富马酸丙酚替诺福韦治疗青岛地区60岁及以上慢性乙型肝炎患者的有效性和安全性

宋玉文; 陈立震; 金文文; 耿宁; 张旸; 杜水仙; 赵本田; 段建平; 周永; 毕春花; 马磊; 胡欣欣; 张吉宏; 孙建涛; 谭杰; 辛永宁

doi:10.3969/j.issn.1001-5256.2023.05.010

富马酸丙酚替诺福韦治疗青岛地区60岁及以上慢性乙型肝炎患者的有效性和安全性

DOI: 10.3969/j.issn.1001-5256.2023.05.010

宋玉文¹,
陈立震¹,
金文文¹,
耿宁¹,
张旸¹,
杜水仙¹,
赵本田¹,
段建平²,
周永²,
毕春花³,
马磊⁴,
胡欣欣⁴,
张吉宏⁵,
孙建涛⁵,
谭杰¹,
辛永宁^1, , ,

1.
青岛大学附属青岛市市立医院感染性疾病科，山东青岛 266000
2.
青岛市第六人民医院感染性疾病科，山东青岛 266000
3.
青岛大学附属医院感染性疾病科，山东青岛 266000
4.
青岛市城阳区人民医院感染性疾病科，山东青岛 266000
5.
青岛市即墨区人民医院感染性疾病科，山东青岛 266000

基金项目:

慢性乙型肝炎临床研究项目 (IN-CN-320-5837)

伦理学声明：本研究方案于2019年11月28日经由青岛市市立医院医学伦理委员会审批，批号：2019临审Y字第028号；已在中国临床试验注册中心注册，注册号：ChiCTR2000034699，患者均签署知情同意书。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：辛永宁、陈立震对研究的思路或设计有关键贡献；辛永宁、陈立震、金文文、耿宁、张旸、杜水仙、赵本田、段建平、周永、毕春花、马磊、胡欣欣、张吉宏、孙建涛、宋玉文、谭杰参与了研究数据的获取；宋玉文完成分析解释过程及论文撰写；辛永宁、陈立震参与起草或修改文章关键内容。

详细信息

通信作者:
辛永宁，xinyongning@163.com (ORCID: 0000-0002-3692-7655)

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出版历程
- 收稿日期: 2022-10-25
- 录用日期: 2022-12-02
- 出版日期: 2023-05-20

Efficacy and safety of tenofovir alafenamide fumarate in treatment of chronic hepatitis B patients aged ≥60 years in Qingdao, China

1.
Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, Shandong 266000, China
2.
Department of Infectious Diseases, Qingdao Sixth People's Hospital, Qingdao, Shandong 266000, China
3.
Department of Infectious Diseases, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, China
4.
Department of Infectious Diseases, Chengyang People's Hospital, Qingdao, Shandong 266000, China
5.
Department of Infectious Diseases, Jimo People's Hospital, Qingdao, Shandong 266000, China

Research funding:

Chronic Hepatitis B Clinical Research Project (IN-CN-320-5837)

More Information

Corresponding author: XIN Yongning, xinyongning@163.com (ORCID: 0000-0002-3692-7655)

摘要

摘要: 目的探讨富马酸丙酚替诺福韦(TAF)在老年慢性乙型肝炎(CHB)患者中的应用价值，明确其对骨骼和肾脏的影响。方法选取2021年6月—2022年10月在青岛市市立医院、青岛大学附属医院、青岛市第六人民医院、青岛市城阳人民医院、青岛市即墨人民医院接受TAF抗病毒治疗的60岁及以上CHB患者36例。所有患者接受TAF(25 mg /d)抗病毒治疗。收集患者基线期、48周病毒学指标、生化指标、尿蛋白电泳指标以及甲胎蛋白(AFP)、肝脏超声瞬时弹性成像测定(FibroScan)、骨密度测定数据。收集24周病毒学指标，生化指标，尿蛋白电泳指标。正态分布计量资料治疗前后进行配对t检验，非正态分布计量资料治疗前后比较采用Wilcoxon符号秩和检验。计数资料的比较采用χ²检验或Fisher确切概率法。结果 36例CHB患者完成了24周随访。TAF治疗24周后，完全病毒学应答率为83.3%(30/36)，与基线期77.8%(28/36)比较，差异无统计学意义(χ²=0.36, P=0.55)。24周DBil(t=-2.42, P=0.02)、Cys C(t=-4.34, P＜0.001) 显著下降，与基线比较差异均有统计学意义。18例CHB患者完成了48周随访。治疗48周后，完全病毒学应答率为94.4%(17/18)，与基线期77.8%(14/18)比较，差异无统计学意义(χ²=2.22, P=0.34)；IBil(t=2.43，P=0.03)和TBA(Z=-2.24，P=0.03)均升高，腰椎(t=2.92，P=0.01)及股骨颈骨密度(t=2.42, P=0.03)T评分均升高，LSM水平降低(t=-2.31, P=0.03)，与基线比较差异均有统计学意义。β2-MG、URBP、α1-MG在治疗前后差异均无统计学意义(P值均＞0.05)。结论 TAF在60岁及以上CHB患者中有良好的抗病毒效果，使更多CHB患者达到完全病毒学应答，未发现对肾脏造成损害，能够改善骨密度及肝纤维化程度。
- 乙型肝炎，慢性 /
- 富马酸丙酚替诺福韦 /
- 治疗结果 /
- 老年人
Abstract: Objective To investigate the application value of tenofovir alafenamide fumarate (TAF) in elderly patients with chronic hepatitis B (CHB) and its influence on bones and kidneys. Methods A total of 36 CHB patients, aged ≥60 years, who received TAF antiviral therapy in Qingdao Municipal Hospital, The Affiliated Hospital of Qingdao University, Qingdao Sixth People's Hospital, Chengyang People's Hospital, and Jimo People's Hospital from June 2021 to October 2022 were enrolled in this study, and all patients received TAF (25 mg/d) antiviral therapy. Related data were collected at baseline and weeks 24 and 48 of treatment, including virological indicators, biochemical parameters, urinary protein electrophoresis indices, transient elastography (FibroScan), and bone mineral density. Virological indicators included high-sensitivity HBV DNA quantification; biochemical parameters included total bilirubin, direct bilirubin (DBil), indirect bilirubin (IBil), alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, total bile acid (TBA), glucose, blood urea nitrogen, creatinine, estimated glomerular filtration rate, and cystatin C (Cys C); urinary protein electrophoresis indices included urinary β2 microglobulin (β2-MG), urinary retinol (URBP), and urinary α1 microspherin (α1-MG). The paired t-test was used for comparison of normally distributed continuous data before and after treatment, and the Wilcoxon signed-rank test was used for comparison of non-normally distributed continuous data before and after treatment; the chi-square test or the Fisher's exact test was used for comparison of categorical data. Results A total of 36 CHB patients completed 24 weeks of follow-up. The complete virological response rate after 24 weeks of treatment was higher than that at baseline [83.3% (30/36) vs 77.8% (28/36), χ²=0.36, P=0.55], and there were significant reductions in DBil (t=-2.42, P=0.02) and Cys C (t=-4.34, P < 0.001) from baseline to week 24. A total of 18 CHB patients completed 48 weeks of follow-up. The complete virological response rate after 48 weeks of treatment was higher than that at baseline (94.4% vs 77.8%, χ²=2.22, P=0.34), and there were significant increases in IBil (t=2.43, P=0.03), TBA (Z=-2.24, P=0.03), and bone mineral density T score of lumbar vertebra (t=2.92, P= 0.01) and femoral neck (t=2.42, P=0.03) and a significant reduction in liver stiffness measurement (t=-2.31, P=0.03). There were no significant changes in β2-MG, URBP, and α1-MG after treatment (all P > 0.05). Conclusion TAF has a good antiviral effect in CHB patients aged ≥60 years and can help more CHB patients achieve complete virological response, without causing damage to the kidney, and it can also improve bone mineral density and liver fibrosis degree.
- Hepatitis B, Chronic /
- Tenofovir Alafenemide Fumarate /
- Treatment Outcome /
- Aged

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图 1 TAF治疗24周后DBil和Cys C变化情况

Figure 1. Changes of DBil and CysC after 24 weeks of TAF treatment

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图 2 TAF治疗24周后G1期与G2G3期患者eGFR变化情况

Figure 2. Changes of eGFR in G1 and G2G3 patients after 24 weeks of TAF treatment

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图 3 TAF治疗48周后IBil、TBA变化情况

Figure 3. Changes of IBil and TBA after 48 weeks of TAF treatment

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图 4 TAF治疗48周后G1期与G2期患者eGFR变化情况

Figure 4. Changes of eGFR in G1 and G2 patients after 48 weeks of TAF treatment

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图 5 TAF治疗48周后腰椎骨密度、股骨颈骨密度和LSM变化情况

Figure 5. Changes of lumbar bone mineral density, femoral neck bone mineral density and LSM after 48 weeks of TAF treatment

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表 1 受试者基线临床特征

Table 1. Baseline clinical characteristics of subjects

指标	结果
年龄(岁)	64.67±3.82
男性[例(%)]	19(52.80)
BMI(kg/m²)	24.81±3.67
BMI分级[例(%)]
低体质量	3(8.30)
正常	13(36.10)
超重	14(38.90)
肥胖	6(16.70)
完全病毒学应答[例(%)]	28(77.80)
合并疾病[例(%)]
高血压病	11(30.60)
糖尿病	4(11.10)
冠心病	3(8.30)
HBeAg阳性[例(%)]	11(30.60)
HBsAg(IU/mL)	752.35(212.14~2 908.23)
TBil(μmol/L)	14.10(12.30~20.40)
DBil(μmol/L)	4.08±1.68
IBil(μmol/L)	10.80(8.60~15.20)
ALT(U/L)	22.18(16.90~30.52)
AST(U/L)	23.71(20.02~32.53)
ALP(U/L)	79.57±26.12
GGT(U/L)	23.46(17.72~33.25)
TBA(μmol/L)	2.40(1.90~4.20)
GLu(mmol/L)	5.68(5.11~6.94)
BUN(mmol/L)	5.92±1.07
eGFR(mL·min^-1·1.73 m^-2)	77.30(62.07~84.65)
Cr(μmol/L)	74.97±16.21
Cys C(mg/L)	0.95±0.22
AFP(IU/mL)	1.88(1.40~2.62)
CAP(dB/m)	240.08±43.94
CAP分级[例(%)]
正常	15(41.70)
轻度脂肪肝	13(36.10)
中度脂肪肝	5(13.90)
重度脂肪肝	3(8.30)
LSM(kPa)	6.50(5.65~8.75)
LSM分级[例(%)]
S0	25(69.40)
S1	3(8.30)
S2	4(11.10)
S3	4(11.10)
骨密度[例(%)]
正常	12(34.30)
骨量减少	13(37.10)
骨质疏松	10(28.60)

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表 2 TAF治疗基线期与24周数据对比

Table 2. Comparison of data at baseline and 24 weeks of TAF treatment

指标	基线期	24周	统计值	P值
TBil(μmol/L)	14.05(12.30~20.38)	16.45(12.35~19.58)	Z=0.36	0.73
DBil(μmol/L)	4.08±1.68	3.53±1.41	t=-2.42	0.02
IBil(μmol/L)	10.80(8.63~15.20)	12.90(9.55~15.61)	Z=1.35	0.19
ALT(U/L)	22.18(16.90~30.52)	22.74(15.87~33.13)	Z=-1.34	0.18
AST(U/L)	23.71(20.02~32.53)	22.93(19.33~31.45)	Z=-1.23	0.22
ALP(U/L)	79.57±26.12	79.45±21.28	t=-0.05	0.97
GGT(U/L)	23.46(17.72~33.25)	22(16.32~27.96)	Z=-0.85	0.39
TBA(μmol/L)	2.50(1.89~4.70)	2.60(1.20~4.40)	Z=-0.69	0.49
GLu(mmol/L)	5.70(5.10~6.96)	5.64(5.12~6.36)	Z=-1.01	0.32
BUN(mmol/L)	5.92±1.07	5.99±1.06	t=0.30	0.77
eGFR(mL·min^-1·1.73 m^-2)	84.25±12.78	86.53±13.85	t=1.84	0.08
Cr(μmol/L)	74.97±16.21	72.64±19.28	t=-1.65	0.11
Cys C(mg/L)	0.94±0.22	0.86±0.24	t=-4.34	＜0.001

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表 3 TAF治疗基线期与48周数据对比

Table 3. Comparison of data at baseline and 48 weeks of TAF treatment

指标	基线期	48周	统计值	P值
HBsAg(IU/mL)	500.43(161.33~2 209.89)	387.29(134.69~2 064.71)	Z=-1.93	0.05
TBil(μmol/L)	14.45(12.30~21.33)	16.75(13.03~22.08)	Z=1.44	0.17
DBil(μmol/L)	4.20(3.25~5.69)	3.38(2.70~5.05)	Z=-1.59	0.11
IBil(μmol/L)	11.92±4.88	14.53±5.30	t=2.43	0.03
ALT (U/L)	27.36(16.97~35.05)	23.83(16.00~32.37)	Z=-0.98	0.33
AST(U/L)	24.71(20.54~40.65)	22.65(19.89~30.47)	Z=-1.07	0.29
ALP(U/L)	75.14±24.65	81.66±20.61	t=1.57	0.14
GGT(U/L)	21.04(17.80~34.06)	24.43(15.72~34.46)	Z=-0.07	0.94
TBA(μmol/L)	2.30(1.90~2.67)	3.00(1.31~4.55)	Z=-2.24	0.03
GLu(mmol/L)	5.66(5.15~6.56)	5.41(4.90~5.97)	t=-1.18	0.26
BUN(mmol/L)	5.96±1.28	5.65±1.41	t=-0.87	0.40
eGFR(mL·min^-1·1.73 m^-2)	85.06±12.89	85.89±11.62	t=0.44	0.67
Cr(μmol/L)	72.76±17.19	70.82±17.08	t=-1.06	0.30
Cys C(mg/L)	0.90±0.15	0.86±0.18	t=-2.02	0.07
AFP(IU/mL)	1.82(1.37~2.26)	1.67(1.04~2.40)	Z=-1.94	0.05
CAP(dB/m)	241.00±39.35	269.00±52.62	t=1.84	0.08
LSM(kPa)	7.57±2.62	6.20±2.05	t=-2.31	0.03
腰椎骨密度(SD)	-0.99±1.80	-0.68±1.75	t=2.92	0.01
股骨颈骨密度(SD)	-1.34±0.98	-1.14±0.90	t=2.42	0.03

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