Chronic
Hepatitis B Patients with Low HBV Viral Load Still Have an Elevated Risk of Liver
Cancer: R.E.V.E.A.L.-HBV Study By
Liz Highleyman Over
time, chronic hepatitis B virus (HBV) infection
can lead to advanced liver disease, including cirrhosis
and hepatocellular
carcinoma (HCC), a form of liver cancer. At
the recent 58th Annual Meeting of the American Association
for the Study of Liver Diseases (AASLD) in Boston,
researchers presented 3 posters describing results from the R.E.V.E.A.L.-HBV study,
which looked at the association between HBV DNA level (viral load) and risk of
HCC. Study 1 The
first analysis, looking at the effect of changes in HBV DNA level over time, included
1289 HBsAg seropositive cohort
members without hepatitis C coinfection and without
liver cirrhosis at study entry; at baseline, HBV DNA was at least 104
copies/mL. A group of 2020 patients with HBV DNA below 104 copies/mL at study
entry was used as a reference group. Low,
medium, high, and very high serum HBV DNA levels were defined as <300, 300
to <105, 105 to 107, and ≥ 107
copies/mL, respectively. Low, medium, and high serum
ALT levels were defined as <15, 15 to 44, and > 45 U/L, respectively. In
addition, among patients with HBV DNA >104 copies/mL,
4 HBV DNA “trajectory classes” were defined to describe changes in viral load
over time: ·
Class I:
medium-to-low (n=148); ·
Class II:
medium-to-medium (n=380); ·
Class III:
high-to-high (n=542); ·
Class IV:
persistently very high (n=219). Similarly,
4 ALT trajectory classes were identified:
·
Class A:
low-to-medium (n=1,056); ·
Class B:
medium-to-medium (n=1,507); ·
Class C:
high-to-medium (n=187); ·
Class D,
medium-to-high (n=174). Results ·
There were
89 new cases of HCC among 3309 participants during 40,024 person-years of follow-up.
·
Patient
sex, hepatitis B “e” antigen (HBeAg) status, and ALT
level at study entry were significantly associated with HBV DNA trajectory. ·
Compared
with the low HBV DNA reference group, the multivariate-adjusted hazard ratios
[HR] of developing HCC by HBV DNA trajectory class were: o
Class I:
0.7 o
Class II:
2.6; o
Class III:
8.5; o
Class IV:
10.0. ·
Compared
with Class A, the adjusted HRs of developing HCC by
ALT trajectory class were: o
Class B:
1.4; o
Class C:
3.2; o
Class D:
2.3. The
researchers concluded that, “Serum HBV DNA level over time is a strong predictor
of HCC independent of gender, age, cigarette smoking, alcohol consumption, and
ALT trajectory.” Study 2 Major
international treatment guidelines classify chronic hepatitis B patients with
low-level viremia (<104 copies/mL) as having “inactive” disease with little or no risk of
disease progression. In the second analysis, the researchers aimed to determine
the risk of HCC in individuals with low HBV viral load. This
analysis included all HBsAg negative subjects without
hepatitis C and the subset of R.E.V.E.A.L.-HBV cohort members without HCV infection
or liver cirrhosis at baseline. The researchers used the National Cancer Registry
and Death Certification System in Taiwan to identify HCC cases. The
risk of HCC progression by baseline and follow-up HBV viral load was determined
in comparison with HBsAg negative control subjects. A total of 18,541 HBsAg negative and 3,584 HBsAg positive
subjects were included in the analysis, for a total of 267,809 person-years of
observation over 12.1 years. Results ·
During the
follow-up period, there were a total of 184 HCC cases. ·
Compared
with HBsAg seronegative individuals,
the adjusted HRs of developing HCC by HBV DNA level
in HBsAg seropositive persons
after adjustment for sex, age, alcohol consumption, cigarette smoking, ALT at
study entry and follow-up, and HBV DNA change during follow-up were: o
Undetectable:
3.0; o
300 to 9,999
copies/mL: 3.3; o
10,000 to
99,999 copies/mL; 14.4; o
100,000
to 999,999 copies/mL: 32.0; o
>1 million
copies/mL: 30.5. ·
Persons
maintaining an HBV DNA level between 300 and 9,999 copies/mL during follow-up had an increased risk of HCC compared with those who had undetectable HBV DNA throughout
follow-up (adjusted HR 2.7). “Results
show that chronic hepatitis B patients with an HBV viral load of less than 104 copies/mL
are at a significantly higher risk of developing HCC than HBsAg
seronegative persons,” the researchers concluded. “The
risk of HCC associated with even the lowest detectable level of HBV DNA was 3-fold
greater and highly significant. During follow-up, an HBV DNA level maintained
between 300-9,999 copies/mL was associated with a significantly
higher risk of HCC when compared to
those achieving a level <300 copies/mL.” These data indicate that chronic low level HBV viremia
carries a “measurable and significant additional risk” of HCC compared to individuals with persistently undetectable
viral load, they added, suggesting that patients with HBV DNA < 104
copies/mL may not truly have “inactive” disease at all.
Study 3
Finally,
the investigators looked at the impact of chronically elevated HBV DNA on the
risk of HCC. This
analysis included a subset of the R.E.V.E.A.L.-HBV study cohort with baseline HBV DNA > 104 copies/mL, no evidence of liver cirrhosis at entry, no HCV coinfection, and at least 2 frozen serum samples available
for HBV DNA testing. Again, HCC was ascertained through linkage with the
Taiwan National Cancer Registry and Death Certification System. Results ·
An interim
analysis identified 71 new HCC cases in 1289 subjects over 15,508 person-years
of follow-up. ·
In the final
model adjusting for sex, age, alcohol consumption, cigarette smoking, serum ALT,
and HBeAg status, the risk of developing HCC was strongly
associated with increasing HBV DNA level in a dose-dependent manner (P <0.001
for trend). ·
The adjusted
HRs for the different HBV DNA levels compared with individuals who spontaneously achieved
undetectable HBV DNA (<300 copies/mL) were: o
300 to 9,999
copies/mL: 6.1; o
10,000 to
99,999 copies/mL: 6.2; o
100,000
to 999,999 copies/mL: 7.7; o > 106
copies/mL: 13.1. ·
Other important
variables included increasing serum ALT, HBeAg positive
serostatus, age, and alcohol consumption. Here,
the researchers concluded that, “The relationship between HBV DNA level and risk
of HCC remained very strong in these analyses using follow-up HBV DNA levels.
The risk increased as HBV DNA level increased.” They added that these results “demonstrate that serum
HBV DNA level is likely the most important modifiable risk predictor of developing
HCC.” 11/16/07 References C Chen, H Yang, U Iloeje, and others.
Changes in Serum HBV DNA Level Using a Trajectory Model Predict the Risk of HCC
in Chronic Hepatitis B Patients: The R.E.V.E.A.L.-HBV Study. 58th
Annual Meeting of the American Association for the Study of Liver Diseases (AASLD
2007). Boston.
November 2-6, 2007. Abstract 906. U Iloeje, H Yang, J Su, and others.
HBV Viral Load Less Than 104 copies/mL is Associated with Significant Risk of Hepatocellular Carcinoma in Chronic Hepatitis B Patients:
An Update from the R.E.V.E.A.L.-HBV Study. AASLD 2007.
Abstract 907. C Chen, H Yang, J Su, and others. Impact of chronically elevated HBV
DNA viral load on risk of HCC occurrence: An update from The R.E.V.E.A.L.-HBV
Study. AASLD 2007. Abstract 920. | 
