Long-term treatment with tenofovir (Viread) lowered
the risk of developing hepatocellular carcinoma among people with chronic
hepatitis B, with a notable divergence from expected rates after about five years, according to a report presented at
the 48th International Liver Congress (EASL 2013) this week
in Amsterdam.
Over
years or decades, chronic hepatitis B virus (HBV) infection can cause advanced
liver disease including cirrhosis and hepatocellular carcinoma (HCC), a type of
primary liver cancer.
W Ray
Kim from the Mayo Clinic in Rochester, Minnesota, evaluated the long-term
effect of antiviral therapy using tenofovir on HCC incidence over time, using a
predictive model know as REACH-B.
Glossary
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.
Prior
research has shown that an older nucleoside analogue, lamivudine (Epivir or 3TC), reduces liver cancer
risk by approximately 50% among chronic hepatitis B patients who achieve good
viral suppression. HBV easily develops resistance to lamivudine, however,
compromising its long-term effectiveness. Tenofovir has a higher barrier to
resistance and can keep HBV suppressed for years.
Kim explained
that they selected REACH-B, which estimates the risk of developing HCC over ten
years, because it is more "granular" than other commonly used models and
provides the most detailed interim predictions. The model takes into account
patient age, sex, ALT level, hepatitis B 'e' antigen (HBeAg) status and HBV DNA
level. It has been validated for both non-cirrhotic and cirrhotic patients.
This
analysis included more than 600 participants in two
large, multinational, placebo-controlled phase III tenofovir trials: Gilead
Sciences' Study 102 (for HBeAg-negative patients) and Study 103 (for
HBeAg-positive patients). In both trials participants were randomly assigned to
treatment with tenofovir or placebo for one year, after which they could elect
to continue on open-label tenofovir for eight years. Development of HCC was not
a study endpoint but it was captured as an adverse event.
In this retrospective analysis,
investigators estimated REACH-B scores using baseline data collected for the
trials. They looked at new cases of HCC developing at any time since study
randomisation and calculated a standardised incidence ratio of observed versus
expected number of cases for patients with and without cirrhosis.
About
three-quarters of the 634 participants were men and the mean age was
approximately 40 years. About 60% were white and 30% were Asian. Just under 25%
had cirrhosis, and this group was a bit older; 40% of cirrhotic patients and
60% without cirrhosis were HBeAg-positive. The mean HBV DNA level at study
entry was approximately 7.7 log and about half had HBV genotype D.
A total of 14
new cases of HCC emerged during seven years of follow-up, nine in the
HBeAg-negative study and five in the HBeAg-positive study. Four cases were
reported during the first two years, four cases during the third year, two
cases each during years 4 and 5, and one case each during years 6 and 7.
As expected, patients
with cirrhosis were more likely to develop liver cancer, with an incidence rate
of 4.5 at seven years – about twice the rate for non-cirrhotics. Six of the 14
people who developed HCC had cirrhosis, despite cirrhotics accounting for just
one-quarter of the study population.
Looking at
non-cirrhotic patients, the observed number of cases began to diverge from the
rising curve of predicted cases after about 2 years, with the difference first
reaching statistical significance between years 5 and 6. By year 7 the standardised incidence ratio was 0.45, indicating a
55% decrease from the predicted number of cases.
Among people with cirrhosis, development
of HCC more closely followed the rising curve of expected cases. A combined
analysis showed the same pattern as the non-cirrhotic group, but with a standardised
incidence ratio of 0.5, or a 50% reduction.
The incidence of HCC in patients on tenofovir in these
two studies was "lower than predicted by the REACH-B model", the
investigators concluded. "Potent antiviral therapy with [tenofovir] may reduce risk
of HCC."
"In non-cirrhotic patients, the
effect of [tenofovir] becomes noticeable at approximately two years of therapy
and became significant (55% reduction) at six years," they added. The
tenofovir effect "was less pronounced in cirrhotic patients", but the
number of people with cirrhosis in this analysis was small and the study
therefore "may not rule out longer-term benefits".