恩替卡韦与替诺福韦酯治疗高病毒载量慢性乙型肝炎患者的效果分析

周珲堃; 江建宁; 苏明华; 王荣明; 胡伯斌; 邓德丽; 韦慧兰; 梁先帅; 何文明; 郭荣晟

doi:10.3969/j.issn.1001-5256.2022.03.008

恩替卡韦与替诺福韦酯治疗高病毒载量慢性乙型肝炎患者的效果分析

DOI: 10.3969/j.issn.1001-5256.2022.03.008

广西医科大学第一附属医院感染性疾病科，教育部区域性高发肿瘤早期防治研究重点实验室，南宁 530021

基金项目:

国家自然科学基金 (81960115);

广西病毒性肝炎防治研究重点实验室开放课题基金项目 (GXCDCKL202001);

教育部区域性高发肿瘤早期防治研究重点实验室自主课题 (GKE2019-04);

广西医科大学青年科学基金项目 (GXMUYSF201910)

伦理学声明：本研究方案于2019年3月6日经由广西医科大学第一附属医院伦理委员会批准，批号：2019-KY-国基-193。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突，特此声明。

作者贡献声明：周珲堃参与设计，实施研究，采集数据，统计分析，文章撰写；苏明华给与指导和支持；邓德丽、韦慧兰、梁先帅、王荣明、胡伯斌、何文明、郭荣晟负责患者随访，数据采集及分析；江建宁负责研究设计，数据分析，审阅和修改文章。

详细信息

通信作者:
江建宁，jjianning@163.com

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出版历程
- 收稿日期: 2021-08-17
- 录用日期: 2021-11-29
- 出版日期: 2022-03-20

Efficacy of entecavir versus tenofovir disoproxil fumarate in treatment of chronic hepatitis B patients with high viral load

Key Laboratory of High-Incidence-Tumor Prevention and Treatment, Ministry of Education, Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China

Research funding:

National Natural Science Foundation (81960115);

Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis (GXCDCKL202001);

Key Laboratory of High-Incidence-Tumor Prevention and Treatment (Guangxi Medical University), Ministry of Education (GKE2019-04);

Guangxi Medical University Youth Science Fundation (GXMUYSF201910)

More Information

Corresponding author: JIANG Jianning, jjianning@163.com(ORCID:0000-0001-8961-417X)

摘要

摘要: 目的探讨恩替卡韦(ETV)与替诺福韦酯(TDF)对于高病毒载量初治患者的疗效及应答不佳的处理方案。方法选取2016年6月—2021年7月广西医科大学第一附属医院感染性疾病科慢性乙型肝炎(CHB)患者抗病毒治疗队列中符合入组条件的患者165例。入组患者为基线HBV DNA＞6 lg拷贝/mL, 使用ETV或TDF满48周的CHB初治患者，并采用荧光定量PCR法检测HBV DNA。统计48周治疗的病毒学应答率；Logistic回归分析影响48周HBV DNA＜500拷贝/mL和＜100拷贝/mL应答的因素；分层分析比较48周后不同年龄、性别、基线HBV DNA、ALT、一线用药种类、HBeAg状态情况下HBV DNA＜500拷贝/mL和＜100拷贝/mL的应答率。非正态分布的计量资料2组间比较采用Mann-Whitney U检验，计数资料组间比较采用χ²检验或Fisher确切概率法，多因素分析采用二分类logistic回归模型分析。结果 48周治疗后85.5%(141/165)的患者HBV DNA＜500拷贝/mL，66.1%(109/165)的患者HBV DNA＜100拷贝/mL，ETV与TDF两组间疗效差异无统计学意义。多因素logistic回归分析显示，性别、基线HBV DNA、基线ALT、基线HBeAg是获得完全病毒学应答的影响因素(OR值分别为2.793、0.369、4.556、0.120，95%CI分别为1.197~6.517、0.142~0.959、1.770~11.732、0.033~0.429，P值均＜0.05)。基线ALT正常(≤40 U/L)的患者，48周治疗后75.6%(34/45)的患者HBV DNA＜500拷贝/mL，53.3%(24/45)的患者HBV DNA＜100拷贝/mL，ETV组与TDF组疗效差异无统计学意义。基线ALT异常(＞40 U/L)的患者，48周治疗后89.2%(107/120)的患者HBV DNA＜500拷贝/mL，TDF组高于ETV组(96.1% vs 84.1%，χ² =4.386，P=0.036)；70.8%(85/120)的患者HBV DNA＜100拷贝/mL，TDF组与ETV组(78.4% vs 65.2%)相比，差异无统计学意义。基线ALT正常组与异常组年龄≤30岁的患者HBV DNA＜100拷贝/mL应答率与年龄＞30岁的患者相比(77.8% vs 47.2%，85.2% vs 66.7%)，差异均无统计学意义。治疗48周后未获得完全病毒学应答即HBV DNA≥100拷贝/mL的患者，接受原方案延长治疗48周后，87.9%(29/33)的患者获得完全病毒学应答，转换或加用与原方案无交叉耐药位点一线核苷(酸)类似物(NUC)延长治疗48周后100%(9/9)的患者获得完全病毒学应答。结论年龄＞30岁患者无论病毒载量高低、ALT是否正常，应及早抗病毒治疗，尤其是有肝硬化或者肝癌家族史患者；年龄≤30岁、ALT正常、病毒载量高的患者，在患者知情同意后可以考虑启动抗病毒治疗。对于治疗48周发生应答不佳的患者应及时转换或加用与原方案无交叉耐药位点的NUC一线药物。
- 肝炎, 乙型, 慢性 /
- 病毒载量 /
- 核酸类, 核苷酸类和核苷类 /
- 治疗结果
Abstract: Objective To investigate the efficacy of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) and the treatment measures for poor response in previously untreated chronic hepatitis B (CHB) patients with high viral load. Methods A total of 165 CHB patients who received antiviral therapy and met the inclusion criteria in Department of Infectious Diseases, The First Affiliated Hospital of Guangxi Medical University, from June 2016 to July 2021 were enrolled. The patients enrolled had a baseline HBV DNA level of > 6lg copies/ml and were previously untreated CHB patients who had used ETV or TDF for 48 weeks, and quantitative real-time PCR was used to measure HBV DNA. Virologic response rate was calculated after 48 weeks of treatment; a logistic regression analysis was used to investigate the influencing factors for the response of HBV DNA < 500 copies/mL and HBV DNA < 100 copies /mL at 48 weeks; a stratified analysis was performed to compare the virologic response rate of HBV DNA < 500 copies /ml and HBV DNA < 100 copies/ml after 48 weeks between the patients with different ages, sexes, baseline HBV DNA levels, baseline alanine aminotransferase (ALT) levels, types of first-line medication, and HBeAg statuses. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups, and the binary logistic regression model was used for multivariate analysis. Results After 48 weeks of treatment, 85.5% (141/165) of the patients achieved an HBV DNA load of < 500 copies/mL, and 66.1% (109/165) of the patients achieved an HBV DNA load of < 100 copies /mL, with no significant difference in treatment outcome between the ETV group and the TDF group. The multivariate logistic regression analysis showed that sex(OR=2.793, 95%CI: 1.197-6.517), baseline HBV DNA(OR=0.369, 95%CI: 0.142-0.959), baseline ALT(OR=4.556, 95%CI: 1.770-11.732), and baseline HBeAg(OR=0.120, 95%CI: 0.033-0.429) were influencing factors for complete virologic response(all P < 0.05). For the patients with normal ALT (≤40 U/L) at baseline, 75.6% (34/45) achieved an HBV DNA load of < 500 copies/mL after 48 weeks of treatment, and 53.3% (24/45) achieved an HBV DNA load of < 100 copies/mL, with no significant difference in treatment outcome between the ETV group and the TDF group. For the patients with abnormal ALT (> 40 U/L) at baseline, 89.2% (107/120) achieved an HBV DNA load of < 500 copies/mL after 48 weeks of treatment, and the proportion of such patients in the TDF group was significantly higher than that in the ETV group (96.1% vs 84.1%, χ²=4.386, P=0.036); 70.8% (85/120) achieved an HBV DNA load of < 100 copies/mL, the proportion of such patients was no significant difference between the TDF group and the ETV group (78.4% vs 65.2%). The response of HBV DNA < 100 copies/ml of the normal baseline ALT group and the abnormal baseline ALT group, there were no significant differences between the patients aged≤30 years and aged > 30 years (77.8% vs 47.2%, 85.2% vs 66.7%). For the patients who did not achieve complete virologic response (HBV DNA ≥100 copies/mL) after 48 weeks of treatment, 87.9% (29/33) achieved complete virologic response after the original treatment regimen was prolonged for 48 weeks, and 100% (9/9) of the patients achieved complete virologic response after switching to or adding the first-line nucleos(t)ide analogues (NUCs) without cross-resistance sites with the original regimen for another 48 weeks. Conclusion The patients aged > 30 years should receive antiviral therapy as early as possible, regardless of viral load and ALT level, especially those with a family history of liver cirrhosis or hepatocellular carcinoma; the patients aged ≤30 years who have a normal ALT level and a high viral load should consider initiating antiviral therapy after providing informed consent. For the patients with poor response after 48 weeks of treatment, first-line NUCs without cross-resistance sites with the original regimen should be switched to or added in time.
- Hepatitis B, Chronic /
- Viral Load /
- Nucleic Acids, Nucleotides, and Nucleosides /
- Treatment Outcome

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表 1 165例患者一般资料

指标	ETV组(n=86)	TDF组(n=79)	统计值	P值
年龄(岁)	36.6±8.0	33.4±6.2	t=2.916	0.004
男[例(%)]	57(66.3)	15(19.0)	χ²=37.442	0.000
基线ALT水平(U/L)	100(43~139)	73(25~150)	Z=-1.951	0.051
基线ALT分组[例(%)]			χ²=5.101	0.024
ALT正常	17(19.8)	28(35.4)
ALT异常	69(80.2)	51(64.6)
基线HBV DNA(lg拷贝/mL)	7.26(6.80~8.04)	7.84(7.19~8.19)	Z=-2.650	0.008
基线HBeAg阳性[例(%)]	64(74.4)	61(77.2)	χ²=0.175	0.675

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表 2 165例患者一线药物治疗48周后HBV DNA＜100拷贝/mL的logistic回归分析

指标	单因素logistic分析				多因素logistic分析
指标	B	OR	95%CI	P值	B	OR	95%CI	P值
性别(男赋值0，女赋值1)	0.721	2.057	1.069~3.955	0.031	1.027	2.793	1.197~6.517	0.018
年龄(≤30岁赋值0，＞30岁赋值1)	-1.152	0.316	0.123~0.813	0.017
ALT(正常赋值0，异常赋值1)	0.754	2.125	1.049~4.303	0.036	1.517	4.556	1.770~11.732	0.002
HBV DNA(6~7 lg拷贝/mL赋值0，＞7 lg拷贝/mL赋值1)	-0.958	0.384	0.164~0.901	0.028	-0.998	0.369	0.142~0.959	0.041
HBeAg(阴性赋值0，阳性赋值1)	-2.206	0.11	0.032~0.376	＜0.001	-2.124	0.120	0.033~0.429	0.001

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表 3 165例CHB患者48周治疗病毒学应答结果亚组分析

指标	例数	HBV DNA＜500拷贝/mL	χ²值	P值	HBV DNA＜100拷贝/mL	χ²值	P值
ALT水平[例(%)]			4.878	0.027		4.470	0.034
正常	45	34(75.6)			24(53.3)
异常	120	107(89.2)			85(70.8)
治疗药物[例(%)]			2.381	0.123		0.857	0.355
ETV	86	70(81.4)			54(62.8)
TDF	79	71(89.9)			55(69.6)
年龄[例(%)]			2.994	0.084		6.127	0.013
≤30岁	36	34(94.4)			30(83.3)
＞30岁	129	107(82.9)			79(61.2)
性别[例(%)]			6.057	0.014		4.735	0.030
男	72	56(77.8)			41(56.9)
女	93	85(91.4)			68(73.1)
基线HBV DNA[例(%)]			4.102	0.043		5.065	0.024
6~7 lg拷贝/mL	41	39(95.1)			33(80.5)
＞7 lg拷贝/mL	124	102(82.3)			76(61.3)
基线HBeAg[例(%)]			8.987	0.003		16.462	＜0.001
HBeAg阳性	125	101(80.8)			72(57.6)
HBeAg阴性	40	40(100.0)			37(92.5)

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表 4 165例患者ALT正常、异常亚组中药物、年龄分层分析

组别	例数	HBV DNA＜500拷贝/mL	HBV DNA＜100拷贝/mL
ALT正常组[例(%)]
ETV组	17	12(70.6)	9(52.9)
TDF组	28	22(78.6)	15(53.6)
χ²值			0.002
P值		0.722	0.967
年龄≤30岁	9	9(100.0)	7(77.8)
年龄＞30岁	36	25(69.4)	17(47.2)
P值		0.087	0.143
ALT异常组[例(%)]
ETV组	69	58(84.1)	45(65.2)
TDF组	51	49(96.1)	40(78.4)
χ²值		4.386	2.478
P值		0.036	0.115
年龄≤30岁	27	25(92.6)	23(85.2)
年龄＞30岁	93	82(88.2)	62(66.7)
χ²值			3.473
P值		0.730	0.062

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