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Rutledge et al. Hepatoma Res 2019;5:31 I http://dx.doi.org/10.20517/2394-5079.2019.19 Page 3 of 12

METHODS
Data sources
A comprehensive literature search was performed using ScienceDirect, Ovid®, Web of Science, MEDLINE,
Google Scholar and the Cochrane Library. Abstract books from the major international hepatology
meetings including European Association for the Study of the Liver and American Association for the
Study of Liver Diseases were also examined thoroughly for additional studies. We searched databases from
inception through January 2019 and included studies with human subjects which measured rates of HCC
occurrence or recurrence in persons infected with HCV.

Study selection
We considered retrospective or prospective observational cohort studies and randomized controlled
trials as eligible studies for analysis. We included studies if they assessed (1): de novo HCC development
in patients with chronic HCV; or (2): HCC recurrence in patients with chronic HCV who had received
successful HCC curative treatment and were believed to be cancer-free at the time of HCV treatment.
HCC treatments which were categorized as being potentially curative included liver resection, microwave
coagulation therapy, percutaneous ethanol injection therapy, radiofrequency ablation, and liver
transplantation. We included HCV-infected patients regardless of the presence or absence of cirrhosis and
regardless of HCV treatment status (DAA-treated, IFN-treated or untreated). Subjects with and without
SVR were included. Where we found multiple studies from the same population, the most recent studies
were included. All full text manuscripts and conference abstracts were considered for inclusion. Studies
with missing essential data or with unclear or less rigorous methodology were excluded. We excluded
studies with a follow-up period of less than 1 year, to avoid including cases where sub-clinical HCC was
likely present at the time of treatment initiation. The quality of evidence in each included study was
assessed using the Cochrane tool for risk of bias [Supplementary Tables 1 and 2].

Data extraction
We manually pulled data from studies into a pre-formatted standardized spreadsheet containing clinical,
demographic and epidemiological headings. In the spreadsheet, studies were categorized by treatment type
(DAA-treated, IFN-treated or untreated) and primary endpoint of HCC occurrence or recurrence. They
were then further sub-divided into SVR and non-SVR groups where this information was available from
studies.

Data analysis
The outcomes evaluated were HCC occurrence and HCC recurrence. Studies with zero events were
excluded from the analysis. The incidence rates of HCC occurrence or recurrence were calculated per
100py. Meta-analyses, stratified by type of HCV treatment received (DAA, IFN and never treated), were
undertaken to determine incidence rates for each group using a random-effects model. Several studies had
performed multivariate analysis adjusting for a variety of factors including age, gender, baseline cirrhosis
status, baseline alpha fetoprotein (AFP), ethnicity and Child-Pugh score. We used a mixed effects meta-
analysis to calculate the overall adjusted and unadjusted hazard ratio of DAA treatment, using studies
with multivariate analyses. Several sub-analyses were performed, including exclusion of any HCC event
diagnosed within the first six months after the completion of treatment for HCV, and the calculation of the
annualized HCC rate for the second year after HCV treatment. In order to obtain this data, we manually
extracted information from studies where the time-to-event for each HCC event was recorded.

For baseline characteristics within individual studies, data were weighted, then pooled and P-value
generated using GraphPad Prism software.