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Hepatitis B virus (HBV) is thought to affect more than 400 million people world-wide. About 1.25 million Americans have chronic HBV. Chronic HBV infection con-tributes to 5,000 deaths annually from cirrhosis and hepatocellular carcinoma (HCC) in the United States. The rate of progression to chronic HBV infection is higher in individuals who are infected at a younger age (25–30 percent before five years of age; 3–5 percent after five years of age or as adults). HBV is especially preva-lent in Southeast Asia, China, and Africa, where more than half the population is affected. It is passed on through vertical (mother to fetus) and horizontal (primar-ily child to child) transmission. In contrast, in the United States and Europe, infection occurs primarily by horizontal transmis-sion among young adults.
HBV belongs to the family of hepad-naviruses. The virus is present in serum in large quantities (108 to 1010 virions) and can be transmitted not only through blood but also through bodily fluids such as semen, saliva, and cervical secretions. There is a 30 percent chance of transmis-sion through needlestick. Acute infection is asymptomatic in 70 percent of adults and 90 percent of children younger than five years old. However, patients can present with nausea, anorexia, fatigue, fever, and right upper quadrant pain. Treatment for acute infection is generally supportive.
The HBV genome is composed of a partially double-stranded circular DNA that is enclosed within a nucleocapsid (or core antigen). This genome is surrounded by a spherical envelope or surface anti-gen. The genome encodes both core and surface proteins and a DNA polymerase, which also acts as a reverse transcriptase. The variable expression of core and surface antigens and antibodies to these proteins serve as useful markers of past, current, or chronic infection.
Four distinct stages of HBV infec-tion have been described. The first stage is characterized by high levels of HBV DNA replication and normal serum transaminase levels. HBeAg, a marker of active viral replication, is positive. The second stage reflects the immune response in which inflammation results in destruction of HBV-infected cells and a subsequent elevation in transaminase levels. The highest risk of progression to cirrhosis and HCC occurs with chronic HBV infection when the patient stays in this stage beyond 6 months. The third stage is thought to indicate the end of viral replication although low levels of HBV DNA may still be present. HBeAg becomes negative, HBe antibody appears, and transaminase levels normalize. The final stage is defined by the clearance of hepatitis B surface antigen (HBsAg). Antibody to HBsAg confers protective immunity.
HBV replication is not directly cyto-toxic. This is supported by the finding that despite ongoing viral replication within hepatocytes, many HBV carriers are asymptomatic and exhibit minimal liver injury. Rather, the liver injury that occurs with HBV infection is thought to be an unfortunate consequence of the immune response, which is directed at viral clear-ance. Clinical studies in patients with acute and self-limited hepatitis B infection have demonstrated strong T-cell responses involving both MHC class II restricted CD4+ cells and MHC class I restricted CD8+ cells to HBV antigens in contrast tothe attenuated responses seen in chronic carriers of HBV. More specifically, cyto-toxic T lymphocytes are targeted at epi-topes in the HBV core, polymerase, and envelope proteins, suggesting the impor-tance of cytotoxic T cells in the immune response.
To further characterize the role of cyto-toxic T cells, transgenic mice that express HBV antigens or viral genomes in the liver have proven useful. These mice are tolerant to HBV proteins and therefore liver damage does not develop. However, when antiviral cytotoxic T cells from syn-geneic mice are introduced to these mice, they develop acute liver injury similar to that seen in hepatitis B. Interestingly, the extent of hepatocyte injury cannot be entirely explained by the few interactions that occur between cytotoxic T cells and their targets. It is believed that the major-ity of the injury is the result of antigen nonspecific cytotoxic by-products such as TNF, free radicals, and proteases, which are released secondary to the effects of cytotoxic T lymphocytes.
Additional studies in mice suggest that the antiviral response does not nec-essarily involve killing the infected cells. When cytotoxic T cells are introduced in mice with active HBV replication, both DNA and RNA replication decreased even in hepatocytes that were uninjured and viable. Antibodies to TNF-α and IFN-γ inhibit this response, suggesting that these cytokines have antiviral effects.
Vaccination against HBV has been the cause of a tremendous decline of hepati-tis B infection in the United States, from 300,000 cases per year to about 79,000 cases. A three-injection series with a recombi-nant vaccine has been found to induce protective antibody levels in 95 percent of children and 90 percent of adults.
Chronic HBV infection impairs the abil-ity of the liver to respond to endogenous interferon. IFN-α-2b, a recombinant IFN, resembles naturally occurring antiviral cytokines. It is thought to up-regulate MHC class I molecules generally not expressed by hepatocytes, thereby increasing their susceptibility to recognition by CD8+ T lymphocytes. In the first year after treat-ment, HBeAg seroconversion was seen in as many as 46 percent of patients treated with IFN-α-2b. The goal of immunomodu-latory therapy using IFN is to accelerate the transition from stage II to stage III by eliminating the hepatocytes that house the replicating virus.
Lamivudine, a nucleoside analog first used to treat HIV infection, was approved for the treatment of HBV in 1999. It inhibits reverse transcriptase, thereby terminating viral DNA synthesis. Despite the advan-tages of lamivudine over IFN-α-2b in terms of its tolerability and safety in patients with decompensated cirrhosis, disadvantages include the uncertainty about the duration of therapy and the development of lami-vudine-resistant strains of HBV. Recently, a nucleotide analog, adefovir dipivoxil has been approved for the treatment of HBV infection. One benefit of this drug over lamivudine is that no adefovir dipivoxil-resistant strains have been developed. It is speculated that because of its tolerability and oral route of administration, it may replace IFN-α-2b as first-line therapy in most patients.
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