替诺福韦联合干扰素-α治疗HBeAg阳性慢性乙型肝炎患者疗效及其血清细胞因子水平变化

doi:10.3969/j.issn.1672-5069.2020.05.009

摘要/Abstract

摘要： 目的探讨应用替诺福韦联合干扰素-α(IFN-α)治疗血清HbeAg阳性的慢性乙型肝炎(CHB)患者疗效及其血清肿瘤坏死因子(TNF-α)、白细胞介素-6(IL-6)和IL-10水平的变化。方法 2017年1月～2018年8月我院肝病科诊治的血清HBeAg阳性的CHB患者89例被随机分为对照组(n=43例)和联合组(n=46例),分别给予替诺福韦口服治疗和替诺福韦联合国产IFN-α2b治疗,两组连续治疗观察48周。采用ELISA法检测血清TNF-α、IL-6和IL-10水平,采用ELISA法检测血清HBV标记物,采用ABI7300荧光定量PCR分析仪检测血清HBV DNA水平。结果在观察结束时,联合组血清ALT和AST水平分别为(39.2±10.8)U/L和(36.4±8.2)U/L,显著低于对照组【分别为(75.2±15.7)U/L和(56.6±12.3)U/L,P<0.05】;联合组血清TNF-α水平为(26.6±6.8)mg/L,显著低于对照组【(35.5±6.8)mg/L,P<0.05】,血清IL-6水平为(15.5±3.3)pg/mL,显著低于对照组【(22.4±4.1)pg/mL,P<0.05】,血清IL-10水平为(21.4±5.7)pg/mL,显著低于对照组【(29.4±6.5)pg/mL,P<0.05】;两组血清HBV DNA均转阴,血清ALT复常率无显著性差异(P>0.05),但联合组血清HBeAg转阴率(44.2%对11.6%,P<0.05)和血清HBsAg转阴率(13.0%对0.0%,P<0.05)显著高于对照组。另外,联合组分别有19例(44.2%)和2例(4.3%)患者发生HbeAg和HBsAg血清转换。结论应用替诺福韦短期联合IFN-α治疗HBeAg阳性的CHB患者能提高血清HBeAg阴转率,并在短期内促进一些患者发生HbeAg和HBsAg血清转换,可能与联合治疗抑制了细胞免疫反应有关,但其长期疗效还需要观察。

关键词: 慢性乙型肝炎, 替诺福韦, 干扰素-α, 治疗, 应答 , ,

Abstract: Objective The aim of this study was to investigate the short-term efficacy of tenofovir and interferon-α2b (IFN-α2b) combination in the treatment of patients with serum HBeAg-positive chronic hepatitis B (CHB). Methods 89 patients with CHB and positive serum HBeAg were admitted to our hospital between January 2017 and August 2018, and were randomly divided into control group (n=43) and observation group (n=46). The patients in the control group were treated with tenofovir, and those in the observation were treated with IFN-α2b subcutaneously on the basis of tenofovir. The regimen lasted continuously for 48 weeks, and all patients were followed-up for 6 months. Serum tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and IL-10 levels were detected by ELISA, and serum hepatitis B viral deoxyribonucleotide (HBV DNA) was assayed by PCR. Results At the end of 48 week observation, serum ALT and AST levels in the combination group were (39.2±10.8)U/L and(36.4±8.2)U/L, significantly lower than 【(75.2±15.7)U/L and (56.6±12.3)U/L, respectively, P<0.05】 in the control; serum TNF-α level was (26.6±6.8)mg/L, much lower than 【(35.5±6.8)mg/L, P<0.05】, serum IL-6 level was (15.5±3.3)pg/mL, significantly lower than 【(22.4±4.1)pg/mL, P<0.05】, and serum IL-10 level was (21.4±5.7) pg/mL, significantly lower than 【(29.4±6.5)pg/mL, P<0.05】 in the control; serum HBV DNA loads in all patients in the two groups lost, and there was no significant difference as respect to serum ALT normalization in the two groups (P>0.05), while serum HBeAg and HBsAg negativity rates in the combination group were much higher than in the control (44.2% vs. 11.6%, and 13.0% vs. 0.0%, respectively, P<0.05). Conclusion Tenofovir combined with IFN-α2b in the treatment of serum HBeAg-positive CHB patients might improve serum HBeAg and HBsAg negativity, which could be related to the inhibition of cytokine reaction, but the long-term efficacy needs investigation further.

Key words: Hepatitis B, Tenofovir, Interferon-α, Therapy, Response

吴雄飞, 方利娟, 陈艳. 替诺福韦联合干扰素-α治疗HBeAg阳性慢性乙型肝炎患者疗效及其血清细胞因子水平变化[J]. 实用肝脏病杂志, 2020, 23(5): 638-641.

Wu Xiongfei, Fang Lijuan, Chen Yan.. Short-term efficacy of tenofovir and interferon-α2b combination in the treatment of patients with serum HBeAg-positive chronic hepatitis B[J]. Journal of Practical Hepatology, 2020, 23(5): 638-641.

参考文献

[1] Shu J, Zhao JN, Han FG, et al. Chronic hepatitis B: correlation of abnormal features on T2-weighted imaging and dynamic contrast-enhanced imaging with hepatic histopathology. Radiol Med, 2017, 122(11): 807-813.
[2] Vedio A, Liu EZH, Lee ACK, et al.Improving access to health care for chronic hepatitis B among migrant Chinese populations: a systematic mixed methods review of barriers and enablers. J Viral Hepat, 2017, 24(7): 526-540.
[3] Van der Ree MH, Jansen L, Kruize Z, et al. Plasma microrna levels are associated with hepatitis B e antigen status and treatment response in chronic hepatitis B patients. J Infect Dis, 2017, 215(9): 1421-1429.
[4] 赵协山, 伍春瑢, 王春峰, 等. 替诺福韦联合安络化纤丸治疗HbeAg阳性慢性乙型肝炎患者疗效及其血清肝纤维化指标的变化研究. 实用肝脏病杂志, 2019, 22(5): 644-647.
[5] Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol, 2016, 1(3): 196-206.
[6] Chuaypen N, Sriprapun M, Praianantathavorn K, et al. Kinetics of serum HBsAg and intrahepatic cccDNA during pegylated interferon therapy in patients with HBeAg-positive and HbeAg-negative chronic hepatitis B. J Med Virol, 2017, 89(1): 130-138.
[7] Chi H, Wong D, Peng J, et al. Durability of response after hepatitis b surface antigen seroclearance during nucleos(t)ide analogue treatment in a multiethnic cohort of chronic hepatitis b patients: results after treatment cessation. Clin Infect Dis, 2017, 65(4): 680-683.
[8] Sokal EM, Paganelli M, Wirth S, et al. Management of chronic hepatitis B in childhood: espghan clinical practice guidelines: consensus of an expert panel on behalf of the european society of pediatric gastroenterology, hepatology and nutrition. J Hepatol, 2015, 59(4): 814-829.
[9] Lee JH, Kim KH.Reply to: In response to identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients. J Hepatol, 2019, 12(19): 30524-30530.
[10] Yin XR, Liu ZH, Liu J, et al. First line nucleos(t)ide analog monotherapy is more cost-effective than combination strategies in hepatitis B e antigen-positive chronic hepatitis B patients in China. Chin Med J (Engl), 2019, 132(19): 2315-2324.
[11] Blackard JT, Kwara A, Sherman KE, et al. In response to identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients. J Hepatol, 2019, 168 (19): 30418-30420.
[12] Papatheodoridi M, Hadziyannis E, Berby F, et al. Predictors of hepatitis B surface antigen loss, relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HbeAg-negative chronic hepatitis B. J Viral Hepat, 2019, 28(10): 13210-13211.
[13] 杨蕊西, 刘茗心, 陈泠忻, 等. 替诺福韦酯挽救治疗HBV DNA聚合酶区204位点突变的经治慢性乙型肝炎患者疗效及安全性分析. 实用肝脏病杂志, 2019, 22(3): 349-352.
[14] Zhang Y, Li W, Liu Z, et al.Combination therapy based on pegylated interferon alfa improves the therapeutic response of patients with chronic hepatitis B who exhibit high levels of hepatitis B e-antigen at 24 weeks: a retrospective researchal study. Medicine (Baltimore), 2019, 98(36): 11-12.
[15] Ren H, Huang Y.Effects of pegylated interferon-α based therapies on functional cure and the risk of hepatocellular carcinoma development in patients with chronic hepatitis B. J Viral Hepat, 2019, 26(1): 5-31.
[16] Ungtrakul T, Sriprayoon T, Kusuman P, et al. Role of quantitative hepatitis B surface antigen in predicting inactive carriers and HBsAg seroclearance in HBeAg-negative chronic hepatitis B patients. Medicine,2017, 96(13):65-68.
[17] Makjaroen J, Somparn P, Hodge K, et al.Comprehensive proteomics identification of IFN-λ3-regulated antiviral proteins in HBV-transfected cells. Mol Cell Proteomics, 2018, 17(11): 2197-2215.
[18] Zheng S, Liu L, Lu J, et al. Efficacy and safety of tenofovir disoproxil fumarate in Chinese patients with chronic hepatitis Bvirus infection: a 2-year prospective study. Medicine (Baltimore), 2019 , 98(42): 72-79.
[19] Liu T, Sun Y, Zhou J, et al. On-treatment changes of serum wisteria floribunda agglutinin-positive mac-2 binding protein are associated with the regression of liver fibrosis in chronic hepatitis B patients on interferon α add-on therapy. Med Virol, 2019, 91(8): 1499-1509.
[20] 卢婷, 李成忠. 替诺福韦酯挽救治疗对核苷(酸)类药物耐药的慢性乙型肝炎研究进展.实用肝脏病杂志, 2016, 19(3): 369-372.