抗病毒治疗慢性乙型肝炎合并非酒精性脂肪性肝病的效果观察

卿玲; 黄伟强; 李晓鹤; 陈凤; 刘映霞

doi:10.3969/j.issn.1001-5256.2021.09.015

抗病毒治疗慢性乙型肝炎合并非酒精性脂肪性肝病的效果观察

DOI: 10.3969/j.issn.1001-5256.2021.09.015

卿玲¹,
黄伟强^{2, 3},
李晓鹤²,
陈凤^{2, 4, ,},
刘映霞^2, ,

1.
南华大学临床医学院，湖南衡阳 421000
2.
深圳市第三人民医院感染科，广东深圳 518112
3.
萍乡市第二人民医院超声科，江西萍乡 337000
4.
中山大学附属第七医院消化医学中心，广东深圳 518107

基金项目:

国家自然科学基金项目 (81873573);

国家自然科学基金项目 (81800525)

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。

作者贡献声明：卿玲、黄伟强负责收集数据; 李晓鹤、陈凤负责资料分析、拟定写作思路、撰写论文；刘映霞负责指导撰写文章。

详细信息

通信作者:
陈凤，1148949465@qq.com

刘映霞，yingxialiu@hotmail.com

中图分类号: R512.62; R575.5
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- 被引次数: 0
出版历程
- 收稿日期: 2021-07-30
- 录用日期: 2021-08-31
- 出版日期: 2021-09-20

Efficacy of antiviral therapy for chronic hepatitis B with nonalcoholic fatty liver disease

Ling QING¹,
Weiqiang HUANG^{2, 3},
Xiaohe LI²,
Feng CHEN^{2, 4
, ,},
Yingxia LIU^{2
, ,}

1.
Clinical Medicine, University of South China, Hengyang, Hunan 421000, China
2.
Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, Guangdong 518112, China
3.
Department of Ultrasound, Pingxiang Second People's Hospital, Pingxiang, Jiangxi 337000, China
4.
Digestive Medicine Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong 518107, China

Research funding:

National Natural Science Foundation of China (81873573);

National Natural Science Foundation of China (81800525)

摘要

摘要: 目的分析合并非酒精性脂肪性肝病(NAFLD)对慢性乙型肝炎(CHB)抗病毒疗效的影响，为此类患者的临床治疗提供参考。方法选取2011年1月—2017年12月在深圳市第三人民医院就诊的患者187例，分为CHB组(43例)、NAFLD组(41例)、CHB合并NAFLD组(103例)。所有患者在入组和随访的不同时间点行身高、体质量、ALT、AST、血脂四项、肝纤维化四项、APRI、HBsAg、HBeAg、抗-HBe、HBV DNA定量检查，比较进行抗病毒治疗的CHB患者和CHB合并NAFLD患者在使用抗病毒药物12、24、48、72、96周的治疗效果。符合非正态分布的计量资料多组间比较采用Kruskal-Wallis H检验，两组间比较采用Wilcoxon秩和检验；计数资料组间比较采用χ²检验。结果基线时CHB组和CHB合并NAFLD组的PLT、ALT、GGT、ALP水平和右叶斜径均显著低于NAFLD组(P值均＜0.05)，CHB合并NAFLD组的BMI、TC、TG水平显著高于CHB组(P值均＜0.05)，其脾脏厚度显著低于CHB组(P＜0.05)，两组中的其他指标水平在基线期差异均无统计学意义(P值均＞0.05)。抗病毒治疗12周时，CHB组和CHB合并NAFLD组患者的肝纤维化指标及炎症指标差异均无统计学意义(P值均＞0.05)，24、48周时CHB组的ALT(Z值分别为-2.128、-3.055，P值均＜0.05)、GGT(Z值分别为-2.025、-1.631，P值均＜0.05)水平下降更明显，48周时CHB组(Z=-6.445, P＜0.001)和CHB合并NAFLD组(Z=-4.415, P＜0.001)的HBV DNA水平均较治疗前显著降低，但CHB组的降低水平更明显。CHB合并NAFLD组在抗病毒治疗的不同时间点，HBV DNA转阴率均显著低于CHB组(χ²值分别为14.237、13.961、15.226、10.462、13.030, P值均＜0.05)。抗病毒治疗48周时，CHB合并NAFLD组的HBeAg转阴率显著低于CHB组(χ²=5.309, P=0.021)，但96周时两组间的转阴率差异无统计学意义(χ²=0.117, P=0.732)。抗病毒治疗24、48、72、96周，CHB合并NAFLD组的ALT复常率均显著低于CHB组(χ²值分别为12.049、5.287、11.407、11.375, P值均＜0.05)。结论合并NAFLD降低了CHB患者的抗病毒治疗效果，使抗病毒治疗时间延长。
- 乙型肝炎, 慢性 /
- 非酒精性脂肪性肝病 /
- 抗病毒药 /
- 治疗结果
Abstract: Objective To investigate the influence of nonalcoholic fatty liver disease (NAFLD) on the antiviral response of patients with chronic hepatitis B (CHB), and to provide a reference for clinical treatment of such patients. Methods A total of 187 patients who attended Shenzhen Third People's Hospital from January 2011 to December 2017 were enrolled and divided into CHB group with 43 patients, NAFLD group with 41 patients, and CHB+NAFLD group with 103 patients. Related indices were measured at enrollment different time points of follow-up, including body height, body weight, alanine aminotransferase (ALT), aspartate aminotransferase, four blood lipid parameters, four indicators of liver fibrosis, aspartate aminotransferase-to-platelet ratio index, HBsAg, HBeAg, anti-HBe, and HBV DNA quantification, and the CHB patients and the CHB+NAFLD patients receiving antiviral therapy were compared in terms of treatment outcome at weeks 12, 24, 48, 72, and 96 of antiviral therapy. The Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups, and the Wilcoxon rank-sum test was used for comparison between two groups; the chi-square test was used for comparison of categorical data between groups. Results Compared with the NAFLD group at baseline, the CHB group and the CHB+NAFLD group had significantly lower platelet count, ALT, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase, and right lobe of liver oblique diameter (all P < 0.05), and compared with the CHB group, the CHB+NAFLD group had significantly higher body mass index, total cholesterol, and triglyceride and a significantly lower spleen thickness (all P < 0.05), while there were no significant differences in the other indicators between the two groups at baseline (all P > 0.05). At week 12 of antiviral therapy, there were no significant differences in liver fibrosis markers and inflammatory indices between the CHB group and the CHB+NAFLD group (all P > 0.05); compared with the CHB+NAFLD group at weeks 24 and 48, the CHB group had significantly greater reductions in ALT (Z=-2.128 and -3.055, both P < 0.05) and GGT (Z=-2.025 and -1.631, both P < 0.05); at week 48, the CHB group and the CHB+NAFLD group had a significant reduction in HBV DNA (Z=-6.445 and -4.415, both P < 0.001), and the CHB group had a significantly greater reduction. The CHB+NAFLD group had a significantly lower HBV DNA clearance rate than the CHB group at different time points of antiviral therapy (χ²=14.237, 13.961, 15.226, 10.462, and 13.030, all P < 0.05). At week 48 of antiviral therapy, the CHB+NAFLD group had a significantly lower HBeAg clearance rate than the CHB group (χ²=5.309, P=0.021), while there was no significant difference between the two groups at week 96 (χ²=0.117, P=0.732). At weeks 24, 48, 72, and 96 of antiviral therapy, the CHB+NAFLD group had a significantly lower ALT normalization rate than the CHB group (χ²=12.049, 5.287, 11.407, and 11.375, all P < 0.05). Conclusion NAFLD reduces the antiviral response of CHB patients and prolongs the duration of antiviral therapy.
- Hepatitis B, Chronic /
- Non-alcoholic Fatty Liver Disease /
- Antiviral Agents /
- Treatment Outcome

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表 1 3组患者临床基线资料比较

指标	NAFLD组(n=41)	CHB合并NAFLD组(n=103)	CHB组(n=43)	统计值	P值
BMI (kg/m²)	26.6(24.9~29.5)	25.3(23.6~27.3)	22.9(20.7~25.7)^{1) 2)}	H=22.051	＜0.001
男[例(%)]	37(90.2)	90(87.4)	41(95.3)	χ²=2.121	0.346
WBC(×10⁹/L)	6.10(5.17~6.75)	6.30(5.58~7.63)	6.00(4.86~7.16)	H=2.784	0.249
PLT(×10¹²/L)	218(173~258)	187(146~210)¹⁾	158(129~189)¹⁾	H=16.392	＜0.001
MPV(fl)	10.5(9.9~11.4)	10.7(10.1~11.4)	10.3(9.8~11.2)	H=1.663	0.435
AFP(ng/ml)	3.55(2.46~5.39)	3.69(2.56~5.64)	3.48(2.34~5.11)	H=0.428	0.807
APRI	0.70(0.36~1.14)	0.45(0.33~0.95)	0.70(0.40~1.08)	H=6.321	0.042
HA(ng/ml)	65.4(50.4~119.9)	80.4(52.4~128.8)	87.3(60.3~133.6)	H=1.730	0.421
PⅢP(ng/ml)	25.5(17.9~31.9)	21.7(18.2~26.8)	21.8(18.9~27.8)	H=1.315	0.518
CⅣ(ng/ml)	24.0(19.8~28.4)	21.2(18.3~26.4)	22.6(19.0~27.9)	H=1.299	0.522
LN(ng/ml)	33.8(23.3~43.9)	33.9(24.4~40.6)	33.4(28.3~42.7)	H=0.830	0.660
TC(mmol/L)	4.60(3.70~5.30)	4.69(4.06~5.32)	4.00(3.55~4.51)²⁾	H=12.604	0.002
TG(mmol/L)	1.49(1.19~2.31)	1.31(0.91~1.96)	0.87(0.71~1.37)¹⁾²⁾	H=16.535	＜0.001
ALT(U/L)	88(61~209)	53(39~89)¹⁾	52(38~75)¹⁾	H=19.273	＜0.001
AST(U/L)	45.0(32.0~79.0)	33.5(25.8~48.8)¹⁾	37.0(29.0~55.0)	H=9.985	0.007
GGT(U/L)	105(42~189)	37(25~61)¹⁾	43(25~74)¹⁾	H=22.936	＜0.001
TBil(μmol/L)	15.1(11.1~22.7)	16.1(12.5~203.0)	14.9(11.9~18.6)	H=0.647	0.724
ALP(U/L))	95.5(79.8~118.5)	80.0(65.0~101.3)¹⁾	74.0(59.0~98.8)¹⁾	H=10.365	0.006
UA(mmol/L)	413.0(320.3~472.5)	369.0(320.3~414.5)	351.0(276.0~433.0)	H=5.391	0.068
右叶斜径(mm)	142.5(136~151.8)	135.0(132.0~139.0)¹⁾	132.0(123.5~139.0)¹⁾	H=27.511	＜0.001
脾厚(mm)	35.0(32.0~39.0)	33.0(30.0~36.0)	37.2(31.8~43.2)²⁾	H=13.252	0.001
HBV DNA(log₁₀IU/ml)		5.03(2.53~7.56)	6.09(5.21~7.06)	Z=-1.733	0.083
注：HBV DNA指标仅对进行抗病毒的患者进行比较；与NAFLD组比较，1) P＜0.05；与CHB合并NAFLD组比较，2) P＜0.05。MPV，平均血小板体积；HA，透明质酸；LN，层粘连蛋白；PⅢP，Ⅲ型前胶原肽；CⅣ，Ⅳ型胶原。

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表 2 治疗前及抗病毒治疗48周时HBV DNA的表达水平

HBV DNA	CHB组(n=43)	CHB合并NAFLD组(n=63)
治疗前(log₁₀ IU/ml)	6.09(5.21~7.06)	5.03(2.53~7.56)
48周(log₁₀ IU/ml)	1.00(1.00~1.13)	2.70(2.00~4.28)
Z值	-6.445	-4.415
P值	＜0.001	＜0.001

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表 3 12周抗病毒治疗不同随访时间点病毒学和临床生化指标的变化

指标	CHB组(n=43)	CHB合并NAFLD组(n=63)	Z值	P值
PLT (×10¹²/L)	155(95~187)	151(138~230)	-0.735	0.303
ALT(U/L)	44.0(32.0~57.0)	53.5(39.0~92.0)	-2.011	0.054
AST(U/L)	34.0(27.0~44.0)	36.0(26.3~47.0)	-0.344	0.739
GGT(U/L)	37.0(24.0~67.0)	50.5(30.3~80.0)	-1.187	0.310
HA(ng/ml)	97.0(44.5~175.6)	90.5(40.6~265.3)	-0.077	0.934
PⅢP(ng/ml)	20.7(17.6~29.6)	20.7(17.0~32.7)	-0.386	0.804
CⅣ(ng/ml)	23.8(20.2~27.4)	20.6(18.5~33.9)	-0.694	0.563
LN(ng/ml)	42.9(31.7~60.6)	26.8(21.9~47.8)	-2.083	0.048
APRI	0.52(0.37~0.79)	0.53(0.31~1.42)	-0.628	0.844
HBV DNA(log₁₀ IU/ml)	2.90(2.00~4.00)	2.50(1.00~3.65)	-1.585	0.445

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表 4 24周抗病毒治疗不同随访时间点病毒学和临床生化指标的变化

指标	CHB组(n=43)	CHB合并NAFLD组(n=63)	Z值	P值
PLT (×10¹²/L)	153(91~178)	156(118~203)	-0.962	0.286
ALT(U/L)	28.0(24.0~39.0)	38.0(26.5~67.0)	-2.128	0.033
AST(U/L)	28.0(24.3~37.0)	33.0(24.5~42.5)	-0.711	0.436
GGT(U/L)	28.0(17.5~50.3)	38.0(27.5~93.0)	-2.025	0.043
HA(ng/ml)	120.7(81.3~209.0)	87.4(71.7~165.5)	-0.843	0.399
PⅢP(ng/ml)	22.7(15.4~44.1)	21.7(16.6~34.5)	-0.109	0.913
CⅣ(ng/ml)	19.7(16.1~44.2)	22.2(18.5~32.8)	-0.027	0.978
LN(ng/ml)	31.9(28.0~65.0)	26.2(22.3~59.2)	-1.496	0.135
APRI	0.49(0.34~1.06)	0.50(0.33~0.92)	-0.012	0.973
HBV DNA(log₁₀ IU/ml)	1.00(1.00~2.29)	2.00(1.00~2.13)	-1.414	0.208

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表 5 48周抗病毒治疗不同随访时间点病毒学和临床生化指标的变化

指标	CHB组(n=43)	CHB合并NAFLD组(n=63)	Z值	P值
PLT (×10¹²/L)	180(106~204)	164(133~207)	-0.306	0.864
ALT(U/L)	29.0(17.0~38.0)	47.0(29.0~71.5)	-3.055	＜0.001
AST(U/L)	27(20~30)	28(23~40)	-1.671	0.083
GGT(U/L)	28.0(17.0~49.0)	37.5(22.3~61.0)	-1.631	0.027
HA(ng/ml)	87.2(57.3~144.7)	77.0(54.0~111.0)	-0.871	0.548
PⅢP(ng/ml)	20.4(17.4~28.8)	21.1(16.5~27.6)	-0.444	0.799
CⅣ(ng/ml)	20.6(19.0~27.6)	20.5(16.3~26.8)	-1.315	0.446
LN(ng/ml)	31.0(25.2~36.9)	24.5(17.1~33.2)	-1.473	0.055
APRI	0.38(0.28~0.68)	0.46(0.31~0.70)	-1.432	0.336
HBV DNA(log₁₀ IU/ml)	1.00(1.00~1.13)	2.70(2.00~4.28)	-2.197	＜0.001

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表 6 抗病毒治疗不同随访时间点HBV DNA转阴率的变化

HBV DNA转阴率	CHB组(n=43)	CHB合并NAFLD组(n=49)	χ²值	P值
12周[例(%)]	11(25.6)	0(0)	14.237	＜0.001
24周[例(%)]	24(55.8)	9(18.4)	13.961	＜0.001
48周[例(%)]	34(79.1)	19(38.8)	15.226	＜0.001
72周[例(%)]	35(81.4)	24(49.0)	10.462	0.001
96周[例(%)]	39(90.7)	28(57.1)	13.030	＜0.001

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表 7 抗病毒治疗不同随访时间点HBeAg转阴率的变化

HBeAg转阴率	CHB组(n=31)	CHB合并NAFLD组(n=38)	χ²值	P值
48周[例(%)]	9(29.0)	3(7.9)	5.309	0.021
96周[例(%)]	11(32.3)	12(31.6)	0.117	0.732

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表 8 抗病毒治疗不同随访时间点ALT复常率的变化[例(%)]

ALT复常率	CHB组(n=30)	CHB合并NAFLD组(n=49)	χ²值	P值
12周[例(%)]	3(10.0)	2(4.1)	1.099	0.294
24周[例(%)]	16(53.3)	8(16.3)	12.049	0.001
48周[例(%)]	19(63.3)	18(36.7)	5.287	0.021
72周[例(%)]	25(83.3)	22(44.9)	11.407	0.001
96周[例(%)]	26(86.7)	24(49.0)	11.375	0.001

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