People treated for hepatitis C have unexpectedly high rate of liver cancer recurrence

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Hepatitis C patients with cirrhosis who were treated with direct-acting antivirals had about twice the expected likelihood of developing hepatocellular carcinoma (HCC), with the excess risk seen in people with a previous history of HCC, according to research presented at the recent 2016 International Liver Congress in Barcelona. These findings underline the importance of ongoing liver cancer monitoring even after successful hepatitis C treatment.

The advent of interferon-free direct-acting antiviral (DAA) therapy has brought about a revolution in hepatitis C treatment, with more than 90% of patients achieving a cure. As with interferon-based therapy, sustained virological response (SVR) to DAA treatment – or permanent clearance of hepatitis C virus (HCV) – is expected to slow liver disease progression and reduce the chances of adverse outcomes such as liver cancer or decompensation, but some risk remains even after the virus is eradicated. Most HCC occurs in people who have developed cirrhosis or scarring of the liver, which can result from chronic viral hepatitis, heavy alcohol use or other causes.

Federica Buonfiglioli and Stefano Brillanti of the University of Bologna and colleagues analysed a cohort of hepatitis C patients with cirrhosis treated with DAAs at a referral centre in Italy between March and November 2015.



Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

direct-acting antiviral (DAA)

Modern drugs for the treatment of hepatitis C, which work directly against the hepatitis C virus. They stop the virus from reproducing by blocking certain steps in its lifecycle.

magnetic resonance imaging (MRI)

A non-invasive, non-x-ray diagnostic technique that provides computer-generated images of the body's internal tissues and organs.

Child-Pugh score

A classification system used to measure liver function, especially in people with chronic liver disease. The score includes 5 clinical measures of liver disease, including ascites, encephalopathy, serum bilirubin level, serum albumin level, and prothrombin time.

The study included 344 HIV-negative participants with hepatitis C-related cirrhosis. A majority (60%) were men and the median age was 63 years. The most common HCV genotype was 1 (69%) and 55% had experienced previous treatment failure using pegylated interferon and ribavirin.

Participants had Child-Pugh class A or B cirrhosis. Child-Pugh scores are used to assess liver disease prognosis; class A indicates well-preserved liver function, class B indicates significant functional impairment and class C indicates decompensation.

Participants were treated with interferon-free DAA regimens including:

  • Sofosbuvir (Sovaldi) + simeprevir (Olysio): 34%
  • Ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekirax/Exviera): 22%
  • Sofosbuvir + ribavirin: 17%
  • Sofosbuvir + daclatasvir (Daklinza): 16%
  • Sofosbuvir/ledipasvir (Harvoni): 10%

At the start of the study participants did not have active liver cancer. However, 17% had a history of prior HCC treated with chemoembolisation or radiation and had magnetic resonance imaging (MRI) or computed tomography (CT) scans showing no evidence of active tumours. Occurrence of HCC during the 24-week post-treatment follow-up period was assessed by ultrasonography and confirmed with MRI or CT scans.

At 12 weeks post-treatment, 89% of patients achieved SVR12, which is considered a cure.

Overall, active HCC was detected in 26 patients (7.6%) between the end of treatment and 24 weeks of follow-up, 22 of whom had achieved SVR. Most (81%) had only a single detectable HCC nodule, but five people had multiple nodules.

Liver cancer developed in 17 (29%) of the 59 patients with a history of previous HCC. However, among participants with no prior history of HCC, just nine patients or 3.2% developed new HCC – not much higher than the expected rate.

Among the patients with HCC the median age was 58 years – younger than the study population as a whole – and more than twice as many were men. People with Child-Pugh class B were significantly more likely to develop HCC (although the numerical majority of those who developed HCC were class A). HCC was also associated with greater liver stiffness according to FibroScan and lower platelet counts. However, there was no difference in HCC occurrence or recurrence according to HCV genotype or specific DAA regimen.

At the time HCC was detected only two patients (8%) had elevated levels of alpha-fetoprotein (AFP), a biomarker often measured to monitor for HCC.

"In this large retrospective cohort study on cirrhotic patients treated with DAAs, we observed a high rate of HCC recurrence and a standard rate of HCC [first time] occurrence in a relatively short follow-up observation," the researchers concluded. "Development of HCC was rarely associated with increase in AFP levels."

"In cirrhotic patients treated with DAAs, development of HCC represents a significant clinical problem, despite a high rate of SVR," the researchers concluded. "This seems particularly true [of] those patients with a history of previous HCC, in whom a surprisingly high rate of HCC recurrence was observed, over a relatively short period of time."

"We believe our findings justify close monitoring for all cirrhotic patients on such treatments," Dr Buonfiglioli said in an EASL press release.

EASL secretary general Prof Laurent Castera noted that a higher than expected rate of HCC recurrence was also seen in a recent Spanish study published online in the current edition of Journal of Hepatology.

That study, by Dr Jordi Bruix of Hospital Clinic Barcelona and colleagues, looked at 103 hepatitis C patients with a prior history of HCC but who had achieved complete response to liver cancer treatment. Among 58 patients who achieved SVR with DAA therapy – those treated with interferon were excluded – 16 (28%) had a recurrence of HCC over a median follow-up period of about 23 weeks, about the same rate as in the Italian study.

"Our data show an unexpected high rate and pattern of tumour recurrence coinciding with HCV clearance and, though based in a very small cohort of patients, should be taken as a note of caution and prime a large scale assessment that exceeds the individual investigators capacity," the study authors wrote. They suggested disruption of immune surveillance may contribute to the increased risk of liver cancer recurrence in this group.


Buonfiglioli F et al. Development of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals. International Liver Congress, Barcelona, abstract LBP506, 2016.

Reig M et al. Unexpected early tumor recurrence in patients with hepatitis C virus -related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution. Journal of Hepatology. April 12, 2016 (online ahead of print).