HCC is one of the serious complications of chronic HCV infection, and the risk is increased with advancing hepatic fibrosis and cirrhosis reaching an incidence of about 3.5% in cirrhotic patients per year [10]. Chronic HCV infection induces inflammation with consequent hepatocarcinogenesis, so the resolution of HCV infection should result in a reduced incidence of HCC [17]. HCV treatment outcomes significantly improved after the introduction of new DAAs in the past few years with a response of > 90% of patients achieving an SVR after 12 weeks of starting treatment [18]. The increased success in HCV treatment has raised the hope in a significant decrease in the rate of HCC occurrence and even its recurrence after treatment of neoplastic lesions [10]. However, the impact of DAA-based treatment on the incidence of hepatocellular carcinoma (HCC) in patients with cirrhosis and particularly on the incidence of HCC recurrence after successful curative treatment has emerged as a controversial issue with potential clinical implications [19].
Previous studies had conflicting results about the effect of DAA on HCC development or recurrence. This study was performed to highlight this effect specially on Egyptian patients. The study was carried out on 50 patients who previously received HCC intervention and treated for HCV using DAAs after confirming HCC regression and response to different treatment modalities. Patients were followed up for at least 1 year after antiviral therapy. We have selected a control group of 50 patients with cured HCC who did not receive DAA therapy, to compare the recurrence rate in both groups and its relation to the antiviral therapy.
The current study addressed an insignificant difference between both groups of patients in demographic data and Child score. Patients in both groups were treated for HCC with RFA, resection, and alcohol ablation. In group I, ten patients underwent liver transplantation which was not recommended in the second group owing to the universal recurrence of HCV infection post-liver transplant that should be treated to avoid allograft cirrhosis [20].
Unlike previous studies which raised the concern that DAA therapy may increase or accelerate the risk of HCC recurrence and lead to more aggressive tumors, the results of our study came different. This study identified lower HCC recurrence rates in patients who received antiviral therapy as compared to those who did not. A recurrence rate of 38% was reported in patients who received antiviral therapy in a median time of 8 months after starting DAA therapy, whereas 62% of patients who did not receive DAAs developed HCC recurrence in a median time of 3 months after HCC intervention. These data were not consistent with Reig et al. [19], who demonstrated an HCC recurrence rate of 27.6% in 58 DAA-treated patients included in their study. This result was significantly higher than that of the non-treated patients, supported by their observations of other studies.
Conti et al. introduced results that matched with Reig et al., concerning HCC recurrence rates where they demonstrated a recurrence rate of 28.8% in 59 DAA-treated patients during 24 weeks of post-treatment follow-up. This study lacked a control arm to identify whether this rate differed from the non-treated patients or not [10]. Although the results of our study showed a larger recurrence rate compared to the previous two studies, yet in comparison to the control group, DAAs did not appear to increase HCC recurrence rates.
Also, these results agreed with those obtained by El Kassas et al. who found that among the 53 patients treated with DAAs, they observed 37.7% recurrence after a median of 16.0 months of follow-up. Among the 63 patients not treated with DAAs, they observed a 25.4% HCC recurrence after a median of 23.0 months of follow-up [8].
Another study by Rewisha et al. presented a case report that included a series of 16 patients who were diagnosed as Child A HCV-related cirrhosis. All patients received IFN-free, sofosbuvir-based regimens. Sofosbuvir plus ribavirin was prescribed to 11 cases (68.8%); 14 patients had predominantly small HCC and an occurrence time of 4.19 ± 3.48 months post-treatment [21]. However, the study did not include HCC intervention.
On the other hand, several studies were consistent with our study, the report published by the French Agency for Research on AIDS and Viral Hepatitis, and the ANRS (France Recherche Nord and Sud For Hepatitis and HIV). The report included 3 ANRS cohorts which showed a lack of evidence on DAAs’ effect on increased HCC recurrence rates. Where the first study showed a recurrence rate of 12.7% in treated versus 20.5% in non-treated patients, the second showed a CO23 CUPILT cohort which showed a recurrence rate of 2.2% in liver transplant recipients receiving DAA therapy. But, this study did not involve a control arm [22].
A study by Kanwal et al. reported that cirrhotic patients with SVR had a significantly reduced risk of HCC compared to patients without SVR (76% risk reduction). They highlighted that the HCV-treated population has changed significantly in the DAA era and now includes many patients with other HCC risk factors (alcohol abuse, age older than 65 years, and patients with advanced cirrhosis), which were excluded before from IFN therapy [23].
A prospective observational study by Calvaruso et al. concluded the early benefit of viral eradication in HCV cirrhosis throughout all stages of cirrhosis. The authors analyzed only patients with cirrhosis (2249 patients: 90.5% Child-Pugh class A, 9.5% Child-Pugh class B) treated with DAA. Only 78 patients (3.4%) developed HCC during a mean observation of 14 months from the start of DAA treatment; the overall cumulative rate of HCC at 1 year was 2.9%. The occurrence of HCC is significantly reduced in patients with compensated cirrhosis. The authors did not support the hypothesis that HCC that develops during DAA treatment or after early follow-up is more aggressive and more difficult to treat with available therapies [24]. These results support that obtained by the present study concerning the recurrence of HCC, but the limitation in our results is the lack of data about the aggressiveness of the recurrent tumor.
The results of this study reported an HCC recurrence rate of 38% in patients with treated HCC who received DAAs compared to 62% in DAA-non-treated patients proving that clearance of HCV infection using DAA therapy did not increase the risk of HCC recurrence and it did not abolish it. So, a proper selection of patients enrolled for antiviral therapy and precise assessment of fibrosis prior to treatment using an accurate test like transient elastography are important. Besides, a close follow-up of the patients after the end of treatment especially those with advanced fibrosis and cirrhosis for a long duration is necessary.