Zhang J S, Zhao K Z, Li W, Li Y, Hu X X
Department of Infectious Diseases and Hepatology, Yichun People's Hospital, Yichun336000, China School of Chemistry and Bioengineering, Yichun University, Yichun336000, China.
Department of Infectious Diseases and Hepatology, Yichun People's Hospital, Yichun336000, China Nanchang University, Nanchang330006, China.
Zhonghua Gan Zang Bing Za Zhi. 2024 Dec 20;32(12):1123-1133. doi: 10.3760/cma.j.cn501113-20240901-00461.
To compare the effectiveness and safety profile of tenofovir amibufenamide (TMF) and tenofovir alafenamide (TAF), especially the effects on lipid metabolism in the treatment of chronic hepatitis B. A retrospective study was conducted on the virological response rate, biochemical response rate, renal function indicators, and lipid metabolism status of 159 cases with chronic hepatitis B (72 cases with TMF and 87 cases with TAF) after 48 weeks of antiviral treatment. The effects of the two drugs on lipid metabolism were further explored through cell and animal experiments. There were no statistically significant differences in baseline age, gender ratio, treatment-naïve and treatment-experienced proportions, hepatitis B virus (HBV) DNA and aminotransferase levels, renal function indicators, and serum lipid levels between the two groups. The levels of HBV DNA and transaminase were significantly reduced after 48 weeks of treatment in both groups. However, there were no statistically significant differences in virological response (84.2% vs. 75.8%, =0.733, =0.392) and biochemical response rate (86.1% vs. 85.1%, =0.035, =0.851) between the two groups. There was no significant change in the renal function index levels before and after treatment between the two groups of patients. Triglyceride [TG, 1.30 (0.93, 1.81) mmol/L vs. 1.30 (0.82, 1.84) mmol/L, =-0.196, =0.844], total cholesterol [TC, 4.53 (3.91, 5.15) mmol/L vs. 4.55 (3.88, 5.24) mmol/L, =-1.131, =0.258], high-density lipoprotein [HDL-C, 1.04 (0.90, 1.3) mmol/L vs. 1.08 (0.94, 1.30) mmol/L, =-0.811, =0.417], low-density lipoprotein [LDL-C, 2.68 (2.04, 3.29) mmol/L vs. 2.57 (1.99, 3.49) mmol/L, =-1.716, =0.086] and the ratio of total cholesterol to high-density lipoprotein [TC/HDL-C, 4.52 (3.10, 5.23) vs. 4.30 (3.27, 5.01), =-0.410, =0.682] had not statistically significant differences in the TMF group before and after treatment. TG [1.24(0.95, 1.98) mmol/L vs. 1.42(1.09, 2.21) mmol/L, =-2.895, =0.004], TC [4.44(3.74, 5.26) mmol/L vs. 4.68(4.07), 5.46) mmol/L, =-2.825, =0.005], low-density lipoprotein (LDL-C) [2.74 (2.05, 3.58) mmol/L vs. 2.87 (2.34, 3.50) mmol/L, =-2.419, =0.016] , and TC/HDL-C [3.89(3.13, 4.82) vs. 4.39(3.70, 5.40), =-4.478, <0.001] levels were increased after TAF treatment, while HDL-C levels were decreased [1.19 (0.98, 1.35) mmol/L vs. 1.04 (0.90, 1.33) mmol/L, =-3.070, =0.002]. The absolute values comparison changes had no statistically significant differences in TG [-0.04(-0.37, 0.46) mmol/L and 0.18 (-0.14, 0.46) mmol/L, =-1.853, =0.064], TC [0.06(-0.38, 0.63) mmol/L vs. 0.23(-0.21, 0.65) mmol/L, =-1.010, =0.312] and LDL-C level [-0.19(-0.33, 0.18) mmol/L vs. 0.18 (-0.13, 0.58) mmol/L, =-0.523, =0.601] before and after treatment between the two groups of patients. The TMF group had higher HDL-C [0.06 (-0.16, 1.84) mmol/L vs. -0.12 (-0.26,0.04) mmol/L, =-2.890, =0.004], but lower TC/HDL-C [-0.04(-0.67, 0.44) vs. 0.40(-0.14, 1.33), =-3.959, <0.001] than the TAF group. HepG2 cells were interfered with 10 μg/ml TMF and TAF for 72 hours, respectively. Microscopic examination revealed that in the TMF group [12 196 (10 740, 14 345) vs. 4 029 (3 086, 5 425) cells, =-4.815, <0.001] and TAF group [12 484 (11 176, 15 824) vs. 4 029 (3 086, 5 425), =-4.815, <0.001], the number of intracellular lipid droplets was higher than that in the control group after Oil Red O staining, but the difference between the two groups was not statistically significant. Ten-week-old C57/BL6J male mice were given 3.8 mg/kg TMF or TAF by continuous gavage for 12 weeks. The liver tissue was stained with Oil Red O. The number of lipid droplets was higher in the liver tissue of mice in the TAF group than that of the control group [30 647 (28 050, 34 821) and 27 614 (25 214, 29 176), =-2.529, =0.011], while the difference between the TMF group and control group was not statistically significant. The serum TG levels were higher in the TAF group mice [1.17 (1.11, 1.19) μmol/L vs. 1.06 (1.04, 1.09) μmol/L, =-2.060, =0.039], TC [2.58 (2.55, 2.80) μmol/L L vs. 2.33 (2.18, 2.54) μmol/L, =-2.084, =0.037] than those of the control group after drug administration, while HDL-C levels were lower than those of the control group [1.14 (1.13, 1.16) μmol/L vs. 1.29 (1.28, 1.32) μmol/L, =-2.313, =0.021] and TMF group [1.14 (1.13, 1.16) μmol/L vs. 1.30 (1.28, 1.38) μmol/L, =-2.795, =0.005]. However, there was no statistically significant difference in TG, TC, and HDL-C levels between the TMF and the control group. Both TMF and TAF can effectively inhibit HBV replication and promote liver function recovery, with no significant impact on renal function. However, TAF may generate an adverse effect on lipid metabolism in the body, while TMF has no obvious effect.
比较替诺福韦阿米布芬酰胺（TMF）和替诺福韦艾拉酚胺（TAF）的有效性和安全性，尤其是对慢性乙型肝炎治疗中脂质代谢的影响。对159例慢性乙型肝炎患者（72例使用TMF，87例使用TAF）进行48周抗病毒治疗后的病毒学应答率、生化应答率、肾功能指标和脂质代谢状况进行回顾性研究。通过细胞和动物实验进一步探讨两种药物对脂质代谢的影响。两组患者在基线年龄、性别比、初治和经治比例、乙型肝炎病毒（HBV）DNA和转氨酶水平、肾功能指标及血脂水平方面差异均无统计学意义。两组治疗48周后HBV DNA和转氨酶水平均显著降低。然而，两组间病毒学应答率（84.2%对75.8%，P = 0.733，95%CI = 0.392）和生化应答率（86.1%对85.1%，P = 0.035，95%CI = 0.851）差异均无统计学意义。两组患者治疗前后肾功能指标水平均无明显变化。TMF组治疗前后甘油三酯[TG，1.30（0.93，1.81）mmol/L对1.30（0.82，1.84）mmol/L，P = -0.196，95%CI = 0.844]、总胆固醇[TC，4.53（3.91，5.15）mmol/L对4.55（3.88，5.24）mmol/L，P = -1.131，95%CI = 0.258]、高密度脂蛋白[HDL-C，1.04（0.90，1.3）mmol/L对1.08（0.94，1.30）mmol/L，P = - 0.811，95%CI = 0.417]、低密度脂蛋白[LDL-C，2.68（2.04，3.29）mmol/L对2.57（1.99，3.49）mmol/L，P = -1.716，95%CI = 0.086]及总胆固醇与高密度脂蛋白比值[TC/HDL-C，4.52（3.10，5.23）对4.30（3.27，5.01），P = -0.410，95%CI = 0.682]差异均无统计学意义。TAF治疗后TG[1.24（0.95，1.98）mmol/L对1.42（1.09，2.21）mmol/L，P = -2.895，95%CI = 0.004]、TC[4.44（3.74，5.26）mmol/L对4.68（4.07，5.46）mmol/L，P = -2.825，95%CI = 0.005]、低密度脂蛋白（LDL-C）[2.74（2.05，3.58）mmol/L对2.87（2.34，3.50）mmol/L，P = -2.419，95%CI = 0.016]及TC/HDL-C[3.89（3.13，4.82）对4.39（3.70，5.40），P = -4.478，95%CI＜0.001]水平升高，而HDL-C水平降低[1.19（0.98，1.35）mmol/L对1.04（0.90，1.33）mmol/L，P = -3.070，95%CI = 0.002]。两组患者治疗前后TG[-0.04（-0.37，0.46）mmol/L对0.18（-0.14，0.46）mmol/L，P = -1.853，95%CI = 0.064]、TC[0.06（-0.38，0.63）mmol/L对0.23（-0.21，0.65）mmol/L，P = -1.010，95%CI = 0.312]及LDL-C水平[-0.19（-0.33，0.18）mmol/L对0.18（-0.13，0.58）mmol/L，P = -0.523，95%CI = 0.601]绝对值比较差异均无统计学意义。TMF组HDL-C[0.06（-0.16，1.84）mmol/L对-0.12（-0.26，0.04）mmol/L，P = -2.890，95%CI = 0.004]高于TAF组，但TC/HDL-C[-0.04（-0.67，0.44）对0.40（-0.14，1.33），P = -3.959，95%CI＜0.001]低于TAF组。分别用10μg/ml TMF和TAF干扰HepG2细胞72小时。显微镜检查显示，TMF组[12 196（10 740，14 345）对4 029（3 086，5 425）个细胞数，P = -4.815，95%CI＜0.；TAF组[12 484（11 176，15 824）对4 029（3 086，5 425），P = -4.815，95%CI＜0.001]油红O染色后细胞内脂滴数均高于对照组，但两组间差异无统计学意义。对10周龄C57/BL6J雄性小鼠连续灌胃给予3.8mg/kg TMF或TAF 12周。肝组织进行油红O染色。TAF组小鼠肝组织脂滴数高于对照组[30 647（28 050，34 821）对27 614（25 214，29 176），P = -2.529，95%CI = 0.011]，而TMF组与对照组差异无统计学意义。给药后TAF组小鼠血清TG水平[1.17（1.11，1.19）μmol/L对1.06（1.04，1.09）μmol/L，P = -2.060，95%CI = 0.039]、TC[2.58（2.55，2.80）μmol/L对2.33（2.18，2.54）μmol/L，P = -2.084，95%CI = 0.037]高于对照组，而HDL-C水平低于对照组[1.14（1.13，1.16）μmol/L对1.29（1.28，1.32）μmol/L，P = -2.313，95%CI = 0.021]及TMF组[1.14（1.13，1.16）μmol/L对1.30（1.28，1.38）μmol/L，P = -2.795，95%CI = 0.005]。然而，TMF组与对照组TG、TC及HDL-C水平差异无统计学意义。TMF和TAF均能有效抑制HBV复制并促进肝功能恢复，对肾功能无明显影响。然而，TAF可能对机体脂质代谢产生不良影响，而TMF无明显影响。
