Examining risk for HCC after HCV

Patients with hepatitis C virus have always carried an increased risk for developing hepatocellular carcinoma. Although antiviral treatment for HCV reduces that risk, it is not eliminated.

Research has shown that liver stiffness after HCV treatment is associated with adverse outcomes, including decompensated cirrhosis and HCC, and that increased risk for HCC can persist up to 10 years following HCV eradication in patients with baseline cirrhosis or high fibrosis scores.

Ira Jacobson

Healio spoke with Ira Jacobson, MD, director of hepatology at NYU Langone Health, about HCC risk after HCV treatment and how best to screen patients.

Healio: What is the relationship between HCV and HCC?
Jacobson: Patients with HCV and cirrhosis have an estimated annual risk for developing HCC of about 2% to 4%. There has been some attention addressing the question of whether non-cirrhotic HCV can lead to liver cancer. The overwhelming consensus is that patients with cirrhosis are by far the most likely to develop HCC, but there has been some concern that patients with F3 fibrosis or bridging fibrosis may have a slightly increased risk as well. That has led to some controversy in the guidelines for screening.

Healio: Has there been a decline in rates of HCC with the advent of direct-acting antivirals?

Jacobson: There has been a well-documented decrease of up to 80% in the risk for HCC, even dating back to when patients with cirrhosis were on interferon. However, that was much harder to achieve then than it is now. Many comparative studies of responders vs. nonresponders to old interferon therapy already had shown this, and that has proven to be equally true with DAAs. We see a reduction in the hazard ratio in statistical analyses of down to 0.2 or 0.25, which is about an 80% reduction in risk.

Healio: What are the existing data on the relationship between DAA treatment and HCC recurrence?

Jacobson: The controversy began with a report from the very respected Barcelona group from Spain that suggested what seemed to be an inordinately high rate of recurrent HCC compared with the authors’ historical experience. In patients who had been treated for their HCV after having been treated for their HCC with ablative techniques, the researchers observed a greater-than-expected increase in the risk for recurrent HCC — somewhere around 27% over a 6-to-12-month period, which seems very high. Another study, conducted elsewhere in Europe, duplicated that finding. From there, the race was on with more robust trials to see if it was a true increase or not.

The emerging literature has evolved fast and furious and the preponderance of that literature and the preponderance of opinion reflected in critical analyses by well-known experts in the field is that this signal has turned out to be a false alarm. There does not seem to be an increased risk for recurrent HCC in people undergoing successful DAA therapy for HCV after having been treated locally for HCC.

Healio: Do data suggest an association between DAA treatment and new HCC?

Jacobson: All the data suggest that the benefit — the marked decline in risk for HCC after successful treatment of HCV — starts from the time you cure the HCV. We do not see an increased blip or an increased rate of occurrence for a finite period of time followed by the decline. There had been a theoretical risk put forward previously of increased risk for HCC in the short time period after you cure. However, there is absolutely nobody who proposes that anybody should have HCV therapy withheld because of this risk, which has been shown not to exist.

Healio: Which patients may be at higher risk for HCC after DAA therapy for HCV?

Jacobson: Very simply, it’s patients with cirrhosis. Decompensated cirrhosis has the highest risk compared with compensated cirrhosis, but compensated cirrhotics do have a much higher risk than non-cirrhotics. It’s been controversial, whether patients with F3 fibrosis have a slightly increased risk; my opinion is that they do and that they should be screened accordingly. That is not embedded in the current guidelines, which state that only patients with cirrhosis need to be followed. Males are always at higher risk than females, and that remains as true post-HCV therapy as it is before HCV therapy. Despite the marked decline in risk, that risk is still substantial. Given the baseline level of risk that occurs before you get cured, the risk afterward, though significantly lower, is still significant.

Healio: Is there any specific period of time patients should be followed?

Jacobson: That is a key question in the field right now. One school of thought is that screening needs to be indefinite. Another school of thought, which is based on our increasing knowledge about the capacity of cirrhosis to regress, is that patients who have regression of their cirrhosis are at such a diminished risk that they do not need to continue to be screened.

Then the question is, how do you identify such patients? The answer is generally by doing noninvasive measurement of fibrosis with techniques, such as a transient elastography or other elastography techniques, or potentially, noninvasive serum markers like we use in patients with baseline liver disease.

There has been some attention in the literature to the idea that if your elastography score goes below a certain level — in one paper, it was 10 kPa, which has less than cirrhosis — the lingering risk for HCC is so small that that screening is no longer justified or necessary.

However, in my opinion, we have not yet reached a point of sufficient confidence to avoid doing periodic HCC screening, even if there’s evidence of cirrhosis regressions. I will readily acknowledge, though, that patients with marked decreases in FibroScan (Echosens) score, in my experience, have not, in fact, developed HCC. It’s very reassuring, but we still screen them all indefinitely.

Healio: What more do we need to know?

Jacobson: It would be a great leap forward if we had noninvasive markers that we could use to identify which patients should be subjected to either the most rigorous screening or any screening at all.

There’s also the question of how to screen. The gold standard according to every society guideline is ultrasound. However, I am of the belief that that cross-sectional imaging with CT or MRI to avoid the radiation are better modalities.

References:

Ioannou GN, et al. Gastroenterol. 2019;doi:10.1053/j.gastro.2019.07.033.

Vutien P, et al. Aliment Pharmacol Thera. 2020;doi:10.1111/apt.16092.