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Direct-Acting Antiviral Treatment Linked with HCC Recurrence for Patients with Hepatitis C Infection

Published Online: Jul 05,2016
Data from 2 recent studies indicate that patients infected with hepatitis C virus (HCV) who were treated with direct-acting antiviral (DAA) therapy were more likely to experience a recurrence of hepatocellular carcinoma (HCC) than those who had no previous history of the disease.

Results from a retrospective cohort study indicate that HCC recurrence occurred at a rate of 29% in patients with cirrhosis who had a history of previous HCC compared with 3.2% of patients with no history of HCC. Federica Buonfiglioli, MD, with the DIMEC, University of Bologna, Italy, and colleagues presented their findings in April 2016 at the International Liver Congress in Barcelona, Spain.1

“Even in a relatively short observation period, we have shown that high recurrence rates of hepatocellular carcinoma can occur in Hepatitis C patients taking direct-acting antivirals,” commented Dr. Buonfiglioli, lead author of the study. She added, “Even though further investigation is needed, we believe our findings justify close monitoring for all cirrhotic patients on such treatments.”2

Hepatitis C virus infection is a significant worldwide healthcare burden and is the most common bloodborne infection in the United States.3 HCV-related death rates have risen since 2010 and are expected to continue to rise into the next decade.4 The prevalence of HCV varies significantly worldwide; current estimates indicate that approximately 3 million people in the United States have chronic HCV infection, with estimates reaching 185 million people worldwide.5,6 Among those infected, about one-fifth will develop cirrhosis, with an elevated risk for developing HCC. As such, chronic HCV infection remains a significant risk factor for the development of HCC.7

Hepatitis C virus‒positive patients have a 15- to 20-fold increased risk for HCC development compared with HCV-negative subjects.8 Hepatocellular carcinoma is the fifth most common cancer type and second most common cause of cancer-related death worldwide.9 Despite improvements in therapeutic options, the 5-year survival rate for HCC remains at just 15% in the United States and 5% in developing countries.10

In recent years, the therapeutic landscape of HCV therapy has changed dramatically. Most notably, the US Food and Drug Administration (FDA) approval of several DAA therapies has given patients additional treatment options. These all-oral, interferon (IFN)-free, antiviral combination therapies have changed the standard of care for those with chronic HCV infection, often producing sustained virologic response (SVR) rates greater than 90% for most HCV genotypes, with improved tolerability compared with previously used treatment regimens.11

However, the current study suggests that the potential shortcomings of DAA therapy should be carefully weighed against the benefits. The results indicate that treatment with DAAs in patients with cirrhosis may significantly impact HCC recurrence rates, even though high rates of SVR were achieved.

In the present analysis, the occurrence of HCC was evaluated in 344 patients without active HCC who were HIV-negative and had HCV-related cirrhosis. Patients had received previous treatments of sofosbuvir and simeprevir (34%); 3D combination consisting of ABT-450 with ritonavir, ombitasvir, and dasabuvir plus ribavirin (22%); sofosbuvir and ribavirin (17%); sofosbuvir and daclatasvir (16%); or sofosbuvir and ledipasvir (10%), with the addition of ribavirin according to the treating physician’s discretion. Active HCC disease was determined using contrast-enhanced ultrasonography and magnetic resonance imaging/computed tomography scans, with comparisons made between baseline images and those taken during the 6-month, posttreatment follow-up.1

By 12-week follow-up, 89% of patients achieved an SVR. At 24-week follow-up, 7.6% of all patients (26/344) developed active HCC. The occurrence rate of HCC among those with a previous history of the disease was 29% (17/59), whereas the occurrence rate among those with no HCC history was 3.2% (9/285). Few patients with detected HCC had a concomitant increase in alphafetoprotein levels (8%).1

“These initial findings provide important insight into how Hepatitis C management strategies could be developed to detect HCC early in patients who are most at risk,” said Laurent Castera, MD, PhD, Secretary General of the European Association for the Study of the Liver (EASL). “These findings deserve further investigation given their clinical significance.”2

“I do not think that direct-acting antivirals are directly responsible,” said Stefano Brillanti, MD, senior investigator of the study. “The hypothesis is that immune surveillance may be reduced too rapidly. You have an immediate drop in viremia, but also attenuation of inflammation. I think inflammation is a bad thing in terms of hepatitis progression, but it may be a good thing in terms of controlling cancer.”12

In a similar study, Spanish investigators also found a “high rate” of HCC recurrence in patients who had received prior DAA therapy for HCV. The study, led by Maria Reig, MD, of the Barcelona Clinic Liver Cancer (BCLC) Group, IDIBAPS, and the University of Barcelona and colleagues, was first published online on April 8, 2016, in the Journal of Hepatology.13

Patient data were obtained from 4 participating hospitals. Of the 103 patients who had prior history of HCV infection and treatment for HCC, 58 patients met the inclusion criteria of complete tumor response after resection, ablation, or chemoembolization, with the absence of noncharacterized nodules at imaging and previous therapy with an all-oral DAA combination. Prior to the initiation of antiviral therapy and during follow-up, baseline characteristics, laboratory values, and radiologic tumor response were monitored.13

Among eligible patients, 3 patients died and 16 (27.6%) developed radiologic tumor recurrence after a median follow-up of 5.7 months. Tumor recurrence patterns included intrahepatic growth (n=3), new intrahepatic lesions (1 nodule, n=5; ≤3 nodules ≤3 cm, n=4; multifocal, n=1) and infiltrative, ill-defined HCC and/or extrahepatic lesions (n=3). The median time from DAA therapy initiation to HCC recurrence was 3.5 months. Of those patients with a short time span (<4 months) between HCC treatment and DAA therapy, 7 of 17 (41%) experienced radiologic tumor progression.13

Senior author of the study, Jordi Bruix, MD, of the BCLC Group, Hospital Clinic Barcelona, CIBEREHD, and University of Barcelona, remarked: “Direct-acting antivirals have made a huge impact on the treatment of Hepatitis C and have made viral clearance possible for many types of patients.” He said of the findings: “Interferon-free regimens in particular are now being studied in many patient cohorts including those with other pre-existing disease such as HCC. Our data, even though from a relatively small number of patients, are so striking that it clearly signals we must exercise caution in the use of these agents in such patients, at least until data from further large-scale assessments are available.”14

The authors attribute, in part, the high rate of HCC recurrence with DAA therapy to disruption of the immune surveillance system. “Abrupt resolution of a chronic inflammatory state (such as chronic hepatitis C) may disturb the baseline status and abolish the immune ‘brake’ to tumor progression. This change may allow the tumor clones to progress and be recognized as a recurrence,” they said.

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Direct-Acting Antiviral Treatment Linked with HCC Recurrence for Patients with Hepatitis C Infection
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