Kim JE, Lee SY, Kim H, Kim KJ, Choe WH, Kim BJ. Naturally occurring mutations in the reverse transcriptase region of hepatitis B virus polymerase from treatment-naïve Korean patients infected with genotype C2. World J Gastroenterol 2017; 23(23): 4222-4232 [PMID: 28694662 DOI: 10.3748/wjg.v23.i23.4222]
Corresponding Author of This Article
Dr. Bum-Joon Kim, Professor, Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea. kbumjoon@snu.ac.kr
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
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World J Gastroenterol. Jun 21, 2017; 23(23): 4222-4232 Published online Jun 21, 2017. doi: 10.3748/wjg.v23.i23.4222
Table 1 Comparison of clinical data between chronic hepatitis and hepatocellular carcinoma patients
Clinical factors
CH (n = 59)
HCC (n = 72)
Total (n = 131)
P value
Age, yr, mean ± SD
38.9 ± 11.1
52.3 ± 9.7
45.7 ± 12.3
< 0.001
Gender, male
47.40%
79.10%
64.80%
< 0.001
HBeAg negative
35.50%
54.10%
45.80%
0.04%
ALT (IU/L), mean ± SD
94.5 ± 105.6
74.2 ± 85.1
106.8 ± 191.2
NS
AST (IU/L), mean ± SD
70.4 ± 92.0
127.1 ± 139.8
113.2 ± 141.0
< 0.001
HBV DNA
6.5 ± 2.0
5.3 ± 1.1
6.53 ± 1.7
< 0.001
HBsAg
3.7 ± 0.6
3.3 ± 0.7
3.43 ± 0.6
< 0.001
Table 2 Correlation between the frequency of potential nucleos(t)ide analog resistance mutation and clinical features
No. of mutations
CH/HCC
HBeAg (positive/negative)
ALT (IU/L)
AST (IU/L)
HBV DNA
HBsAg
0
27/25
29/23
108.51 ± 105.8
122.92 ± 106.8
6.50 ± 6.5
3.97 ± 3.8
1
18/16
21/13
101.61 ± 108.7
71.42 ± 126.1a
6.91 ± 6.4
3.95 ± 3.8
2
9/19
15/13
81.10 ± 113.8
113.75 ± 113.0
6.65 ± 6.1
3.65 ± 3.9a
3
4/7
3/8
211.45 ± 97.3
205.18 ± 104.8a
6.84 ± 6.5
3.84 ± 3.8
4
1/4
2/3
56.60 ± 108.8
72.00 ± 114.8
5.85 ± 6.5
3.68 ± 3.8
5
0/1
1/0
24.23
39.05
7.49
2.83
≥ 1 (n = 79)
32/47
42/37
105.81 ± 216.19
106.86 ± 131.51
5.11 ± 1.55
3.37 ± 0.77
Total (n = 131)
59/72
71/60
107.21 ± 191.16
113.2 ± 141.06
4.98 ± 1.51
3.43 ± 0.73
Table 3 Characterization of potential 42 NAr mutation from treatment naive Korean patients of genotype C2 infections
Category
Mutation
Drug resistance
CH
HCC
P value
Primary drug resistance
T184A/C/F
ETV
1
-
0.021
M204I/V
LMV, ETV, TNF
-
9
Mutation number (%)/no. of patients number
1/472 (0.21%)
9/576 (1.56%)
1
9 patients
Secondary mutation
L80I
LMV
-
5
NS
L180M
LMV, ETV, LdT
1
2
Mutation number (%)/no. of patients number
1/177 (0.56%)
7/216 (3.24%)
1
6
Putative NAr mutation
S53N
LMV
1
1
N.S
L82M/V
LMV
-
1
V84M/I
ADV
1
-
H126C/Y/Q
ADV
5
6
I128I/N/A
LMV
11
5
R/W153Q
LMV
2
-
V191I/D
LMV, ADV
2
3
V207I
LMV
-
1
S213T
ADV
-
3
Q215P/S/H
LMV, ADV
-
2
L217R
ADV
1
-
F221Y
ADV
3
9
L229G/V/W
LMV
-
2
P237H
ADV
-
2
N238D/S/T
ADV
3
6
Mutation number (%)/no. of patients number
29/1475 (1.96%)
41/1800 (2.27%)
23
31
Pre-treatment mutation
T38A
9
5
NS
Y124H
Found
4
6
D134E/N/C
Before
4
8
N139K/H
Therapy
-
8
I224V
4
12
Mutation number (%)/no. of patients number
21/351 (5.93%)
39/432 (9.02%)
17
31
Total Mutation number (%)/no. of patients (%)
52/2478 (2.09)
96/3024 (3.17)
0.003
32 patients (54.2)
47 patients (65.2)
148/5502 (2.68)
79 (60.3)
Table 4 Mutation site distributions and mutation rate in different sections of hepatitis B virus RT and overlapped hepatitis B surface antigen regions
Region (amino acid)
No. of mutation site
Mutation frequency
P value
Reverse transcriptase
Domain (22)
9 (40.9)
1.07%
0.008
A-B interdomain (6)
6 (100)
7.50%
-
Non A-B interdomain (14)
10 (71.4)
3.16%
NS
Total (42)
25 (59.5)
2.68%
-
HBsAg
A-determinant (3)
2 (66.6)
3.81%
Non A-determinant (37)
8 (21.6)
0.55%
< 0.001
Total (40)
10 (28.5)
0.80%
-
Table 5 Frequency and patterns of 3 types of NAr Mutations related to hepatocellular carcinoma
Mutations
No. of patients
Nucleotide sequences
Codons in RT genes (patients)
Codons in HBsAg genes (patients)
P value
CH
HCC
rtL80I
0
5
GGCTAT→GGATAT
CTA(L)→ATA(I) (5)
TAT(Y)→TAT(Y) (5)
0.036
rtN139K/T/H (sT131N/P)
0
8
GGAACC→GGAAAC
AAC(N)→AAA(K) (4)
ACC(T)→AAC(N) (4)
→GGCACC
→CAC(H) (3)
→ACC(T) (3)
0.008
→GGACCC
→ACC(T) (1)
→CCC(P) (1)
rtM204I/V (sW196L/S/W)
0
9
ATATGG→ATATTG
ATG(M)→ATT(I) (7)
TGG(W)→TTG(L) (7)
→ATATCG
→ATC(I) (1)
→TCG(S) (1)
0.004
→ATGTGG
→GTG(V) (1)
→TGG(W) (1)
Table 6 Comparison of clinical features between patients with or without L80I
Clinical factors
Wild type (n = 126)
L80I (n = 5)
Total (n = 131)
P value
Age, yr, mean ± SD
45.8 ± 12.2
57.2 ± 8.1
45.7 ± 12.3
0.043
Gender, Male
63.50%
100%
64.80%
NS
HBeAg negative
45.20%
60.00%
45.80%
NS
ALT (IU/L), mean ± SD
84.0 ± 96.8
68.6 ± 19.7
100.8 ± 191.2
NS
AST (IU/L), mean ± SD
100.9 ± 125.3
118.6 ± 65.0
113.2 ± 141.0
NS
HBV DNA
5.8 ± 1.7
6.7 ± 0.2
6.5 ± 1.7
< 0.001
HBsAg
3.4 ± 0.65
3.5 ± 0.32
3.4 ± 0.6
NS
CH: HCC, HCC (%)
59/67 (53.9)
0/5 (100)
59/72 (54.9)
0.036
Citation: Kim JE, Lee SY, Kim H, Kim KJ, Choe WH, Kim BJ. Naturally occurring mutations in the reverse transcriptase region of hepatitis B virus polymerase from treatment-naïve Korean patients infected with genotype C2. World J Gastroenterol 2017; 23(23): 4222-4232