HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma

Highlights

• DAA-induced SVR is associated with a 71% reduction in HCC risk.

• SVR is associated with a similar reduction in HCC risk no matter what regimen is used to achieve it.

• Treatment with DAAs is not associated with increased HCC risk compared with interferon.

Background & Aims

It is unclear whether direct-acting antiviral (DAA) treatment-induced sustained virologic response (SVR) reduces the risk of hepatocellular carcinoma (HCC) in patients with HCV infection. Therefore, in the current study, our aim was to determine the impact of DAA-induced SVR on HCC risk.

Methods

We identified 62,354 patients who initiated antiviral treatment in the Veterans Affairs (VA) national healthcare system from 1 January 1999 to 31 December 2015, including 35,871 (58%) interferon (IFN)-only regimens, 4,535 (7.2%) DAA + IFN regimens, and 21,948 (35%) DAA-only regimens. We retrospectively followed patients until 15 June 2017 to identify incident cases of HCC. We used Cox proportional hazards regression to determine the association between SVR and HCC risk or between type of antiviral regimen (DAA-only vs. DAA + IFN vs. IFN-only) and HCC risk.

Results

We identified 3,271 incident cases of HCC diagnosed at least 180 days after initiation of antiviral treatment during a mean follow-up of 6.1 years. The incidence of HCC was highest in patients with cirrhosis and treatment failure (3.25 per 100 patient-years), followed by cirrhosis and SVR (1.97), no cirrhosis and treatment failure (0.87), and no cirrhosis and SVR (0.24). SVR was associated with a significantly decreased risk of HCC in multivariable models irrespective of whether the antiviral treatment was DAA-only (adjusted hazard ratio [AHR] 0.29; 95% CI 0.23–0.37), DAA + IFN (AHR 0.48; 95% CI 0.32–0.73) or IFN-only (AHR 0.32; 95% CI 0.28–0.37). Receipt of a DAA-only or DAA + IFN regimen was not associated with increased HCC risk compared with receipt of an IFN-only regimen.

Conclusions

DAA-induced SVR is associated with a 71% reduction in HCC risk. Treatment with DAAs is not associated with increased HCC risk compared with treatment with IFN.

Lay summary

It was unclear whether direct-acting antiviral treatment-induced sustained virologic response reduces the risk of liver cancer in patients with HCV infection. We demonstrated that eradication of HCV infection with direct-acting antiviral agents reduces the risk of liver cancer by 71%.

Introduction

Eradication of HCV might be expected to reduce the risk of hepatocellular carcinoma (HCC) by preventing the future development of cirrhosis or by reversing early cirrhosis, a major risk factor for HCC. In addition, HCV might itself promote carcinogenesis,¹ such that its eradication directly decreases HCC risk. Indeed, a meta-analysis of 18 studies of interferon (IFN)-based antiviral treatments for HCV suggested that sustained virologic response (SVR) was associated with reduced risk of HCC (relative risk 0.24; 95% CI 0.18–0.31).² IFN-based treatments have now been replaced by direct-acting antiviral agents (DAAs). It is unclear whether the impact of SVR on HCC risk is different depending on whether SVR is achieved with either IFN-based regimens or DAAs. Surprisingly, recent studies suggested little or no impact of DAA-based antiviral treatment on HCC risk and even reported that DAAs might increase the risk of HCC recurrence.[3], [4], [5], [6], [7], [8] However, these studies were grossly underpowered, had limited follow-up time, mostly studied HCC recurrence rather than incidence, and did not compare those who achieved SVR because of DAAs to those who did not with respect to HCC risk.

In the current study, our aim was to determine the extent to which eradication of HCV with DAA-based treatments was associated with reduction in the risk of HCC, and whether this association was different for SVRs achieved by DAA vs. IFN-based regimens. We also aimed to determine whether receipt of DAA-based treatment compared with IFN-based treatment was associated with HCC risk.