Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients?

Table 1 Summary of relevant NA treatment discontinuation studies

	Patients off NA, n							Treatment characteristics		Outcomes
Study	Total	HBeAg(+)	HBeAg(-)	Cirrhosis	Age in year	Sex, male	Ethnicity	NA	Treatment duration in mo	Durable virologic response, n	HBsAg loss, n	Deaths, n
Fung et al[100] (2004)	27	0	27	7	45	40	Asian	LMV	24	15	NR	0
Enomoto et al[101] (2008)	22	0	22	3	49	15	Asian	LMV	NR	5	NR	0
Yeh et al[102] (2009)	71	71	0	11	41	55	Asian	LMV	NR	52	0	0
Fung et al[103] (2009)	22	22	0	NR	28	16	Asian	LMV	74	8	NR	0
Wang et al[104] (2010)	125	125	0	0	26/32	95	Asian	LMV	24-36	87	NR	0
Kuo et al[105] (2010)	124	124	0	NR	NR	NR	Asian	LMV	14	42	NR	1
Cai et al[106] (2010)	11	11	0	NR	29	12	Asian	TBV	24	4	NR	0
Liu et al[40] (2011)	61	0	61	0	32	50	Asian	LMV	27	30	8	0
Jung et al[107] (2011)	19	10	9	4	37	12	Asian	ADV	33	13	0	0
Chan et al[30] (2011)	53	0	53	18	56	43	Asian	LMV	27	16	9	NR
Chaung et al[108] (2012)	39	39	0	NR	34	24	Asian	LMV, ADV, ETV	21	4	0	0
Hadziyannis et al[29] (2012)	33	0	33	0	53	38	Caucasian	ADV	56	18	14	0
Ha et al[41] (2012)	145	0	145	NR	33	101	Asian	ADV	26	50	NR	0
Song et al[109] (2012)	48	48	0	0	42	29	Asian	ETV, CLE	26	28	NR	NR
He et al[110] (2013)	66	0	66	0	35	50	Asian	LMV, ADV, ETV, TBV	37	47	2	0
Kim et al[111] (2013)	45	0	45	9	45	33	Asian	LMV, ADV, ETV	38	12	NR	NR
Jeng et al[44] (2013)	95	0	95	39	52	83	Asian	ETV	24	40	0	0
Kwon et al[112] (2013)	16	NR	NR	NR	NR	NR	Asian	LMV	79	12	2	0
Ridruejo et al[113] (2014)	35	33	2	0	NR	NR	Caucasian	ETV	42	26	18	NR
Sohn et al[114] (2014)	95	41	54	44	47	53	Asian	LMV, ETV, CLE	22	16	0	0
Patwardhan et al (2014)	33	0	33	0	42	24	Mixed	LMV, ADV, ETV, TDF	64	12	0	0
He et al[115] (2014)	97	97	0	NR	26	53	Asian	LMV, ADV, ETV, TBV	35	89	11	0
Chen et al[31] (2014)	188	83	105	12	38/49	143	Asian	LAM	20-22	63	23	NR
Jiang et al[116] (2015)	72	33	39	8	36	53	Asian	LMV, LMV + ADV, ADV, ETV, TBV	33	25	NR	0
Seto et al[117] (2015)	184	0	184	34	54	125	Asian	ETV	37	15	0	0
Huang et al[118] (2003)	32	0	32	NR	46	29	Asian	LMV	9	14	NR	NR
Marcellin et al[119] (2004)	181	0	181	53	40	156	Asian	LMV	12	53	0	0
Lai et al[120] (2006)1	325/313	0	325/313	16/31	44/44	248/236	Mixed	ETV/ LMV	≥13	124/78	1/1	22
Marcellin et al[121] (2009)3	181/85	0	181/85		40/39	156/74	Asian	LMV	12	52/33	0/0	12
Paik et al[122] (2010)	50	0	50	15	39	43	Asian	LMV	24	25	NR	0
Liang et al[123] (2011)	84	41	43	0	37	56	Asian	LMV, ADV, ETV or LMV +ADV	33	47	5	NR
Jin et al[124] (2012)	138	102	36	17	39	82	Asian	LMV	35	116	82	0
Berg et al[32] (2017)	21	0	21	0	45	33	Caucasian	TDF	≥ 48	13	4	0
Van Hees et al[35] (2018)	62	62	0	11	43	45	Caucasian	LMV, TDF, ETV, LMV + ADV	70	32	6	2
Rivino et al[43] (2018)4	21/27	0/0	21/27	0/0	43/51	14/19	Caucasian/Asian	TDF, LMV	≥ 24/≥ 24	4/14	0/0	NR

Virologic response is considered as defined in the original study.

¹Results expressed as ETV/LMV;

²Deaths not related with treatment discontinuation according to the authors;

³Two follow-up durations in this study, expressed as: Initial (6 mo)/Long-term (36 mo);

⁴Results obtained in two different cohorts, expressed as: cohort 1/cohort 2. ADV: Adefovir; CLE: Clevudine; ETV: Entecavir; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen; LMV: Lamivudine; NA: Nucleos(t)ide analogue treatment; NR: Not reported; TBV: Telbivudine; TDF: Tenofovir.

Table 2 NA treatment cessation recommendations in the current hepatitis B virus guidelines

Society	HBeAg(+)	HBeAg(-)	Cirrhosis
EASL (2017)[9]	HBsAg clearance (safest) HBeAg seroconversion and HBV DNA undetectability with 6-12 mo of ensuing consolidation therapy	HBsAg clearance Selected patients with ≥ 3 yr virological suppression if guaranteed close postNA monitoring for at least 1 yr	Not recommended
AASLD (2016)[20]	HBsAg clearance HBeAg seroconversion with at least 12 mo of persistently normal ALT levels and undetectable serum HBV DNA levels (close monitoring for at least 1 yr)	HBsAg clearance	Not recommended
APASL (2016)[22]	HBeAg seroconversion with undetectable HBV DNA and persistently normal ALT levels with 1-3 yr of consolidation therapy	HBsAg clearance with antiHBs seroconversion HBsAg loss with at least 12 mo of consolidation period After treatment for at least 2 yr with undetectable HBV DNA documented on 3 separate occasions, 6 mo apart	Could be considered in compensated cirrhosis with careful monitoring

AASLD: American Association for the Study of Liver Diseases; ALT: Alanine aminotransferase; APASL: Asian Pacific Association for the Study of the Liver; EASL: European Association for the study of the Liver; HBeAg: Hepatitis B e antigen; HBs: Hepatitis B surface protein; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; NA: Nucleos(t)ide analogue treatment.