Clinical significance of hepatitis B surface antigen mutants

Table 1 Mutations reported in the hepatitis B surface antigen regions

Codon	Type mutation	Mutation	Phenotypic consequence	HBV genotype	Ref.
Wt1 atg, Mt1 acg, Wt2/3 tac, Mt2 tgc, Mt3 cac, Wt4 ttt, Mt4 ttg	AAS	M197T1, Y206C2/H3, F220L4	Low serum HBV DNA	D	[23]
Wt1 gga	AAS	G145A1	Immune escape1	A-B-C-D	[24,31,47]
Mt1 gca			Lamivudine resistance1
	AAS	G145R	Immune escape	A, B-C-D	[28,35,36,40,41,45,47-50]
Wt tgc	AAS	C121W	Immune escape	A	[25]
Mt tgg
Wr tgc, Mt tgg	AAS	C147W	Immune escape	D	[25,26]
Wt act, Mt att	AAS	T189I	Immune escape, reducing HBsAg detection signal	E-A	[27,28,33]
WT act, Mt aat	AAS	I126N	Immune escape	C	[29]
WtCaa, Mt cga	AAS	Q129R	Vaccine escape	B	[30,34]
Wt ttc, Mt tac	AAS	F161Y	Immune escape	C	[31,51]
Wt atg, Mt atc	AAS	M103I	Immune escape	D	[24,52]
Wt ttg, Mt tcg	AAS	L94S	HCC	D	[32]
WT gac, Mt gaa	AAS	D144E	Immune escape	D, C, A	[28,33,40,52]
Wt cct, Mt Tct	AAS	P127S	Immune escape	B, D	[33,34,39]
Wt act, Mt agt	AAS	T126S	Immune escape	B	[33,34,38]
WT act, MT atc	AAS	T126I	Immune escape	C, D	[28,34,53]
WT act, Mt agc	AAS	T143S	Immune escape	C, A	[34,53]
WTcca, Mt aca	AAS	P120T	Immune escape	B, D	[34,53]
Wt gca, Mt Gta	AAS	A184V	Immune escape	E	[27]
Wt gta, Mt gca	AAS	V184A	Immune escape	E	[27]
Wt Tcg, Mt acg	AAS	S143t	Immune escape	E	[25,27,53]
Wt tgt, Mt ttc	AAS	C76F	Immune escape	E	[27]
Wt cct, Mt act	AAS	P70T	Immune escape	E	[27]
Wt ata, Mt act	AAS	I82T	Immune escape	E	[27]
Wt att, Mt ctt	AAS	I110L	Immune escape	A, C	[25,53]
Wt tat, Mt ttt	AAS	Y134F	Immune escape	D	[25,55]
Wt agt, Mt aac	AAS	S207N	Immune escape	D	[25,56]
Wt tat, Mt cat	AAS	Y134H	Immune escape	D	[52]
Wt acg, Mt aat	AAS	T125N	Increased HBsAg reactivity in immunological diagnostic assays	D	[43]
Wt atg, Mt atc, WT aag, Mt agg	AAS	M103I-K122R	Immune escape	A-C-D	[24]
Wt tat, Mt tgt	AAS	Y100C	Immune escape	B-C	[45]
Wt ccc, Mt ctc, MtQ caa, MtS tcg, Mtt acc	AAS	P120L/Q/S/T	Immune escape	B-C	[45]
Wt tcg, Mt cta	AAS	S143L	Immune escape	D	[52]
Wt ctt, Mt cct	AAS	L127P	Immune escape	E	[27]
Wt cct, Mt ctt	AAS	P127L	Immune escape	A	[27]
Mutations in pre-S1 region
Wt tct, Mt aca	AAS	S98T	Significant association with disease progression (LF, LC, HCC)	D	[57]
Wt aac, Mt act	AAS	N48T	Reduced HBsAg detection signals	C	[27]
Wt cag, Mt cct	AAS	Q82P	Reduced HBsAg detection signals	C	[27]
Wt acc, Mt aat	AAS	T97N	HBsAg not detected	C	[27]
Wt aat, Mt acc	AAS	N97T	HBsAg not detected	E	[27]
Wt cct, Mt cag	AAS	P93Q	HBsAg not detected	E, C	[27]
Deletion size (bp) 39	D	Region (nt) 3046-3084	Progression to advanced liver disease	C	[58]
Deletion size (bp) 108	D	Region (nt) 2959-3066	Progression to advanced liver disease	C	[58]
Deletion size (bp) 39	D	Region (nt) 3046-3084	Progression to advanced liver disease	C	[58]
Deletion size (bp) 108	D	Region 2959-3066	Progression to advanced liver disease	C	[58]
104th codon	AAS	Q104Stop	HCC development and immune escape	C	[59]
preS1 start	D	Not specified	HCC development and immune escape	C	[59]
Wt ucc, Mt gcc	AAS	S17A	Immune escape	C	[59]
Wt cct, Mt ctt	AAS	P32L	Immune escape	C	[59]
Wt tgg, Mt ctg, Mt agg	AAS	W43L/R	Immune escape	C	[59]
104th codon	AAS	Q104Stop	HCC development and immune escape	C	[59]
Mutations in pre-S2 region
Not specified	AAS	preS2-W3Stop	Immune escape	C	[59]
From 8th codon to 23rd codon	D		Immune escape	C	[59]

AAS: Amino acid substitution; D: Deletion; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HBsAg: Hepatitis B surface antigen; LC: Liver cirrhosis; LF: Liver fibrosis.

Table 2 Studies on hepatitis B surface antigen mutations associated with immune escape and failure to detect hepatitis B surface antigen

Ref.	Country	No. of patients	Type of study	Patients with HBsAg mutation, n (%)	Clinical significance	HBsAg mutation
Sticchi et al[77]	Italy	256	Cross-sectional	8 (3.1)	Detection failure; vaccine escape	G145R, T126I
Luongo et al[79]	Italy	1	Case report	1	Vaccine escape	M125T, T127P Q129H
Lee et al[66]	South Korea	1	Case report	1	Vaccine escape	G145R, P120Q, I126T
Seddigh-Tonekaboni et al[68]	United Kingdom	4		2	Vaccine escape	P142S, G145R, G145A
Ngui et al[73]	England, Wales	17	Cross-sectional	2 (12)	Vaccine escape	P120Q, F134Y, D144A, I126N
Carman et al[62]	Multinational	32	Cross-sectional	1	Vaccine escape	G145R
Laoi et al[78]	Ireland	32	Cross-sectional	6 (18.5)	Vaccine escape, detection failure	G145A, F134L, D144E, S143L
Foy et al[80]	United States	1	Case report	1	Immune escape	D144E

HBsAg: Hepatitis B surface antigen.

Table 3 Clinical significance of hepatitis B surface antigen mutations in chronic hepatitis B

Ref.	Country	No. of patients	Type of study	Patients with HBsAg mutation, n (%)	Clinical significance
Abe et al[103]	Japan	40	Case-control	27/30 (90) in HCC+	Correlation between preS1-S2 deletion and HCC (P < 0.001)
				0/10 (0) in HCC-
Bläckberg et al[106]	Sweden	35	Case-control	8/16 (50) in HCC+	No correlation between Pre-S2 mutations and HCC (P > 0.05)
				4/19 (21) in HCC-
Cao et al[94]	China	97	Case-control	34/47 (72.3) in HCC+	Correlation between pre-S deletion or pre-S2 start codon mutation and HCC (P < 0.001)
				13/50 (26) in HCC-
Chen et al[88]	Taiwan	152	Cross-sectional	26/50 (52.0) in HCC+	Correlation between pre-S deletion and HCC (P < 0001)
				30/102 (29.4) in HCC-
Chen et al[95]	Taiwan	240	Case-control	Pre-S deletion: 28/80 (35) in HCC+ vs 27/160 (16.9) in HCC-	Correlation between pre-S deletion (P = 0.002), W4P/R (P = 0.021) and M1V/I/A mutations (P = 0.011) and HCC
Choi et al[90]	South Korea	300	Cross-sectional	W4P/R: 10/80 (12.5) in HCC+ vs 7/160 (4.4) in HCC- M1V/I/A: 23/80 (28.8) in HCC+ vs 24/160 (15) in HCC-	Correlation between pre-S deletion or pre-S2 start codon mutation and HCC (P < 0.001)
				31/72 (43.1) in HCC+
Fang et al[93]	China	66	Case-control	51/228 (22.4) in HCC-	Correlation between pre-S deletion and HCC (P < 0.01)
				15/33 (45.5) in HCC+
Gao et al[91]	China	79	Cross-sectional	6/33 (18.2) in HCC-	Correlation between pre-S deletion and HCC (P = 0.001)
				10/26 (38.5) in HCC+
Huang et al[104]	Taiwan	38	Case-control	3/53 (5.7) in HCC-	Correlation between pre-S deletion and HCC (P = 0.008)
				9/19 (47.4) in HCC+
Hung et al[110]	Taiwan	313	Cross-sectional	1/19 (5.3) in HCC-	Correlation between pre-S deletion and HCC (P < 0.001)
				41/146 (40) in HCC+
Huy et al[85]	12 countries	352	Cross-sectional	5/167 (3.0) in HCC-	Correlation between pre-S1/S2 deletion and pre-S2 start codon mutations and HCC (P < 0.05)
				17/49 (34.7) in HCC+
				50/303 (16.5) in HCC-
Jang et al[96]	South Korea	119	Cross-sectional	17/48 (35.4) in HCC+	Correlation between pre-S deletion and HCC (P < 0.05)
				13/71 (18.3) in HCC-
Kao et al[99]	Taiwan	168	Case-control	56/112 (50.0) in HCC+	Correlation between pre-S deletion and HCC (P < 0.001)
				4/56 (7.1) in HCC-
Lee et al[98]	South Korea	270	Case-control	28/135 (18.5) in HCC+	Correlation between pre-S2 deletion and HCC (P < 0.001)
				6/135 (4.4) in HCC-
Lee et al[107]	South Korea	247	Cross-sectional	19/153 (12.4) in advanced liver disease (LC or HCC) 1/94 (1.1) in non-advanced liver disease	Correlation between W4P/R mutation and HCC or cirrhosis (P < 0.05)
Lin et al[89]	Taiwan	266	Cross-sectional	19/64 (29.7) in HCC+	Correlation between pre-S deletion and HCC (P = 0.02)
				25/202 (12.4) in HCC-
Mun et al[92]	South Korea	120	Cross-sectional	Pre-S1: 13/40 (32.5) in HCC+ vs 11/80 (13.7) in HCC-	Correlation between pre-S1 (P = 0.027) and pre-S1 start codon mutations (P = 0.048) and HCC. Correlation between pre-S2 deletions and cirrhosis (P = 0.001)
				Pre-S1 start codon: 9/40 (22.5) in HCC+ vs 4/80 (5.0) in HCC- Pre-S2: 8/21 (38.1) in LC+ vs 4/59 (6.8) in LC-
Qu et al[102]	China	193	Case-control	Pre-S deletion: 28/96 (29.2) vs 11/97 (11.3), Pre-S2 start codon: 17/96 (17.7) vs 7/97 (7.2), T31C: 23/96 (24.0) vs 37/97 (38.1), T53C: 36/96 (37.5) vs 23/97 (23.7), T766A: 13/96 (13.5) vs 14/97 (14.4) in HCC+ vs HCC-	Correlation between pre-S deletion (P = 0.003), pre-S2 start codon (P = 0.027), T31C (P = 0.044), T53C (P = 0.027) but not T766A mutation (P = 0.966) and HCC
Raimondo et al[87]	Italy	110	Cross-sectional	16/19 (84.2) in HCC	Correlation between pre-S2 deletion or start codon mutation and HCC (P < 0.02)
				40/91 (43.9) in HCC-
Sinn et al[100]	South Korea	195	Cohort	13/24 (54.2) in HCC+	Correlation between pre-S mutation and HCC (P < 0.001)
				31/171 (18.1) in HCC-
Sugauchi et al[86]	Japan	160	Cross-sectional	20/58 (34.5) in advanced liver disease (LC or HCC)	Correlation between pre-S deletion and HCC or cirrhosis (P < 0.05)
				17/102 (16.7) in non-advanced liver disease
Sung et al[108]	Hong Kong	26	Case-control	T31C: 6/16 (37.5) in HCC+ vs 0/10 (0.0) in HCC- T53C: 6/16 (37.5) in HCC+ vs 1/10 (10.0) in HCC-	Correlation between T31C and T53C mutations and HCC (P < 0.05)
Thongbai et al[105]	Thailand	154	Cross-sectional	24/65 (36.9) in HCC+	No correlation between pre-S1/S2/S deletion or start codon mutation and HCC (P > 0.1)
				34/89 (38.2) in HCC-
Yeung et al[97]	Taiwan	192	Case-control	28/96 (29.2) in HCC+	Correlation between pre-S deletion and HCC (P = 0.015)
				14/96 (14.6) in HCC-
Zhao et al[101]	China	317	Case-control	74/157 (47.1) in HCC+	Correlation between pre-S deletion and HCC (P < 0.001)
				45/160 (28.1) in HCC-
Zhu et al[109]	China	55	Case-control	4/20 (20.0) with Pre-S2 start codon, 5/20 (25.0) with T53C and 3/20 with T766A in HCC+ vs 0/20 in HCC-	Correlation between pre-S2 start codon (P = 0.014), T53C (P = 0.004) and T766A mutation (P = 0.043) and HCC

HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HBsAg: Hepatitis B surface antigen; LC: Liver cirrhosis.