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Chronic Hepatitis B Virus Infection: Treatment Strategies for the Next Millennium

Arshad H. Malik, MD; and William M. Lee, MD
[+] Article and Author Information

From University of Texas Southwestern Medical Center, Dallas, Texas.


Requests for Single Reprints: William M. Lee, MD, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9151.

Requests To Purchase Bulk Reprints (minimum, 100 copies): the Reprints Coordinator; phone, 215-351-2657; e-mail, reprints@mail.acponline.org.

Current Author Addresses: Drs. Malik and Lee: Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9151.


Ann Intern Med. 2000;132(9):723-731. doi:10.7326/0003-4819-132-9-200005020-00007
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Chronic hepatitis B virus (HBV) infection is a leading cause of cirrhosis and hepatocellular carcinoma worldwide. Its prevalence approaches 10% in hyperendemic areas, such as southeast Asia, China, and Africa. Although chronic HBV infection is seen less frequently in North America and Europe, an estimated 1.25 million persons in the United States are infected. In the past decade, revolutionary strides have been made toward the treatment of chronic HBV infection. Interferon-α was once the only available therapy but has recently been joined by the nucleoside analogues, the most extensively studied of which is lamivudine. Interferon therapy continues to have a role in the treatment of a carefully selected group of patients. Lamivudine therapy, which has less stringent selection criteria, suppresses HBV DNA in almost all treated patients: Seventeen percent to 33% experience loss of hepatitis B e antigen, and 53% to 56% have a histologic response. Extended lamivudine treatment leads to the development of a specific lamivudine-resistant virus with base-pair substitutions at the YMDD locus of the DNA polymerase. Newer nucleoside analogues and other immunomodulator therapies are being investigated. In the future, combination therapy with different classes of agents may yield improved response rates and delay the development of resistance.

Figures

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Figure 1.
Genome of hepatitis B virus (HBV).SCPX3

The viral genome is partially double stranded. Four overlapping reading frames (surface [ ], core [ ], polymerase [ ], and the x gene [ ]) encode for the viral proteins. Three upstream regions (preC, preS1, and preS2) are also shown. The size of each segment is shown in parentheses. aa = amino acids. Adapted with permission from reference .

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Grahic Jump Location
Figure 2.
Mechanism of hepatitis B virus (HBV) replication and the site of action of different treatment methods.cccDNA

After HBV endocytosis into hepatocytes, the genome is translocated to the nucleus and converted to covalently closed circular DNA ( ), which is transcribed and translated to form an RNA intermediate. Translocation of pregenomic RNA can be inhibited by interferon-α, and reverse transcription of the pregenomic RNA by polymerase to HBV DNA can be inhibited by nucleoside analogues. Association of the partially double-stranded DNA with envelope proteins leads to the formation of mature HBV particles that are then released from the hepatocyte. mRNA = messenger RNA. Adapted with permission from Glaxo-Wellcome Pharmaceuticals.

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Grahic Jump Location
Figure 3.
Interferon for chronic hepatitis B virus (HBV) infection. Top.ALTHBeAgBottom.solid linesdashed lines10

Sustained response. A “flare” of alanine aminotransferase ( ) activity is associated with the loss of hepatitis B e antigen ( ). Transient response. Serum levels of ALT ( ) and HBV DNA ( ) return to pretreatment levels after interferon therapy is discontinued. Hepatitis B e antigen remains positive (+). Anti-HBe = hepatitis B e antibody. Adapted with permission from reference .

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Grahic Jump Location
Figure 4.
Proposed algorithm for treatment of chronic hepatitis B virus (HBV) infection.

ALT = alanine aminotransferase; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen.

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