Natural History and Treatment of Chronic Hepatitis B:
A Critical Evaluation
of Standard Treatment Criteria and Endpoints
By
Liz Highleyman  |
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photograph shows a magnified image of the hepatitis B virus. Color has been added
to the photograph to make the virus easier to see. |
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The
natural history of chronic hepatitis B virus (HBV)
differs between patients infected as
adults and those infected early in life, usually through mother-to-child transmission,
which is the predominant route of transmission in countries where the disease
is endemic (which includes much of southeast Asia). In
the July 3, 2007 issue of the Annals of Internal Medicine, Ching-Lung Lai
and Man-Fung Yuen from the University of Hong Kong provided an overview of the
natural history and treatment of chronic hepatitis B in these 2 populations, with
an emphasis on current treatment criteria and end-points. In an accompanying editorial,
Bulent Degertekin and Anna S.F. Lok asked whether the same set of criteria should
apply to all patients regardless of age at the time of infection.
Lai
and Yuen noted that according to current guidelines from the American Association
for the Study of Liver Diseases, the European Association for the Study of the
Liver, and the Asian Pacific Association for the Study of the Liver, the "definite
indications" for the treatment of chronic hepatitis B are serum HBV DNA levels
greater than 105 copies/mL (or 20,000 IU/mL) and alanine aminotransferase (ALT)
levels more than 2 times the upper limit of normal (x ULN). In patients with liver
cirrhosis, HBV DNA greater than 105 copies/mL is the sole criterion.
Treatment
end-points include hepatitis B "e" antigen (HBeAg) seroconversion for
patients who start out HBeAg-positive, reduction of HBV DNA to less than 105 copies/mL,
and ALT normalization. The guidelines indicate that treatment can be discontinued
after anti-HBe antibody seroconversion, ALT normalization, and achievement of
HBV DNA less than 105 copies/mL.
But the guidelines, the authors assert,
"assume that chronic HBV infection is likely to progress to cirrhosis and
hepatocellular carcinoma only in patients with these markers of active infection
and that treatment can be stopped once a patient achieves a healthy hepatitis
B carrier state."
In their article, Lai and Yuen reviewed the growing
body of evidence showing that patients infected early in life are prone to develop
advanced liver disease -- including cirrhosis and hepatocellular carcinoma (HCC)
-- even in the absence of these traditional indicators of disease progression.
In this population, complications of advanced liver disease often occur
despite HBeAg seroconversion, HBV DNA levels less than 104 copies/mL, and/or ALT
levels between 0.5 and 2 x ULN. This has become more apparent as more individuals
infected as infants or children reach the older ages at which symptoms of advanced
liver disease typically manifest themselves. "These
guidelines may apply to patients who acquire the hepatitis B infection during
adolescence or adulthood, but are less suitable for most hepatitis B carriers,
who are infected in early life," Lai and Yuen concluded. "HBeAg seroconversion
may not be an adequate end-point for these patients." Instead,
they suggested, "the ideal treatment end-points are permanent suppression
of HBV DNA to levels undetectable by polymerase chain reaction and reduction of
ALT levels to less than 0.5 times the upper limit of normal."
With
regard to the potential drawbacks of prolonged therapy, they argued that there
is little evidence of long-term side effects (including development of cancer)
associated with the approved anti-HBV drugs lamivudine
(Epivir-HBV), adefovir (Hepsera), and telbivudine
(Tyzeka). Even though HBV rapidly develops resistance to 3TC, studies indicate
that treatment still reduces liver disease progression. With regard to cost, they
wrote, "the cost of prolonged treatment should be balanced against the substantially
higher medical cost incurred when the disease progresses from chronic hepatitis
to compensated cirrhosis, decompensated cirrhosis, and hepatocellular carcinoma,
or when it progresses so far that liver transplantation is needed."
But
in their editorial, hepatology experts Degertekin and Lok took issue with Lai
and Yuen's recommendation. In particular, they suggested that permanent suppression
of HBV DNA to an undetectable level in all patients is not a realistic goal of
current therapies.
"Until treatments that are safe and affordable
for long-term use can achieve permanent suppression of HBV replication in all
or most patients, we recommend treatment only for patients who have high serum
HBV DNA levels and active or advanced liver disease and deferral of treatment
for patients with normal ALT levels who have a low likelihood of progressive liver
disease (those who are young, are HBeAg- positive, and have persistently normal
ALT levels) until it is indicated," they wrote. "Likewise, discontinuation
of treatment in HBeAg-positive patients who have confirmed HBeAg seroconversion
and have completed an additional 6 months of consolidation treatment is appropriate
as long as they continue to be monitored and treatment is reinitiated if HBV is
reactivated."
They added that, "We believe that these recommendations
apply to all patients with hepatitis B regardless of their age at infection." 
7/20/07 References CL
Lai and MF Yuen. The natural history and treatment of chronic hepatitis B: a critical
evaluation of standard treatment criteria and end points. Annals of Internal
Medicine 147(1): 58-61. July 3, 2007. B
Degertekin and ASF Lok. When to Start and Stop Hepatitis B Treatment: Can One
Set of Criteria Apply to All Patients Regardless of Age at Infection? Annals
of Internal Medicine 147(1): 62-64. July 3, 2007.
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