HBV viral load is an independent predictor of progression to
hepatocellular carcinoma in chronic HBV patients
The risk of hepatocellular carcinoma (HCC) is closely associated
with hepatitis B virus (HBV) viral load, according to a Taiwanese study .
This association was shown to be independent of other risk factors, and to
have a dose-response relationship. The study also showed that HBV DNA levels
were persistently elevated in patients at highest risk of liver cancer.
HBV infection is endemic in Taiwan. It is usually acquired perinatally
or in early childhood. An earlier small case-control study had found a significant
association between HBV viral load and risk of liver cancer in individuals
who were HBeAg negative (a marker of HBV active replication in chronic HBV
infected patients). To confirm this finding, the authors conducted a long-term,
follow-up, population-based, prospective study of 3653 individuals who were
HBsAg seropositive (and HCV antibodies seronegative) at baseline. The study’s
aim was to assess the biological gradient of HCC risk by HBV viral load
at entry and the effect of persistent high HBV viral load on this risk.
The study was conducted within a community-based cancer-screening programme,
between 1991 and 2004. Out of 89 293 subjects invited to participate during
1991-92, 23 820 (27%) accepted, 4155 (17%) of these were HBsAg positive,
and 3653 (88%) of the HBsAg positive participants were anti-HCV negative
and provided sufficient serum at baseline. All were free of HCC at baseline.
Participants were aged between 30 and 65 years (67% older than 39 years).
The majority were male (62%), never smoked (66%), never drank alcohol (87%),
had a serum alanine aminotransferase (ALT) level of <45U/L (94%), were
seronegative for HbeAg (85%) and free of cirrhosis (98%).
There were 164 incident cases of hepatocellular carcinoma and 346 deaths
during follow up (mean follow up of 11.4 years and a total of 41 779 person-years).
The incidence of HCC increased with baseline HBV viral load in a dose-response
relationship ranging from 108 /100 000 person years for undetectable viral
load (<300 copies/mL) to an incidence of 1152/100 000 person years for
an HBV viral load >1 million copies/mL. The cumulative incidence rates
of HCC were 1.3% and 14.9%, respectively. The biological gradient remained
significant after adjusting for other risk factors (sex, age, smoking, alcohol
consumption, HBeAg serology, ALT level, and liver cirrhosis at baseline).
The dose-response association was strongest for participants who were HBeAg
seronegative and with normal ALT and no liver cirrhosis at baseline. Participants
with persistent high HBV viral load during follow-up had the highest HCC
HBV antiviral treatment was not available in Taiwan until 2003. To the
knowledge of the authors, this study is one of the largest and the longest
prospective studies of HBV natural history to look at HCC risk in relation
to HBV viral load.
HBeAg is known to be a strong predictor of progression to HCC. In this
study, the strength of the association between HBV viral load at baseline
and the risk of HCC remained high after adjusting for HBeAg positivity.
The majority (72%) of HBeAg seronegative participants had a detectable HBV
The prominence of HBV viral load as an independent predictor of HCC risk
and the demonstration of a significant and consistent biological gradient
suggest the importance of both close clinical monitoring and antiviral treatment
for individuals with high HBV viral load (>10 000 copies/ml ). The authors
also propose that their findings of increased risk associated with persistently
high HBV viral load suggest effective antivirals could be expected to lower
the risk of HCC, and that lowering HBV viral load may be seen as a good
surrogate marker for slower clinical progression.
HBV genotypes B and C are predominant in Taiwan, and in this study. Genotype
C has been shown to be associated with higher HBV levels and a greater risk
of HCC than genotype B. The impact of genotype on the risk of HCC is the
subject of ongoing study by the authors.