Received: 26 June 2020

| First decision: 24 July 2020 | Accepted: 28 July 2020

DOI: 10.1002/ygh2.418

Impact of COVID-19 pandemic on surveillance ofhepatocellular carcinoma: A study in patients with chronic
hepatitis C after sustained virologic response
Hidenori Toyoda| Satoshi Yasuda | Seiki Kiriyama | Makoto Tanikawa |Yasuhiro Hisanaga | Akira Kanamori | Shusuke Kitabatake | Satoshi Yamamoto |Shohei Shiota | Manabu Furoi | Takahiro Koyabu | Daiju Furukawa | Takashi Kumada
Yoshio Sumida
Department of Gastroenterology, Ogaki
Municipal Hospital, Ogaki, Japan
Correspondence
Hidenori Toyoda, Department of
Gastroenterology, Ogaki Municipal Hospital,
4-86 Minaminokawa, Ogaki, Gifu 503-8502,
Japan.
Email: hmtoyoda@spice.ocn.ne.jp
Funding information
None.

|

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 forhepatocellular 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 theirscheduled 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 February2020 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.

1 | I NTRO D U C TI O N

when it develops.1-5 The risk of HCC persists in patients withchronic hepatitis C virus (HCV) infection even after the achieve-

Surveillance for hepatocellular carcinoma (HCC) impacts favourably

ment of sustained virologic response (SVR), that is the eradication

on prognosis of patients with chronic liver disease by increasing theof HCV,6 and it remains necessary for patients with SVR continuing

rate of early HCC detection and the use of curative treatments,

to visit the hospital and receive examinations regularly. In particular,

GastroHep. 2020;00:1–6.

wileyonlinelibrary.com/journal/ygh2
© 2020 John Wiley & Sons Ltd

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TOYODA et al.

the risk of HCC development after SVR has increased since inter-

informed consent was waived, as we used only de-identified data

feron (IFN)-free, oral direct-acting antivirals (DAAs) were first usedcollected from medical records.

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

2.2 | Policy regarding patient surveillance after
SVR and during the COVID-19 pandemic

surveillance of HCC.
Since social distancing and stay-at-home policies have been in-

At our hospital, all patients with chronic HCV infection who havestituted to slow the spread of coronavirus disease 2019 (COVID-

achieved SVR are advised to continue regular visits for HCC surveil-19), unexpected outcomes have been observed among patientslance. Principally, patients are advised to visit the hospital at 6- towith chronic diseases, including those who are under surveillance

8-month intervals and to undergo laboratory tests and ultrasonog-

for HCC. The COVID-19 pandemic may restrict patients’ daily be-raphy examination. Patients with a history of HCC are advised tohaviour, and may prevent some from making their regular hospital

visit the hospital at 3- to 6-month intervals. Patients usually visit thevisits. This also applies to patients under surveillance for HCC and to

hospital, undergo laboratory tests and an ultrasonography examina-

those participating in other cancer-screening programs.9 Therefore,tion before meeting with their doctors, meet with their doctor onin this study, we investigated how the current COVID-19 pandemic

the same day of examination and then schedule their next appoint-

influenced surveillance for HCC, focusing on patients who are sur-ment. If they miss a scheduled visit without contacting the hospitalveyed after SVR in Japan.

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 pan-

2 | M E TH O DS

demic. The hospital is located in the countryside in central Japan,
and there were relatively few cases of COVID-19 in our region in

2.1 | Study patients

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

A total of 1405 patients with chronic HCV infection achieved SVR

to postpone their visits, and laboratory test, imaging examinations

between 1992 and 2017 at Ogaki Municipal Hospital (578 by IFN-

and meetings with doctors were performed as usual.

based 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

2.3 | Data collection and analysis

required continuous treatment or follow-up. The remaining 935 patients who continued to regularly visit the hospital for HCC surveil-

We used electronic medical records to collect information on thelance and who did not have active HCC in July 2019 were enrolled

visits of 935 patients. When patients visited on the scheduled day,in the study (Figure 1).

this was counted as a visit. When a visit was postponed to anotherThe study protocol complied with the Helsinki Declaration anddate, this was counted as rescheduling. When patients informed us

was approved by our institutional review board. The requirement forthat they would miss their visit but did not set up another date, this1405 patients who achieved SVR at Ogaki Municipal Hospital(578 by IFN-based therapy/827 by IFN-free therapy)

432 discontinued surveillance
before study initation

38 had active HCC at the start of the study

935 patients maintained surveillance visits for HCC
after SVR as of July 2019

F I G U R E 1 Schematic representationof study patient enrolment

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TOYODA et al.

was defined as failure to reschedule. When patients missed their

2.4 | Statistical analysis

visit and did not inform us ahead of time, we telephoned them once
and advised them to set up another date. If they agreed, this was

Categorical variables are expressed as numbers and percentages,

defined as rescheduling. When patients refused to set up anotherand continuous variables are expressed as medians and interquar-

date or if we could not contact them, this was counted as failure to

tile ranges. Monthly differences in the percentages of patients who

reschedule.

kept their scheduled visits were analysed with the Chi-square test.

We compared the monthly percentages of patients who success-

Statistical analysis was performed using JMP statistical software,

fully visited the hospital for their scheduled visit. We also comparedversion 11.0 (SAS Institute). All P values were derived from two-the corresponding percentages in patients with cirrhosis or ad-

tailed tests, with P < 0.05 accepted as statistically significant.

vanced 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 oesoph-

3 | R E S U LT S

ageal or gastric varices, collateral veins due to portal hypertension
and splenomegaly. Advanced fibrosis was defined by a FIB-4 index10

Table 1 shows the characteristics of the study patients. Patientsabove 3.25 before anti-HCV therapy. For patients who cancelled

who achieved SVR by IFN-based therapy (n = 306) entered sur-their visits, we compared the distribution of patients who did andveillance between 1995 and 2013, and those who achieved SVR

did not reschedule their visits.

by IFN-free DAA therapy (n = 629) entered surveillance between
2014 and 2017. Because Japanese patients with HCV infection

TA B L E 1

are older than those in Western countries, the ages of patients

Background of study patients (n = 935)

who achieved SVR and who were receiving surveillance wereAge (y)a70.1 (63.0-77.0)

Gender (male/female)430 (46.6)/505 (54.0)

rhosis or advanced liver fibrosis and 120 patients (12.8%) with aTreatment (IFN-based/DAA-based)b306 (32.7)/629 (67.3)

history of HCC.

Advanced fibrosis/cirrhosis (no/yes)579 (61.9)/356 (38.1)

Figure 2 shows the monthly percentages of patients who vis-

815 (87.2)/120 (12.8)

ited the hospital on the day of their appointment. These were

History of HCC (no/yes)high as of July 2019. There were 356 patients (38.1%) with cir-above 95% in all months until February 2020, but they declined

Note: Values in parentheses are interquartile ranges or percentages.

suddenly in March 2020. The percentages of patients who kept

Abbreviations: DAA, direct-acting antiviral; HCC, hepatocellular
carcinoma; IFN, interferon.
atheir scheduled visits in March, April and May 2020 were 79.7%,

Age in July 2019.

63.0% and 49.1% respectively. The overall percentage from Marchbto May 2020 was significantly lower than that from July 2019 to

Antiviral treatment used to achieve SVR.

100%
90%
80%
70%
60%
50%
40%
30%
20%

May (n=106)

April (n=189)

March (n=143)

February (n=147)

January(n=196)

December (n=212)

November (n=160)

October (n=172)

September (n=134)

0%August (n=147)

10%
July (n=103)

F I G U R E 2 Monthly percentages ofpatients who kept their scheduled visits(blue bars) between July 2019 and May
2020. Blue bars, the percentages ofpatients who kept their scheduled visits;
red bars, the percentages of patients whocancelled their visits. The first COVID-19
death was reported on February 13, 2020.
The Japanese government closed publicschool early in March; it also declared astate of emergency on April 16, which wasterminated on May 14

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TOYODA et al.

February 2020 (1236 of 1271 visits, 97.2% vs 279 of 438 visits,

between March and May 2020. Fortunately, we experienced no pa-

63.7% respectively; P < 0.0001). Subanalyses of 356 patients withtient who had the evidence of COVID-19 during the study period.

cirrhosis or advanced fibrosis and of 120 patients with a history of

Table 2 shows the number of patients, stratified by gender and

HCC showed less marked declines in the percentage of patientsage, who kept their scheduled visits in March, April and May 2020.

who kept their scheduled visits (Figure 3). The percentages of pa-

The only significant findings were that the frequency of missed visits

tients who visited the hospital in March, April and May 2020 were

was higher in females than males in April and May, and was higher in

81.5%, 68.4% and 71.0%, respectively, in patients with cirrhosis

April in patients aged over 75 years than in other age groups.

or advanced fibrosis, and 100%, 80.6% and 76.5%, respectively,

Table 3 shows the monthly number of patients who missed theirin patients with a history of HCC. However, in 257 patients withregular visits and then did or did not reschedule. Prior to February

cirrhosis or advanced fibrosis but with no history of HCC, the per-2020, the majority of patients who cancelled their visits did not re-centages were low (72.2%, 51.9% and 38.5% respectively) despite

schedule and quitted receiving surveillance, whereas after March

the high risk of HCC development.

2020, most patients did reschedule. However, 16 patients subse-

Among 416 patients who had an appointment to visit the hospital between March and May 2020, 273 patients kept their sched-

quently cancelled their rescheduled visits (14 patients rescheduled
again and the remaining two patients did not).

uled visit and 143 patients did not. There was no difference in thepercentage of patients who kept their scheduled visit based on thetype of antiviral treatment used to achieve SVR (IFN-based, 62.5%

4 | D I S CU S S I O N

vs DAA-based, 65.7%; P = 1.0000). When comparing patients withment efficacy. Individuals without decompensation or active HCC whopatient with a history of HCC who maintained the scheduled visit

are under surveillance after SVR are relatively homogenous in that they

30%

20%

20%

10%

10%

0%

0%
May (n=31)

40%

30%

April (n=79)

40%

March (n=54)

50%

February (n=69)

60%

50%

January(n=80)

60%

December (n=81)

70%

November (n=78)

80%

70%

October (n=79)

90%

80%

September (n=49)

100%

90%

August (n=47)(B)

July (n=34)

(A)
100%

May (n=17)

of oral molecular-targeted drugs against HCC) or for evaluation of treat-

who missed their visit; P = 0.9736). HCC was detected only in one

April (n=31)

in patients who kept their visit vs 2.60 [1.55-4.40] years in patients

March (n=22)

tive HCC frequently visit the hospital for treatment (eg for prescription

February (n=37)

not approved for this population in Japan before 2019. Patients with ac-nance of their scheduled visit (median [IQR], 2.50 [1.80-3.78] years

January(n=37)

for IFN-based anti-HCV therapy, and IFN-free DAA-based therapy was

the duration from the last treatment of HCC based on the mainte-

December (n=33)

pensated cirrhosis were not included because they were not candidates

In 65 patients with a history of HCC, there was no difference inNovember (n=43)[3.66-4.61] years in patients who missed their visit; P = 0.2809).

October (n=34)

who were undergoing treatment. Furthermore, patients with decom-

September (n=21)

tion who achieved SVR. We did not analyse patients with active HCC[IQR], 4.22 [3.82-4.69] years in patients who kept their visit vs 4.16

August (n=7)

In this study, we focused on patients with previous chronic HCV infec-

difference in the duration from the achievement of SVR (medianJuly (n=10)

or without the maintenance of their scheduled visit, there was no

F I G U R E 3 Monthly percentage of patients who kept their scheduled visits (blue bars) between July 2019 and May 2020 (A) in patientswith cirrhosis or advanced fibrosis, and (B) in patients with a history of hepatocellular carcinoma. Blue bars, the percentages of patients who
kept their scheduled visits; red bars, the percentages of patients who cancelled their visits

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TOYODA et al.

TA B L E 2 Number of patients who kept scheduled visits in
March, April and May 2020 based on patient gender and age

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 inMarch 2020

April 2020

May 2020

Total

108/143 (75.5)

119/189 (63.0)

52/106 (49.1)

Male43/58 (74.1)

66/89 (74.2)

27/50 (54.0)

Female65/85 (76.5)

53/100 (53.0)

25/56 (44.6)<55

10/14 (71.4)

15/23 (65.2)

5/8 (62.5)

55-65

23/29 (79.3)

27/37 (73.0)

7/19 (36.8)

65-75

38/52 (73.1)

46/65 (72.3)

19/39 (48.7)

emergency. Individuals still may have been reluctant to use public≥75

37/48 (77.1)

31/64 (48.4)

21/40 (52.5)transportation, but the hospital where this study was conducted isAge (y)early March it closed public schools and on April 16 it declared astate of emergency that was terminated on May 14. The Japanese
government requested that individuals stay at home and practicesocial distancing behaviour, but these were not legal requirements.
The Japanese constitution makes it difficult for the government toestablish laws restricting people's behaviour. Importantly, public
transportation was functioning as usual even during the state of

Note: Values in parentheses are percentages.

located in the countryside, and most patients access it by car. ThisTA B L E 3 Number of patients by month who did and did notreschedule cancelled visits

examinations than in the United States or Singapore.11

resulted in a less marked decline in the number of patient visits andDespite this, we found that the number of patients with SVR
who kept their scheduled visits declined rapidly after March 2020.

PeriodAction aftercancellation

Patient number(percentage)

July, 2019 (n = 3)

No reschedule

3 (100)Reschedule0

No reschedule

5 (100)Reschedule0

No reschedule

2 (100)Reschedule0

No reschedule

3 (60.0)

Reschedule

2 (40.0)

The main reason for the cancellation of scheduled visits afterNo reschedule

3 (100)March 2020 was concern about COVID-19, as indicated by medical

Reschedule0

record data on telephone contacts with patients. Most of the time,

No reschedule

5 (83.3)

patients who cancelled their scheduled visits after March 2020 re-

Reschedule

1 (16.7)

scheduled them, indicating that the majority did not want to discon-

No reschedule

4 (80.0)

Reschedule

1 (20.0)

No reschedule

4 (66.7)

Reschedule

2 (33.3)

No reschedule

3 (10.3)

Reschedule

26 (89.7)

No reschedule

15 (21.4)

Reschedule55 (78.6)

visits remained low in May 2020, despite the fact that the state of

No reschedule

4 (7.4)emergency was terminated in this region on May 14. It is unclear when

Reschedule

50 (92.6)

this pandemic will end. In addition, the worldwide economic crisis that

August, 2019 (n = 5)September, 2019 (n = 2)
October, 2019 (n = 5)
November, 2019 (n = 3)
December, 2019 (n = 6)
January, 2020 (n = 5)
February, 2020 (n = 6)
March, 2020 (n = 29)
April, 2020 (n = 70)
May, 2020 (n = 54)

Note: Values in parentheses are percentages.

Strikingly, more than 97% of patients had kept their scheduled visits
before February 2020, which indicates that Japanese patients arehighly interested in their health and are well-educated regarding theimportance of surveillance. By contrast, the percentage of patients
who kept their scheduled visits declined to 75% in March, 60% in
April and below 50% in May. These results show that the COVID-19
pandemic had a strong impact on the surveillance system for HCC
and may destroy it, even in patients with a high interest in HCC
surveillance and in an area where COVID-19 spread has been mild.

tinue surveillance. However, some patients rescheduled multiple
times, which may ultimately result in complete failure to follow-up.
By contrast, no patients indicated that they had economic reasonsfor not visiting the hospital during the study period. This is partly because the national insurance system covers the medical costs of all
Japanese citizens. Although patients who missed visits, with or without rescheduling, are expected to return to surveillance, this is notcertain. Indeed, the percentage of patients who kept their scheduled

is expected to occur in the near future will also involve Japan, and atthat point some patients may cancel their visits for economic reasons.

regularly visit the hospital purely for surveillance and not drug treat-

There are several limitations to this study. The study sample wasment, so we considered this population to be useful for evaluating the

restricted to HCV patients who had achieved SVR. Therefore, the in-

impact of the COVID-19 pandemic on the HCC surveillance system.

fluence of the COVID-19 pandemic on HCC surveillance should also

The influence of the COVID-19 pandemic on medical care var-be studied in patients with HBV infection or those with nonviral liver

ies largely by countries and regions. In Japan, the impact is lessdiseases. In addition, it is necessary to compare the progression ofmarked than in European countries or the United States because

HCC at detection and survival of HCC patients diagnosed betweenof less widespread disease. The first COVID-19 death was reported

before and after the COVID-19 pandemic in long-term observation

on February 13, 2020, but the subsequent increase in number was

to determine the real impact of the pandemic on HCC surveillance.

not very rapid. Indeed, the number of patients who have died due toFinally, this was a single-institution study. The policy for dealing

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TOYODA et al.

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 andglobal 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 COVID19 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.
C O N FL I C T O F I N T E R E S T
No other authors had conflict and interest.
AU T H 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 thepaper. All authors approved the final version of the manuscript.
Declaration of personal interests: Hidenori Toyoda has served asa speaker for AbbVie, MSD, and Bayer, and Takashi Kumada hasserved as a speaker for AbbVie and Gilead Sciences.
PEER REVIEWThe peer review history for this article is available at https://publo​ns.
com/publo​n/10.1002/ygh2.418.

2. Toyoda H, Kumada T, Kiriyama S, et al. Impact of surveillance on
survival of patients with initial hepatocellular carcinoma: a study
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8. Toyoda H, Tada T, Takaguchi K, et al. Difference in backgroundcharacteristics of patients with chronic hepatitis C who achieved
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ORCID
Hidenori Toyoda

https://orcid.org/0000-0002-1652-6168

Takashi Kumada

https://orcid.org/0000-0003-2211-495X

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How to cite this article: Toyoda H, Yasuda S, Kiriyama S, et al.
Impact of COVID-19 pandemic on surveillance ofhepatocellular carcinoma: A study in patients with chronic
hepatitis C after sustained virologic response. GastroHep.
2020;00:1–6. https://doi.org/10.1002/ygh2.418