Increase in Incidence of Hepatocellular Carcinoma in Chronic Hepatitis C Chinese After Sustained Virologic Response with Direct Acting Antiviral Agents as Compared to Pegylated Interferon Plus Ribavirin Therapy: A Prospective Open-Label Study

Background: The incidence of hepatocellular carcinoma (HCC) decreased significantly in persons with chronic hepatitis C (CHC) who achieved sustained virologic response (SVR) after pegylated-interferon plus ribavirin (PR) therapy. It remains controversial whether there is any difference in HCC incidence after SVR using direct-acting antiviral agents (DAAs), as compared to PR therapy. We report a prospective observational study which compare the SVR and post-SVR HCC incidence in CHC Chinese who had completed either DAAs or PR therapy. Methods: This prospective observational study (NCT02578693) was conducted at two sites in Beijing and Hong Kong, to evaluate SVR in CHC Chinese with completion of DAAs or PR therapy. Those with SVR were followed up at 12-24 weekly intervals with surveillance for HCC performed by ultrasonography and alpha-fetoprotein at each visit. Multivariate Cox analysis was used to explore factors associated with post-SVR occurrence of HCC. Findings: Between October 2015 and May 2017, SVR was observed in 519 of the 533 (97.4%) and 817 of 1202 (68.0%) CHC patients with completion of anti-HCV therapy (p = 0.0001), respectively. Subjects that achieved SVR were followed with a median duration of 3 years. During the follow-up period, HCC developed in 28 (5.8%) and 25 (3.3%) post-SVR patients treated with DAAs and PR therapy, respectively (p = 0.036). The use of DAAs, older age (≥55 years), diabetes mellitus, higher LSM (≥17.5 kPa), and higher AFP level (≥30 ng/ml) at SVR were associated with increased risk of HCC (hazard ratios: 1.9, 3.1, 3.9, 4.9 and 5.2 respectively). Interpretation: After a median follow-up of 3 years, a lower incidence of HCC was observed in CHC patients who had SVR with PR therapy compared to those treated with DAAs. HCC surveillance in CHC patients with SVR should be performed more stringently in those with high risk factors and treated with DAAs. Clinical Trial Registration: The clinical protocol was registered at ClinicalTrials.gov (NCT02578693). Funding Statement: This is an investigator-initiated study supported by Chinese medical association (Grant No.13071110496) and capital characteristic clinic project of the Beijing municipal science and technology commission (Grant No. Z181100001718034). RFS is supported by the Emory Center for AIDS Research NIH grant 2P30-AI-050409. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: Approval was obtained from the Ethics Committees in Hong Kong (Hong Kong Clinical Research Ethics Committee, HKCREC) and Beijing (Ethics Committee of Beijing 302 hospital). Informed consent was obtained from all patients and the study was conducted in compliance with the 1975 Declaration of Helsinki, Good Clinical Practice guidelines, and local regulatory requirements.