Hepatocellular carcinoma and direct‐acting antivirals: A never ending story?

A large body of evidence accumulated over the two decades of the “interferon era” shows conclusively that HCV eradication (sustained virological response, SVR) in patients with cirrhosis reduces both liver and nonliverrelated deaths.1,2 When cirrhosis is subclassified ac‐ cording to the stage of portal hypertension, it is apparent that the benefit of SVR is higher in patients without clinically significant portal hypertension.3 In all cohorts studied the risk of developing hepatocel‐ lular carcinoma (HCC) for patients with IFNinduced SVR, albeit re‐ duced in comparison to those with persistent HCV infection, is not cancelled altogether.4,5 Hence, continuing HCC surveillance is recom‐ mended in patients with HCV cirrhosis after SVR.5 The introduction of directacting antivirals (DAAs) made possible to eradicate HCV effectively at all stages of liver disease and has led to the rapid accumulation of large cohorts of patients with cirrhosis in whom treatment has been initiated regardless of the stage of the disease, including decompensated cirrhosis, in order to obtain an im‐ provement of liver function and thus ameliorate the short and longterm outcome. This “allcomers” approach has included patients with HCC whose tumour had been successfully treated. Also in this setting, DAAs ob‐ tain exceedingly high SVR rates thus likely prolonging the life span of these patients and creating a further period of time for HCC recur‐ rence. After the first report by Reig et al.,6 who raised a first warning about an unexpected high rate of recurrence of HCC in these patients, various groups have reported their experience on the recurrence and/ or occurrence of HCC in cirrhotic patients treated with DAAs, mostly with negative results. The “Debates” section of this issue of Liver International hosts a thoughtful review by Alberti and Piovesan focus‐ ing on this highly controversial issue.7 When discussing recurrence, we should bear in mind that the estimated likelihood of HCC recurrence after its presumed cure in patients with HCV cirrhosis untreated with antivirals approximates 10% at 6 months, 20% at 12 months and 50% after 24 months since HCC treatment.8 Hence, against such a high background of reappearance of cancer in viraemic patients, a healthy dose of caution should be exercised before concluding that DAAinduced SVR is associated with an unexpected rate of HCC recurrence. An extensive body of data not confirming the Spanish hypothe‐ sis comes from the pooling of DAAtreated patients who under‐ went curative HCC therapies enrolled in three French prospective multicenter ANRS cohorts. These data, encompassing over 500 subjects with sufficient followup, do not show an increased risk of HCC recurrence after DAAinduced SVR and report instead a comparable rate of reappearance of cancer among DAAtreated and untreated patients.9 In support of the French findings, data from the large cohort from the UK show a reduction in HCC rates in DAAtreated patients with advenced cirrhosis.10 Last but not least, when the interval between complete tumour eradication and antiviral therapy is quite long as in the cohort reported by Zavaglia et al.,11 the recurrence rate is actually low suggesting that the lon‐ ger the interval, the lower the risk that residual cancer is still pres‐ ent at the start of DAA therapy. We recently evaluated in the setting of a regional database (RESISTHCV), 185 cirrhotic patients (84% Child A) with complete response after curative treatment of HCC treated with DAAs.12 Over a mean followup of 24 weeks (range 860) since starting treatment, 24 patients had a recurrence of HCC with a crude rate of 13%. The 6 and 12 months. HCC recurrence rates were 7.9% and 16.3% re‐ spectively. One patient died during followup. The pattern of HCC recurrence was nodular in 83% patients (20/24) and infiltrative in 17% (4/24). Many concerns about this side of the controversy can be linked to: