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Hepatitis B Surface Antigen Loss: Not
All That We Hoped It Would Be
It is not often that a letter to the editor is the subject
of an editorial, but such is the case in this issue
of HEPATOLOGY.(1) The correspondence relates to
an article published 6 years ago that reported on the
risk of hepatocellular carcinoma (HCC) in a group of
patients chronically infected with hepatitis B who
cleared hepatitis B surface antigen (HBsAg) from their
bloodstream.(2) It was a relatively unique cohort of
1,271 Alaskan Native persons who were followed prospectively
for nearly 20 years on average, and 158 of
them lost surface antigen (rate of 0.75 per year). With
an average 9-year follow-up after HBsAg clearance, 6
of these individuals subsequently developed HCC, 2
with cirrhosis and 4 without, corresponding to an
HCC rate of 37 cases per 100,000 person-years (95%
confidence interval 13.5-80.0).(2) However, recently
the authors identified an arithmetic error in this calculation
and in a published erratum indicated that the
actual rate of HCC among those who achieved HBsAg
clearance was 442 cases per 100,000 person-years (95%
confidence interval 162-958).(3) For comparison, the
corresponding rate in patients who did not clear their
surface antigen was 196 cases per 100,000 person-years
(95% confidence interval 141.1-264.5). Notably this
newly corrected rate of HCC in persons clearing
HBsAg is no longer significantly different from that in
persons who remained HBsAg-positive. Nonetheless,
the conclusion stated in the abstract remains correct,
that HCC can still occur after loss of HBsAg, even in
the absence of cirrhosis. The article goes on to advocate
for continued screening for HCC, even among
those who have lost surface antigen. In fact, in light of
the recalculated incidence rate, this conclusion might
even be made more forcefully, given that the rate of
HCC does not appear to be reduced in those who have
cleared surface antigen. The editors felt that it was
important to draw attention to this erratum for two
reasons: first, because a major finding in this article
was incorrectly (albeit inadvertently) represented and,
second, that the correction leaves the principal message
of the article unchanged and worthy of reemphasis,
namely, that HCC remains a concern post-HBsAg
clearance.
What have we learned about clearance of surface
antigen and risk of HCC in the 6 years that have
passed since this article was published? The short
answer is, disappointingly little. In the Risk Evaluation
of Viral Load Elevation and Associated Liver Disease/
Cancer-Hepatitis B Virus (REVEAL-HBV) study
from Taiwan of nearly 3,000 mostly hepatitis B e
antigen-negative persons with chronic HBV without
cirrhosis followed for an average of 28 years, HBsAg
seroclearance was seen in 1% per year and, among the
1,151 patients who were HBV DNA undetectable at
baseline, the incidence rate of HCC was 93.7 per
100,000 person-years in those who achieved HBsAg
clearance compared to 106.2 per 100,000 person-years
in those who did not (P 5 0.37). In multivariate analysis,
clearance of HBV DNA, but not HBsAg, was
associated with a reduced risk of HCC.(4) This essentially
corroborates the revised results from the Alaskan
Native cohort reported by Simonetti and coworkers.(2)
However, it must be acknowledged that both studies
likely suffer from insufficient power to detect differences
in HCC rates between groups. As Simonetti and
coworkers articulate in their reply to the letter to the
editor,(5) loss of HBsAg and development of HCC are
relatively rare events, so it is even less common to find
patients in both categories. This in turn makes it more
challenging to ascertain significant differences between
groups. In fact, others studying this made a similar
point.(4)
The achievement of low or undetectable HBV
DNA levels, either spontaneously or with treatment,
has been most consistently associated with a reduced
rate of HCC. In a large retrospective study of
entecavir-treated patients compared to propensity
score-matched untreated controls, treatment was associated
with a 63% reduction in HCC rates over a
median 5-year period (3.7% and 13.7%, P 5 0.03).(6)
Because undetectable or low HBV DNA is a prerequisite
for HBsAg clearance, the independent effects of
these two markers (HBV DNA suppression and
HBsAg loss) on HCC risk can be difficult to tease out.
Thus, the importance of HBsAg clearance in reducing
HCC risk remains to be determined by studies with
longer follow-up and merged large cohorts.
It is well recognized that the risk of HCC is much
higher in patients with cirrhosis than in patients without
cirrhosis chronically infected with HBV,(7) and in
this group of patients achievement of an undetectable,
rather than a low (<2,000 IU/mL), HBV DNA level
appears to be the most desirable treatment endpoint.(8)
The presence of advanced fibrosis appears to attenuate
the benefits of HBsAg clearance, arguing for the
appropriate application of antiviral therapy to prevent
cirrhosis development. Another concept that has
emerged is that cirrhosis is often missed in cohort
studies of chronic HBV, and this may confound the
assessment of benefits of HBsAg seroclearance. Studies
using noninvasive methods such as transient elastography(
9) and the FIB-4 index(10) demonstrate an
increased risk of HCC in patients with cirrhosis that is
not yet clinically apparent.
In any case, while the jury is still out in terms of the
benefits of HBsAg seroclearance on HCC risk, the
message regarding need for surveillance remains
unchanged. The available evidence indicates that
patients chronically infected with HBV remain at risk
for development of HCC, whether or not they lose
HBsAg. As we look forward to an era of therapeutics
that is increasingly focused on HBsAg loss as the most
clinically desirable endpoint,(11) a larger proportion of
patients will hopefully achieve HBsAg loss and the
question of how this influences the subsequent risk of
HCC and need for surveillance will be finally
answerable.
Michael H. Nathanson, M.D., Ph.D.1
Norah Terrault, M.P.H., M.D.2
1Yale University School of Medicine
New Haven, CT
2University of California
San Francisco, CA
REFERENCES
1) Tan CK. Incidence of hepatocellular carcinoma after seroclearance
is not reduced. HEPATOLOGY 2016; doi: 10.1002/hep.28505.
2) Simonetti J, Bulkow L, McMahon BJ, Homan C, Snowball M,
Negus S, et al. Clearance of hepatitis B surface antigen and risk
of hepatocellular carcinoma in a cohort chronically infected with
hepatitis B virus. HEPATOLOGY 2010;51:1531-1537.
3) Gounder P, Bulkow L, McMahon B. Correction. HEPATOLOGY
2015;62:1330.
4) Liu J, Yang HI, Lee MH, Lu SN, Jen CL, Batrla-Utermann R,
et al. Spontaneous seroclearance of hepatitis B seromarkers and
subsequent risk of hepatocellular carcinoma. Gut 2014;63:1648-
1657.
5) Simonetti JB, Bulkow L, McMahon BJ, Homan C, Snowball
M, Negus S, et al. Reply. HEPATOLOGY 2016; doi: 10.1002/
hep.28501.
6) Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y,
Sezaki H, et al. Long-term entecavir treatment reduces hepatocellular
carcinoma incidence in patients with hepatitis B virus
infection. HEPATOLOGY 2013;58:98-107.
7) Yang JD, Kim WR, Coelho R, Mettler TA, Benson JT,
Sanderson SO, et al. Cirrhosis is present in most patients with
hepatitis B and hepatocellular carcinoma. Clin Gastroenterol
Hepatol 2011;9:64-70.
8) Sinn DH, Lee J, Goo J, Kim K, Gwak GY, Paik YH, et al.
Hepatocellular carcinoma risk in chronic hepatitis B virusinfected
compensated cirrhosis patients with low viral load.
HEPATOLOGY 2015;62:694-701.
9) Jung KS, Kim SU, Song K, Park JY, Kim do Y, Ahn SH, et al.
Validation of hepatitis B virus-related hepatocellular carcinoma
prediction models in the era of antiviral therapy. HEPATOLOGY
2015;62:1757-1766.
10) Suh B, Park S, Shin DW, Yun JM, Yang HK, Yu SJ, et al.
High liver fibrosis index FIB-4 is highly predictive of hepatocellular
carcinoma in chronic hepatitis B carriers. HEPATOLOGY
2015;61:1261-1268.
11) Liang TJ, Block TM, McMahon BJ, Ghany MG, Urban S, Guo
JT, et al. Present and future therapies of hepatitis B: from discovery
to cure. HEPATOLOGY 2015;62:1893-1908.
Abbreviations: HBsAg, hepatitis B surface antigen; HBV, hepatitis
B virus; HCC, hepatocellular carcinoma.
Received April 29, 2016; accepted May 3, 2016.
Copyright VC 2016 by the American Association for the Study of
Liver Diseases.
View this article online at wileyonlinelibrary.com.
DOI 10.1002/hep.28640
Potential conflict of interest: Dr. Terrault received grants from
Bristol-Myers Squibb and Gilead.
ADDRESS CORRESPONDENCE AND
REPRINT REQUESTS TO:
Michael H. Nathanson, M.D., Ph.D.
Digestive Diseases Section, Yale University School of Medicine
300 Cedar Street, Room TAC S241D
New Haven, CT 06520-8019
Tel: 11-203-785-7312
E-mail: [email protected]
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发表于 2016-7-22 13:57