Alt

Non-replicative phase

Years

Fig. 1. Natural history of chronic HBV infection. (dashed lines) Represent typical fluctuations that occur with HBV infection. (straight lines) Represent average trends for both HBV DNA and ALT. (A) Course of perinatally acquired HBV infection. (B) Course of adult-acquired HBV infection.

Non-replicative phase

Years

Fig. 1. Natural history of chronic HBV infection. (dashed lines) Represent typical fluctuations that occur with HBV infection. (straight lines) Represent average trends for both HBV DNA and ALT. (A) Course of perinatally acquired HBV infection. (B) Course of adult-acquired HBV infection.

often is used as an endpoint of therapy [10]. During the inactive phase, 1% to 2% of individuals per year will clear HBsAg, but as many as 30% of people may relapse back to the immunoactive phase.

Approximately 5% to 10% of individuals who lose HBeAg will continue to have detectable HBV DNA, elevated aminotransferase levels, and active inflammation on liver biopsy. These cases are defined as the HBeAg-nega-tive or atypical form of CHB and remain in the immunoactive phase [11].

Based on this knowledge, the natural history of HBV infection can be defined by three clinical, serologic, and virologic patterns:

1. HBeAg-positive or classic CHB. This is the most common pattern and is defined by the presence of HBeAg and elevated HBV DNA in serum. The prognosis is variable and is in part dependent upon whether the infection is in the immunoactive phase (associated with elevated aminotransaminase levels and chronic hepatitis on liver biopsy) or the immunotolerant phase (associated with normal aminotransaminase levels and minimal to absent inflammation on liver biopsy).

2. HBeAg-negative or atypical CHB. This form of the infection is characterized by the absence of HBeAg but with detectable HBV DNA in serum and elevated aminotransferase levels. Features of chronic hepatitis are seen on liver biopsy, and the disease is generally active as defined by abnormal serum aminotransferase levels and liver histology [12,13]. Molecular analysis of HBV has identified the cause of this clinical presentation. Mutations in the HBV precore and core gene lead to an abrogation or reduction of HBeAg synthesis [12,13]. The clinical course can be quite severe, with more frequent episodes of acute aminotransferase flares that may lead to a greater number of liver-related complications [14]. Patients presenting with this pattern of disease should have other forms of chronic hepatitis excluded, such as hepatitis C and D infections and autoimmune and drug-induced liver disease.

3. The inactive carrier state. This is typified by the presence of anti-HBe in serum, normal alanine aminotransferase (ALT) levels, undetectable HBV DNA by hybridization assays, and minimal changes on liver biopsy. Viral replication is low in these individuals. Patients in this phase of the disease usually have a favorable prognosis and are at low risk for liver disease progression [8,15]. Occasionally, spontaneous reactivation may occur.

Assessment and monitoring

The primary goals of assessment are to determine the level of disease (active or inactive) and to stage the disease as mild, moderate, or severe. The initial evaluation of the patient should include a complete history and physical examination with particular attention directed toward eliciting signs, symptoms, and risk factors for chronic liver disease. A family history of liver disease should be sought and a detailed alcohol history obtained. Routine blood tests should include standard biochemical and hematological profiles and specific viral serologic assays for HBsAg, HBeAg, antibody to hepatitis B core antigen (anti-HBc), anti-HBe, antibody to hepatitis B

surface antigen (anti-HBs), and quantitation of HBV DNA [16,17]. Which HBV DNA assay to use in clinical practice is an unresolved issue. Quantitative assays vary significantly in their sensitivity, with the lower limit of detection varying by as much as 103 log copies per mL. Testing for hepatitis A, C, and D and HIV should be performed routinely, as most of these viruses share similar routes of transmission as HBV, and coinfection with another virus may modify the course of HBV. Other causes of chronic liver disease should also be excluded. A baseline ultrasound examination is recommended to exclude abnormal masses or anatomical variants. A liver biopsy provides information on the grade (severity of inflammation) and the stage (severity of fibrosis) of the disease. A liver biopsy, however, can confirm the diagnosis, provide prognostic information for the patient, and assist in determining the need for therapy. Although the information gained from liver biopsy is helpful in clinical decision making, it is not an absolute requirement before treatment and should be individualized in each patient. Patients should be informed of other factors that might exacerbate progression of underlying liver disease, notably alcohol consumption, use of hepa-totoxic medications, and immunosuppressants. Counseling on reducing the risk of transmission should be undertaken, especially for teenagers, young adults, and injection drug users, populations among whom the risk of sexual and parenteral transmission is high. Close family, household, and sexual contacts should be vaccinated against HBV. Individuals who do not have immunity against hepatitis A virus (HAV) should be offered hepatitis A vaccination. If bridging fibrosis or cirrhosis is found on liver biopsy, or if there is clinical evidence of advanced liver disease, a screening esophagogastro-duodenoscopy is advisable to assess for portal venous hypertension via the presence of esophageal varices. Attention should be given to initiating a screening program for HCC in patients with established cirrhosis and particularly in males, older individuals, and those with a strong family history of liver cancer.

Selection of patients for treatment

There is no consensus on how to treat chronic HBV; however, several treatment guidelines have been published [16-19]. Minor differences exist in the recommendations. Identifying patients who require treatment may appear to be a straightforward task, but it is usually quite complicated in practice. There are many factors to consider in the decision-making process, including the age of the patient, stage of disease, pattern of liver disease, the patient's willingness to be treated, coinfection with other hepatotrophic viruses (HCV, HDV) and HIV, presence of other comorbid conditions and adverse effects of treatment. CHB often has a fluctuating course; therefore, after an initial assessment patients should be monitored with liver chemistries for a period of at least 6 months to assess the pattern of disease before initiating therapy (Fig. 2). Patients with inactive CHB are not

Inactive carrier

Normal ALT

HBsAg + HBeAg

HBV DNA <105 copies / ml; normal ALT

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