The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C‐infected patients treated with direct‐acting antivirals with and without pegylated interferon: A Belgian experience

Recently, concerns were raised of high rates of HCC recurrence in patients treated with direct‐acting antivirals (DAA) for hepatitis C infection. We investigated the HCC occurrence and recurrence rates within 6 months after treatment with DAA with or without pegylated interferon (PEG‐IFN) in real life. This is a retrospective, multicenter cohort trial, executed in 15 hospitals distributed across Belgium. Populations were matched based on fibrosis score (Metavir F3‐F4). Patients with a Child‐Pugh score ≥ B were excluded. In total, 567 patients were included, of whom 77 were treated with PEG‐IFN+DAA between 2008 and 2013 and 490 with DAA without PEG‐IFN between 2013 and 2015. Patients treated with PEG‐IFN+DAA (53±9y) were younger than patients treated with DAA without PEG‐IFN (59±12y) (P=.001). 47% of patients treated with PEG‐IFN+DAA were in the F4 stage vs 67% of patients treated with DAA without PEG‐IFN (P=.001). Screening was inadequate in 20% of both patient groups (P=.664). The early occurrence rate of HCC was 1.7% and 1.1% in patients treated with DAA with and without PEG‐IFN, respectively (P=.540). The early recurrence rate was 0% in patients treated with PEG‐IFN+DAA and 15.0% in patients treated with DAA without PEG‐IFN (P=.857). There is no difference in early occurrence of new HCC between patients treated with DAA with and without PEG‐IFN. We did observe a high early recurrence rate of HCC in patients treated with DAA without PEG‐IFN. However, these patients were at baseline more at risk for HCC. Finally, in 20%, screening for HCC was inadequate.


| INTRODUCTION
Patients with cirrhosis whether or not caused by hepatitis C viral infection (HCV) are at risk for development of hepatocellular carcinoma (HCC). 1,2 Multiple studies have provided evidence that achieving a sustained viral response (SVR) is associated with a reduced risk of HCC. [3][4][5][6][7][8][9][10][11] Nevertheless, the risk of HCC persists also after SVR and continued monitoring is necessary; 9 especially in patients with cirrhosis, older patients and patients with diabetes, the risk of HCC is estimated to be higher. 9,12,13 The introduction of direct-acting antiviral therapy (DAA) has revolutionized HCV therapy these last years. [14][15][16][17] These regimens are highly effective, and with the arrival of new pan-genotypic regimens in the near future, nearly 100% of the patients can be cured with even more simplified regimens. [18][19][20][21] However, caution has been raised for high rates of HCC occurrence and recurrence in patients treated with DAA. [22][23][24][25] This heightened the discussion regarding the use of DAA in high-risk patients. 26,27 However, a retrospective study of three distinct cohorts (HEPATHER, CirVir and CUPILT cohorts) of 660 patients in total of whom 516 received DAA therapy did not report an increased risk of HCC recurrence after DAA treatment. 28 Therefore, the evidence is still unclear whether there is a real increased risk of HCC after DAA treatment. We have performed a retrospective analysis of patients treated with DAA with and without pegylated interferon (PEG-IFN) to further investigate the link between HCC recurrence or occurrence and DAA therapy.

| Study design
We performed a national, retrospective cohort study in 15 hospitals, distributed across Belgium. Data were available from two studies which used the same methodology, focusing on the outcome of DAA with and without PEG-IFN in HCV-infected PWID vs non-PWID. 29,30 Data were collected from the medical patient files.
From the first study, all patients treated with PEG-IFN + ribavirin + telaprevir or boceprevir with a Metavir score of F3/F4 were included.
Data were collected between 2008 and 2013 in 11 hospitals. From the second study, all patients treated with simeprevir + sofosbuvir ± ribavirin, daclatasvir + sofosbuvir ± ribavirin or ombitasvir/paritaprevir ritonavir -dasabuvir ± ribavirin were included. As the Belgian reimbursement criteria were applicable on all these patients, this cohort existed of patients with F3-F4 fibrosis only. Patients with Child-Pugh B and C cirrhosis were excluded. Data were collected between December 2013 and December 2015 in 15 hospitals.

| Endpoints of study
The main objective of this trial was to compare the occurrence and recurrence rates of HCC in patients treated with DAA with and without PEG-IFN. As a secondary objective, we analysed the percentage of patients who have received radiological follow-up within 6 months after DAA therapy.

| Statistical analysis
Descriptive statistics of patient characteristics are presented: for continuous variables, means and standard deviation, and for categorical variables, proportions and percentage are given. To compare patient groups, regression methodology was used for continuous variables (such as age and BMI), and chi-square test for categorical variables (such as fibrosis score, treatment completion). A P-value <.05 was considered statistically significant.

| Baseline characteristics
Patient characteristics are described in Table 1 The characteristics of HCC staging and treatment are described in Table 2. Most patients had a BCLC stage A score, and the median follow-up time between the treatment for HCC and start of HCV treatment was 12 months. Data of the follow-up time were prone to large outliers of patients in follow-up for more than 10 years. 17 patients had follow-up of less than 1 year.
T A B L E 1 Differences in patient characteristics between patients treated with DAA with and without PEG-IFN

| Results of follow-up
The results of follow-up for HCC are visualized in Figure 1.

| DISCUSSION
Due to the development of DAA, our ability to treat HCV-infected patients has increased significantly, and more difficult to treat patients can be cured. 18,21,31,32 Earlier trials in the interferon era have provided evidence that reaching sustained viral response (SVR) significantly improves patient outcome, with less development of decompensated cirrhosis and HCC. [3][4][5][6][7][8][9][10][11] However, this has not been shown for patients treated with DAA, as long-term follow-up is not yet available for these patients. Recently, questions were raised regarding higher-thanexpected recurrence rates of HCC in patients treated with DAA. 22,23 This conclusion was not confirmed in a retrospective evaluation of patients with HCC in three large cohorts. 28 Furthermore, not only recurrence rates were estimated to be higher, but two more trials warned for higher-than-expected occurrence rates. 24,25 We investigated the occurrence and recurrence rates in a large, multicenter, real-life cohort. To compare this with the interferon era, only patients with a fibrosis stage of F3 or F4 (Child-Pugh A) were included. This was based on the reimbursement criteria for DAA in Belgium, and on the treatment paradigm in the interferon era to not treat patients with advanced liver disease.
In our cohort, we could not find higher-than-expected early occurrence rates of HCC in patients treated with DAA without PEG-IFN (1.1%; n=4/355) vs people treated with PEG-IFN + DAA (1.7%; n=1/59). These rates were comparable to the estimated 1%/year frequency of HCC in patients with SVR treated with PEG/IFN and ribavirin dual therapy. [33][34][35][36] We did find a high recurrence rate of 15.0% (n=6/41) 6 months after treatment with DAA without PEG-IFN. We could not compare this to the cohort of patients treated with PEG-IFN + DAA, as only one patient was treated who had a HCC in the history. In our cohort, we found that patients with a HCC recurrence also had a lower SVR rate, but this was due to development of HCC even during treatment. This was the reason to stop treatment in a palliative setting for two of three patients. Importantly, only patients treated by LR or RFA of the primary HCC developed recurrence, whereas patients with a liver transplantation did not. Thus 33.3% (3/9) of patients treated with LR had a recurrence and also 33.3%  This was important in the interferon era and will remain important in patients treated with DAA. (33)(34)(35)(36). In this real-life cohort, follow-up rates were not ideal, as 20% of the people are not screened by radiographic (ultrasound/CT or MRI) analysis at least 6 months after the end of treatment. Therefore, it is imperative to inform clinicians and patients that a risk of developing HCC remains even after the cure of HCC, and regular follow-up is necessary.