Some people remain at risk for liver cancer after being cured of hepatitis C

People who are cured of hepatitis C with direct-acting antiviral (DAA) therapy have a much lower risk for liver cancer. The likelihood of developing liver cancer after successful treatment declines over time, but some people remain at risk and can benefit from screening, especially those with liver cirrhosis, researchers reported this month at the AASLD Liver Meeting.

Over years or decades, chronic hepatitis C virus (HCV) infection can lead to serious complications including liver cirrhosis and hepatocellular carcinoma (HCC), the most common type of liver cancer. HCC is often detected at a late stage and is difficult to treat, making it a leading cause of cancer mortality worldwide. AASLD and EASL guidelines recommend that people with cirrhosis should undergo regular surveillance to detect HCC at an early stage, but screening for liver disease patients without cirrhosis is controversial.

Dr Naveed Janjua of the British Columbia Centre for Disease Control in Canada and colleagues evaluated the effect of sustained virologic response (SVR) to treatment on HCC risk among people with and without cirrhosis. SVR, or continued undetectable HCV viral load after completion of treatment, is considered a cure.

The researchers analysed data from the British Columbia Hepatitis Testers Cohort, which includes approximately 1.5 million people tested for HCV or HIV, and all cases of hepatitis B or C, HIV or active tuberculosis reported to the public health system since 1990. Individuals who were treated with DAA therapy were matched with people with hepatitis C who never received treatment.

A total of 10,118 people treated with DAAs and 10,118 matched untreated people were followed for a median of 1.9 and 1.7 years, respectively. Of those treated and matched, 97% achieved SVR.

The HCC incidence rate was 5.7 cases per 1000 person-years among people who achieved SVR compared with 58.6 cases among people who were treated but not cured and 12.7 cases among untreated individuals. In all groups, liver cancer incidence was higher in people who had progressed to cirrhosis (20.5, 187.2 and 53.5 case per 1000 person-years, respectively).

In a multivariate analysis, SVR was associated with a substantial reduction in HCC compared with the untreated group, and this effect was stronger among people who did not have cirrhosis at the time of treatment. Older age was also associated with a higher risk of liver cancer following SVR.

“These results highlight the continued need for early treatment [to] realize the fuller benefits of DAA treatment to prevent development of advanced stage liver disease,” the researchers concluded.

Most studies to date have looked at the development of liver cancer over a fairly short time period after hepatitis C treatment. Dr Philip Vuiten of the University of Washington Medical Center in Seattle and colleagues aimed to determine whether HCC risk declines as the time since SVR increases. If this is the case, the risk may eventually become low enough that the costs and harms of screening exceed the benefits, Vuiten suggested.

This analysis included 75,965 people with hepatitis C managed by the US Veterans Affairs healthcare system who had achieved SVR and were still alive, had not undergone liver transplantation and had not developed HCC prior to January 2018. They were followed to the end of 2019. As is typical of a US veteran population, almost all were men and the average age was approximately 65 years. Just over a quarter had cirrhosis. People who were cured more than six years ago were more likely to have HCV genotypes 2 or 3, which are easier to treat.

Overall, 547 participants developed liver cancer during follow-up, but the risk was higher for people with cirrhosis, Vuiten reported. Among those with cirrhosis, HCC incidence was highest for those who achieved SVR one to two years ago (2.71 cases per 100 person-years), lower for those who were cured two to four years prior (2.11 cases) and lowest for those who were cured four to six years ago (1.65 cases) or more than six years ago (1.68 cases).

After adjusting for baseline characteristics (including demographics, HCV genotype, fibrosis score and hepatitis B or HIV co-infection), people who were cured two to four years ago were 21% less likely to develop HCC, and those who had accrued more than four years after SVR were 38% less likely, compared to those cured only one or two years ago. Among people without cirrhosis, however, there was no significant association between HCC risk and time since SVR.

For people with cirrhosis, HCC decreases as time increases after SVR, but the risk appears to bottom out at six years. Nonetheless, the risk remains “substantial” at approximately 1.7% per year. Using a cost-effectiveness cut-off of about 1.5%, HCC risk remains high enough even six years after SVR to warrant ongoing screening, the researchers concluded.

While cirrhosis is clearly a major risk factor for liver cancer, some people without advanced fibrosis can still develop HCC after successful hepatitis C treatment.

Dr Yuki Tahata of Osaka University Graduate School of Medicine in Japan and colleagues aimed to develop a scoring system to predict the likelihood of HCC in people without advanced fibrosis, which could help clinicians identify those who require HCC surveillance.

This analysis included 1682 people with hepatitis C at 26 Japanese hospitals who did not have advanced liver fibrosis (FIB-4 index score less than 3.25). They started DAA treatment between September 2014 and October 2020 and achieved SVR 24 weeks after the end of treatment. People with hepatitis B or HIV, those with a history of liver cancer prior to SVR and liver transplant recipients were excluded. About 60% were women and the median age was 66 years.

The participants underwent HCC surveillance using abdominal ultrasound prior to DAA treatment, at the end of treatment and every six months thereafter. A total of 28 people developed HCC during follow-up, Tahata reported. The cumulative HCC incidence rates at one, three and five years after SVR were 0.6%, 1.8% and 2.5%, respectively, with an annual rate of less than 1.0%.

In a multivariate analysis, factors that were significantly associated with HCC incidence after being cured were older age (65 or over), elevated ALT liver enzymes (30 U/l or higher) and elevated alpha-fetoprotein levels (5.0 ng/ml or higher) at the time of SVR.

This enabled the researchers to develop a scoring system, called 3A, to predict the occurrence of HCC after SVR, allocating one point for each of these factors. The cumulative HCC incidence rate at one, three and five years post-SVR was 2.9%, 6.0% and 7.9%, respectively, for people with a score of 2 or 3. For those with a score of 1, the corresponding rates were 0.5%, 2.1% and 2.9%. But no patients with a score of 0 developed HCC.

“We developed a new scoring system using these three factors to enclose patients who need HCC surveillance after SVR, and this score may be useful for stratification of HCC risk in patients without advanced liver fibrosis,” the researchers concluded.