Direct‐acting antivirals and recurrence of hepatocellular carcinoma

Given the high prevalence of hepatitis C virus (HCV) in an aging population, it is estimated that HCVrelated hepatocellular carcinoma (HCC) will continue to be a major source of morbidity and mortality until at least 2030. Direct-acting antiviral (DAA)–based therapy has substantially increased the proportion of HCV-infected patients who can achieve a sustained virological response (SVR). DAA-based therapy improves hepatocellular function and decreases the need for liver transplant. However, an important question that remains unanswered is whether DAAs can be effective in the tertiary prevention of HCVrelated HCC following definitive therapy of the tumor. Interferon (IFN)–based therapies have reduced the risk of HCC recurrence in patients who achieved an SVR. It was initially expected that SVR from DAA therapy would similarly reduce the risk of HCC recurrence; however, a recent study with 58 patients from 4 centers in Spain suggested a possible increase in HCC recurrence rates after DAA therapy. The authors observed a 27.6% early recurrence rate over a 5.7month (95% CI 0.4-14.6) median follow-up after DAA therapy. In a post hoc analysis, the highest recurrence rates were noted in those patients who had undergone DAA therapy within 6 months of HCC complete response. A couple of small cohort studies have demonstrated early recurrence rates below 5% after DAA therapy. Studies have typically had limitations including lack of a comparator group, such as untreated HCV patients, non-HCV patients, or a historical cohort of patients treated with IFN-based therapy. Although most patients had Barcelona Clinic Liver Cancer (BCLC) stage A HCC, few studies included detailed information on tumor burden. BCLC stage A can include a wide variety of patients: from a single tumor up to 5 cm and multinodular tumors each up to 3 cm in diameter. The initial complete response to local ablative therapy and the subsequent risk of local recurrence is inversely proportional to tumor size. The best data to date come from 3 French cohorts, which included a larger number of patients, had longer follow-up times, and included a comparator group. The authors of the French cohorts study did not observe increased HCC recurrence risk following DAA treatment after curative HCC therapy. Despite these subsequent negative studies, there continues to be concern about a potential for increased HCC recurrence with DAA therapy. Zanetto et al. compared dropout from the transplant waiting list from tumor progression among HCVrelated HCC patients who were and were not treated with DAA therapies. Among the 46 HCV-infected patients with HCC listed for liver transplantation, 23 were treated with DAAs and the other 23 remained untreated. Although the groups were not matched, there were no significant differences in total tumor volume or the proportion of patients exceeding Milan criteria. However, patients in the untreated group appeared to have more advanced liver dysfunction. Locoregional therapy was used in 61% of the DAAtreated group while on the transplant list compared with only 26% of the DAA-untreated group (P5 0.003), which was likely in part related to liver dysfunction precluding HCC-directed therapy. The authors found no significant difference in the study’s primary outcome: dropout from the waiting list due to tumor progression. In competing risk analyses, the authors found no difference in dropout probabilities among the groups (P5 0.8), but conversely, they found a lower probability to be transplanted in the DAA-treated group compared with controls (P5 0.04). There were no reported differences in the secondary outcomes of radiological tumor Abbreviations: BCLC, Barcelona Clinic Liver Cancer; DAA, directacting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IFN, interferon; SVR, sustained virological response.