Effects of SARS-CoV-2 infection on incidence and treatment strategies of hepatocellular carcinoma in people with chronic liver disease

Table 1 Baseline characteristics of chronic liver disease patients with coronavirus disease 2019 and chronic liver disease patients without coronavirus disease 2019 (matched controls) after 1:1 propensity score matching

Baseline characteristics	After matching
	2020-2022				2020					2021					2022
	COVID-19 patients (n = 55163)		Control (n = 55163)		SMD	COVID-19 patients (n = 2397)		Control (n = 2397)		SMD	COVID-19 patients (n = 375)		Control (n = 375)		SMD	COVID-19 patients (n = 52391)		Control (n = 52391)		SMD
	n/Mean	%/SD	n/Mean	%/SD		n/Mean	%/SD	n/Mean	%/SD		n/Mean	%/SD	n/Mean	%/SD		n/Mean	%/SD	n/Mean	%/SD
Age, yr1	58.8	14.7	58.7	13.9	0.01	54.8	17.2	54.5	16.2	0.02	57.6	15.6	57.5	14.2	0	59	14.5	58.9	13.8	0.01
≤ 50	15482	-28.1	14659	-26.6	0.03	878	-36.6	906	-37.8	0.02	127	-33.9	110	-29.3	0.1	14477	-27.6	13643	-26	0.04
> 50	39681	-71.9	40504	-73.4		1519	-63.4	1491	-62.2		248	-66.1	265	-70.7		37914	-72.4	38748	-74
Sex					0.01					0.03					0.05					0.01
Male	28244	-51.2	28484	-51.6		1274	-53.1	1244	-51.9		192	-51.2	183	-48.8		26778	-51.1	27057	-51.6
Female	26919	-48.8	26679	-48.4		1123	-46.9	1153	-48.1		183	-48.8	192	-51.2		25613	-48.9	25334	-48.4
Fully vaccinated	27633	-50.1	27576	-50	0	0	0	0	0	NA	0	0	0	0	NA	27633	-52.7	27576	-52.6	0
Pre-existing comorbidities
Charlson's Comorbidity Index1,2	3.2	2.3	3.1	2.2	0.04	2.3	1.9	2.4	1.9	0	2.5	1.8	2.5	1.6	0	3.2	2.3	3.1	2.2	0.05
0-4	42972	-77.9	44994	-81.6	0.09	2153	-89.8	2145	-89.5	0.01	334	-89.1	340	-90.7	0.11	40485	-77.3	42509	-81.1	0.1
5-6	8338	-15.1	7168	-13		191	-8	200	-8.3		33	-8.8	32	-8.5		8114	-15.5	6936	-13.2
7-16	3853	-7	3001	-5.4		53	-2.2	52	-2.2		8	-2.1	3	-0.8		3792	-7.2	2946	-5.6
Cirrhosis	1898	-3.4	1737	-3.1	0.02	11	-0.5	41	-1.7	0.12	2	-0.5	4	-1.1	0.06	1885	-3.6	1692	-3.2	0.02
HCC	1199	-2.2	1189	-2.2	0	5	-0.2	24	-1	0.1	0	0	2	-0.5	0.1	1194	-2.3	1163	-2.2	0
Liver decompensation	1563	-2.8	1420	-2.6	0.02	14	-0.6	41	-1.7	0.11	1	-0.3	4	-1.1	0.1	1548	-3	1375	-2.6	0.02
Hepatorenal syndrome	158	-0.3	160	-0.3	0	2	-0.1	3	-0.1	0.01	0	0	0	0	0.07	156	-0.3	157	-0.3	0
Liver failure	298	-0.5	303	-0.5	0	5	-0.2	15	-0.6	0.06	0	0	1	-0.3	0.07	293	-0.6	287	-0.5	0
Hepatic coma/encephalopathy	218	-0.4	159	-0.3	0.02	0	0	0	0	NA	1	-0.3	0	0	0.07	217	-0.4	159	-0.3	0.02
Ascites	394	-0.7	330	-0.6	0.01	5	-0.2	5	-0.2	0	0	0	0	0	NA	389	-0.7	325	-0.6	0.01
Variceal bleeding	973	-1.8	842	-1.5	0.02	6	-0.3	24	-1	0.1	0	0	3	-0.8	0.13	967	-1.8	815	-1.6	0.02
Treatment for HCC used before index date
Curative treatment to HCC	1111	-2	1065	-1.9	0.01	4	-0.2	25	-1	0.11	0	0	3	-0.8	0.13	1107	-2.1	1037	-2	0.01
Non-curative treatment to HCC	2388	-4.3	2125	-3.9	0.02	19	-0.8	53	-2.2	0.12	0	0	4	-1.1	0.15	2369	-4.5	2068	-3.9	0.03
Palliative care	1811	-3.3	1675	-3	0.01	20	-0.8	43	-1.8	0.08	1	-0.3	8	-2.1	0.17	1790	-3.4	1624	-3.1	0.02

¹Age, and Charlson Comorbidity index are presented in mean ± SD.

²The calculation of Charlson Comorbidity Index does not include Acquired Immune Deficiency Syndrome.

COVID-19: Coronavirus disease 2019; HCC: Hepatocellular carcinoma; NA: Not available; SMD: Standardized mean difference.

Table 2 Incidence rates of clinical sequelae of chronic liver disease patients with coronavirus disease 2019 diagnosis in 2020-2022 and controls after 1:1 propensity score matching

Outcomes	2020-2022
	COVID-19 patients (n = 55163)					Control (n = 55163)					COVID-19 patients vs control
	Cumulative incidence		Crude incidence rate			Cumulative incidence		Crude incidence rate
			(Events/10000 person-yr)					(Events/10000 person-yr)
	New events	Rate, %	Estimate	95%CI	Person-years	New events	Rate, %	Estimate	95%CI	Person-years	IRR1	95% CI	P value
HCC	211	0.39	64.2	(55.8, 73.5)	32870	276	0.51	54	(47.8, 60.8)	51087	1.19	(0.99, 1.42)	0.06
All-cause mortality	2273	4.12	676.5	(648.9, 704.9)	33601	1600	2.9	306.2	(291.4, 321.6)	52258	2.21b	(2.07, 2.36)	< 0.001
Adverse hepatic outcomes	2407	4.62	789.3	(758.1, 821.5)	30495	2183	4.19	453.5	(434.7, 473.0)	48133	1.74b	(1.64, 1.85)	< 0.001
Cirrhosis	2493	4.68	803.8	(772.6, 836.0)	31014	2206	4.14	450.1	(431.5, 469.2)	49015	1.79b	(1.68, 1.89)	< 0.001
Liver decompensation hepatorenal syndrome	88	0.16	26.3	(21.1, 32.4)	33468	106	0.19	20.4	(16.7, 24.6)	52070	1.29	(0.97, 1.71)	0.08
Liver failure	71	0.13	21.3	(16.6, 26.8)	33371	91	0.17	17.5	(14.1, 21.5)	51902	1.21	(0.89, 1.66)	0.22
Hepatic coma/encephalopathy	60	0.11	17.9	(13.7, 23.1)	33454	61	0.11	11.7	(9.0, 15.1)	52033	1.53a	(1.07, 2.18)	0.02
Ascites	129	0.24	38.7	(32.3, 46.0)	33341	154	0.28	29.7	(25.2, 34.8)	51882	1.30a	(1.03, 1.65)	0.03
Variceal bleeding	150	0.28	45.5	(38.5, 53.4)	32977	159	0.29	31	(26.4, 36.2)	51316	1.47b	(1.17, 1.84)	< 0.001
Curative treatment to HCC	130	0.24	39.5	(33.0, 46.9)	32892	174	0.32	34	(29.1, 39.5)	51156	1.16	(0.93, 1.46)	0.2
Hepatic resection	86	0.16	25.9	(20.7, 32.0)	33206	109	0.2	21.1	(17.3, 25.5)	51664	1.23	(0.93, 1.63)	0.16
Liver transplantation	13	0.02	3.9	(2.1, 6.6)	33442	20	0.04	3.8	(2.3, 5.9)	52028	1.01	(0.50, 2.03)	0.97
Radiofrequency ablation of liver	51	0.09	15.3	(11.4, 20.1)	33294	75	0.14	14.5	(11.4, 18.2)	51784	1.06	(0.74, 1.51)	0.76
Non-curative treatment to HCC	394	0.75	122.5	(110.7, 135.3)	32151	627	1.19	125.6	(116.0, 135.8)	49916	0.98	(0.86, 1.11)	0.7
Transarterial chemoembolization	83	0.15	25	(19.9, 31.0)	33239	125	0.23	24.2	(20.1, 28.8)	51691	1.03	(0.78, 1.36)	0.82
Radiotherapy to liver	3	0.01	0.9	(0.2, 2.6)	33543	3	0.01	0.6	(0.1, 1.7)	52189	1.56	(0.31, 7.71)	0.59
Systemic chemotherapy or immunotherapy	351	0.66	108.2	(97.2, 120.2)	32434	547	1.03	108.6	(99.7, 118.1)	50363	1	(0.87, 1.14)	0.96
Palliative care	924	1.73	285.8	(267.7, 304.8)	32332	904	1.7	179	(167.5, 191.0)	50510	1.60b	(1.46, 1.75)	< 0.001

¹IRR > 1 (or < 1) indicates COVID-19 patients had higher (lower) risk of clinical outcome compared to the matched control group.

^aP < 0.05.

^bP < 0.01. IRR is considered statistically significant, with indicates ^aP < 0.05 and indicates ^bP < 0.01. COVID-19: Coronavirus disease 2019; HCC: Hepatocellular carcinoma; IRR: Incidence rate ratio.

Table 3 Incidence rates of clinical sequelae of chronic liver disease patients with coronavirus disease 2019 in 2022 and matched controls in the acute and post-acute phases of infection

Outcomes	Acute phase of infection (within 21 d)													Post-acute phase of infection (beyond 21 d)
	COVID-19 patients in 2022 (n = 52391)					Control (n = 52391)					COVID-19 patients in 2022 vs control			COVID-19 patients in 2022 (n = 47986)
	Cumulative incidence		Crude incidence rate (Events/10000 person-yr)			Cumulative incidence		Crude incidence rate (Events/10000 person-yr)						Cumulative incidence		Crude incidence rate (Events/10000 person-yr)
	New events	Rate	Estimate	95%CI	Person-yr	New events	Rate	Estimate	95%CI	Person-yr	IRR1	95%CI	P value	New events	Rate	Estimate	95%CI	Person-yr
HCC	30	0.06	107.9	(72.8, 154.0)	2781	16	0.03	57.1	(32.6, 92.8)	2,801	1.89a	(1.03, 3.47)	0.04	151	0.32	66.2	(56.1, 77.7)	22,797
All-cause mortality	764	1.46	2683.7	(2496.7, 2880.9)	2847	109	0.21	380.1	(312.1, 458.5)	2868	7.06b	(5.78, 8.63)	< 0.001	854	1.78	365.6	(341.5, 391.0)	23356
Adverse hepatic outcomes	1180	2.39	4469.6	(4218.2, 4732.1)	2640	607	1.23	2259.6	(2083.4, 2446.7)	2686	1.98b	(1.79, 2.18)	< 0.001	895	1.99	415	(388.3, 443.1)	21564
Cirrhosis	1260	2.49	4676.2	(4421.6, 4941.8)	2694	683	1.35	2490	(2306.7, 2683.9)	2743	1.88b	(1.71, 2.06)	< 0.001	900	1.96	409.6	(383.2, 437.2)	21974
Liver decompensation hepatorenal syndrome	20	0.04	70.5	(43.1, 108.9)	2837	6	0.01	21	(7.7, 45.7)	2859	3.36b	(1.35, 8.36)	0.009	54	0.11	23.2	(17.4, 30.3)	23278
Liver failure	14	0.00%	49.5	(27.0, 83.0)	2831	4	0.01	14	(3.8, 35.9)	2852	3.53a	(1.16, 10.71)	0.03	43	0.09	18.5	(13.4, 24.9)	23217
Hepatic coma/encephalopathy	8	0.02	28.2	(12.2, 55.6)	2835	6	0.01	21	(7.7, 45.7)	2856	1.34	(0.47, 3.87)	0.59	38	0.08	16.3	(11.6, 22.4)	23261
Ascites	22	0.04	77.9	(48.8, 117.9)	2826	10	0.02	35.1	(16.8, 64.6)	2847	2.22a	(1.05, 4.68)	0.04	82	0.17	35.4	(28.1, 43.9)	23176
Variceal bleeding	37	0.07	132.5	(93.3, 182.6)	2793	12	0.02	42.6	(22.0, 74.5)	2,815	3.11b	(1.62, 5.96)	< 0.001	85	0.18	37.1	(29.7, 45.9)	22898
Curative treatment to HCC	9	0.02	32.3	(14.8, 61.3)	2786	16	0.03	57	(32.6, 92.6)	2807	0.57	(0.25, 1.28)	0.17	93	0.2	40.7	(32.9, 49.9)	22,828
Hepatic resection	4	0.01	14.2	(3.9, 36.4)	2815	10	0.02	35.3	(16.9, 64.8)	2836	0.4	(0.13, 1.28)	0.12	64	0.13	27.7	(21.4, 35.4)	23072
Liver transplantation	3	0.01	10.6	(2.2, 30.9)	2835	1	0	3.5	(0.1, 19.5)	2856	NA	NA	NA	6	0.01	2.6	(0.9, 5.6)	23268
Radiofrequency ablation of liver	2	0	7.1	(0.9, 25.6)	2822	5	0.01	17.6	(5.7, 41.0)	2,843	0.4	(0.08, 2.08)	0.28	41	0.09	17.7	(12.7, 24.0)	23137
Non-curative treatment to HCC	37	0.07	136.1	(95.8, 187.6)	2719	30	0.06	109.6	(73.9, 156.4)	2738	1.24	(0.77, 2.01)	0.38	289	0.63	129.5	(115.0, 145.4)	22309
Transarterial chemoembolization	9	0.02	31.9	(14.6, 60.6)	2817	11	0.02	38.8	(19.4, 69.4)	2837	0.82	(0.34, 1.99)	0.67	64	0.13	27.7	(21.3, 35.4)	23096
Radiotherapy to liver	0	0	0	NA	2845	1	0	3.5	(0.1, 19.4)	2866	NA	(0.00, 0.00)	NA	3	0.01	1.3	(0.3, 3.8)	23338
Systemic chemotherapy or immunotherapy	28	0.06	102	(67.8, 147.5)	2744	21	0.04	76	(47.0, 116.2)	2763	1.34	(0.76, 2.36)	0.31	261	0.56	115.9	(102.2, 130.8)	22527
Palliative care	221	0.44	805	(702.3, 918.4)	2745	50	0.1	180.5	(134.0, 238.0)	2770	4.46b	(3.28, 6.06)	< 0.001	447	0.96	198.1	(180.2, 217.3)	22565

¹IRR > 1 (or < 1) indicates COVID-19 patients had higher (lower) risk of clinical outcome compared to the matched control group. IRR was estimated only if the total number of events in the two comparison groups were greater than 1.

^aP < 0.05.

^bP < 0.01. IRR is considered statistically significant, with indicates ^aP < 0.05 and indicates ^bP < 0.01. HCC: Hepatocellular carcinoma; HR: Hazard ratio; IRR: Incidence rate ratio; COVID-19: Coronavirus disease 2019.