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.3HCV-related death rates have risen since 2010 and are expected to continue to rise into the next decade.4The 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.5,6Among 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.8Hepatocellular carcinoma is the fifth most common cancer type and second most common cause of cancer-related death worldwide.9Despite 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 theJournal 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.
The authors noted that HCC recurrence has not been associated with previously supported IFN-based regimens. This likely may be due to differences in the kinetics of viral suppression and associated inflammation, which are drastically different with DAAs and the less-efficient IFN therapies. Hepatitis C virus eradication with DAA treatment is rapid and often occurs within days after administration, unlike IFN-based regimens that take much longer.
Given that IFNs are associated with antiproliferative effects via regulation of angiogenesis and immune cells, IFN-based therapy may inherently lend itself to targeting disseminated cancer cells and minimal residual disease, thus enhancing an antitumor immune response.
“It is important that hepatologists continue to weigh up the risks and the benefits of DAA treatment for each individual patient, as these drugs are still relatively new,” said Professor Massimo Colombo, MD, professor of Gastroenterology at the University of Milan, and former editor-in-chief of theJournal of Hepatology. “Meanwhile, we look forward to further data examining the mechanisms of metastatic awakening and the immune system so that we can accordingly tailor treatment for our patients.”14
Additional studies have addressed the impact of DAA therapy on host immune status. In one analysis of intrahepatic natural killer (NK) cell function after DAA therapy, Serti et al15found that IFN-free therapy was associated with a loss of IFN alfa (IFNα)- mediated immune activation, demonstrated by a decrease in chemokines CXCL10 and CXCL11, and normalization of a NK cell phenotype. Similarly, Meissner and colleagues16noted a down-regulation of IFNs and IFN-stimulated genes after viral clearance with the DAA regimen of sofosbuvir plus ribavirin.
Together, these studies suggest that extra screening and follow-up might be necessary for patients receiving DAAs, as there may be a higher risk for HCC recurrence with treatment. Additionally, HCV eradication may not be a reason in and of itself to screen less.
HISTORIC EVIDENCE OF RISK REDUCTION WITH ANTIVIRAL THERAPY
Strong evidence supports the link between HCV infection and the development of HCC. Both HCV and hepatitis B virus (HBV) promote the development of fibrosis, and eventually, cirrhosis of the liver, which is associated with 80%-90% of cases of HCC. As such, cirrhosis is a strong risk factor for HCC; in the 25-30 years after infection, the incidence of cirrhosis and subsequent development of HCC ranges from 15%-35%.8
Although HCV infection is the strongest risk factor for HCC development, other risk factors include male sex, comorbidities (HBV or HIV co-infection, diabetes, obesity, steatosis), viral genotype (HCV 1b), alcohol consumption, and older age. In the United States, 50%-60% of patients with HCC are infected with HCV, 10%- 15% are infected with HBV, 5% or less are infected with both viruses, and 30%-35% are infected with neither virus. Given that the majority of cases of HCC are linked to HCV, eradication of the infection is still a major focus for the clinical management of HCC.8
The incidence of HCV-related cirrhosis and HCC has steadily increased in the United States in recent decades. Recent National Health and Nutrition Examination Survey (NHANES) data indicate that approximately two-thirds of those infected with HCV were born between 1945 and 1965. In 2012, the Centers for Disease Control and Prevention (CDC) updated its recommended guidelines to include the universal screening of all persons born in that time span, not just those with the highest risk. Alarmingly, estimates suggest that in the United States, up to 50% of those with chronic HCV infection go undiagnosed. In the absence of effective treatment, the number of patients with cirrhosis or HCC is projected to double by 2020.17
Results of the current studies linking use of DAA therapy with an increased incidence of HCC present an interesting dilemma for clinicians, in that achieving SVR poses an additional risk to the patient. Historically, many studies have demonstrated a decreased risk of HCC with antiviral treatment. However, that was based on clinical trial data using IFN-based regimens. In one retrospective analysis by Ikeda et al,18over 1600 patients with HCV-associated chronic liver disease had reported 3-, 5-, and 10-year HCC cumulative rates of 2.8%, 4.8%, and 12.4%, respectively, for those not treated with IFN therapy compared with rates of 1.1%, 2.1%, and 7.6%, respectively, for those treated with IFN. Other long-term observational and retrospective studies have shown similar results, many of which were performed in Japan, where there is a significantly greater prevalence of HCV-associated HCC.19
In a more recent analysis, over 500 patients with advanced fibrosis were treated with IFN monotherapy, IFN and ribavirin, or pegylated-IFN and ribavirin, and followed for a median duration of 8.4 years. Compared with those who did not achieve SVR, those with SVR had a significantly reduced risk of all-cause mortality (hazard ratio [HR], 0.26; P <.001) and liver-related mortality or transplantation (HR, 0.06; P <.001), as well as a reduced 10-year cumulative incidence rate (5.1% vs 21.8%; P <.001).20
Despite the potential benefits of IFN therapy, several substantial limitations are associated with its use, including modest SVR rates of 40%-50%, significant adverse events (AEs), poor tolerance, and low efficacy in patients with advanced disease.11These shortcomings, along with a greater understanding of HCV pathogenesis, prompted the development of DAAs. Although IFN-based therapy was the backbone of HCV treatment regimens for over 20 years, most IFN-containing regimens are no longer recommended by the American Association for the Study of Liver Diseases (AASLD) for most HCV genotypes because of their association with higher rates of serious AEs, longer treatment duration, high pill burden, numerous drug-drug interactions, more frequent dosing, and higher intensity of monitoring.21
Even after achieving SVR, patients still are at risk for developing HCC. Using more aggressive screening and follow-up will help to identify those at highest risk, a point that clinicians should be especially mindful of given the high rates of SVR with DAA-based regimens. For patients who have achieved SVR, the most important risk factors for developing HCC are advanced fibrosis and cirrhosis. Additional risk factors, such as older age, male sex, and alcohol use, have also been associated with HCC after SVR. Ongoing studies should aim to identify suitable biomarkers that can predict the development of HCC in patients who achieved SVR.22
Dr. Brillanti remained positive on the use of DAAs for HCV therapy despite the associated HCC risk. “This is a different cancer than elsewhere in oncologyit is a cancer within an advanced chronic disease—so the prognosis, the life expectancy, is related not only to the liver cancer but also to the liver disease and liver function,” he explained. “If you don’t treat these patients and ameliorate their liver function, and if hepatocellular carcinoma occurs, you have no chance of curing them. But if you ameliorate liver function and they develop hepatocellular carcinoma, you can cure it better because their improved liver function will allow an ablation.”12