Impact of COVID‐19 pandemic on surveillance of hepatocellular carcinoma: A study in patients with chronic hepatitis C after sustained virologic response

Abstract Background The current coronavirus disease 2019 (COVID‐19) pandemic has strongly influenced many aspects of the medical care, including cancer surveillance. Aims We investigated how the COVID‐19 pandemic influenced surveillance for hepatocellular carcinoma (HCC), focusing on patients with hepatitis C virus infection who were receiving surveillance for HCC after sustained virologic response (SVR) in Japan. Methods Patients who achieved SVR between 1995 and 2017 and continued receiving surveillance were compared by month in terms of the rate at which they kept their scheduled visits for HCC surveillance from July 2019 to May 2020. Results The percentage of kept scheduled visits was above 97% before February 2020. By contrast, it declined sharply after March 2020 when COVID‐19 became pandemic; the percentages were 75.5% in March, 63.0% in April and 49.1% in May 2020 (July 2019–February 2020 vs March–May 2020, P < 0.0001). Similar declines were observed in patients with cirrhosis or advanced fibrosis and in those with a history of HCC. Whereas most patients who cancelled a scheduled visit before February 2020 did not reschedule it, the majority of patients with cancellations after March 2020 did want to reschedule. Conclusions The percentages of scheduled visits that were kept declined rapidly after COVID‐19 became pandemic in Japan, although the spread of COVID‐19 is relatively mild and the legal restriction of people's behaviour and movement is absent. Instituting measures to follow‐up with cancelled patients and resume surveillance will be necessary in the future.


| INTRODUC TI ON
Surveillance for hepatocellular carcinoma (HCC) impacts favourably on prognosis of patients with chronic liver disease by increasing the rate of early HCC detection and the use of curative treatments, when it develops. [1][2][3][4][5] The risk of HCC persists in patients with chronic hepatitis C virus (HCV) infection even after the achievement of sustained virologic response (SVR), that is the eradication of HCV, 6 and it remains necessary for patients with SVR continuing to visit the hospital and receive examinations regularly. In particular, the risk of HCC development after SVR has increased since interferon (IFN)-free, oral direct-acting antivirals (DAAs) were first used to treat HCV in Japan, where patients with SVR after DAA therapy are older and frequently have advanced liver fibrosis or cirrhosis. 7,8 In Japan, it is recommended that all patients with previous HCV infection fundamentally continue visiting hospitals regularly for surveillance of HCC.
Since social distancing and stay-at-home policies have been instituted to slow the spread of coronavirus disease 2019 (COVID-19), unexpected outcomes have been observed among patients with chronic diseases, including those who are under surveillance for HCC. The COVID-19 pandemic may restrict patients' daily behaviour, and may prevent some from making their regular hospital visits. This also applies to patients under surveillance for HCC and to those participating in other cancer-screening programs. 9 Therefore, in this study, we investigated how the current COVID-19 pandemic influenced surveillance for HCC, focusing on patients who are surveyed after SVR in Japan.

| Study patients
A total of 1405 patients with chronic HCV infection achieved SVR between 1992 and 2017 at Ogaki Municipal Hospital (578 by IFNbased therapy and 827 by IFN-free DAA therapy). Of these patients, 432 patients had discontinued HCC surveillance before study initiation in July 2019. In addition, 38 patients had active HCC that required continuous treatment or follow-up. The remaining 935 patients who continued to regularly visit the hospital for HCC surveillance and who did not have active HCC in July 2019 were enrolled in the study ( Figure 1).
The study protocol complied with the Helsinki Declaration and was approved by our institutional review board. The requirement for informed consent was waived, as we used only de-identified data collected from medical records.

| Policy regarding patient surveillance after SVR and during the COVID-19 pandemic
At our hospital, all patients with chronic HCV infection who have achieved SVR are advised to continue regular visits for HCC surveillance. Principally, patients are advised to visit the hospital at 6-to 8-month intervals and to undergo laboratory tests and ultrasonography examination. Patients with a history of HCC are advised to visit the hospital at 3-to 6-month intervals. Patients usually visit the hospital, undergo laboratory tests and an ultrasonography examination before meeting with their doctors, meet with their doctor on the same day of examination and then schedule their next appointment. If they miss a scheduled visit without contacting the hospital beforehand, we telephone them to ask them why they did not keep their appointment and advise them to reschedule.
We have not restricted hospital visits during the COVID-19 pandemic. The hospital is located in the countryside in central Japan, and there were relatively few cases of COVID-19 in our region in March, April and May (150 cases and seven deaths as of May 31, 2020). During this period, we did not telephone patients to ask them to postpone their visits, and laboratory test, imaging examinations and meetings with doctors were performed as usual.

| Data collection and analysis
We used electronic medical records to collect information on the visits of 935 patients. When patients visited on the scheduled day, this was counted as a visit. When a visit was postponed to another date, this was counted as rescheduling. When patients informed us that they would miss their visit but did not set up another date, this We compared the monthly percentages of patients who successfully visited the hospital for their scheduled visit. We also compared the corresponding percentages in patients with cirrhosis or advanced fibrosis, and in those with a history of HCC. The presence of cirrhosis was assessed clinically prior to anti-HCV therapy based on imaging and endoscopic findings, including the presence of oesophageal or gastric varices, collateral veins due to portal hypertension and splenomegaly. Advanced fibrosis was defined by a FIB-4 index 10 above 3.25 before anti-HCV therapy. For patients who cancelled their visits, we compared the distribution of patients who did and did not reschedule their visits.

| Statistical analysis
Categorical variables are expressed as numbers and percentages, and continuous variables are expressed as medians and interquartile ranges. Monthly differences in the percentages of patients who kept their scheduled visits were analysed with the Chi-square test.
Statistical analysis was performed using JMP statistical software, version 11.0 (SAS Institute). All P values were derived from twotailed tests, with P < 0.05 accepted as statistically significant. Table 1 shows the characteristics of the study patients.     The only significant findings were that the frequency of missed visits was higher in females than males in April and May, and was higher in April in patients aged over 75 years than in other age groups. Table 3 shows the monthly number of patients who missed their regular visits and then did or did not reschedule. Prior to February 2020, the majority of patients who cancelled their visits did not reschedule and quitted receiving surveillance, whereas after March 2020, most patients did reschedule. However, 16 patients subsequently cancelled their rescheduled visits (14 patients rescheduled again and the remaining two patients did not).

| D ISCUSS I ON
In this study, we focused on patients with previous chronic HCV infection who achieved SVR. We did not analyse patients with active HCC who were undergoing treatment. Furthermore, patients with decom- regularly visit the hospital purely for surveillance and not drug treatment, so we considered this population to be useful for evaluating the impact of the COVID-19 pandemic on the HCC surveillance system.
The influence of the COVID-19 pandemic on medical care varies largely by countries and regions. In Japan, the impact is less marked than in European countries or the United States because of less widespread disease. The first COVID-19 death was reported on February 13, 2020, but the subsequent increase in number was not very rapid. Indeed, the number of patients who have died due to COVID-19 is under 1000 as of May 31, 2020, whereas it is more than 100 000 in Europe and in the United States. In addition, the Japanese government did not issue strict stay-at-home orders, although in early March it closed public schools and on April 16 it declared a state of emergency that was terminated on May 14. The Japanese government requested that individuals stay at home and practice social distancing behaviour, but these were not legal requirements.
The Japanese constitution makes it difficult for the government to establish laws restricting people's behaviour. Importantly, public transportation was functioning as usual even during the state of emergency. Individuals still may have been reluctant to use public transportation, but the hospital where this study was conducted is located in the countryside, and most patients access it by car. This resulted in a less marked decline in the number of patient visits and examinations than in the United States or Singapore. 11 Despite this, we found that the number of patients with SVR who kept their scheduled visits declined rapidly after March 2020. TA B L E 3 Number of patients by month who did and did not reschedule cancelled visits with patients during the COVID-19 pandemic differs largely among regions and hospitals. For instance, some hospitals have advised patients to cancel non-urgent appointments, which will of course strongly influence the rate of patient visits. Further nationwide and global assessment of the impact of the COVID-19 pandemic on HCC surveillance will be necessary in the future.
In conclusion, the results of this study showed that the COVID-19 pandemic strongly hampered the surveillance system for HCC in HCV patients who achieved SVR. Clinicians should carefully monitor the outcomes of patients who do not attend their scheduled visits, and take measures to ensure that they resume surveillance for HCC.

CO N FLI C T O F I NTE R E S T
No other authors had conflict and interest.

AUTH O R S H I P
Guarantor of the article: Hidenori Toyoda.

Specific author contributions: All authors collected the data, Hidenori
Toyoda analysed the data, designed the research study, and wrote the paper. All authors approved the final version of the manuscript.
Declaration of personal interests: Hidenori Toyoda has served as a speaker for AbbVie, MSD, and Bayer, and Takashi Kumada has served as a speaker for AbbVie and Gilead Sciences.

PE E R R E V I E W
The peer review history for this article is available at https://publo ns.