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Some people remain at risk for liver cancer despite hepatitis C treatment

Liz Highleyman
22 December 2021

Some people with liver cirrhosis remain at risk for developing hepatocellular carcinoma (HCC) even after hepatitis C treatment, according to study results presented at The Liver Meeting. Not achieving a cure was the biggest risk factor. A related study found that among people who were cured, HCC risk factors differed for people with and without cirrhosis.

Over years or decades, chronic hepatitis C virus (HCV) infection can lead to the development of cirrhosis and HCC, the most common type of liver cancer. People who are successfully treated for hepatitis C are less likely to develop HCC, but some risk remains, especially for those who have already progressed to advanced fibrosis or cirrhosis. Liver cancer is often diagnosed late, when it is more difficult to treat, and being able to predict who is at risk could enable targeted surveillance and prompt treatment.

HCC in people with cirrhosis

In the first study, Dr Loreta Kondili of Istituto Superiore Di Sanità in Rome and colleagues evaluated the medium- to long-term impact of direct-acting antiviral (DAA) treatment on development of HCC in hepatitis C patients with cirrhosis.

The analysis included 2214 participants in the Italian multicentre PITER cohort who were treated with DAAs after they had developed cirrhosis and were followed for at least one year. Most (93%) achieved a sustained virological response (SVR), which is considered a cure. The median age was 64 years. Patients who had undergone liver transplantation or previously had HCC were excluded.

Over a median 30 months of follow-up after the end of treatment, 149 people (6.7%) overall developed HCC for the first time, Kondili reported. This included 119 people (5.8%) who achieved SVR and 30 (20%) who did not. This meant that those who were not cured had a more than sevenfold higher risk of new HCC. People without SVR also developed liver cancer sooner after completing treatment. At two years post-treatment, 98% of people who achieved SVR were still alive without HCC, compared with just 65% of those who were not cured.

Among people who did achieve SVR, other independent risk factors for HCC included HCV genotype 3 (adjusted hazard ratio 3.51), low platelet count (adjusted hazard ratio 2.43), low albumin level (adjusted hazard ratio 2.36) and older age (adjusted hazard ratio 1.06). Male sex, hepatitis B virus (HBV) co-infection and diabetes were also linked to increased HCC risk, but these associations did not reach statistical significance. No association was seen with liver stiffness (a measure of fibrosis severity), body mass index, alcohol use, HIV co-infection, liver fat, use of sofosbuvir or ribavirin, or previous treatment with interferon-based therapy.

At the time of diagnosis, 80% of people with liver cancer were classified as BCLC stage B or C, meaning intermediate to advanced HCC. During follow-up, 26% of people with HCC died and 7.6% underwent liver transplantation. Having more advanced liver fibrosis before DAA treatment, as determined by liver stiffness measurements, was an independent predictor of death.

"Failure to achieve SVR after DAA treatment is significantly associated with the probability of development of de novo HCC in the first two years," the researchers concluded, adding that ongoing monitoring and prompt cancer treatment are necessary.

HCC after SVR

A second study, by Dr Jennifer Kramer of the Center for Innovations in Quality, Effectiveness and Safety and colleagues looked at liver cancer risk factors among people who were cured of hepatitis C, assessed at one year and two years after treatment.

This analysis included 98,612 US veterans with hepatitis C who achieved SVR with DAA treatment between January 2014 and December 2018. Almost all were men, half were White, 39% were Black and the mean age was 61 years. Nearly a third had cirrhosis at the time of treatment. Patients with and without cirrhosis were demographically similar, but the former group had higher bilirubin and albumin levels and higher rates of diabetes, hypertension and obesity.

A total of 2298 people developed HCC. Annual incidence rates for people with cirrhosis were 1.6% during the first year post-treatment and 1.9% during the second year, compared with 0.21% and 0.27%, respectively, for those without cirrhosis.

The researchers found that liver cancer risk factors differed based on cirrhosis status. Among people with cirrhosis, HCC predictors at 12 months included male sex, White race, HCV genotype 3, longer cirrhosis duration, higher bilirubin levels and the presence of oesophageal varices. Changes in albumin levels and worsening fibrosis (as indicated by FIB-4 score) also predicted HCC risk. However, race, HCV genotype and bilirubin were no longer significant predictors at 24 months while changes in haemoglobin level became a significant factor. Non-smokers had a lower HCC risk.

Among people without cirrhosis, metabolic factors such as diabetes and hypertension, as well as worsening fibrosis, were strongly associated with HCC risk at both time points.

"In a cohort of patients with virologically cured HCV infection, risk factors for HCC were different in patients with and without cirrhosis," the researchers concluded. "In patients with cirrhosis, they were mostly disease severity related, whereas metabolic traits were important in patients without cirrhosis."

These findings, they added, could inform decisions about HCC surveillance in people cured of hepatitis C. Because risk factors can change over time, they suggested that repeated assessment at two years "is practical and can improve risk stratification" in patients cured of HCV, regardless of their cirrhosis status.


Kondili LA et al. De novo hepatocellular carcinoma occurrence following the HCV viral eradication by direct anting antivirals (DAA): medium to long term observations from the ongoing PITER cohort. The Liver Meeting, abstract 99, 2021.

Kramer J et al. Longitudinal associations between risk factors and subsequent risk of hepatocellular cancer in patients with hepatitis C virus infection and virological cure. The Liver Meeting, abstract 903, 2021.