Hepatitis B virus rtCYE/rtCYEI mutations may contribute limited tenofovir resistance: Analysis of a large sample of Chinese patients

doi:10.4254/wjh.v17.i8.107456

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World Journal of Hepatology

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1948-5182

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Hepatol. Aug 27, 2025; 17(8): 107456
Published online Aug 27, 2025. doi: 10.4254/wjh.v17.i8.107456

Table 1 Clinical prevalence of rtCYE and rtCYEI mutations in patients infected with different hepatitis B virus genotypes assessed by direct sequencing, n (%)

Mutation(s)	Genotype A (n = 9)	Genotype B (n = 4266)	Genotype C (n = 23718)	Genotype D (n = 243)
rtS106C	0 (0.00)	56 (1.31)	1947 (8.21)	1 (0.41)
rtH126Y	7 (77.78)	75 (1.76)	759 (3.20)	3 (1.23)
rtD134E	0 (0.00)	9 (0.21)	605 (2.55)	0 (0.00)
rtL269I	2 (22.22)	3939 (92.33)	14584 (61.49)	231 (95.06)
rtS106C+H126Y	0 (0.00)	0 (0.00)	114 (0.48)	0 (0.00)
rtS106C+H126Y+D134E	0 (0.00)	0 (0.00)	6 (0.03)	0 (0.00)
rtS106C+H126Y+D134E+L269I	0 (0.00)	0 (0.00)	6 (0.03)	0 (0.00)

rtCYE: rtS106C+H126Y+D134E; rtCYEI: rtS106C+H126Y+D134E+L269I.

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Table 2 Mutation patterns and clinical information of the patients with hepatitis B virus rtCYE/rtCYEI mutations

Patient	Date¹	GT	HBV DNA (log₁₀ IU/mL)	ALT (U/L)	HBeAg	NAs exposure (month)	Direct sequencing	Clonal sequencing (positive clone number/total tested clone number)
P1	2009.02	C	8.16	55	+	LAM (19)	rtS106C+H126Y+D134E	rtS106C+H126Y+D134E (18/20), rtS106C+H126Y+D134E+L80I+M204I (1/20), rtS106C+H126Y+D134E+L269I (1/20)
P2	2009.05	C	8.66	53	+	LdT (18)	rtS106C+H126Y+D134E+M204I	rtS106C+H126Y+D134E+M204I (19/20), rtS106C+H126Y+D134E+L80I+M204I (1/20)
P3	2012.04	C	8.10	589	+	LAM (33)	rtS106C+H126Y+D134E+L80I+L180M+M204I	rtS106C+H126Y+D134E+L80I+L180M+M204I (17/20), rtS106C+H126Y+D134E+L269I+L80I+L180M+M204I (3/20), rtS106C+H126Y+L80I+L180M+M204I (1/20)
P4	2013.06	C	6.77	375	+	ADV (55)	rtS106C+H126Y+D134E+L269I+A181V	rtS106C+H126Y+D134E+L269I+A181V (17/20), rtH126Y+L269I+A181V (3/20)
P5	2013.08	C	1.60	20	+	ADV (17)→ETV (15)	rtS106C+H126Y+D134E+L269I	rtS106C+H126Y+D134E+L269I (20/20)
P6	2013.08	C	5.52	20	-	LdT (16)	rtS106C+H126Y+D134E+L269I+M204I	rtS106C+H126Y+D134E+L269I (18/20), rtS106C+H126Y+D134E+L269I+M204I (2/20)
P7	2008.06	C	5.21	37	+	LAM (24)→ADV (18)	rtS106C+H126Y+D134E	rtH126Y (6/20), rtS106C+H126Y+D134E (14/20)
P8	2008.08	C	6.61	109	+	LdT (16)	rtS106C+H126Y+D134E+L80I+M204I	rtS106C+H126Y+D134E+L80I+M204I (19/20), rtS106C+H126Y+D134E+L269I+L80I+M204I (1/20)
P9	2009.04	C	3.77	87	-	ADV (32)	rtS106C+H126Y+D134E+L269I+N236T	rtS106C+H126Y+D134E+L269I (16/20), rtS106C+H126Y+D134E+L269I+N236T (4/20)
P10	2010.08	C	6.88	165	-	LAM (28)→ADV (12)	rtS106C+H126Y+D134E	rtS106C+H126Y+D134E (20/20)
P11	2012.09	C	4.50	35	-	LAM (38)	rtS106C+H126Y+D134E+L269I+M204I	rtS106C+H126Y+D134E+L269I+M204I (20/20)
P12	2014.06	C	4.18	75	-	LAM (36)→ADV (25)	rtS106C+H126Y+D134E+L269I	rtS106C+H126Y+D134E+L269I (16/20), rtS106C+H126Y+D134E (4/20)

¹Date for serum sampling for resistance testing.

HBV: Hepatitis B virus; ALT: Alanine aminotransferase; rtCYE, rtS106C+H126Y+D134E; rtCYEI, rtS106C+H126Y+D134E+L269I; GT: Genotype; NAs: Nucleoside/nucleotide analogues; LAM: Lamivudine; LdT: Telbivudine; ADV: Adefovir dipivoxil; ETV: Entecavir.

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Table 3 Analysis of clinical features between hepatitis B virus rtCYE/rtCYEI mutation-positive and negative patients, n (%)/median (25^th-75^th percentiles)

	rtCYE/rtCYEI (+) (n = 12)	rtCYE/rtCYEI (-) (n = 28224)	Univariate OR (95%CI)	P value
Age (years)	43 (33-49)	42 (32-51)	3.78 (-7.88-6.95)	0.903
Gender (male)	10 (83.33)	22419 (79.43)	0.77 (0.17-3.53)	1.00
Genotype (A/B/C/D%)	0/0/100/0	0.03/15.11/84.00/0.86		0.515
HBV DNA (log₁₀ IU/mL)	5.37 (3.40-6.69)	4.03 (2.72-6.00)	0.64 (-1.96-0.56)	0.275
ALT (U/L)	65.0 (35.5-151.0)	38.00 (23.0-72.0)	57.48 (-153.95-71.37)	0.473
AST (U/L)	33.0 (29.0-114.5)	35.0 (25.0-66.0)	73.71 (-179.46-109.51)	0.635
TBIL (µmol/L)	13.85 (12.5-21.1)	14.2 (10.2-22.0)	20.32 (-29.46-50.21)	0.610
HBeAg (+)	7 (58.33)	17438 (61.78)	0.87 (0.28-2.73)	0.806
LAM/LdT exposure¹	9 (75.00)	15419 (54.63)	0.40 (0.11-1.48)	0.260
ADV exposure¹	6 (50.00)	16971 (60.13)	1.51 (0.49-4.68)	0.474
ETV exposure¹	1 (8.33)	8698 (30.82)	4.90 (0.63-37.96)	0.169
TDF exposure¹	0 (0.00)	390 (1.38)	0.986 (0.98-0.99)	1.000
TAF exposure¹	0	0

¹Number of nucleoside/nucleotide analogues (NAs) exposure is counted under inclusion of each NA usage. A drug experience is defined as ≥ 3 months of administration of the drug either alone or in combination with another drug.

(+): Positive; (-): Negative; rtCYE: rtS106C+H126Y+D134E; rtCYEI: rtS106C+H126Y+D134E+L269I; ALT: Alanine aminotransferase; AST: Aspartate transferase; TBIL: Total bilirubin; LAM: Lamivudine; LdT: Telbivudine; ADV: Adefovir dipivoxil; ETV: Entecavir; TDF: Tenofovir disoproxil fumarate; TAF: Tenofovir alafenamide.

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Table 4 Drug susceptibility analysis of representative hepatitis B virus strains, mean ± SD

Viral strain	Tenofovir disoproxil fumarate
Viral strain	EC₅₀ (μmol/L)²	Fold³	P value¹
rtWT (wild-type)	5.79 ± 1.59	1.0	-
rtWT (laboratory)	5.90 ± 1.95	1.0	0.93
rtCYE	7.41 ± 0.97	1.3	0.09
rtCYEI	8.51 ± 1.29	1.5	< 0.05
rtCYE+M204I	6.95 ± 0.64	1.2	0.17
rtCYE+L80I+L180M+M204I	6.92 ± 1.69	1.2	0.31
rtCYEI+M204I	8.92 ± 0.87	1.5	< 0.05
rtCYEI+L80I+L180M+M204I	10.23 ± 1.01	1.8	< 0.05
rtCYEI+A181V	36.15 ± 5.99	6.2	< 0.05
rtCYEI+N236T	57.33 ± 5.30	9.9	< 0.05

¹Comparison with rtWT.

²EC₅₀: Half maximal effective concentration.

³Fold: The EC₅₀ of mutant/the EC₅₀ of wild-type. Experiments were performed at least three times independently.

WT: Wild-type; rtCYE: rtS106C+H126Y+D134E; rtCYEI: rtS106C+H126Y+D134E+L269I.

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Citation: Si LL, Fan ZP, Liu WH, Chen RJ, Chen XY, Ji D, Li L, Chen C, Liao H, Wang J, Xu DP, Zhao J, Liu Y. Hepatitis B virus rtCYE/rtCYEI mutations may contribute limited tenofovir resistance: Analysis of a large sample of Chinese patients. World J Hepatol 2025; 17(8): 107456
URL: https://www.wjgnet.com/1948-5182/full/v17/i8/107456.htm
DOI: https://dx.doi.org/10.4254/wjh.v17.i8.107456