Hepatitis C patients with cirrhosis who were
treated with direct-acting antivirals had about twice the expected likelihood
of developing hepatocellular carcinoma (HCC), with the excess risk seen in
people with a previous history of HCC, according to research presented at the
International Liver Congress in Barcelona. These
findings underline the importance of ongoing liver cancer monitoring even
after successful hepatitis C treatment.
The advent of interferon-free direct-acting antiviral
(DAA) therapy has brought about a revolution in hepatitis C treatment, with
more than 90% of patients achieving a cure. As with interferon-based therapy,
sustained virological response (SVR) to DAA treatment – or permanent clearance
of hepatitis C virus (HCV) – is expected to slow liver disease progression and
reduce the chances of adverse outcomes such as liver cancer or decompensation,
but some risk remains even after the virus is eradicated. Most HCC occurs in
people who have developed cirrhosis or scarring of the liver, which can result
from chronic viral hepatitis, heavy alcohol use or other causes.
Federica Buonfiglioli and Stefano Brillanti of the
University of Bologna and colleagues analysed a cohort of hepatitis C patients
with cirrhosis treated with DAAs at a referral centre in Italy between March
and November 2015.
- alpha-fetoprotein (AFP)
A protein found in the blood, used to detect early signs of liver cancer.
A non-invasive test, used instead of a biopsy, to measure the stiffness
or elasticity of the liver using an ultrasound probe.
- hepatocellular carcinoma (HCC)
Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.
- sustained virological response (SVR)
Undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 24 weeks (six months) after ending treatment and is considered to be a cure. SVR4 and SVR12 refer to RNA remaining undetectable for 4 and 12 weeks respectively.
The study included 344 HIV-negative participants with
hepatitis C-related cirrhosis. A majority (60%) were men and the median age was
63 years. The most common HCV genotype was 1 (69%) and 55% had experienced
previous treatment failure using pegylated interferon and ribavirin.
Participants had Child-Pugh class A or B cirrhosis.
Child-Pugh scores are used to assess liver disease prognosis; class A indicates
well-preserved liver function, class B indicates significant functional
impairment and class C indicates decompensation.
Participants were treated with interferon-free DAA
(Sovaldi) + simeprevir (Olysio): 34%
+ ribavirin: 17%
+ daclatasvir (Daklinza): 16%
At the start of the study
participants did not have active liver cancer. However, 17% had a history of
prior HCC treated with chemoembolisation or radiation and had magnetic resonance
imaging (MRI) or computed tomography (CT) scans showing no evidence of active tumours. Occurrence
of HCC during the 24-week post-treatment follow-up period was assessed by
ultrasonography and confirmed with MRI or CT scans.
At 12 weeks post-treatment, 89% of patients achieved
SVR12, which is considered a cure.
Overall, active HCC was detected in 26 patients (7.6%)
between the end of treatment and 24 weeks of follow-up, 22 of whom had achieved
SVR. Most (81%) had only a single detectable HCC nodule, but five people had
Liver cancer developed in 17 (29%) of the 59 patients
with a history of previous HCC. However, among participants with no prior history
of HCC, just nine patients or 3.2% developed new HCC – not much higher than
the expected rate.
Among the patients with HCC the median age was 58
years – younger than the study population as a whole – and more than twice as
many were men. People with Child-Pugh class B were significantly more likely to
develop HCC (although the numerical majority of those who developed HCC were
class A). HCC was also associated with greater liver stiffness according to FibroScan and lower platelet counts.
However, there was no difference in HCC occurrence or recurrence according to
HCV genotype or specific DAA regimen.
At the time HCC was detected only two patients (8%)
had elevated levels of alpha-fetoprotein (AFP), a biomarker often measured to
monitor for HCC.
"In this large retrospective cohort study on
cirrhotic patients treated with DAAs, we observed a high rate of HCC recurrence
and a standard rate of HCC [first time] occurrence in a relatively short
follow-up observation," the researchers concluded. "Development of
HCC was rarely associated with increase in AFP levels."
"In cirrhotic patients treated with DAAs, development of
HCC represents a significant clinical problem, despite a high rate of
SVR," the researchers concluded. "This seems particularly true [of]
those patients with a history of previous HCC, in whom a surprisingly high rate
of HCC recurrence was observed, over a relatively short period of time."
believe our findings justify close monitoring for all cirrhotic patients on
such treatments," Dr Buonfiglioli said in an EASL press release.
EASL secretary general Prof Laurent Castera noted that
a higher than expected rate of HCC recurrence was also seen in a recent Spanish study published online in the current edition of Journal of Hepatology.
That study, by Dr Jordi Bruix of Hospital Clinic
Barcelona and colleagues, looked at 103 hepatitis C patients with a prior
history of HCC but who had achieved complete response to liver cancer
treatment. Among 58 patients who achieved SVR with DAA therapy – those treated
with interferon were excluded – 16 (28%) had a recurrence of HCC over a median
follow-up period of about 23 weeks, about the same rate as in the Italian
"Our data show an unexpected high rate and
pattern of tumour recurrence coinciding with HCV clearance and, though based in
a very small cohort of patients, should be taken as a note of caution and prime
a large scale assessment that exceeds the individual investigators
capacity," the study authors wrote. They suggested disruption of immune
surveillance may contribute to the increased risk of liver cancer recurrence in