Hepatocellular carcinoma after direct-acting antiviral drug treatment in patients with hepatitis C virus

Abstract

Background and aim: Given the use of direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV), their effects on hepatocarcinogenesis should be determined.

Methods: This study enrolled 349 patients with HCV who underwent DAA treatment at our hospital between 2014 and 2018. Their median age was 65 years, and 184 were male; 301 cases were of HCV serotype 1, and 48 were of serotype 2. The DAA treatment was daclatasvir/asunaprevir in 107 cases, sofosbuvir (SOF)/ledipasvir in 147 cases, ritonavir-boosted ombitasvir/paritaprevir in 28 cases, elbasvir/grazoprevir in 19 cases, and SOF/ribavirin in 48 cases. The patients' histories included hepatocellular carcinoma (HCC) in 45 cases, liver transplant (LT) in 10 cases, and kidney transplant (KT) in 17 cases.

Results: Sustained virological responses occurred in 335 cases (96%). DAA treatment was initiated a median of 16.3 months after HCC treatment. After DAA treatment, 15 cases (33%) had recurrence of HCC after a median of 11.6 months, and 3 cases (1%) developed de novo HCC. Six LT patients and one KT patient had HCC; however, no HCC was observed after DAA. The incidence of HCC was significantly higher in patients with multiple HCC treatments in the Cox hazard model (hazard ratio 1.664, 95% confidence interval 1.134-2.441, P < 0.01). Surgical resection or LT reduced the risk of HCC.

Conclusions: DAA did not increase the rate of HCC, even in immunosuppressed patients. However, careful follow-up for HCC recurrence is required in previously treated cases.

Keywords: direct‐acting antivirals; hepatocarcinogenesis; hepatocellular carcinoma.

Figure 1

Flow chart of the study. In total, 349 cases were analyzed, and 45 cases had a history of hepatocellular carcinoma (HCC) before direct‐acting antiviral drug (DAA) treatment. After DAA treatment, 18 cases were complicated with HCC.

Figure 2

Hepatocellular carcinoma (HCC) occurrence and recurrence in patients with and without a previous history of HCC. HCC occurred significantly more often in patients with a history of previous HCC by Kaplan–Meier analysis (P < 0.01).

Figure 3

Hepatocellular carcinoma (HCC) recurrence according to type of previous HCC treatment. (a) HCC treatment regimen, (b) number of treatments. Kaplan–Meier analysis showed that the rate of HCC tended to be reduced by surgery (surgical resection or LT [a, P = 0.07]) and significantly increased with multiple treatments (b, P < 0.01).

Figure 4

Hepatocellular carcinoma (HCC) recurrence according to liver/kidney transplant (LT/KT). Compared with nonrecipients, LT/KT recipients did not show significantly increased HCC occurrence, even under immunosuppression, during 29.0 (range: 5.2–40.7) months of follow‐up (Kaplan–Meier analysis, P = 0.16).

Figure 5

Representative computed tomography findings in case no. 15 after direct‐acting antiviral (DAA) HCC recurrence: (a) 2.5 years before DAA treatment; (b) after RFA therapy; (c) at the time of sofosbuvir + ribavirin (SOF + RBV) treatment; and (d) 8 and (f) 19 months after DAA treatment. Red arrows, hepatocellular carcinoma (HCC). (e) Abdominal angiography 8 months after DAA treatment. HCC was observed 2.5 years before DAA treatment (a) and was completely cured by radiofrequency ablation (RFA) therapy (b). SOF + RBV was administered for 3 months (c). Tiny HCCs were observed 8 months after DAA treatment (d), and hepatic arteriography showed multiple tumors with des‐gamma‐carboxy pro‐thrombin (DCP) elevation (e). HCC was uncontrollable despite many treatments (f). AFP, alpha fetoprotein.