Challenges in the discontinuation of chronic hepatitis B antiviral agents

Table 1 Guidelines for stopping nucleos(t)ide analog therapy

Guidelines	HBeAg-positive CHB	HBeAg-negative CHB
APASL 2015[11]	HBeAg seroconversion: + undetectable HBV DNA + normal ALT for ≥ 12 mo (or preferably 3 yr). Cirrhotic patients may be stopped with careful monitoring	Undetectable HBV DNA at least 2 yr with documented on three separate occasions, 6 mo apart: Or HBsAg clearance either at least for 1 yr; Or until anti-HBs seroconversion. Cirrhotic patients may be stopped with careful monitoring
AASLD 2018[10]	HBeAg seroconversion + undetectable DNA + normal ALT for ≥ 12 mo. Not recommended in cirrhosis	HBsAg clearance. Not recommended in cirrhosis
EASL 2017[9]	HBeAg seroconversion + undetectable DNA for ≥ 12 mo. Not recommended in cirrhosis	HBsAg clearance. Or selected noncirrhotic with undetectable HBV DNA ≥ 3 yr. Not recommended in cirrhosis

AASLD: American Association for the Study of the Liver; ALT: Alanine aminotransferase; APASL: Asian Pacific Association for the Study of the Liver; CHB: Chronic hepatitis B; EASL: European Association for the Study of the Liver; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus.

Table 2 Off-therapy virological relapse, clinical relapse, and hepatitis B surface antigen loss in chronic hepatitis B patients

Ref.	Country	n (%)	HBeAg-negative, n (%)	Follow-up time (mo)	Virological relapse rate (%)	Clinical relapse rate (%)	HBsAg loss, n (%)
Fung et al[67], 2004	Canada	27	27	18	44.4	25.9	NR1
Enomoto et al[68], 2008	Japan	22	22	48	68.7	68.7	NR
Yeh et al[69], 2009	Taiwan	71	0	15	26.8	26.8	0
Fung et al[70], 2009	Hongkong	22	0	20	63.6	31.8	NR
Wang et al[71], 2010	China	125	125	24	30.4	NR	NR
Kuo et al[72], 2010	Taiwan	124	0	> 12	66.1	66.1	NR
Cai et al[73], 2010	China	11	0	22	42.8	0	NR
Liu et al[74], 2011	China	61	61	15	50.8	45.9	8/61
Jung et al[75], 2011	South Korea	19	9	12	31.6	21	0
Chan et al[76], 2011	Hongkong	53	53	47	69.8	NR	9/53
Liang et al[77], 2011	Hongkong	84	43		44	14.3	NR
Chaung et al[78], 2012	United States	39	0	14	89.7	38.5	0
Hadziyannis et al[15], 2012	Greece	33	33	69	45.4	45.4	13/33
Ha et al[79], 2012	China	145	145	16	65.5	64.1	NR
Song et al[80], 2012	South Korea	48	0	18	41.6	NR	NR
He et al[81], 2013	China	66	66	17	28.8	NR	2/66
Kim et al[82], 2013	Korea	45	45	26	73.3	53.3	NR
Jeng et al[83], 2013	Taiwan	95	95	> 12	57.9	45.3	0/95
Kwon et al[84], 2013	South Korea	16	NR	32	25	25	2/16
Ridruejo et al[85], 2014	Argentina	35	0	15	25.7	NR	18/35
Sohn et al[86], 2014	South Korea	95	54	22	83.1	NR	0/95
Patwardhan et al[87], 2014	United States	33	33	36	63.6	48.5	0/33
He et al[88], 2014	China	97	0	32	8.2	1	11/97
Chen et al[40], 2014	Taiwan	188	105	49	66.5	NR	33/185
Jiang et al[89], 2015	China	72	39	13	65.3	41.7	NR
Seto et al[90], 2015	Hongkong	184	184	12	91.8	22.8	0
Peng et al[91], 2015	China	65	21	12	43.1	27.7	1/65
Jeng et al[92], 2016	Taiwan	85	85	155	69	52	2/85
Qiu et al[93], 2016	China	112	0	52	48.2	NR	1/112
Yao et al[94], 2017	Taiwan	119	119	6 yr	25.2	12.7	44/1192
Cao et al[95], 2017	China	82	22	91	70.7	34.1	5/82
Chen et al[96], 2018	Taiwan	143	104	104	67.1	48.9	7/143
Hung et al[97], 2017	Taiwan	73	73	6 yr	54.8	6.8	20/73
Berg et al[42], 2017	German	21	21	144	52	23	4/21
Jeng et al[33], 2018	Taiwan	691	691	6 yr	79.2	60.6	42/691
Liem et al[39], 2019	Canada	45	27	72	71	13	1/45
Kaewdech et al[12], 2020	Thailand	92	70	48	63	33.7	2/92

¹Not reported.

²All patients had hepatitis B surface antigen level < 200 IU/mL at the end of treatment.

EOT: End of treatment; HBsAg: Hepatitis B surface antigen; NR: Not reported.

Table 3 Factors predictive of hepatitis B virus relapse

Baseline at pretreatment	On-treatment	End of treatment
Virological relapse
High age[40,44]	Short consolidation duration[38]	High HBsAg level[40,41]
Male sex[40]		High HBcrAg level[12]
High HBsAg level[44]		High HBV RNA level[12]
Clinical relapse
High HBsAg level[44]	Short consolidation duration[44]	High HBsAg level[13,40,41]
		High HBcrAg level[12,13,52]
		High HBV RNA level[12,52]

HBcrAg: Hepatitis B core-related antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus.

Table 4 Factors predictive of hepatitis B surface antigen clearance

Baseline at pretreatment	On-treatment	End of treatment
Low ALT level[40]	Long treatment duration[40]	Low HBsAg level especially < 100 IU/mL[41]
Low HBV DNA level[40]	HBsAg level reduction > 1 log10 IU/mL[33]	Low HBcrAg level[13]

ALT: Alanine aminotransferase; HBcrAg: Hepatitis B core-related antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus.

Table 5 Hepatitis B core-related antigen level and clinical application

Ref.	n (%)	End of treatment HBcrAg level (log10 U/mL)	Clinical application
Shinkai et al[98], 2006	22	< 3.4	Predictive factor for absence of the off-therapy relapse
Matsumoto et al[47], 2007	34	< 3.2	Predictive factor for absence of the off-therapy relapse
Jung et al[99], 2016	113	≤ 3.7	Virological relapse within 1 yr of NA cessation
Hsu et al[48], 2019	135	NR	Predictive factors of HBsAg loss and lower clinical relapse
Kaewdech et al[12], 2020	92	< 3	Low risk of off-therapy relapse
Papatheodoridi et al[54], 2020	57	< 2	Predictive factor of HBsAg loss, not required retreatment
Sonneveld et al[13], 2020	572	< 2	Higher risk of sustained response and HBsAg loss

ALT: Alanine aminotransferase; HBcrAg: Hepatitis B core-related antigen; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; NA: Nucleos(t)ide analog; NR: Not reported.

Table 6 Summary of follow-up interval and retreatment criteria

Ref.	Follow-up interval	Criteria of retreatment
Berg et al[42], 2017	Every 2 wk in the first 3 mo, every 4 wk until week 48, and every 12 wk thereafter until week 144	Two consecutive total bilirubin > 1.5 mg/dL plus ALT > ULN
		Two consecutive PT ≥ 2.0 seconds (INR ≥ 0.5) prolonged from baseline with adequate vitamin K therapy plus ALT > ULN
		Two consecutive ALT > 10 × ULN
		ALT > 2 × but ≤ 5 × ULN persisting for ≥ 12 wk plus HBV DNA > 20000 copies/mL
		ALT 5 × but ≤ 10 × ULN persisting for ≥ 4 wk
Papatheodoridi et al[63], 2018	Every mo in the first 3 mo then at least every 3 mo until month 12	Greece cohort: (1) ALT > 10 × ULN; (2) ALT > 5 × ULN plus total bilirubin > 2 mg/dL; (3) ALT > 3 × ULN plus HBV DNA > 100000 IU/mL; and (4) ALT > ULN plus HBV DNA > 2000 IU/mL on three sequential occasions
		Taiwanese cohort: (1) ALT > 2 × ULN twice 3 mo apart plus HBV DNA > 2000 IU/mL; (2) Total bilirubin > 2 mg/dL; and (3) PT ≥ 3 seconds of control range
Liem et al[39], 2019	Wk 4, 6, 12, 18, 24, 36, 48, 60, and 72	HBeAg seroreversion
		HBV DNA > 2000 IU/mL plus ALT > 600 IU/mL
		HBV DNA > 2000 IU/mL plus ALT > 5 × ULN (40 IU/mL) on two consecutive visits
		HBV DNA > 2000 IU/mL plus ALT > 200 IU/mL but < 600 IU/mL for > 6–8 wk
		HBV DNA > 20000 IU/mL on two consecutive visits at least 4 wk apart
García-López et al[60], 2020	Monthly in the first 6 mo then every 3-4 mo until 24 mo	Two consecutive ALT > 10 × ULN regardless of HBV DNA level
		ALT > 5-10 × ULN and HBV DNA > 2000 IU/mL persisting for ≥ 4 wk
		ALT > 2-5 × ULN and HBV DNA > 2000 IU/mL persisting for ≥ 6 mo
		Need for immunosuppressive treatment

ALT: Alanine aminotransferase; HBeAg: Hepatitis B e antigen; HBV: hepatitis B virus; INR: International normalized ratio; PT: Prothrombin time; ULN: Upper limit of normal.