Latest news about HBV

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[B]By Ed Edelson
HealthDay Reporter[/B]


[B]New way to treat Hepatitis B[/B]

THURSDAY, March 18 (HealthDayNews) -- Swiss researchers have found that an enzyme can block reproduction of the hepatitis B vaccine, a discovery they say could lead to a new treatment for this dangerous liver infection.

Their theory is that if the enzyme can block the genetically engineered hepatitis B proteins found in the vaccine, it might also work against the virus itself.

More than 250 million people worldwide are infected with hepatitis B, which can cause cirrhosis and liver cancer. About 300,000 Americans contract the infection each year. In about 90 percent of such cases, the virus disappears after several months. But an estimated 1 million Americans are chronically infected.

Hepatitis B is spread by infected blood and other body fluids, such as semen, so drug users who share needles and people who have unprotected sex are vulnerable to the infection. There is a vaccine that can be effective if given immediately after infection. Chronic infections are treated by injections of interferon and by two relatively new antiviral drugs, which are not completely effective. Chronic infection carries the risk of potentially fatal liver conditions.

Now the researchers from the University of Geneva report in the March 19 issue of Science that an enzyme designated as [B]APOBEC3G[/B] (understandably abbreviated to A3G) has blocked reproduction of the hepatitis B vaccine in laboratory-grown cell lines.

The discovery is something of a surprise because A3G until now has been identified only as a molecule that defends against retroviruses that have RNA as their genetic material. The best-known retrovirus is HIV, which causes AIDS and is spread in the same way as hepatitis B, by infected blood and sexual contact.

This is the first study to show that A3G can act against a DNA-containing virus such as hepatitis B, according to study author Dr. Didier Trono, chairman of microbiology and molecular medicine at Geneva.

But, he adds, making medical use of that discovery requires a lot of work and some imagination.

"In a wild scheme, one could imagine using gene therapy to express A3G in the liver of chronically infected people," Trono says. "But one could also learn how to activate the expression of this or related genes by pharmacological means."

"We do not know precisely" what A3G does to prevent reproduction of hepatitis B, Trono acknowledges. It is a complicated subject because hepatitis B is "a retrovirus in disguise," using RNA in its reproductive cycle, he explains.

"erhaps A3G blocks the assembly of the complex necessary for its reproduction," Trono says.

Research on how and why A3G acts as it does will continue, he adds.


SOURCES: Didier Trono, M.D., chairman, microbiology and molecular medicine, University of Geneva, Switzerland; March 19, 2004, Science

[此贴子已经被作者于2004-4-17 6:55:51编辑过]

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[B]Ribozyme Package Effective Against Hepatitis B Virus[/B]

[B]HERSHEY, PA -- Penn State College of Medicine researchers have developed a tiny package that searches for and destroys up to 80 percent of hepatitis B virus in the livers of mice.[/B]


"This marks one of the few successful in vivo, or in-animal, models of an effective therapy to reduce the production of hepatitis B virus," said Gary Clawson, M.D., Ph.D., professor of pathology, biochemistry and molecular biology, Penn State College of Medicine. "Although this work focused on hepatitis B virus, our method of targeting and packaging ribozymes should also be applicable to the development of therapies to fight other viruses."

The study was published March 5 in the online version of the journal, Molecular Therapy, the official journal of the American Society of Gene Therapy, and will appear in the journal's April print edition.

Hepatitis B virus (HBV) attacks the liver and can cause lifelong infection, liver cancer and, eventually, death. Although HBV is treated with drugs, it cannot be cured. The chronic disease affects about 1.25 million Americans, 20 percent to 30 percent of whom acquired the virus in childhood. HBV is transmitted via blood or sexual activity, but also may be transmitted from mother to child during childbirth. Once infected, the virus continues to reproduce in the liver.

Clawson, who is also director of the Jake Gittlen Cancer Research Center at Penn State Milton S. Hershey Medical Center, and his team developed the SNIPAA cassette, which contains a double-dose of a special type of ribozyme called a trans-acting hammerhead ribozyme. Ribozymes are ribonucleic acid (RNA) segments that, like enzymes, cause chemical changes or splitting in other RNA segments. RNA, which is critical to the replication of DNA - life's instruction book - also is critical to the replication of viruses. The SNIPAA cassette was packaged in liposomes, typical vehicles for delivering drugs in the body, and the liposomes in turn were modified with proteins so that they would seek out the liver cells where the HBVs replicate.

Once at the liver cell, the SNIPAA cassette package is released into the cell and finds its way to the cell nucleus, where the active ribozymes are produced. The ribozymes destroy the viral RNA's ability to produce proteins by cleaving, or cutting, the viral RNAs, rendering them useless. Proteins are critical to virus replication.

First, Clawson and co-workers used proprietary in vitro selection techniques to identify the best target sites in HBV RNA, and then used cells in culture to test the effectiveness of the cassette. In the cell cultures, he found that the SNIPAA cassette containing a double-dose of ribozymes eliminated more of the virus over a period of three to five days than did cassettes containing a single dose of the ribozymes.

Specialized transgenic mice, which contain the HBV in their DNA and which are chronic carriers of HBV, were treated with the tiny HBV-fighting packages. Clawson and co-workers chose the dosage and schedule of the drug delivery to the mice based on their cell culture work. Studies with the transgenic mice were performed with John Morrey, Ph.D., at Utah State, under the auspices of an NIH contract which supports testing of antiviral reagents.

"The treatment effects were quite dramatic," Clawson said. "We recorded a greater than 80 percent reduction in the HBV liver DNA, meaning far less virus was being produced, and staining for the virus using antibodies also showed a dramatic decrease in residual viral production. This is significant because there are so few examples of successful in vivo applications of ribozymes against bona fide naturally-occurring, disease-causing organisms."

Clawson believes this cassette is more effective than previous ones for a number of reasons. First, the best target sites were chosen using a "library selection" process. Second, the ribozyme cassette is engineered to cut itself into pieces, thereby freeing the HBV-targeted ribozymes from extraneous sequences that could interfere with their activity. In addition, Clawson's cassette included two distinct trans-acting ribozymes, whereas previous versions included only one. With two trans-acting hammerhead ribozymes in the SNIPAA cassette, twice the amount of "medicine" was present and was delivered over a longer period.


Co-authors on the study were: Wei-Hua Pan, Pin Xin, Departments of Pathology and Biochemistry and Molecular Biology, The Gittlen Cancer Research Institute, Penn State Milton S. Hershey Medical Center, and John D. Morrey, Institute for Antiviral Research, Utah State University.


[B]This work was supported by a research and development contract with Biosan Laboratories/Hexal AG and by a contract from the National Institutes of Health.[/B]

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Hepatitis B

KENNETH W. LIN, M.D., and JEFFREY T. KIRCHNER, D.O., Lancaster General Hospital, Lancaster, Pennsylvania

Hepatitis B causes significant morbidity and mortality worldwide. More than 400 million persons, including 1.25 million Americans, have chronic hepatitis B. In the United States, chronic hepatitis B virus infection is responsible for about 5,000 annual deaths from cirrhosis and hepatocellular carcinoma. Hepatitis B virus is found in body fluids and secretions; in developed countries, the virus is most commonly transmitted sexually or via intravenous drug use. Occupational exposure and perinatal transmission do occur but are rare in the United States. Effective vaccines for hepatitis B virus have been available since 1982; infant and childhood vaccination programs introduced in the 1990s have resulted in a marked decrease in new infections. Risk factors for progression to chronic infection include age at the time of infection and impaired immunity. From 15 to 30 percent of patients with acute hepatitis B infection progress to chronic infection. Medical therapies for chronic hepatitis B include interferon alfa-2b, lamivudine, and the nucleotide analog adefovir dipivoxil. (Am Fam Physician 2004;69: 75-82,86. Copyright 2004© American Academy of Family Physicians.)

[B](1).[/B]

Hepatitis B virus (HBV) is a common cause of liver disease throughout the world. An estimated one third of the world''''''''''''''''s population has serologic evidence of past infection, and the virus causes more than 1 million deaths annually.1 In the United States, the incidence of HBV infection declined from about 14 cases per 100,000 population in the mid-1980s to about three cases per 100,000 population in 1998.2 However, there are still 1.25 million adults and children in the United States with chronic HBV infection.


HBV is transmitted through blood and other body fluids, including semen and saliva. The virus is 100 times more infectious than human immunodeficiency virus (HIV) and, unlike HIV, it can live outside the body in dried blood for longer than a week.3 In Southeast Asia, China, and sub-Saharan Africa, HBV infection usually is acquired perinatally or in early childhood, leading to a high prevalence of chronic infection (5 to 20 percent). In contrast, 80 percent of infections in the United States, Canada, and Western Europe occur in adults via sexual contact or intravenous drug use, leading to a much lower baseline prevalence (0.1 percent). In the United States, groups at increased risk for HBV infection have been identified (Table 1).4



TABLE 1
Groups at Increased Risk for HBV Infection

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Persons with a history of sexually transmitted disease
Household contacts of HBV-infected persons
Health care workers
Hemodialysis patients
Intravenous drug users
Infants born to HBV-infected mothers
Immigrants and children of immigrants from hyperendemic areas
Men who have sex with men
Persons who have more than one sexual partner in a six-month period
Sexual partners of HBV-infected persons
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HBV = hepatitis B virus.

Information from reference 4.



TABLE 2
Laboratory Markers for HBV Infection

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Hepatitis B surface antigen (HBsAg): present in acute or chronic infection
Hepatitis B surface antibody (anti-HBs): marker of immunity acquired through natural HBV infection, vaccination, or passive antibody (immune globulin)
Hepatitis B core antibody (anti-HBc):
IgM--indicative of infection in the previous six months
IgG--indicative of more distant HBV infection that may have been cleared by the immune system or that may persist; positive HBsAg and anti-HBc IgG--indicative of persistent chronic HBV infection
Hepatitis B e antigen (HBeAg)*: correlates with a high level of viral replication; often called a "marker of infectivity"
Hepatitis B e antibody (anti-HBe): correlates with low rates of viral replication
HBV DNA: correlates with active replication; useful in monitoring response to treatment of HBV infection, especially in HBeAg-negative mutants
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HBV = hepatitis B virus.

*--A small but significant number of persons infected with a mutant strain of HBV cannot synthesize HBeAg; nevertheless, HBeAg is associated with a high rate of viral replication and infectivity.

Information from reference 5


Because newborns have an immature immune system, 90 percent of infants infected perinatally progress to chronic infection. Progression to chronic HBV infection occurs in 25 to 30 percent of persons infected before five years of age, and in 3 to 5 percent of those infected later in childhood or as adults. Immunosuppressed patients are at greater risk of becoming chronically infected.(1,5,6)


[B]Levels of Evidence in AFP[/B]

American Family Physician has introduced guidelines for preparing evidence-based clinical review articles (available online through AFP’s “Information for Authors” at http://www.aafp.org/afpauthors.xml). Select articles will contain labels identifying the strength of evidence supporting key recommendations. AFP has adopted the following convention for labeling the strength of evidence, using an ABC rating scale:

Level A (randomized controlled trial/meta-analysis): High-quality randomized controlled trial (RCT) that considers all important outcomes. High-quality meta-analysis (quantitative systematic review) using comprehensive search strategies.
Level B (other evidence): A well-designed, nonrandomized clinical trial. A nonquantitative systematic review with appropriate search strategies and well-substantiated conclusions. Includes lower quality RCTs, clinical cohort studies and case-controlled studies with nonbiased selection of study participants and consistent findings. Other evidence, such as high-quality, historical, uncontrolled studies, or well-designed epidemiological studies with compelling findings, is also included.
Level C (consensus/expert opinion): Consensus viewpoint or expert opinion.
Each rating is applied to a single reference in the article, not to the entire body of evidence on a topic. Each label should include the letter rating (A, B, C), followed by the specific type of study for that reference. For example, following a level B rating, include one of these descriptors:
(1) nonrandomized clinical trial;
(2) nonquantitative systematic review;
(3) lower quality RCT;
(4) clinical cohort study;
(5) case-controlled study;
(6) historical uncontrolled study; (7) epidemiological study.

Here are some examples of the way evidence ratings will appear in the text of an article:

“To improve morbidity and mortality, most patients in congestive heart failure should be treated with an angiotensin-converting enzyme inhibitor. [Evidence level A, RCT]”
“The USPSTF recommends that clinicians routinely screen asymptomatic pregnant women 25 years and younger for chlamydial infection. [Evidence level B, nonrandomized clinical trial]”

“The American Diabetes Association recommends screening for diabetes every three years in all patients at high risk of the disease, including all adults 45 years and older. [Evidence level C, expert opinion]”

See the AFP Web site (www.aafp.org/afp/afpauthors.xml) for additional information about levels of evidence, including a sample article with evidence labels.

[此贴子已经被作者于2004-4-17 7:22:04编辑过]

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[B](2).Virologic Characteristics[/B]

HBV belongs to the Hepadnaviridae family of viruses. Its genome consists of partially double-stranded circular DNA. The DNA is enclosed in a nucleocapsid, or core antigen, which is surrounded by a spherical envelope (surface antigen). The entire virion is known as the Dane particle. In addition to the core and surface proteins, the HBV genome encodes a DNA polymerase that also acts as a reverse transcriptase.

In the hepatocyte nucleus, the viral genome is converted into covalently closed circular DNA (cccDNA). This cccDNA is the template for messenger RNA (mRNA). The mRNA transcribes viral proteins as well as "pre-genomic" RNA that is reverse transcribed into the HBV DNA of new virions. Without the reverse transcriptase, new virions cannot be produced, and replication ceases. The core gene also produces a circulating peptide, the "e" antigen, that is associated with high levels of viral replication. These antigens, as well as corresponding antibodies produced by the immune system, serve as useful laboratory markers of past, current, or chronic infection (Tables 25 and 37).



TABLE 3
Interpretation of HBV Tests

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Test Result Interpretation

HBsAg        Negative Susceptible (not immune) to HBV infection
Anti-HBc      Negative
Anti-HBs      Negative
HBsAg         Negative Immune because of natural infection
Anti-HBc      Positive
Anti-HBs      Positive
HBsAg         Negative Immune because of hepatitis B vaccination
Anti-HBc      Negative
Anti-HBs       Positive
HBsAg          Positive Acute HBV infection
Anti-HBc       Positive
IgM anti-HBc  Positive
Anti-HBs        Negative
HBsAg           Positive Chronic HBV infection
Anti-HBc        Positive
IgM anti-HBc   Negative
Anti-HBs         Negative
HBsAg            Negative Four possible interpretations*
Anti-HBc         Positive
Anti-HBs         Negative

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HBV = hepatitis B virus; HBsAg = hepatitis B surface antigen; anti-HBs = hepatitis B surface antibody; anti-HBc = hepatitis B core antibody.

*--Possible interpretations: (1) patient may be recovering from acute infection; (2) patient may be distantly immune--testing does not detect very low level of anti-HBs; (3) patient may be susceptible, with a false-positive anti-HBc; or (4) there may be an undetectable level of HBsAg in the serum, and the patient is actually a carrier.

Information from reference 7

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[B](3).Acute Infection[/B]

Acute HBV infection is subclinical in 70 percent of adults and 90 percent of children younger than five years. The incubation period after infection lasts one to four months. Symptoms of acute HBV infection include nausea, anorexia, fatigue, low-grade fever, and right upper quadrant or epigastric pain. Clinical jaundice appears as constitutional symptoms are resolving. Extrahepatic manifestations of acute HBV infection include myalgias, joint pain, and urticaria. Symptoms of acute disease resolve by one to three months, although some persons have prolonged fatigue. Treatment for acute infection is generally supportive, although some patients require hospitalization.

Hepatic transaminase levels (alanine transaminase [ALT] and aspartate transaminase [AST]) reflect hepatocellular injury and range from several hundred to 20,000 IU per L. These values tend to rise one to two weeks before the onset of jaundice. Serum bilirubin values are usually less than 20 mg per dL (342 µmol per L). Mild anemia is common, as is relative lymphocytosis. More severe disease results in an elevation in the prothrombin time and a decrease in the serum albumin level. HBV is not cytopathic, and liver injury is caused by the host's immune response against infected hepatocytes.

Acute HBV infection leads to fulminant hepatic failure from massive hepatocellular necrosis in about 1 percent of infections. Rarely, patients with an "exuberant" immune response present with clinical symptoms but progress to hepatic decompensation, including encephalopathy and coagulopathy. Mortality is high, and liver transplantation often is necessary.8

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[B](4). Chronic Infection[/B] Chronic HBV infection is defined as hepatitis B surface antigen (HBsAg) positivity for at least six months (Table 4).9 Current thinking endorses the concept of four distinct stages of HBV infection, which may be used to describe acute and chronic disease.5,9 TABLE 4 Diagnostic Criteria for HBV Infection -------------------------------------------------------------------------------- Chronic disease HBsAg positive for longer than six months Serum HBV DNA > 100,000 copies per mL Persistent or intermittent elevation of alanine transaminase and aspartate transaminase levels Liver biopsy showing chronic hepatitis (necroinflammatory score >=4) Inactive HBsAg carrier state HBsAg positive for longer than six months HBeAg negative, anti-HBe positive Serum HBV DNA < 100,000 copies per mL Persistently normal alanine transaminase or aspartate transaminase levels Liver biopsy to confirm absence of significant hepatitis (necroinflammatory score <4) Resolved disease History of acute or chronic hepatitis B Presence of anti-HBc, with or without anti-HBs HBsAg negative Normal alanine transaminase level -------------------------------------------------------------------------------- HBV = hepatitis B virus; HBsAg = hepatitis B surface antigen; HBeAg = hepatitis B e antigen; anti-HBe = hepatitis B e antibody; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antibody. Information from reference 9. The first stage, the "immune tolerant" phase, is characterized by high levels of HBV DNA replication, hepatitis B e antigen (HBeAg) positivity, and normal serum transaminase levels. In the acutely infected child or adult, this stage represents the incubation period before immune response to HBV. In neonates, the immune-tolerant stage may last for years to decades. The second stage reflects the "immune response," which is the inflammatory process that results in the destruction of HBV-infected cells, elevating transaminase levels. Persistence of the immune response phase beyond six months is considered chronic HBV infection. This stage carries the highest risk of progression to cirrhosis and hepatocellular carcinoma. Chronic HBV infection has been associated with polyarteritis nodosa, a systemic vasculitis, and membranous or membranoproliferative glomerulonephritis.8 The third stage, the "inactive carrier" state, is thought to mark the end of active viral replication. HBeAg becomes negative, hepatitis B e antibody (anti-HBe) appears (seroconversion), and transaminase levels normalize. A low level of HBV DNA still may be present. The majority of adults with acute HBV infection enter this stage rapidly. In most chronically infected neonates and some children and adults, the conversion rate is 5 to 15 percent per year; a higher rate is associated with increasing age and elevated ALT levels.5 From 10 to 30 percent of carriers will have disease flares similar to acute HBV infection. These flares may be caused by other viral infections, or they may be secondary to viral reactivation and an unregulated immune response. The latter situation can occur during interferon therapy for HBV infection or after the withdrawal of corticosteroids or chemotherapy for other diseases.10 The fourth, or "immune," stage is characterized by the clearance of HBsAg. HBV DNA is usually undetectable, and reactivation or reinfection is uncommon. Progression from the third to the fourth stage occurs in approximately 3 percent of HBV-infected persons per year.8

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[B](5).Natural History and Complications[/B]

It has been estimated that 12 percent of patients with chronic HBV infection develop cirrhosis annually, and that a smaller percentage develop hepatocellular carcinoma.8 The absolute lifetime risk of death from cirrhosis or hepatocellular carcinoma is 15 to 25 percent.4

As with acute HBV infection, cirrhosis and hepatocellular carcinoma are not the result of a direct effect of the virus but develop because of an immune-mediated inflammatory response. This response results in the destruction and regeneration of liver cells, eventually leading to chromosomal mutations and unchecked cellular growth.

[B](6).Screening for Hepatocellular Carcinoma[/B]

Screening patients with chronic HBV infection for hepatocellular carcinoma using alpha-fetoprotein measurements or ultrasonography remains controversial. Hepatocellular carcinoma may not develop for 25 to 30 years after chronic infection develops, although it occasionally appears earlier. Men are at greater risk than women.

No randomized trials of patients with chronic HBV infection have been performed to determine if early detection and resection of hepatic tumors has an effect on mortality. Nonetheless, the American Association for the Study of Liver Disease (AASLD) recommends screening for hepatic tumors every six months when chronic HBV infection is present in men older than 45 years, in patients with biopsy-proven cirrhosis, and in patients with a family history of hepatocellular carcinoma.9 They also note that annual screening for hepatocellular carcinoma in low-risk patients should be considered.9

[B](7). Prevention[/B]

HBV vaccine has had an enormous impact. From the late 1980s to 2001, the incidence of acute hepatitis B in the United States decreased from more than 300,000 cases per year to 79,000 cases per year.11 Predictably, the largest decreases have occurred in children and health care workers--the two groups with the highest rates of vaccination.2

Vaccination is recommended for all children and adolescents, adults in certain ethnic groups, health care workers, and other high-risk groups (Table 1).4 [Evidence Level C, consensus/expert guidelines] A three-injection series induces protective antibody levels in 95 percent of children and 90 percent of adults. Those who fail to respond may be re-vaccinated; in this group, 30 to 50 percent will achieve protective levels.12

Because HBV vaccine is so effective, the Centers for Disease Control and Prevention recommends initiation of the series even if completion cannot be guaranteed. Booster vaccination is recommended only for immunocompromised persons who do not respond after the initial series. The only contraindication to vaccination is a history of anaphylaxis after a previous dose of the vaccine or a known previous anaphylactic reaction to yeast.4

In the United States, screening for HBV infection in the absence of symptoms or liver function abnormalities is indicated only in pregnant women and in the sexual partners or household contacts of known HBsAg-positive patients. Some investigators argue convincingly that the high prevalence of HBV infection observed in sexually transmitted disease (STD) clinics and prisons indicates a need for testing in those populations. Others advocate screening immigrants from areas where HBV-infection is endemic.2,12

[B](8). Hepatitis B and Pregnancy[/B]

Testing for HBsAg is recommended for all pregnant women at the first prenatal visit. A positive result mandates the administration of HBV immune globulin and HBV vaccine to the infant within 12 hours of birth. These interventions reduce the risk of perinatal transmission of HBV to less than 3 percent.13 In the absence of prophylaxis, the risk of perinatal transmission is 10 percent if the mother is positive for HBsAg alone but 90 percent if the mother is HBeAg positive.14


The absolute lifetime risk of death from cirrhosis or hepatocellular carcinoma is 15 to 25 percent in persons with chronic hepatitis B.  


Women who are HBsAg negative may be vaccinated safely during pregnancy. No current evidence supports the use of cesarean delivery to reduce vertical transmission of HBV. Recent data suggest that breastfeeding by mothers with chronic HBV infection does not appear to increase the risk of viral transmission to their infants.15

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[B](9). Treatments for Chronic HBV Infection[/B]

Family physicians should become familiar with the evaluation of patients with newly diagnosed HBV infection, including the recommended laboratory work-up (Table 5).9 The decision to treat chronic HBV generally is based on a combination of clinical, laboratory, and histologic factors (Table 6).9,16


TABLE 5
Evaluation of HBsAg-Positive Patients

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Laboratory studies to assess liver disease: aspartate transaminase, alanine transaminase, bilirubin, and albumin levels; complete blood count; prothrombin time; tests for anti-HBc, anti-HDV, HBeAg, anti-HBe, anti-HCV, HBV DNA level, anti-HAV (IgG or total); alpha-fetoprotein level
Human immunodeficiency virus serology
Hepatic ultrasonography (in the high-risk patient)
Liver biopsy to grade and stage disease (if the patient meets criteria for chronic hepatitis B)
Assessment for other sexually transmitted diseases
Assessment for family history of hepatocellular carcinoma
Counseling: safe sexual practices, abstinence from alcohol
Serologic testing for hepatitis A (vaccinate if patient is not immune)
Testing of sexual and household contacts
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HBsAg = hepatitis B surface antigen; anti-HBc = hepatitis B core antibody; anti-HDV = hepatitis D virus antibody; HBeAg = hepatitis B e antigen; anti-HBe = hepatitis B e antibody; anti-HCV = hepatitis C virus antibody; HBV = hepatitis B virus; anti-HAV = hepatitis A virus antibody.

Information from reference 9.




Treatments are not curative because they rarely produce permanent remission of the disease. Therefore, the goals of therapy are long-term suppression of viral replication and prevention of end-stage liver disease.16 Markers of successful therapy include HBeAg seroconversion, decreased or undetectable levels of HBV DNA, and lack of disease progression.


TABLE 6
Indications for Treating Patients with Chronic HBV Infection

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Presence of HBeAg plus a serum alanine transaminase level greater than twice the normal level
Presence of HBV DNA plus a serum alanine transaminase level greater than twice the normal level
Moderate to severe hepatitis on liver biopsy
Presence of HBV DNA plus cirrhosis*
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HBV = hepatitis B virus; HBeAg = hepatitis B e antigen.

*--If the patient has decompensated cirrhosis, treatment with interferon alfa-2b is contraindicated.

Information from references 9 and 16.




Approved drugs and agents in development for the treatment of chronic HBV infection fall into two categories: immune modulators, namely recombinant interferon alfa-2b (Intron A); and direct inhibitors of HBV replication, including lamivudine (Epivir) and adefovir dipivoxil (Hepsera). Dosing information is provided in Table 7.9,16,17 An AASLD treatment protocol recommends testing for HBsAg, HBeAg, and HBV DNA at baseline, at the end of treatment, and six months afterward.9


TABLE 7
FDA-Approved Treatments for Chronic HBV Infection

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Recombinant interferon alfa-2b (Intron A)
Recommended dosage: adults--5 million IU SC per day, or 10 million IU SC three times per week; children--3 million IU per m2 SC three times in the first week, 6 million IU per m2 SC three times per week after that (not recommended for children younger than one year)
Recommended duration of therapy: HBeAg-positive patients--16 weeks; HBeAg-negative patients--one year
Cost for 16 weeks of therapy: $5,600*
Cautions: Interferon alfa-2b may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations.
Lamivudine (Epivir)
Recommended dosage: adults--100 mg orally per day; children--3 mg per kg orally per day (maximum: 100 mg per day)
Recommended duration of therapy: HBeAg-positive patients--one year but may be longer in those with HBeAg seroconversion; HBeAg-negative patients with chronic HBV infection--longer than one year, although duration has not been established
Cost for one month of therapy: $156
Cautions: Lactic acidosis and severe, possibly fatal, hepatomegaly have been reported. If lamivudine is prescribed for patients with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely.
Adefovir dipivoxil (Hepsera)
Recommended dosage: adults--10 mg orally per day
Recommended duration of therapy: one year
Cost for one month of therapy: $528
Cautions: Discontinuation of adefovir dipivoxil therapy may result in severe acute exacerbation. Chronic use may result in nephrotoxicity in patients at high risk for underlying renal dysfunction. Lactic acidosis and severe hepatosplenomegaly with steatosis have been reported. Rapid emergence of HIV resistance may occur in patients with unrecognized or untreated HIV infection. This drug is not FDA-approved for use in children.
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FDA = U.S. Food and Drug Administration; HBV = hepatitis B virus; SC = subcutaneously; HBeAg = hepatitis B e antigen; HIV = human immunodeficiency virus.

*--Approximate cost provided by the author.

Information from references 9, 16, and 17.

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[B]INTERFERON ALFA-2b[/B]

Approved in the United States as therapy for chronic HBV infection in 1992, interferon alfa-2b is thought to work by affecting viral replication and, as an immunomodulator, by up-regulating cytokines involved in the response to infection. Predictors of successful therapy include low HBV DNA levels, elevated transaminase levels, lack of fibrosis on liver biopsy, female sex, and absence of HIV coinfection.16 Contraindications to interferon alfa-2b therapy include preexisting neutropenia, thrombocytopenia, severe uncontrolled depression, decompensated cirrhosis, and current alcohol or drug abuse. Because interferon alfa-2b has numerous side effects, tolerance is a problem in many patients.

Overall, 46 percent of patients treated with interferon alfa-2b have HBeAg seroconversion in the first year after treatment.8 Hepatitis B surface antibody (anti-HBs) develops in 8 percent of treated patients. Follow-up studies (five to 10 years) in North America and Europe have demonstrated 80 to 95 percent persistence of HBeAg negativity.6 Response rates and durability of response are significantly lower in neonates and Asians. To date, long-term follow-up has demonstrated two different patterns of benefit from interferon alfa-2b therapy in patients with chronic hepatitis B: (1) reduction in mortality from hepatocellular carcinoma in Asian patients, and (2) decreased mortality from decompensated cirrhosis in North American and European patients.6

[B]LAMIVUDINE[/B]

A nucleoside analog, lamivudine was first used to treat HIV infection and was approved for the treatment of HBV infection in 1999. This agent competitively inhibits reverse transcriptase, thereby terminating proviral DNA chain extension. A 1998 Chinese double-blind trial18 showing substantial histologic improvement after one year of treatment in adult patients was soon followed by a U.S. study19 demonstrating decreased HBV DNA levels, diminished transaminase levels, and loss of HBeAg in adult patients with chronic hepatitis B. A more recent study20 showed that lamivudine also is effective in children with chronic HBV infection.

The advantages of lamivudine over interferon alfa-2b include oral administration, high degree of tolerability, and safety in patients with decompensated cirrhosis. Lamivudine can be used as first-line therapy or following interferon failure. Disadvantages include uncertainty about the duration of therapy and the long-term durability of response. In addition, lamivudine-resistant strains of HBV develop at a rate of 15 to 20 percent per year of therapy. Despite the persistence of HBeAg, resistant virus appears to be less infective than wild-type virus, and continuing lamivudine therapy still results in improvement of laboratory and histologic markers of HBV infection.21

[B]adefovir dipivoxil[/B]

As early as 2000, adefovir dipivoxil was noted to be effective in suppressing HBV strains that had developed resistance to lamivudine.22 In September 2002, this nucleotide analog was approved for the treatment of HBV infection.23

Two recent clinical trials of adefovir dipivoxil in HBeAg-negative and HBeAg-positive patients demonstrated significant improvements in histologic, virologic, and biochemical markers after 48 weeks of treatment; no adefovir dipivoxil&shy;resistant HBV strains were noted, and the drug's safety profile was similar to that for placebo.24,25 [References 24 and 25--Evidence level A, randomized controlled trials] Dosing adjustment is recommended for patients with renal insufficiency.

Where adefovir dipivoxil fits into the treatment of HBV infection--as first-line monotherapy, combination therapy, or salvage therapy for lamivudine-resistant infection--remains to be determined. Because of its tolerability and oral route of administration, it is likely that this agent will supplant interferon alfa-2b as first-line therapy in most patients.

[B]Future Prospects[/B]

The decline in the rate of new HBV infections in the United States over the past two decades is encouraging, and new oral agents for treatment are in clinical trials. However, problems must be resolved before hepatitis B can be eradicated. One obstacle is the unsubstantiated fear of neurologic side effects of HBV vaccines. A recent large case-control study26 failed to demonstrate a connection between the recombinant vaccine and an increased risk of multiple sclerosis, which had been suggested by earlier case reports. Another obstacle is the current failure to offer hepatitis vaccination in STD clinics and correctional facilities, as well as to other high-risk groups.12

Jeffrey T. Kirchner, D.O. receives a supporting grant from the HIV/AIDS Bureau of the Department of Health and Human Services in Washington, D.C.

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