People with HIV and hepatitis C virus (HCV) co-infection who are
successfully treated for hepatitis C using interferon-free direct-acting
antiviral (DAA) therapy do not appear to have an increased likelihood of
developing hepatocellular carcinoma (HCC), according to a study presented at
the Conference on Retroviruses and Opportunistic Infections (CROI 2017) this
month in Seattle.
More HCC cases are being diagnosed among people with co-infection cured of hepatitis C with DAAs compared to the old interferon-based
therapy, but this could be due to the fact that more people with advanced liver
disease are now being treated, suggested presenter Nicolás Merchante of Hospital Universitario de Valme in Seville, Spain.
Over years or decades chronic HCV
infection can lead to advanced liver disease including cirrhosis and HCC, a
type of liver cancer. Progression seems to be faster, on average, in
HIV-positive people who have co-infection with HCV.
- 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.
Successful treatment of hepatitis C – indicated by
sustained virological response (SVR), or continued undetectable HCV after
completing treatment – can slow or halt liver disease progression and reduce
liver-related mortality. But liver damage is not fully reversed, and people who
developed cirrhosis before treatment remain at risk for liver cancer and need
Recent research has produced conflicting evidence
about the link between DAAs and HCC. Studies presented at last year's International Liver Congress and published in the October 2016 Journal of Hepatology showed that people with HCV mono-infection with cirrhosis who achieved SVR
had a higher than expected risk of developing liver cancer. This was not due to
new HCC cases, but rather attributable to a high rate of HCC recurrence – about
28% in both studies – among people who had previously been successfully treated
for liver cancer.
Further exploration of the association between DAAs
and liver cancer in larger HCV mono-infected populations showed that people
treated with DAAs do not appear to have a higher risk of developing HCC – and
probably have a lower risk – according to studies from Italy and Canada presented at last year's AASLD Liver Meeting.
Merchante's team set out to
look at the link between DAA therapy and development of HCC among people with HIV/HCV
co-infection in GEHEP-002, a cohort of HIV-positive people with
liver cancer at 32 centres in Spain.
This analysis included 319 cohort members with HIV/HCV
co-infection identified between 1996 and 2016. The researchers broke this up
into four time periods based on the evolving standard of care for hepatitis C:
- Period 1: before 2002, non-pegylated interferon
- Period 2: 2002-2011, pegylated interferon plus
- Period 3: 2012-October 2014, early DAAs in
combination with interferon
- Period 4: October 2014-2016: DAAs in
Most of the co-infection
cohort members were men (90%) and the median age was 49 years. About a quarter
reported heavy alcohol use, another risk factor for liver cirrhosis and cancer.
About half had HCV genotype 1, 1% had genotype 2, 36% had genotype 3 and 14%
had genotype 4; about 14% had triple infection with hepatitis B virus. Under half
(45%) had been treated for hepatitis C and 12% had achieved SVR.
A total of 40 HCC
cases occurred in people who were treated and cured of hepatitis C. The proportion of HCC occurring among people with SVR was 17% (only
one case) before 2002, 10% (16 of 161 cases) during period 2 and 9% (10 of 111
cases) during period 3. But the percentage rose significantly, to 32% (13 of 41
cases), during the interferon-free DAA period.
HCC cases prior to 2014 occurred a median of 24 months
after SVR, compared with 16 months in 2014-2016. Whereas about 60% of HCC
cases before 2014 occurred in people with HCV genotype 3, this fell to 31% in 2014-2016.
Interferon-free DAA therapy is more effective and
better tolerated than earlier treatments, and more people with advanced liver
disease are now being treated and achieving SVR. Of the total 1305 people with HIV/HCV
co-infection with cirrhosis cured before January 2017, more than
two-thirds were cured with interferon-free DAAs.
Looking at the likelihood of HCC development only
among people with cirrhosis, the rate rose from 6.66 to 11.72 per 100
person-years between period 1 and period 2, then fell steeply to 1.68 per 100
person-years during period 3, and declined even further to 0.88 per 100
person-years in the interferon-free DAA era.
Among eight people who had been successfully
treated for liver cancer before receiving interferon-based therapy, one (13%)
developed recurrent HCC. Among the 19 people who had curative liver cancer
treatment before receiving interferon-free DAAs, four (21%) experienced HCC
recurrence – approaching the percentages seen in the previously noted HCV
People diagnosed later generally had less advanced
liver cancer. Both before and after 2014 about half of diagnosed patients had
multiple HCC lesions, but those diagnosed before 2014 were more than twice as
likely to have metastases, or spread beyond the liver (19% vs 8%).
Looking at Barcelona Clinic Liver Cancer (BCLC) staging, based on size and number of tumours
and overall liver function, 37% of the pre-2014 patients were classified as
stage 0-A or least severe, compared to 54% in the period 2014-2016. In contrast, 48%
of the pre-2014 and 31% of the 2014-2016 patients were classified as stage C,
and 11% of the earlier group but none of the later group were at the most
severe stage D.
The proportion of HCC cases diagnosed among
people with HIV/HCV co-infection with previous SVR "significantly increased parallel
to the arrival of DAA interferon-free strategies," the researchers
"This finding may be, at least partially,
explained by the fact that DAAs have allowed treating patients at advanced
stages of liver disease in which the protective effect of SVR on the risk of
HCC could be less marked," they suggested.
As a limitation, they noted that the follow-up
period was shorter for the interferon-free DAA period, so this study might
underestimate the frequency of liver cancer developing in that group.
While the potential role of DAAs in HCC development warrants
more research, they came to the reassuring conclusion that this study "has
not found evidence for an increased incidence of HCC with DAA use."
group of investigators presented data on HCC occurrence in the Italian SCOLTA
project, a prospective observational cohort of people with HCV mono-infection and people with HIV/HCV
co-infection who started DAA treatment. This analysis included 1154
participants. Around two-thirds were men, the median age was 56 years and 34% had co-infection.
median follow-up period of about 17 months, 21 people (1.44 per 100
person-years) developed HCC for the first time and six (16.61 per 100
person-years) experienced HCC recurrence. Eight new HCC cases and two
recurrences were diagnosed during DAA treatment. People with co-infection accounted
for four of the new HCC cases but no recurrences. Older age and more advanced
fibrosis stage were associated with greater HCC risk, but not having HIV.
findings indicate that, in cirrhotic patients, the incidence rate of HCC during
the first 16 months following initiation of DAA therapy is not different from
that expected in untreated patients," the researchers concluded.
Merchante's group also presented findings from a related study looking
at real-life treatment rates for HIV-positive people with liver cancer. They
found that a high proportion of HIV-positive
people diagnosed with HCC did not receive therapy, or received less effective
treatment, relative to recommendations based on BCLC stage.
situation becomes more frequent as HCC diagnosis is made in a more advanced
stage," they stated. However, they added that access to therapy has
improved in recent years, probably as a consequence of the increase in the
proportion of HCC cases that are diagnosed at earlier stages.