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Editorial Board: Emmet B. Keeffe, MD (Chair);
Anna Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron Tong, MD; Naoky Tsai,
MD; Bruce Tung, MD
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HBV
Watch™
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Timely Information for Practicing Physicians
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FEBRUARY 2006
Serum HBV DNA level as a predictor of hepatocellular carcinoma (HCC). Several large cohort studies from China, Taiwan, and Senegal reported that high serum hepatitis
B virus (HBV) DNA levels at the time of enrollment were associated with an increased
risk of cirrhosis and HCC. The investigators proposed that serum HBV DNA level,
and not liver disease activity, might be used as an indication for antiviral
therapy. In a recent article, Chen and colleagues reported that among 3653 hepatitis
B surface antigen (HBsAg) carriers, 164 had HCC after a mean follow-up of 11.4
years. There was a dose-response relationship between serum HBV DNA level at
entry and subsequent HCC development. The authors concluded that high serum HBV
DNA levels (³4 log10 copies/mL) were a strong predictor of HCC
independent of hepatitis B e antigen (HBeAg), serum aminotransferase levels,
and the presence of cirrhosis. The authors suggested that effective control of
HBV replication with antiviral therapy may lower the risk of HCC. These data
are important, but several points need to be considered before revising current
recommendations for HBV treatment: (1) Are high serum HBV DNA levels a strong
predictor of HCC? In this paper, the adjusted hazard ratio (95% confidence
interval [CI]) for HCC among participants with baseline HBV DNA levels of 4 to 5
log10 copies/mL was 2.3 (1.1 to 4.9), which is marginally
significant, and among participants with baseline and follow-up HBV DNA levels
of 4 to 5 log10 copies/mL it was 0.4 (0.1 to 3.2), which is not
significant. (2) Can the results be generalized to other HBV carriers when the
population studied included mostly participants who had been chronically
infected with HBV for more than 40 years, lacked cirrhosis (98%), had normal
alanine aminotransferase (ALT) levels (94%), and were HBeAg negative (85%)? The
predictive value of a high serum HBV DNA level for HCC may be very different
for a 20-year-old carrier with perinatally acquired HBV infection or a
45-year-old carrier with adult-acquired HBV infection. (3) Can assessment at a
single time point predict the prognosis of HBV carriers? If treatment is
recommended based on a high serum HBV DNA level on a single occasion, can it be
withheld based on a low or undetectable serum HBV DNA level on one random test?
(4) Is there evidence that antiviral therapy can prevent HCC? The best evidence
that it may was derived from a prospective, randomized, placebo-controlled
trial of lamivudine (Liaw YF, et al. N
Eng J Med 2004;351:1521–1531), in which treatment was associated with a
decrease in HCC (P = 0.047), but the
difference was not significant (P = 0.052)
when prevalent cases of HCC (those diagnosed during the first year of the
trial) were excluded. In this study >60% of the patients had cirrhosis, and
all were HBeAg positive or had high serum HBV DNA levels. The efficacy of
antiviral therapy in preventing HCC among HBV carriers with less advanced liver
disease and lower HBV DNA levels has not been established. (Chen CJ, et al. JAMA
2006;295:65–73.)
Immunoglobulin M (IgM) antibody to
hepatitis B core antigen (anti-HBc) predicts poor response to lamivudine. IgM anti-HBc in serum is detected
in 14% to 16% of patients with chronic HBV infection and usually is associated
with active liver necroinflammation or an exacerbation of hepatitis. In
addition, serum IgM anti-HBc positivity has been shown to be a predictor of
beneficial response to interferon-alpha therapy. Chen and associates compared
the outcomes of an 18-month course of lamivudine therapy in IgM anti-HBc(+)
patients with those in IgM anti-HBc(–) patients enrolled in a nationwide study
in Taiwan for chronic hepatitis B patients
with acute exacerbation (AE). The study population comprised 15 consecutive
hepatitis B patients with AE who were serum IgM anti-HBc(+) and 60 consecutive
HBV patients with AE who were serum IgM anti-HBC(–). The median ages of the two
groups were 30.5 years (range, 22 to 50 years) and 33.5 years (range, 18 to 65
years), respectively. Ten (67%) of the 15 seropositive patients and 38 (63%) of
the 60 seronegative patients had serum HBV DNA levels >1000 pg/mL. At the
end of therapy, only 2 (13.3%) IgM anti-HBc(+) patients but 26 (43.3%) IgM
anti-HBc(–) patients achieved a sustained response (P = 0.039). These data suggest that IgM anti-HBc positivity may be
a predictor of poor response to lamivudine monotherapy in patients with chronic
hepatitis B with AE. These findings should be considered from the perspective
that the analysis was retrospective, the sample size was small, the serum HBV
DNA levels in most study patients were high, and the study patients were
derived from a population in which perinatal HBV infection is frequent. A study
determining the predictability of measuring serial assessments of IgM anti-HBc
rather than a single measurement of IgM anti-HBc should be undertaken. (Chen
J-J, et al. Aliment Pharmacol Ther
2006;23:85–90.)
Adefovir dipivoxil therapy for HBV/human
immunodeficiency virus–1 (HIV-1) coinfection. Recent studies have shown that
patients with HBV/HIV-1 coinfection have a greater risk of progression of liver
disease than do patients with HBV monoinfection. As observed in HBV
monoinfected patients, the development of lamivudine resistance is associated
with loss of viral suppression and progressive liver disease in HBV/HIV-1
coinfected patients. These findings led Benhamou and colleagues to assess
adefovir dipivoxil therapy in a cohort of 35 HBV/HIV-1 coinfected patients who
had developed lamivudine resistance. In this prospective, open-label study,
adefovir dipivoxil 10 mg/day for up to 144 weeks was added to the pre-existing
lamivudine and antiretroviral regimen. Twenty-nine patients (83%) completed 144
weeks of study treatment. Median serum HBV DNA levels declined from a baseline
of 9.76 log10 copies/mL to 4.68, 5.24, and 5.90 log10
copies/mL at weeks 48, 96, and 144, respectively (P <0.0001). Serum ALT levels normalized in 71% of patients, and two
patients became anti-HBe(+) by week 144. No adefovir dipivoxil–associated
resistance mutations in HBV DNA polymerase or HIV-1 reverse transcriptase were
detected. No serious adverse events related to adefovir dipivoxil were
reported. HIV-1 RNA and CD4+ counts remained stable. This pilot
study showed that treatment with adefovir dipivoxil for 144 weeks was well tolerated
and efficacious in patients with lamivudine-resistant HBV/HIV-1 coinfection,
although a more potent agent that can lower HBV DNA to below 4 log10
copies/mL would be desirable. (Benhamou Y, et al. J Hepatol 2006;44:62–67.)
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