Serum hepatitis B surface antigen levels predict treatment response to nucleos(t)ide analogues

Table 1 Comparison of hepatitis B surface antigen kinetic between interferon and nucleos(t)ide analogues

Interferon vs NA	HBeAg status	Mean decline of HBsAg (log IU/mL) at week 48		Ref.
Peginterferon alfa-2a + lamivudine vs lamivudine	HBeAg (-) patients	0.71 vs 0.02	P < 0.001	[13]
Peginterferon alfa-2a vs lamivudine alone		0.67 vs 0.02	P < 0.001
Peginterferon vs entecavir	HBeAg (+) patients	0.94 vs 0.38	P = 0.07	[26]
	HBeAg (-) patients	0.56 vs -0.10	P < 0.001

NAs: Nucleos(t)ide analogues; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen.

Table 2 Hepatitis B surface antigen predict virological response or hepatitis B e antigen loss/seroconversion during nucleos(t)ide analogues therapy

NAs	Treatment duration	Case number	Comments	Ref.
Entecavir	2 yr	95	HBeAg (+) patients: baseline HBsAg cutoff level of 9550 IU/mL yielded the highest predictive value in predicting the VR	[31]
			HBeAg (-) patients: baseline HBsAg or HBsAg decline levels could not predict VR
Entecavir	2 yr	101	HBeAg (+) patients: HBsAg level at baseline was an independent factor of HBeAg loss/seroconversion	[32]
			HBsAg level < 3000 IU/mL at 3 mo of treatment was an independent factor for achieving VR
			HBeAg (-) patients: HBsAg levels could not predict VR
Entecavir	More than 2 yr	50	Low baseline HBsAg levels were the most significant factor for achieving VR at year 2 of treatment	[33]
Tenofovir	6 yr	104 HBV + HIV	A higher level of HBsAg decline in patients with HBeAg loss compared to patients remaining HBeAg-positive (2.5 log IU/mL vs 1.8 log IU/mL, P < 0.001)	[36]
			Baseline HBsAg levels could not predict HBeAg loss

VR: Virological response; NAs: Nucleos(t)ide analogues; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; HIV: Human immunodeficiency virus.

Table 3 Hepatitis B surface antigen predict hepatitis B surface antigen loss during nucleos(t)ide analogues therapy

NAs	Treatment duration	Case number	Condition of HBsAg predict HBsAg loss	Ref.
Telbivudine	more than 3 yr	162 HBeAg (+)	HBsAg decline ≥ 1 log after 1 yr of treatment	[50]
Tenofovir	3 yr	263 HBeAg (+)	Steeper declines in HBsAg (-2.41 log10 IU/mL vs -0.20 log10 IU/mL) at month 6	[51]
Tenofovir	6 yr	104 HBV + HIV	HBsAg decline ≥ 2 log IU/mL at month 6	[36]
Lamivudine	more than 10 yr	70	Baseline HBsAg < 1000 IU/mL and on-treatment reduction of HBsAg > 0.166 log IU/mL per year	[38]
Lamivudine as their first drug	9 yr	791	HBeAg (+) patients: HBsAg decline ≥ 0.5 log IU/mL within 6 mo	[53]
			HBeAg (-) patients: HBsAg decline at 6 mo and baseline HBsAg levels of < 730 IU/mL

NAs: Nucleos(t)ide analogues; HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; HIV: Human immunodeficiency virus.

Table 4 Hepatitis B surface antigen predict hepatitis B virus relapse after stopping nucleos(t)ide analogues therapy

Patients	NAs and treatment duration	Definition of HBV relapse or sustained response (SR)	Comments	Ref.
17 HBeAg (+) patients	telbivudine for 104 wk	SR: HBV DNA < 300 copies/mL, HBeAg seroconversion, ALT normalization at 2 yr off-treatment	HBsAg levels < 100 IU/mL at the end of treatment and HBsAg decline of > 0.8 and > 1 log IU/mL at treatment weeks 24 and 52 were predictive of SR	[59]
51 HBeAg (+) patients	lamivudine, adefovir or entecavir	SR: HBV DNA levels < 10000 copies/mL until 6 or 12 mo off-treatment without reappearance of HBeAg	A decline in HBsAg of 0.5 log IU/mL at 6 mo was the independent factor for SR at 6 mo off-treatment	[60]
	Stop treatment: HBeAg loss/seroconversion and ≥ 12 mo of additional therapy		A decline in HBsAg was not a significant factor for SR at 12 mo off-treatment
41 HBeAg (+), 43 HBeAg (-) patients	lamivudine, adefovir or entecavirStop treatment: according to the 2008 APASL guidelines	Virological relapse: HBV DNA > 1000 copies/mL after discontinuation of treatment	HBsAg levels < 100 IU/mL at the end of treatment was predictive of SR	[61]
53 HBeAg (-) patients	Lamivudine for 34 ± 23 mo	SR: HBV DNA ≤ 200 IU/mL at 12 mooff-treatment.	Combined HBsAg ≤ 100 IU/ml and HBsAg reduction > 1 log at the end of treatment were predictive of SR	[62]
83 HBeAg (+), 105 HBeAg (-) patients	Lamivudine for 89.3 ± 35.9 wk	SR: serum HBV DNA to ≤ 2000 IU/mL after discontinuation of treatment	HBeAg (+) patients: HBsAg (cut-off value of < 300 IU/mL) at the end of treatment was predictive of HBsAg loss	[63]
			HBeAg (-) patients: HBsAg (cut-off values of < 120 and < 200 IU/mL) at the end of treatment was predictive of HBsAg loss and SR respectively.
46 HBeAg (+), 96 HBeAg (-) patients	Entecavir for 153.6 ± 43.9 wk	Virological relapse: HBV DNA > 2000 IU/mL.	HBeAg (+) patients: HBsAg (cut-off value of < 4000 IU/mL) at baseline was predictive of virological and clinical relapse	[64]
	Fulfilled the stopping criteria of the APASL 2012	Clinical relapse: HBV DNA > 2000 IU/mL and ALT > 2 X ULN	HBeAg (-) patients: HBsAg (cut-off values of < 200 and < 500 IU/mL) at the end of treatment were predictive of virological and clinical relapse respectively

HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; APASL: Asian pacific association for the study of the liver; ALT: Alanineaminotransferase; ULN: Upper limit of normal.