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Viral Infections
Treatment of Chronic Hepatitis B—When to Start,
When to Stop, and When to Alter Therapy
a report by
Emmet B Keeffe, MD, MACP
Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine
It is estimated that up to 400 million people worldwide are chronically infected The primary goal of therapy for CHB is long-term suppression of serum
with the hepatitis B virus (HBV), and treatment options to control active viral HBV DNA, which is likely to reduce progression to cirrhosis and HCC. In
replication and disease progression continue to expand.
1–6
Although the patients with advanced hepatic fibrosis, long-term lamivudine therapy has
prevalence of HBV infection in the US is lower than in many other countries, been shown to decrease the likelihood of decompensation and the
an estimated 1.25 million people are infected. However, this estimate of the incidence of new HCC.
9
The therapies approved by the US Food and Drug
number of individuals with chronic hepatitis B (CHB) in the US is likely to be an Administration (FDA) for CHB include interferon alfa-2b (1991), lamivudine
underestimate. The size of the Asian-American population has increased (1998), adefovir (2002), entecavir (2005), peginterferon alfa-2a (2005),
significantly over the last decade and is now approximately 10.5 million people, and telbivudine (2006). The currently preferred treatment options are
and recent surveys of Asian-, Korean-, and Vietnamese-Americans found that adefovir, entecavir, peginterferon alfa-2a, and, potentially, telbivudine.
10–23% were positive for hepatitis B surface antigen (HBsAg). For those Standard interferon alfa-2b has been replaced by peginterferon alfa-2a in
infected with HBV early in life, the lifetime risk of developing cirrhosis and/or routine practice, and lamivudine is not a preferred first-line drug due to
hepatocellular carcinoma (HCC) ranges from 15 to 25%, and the risk of these high rates of resistance.
2
complications has been directly related to the level of serum HBV DNA.
7,8
A treatment algorithm for CHB previously developed and published by a
Treatment panel of US hepatologists was revised based on new developments in the
The natural history of HBV infection can be divided into four phases: understanding of CHB, the availability of more sensitive molecular
immune tolerance; immune clearance (hepatitis ‘e’ antigen (HBeAg)- diagnostic testing, the addition of new treatments, and better
positive CHB); inactive HBsAg carrier; and reactivation (HBeAg-negative understanding of the advantages and disadvantages of approved
CHB).
1
CHB is diagnosed in patients with high serum HBV DNA levels, therapies.
2
This updated algorithm was based on available evidence using
elevated alanine aminotransferase (ALT) levels, and necroinflammation on a systematic review of the scientific literature in addition to consensus
liver biopsy (an optimal test best used selectively when diagnostic expert opinion. This revised algorithm supplements evidence-based
categorization and candidacy for therapy are uncertain). The revised recommendations available from published society guidelines from the US,
normal ALT levels should be used when considering criteria for treatment: Europe, and Asia.
3–6
upper limits of normal for men = 30IU/ml, and for women = 19IU/ml.
2
Treatment is recommended only for patients in the immune clearance and When to Start Therapy
reactivation phases with CHB as defined above: elevated HBV DNA and ALT The primary aim of antiviral therapy is durable suppression of serum HBV
levels, or significant disease on biopsy. DNA to the lowest level possible.
2–6
The threshold level of HBV DNA for
determination of candidacy for therapy is ≥20,000IU/ml for patients with
HBeAg-positive CHB (see Table 1).
2
A lower serum HBV DNA threshold of
Emmet B Keeffe, MD, MACP, is Professor of Medicine, Chief of
Hepatology, and Co-Director of the Liver Transplant Program at
≥2,000IU/ml is recommended for patients with HBeAg-negative CHB (see
Stanford University Medical Center, California. He serves as Table 2) and those with compensated cirrhosis (see Table 3), while a yet
Chair of the Subspecialty Board on Gastroenterology for the
lower level of ≥200IU/ml is recommended for those with decompensated
American Board of Internal Medicine (ABIM). Dr Keeffe is a
Master of the American College of Physicians (MACP) and a
cirrhosis (see Table 3).
2
Interferon alfa-2b, lamivudine, adefovir dipivoxil,
Fellow of the American Gastroenterological Association (FAGA), entecavir, peginterferon alfa-2a, and telbivudine are all FDA-approved as
the American Society for Gastrointestinal Endoscopy (ASGE), the
initial therapy for CHB, and have a number of advantages and
American College of Gastroenterology (ACG), and the Royal
College of Physicians of Ireland. He is a former President of the American Gastroenterological
disadvantages, which are outlined in Table 4. Matters for consideration in
Association (AGA) and the American Society for Gastrointestinal Endoscopy. He is Editor of the selection of therapy include efficacy, safety, incidence of resistance,
Current Hepatitis B Reports, Associate Editor of Reviews in Gastroenterological Disorders, the
method of administration, and cost. Genotyping may be useful to help
Section Editor of Liver Transplantation for Current Opinion in Organ Transplantation, and Executive
Editor of GastroHep.com. He also serves on the Editorial Boards of Liver Transplantation, and
decide whether treatment with peginterferon alfa-2a is warranted, because
Alimentary Pharmacology & Therapeutics. Dr Keeffe’s research interests include antiviral therapy of it has been shown to be most effective in patients with genotype A. The
chronic hepatitis B and C, use of hepatitis vaccines, and liver transplant selection criteria and
preferred options for the treatment of CHB include adefovir, entecavir,
outcomes. He has published more than 500 papers, book chapters, and miscellaneous
publications, and lectures widely at national and international scientific meetings, post-graduate
peginterferon alfa-2a, and, potentially, telbivudine (providing serum HBV
courses, and miscellaneous educational programs. DNA is undetectable after 24 weeks of therapy, which predicts the absence
or very low rate of resistance at year one and year two of therapy).
28 © T OUCH BRIEFINGS 2007
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