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Large Italian studies confirm no increase in liver cancer risk after hepatitis C treatment

Keith Alcorn
19 April 2018

Further research presented at this year’s International Liver Congress confirms that direct-acting antiviral (DAA) treatment leading to the cure of hepatitis C infection does not raise the risk of developing hepatocellular carcinoma (HCC).

Recurrence of HCC has been observed in previous studies of people with hepatitis C treated with DAAs. In 2016 Italian researchers reported an unexpectedly high rate of liver cancer recurrence in people treated with DAAs and warned of the need for close monitoring for HCC after DAA treatment. Subsequent research concluded that there was no increase in the risk of HCC after DAA treatment.

Three studies, two multicentre prospective cohort studies and one retrospective study, all conducted in Italy, reported on the potential risk of recurrence. The studies found that:



An accumulation of fluid in the abdomen; may be caused by liver damage, especially cirrhosis. 

direct-acting antiviral (DAA)

A drug which prevents hepatitis C from reproducing by blocking certain steps in its lifecycle.


Something that has an effect outside the liver, for example when viral hepatitis affects the kidneys or causes depression.

hepatocellular carcinoma (HCC)

Liver cancer. A long-term complication of chronic inflammation of the liver or cirrhosis.


Stretched veins which may burst and cause severe bleeding; a complication of cirrhosis.

  • The risk of liver cancer recurrence was strongly associated with a lack of cure after DAA treatment and with a shorter duration between achieving a complete response to liver cancer treatment and starting DAA therapy.
  • The majority of new and recurrent cases occurred within a year of starting DAA treatment.

The first study, conducted by Pietro Lampertico and Angelo Sangiovanni of Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, and colleagues at other hepatology clinics in Italy, looked at the incidence of HCC in 1285 consecutive patients with hepatitis C and cirrhosis who received DAA therapy between June 2014 and September 2017. Of these, 125 people had been treated for HCC and had a radiologically confirmed cure. The remainder (1160) had no prior history of HCC.

Cure rates were high in both groups of people (95.2% in those with a prior history of HCC and 96.7% in those with no prior history of HCC).

In those with no prior history of HCC the mean annual incidence of HCC after hepatitis C virus cure was 3.1% per year but a progressive decrease in new cases of HCC was observed from 20 weeks of follow-up onwards. Multivariate analysis showed that ascites, non-malignant nodules and elevated alpha-fetoprotein were each associated with an increased risk of developing HCC.

In those with a prior history of HCC that was confirmed cured by radiological imaging, recurrence of HCC was frequent: the two-year cumulative incidence was 41.8% in those who achieved sustained virologic response but the incidence of recurrence began to decline after 35 week of follow-up. Risk factors for recurrence were not presented.

Martina Gambato presented data on the recurrence of HCC in 87 people with hepatitis C and cirrhosis who had a radiologically confirmed cure of HCC prior to DAA therapy. Study subjects were identified from the Navigatore database of people with hepatitis C with cirrhosis who underwent treatment in the Veneto region of northern Italy between January 2015 and April 2017. The cohort of patients with a confirmed radiological response had a median age of 66 years, 62% were male, 92% had Child-Pugh A cirrhosis and 92% achieved a sustained virological response to treatment (SVR12).

HCC recurred in 36 people (42%) a median of eight months after starting DAA treatment for hepatitis C. HCC recurred in 20% of people within six months of starting DAA treatment and in 31% of people within a year. The only significant predictor of recurrence was the time that had elapsed between complete response to first treatment for HCC and initiation of DAA treatment; people with a complete response confirmed more than six months before initiating DAAs had a reduced risk of recurrence (HR 0.94, 95% CI 0.91-0.98, p = 0.007). Whereas 46% of those who had initiated DAAs less than six months after confirmation of complete response subsequently experienced recurrence within a year, only 17% of those who initiated more than six months after complete response had a recurrence.

Tumours in those who experienced recurrence were not especially aggressive. Only 5% developed extrahepatic lesions and 47% of tumours were confined to a single nodule. Of those who experienced recurrence approximately two-thirds had a partial or complete response to treatment, 11% underwent a liver transplant and 22% experienced progression or died.

Ana Lleo de Nalda of Humanitas University, Milan, presented data from a second prospective multicentre study carried out in Italy, covering people treated at ten tertiary-level liver clinics in Italy. The study reviewed the incidence of new cases of HCC and recurrence of HCC in previously cured individuals in a large cohort of people with hepatitis C and cirrhosis who received DAA treatment during 2015.

The study reviewed 1927 people, of which 161 (8.3%) had a previous history of HCC. New cases of HCC were diagnosed in 50 people with no prior history of HCC after DAA treatment, an annual incidence of 2.4%. The incidence of HCC was higher in people who did not achieve SVR (p < 0.001). In a multivariate analysis lack of SVR strongly predicted the subsequent diagnosis of HCC (HR 4.85, 95% CI 2.25-10.5, p < 0.0001). The presence of gastric or oesophageal varices also predicted a diagnosis of HCC (HR 2.41, 95% CI 1.23-4.69, p = 0.01). Whereas the incidence of HCC was 13.2 cases per 100 person-years of follow-up in people with varices who did not achieve SVR12, incidence was 1 case per 100 person-years in those without varices who achieved SVR12.

Recurrence of HCC was also strongly associated with lack of SVR (HR 5.21, 95% CI 1.75-15.5, p = 0.003) and with higher alpha-fetoprotein (per 10ng/dL, HR 6.19, 95% CI 1.81-21.2, p = 0.004).    


Gambato M et al. HCC recurrence under all-oral DAAs-based antiviral therapy in HCV-infected patients: data from Navigatore web platform. The International Liver Congress, Paris, abstract PS-153, 2018. Journal of Hepatology 68: S85, 2018.

Lleo A. SVR is the strongest predictor of occurrence and recurrence of hepatocellular carcinoma in HCV cirrhotic patients after treatment with DAAs: a prospective multi-centric Italian study. The International Liver Congress, Paris, abstract PS-154, 2018. Journal of Hepatology 68: S86, 2018.

Sangiovanni A et al. IFN-free DAA treatment of cirrhotic HCV patients with or without history of HCC: a multicenter prospective trial in Italy. The International Liver Congress, Paris, abstract PS-152, 2018. Journal of Hepatology 68: S85, 2018.