Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression

Table 1 Distribution of preexisting RT mutation in 42 potential NAr regions in treatment naïve patients

Mutation	RT mutation type	Change in HBsAg3	Drug resistance	Genotype	Location	Ref.
Primary1	I169T		ETV	B, C	China	[20,53]
	A181T/V	sW172 stop	LMV, LdT, ADV, TNF	A, B, C, D	Canada, Italy, China, United States	[24,25,30,39,45,51,53]
	T184A/C/F/G/I/L/M/S		ETV, LMV	A, B, C, D	Canada, China, South Korea	[24,27,33]
	A194T	no change in HBsAg	ADV, TNF	B, C, D	Indonesia, Italy	[38,51]
	S202C/G/I		ETV, LMV	A, B, C, D	Canada, China, Spain, Italy	[24,27,30,57,59]
	M204I/V/S	V-sI195M, I- sW196S/L/Stop	LMV, LdT, ADV, TNF, ETV	A, B, C, D	Canada, Italy, South Korea, China, Indonesia, United States, Turkey	[24,25,27,30,33-36,38, 39,47,52,53]
	N236T		ADV, TNF	B, C	China	[27,30,47]
	M250I/L/V		ETV	A, B, C, D	Canada, Italy, China, United States	[24,25,27,45]
Secondary1	L80I/V	no change in HBsAg	LMV	A, B, C, D	Canada, Italy, South Korea, Indonesia, China	[24,25,33,38,47,53]
	V173L	sE164D	LMV	A, B, C, D	China, Canada, Italy	[20,24,25,30,39,47]
	L180M	no change in HBsAg	LMV, ETV, LdT	A, B, C, D	Canada, South Korea, China, Italy, Indonesia	[24,25,27,30,33,38, 39,47,53]
Putative2	S53N		LMV	B, C	China, South Korea	[21,33,58]
	T54N	sP46T	ADV	A, B, C, D	Italy	[83]
	L82M		LMV	C	South Korea	[33]
	V84M, S85A		ADV	B, C	South Korea, China	[33,53,127]
	I91L	no change in HBsAg	LMV	B, C, D	China, Indonesia, India	[21,38,54,58]
	Y126C/R/H	C-sT118A	ADV	A, B, C, D	South Korea, China, India	[33,54,58]
	T128I, T128N	N-sG145R, I-sP120S	LMV	B, C, D	Indonesia, China, India	[38,53,54,58]
	N139D/E/Q			A	India	[54]
	W153Q/R/E	Q- sP120T/ sG145R, E-sD144E/G145R	LMV	B, C, D	South Korea, Indonesia, China, India	[33,38,54,58]
	F166L	sF158Y	LMV
	V191I	sW182 stop	LMV, ADV	B, C, D	South Korea, China, Italy	[33,39,51,58]
	A200V	sL192F	LMV	B, C	South Korea, China	[27,33,42]
	V207I	sW199 stop, sM198I	LMV	A, B, C, D	Germany, China, Italy	[27,32,39,83]
	S213T		LMV, ETV	A, B, C, D	China, India	[39,40,42,58]
	V214A	T-sS204R	ADV	B, C, D	South Korea, Italy, China,	[30,33,53,83]
	Q215E/H/P/S		LMV, ADV	A, B, C, D	China, Italy, India, Turkey	[30,39,51,53-55]
	L217R, E218D, F221Y	D-sS210I/T	ADV	A, B, C, D	South Korea, China	[21,33,42,58]
	L229G/V/W		LMV	B, C	South Korea, China	[33,42,58]
	L229F	F-sC221L, V-sF220L	LMV	B, C, D	China, India	[54,58,128]
	I233V		ADV	A, C, D	Indonesia, Italy, India, China, South Korea, Germany	[25,38,40,58,78,79]
	P237H, N238D/S/T, Y245H	N/A	ADV	B, C	South Korea, China	[21,33,39,58]
	S/C256G		LMV, ETV	B, C	China, Indonesia	[21,38,58]
Pretreatment2	T38A, T38K	K-sQ30K		B, C	South Korea, China	[33,58]
	Y124H/D/N			B, C,	China, South Korea	[21,33,58]
	D134E/N	sI126S/N		B, C, D	China, South Korea, Indonesia	[21,33,38,58]
	N139K/H	K-sT131N, T-sT131P, H-sG139N		A, B, C	South Korea, India, Indonesia, China	[33,38,54,58]
	I224V	No change in HBsAg		B, C,	China, South Korea	[21,33,39,58]
	R242A

¹Well known NA resistance mutations (primary and secondary) with phenotypic data;

²Putative and pretreatment mutations relevant to NA resistance but not experimentally confirmed;

³Changes in HBsAg, reported in Sheldon et al[17], Liu et al[21], Locarnini et al[72], and Yang et al[77]. Rt139 is shared in both Categories 3 (N139D/E/Q) and 4 (N139K/H). Overall, 42 positions in the RT region were studied. ADV: Adefovir dipivoxil; ETV: Entecavir; Ldt: Telbivudine; LMV: Lamivudine; TNF: Tenofovir.