Hepatitis B -- What's New and What's on the Horizon?

[Guest guest]

http://www.medscape.com/viewarticle/546599

American College of Gastroenterology 2006 Annual Scientific Meeting and

Postgraduate Course

Hepatitis B -- What's New and What's on the Horizon?

Disclosures

S. Reau, MD

Las Vegas, Nevada; Tuesday, October 24, 2006 -- The diagnosis and treatment

of hepatitis B is rapidly evolving. Currently, there are 5 US Food and Drug

Administration-approved therapies available for hepatitis B, including

standard interferon alfa-2b, lamivudine, adefovir, peginterferon alfa-2a,

and entecavir, with several compounds in various stages of development. Over

the last decade there has been a shift in the treatment paradigm for chronic

hepatitis B infection from that of limited treatment to long-term viral

suppression. This change is a result of emerging data suggesting that viral

suppression decreases downstream risk of complications, including

hepatocellular carcinoma (HCC), coupled with the availability of

well-tolerated oral agents. As the benefits of effective treatment become

clear, a fundamental reappraisal of this disease is being performed. Several

of these issues were addressed during the annual scientific meeting of the

American College of Gastroenterology (ACG).

Natural History

Disease Prevalence

Although hepatitis B surface antigen (HBsAg) is a serologic hallmark of

hepatitis B infection, hepatitis B virus (HBV) may be present in the absence

of HBsAg. This concept of occult hepatitis B is gaining recognition and it

is most prevalent in certain high-risk groups, being previously described in

hemodialysis patients, injection-drug users, patients coinfected with HIV

and hepatitis C virus (HCV), and in those with cryptogenic cirrhosis.[1-3]

The clinical implications of this discovery are controversial. Kikuchi and

colleagues[4] found a high prevalence of occult HBV infection -- 16% -- in a

retrospective review of HCV-infected patients. This finding was associated

with a significant decrease in the effectiveness of interferon therapy.

Agarwal and colleagues[5] found a high prevalence of hepatitis B (1.07%

HBsAg-positive and 4.1% with occult HBV infection) among healthcare workers

in India. In this population, 15.06% were never vaccinated against HBV,

demonstrating the importance of vaccination compliance in this at-risk

patient group. Because occult HBV infection may have clinical

implications,[6,7] it is reasonable to assess for HBV DNA in patients at

high risk for the disease, such as hemodialysis patients, patients

coinfected with HCV or HIV, and injection-drug users -- especially those

from endemic areas. The importance of vaccination in groups at risk for

exposure cannot be overemphasized.

Practice Patterns

Several studies focused on practice patterns among physicians treating

patients with hepatitis B. An evaluation of 2 Minneapolis gastroenterology

practices found that between 1999 and 2003, only 25% of all patients with

chronic hepatitis B underwent treatment even though 50% had viremia

documented greater than 104 copies/mL.[8] This finding may be a reflection

of practice guidelines recommendations during that time, which emphasized

elevated alanine aminotransferase levels (ALT) levels, as well as of the

available antiviral agents. However, by 2001,[9] recommendations were

evolving to include broader subsets of patients. Another study presented

during this year's ACG meeting examined practice patterns through a survey

distributed to physicians attending hepatitis B educational programs.[10]

Most physicians surveyed had practice patterns that were quite independent

of current treatment guidelines. Over 25% offered testing for noninvasive

fibrosis markers and HBV genotyping, which are not recommended in current

guidelines. However, only 15% of physicians would discontinue therapy 6-12

months after hepatitis B e antigen (HBeAg) loss or seroconversion. Ten

percent of physicians chose to treat this population indefinitely,

independent of the presence of significant fibrosis; few monitored genotypic

resistance, and those that did chose to do so only after combined clinical

and viral breakthrough. These findings strongly suggest that even physicians

attending educational forums may not use our clinical tools optimally and

may not be following evidence-based endpoints.

The Management of Special Populations

Acute HBV Infection

Most acute hepatitis B is subclinical, and less than 1% of patients

experience acute liver failure.[11] In addition, less than 5% of infected

adults progress from acute to chronic disease.[12] However, occult HBV

infection (HBsAg-negative, but HBV-DNA PCR [polymerase chain

reaction]-positive) with histologic changes can be demonstrated years after

recovery.[13] The efficacy of antiviral therapy in the setting of acute

hepatitis B is largely unknown. Despite this, many patients with severe

acute hepatitis B are empirically placed on treatment in hopes of

ameliorating symptoms and decreasing the risk for a fulminant course.

Previous uncontrolled studies have suggested that treatment with lamivudine*

may improve the clinical course of patients with acute severe hepatitis

B.[14,15] In a study presented during this year's ACG meeting, Kumar and

colleagues[16] contradicted these findings. In their placebo-controlled

evaluation of 71 patients with severe acute hepatitis B, 31 received

lamivudine. Although antiviral therapy was associated with a greater fall in

HBV-DNA level, there was minimal clinical benefit and a trend towards a

lower chance for hepatitis B surface antibody seroconversion. These study

findings suggest that further evaluation is needed before nucleos(t)ide

antiviral therapy is considered standard of care for severe acute hepatitis

B.

Inactive r

HBeAg-negative patients with normal serum ALT and low-level viremia are

often labeled " inactive carriers " and are thought to have a more favorable

prognosis. It is recognized that viral replication continues in this

population.[17] Kumar and colleagues[18] demonstrated that one third of

inactive carriers continued to have significant viremia (HBV DNA > 5 log

copies/mL), with inflammation or fibrosis on liver biopsy. This finding

nicely reminds us that this population continues to be at risk for

significant liver disease and should be monitored closely.

Vertical Transmission

The risk for maternal-fetal transmission of hepatitis B is as high as

90%.[19] Previous studies have suggested that HBeAg status and level of

viremia contribute to this risk.[20,21] This relationship was confirmed by

following HBsAg-positive women in a New Delhi antenatal clinic.[22] The

authors found a strong linear correlation between maternal HBV-DNA level and

transplacental HBV-DNA transmission, defined as cord blood positive for

HBsAg and HBV DNA. However, HBeAg negativity had little influence. These

study results emphasize the importance of standard hepatitis B

immunoglobulin administration regardless of HBeAg status and of vaccination

for infants born to HBsAg-positive mothers. They also suggest a role for

antiviral therapy in mothers with high levels of viremia.

The Role of Genotype

Unlike in HCV infection, where viral genotype has a well-established role in

treatment, the utility of HBV genotype is controversial. There is growing

evidence that genotype may influence treatment response and clinical course,

including the risk of developing HCC.[23] However, even with this knowledge,

genotype may not truly influence treatment decisions in hepatitis B, except

with respect to consideration of the use of interferon in the genotype A

population, which has increased seroconversion compared with other

genotypes.

Concluding Remarks

Our understanding of hepatitis B continues to evolve, resulting not only in

a shift in the treatment paradigm but also in our basic understanding of the

viral-host relationship. Today's sessions offered insight into the growing

clinical challenges surrounding this complicated disease. This serves as an

excellent preface to future research where these issues will certainly be

revisited.

*The US Food and Drug Administration has not approved this medication for

this use.

References<cut>

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