The Impact of HCV Eradication by Direct-acting Antivirals on the Transition of Precancerous Hepatic Nodules to HCC

A Prospective Observational Study

Hidenori Toyoda; Takashi Kumada; Toshifumi Tada; Kazuyuki Mizuno; Yasuhiro Sone; Tomoyuki Akita; Junko Tanaka; Philip J. Johnson

Disclosures

Liver International. 2019;39(3):448-454. 

In This Article

Patients and Methods

Study Patients

Between September 2014 and May 2016, 561 patients with chronic HCV hepatitis or compensated HCV-related cirrhosis were initiated on DAA therapy. Of these, 470 underwent EOB-MRI within 2 weeks of starting therapy. Ninety-one patients did not undergo EOB-MRI for the following reasons; implantation of metal materials, including pacemakers, bolts for bone fractures, etc., in 29 patients; renal dysfunction in 47 patients; claustrophobia in nine patients; and patient refusal in six patients. Sixty-nine of the 470 patients who underwent pretreatment EOB-MRI had a history of curative HCC treatment. Because this study focused on the development of de novo HCC rather than recurrence, these patients were excluded. The remaining 401 patients were enrolled in this study (Figure 1). No patient with decompensated liver cirrhosis was included in these 401 patients because Japanese Medical Insurance does not allow anti-HCV therapy with DAAs in patients with decompensation. Also, no patients with coinfection with hepatitis B virus or HIV were included.

Figure 1.

Schematic flowchart of the enrollment of study patients

After DAA therapy, patients underwent routine ultrasound surveillance for HCC every 3 to 6 months according to Japanese guideline.[24] EOB-MRI examination was repeated every 6 to 9 months in patients in whom NHHNs had been detected at baseline. In patients without NHHNs at baseline, EOB-MRI examination was repeated every 6 to 12 months in addition to routine surveillance ultrasonography.

This prospective study was conducted after approval by the institutional review board of Ogaki Municipal Hospital and was carried out in compliance with the Helsinki Declaration. Written informed consent was obtained from all participating patients.

Patients underwent EOB-MRI within 2 weeks of the start of anti-HCV therapy using a 3.0-T whole-body MRI system (Discovery MR 750 W 3.0 T; GE Healthcare Japan, Tokyo, Japan). All imaging findings were independently evaluated by a radiologist (YS) and two hepatologists (HT and TT) who were blinded to the clinical data. Existence of NHHNs was evaluated by comparing the dynamic arterial phase and the hepatobiliary phase of EOB-MRI images. When liver nodules that were not typical for NHHNs were noted, other imaging examinations including contrast-enhanced ultrasonography or contrast-enhanced computed tomography were conducted as appropriate. If imaging assessments between the reviewers were discordant, consensus was achieved through discussion.

Control Patients

To compare the incidence of hypervascularization of NHHNs and the emergence of new NHHNs between patients in whom HCV was eradicated by DAA therapy and patients with persistent HCV infection, the rates of hypervascularization and new emergence were investigated in patients with persistent HCV infection who had undergone EOB-MRI. A total of 217 patients with chronic HCV infection who did not have a history of HCC underwent EOB-MRI between 2010 and 2015. Among these patients, NHHNs were detected in 59 patients (27.2%). After propensity score matching, the incidence of hypervascularization of these nodules was analysed and compared with that of patients in whom HCV was eradicated. Similarly, among 158 patients in whom NHHNs were not detected at baseline, the incidence of new NHHNs was analysed and compared with that of patients in whom HCV was eradicated after propensity score matching (Figure 2).

Figure 2.

Schematic flowchart comparing propensity score-matched patients with and without non-hypervascular hypointense nodules at baseline. These patients were derived from two groups: patients with HCV eradication (cases) and those with persistent HCV infection (controls)

Statistical Analysis

Differences in percentages between groups were analysed using the chi-squared test. Quantitative values were compared using the Mann-Whitney U test. The date of the baseline MRI study was defined as time zero for calculations of the incidence of hypervascularization of NHHNs or new emergence of such nodules. In the analysis of the incidence of hypervascularization of NHHNs among patients with NHHNs at baseline, those who demonstrated hypervascularization of these nodules were not censored, while those with no hypervascularization were censored. In the analysis of the emergence of new NHHNs among patients without NHHNs at baseline, those in whom NHHNs newly emerged were not censored, while those who did not develop NHHNs were censored. Statistical analysis was performed using JMP statistical software, version 11.0.0 (Macintosh version; SAS Institute, Cary, NC). All P values were derived from two-tailed tests, with P < 0.05 accepted as statistically significant.

For propensity score matching to compare the incidence of hypervascularization of baseline NHHNs by Gd-EOB-DTPA-enhanced MRI and the incidence of new NHHNs between patients in whom HCV was eradicated by DAA therapy and those with persistent HCV infection, we conducted one-to-one pairing of patients based on age, AST, ALT, platelet count, AFP, and FIB-4 index with propensity scores matched to two decimal places. The discriminative ability of the propensity score model was assessed using an area under the receiver operating characteristic (ROC) curve. Calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. Statistical analysis was performed using SPSS, version 18.0 (IBM, Tokyo, Japan).

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