Earlier suggestions not supported in retrospective study of 857 patients Successful treatment of cirrhotic patients with hepatitis C virus (HCV) with direct-acting interferon (IFN)-free antiviral therapy did not increase the risk of incident hepatocellular carcinoma (HCC), researchers said, nor was it associated with increased nodule size or number in those diagnosed with HCC. According to a Scottish study published in the Journal of Hepatology, the elevated risk suggested by previous research was attenuated after accounting for differing characteristics between patients given regimens with or without interferon. While initial univariate analysis found that IFN-free therapy was associated with more than double the risk, that risk all but disappeared after multivariate adjustment for baseline variables. "These findings suggest that the higher incidence of HCC following sustained virologic response with IFN-free therapy relates to baseline risk factors/patient selection, and not the use of IFN-free therapy per se," wrote Hamish Innes, MSc, from Glasgow Caledonian University, and colleagues. They pointed to recent troubling research from Spain and Austria warning that the risk of HCC in cirrhotic individuals may be higher after attaining IFN-free HCV clearance versus clearance with an IFN-containing cure. "Although this finding could have major implications for the treatment of HCV, the studies on which it was predicated did not carry out multivariate adjustment for confounding factors, and involved small sample sizes only," the researchers wrote. To clarify this question, the group examined data on 857 patients who attained sustained viral response (SVR) at 12 HCV clinics during 1997-2016. The patients' mean age was just under 50, and more than 70% were male. All had been diagnosed with liver cirrhosis before enrollment, but none had a prior diagnosis of HCC, hepatitis B, or HIV coinfection. Patients who received IFN-free therapy (31.7%) were slightly older (age 52.1 versus 48.1) and more likely to be white (96% versus 90.6%). They were also more likely than those given IFN to have a Child-Turcotte-Pugh score of B or C (30.4% vs 9.5%). Thrombocytopenia was more frequent in the IFN-free group (39.3% versus 22.1%), as was non-genotype 3 disease (72.8% versus 35.7%) and at least two prior treatment failures (16.9% versus 6.7%). With a median overall follow-up for the two treatment groups of 2.4 years, the crude rate of HCC occurrence was 1.45 events per 100 person-years (95% CI 1.09-1.94), but this rate differed by regimen. Over a median 1.7 years of follow-up, 12 patients on the IFN regimen experienced incident HCC at an event rate of 1.26 per 100 person-years. In the IFN-free group, 34 had incident HCC over a median of 3.5 years of follow-up at an event rate of 2.53 per 100 person-years. On univariate analysis, that incidence translated to a significantly higher prima facie risk of HCC for those on IFN-free treatment, for a hazard ratio (HR) of 2.48 (95% CI 1.14-5.37). On multivariate analysis, however, the risk was attenuated to an adjusted (a) HR of 1.15 (95% CI 0.49-2.71), and other baseline factors associated with increased HCC risk emerged. One of these was older age, with those in the age 50-59 bracket having an aHR of 2.75 (95% CI 1.4-5.41) and those 60 and older having an aHR of 3.31 (95% CI 1.37-8.02) compared with participants 40-49. A Child-Turcotte-Pugh score of B conferred an aHR of 5.24 (95% CI 2.63-10.46) compared with A, and thrombocytopenia, an aHR of 3.96 (95% CI 2.14-7.3). Having two or more previous HCV treatments had an aHR of 3.52 (95% CI 1.56-7.95). After adjustment for such differences, particularly in Child-Turcotte-Pugh score and platelet count, the elevated risk of HCC was almost entirely attenuated (aHR 1.15; 95% CI 0.49-2.71). "This would tend to indicate that the higher risk of HCC occurrence among individuals receiving IFN-free therapy is a reflection of the shifting patient case mix, as opposed to the pharmacodynamics of IFN-free therapy or any other direct or indirect consequence of IFN-free therapy," Innes and colleagues wrote. They called, however, for confirmatory data from other large cohorts. The possible mechanism of action of these direct-acting antivirals on HCC has been debated. "There was speculation as to whether the rapid decline in hepatitis C viral load upon starting antiviral therapy, and the abrupt cessation of liver inflammation that resulted from this, may have had the unintended consequence of adversely dampening cancer immune-surveillance activities that serve to identify and remove cancer-prone hepatocytes," Innes told MedPage Today. "These agents are so potent in eradicating hep C that the switch may have been too abrupt for the liver's immunity," added Amy Kim, MD, of Johns Hopkins Medicine in Baltimore, who was not involved in the study. She told MedPage Today that hepatologists have been on the alert about the IFN-excluding regimens since a 2016 study showed an almost 30% rate of HCC recurrence in cancer patients also treated for HCV with direct-acting antivirals versus 6% for those with IFN-included regimens. "We weren't sure whether we should treat their hep C or not if they had had a good response to cancer treatment," Kim said. It later emerged, however, that as in the Glasgow study, the recurrence rates were comparable once you looked at confounding factors and disease background. She noted that while the results of this study are reassuring, more data are needed, and several U.S. studies are under way to address the more concerning issue of recurrence in HCC patients who also receive HCV treatment with non-IFN regimens. Last year, MedPage Today reported on findings also suggesting that higher HCC rates were associated with disease severity. Innes et al said that study limitations included that even the large sample size may have been inadequate to detect a small difference in the risk of HCC by treatment regimen. Another problem was that patients were not necessarily screened for HCC at the start of antiviral therapy, and some incident HCC cases might already have been present. Furthermore, the study had no data on the precise modalities used to diagnose HCC, nor was there an examination of the issue of HCC recurrence, which could still be associated with an IFN-free cure. Finally, treatment responders who developed HCC during treatment and died soon after would have been excluded from the study since they did not live long enough to demonstrate SVR and the study may have missed a small number of patients with rapidly progressing disease. Source
