Treatment with nucleoside/nucleotide
antiviral therapy was associated with longer overall survival and reduced risk
of developing liver cirrhosis and hepatocellular carcinoma (HCC) for hepatitis
B patients with high viral load but minimal liver inflammation – a group generally
not prioritised for treatment – according to a report presented at the 2016
International Liver Congress last month in Barcelona.
Previous research has shown that high hepatitis B
virus (HBV) DNA levels are a risk factor for cirrhosis and liver cancer in
people with chronic hepatitis B. Current therapy using nucleoside/nucleotide analogues
such as entecavir (Baraclude) or
tenofovir (Viread) can suppress HBV
replication long-term but seldom leads to a cure.
Antiviral treatment is recommended for people with active disease,
indicated by high HBV DNA levels and elevated liver enzymes showing liver
inflammation – a sign that the immune system is attacking the virus in liver
cells, which can lead to scarring and development of cancer as the liver
attempts to repair itself. Therapy is generally not recommended for people with
low HBV viral load and low liver enzymes.
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.
But the benefits of treatment for people
with high HBV DNA and little or no inflammation are not well understood. This
is known as the immune-tolerant phase of hepatitis B, in which the immune
system seems to not recognise and fight the virus. Some people can
remain in this stage for many years with high viral replication but little or
no apparent liver damage.
Young Chang of Seoul National University Hospital and
colleagues performed a retrospective study to assess the benefits of therapy
for chronic hepatitis B patients with minimal liver inflammation, indicated by
normal or mildly elevated alanine aminotransferase (ALT).
The initial abstract for her talk referred to the immune-tolerant phase of
hepatitis B, but this was changed to "no or mild inflammatory phase,"
as the patients were not all truly immune-tolerant.
The analysis included 602 treatment-naive hepatitis B 'e'
antigen (HBeAg) positive Korean patients followed from January 2006 to December
2012. About 60% were men and the mean age was approximately 43 years. They had HBV DNA
> 20,000 IU/ml, ALT levels within two times the upper limit of normal (< 80
IU/l) and no evidence of liver cirrhosis at baseline. Just under half had
normal ALT and were considered truly immune-tolerant. People with hepatitis C,
hepatitis delta or HIV co-infection were excluded.
Participants were divided into two groups: 69 received
immediate nucleoside/nucleotide therapy, while 533 people in the control group
remained untreated until they reached the immune-active phase of disease as per current guidelines. Baseline liver function was worse in the treated group,
but the degree of fibrosis was similar. The primary endpoint was overall
survival, and secondary endpoints were development of cirrhosis and HCC.
Overall, in an unadjusted analysis, there were no
significant differences in overall survival or in the rates of liver cirrhosis
or HCC between the two groups.
After adjusting for demographics and liver function
markers at baseline, however, the treated group had significantly greater
survival, with an 86% reduction in the risk of death (adjusted hazard ratio
[HR] 0.14; p = 0.05).
In the adjusted analysis the treated group also had a
significant 67% lower likelihood of developing cirrhosis (adjusted HR 0.33;
p = 0.006) and an 80% reduction in the risk of HCC (adjusted HR 0.20; p = 0.02).
When baseline characteristics of the two groups were
balanced using inverse probability weighting, antiviral treatment was again
associated with significantly prolonged overall survival relative to the
control group (HR 0.14; p = 0.01). In this analysis the risks of developing
cirrhosis and HCC were also significantly lower in the treated group.
The proportion of people in the control group who started treatment
increased over time; on average the immediate therapy group received treatment
for 30.1 months more than the control group. An additional 30.1 months of
treatment reduced the risk of cirrhosis by 28.9%, HCC by 12.0% and death by
A cost-benefit analysis found that 100 people would need to be treated
for about one month to prevent a single patient from developing cirrhosis,
about 2.5 months to prevent a case of HCC and about 4.4 months to avert a
single death. This would cost US$148,200, $370,500 and $652,080, respectively,
in the US, but considerably less in other countries – for example $10,320,
$25,800 and $45,408, respectively, in Korea – leading Dr Chang to suggest that
the cost-benefit balance should be assessed by each country.
"Antiviral therapy for chronic hepatitis B
patients with high viral load prolongs overall survival and reduces the risk of
liver cirrhosis and HCC even if ALT levels would not exceed two times [the
upper limit of normal]," the investigators concluded.
"Our study demonstrates that [nucleoside/nucleotide] analogue
treatment offers promising results in reducing the risk of liver cancer and
damage among those patients who have limited treatment options," co-author
Jeong-Hoon Lee stated in an EASL press release. "Furthermore, in contrast
to the control group who received no treatment during [the] immune-tolerant
phase, overall survival was significantly prolonged for those who received
[nucleoside/nucleotide] analogue treatment."
results are significant in helping to advance medical alternatives for patients
with immune-tolerant hepatitis B, a sub-group of patients who, thus far,
doctors have been hesitant to treat," added EASL vice secretary Tom