this is the current upper limit of normal (ULN) recommended in clinical practice irrespective of institutional laboratory limits. The key to determining true immune tolerance is close long-term follow-up. Therefore, ALT levels should be tested every 6 months for adults with immune-tolerant CHB to monitor the transition to immune active or inactive carrier states.

In general, antiviral therapy is not recommended in this subset of pediatric or adult patients, as achieving treatment end points is unlikely. If HBV has been acquired perinatally or in early childhood, the immune-tolerant phase is long, typically lasting 2 or 3 decades; in contrast, it may be absent or very short in adult-acquired HBV. It is recommended to consider initiation of antiviral therapy in adults if they are older than 40 years with normal ALT and elevated HBV DNA of 1,000,000 IU/mL or greater and a liver biopsy demonstrating significant necroinflammation or fibrosis. Additionally, clinicians should take into account fluctuating ALT levels and whether there is a family history of cirrhosis or HCC into decision management considerations.

Immune-active phase

After a variable period of immune tolerance, immune activity may begin, in which patients show evidence of elevated ALT levels, fluctuating viremia, and liver biopsies consistent with inflammation and injury. If the immune activity is successful, immune clearance occurs with HBeAg loss and development of anti-HBe, a transition to inactive carrier status. If clearance fails to occur, the liver damage may ensue potentially leading to cirrhosis and increased risk for HCC. The immune-active state is an appropriate time to initiate antiviral therapy, as there is a greater risk of progression of liver disease. Elevated baseline ALT, 2 to 5 times the ULN, and moderate to high inflammation on biopsy are associated with higher likelihood of achieving the intermediate outcomes with treatment (HBeAg seroconversion and HBV DNA <2000 IU/mL after treatment). The American Association for the Study of Liver Disease (AASLD) recommends indefinite therapy in HBeAg-negative immune-active CHB unless there is a compelling reason to stop. Noninvasive tests, such as transient elastography, may be helpful in ruling out cirrhosis but are less accurate in evaluating fibrosis.

If the ALT is elevated but not greater than 2 times the ULN, or HBV DNA is less than the threshold of greater than 2000 IU/mL, additional factors should be included in the treatment decision. Again, risk factors for more severe disease include older age (>40 years), family history of HCC, male sex, and extrahepatic manifestations of CHB. Treatment of HBV with antivirals does not eliminate the risk of HCC, and those at risk should continue surveillance.

Inactive carrier

In the inactive-carrier phase, the immune system has effectively cleared the HBeAg and an anti-HBe becomes present. HBV DNA levels are low and ALT levels have normalized. Liver histology is variable depending on previous liver injury during the immune-active phase. Unless advanced liver disease has developed during the preceding immune-clearance phase, the inactive-carrier phase confers a favorable prognosis, with improvements in liver histology and a halt of disease progression. Guidelines recommend close monitoring rather than treatment of people in this state. Patients in this phase typically have a low risk of disease progression; however, a cohort of 146 inactive carriers was followed for 23 years and 43 patients had increases in ALT levels greater than normal, one had spontaneous reactivation to the HBeAg-negative state, and 2 developed HCC. This finding highlights the importance of continued monitoring for disease activity and HCC progression.

Resolved CHB infection is defined by clearance of hepatitis B surface antigen (HBsAg) with acquisition of HBsAg antibody. Approximately 0.5% of those with inactive CHB will clear HBsAg yearly, which is considered a functional cure, a state as close to remission as possible. However, if this occurs late in life (after ∼40 years of age), the prolonged immune response may still allow liver disease to progress. Low levels of HBV DNA are transiently detected in the serum in the minority of persons achieving seroclearance. Clearance of HBsAg, whether spontaneous or following antiviral therapy, reduces the risk of hepatic decompensation and improves survival.

Among persons who undergo spontaneous HBeAg seroconversion, 67% to 80% will continue to remain in the inactive CHB phase. Approximately 4% to 20% of inactive carriers will revert back to HBeAg positivity, with the highest rates in men, genotype C–infected patients, and those achieving HBeAg seroconversion after 40 years of age.

Reactivation/hepatitis B e antigen–negative CHB

Even after HBeAg seroconversion and entrance into a quiescent HBV inactive-carrier state, a subset of patients may enter a disease state of viral reactivation. This disease state may happen after being in the inactive-carrier state for several years. Similar to the inactive-carrier state, this phase is notable for an absence of HBeAg due to a precore stop codon mutation that becomes dominant, whereas the wild-type e antigen is eliminated. These subset of patients have a 2-fold risk of progressing to cirrhosis and/or HCC versus those with HBeAg-positive infection. HBsAg levels may also help differentiate between inactive carriers and chronic active HBeAg negative infection. Inactive carriers have lower HBsAg levels (<1000 U/mL have 87.9% positive predictive value and 96.7% negative predictive value for patients with HBV DNA <2000 IU/mL). This clinical entity highlights the dynamic natural history of HBV with variable duration, severity, and reversibility from one stage to another.