Anti-hepatitis B virus effects of traditional Chinese medicine: Learning from clinical trials in the past twenty years

Table 1 The anti-hepatitis B virus effects of traditional Chinese medicine

Number	Traditional Chinese medicine	Experimental group	Control group	HBsAg	HBeAg	HBV DNA	Ref.
1	BSJPFa	271 HBeAg-negative CHB patients treated with BSJPFa combined with entecavir for 96 weeks	272 HBeAg-negative CHB patients treated with Chinese herbal placebo combined with entecavir for 96 weeks	Increase negative conversion rate (5.5% vs 1.8%, P = 0.03)	Not mentioned	Could not increase negative conversion rate (97.8% vs 98.2%, P = 0.77)	Zhang et al[3]
2	LMF	136 HBeAg-positive CHB patients treated with LMF combined with entecavir for 52 weeks	135 HBeAg-positive CHB patients treated with Chinese herbal placebo combined with entecavir for 52 weeks	Slightly increase negative conversion rate (1.5% vs 0.7%, P = 1.0)	Increase negative conversion rate (22.8% vs 12.6%, P = 0.038)	Increase the proportions of ≥ 2 Log copies/mL reduction compared to baseline (98.5% vs 92.6%, P = 0.019)	Zhu et al[5]
3	TGJPJD	285 HBeAg-positive patients treated with TGJPJD combined with entecavir for 108 weeks	283 HBeAg-positive patients treated with Chinese herbal placebo combined with entecavir for 108 weeks	Slightly increase negative conversion rate (0.7% vs 0.35%, P > 0.05)	Increase negative conversion rate (37.54% vs 27.21%, P = 0.08)	Slightly increase negative conversion rate (91.5% vs 90.11%, P > 0.05)	Li et al[11]
4	SQG and YYJG	134 HBeAg-positive CHB patients treated with SQG and YYJG combined with Lamivudine for 48 weeks	134 HBeAg-positive CHB patients treated with Chinese herbal placebo combined with Lamivudine for 48 weeks	Not mentioned	Increase negative conversion rate (38% vs 24%, P < 0.05)	Virological response between the two groups were similar (P > 0.05)	Ye et al[12]
5	BSJPFb	200 HBeAg-positive HBV carriers treated with the BSJPFb for 52 weeks	100 HBeAg-positive HBV carrier treated with Chinese herbal placebo for 52 weeks	Promote HBsAg level decline (0.416 Log IU/mL vs 0.178 Log IU/mL, P = 0.0069)	Promote HBeAg level decline (291.6 S/Co vs 14.0 S/Co, P < 0.0001)	Promote HBV DNA decline (0.996 Log IU/mL vs 0.077 Log IU/mL, P < 0.001)	Chen et al[14]
6	Oxymatrine	102 HBeAg-positive CHB patients treated with Oxymatrine capsule for 24 weeks	67 HBeAg-positive CHB patients treated with Chinese herbal placebo for 24 weeks	Slightly increase negative conversion rate (1.98% vs 0.0%, P = 0.269)	Increase negative conversion rate (31.91% vs 6.45%, P = 0.001)	Increase negative conversion rate (38.61% vs 7.46%, P = 0.001)	Lu et al[16], Lu et al[17]
7	Phyllanthus urinaria	CHB patients treated with Phyllanthus urinaria combined with antiviral drugs	CHB patients treated with antiviral drugs	Could not significantly promote HBsAg clearance	Increase negative conversion rate (P < 0.05)	Increase negative conversion rate (P = 0.008)	Xia et al[20]
8	XYSJJ	CHB patients treated with XYSJJ combined with antiviral drugs	CHB patients treated with antiviral drugs	Not mentioned	Increase negative conversion rate (P < 0.00001)	Increase negative conversion rate (P < 0.00001)	Yu et al[21]
9	LWWLP	CHB patients treated with LWWLP and enticavir	CHB patients treated with enticavir	Not mentioned	Increase negative conversion rate (P = 0.0002)	Slightly increase negative conversion rate (P = 0.17)	Zhou et al[22], He et al[23]
10	FZHYJN	CHB patients treated with FZHYJN and enticavir	CHB patients treated with enticavir	Not mentioned	Increase negative conversion rate (P < 0.05)	Increase negative conversion rate (P < 0.05)	Lou[24]
11	ALHXW	CHB patients treated with ALHXW and enticavir	CHB patients treated with enticavir	Not mentioned	Increase negative conversion rate (P < 0.05)	Increase negative conversion rate (P < 0.05)	Lou[24]
12	BJRGP	CHB patients treated with BJRGP with enticavir	CHB patients treated with enticavir	Not mentioned	Increase negative conversion rate (P < 0.05)	Increase negative conversion rate (P < 0.05)	Lou[24]

ALHXW: Anluo Huaxian Pills; BJRGP: Biejia Ruangan Tablets; BSJPFa: Bushen Jianpi formula A; BSJPFb: Bushen Jianpi formula B; FZHYJN: Fuzheng Huayu Capsules; HBeAg: Hepatitis B virus e antigen; HBsAg: Hepatitis B virus surface antigen; LMF: Lingmao Formula; LWWLP: Liuwei Wuling Pian; SQG: Shuanghu Qinggan Granule; TGJPJD: Tiao-Gan-Jian-Pi-Jie-Du granule; XYSJJ: Xiaoyao San Jiajian; YYJG: Yiqi Jieyu Granule.

Table 2 The anti-hepatitis B virus mechanism of traditional Chinese medicine

Number	Immune cells or cytokines	Mechanism	Traditional Chinese medicine	Ref.
1	Plasma cells	The frequency increased	LMF	Li et al[6]
2	CD4+CD25+T cells	The frequency decreased	LMF	Li et al[7]
3	CD4+T cells	The expression level of IFN-γ on CD4+T cells increased	LMF	Li et al[7]
4	Th1 cells	The count increased	LMF	Ji et al[8]
5	Dendritic cells	The count increased; the levels of PD-L1 decreased	LMF	Ji et al[8]
6	Regulatory T cells	The levels of PD-L1 decreased	LMF	Ji et al[8]
7	Natural killer T cells	The proportion of NKG2A+NKT and PD-1+NKT decreased	LMF	Le et al[9]
8	IFN-β	Increased through mitochondrial antiviral signaling protein pathway	LMF	Zhang et al[10]
9	IL-10	Decreased	SQG; BSJPFb, oxymatrine	Zhu et al[13], Chen et al[15], Dong et al[18]
10	Transforming growth factor-β	Decreased	SQG	Zhu et al[13]
11	IFN-γ	Increased	BSJPFb, oxymatrine	Chen et al[15], Dong et al[18]
12	IL-1	Increased	BSJPFb	Chen et al[15]
13	IL-4	Decreased	BSJPFb, oxymatrine	Chen et al[15], Dong et al[18]
14	IL-2	Increased	Oxymatrine	Dong et al[18]
15	HBV-specific CTLs	The count increased, the PD-L1 Levels of HBV-specific CTLs decreased	Oxymatrine	Gu et al[[19]

BSJPFb: Bushen Jianpi formula B; CTLs: Cytotoxic T lymphocytes; HBV: Hepatitis B virus; IFN: Interferon; IL: Interleukin; LMF: Lingmao Formula; PD-L1: Programmed cell death ligand 1; SQG: Shuanghu Qinggan Granule.