Liver cancer risk reduced after hepatitis C treatment, but vigilance needed for aggressive cancers in months after treatment

People who are cured of hepatitis C after a course of direct-acting antiviral (DAA) treatment do not have a higher risk of developing liver cancer (hepatocellular carcinoma), and probably have a reduced risk, studies from Italy and Canada presented at the 2016 AASLD Liver Meeting this week in Boston have shown.

However, Italian researchers also found that those people who did develop liver cancer during or shortly after antiviral treatment were more likely to develop an aggressive form of liver cancer, perhaps because of changes in immune surveillance in the liver as a result of treatment.

Hepatitis C infection can be cured with a course of DAA treatment, but eliminating the infection may not heal the liver sufficiently to prevent the development of liver cancer. Furthermore, there is evidence that people with cirrhosis previously treated for liver cancer have a high rate of recurrence of liver cancer. Two studies, conducted in Italy and Spain, both found that around 30% of people previously treated for liver cancer experienced a recurrence of liver cancer within a median of six months of completing hepatitis C treatment. Both research groups considered the rate of recurrence in their patients to be unusual and warned doctors to be on the lookout for liver cancer recurrence.

To investigate whether these findings hold true in a larger population, researchers at hospitals in the Veneto region of northern Italy analysed the incidence of hepatocellular carcinoma (HCC) in a prospective study of 3075 consecutive patients with F3 or F4 fibrosis treated with DAAs between January 2015 and June 2016. People previously diagnosed with liver cancer were excluded from the analysis, as were people who had undergone liver transplant prior to DAA treatment.

Seventy-two per cent had cirrhosis, in the vast majority of cases less advanced (Child-Pugh stage A, 65.3%). The population was almost two-thirds (63%) male, 62% had genotype 1 infection, 12.7% genotype 2, 17% genotype 3 and 7.7% genotype 4.

After average follow-up of approximately ten months from the time of beginning treatment (300 days), 41 people had developed liver cancer, an incidence of 1.64 cases per 100 patient-years. Incidence ranged from 0.23 per 100 person-years in people without cirrhosis to 1.93 per 100 patient-years in those with cirrhosis. Incidence was higher in those with Child-Pugh stage B cirrhosis (2.92) than in those with Child Pugh stage A (1.64) but this difference was not statistically significant.

These incidence rates compare to observed incidence rates of 2.8 per 100 person-years in untreated people in the same region of Italy previously reported by the same research network.

Incidence was higher in people with genotype 3 or 4 infection but genotype was not significantly associated with the development of HCC. Multivariate analysis showed that the only factors associated with development of HCC were baseline AST and platelet counts. The baseline APRI score – indicating the degree of liver scarring – was the strongest predictor of the development of liver cancer, with each 1-point increase in APRI score being associated with a 10% increase in the risk of liver cancer.

Although the study found a reduced risk of liver cancer in those who were cured of hepatitis C virus infection, it also found an unusually high proportion of the cases of liver cancer that did occur were more aggressive, manifesting as multiple HCC nodules or infiltrative HCC. Sixteen of 41 cases took this form (39%), and these aggressive cases of HCC were more frequently seen in the first six months after the initiation of DAA treatment. Single-nodule cases of HCC were more likely to occur at least six months after the initiation of DAA treatment.

Speaking at a press conference, Alfredo Alberti, Professor of gastroenterology at the University of Padova said that changes in the immunological and tumour-suppressive environment in the liver as a result of the rapid elimination of viral replication might permit more rapid growth of tumours already present in the liver. Participants in the study were screened for the presence of tumours by ultrasound three months before initiating treatment, so the presence of tumours at the time of treatment initiation cannot be ruled out definitively.

A larger study, of the entire population of people treated for hepatitis C in British Columbia province, Canada, between 1990 and 2013, found that the risk of liver cancer was reduced by 80% in people cured of hepatitis C compared to those who were not cured. This study did not look at the relationship between exposure to DAAs and liver cancer risk.

The study identified 8147 people treated with interferon-based regimens, 57% of whom were cured. Treated individuals were followed for a median of 5.6 years.

Liver cancer incidence was highest among those with cirrhosis who did not achieve a sustained virologic response (21 cases per 1000 patient-years of follow-up). In comparison, liver cancer incidence was 6.4 per 1000 patient-years in those with cirrhosis who achieved SVR, 7.2 in those without cirrhosis who did not achieve SVR12 and 1.1 per 1000 patient-years in those without cirrhosis who achieved SVR12.

In a multivariable analysis liver cancer was associated with cirrhosis, age over 50 years, genotype 3 infection versus genotype 1, alcohol consumption and being male in those who were not cured. In those who were cured of hepatitis C, only cirrhosis, age over 50 and being male were associated with an increased risk of liver cancer.

The British Columbia researchers concluded that although curing hepatitis C infection greatly reduces the risk of developing liver cancer, it does not eliminate the risk entirely. Older people and those with cirrhosis are at higher risk than others, underlining the importance of early diagnosis and treatment.