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The current treatment measures for hepatitis B virus (HBV) are very effective in inhibiting both viral replication and liver disease progression, but they are unlikely to eradicate the infection.1–3 Therefore, only chronic HBV patients with at least moderate fibrosis or those who are at risk of progression to severe fibrosis or cirrhosis and advanced liver disease are usually considered for treatment.1, 2, 4 Conversely, treatment is deferred in chronic HBV patients with mild liver disease who are at low risk of progression to severe fibrosis, cirrhosis, or hepatocellular carcinoma (HCC) in the near future. Thus, knowledge of the natural history of HBV infection and a proper evaluation of the severity of liver disease are critical for identification of chronic HBV patients who are at the highest risk of progression and to determine treatment. The use of noninvasive markers of fibrosis is becoming popular in several countries, but the clinical use of each marker, either alone or combination, is hampered by the lack of well-established cutoff points to indicate degree of fibrosis or severity of disease.
After their initial evaluation (Fig. 1), patients can be broadly classified according to their alanine aminotransferase (ALT) levels and hepatitis B virus e antigen (HBeAg) status. After a follow-up of 3 to 12 months, chronic HBV patients may be classified into cases with active, intermediate (i.e., “gray zone”), and inactive chronic HBV infection.
antibody to HBeAg
hepatitis B virus e antigen
hepatitis B virus
persistently normal ALT
upper limit of normal
Active Chronic HBV Infection
Current guidelines recommend treatment for all HBeAg-positive or HBeAg-negative patients with ALT >2× upper limit of normal (ULN) and HBV DNA >20,000 IU/mL1, 2, 5 who are patients in the immunoreactive phases of HBeAg-positive or HBeAg-negative chronic HBV (Fig. 2). Because there is a probability of spontaneous remission, particularly in HBeAg-positive patients, a monthly follow-up for 3 months is usually useful and safe if there are no signs of advanced liver disease. Since active necroinflammation with variable degrees of fibrosis are almost universally present in patients with high ALT and HBV DNA,6 a liver biopsy is not considered to be necessary before treatment initiation, as it is not expected to change the decision for treatment.1, 2, 5
Intermediate (“Grey Zone”) Chronic HBV Infection
HBeAg-Positive Patients with Marginally Elevated ALT and/or HBV DNA <20,000 IU/mL
There are neither good data nor strong recommendations for the management of HBeAg-positive patients with ALT levels 1 to 2× ULN. Thus, therapeutic decisions and the need for biopsy should be individualized.1, 2, 5 A biopsy is often useful in this subgroup, but close follow-up for 6 to 12 months can be more helpful. Patients with increasing or even stable HBV DNA over 6 months need to undergo biopsy and will probably benefit from therapy even if their ALT levels remain between 1 and 2× ULN. In contrast, patients with decreasing HBV DNA regardless of ALT level can have treatment deferred, at least temporarily, because they may experience spontaneous seroconversion to antibody to HBeAg (anti-HBe) (Fig. 2).
HBeAg-Positive Patients with Persistently Normal ALT
HBeAg-positive patients with persistently normal ALT (PNALT) who are in the initial immunotolerant phase usually have high HBV DNA levels and no or minimal histological changes.1, 2, 5 Given the low rates of either significant histological disease and anti-HBe seroconversion under therapy, treatment is often deferred.1, 2, 5 On the other hand, the severity of histological injury varies widely in HBeAg-positive patients with PNALT. Furthermore, continued high HBV replication and prolongation of HBeAg-positive status may increase the risk of HCC and liver disease progression.7, 8 Consequently, the decision to proceed to liver biopsy and antiviral treatment in HBeAg-positive patients with high viremia and PNALT should be made on a case-by-case basis,1, 3 taking into account the patient's age and family HCC history, two factors associated with histological severity and worse patient outcomes.8 Treatment can be deferred in HBeAg-positive patients with PNALT if they are <30 years of age but should be recommended for those >40 years of age. Among patients 30 to 40 years of age, a biopsy is often helpful (Fig. 3). A positive family history for HCC should reduce the age limit for treatment initiation.1, 2
Two subgroups of HBeAg-positive patients with PNALT may be exceptions to the plans outlined above. First, health care professionals whose responsibilities require participation in invasive procedures (particularly surgeons, dentists, and phlebotomists) may not be able to work while they are HBeAg-positive and have high HBV DNA and therefore may require treatment. Second, HBeAg-positive pregnant women with PNALT and high HBV DNA (>108 IU/mL or even 106-107 IU/mL) are recommended to receive oral antiviral therapy during the last trimester to reduce the risk of vertical HBV transmission from mother to baby.1
HBeAg-Negative Patients with Marginally Elevated ALT and/or HBV DNA Between 2,000 and 20,000 IU/mL
Mild ALT elevations are often observed in patients with HBeAg-negative chronic HBV, who may sometimes have HBV DNA between 2,000 and 20,000 IU/mL or transiently <2,000 IU/mL.6 However, it is impossible to differentiate such patients from inactive chronic HBV carriers with another cause of mild ALT elevations (such as nonalcoholic fatty liver disease). Close monitoring for 3 to 6 months with monthly ALT determinations and a 3- to 6-month interval HBV DNA test is the best way to approach this group. A biopsy is recommended before initiating antiviral therapy1, 2 (Fig. 2).
HBeAg-Negative Patients with PNALT and HBV DNA ≥2,000 IU/mL
The optimal management of HBeAg-negative patients with PNALT and HBV DNA ≥2,000 IU/mL has been the subject of a recent systematic review.9 HBeAg-negative patients with PNALT and HBV DNA >20,000 IU/mL should undergo biopsy, because the risk for significant histological lesions may be relatively high. Antiviral treatment can be deferred in those patients with minimal necroinflammation and mild (stage 1) fibrosis on biopsy.1, 2, 5 HBeAg-negative patients with PNALT under a strict follow-up and HBV DNA 2,000-20,000 IU/mL can usually be considered as inactive chronic HBV carriers who require neither liver biopsy nor immediate therapy.9 These patients should be managed with close follow-up for ≥3 years with 3 to 4 ALT measurements per year and one HBV DNA measurement per year. They should be considered inactive carriers as long as ALT levels stay normal and HBV DNA levels are within the 2,000 to 20,000 IU/mL range (Fig. 4).
Inactive Chronic HBV Infection
HBeAg-negative patients with PNALT (ALT every 3-4 months for ≥1 year) and HBV DNA <2,000 IU/mL represent true inactive carriers. While they remain inactive carriers, they have excellent long-term outcome with normal overall life expectancy.10 Inactive carriers require neither biopsy1, 2, 5 nor treatment, but they should remain under life-long surveillance with ALT determinations every 6 months and periodical HBV DNA testing1, 2, 5, 9 (Fig. 4).
Treatment can be deferred in chronic HBV patients with inactive or mild liver disease without risk of liver disease progression, while patients with active or advanced liver disease should be treated. All patients in whom treatment is deferred should be monitored regularly according to the presented algorithms, and treatment should be initiated if liver disease becomes more active during follow-up.