Hepatocellular carcinoma after direct-acting antivirals for hepatitis C is associated with KIR-HLA types predicting weak NK cell-mediated immunity

Abstract

Background and aims: Second-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC.

Methods: Participants underwent full HLA class I/KIR typing and long-term HCV follow-up.

Results: A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC.

Conclusion: Cirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.

Keywords: Antiviral Agents; Carcinoma; Hepatitis C; Hepatocellular; Immunity; Innate; Killer Cells; Natural.

Figure 1.

Associations of HCC and Cirrhosis with putative KIR-mediated immunity are discordant in 2G DAA-treated individuals compared with HCC and Cirrhosis in DAA-naive HCV patients. The development of post-treatment HCC and the incidence of cirrhosis in 152 patients treated with 2G DAA (panels A, C), is compared to the treatment naive (or pre-treatment) incidence of HCC and cirrhosis in 353 BASIC-HepC patients (naive or pre-treatment, panels B, D). The development of both cirrhosis (panel D) and HCC (panel B) were similarly distributed in each NK cell immunity group (strong, intermediate, or weak) in DAA naive subjects. In 2G DAA-treated subjects, the development of post-2G DAA HCC was uniquely skewed toward patients with the weak NK cell immune groups (panel A), but not in cirrhotic subjects with predicted strong immunity (panel C).