Treatment efficacy for patients with chronic hepatitis C and preexisting hepatocellular carcinoma by directly acting antivirals

Aim: Despite the high cure rate of interferon-free directly acting antivirals (DAAs) for chronic hepatitis C (CHC) patients, the treatment efficacy for patients with preexisting hepatocellular carcinoma (HCC) remains undefined. We aimed in the present study to address the issue by using novel DAAs in treating CHC patients who were adherent to treatment in Taiwan. Methods: CHC patients with or without HCC were consecutively enrolled. The primary objective was sustained virological response (SVR) defined as undetectable HCV RNA throughout 12 weeks of a post-treatment follow-up period (SVR12). Only patients with available SVR12 were enrolled for final analysis. Results: A total of 1237 patients (1113 non-HCC, 101 inactive HCC and 23 active HCC) were enrolled. The overall SVR12 rate was 98.9%, and was similar between HCV patients with and without pre-existing HCC (98.4% vs. 98.9%, P = 0.64). While HCC patients were classified as those who had active or inactive HCC, the SVR12 was also similar between patients with and without active HCC (95.7% vs. 99.0%, P = 0.34). Among the 101 patients without viable HCC at the time of DAA initiation, eighty-four patients exhibited curative therapy and the other 17 Page 2 of 9 Dai et al. Hepatoma Res 2020;6:16 I http://dx.doi.org/10.20517/2394-5079.2019.40 patients experienced HCC recurrence before DAAs. Among the 23 patients with viable HCC at the time of DAA treatment, 10 patients had received curative therapy for HCC whereas the remaining 13 patients had HCC that was never cured. The SVR12 rates were also similar among the four subpopulations, being 98.8% (83/84), 100% (17/17), 90% (9/10) and 100% (13/13) respectively. Conclusion: CHC patients with HCC who were adherent to potent DAAs achieved similar SVR12 rate compared to those without HCC and could be effectively treated.


INTRODUCTION
Hepatocellular carcinoma (HCC) is one of the most common malignancies [1] , which attributes to the second cause of cancer-related death worldwide [2] . Hepatitis C virus (HCV) infection is one of the leading etiologies of HCC, which may account for one third of HCC patients [3] . On the other hand, the risk of HCC decreases drastically after successful antiviral therapy [4] . Interferon-free all oral directly acting antivirals (DAAs) have become a standard of care since 2014, providing ultimately high HCV cure rate and satisfactory safety profiles [5,6] . Emerging evidence has also shown the benefit of DAAs in reducing the development of HCVrelated HCC [7] .
Recently, the issue concerning whether pre-existing HCC would compromise the sustained virological response (SVR) rate in chronic hepatitis C (CHC) patients with DAAs has been raised, although discordant results might in part be attributed to different treatment regimens and patient characteristics [8] . In patients with pre-existing HCC, a recent meta-analysis has shown that different treatment responses might exist between patients with or without viable HCC at the time of initiating DAAs [9] . Some of the earlier studies used suboptimal treatment regimens that could not truly reflect the real world situation nowadays [10] . By using current DAAs, an SVR rate of > 95% could be accomplished across populations [11,12] . It is therefore crucial to revisit the issue by using potent DAAs in daily practice. In addition, HCC patients might have more safety concerns and are more likely to have experienced treatment discontinuation [5] . Unequal tolerability might further compromise efficacy evaluation in these patients. Herein, we aimed to explore the issue by recruiting a well-characterized patient group in terms of HCC status who were adherent to novel DAA regimens.

METHODS
Patients receiving DAAs were consecutively enrolled from Aug 2015 to Mar 2019. The treatment strategies were based on regional guidelines [13] and regulations of the Ministry of Health and Welfare of Taiwan. Daclatasvir (DCV)/Asunaprevir (ASV) for HCV genotype 1 (HCV-1) and Sofosbuvir (SOF)/ribavirin for HCV-2 have been reimbursed in Taiwan since 2017. Due to the previous relatively suboptimal treatment responses, patients who used these regimens were excluded in the current study.
The diagnosis of HCC was ascertained by pathology or clinical judgments based on the guidelines of the Asian Pacific Association for the Study of the Liver [14] and the American Association for the Study of Liver Diseases [2] . HCC was defined as curative if the initial presentation could be managed by surgical resection, local ablation or liver transplantation. The inactive HCC indicated that patients who had non-viable HCC were defined as if there were no image evidence of recurrence within 6 months before initiating DAA treatment. Other patients were defined with active HCC. The Review Board of the Kaohsiung Medical University Hospital approved the protocols that followed the guidelines of the International Conference on Harmonization for Good Clinical Practice. All patients provided written informed consent.
The primary outcome was treatment efficacy defined as undetectable HCV RNA at the 12-week follow-up period after completing the anti-HCV therapy (SVR12). Only patients with available SVR12 were enrolled for final analysis.

Statistical analyses
Frequency was compared between groups using the χ 2 test with the Yates correction or Fisher's exact test. Group means (presented as the mean standard deviation) were compared using analysis of variance and Student's t-test or the nonparametric Mann-Whitney test when appropriate. The fibrosis-4 score (FIB-4) was calculated as age (years) × AST (U/L)/{platelets (10 9 /L) × [alanine transaminase (ALT) (U/L)]} 1/2 . The statistical analyses were performed by using the SPSS 12.0 statistical package (SPSS, Chicago, IL, USA). All the statistical analyses were based on two-sided hypothesis tests with a significance level of P < 0.05.

Patient characteristics
As shown in Table 1, 1237 patients were enrolled in the current study, with their patient and viral characteristics and treatment regimens also shown.

DISCUSSION
In the present study in Taiwanese patients with HCC, in addition to the similar effectiveness compared to patients without HCC by high potency DAAs, we demonstrate equivalent effectiveness also in both patients with and without HCC. With a relatively high SVR rate by interferon-based therapy in Taiwan compared to Western countries [20,21] , the Taiwanese National Health Insurance Scheme has reimbursed the cost of the PegIFN/RBV therapy since 2013 [22] . Due to the adverse effects of the IFN-based regimen, the treatment of patients with HCC is quite limited, even though the SVR rate is equivalent in patients with and without HCC when patients achieved good adherence, particularly in CHC patients after successful eradication of HCC [23] . Since 2017, DAAs have been reimbursed by TNHI (free of charge for DAA medication) in patients with limited to advanced fibrosis and cirrhosis. The DAA treatment then became the standard treatment of CHC in Taiwan for patients fulfilling the reimbursement criteria, instead of interferon-based therapy. The high SVR rate has been reported as more than 97% in patients who completed the duration of therapy by ASV plus DCV if the patients had no NS5A mutants, PrOD with/without RBV and GZR/EBR with/without RBV [24] . Since 2019, patients with all stages of fibrosis have been reimbursed for DAA therapy, and all high potency first-line DAAs are available. The treatment of CHC has come to a new era including all subgroups of patients including patients with HCC particularly in patients with liver function impairment with the administration of new agents with SOF/LDV or SOF/VEL but not protease inhibitors.
The cure for HCV in HCC patients is encouraged by association with increased overall survival in these patients by interferon-based therapy, as per reports by Singal et al. [25] and Morgan et al. [26] Recently the benefits of the eradication of HCV infection by DAAs have also been elucidated by Kamp et al. [27] and Dang et al. [28] Nevertheless, the potentially suboptimal antiviral treatment efficacy by DAAs has been reported by some studies indicating treatment inferiority for HCC patients. Beste et al. [29] reported the presence of HCC being associated with lower likelihood of SVR with SOF, SOF/LDV, and PrOD with or without ribavirin. Saberi et al. [10] have observed a high rate of viral relapse after DAA treatment in patients with a concurrent HCC diagnosis in their case series. Prenner et al. [30] have reported that when considering the treatment efficacy, presence of active HCC at the initiation of HCV therapy is significantly associated with DAA treatment failure. Radhakrishnan et al. [31] reported the presence of HCC was associated with significantly lower odds of achieving SVR compared to those who had no HCC. However, HCC treatment status was not associated with SVR among those with HCC.
A recent meta-analysis including 49 studies from 15 countries concluded that compared to those without HCC, SVR rates were lower in patients with HCC, especially with active HCC [9] . Patients with HCC treated with SOF/LDV had lower SVR rates than patients without HCC (92.6%, n = 884 vs. 97.8%, P = 0.026) and active/residual HCC than patients with inactive/ablated HCC (SVR 73.1% vs. 92.6%, P = 0.002). The role of 4.0 ± 0.5 3.9 ± 0.5 4.1 ± 0.3 3.9 ± 0.6 Serum bilirubin, mg/dL (mean ± SD) 1.1 + 0. the different DAA regimens on the impact of SVR in patients with HCC remains unclear [32] . It is noteworthy that in some studies, patients may receive possibly inadequate or low-potency treatments such as simeprevir/ SOF 12 weeks, SOF/LDV 12 weeks in treatment-experienced patients or SOF/ribavirin regimens. It is interesting as to whether the regimens influence the SVR rate. In the present study, we observed similar SVR rates between patients with and without HCC, or HCC patients with and without active diseases in patients with adherence to potent DAAs. The very high SVR rates (> 98%) might prevent negative impact on the responses. Our study has emphasized the importance of potent DAAs in addition to good compliance in patients with HCC.
It is not clear why the presence or history of HCC might influence the likelihood of achieving SVR. We propose some mechanisms for the suboptimal effects of DAAs in patients with HCC. Firstly, tumor cells serve as a sanctuary site for HCV where the replication of the HCV is preserved [33] . Secondly, HCV within tumor cells might evade the antiviral effects of DAA therapy due to ineffective blood delivery to the target site [34] . Thirdly, poor cancer immunity and altered tumor microenvironment has also been linked to altered antiviral efficacy of DAA therapy [35] . Since the SVR is highly related to the effective distribution of the drug, different vascularity changes in HCC or the treated HCC might also be causative. In our patients, good adherence and sufficient duration and dosage of the DAAs might have possibly overcome the barriers for efficacy by HCC. There are some limitations in the present study. Firstly, a retrospective observational study design may possess some selection bias in obtaining the real efficacy of the therapy. Secondly, we did not record the real-world withdrawal rate of the HCC patients receiving the DAAs although the treatment duration was shortened and the potency increased by the currently widely used DAAs, which may have improved the rate of complete treatment and discontinuation significantly. Thirdly, with a high cure rate for HCV, we did not observe any impact of the DAA therapy on the natural course of the HCC. The controversies of the influence of HCV therapy by DAAs have been discussed with more evidence from the recent systematic reviews and meta-analyses disputing the unfavorable effects on the development of more advanced recurrence or early recurrence in patients with HCC [35] . Lastly, because of the relatively small number of HCC patients treated by DAAs in our study, the statistical non-significance in HCC and non-HCC patients possibly needs further large-scale studies for validation.
In conclusion, we have demonstrated similar SVR rates in patients with HCC, either active or inactive, receiving a complete course of potent DAAs in Taiwan. With high potent DAAs available and easier and more convenient care including shorter duration and less adverse effects during treatment, our results suggest the importance of adherence to DAA therapy and the preference of treating HCV aggressively for HCC patients in clinical settings in Taiwan.