Evidence-Based Complementary and Alternative Medicine

Evidence-Based Complementary and Alternative Medicine / 2019 / Article

Review Article | Open Access

Volume 2019 |Article ID 6486293 | 12 pages | https://doi.org/10.1155/2019/6486293

An Overview of the Randomized Placebo-Controlled Trials of Chinese Herbal Medicine Formula Granules

Academic Editor: Danilo Ranieri
Received22 Oct 2018
Accepted21 Mar 2019
Published11 Apr 2019

Abstract

Objective. To summarize the characteristics and the outcomes of the Randomized Placebo-Controlled Trials of Chinese Herbal Medicine Granules manufactured by China Resources Sanjiu Pharmaceutical Co., Ltd. Methods. Databases including China National Knowledge Infrastructure, VIP, Wanfang, PubMed, Cochrane Library, and clinicaltrials.gov were searched in March 2018 for relevant randomized controlled trials (RCTs). Two reviewers independently screened for and selected studies, extracted data, and checked data extraction. Methodological quality was evaluated using the Cochrane Risk of Bias tool. For the outcome, the characteristics of the study, the cure rate, the effectiveness rate, and advert events were described with a method of bibliometrics. Also, we performed meta-analysis only if there were ≥2 studies treated by the same intervention and evaluated by the same outcome. Results. A total of 40 placebo-controlled RCTs treated for 17 diseases were included in our analysis involving 4,632 patients. 16 of 19 studies treated by CHM granules only showed positive result in patients with HBV, HCV, fever, depression, nonalcoholic fatty liver disease, AIDS, and asthma while negative result was shown in patients with migraine. 17 of 21 studies treated by combination therapy against conventional therapy showed positive result in patients with HBV, herpes simplex keratitis, COPD, liver cirrhotic ascites, Parkinson’s disease, and diabetic peripheral neuropathy while negative result was shown in patients with myasthenia gravis, angina pectoris, and depression. The pooled result cannot demonstrate that the notifying kidney formula granules had the superior effect with placebo on the clearance of serum HBV DNA and HBeAg in HBV carriers with a RR (and the 95% CI) of 2.97 and 1.99 , respectively. But, the CHM granules can reduce within-group HBV DNA levels by more than 2 lgIU/ml; the RR (and 95% CI) was 4.64 . Qizhu granules had a significant effect on clearance of HCV RNA with a RR (and 95% CI) of 6.26 . And, the heat-clearing and detoxifying formula granules were superior to placebo in resolution of cold symptom among patients with fever with a RR and 95% CI of 2.58 . Based on the conventional therapy, the pooled result demonstrated that the Regulating liver formula granules were superior to placebo on the clearance of serum HBeAg in chronic hepatitis B patients with a RR (and the 95% CI) of 1.73 . The EeChen decoction granules were superior to placebo in COPD patients with a RR (and the 95% CI) of 1.13 . 28 of the 40 studies reported adverse events. There were 51 adverse events in CHM formula granules group or combination group (n=2,483) and 26 in control group (n=2,122) totally. Most of the adverse symptoms spontaneously resolved after completing the courses of treatment and the other adverse symptoms improved after symptomatic treatment. Conclusion. 16 of 19 studies treated by CHM granules only showed positive result in 7 diseases and negative result in 1 disease. 17 of 21 studies treated by combination therapy against conventional therapy showed positive result in 6 diseases and negative result in 3 diseases. However, both the absolute and relative effectiveness of CHM formula granules compared with placebo need to be considered clinically.

1. Introduction

Chinese herbal medicine (CHM) formula granules are concentrated extracts of Chinese herbs which is a convenient and increasingly popular method of administering Chinese herbal medicine (CHM) [1]. Traditionally, CHMs are prescribed as dried herbs that are decocted daily with water by the patient and could be time-consuming. Manufacturers claim that CHM formula granules are superior to traditional decoction methods in terms of the ease of administration which improves patient adherence to treatment and retains the properties of CHMs to maintain effectiveness [2].

In the early 2000s, traditional Chinese medicine became increasingly industrialized and has continued to develop rapidly and widely with increasing investment into developing CHM formula granules [3]. Given that traditional use of CHMs has typically involved decoctions, research on CHM formula granules has increasingly focused on its equivalence with decoction methods, whether it is the chemical composition of CHM formula granules or clinical efficacy [2]. Comparative studies of chemical composition have compared single Chinese herbs as well as CHM formula granules and although the differences are clear in terms of chemical constituents, the conclusions drawn from these studies are varied [4]. Looking at the available clinical research, however, most studies appear to show that formula granules are equivalent to that of traditional decoction methods [46], but a few studies show the traditional decoction methods were better in some outcomes for some diseases [4, 7].

Compared with traditional decoction methods, research into the efficacy and safety of CHM formula granules is limited, despite growing popularity of its use. We aimed to describe the status and summarize the outcomes of the studies treated by CHM formula granules compared to placebo by conducting a research of bibliometrics and meta-analysis.

2. Methods

2.1. Inclusion/Exclusion Criteria

We only included RCTs and accepted interventions involved CHM formula granules compared with placebo granules. We placed no limits on the topic of disease of the research. The intervention group is treated by CHM formula granules only or combined with conventional therapy, and the control group is treated by CHM formula placebo granules or combined with conventional therapy. We placed no limits of the outcomes. Since there is currently no national quality standard for CHM formula granules, the quality of CHM formula granules can differ among manufacturers [8]. For this reason, only studies involving the most widely used CHM formula granules were accepted. These are manufactured by China Resources Sanjiu Pharmaceutical Co., Ltd., which is one of the six manufacturers first certified by the National Food and Drug Administration and supplies the largest number of terminal hospitals in China [3].

2.2. Literature Search

We searched for published literature in databases including China National Knowledge Infrastructure (CNKI), Wanfang Data, Chong Qing VIP, PubMed, and Cochrane Library. We retrieved completed but unpublished studies from clinicaltrials.gov and tracked the results of these studies. Only Chinese and English articles were retrieved, and the last search was carried out on 31st March 2018. The search words included “CHM formula granules”, “Chinese Herbal Medicine granules”, “dispensing granules”, “traditional Chinese medicine particle”, “pellet formula of traditional Chinese medicine”, “concentrated granule”, “TCM formula granule”, “TCM formula particles”, “Sanjiu”, “999’’, and “placebo”. Depending on the characteristics of each database, search strategies including keywords or full phrases were used.

2.3. Literature Screening

Identified articles were initially imported into NoteExpress and initial screening carried out based on inclusion/exclusion criteria after reading article titles and abstracts. For the next stage of screening, full texts were acquired and checked for eligibility before including articles in the final analysis.

2.4. Quality Evaluation

The risk of bias was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions [9], which involves assessing bias relating to random sequence generation, allocation concealment, blinding, data integrity, selective reporting of positive and/or negative findings, and other sources of bias. Among them the “other sources of bias” (a) were the clear inclusion/exclusion criteria; (b) were the baseline data comparable; and (c) was any conflict of interest. For selective outcome reporting, since most of the included studies did not register their research protocols, the risk of bias was defined as low if the outcome measures included all the important outcomes according to the target diseases of the original studies. The risk of bias was assessed and validated independently by two reviewers (Mei Han and Jing Li); the results were cross-referenced, and any disagreements were resolved by discussion with a third reviewer (Jian-ping Liu).

2.5. Outcome Measures

The cure rate (percentage of the total number of people cured) and the overall effectiveness rate (percentage of the total number of people improved) were described. Other indicators of effectiveness will be described if there is no information of effective rate and cure rate; and adverse events as the key safety indicator will be described as well. The cure rate and the overall effectiveness rate are calculated with the data from the included studies according to their standard method for clinical evaluation of therapeutic effects.

2.6. Data Analysis

Descriptive statistics (frequency and percentage) were used to describe the characteristics and the outcome of the studies. Statistical pooling was carried out using the Cochrane Collaboration software RevMan5.3.5 for meta-analysis only if there were ≥2 studies treated by the same intervention and evaluated by the same outcome. The relative risk (RR) and 95% confidence interval (CI) were selected as the statistic for dichotomous data. To evaluate heterogeneity, chi-square test was first performed and based on this finding; estimates of heterogeneity (I2) were then applied. We used a fixed-effects model when I2 was ≤50% and the P value was ≥0.10; when I2 was >50% or the P value was <0.10, we applied a random-effects model.

3. Results

3.1. Literature Searching and Screening Flowchart

252 articles were retrieved in total based on our search strategies. After removing duplicates and screening titles and abstracts, we obtained 50 full-text articles. 40 articles were eventually eligible for inclusion in this review (Figure 1).

3.2. Characteristics of Included Literature

A total of 40 RCTs involving 4632 patients [1049] were included. 19RCTs compared the effects of CHM formula granules alone versus placebo granules and involved the treatment of 8 conditions. These conditions include chronic hepatitis B or hepatitis B virus (HBV) carrier [11, 18, 19, 21, 22, 24, 28], chronic hepatitis C [27, 49], nonalcoholic fatty liver disease [25], migraine [1416], fever [10, 11], depression [25, 26], acquired immune deficiency syndrome (AIDS) [12], and asthma [17]. 21 RCTs compared the effects of CHM formula granules versus placebo granules based on conventional therapy and involved the treatment of 9 conditions. These conditions include Parkinson’s disease [3240], COPD [2830], chronic hepatitis B [4547], diabetic peripheral neuropathy [31], depression [41], angina pectoris [42], myasthenia gravis [43], herpes simplex keratitis [44], and liver cirrhotic ascites [48].

The total composition of the CHM formula was described in 37 studies [1045, 48, 49] and, among them, 32 studies described the dosage for each kind of the granule. 28 studies described the ingredients of the placebo which included a small dose of CHM formula granules in 6 studies [10, 11, 13, 27, 28, 49], the Chinese herb Huo Xiang (wrinkled giant hyssop) in 6 studies [18, 20, 21, 23, 24, 45], and no pharmaceutical ingredients in 3 studies [17, 25, 26, 3144, 48]; also, the placebo contains some food colorings, starch, maltodextrin, or anhydrous glucose. The specific characteristics of these studies were summarized in Table 1.


Study IDDiseasesSample
T/C
Age
(years)
Gender
M/F
TreatmentDurationMain outcomes

Cheng Y 2016 [10]fever41/40T:38.03 ± 14.65
C:37.21 ± 15.43
T:22/19
C:20/20
Clearing heat and removing toxicity formula3 dFever clearance time, AE

Xie JH 2017 [11]fever48/48T:36.7 ± 6.7
C:39.4 ± 2.1
T:25/23
C:20/28
Clearing heat and removing toxicity formula3 dsymptoms improving, AE

Li Y 2012 [12]AIDS36/3618-7046/26Improving immunity formula180 dCD4

Cheng Y 2017 [13]non-alcoholic
fatty liver
48/48T:45.07 ± 11.23
C:41.65 ± 9.38
T:23/17
C:25/15
Invigorating spleen, regulating Qi and resolving dampness formula24 wFree fatty acids, ALT, AE

Fu CH 2014 [14]migraine150/78T:37.11 ± 11.96
C:34.97 ± 10.40
T:33/96
C:12/52
Modified Rhizoma Chuanxiong releasing pain decoction or Wuzhuyu decoction12 wNo. and degree of headache

Xu YL 2011 [15]migraine24/2418~65T:5/19
C:11/13
Regulating liver, dispelling wind and removing blood stasis formula12 wNo. and degree of headache, AE

Zhang Y 2013 [16]migraine86/42T:23 ~ 56
C:24 ~ 54
T:23/63
C:11/31
Modified Chuanxiong Dingtong decoction12 wNo. of headache, PSQI scale, EO

Geng YY 2015 [17]asthma40/20T:3.62 ± 0.88
C:3.37 ± 0.90
T:30/10
C:17/3
Nourishing Qi to invigorate spleen and invigorating the kidney formula12 wNo. of asthma attacks, AE

He JS 2012 [18]HBV
carrier
200/100T:33.6 ± 7.1
C:34.4 ± 8.2
T:137/63
C:60/40
Notifying kidney and spleen formula52 wHBV DNA, HBeAg, HBsAg, AE

Li HZ 2012 [19]HBV
carrier
200/100T:34.33 ± 6.22
C:34.39 ± 8.18
T:118/82
C:59/41
Notifying and clearing kidney formula52 wHBV DNA, HBeAg

Ni W 2015 [20]HBV
carrier
40/2036. 24 ± 8. 22T:19/21
C:12/8
Notifying and clearing kidney formula48 wHBV DNA, HBeAg, AE

Peng DT 2016 [21]HBV
carrier
50/25T:34.67 ± 5.12
C:32.20 ± 3.95
T:24/26
C:14/11
Notifying kidney and detoxifying formula48 wHBV DNA, HBeAg, HBsAg, AE

Xing YF 2012 [22]HBV
carrier
200/200T:34.33 ± 6.22
C:34.39 ± 8.18
T:113/78
C:112/75
Notifying and clearing kidney formula52 wHBV DNA, AE

Zheng YJ 2012 [23]HBV
carrier
60/60T:35.0 ± 5.0
C:34.0 ± 6.0
T:42/18
C:45/15
Notifying kidney and spleen formula48 wHBV DNA, HBeAg, AE

Zhang ZE 2013 [24]HBV
recrudescence
23/23T:37.7 ± 12.5
C:38.1 ± 12.0
T:12/11
C:13/10
Notifying kidney and spleen formula48 wHA, PCIII, AE

Xu F 2013-1 [25]depressed50/50T:30.43 ± 3.43
C:30.07 ± 3.34
-Benefiting brain and relieving depression formula6 wEdinburgh Postnatal Depression Scale, AE

Xu F 2013 [26]depressed47/46--Ease powder6 wcognitive function, AE

Zhao L 2014 [16]HCV102/1021b:54.7 ± 12.47
other:49.5 ± 16.7
T:81/48
C:24/20
Qizhu (astragalus and atractylodes) granules48 wHCV RNA

Zhao L2014-1 [27]HCV96/96T:53.47 ± 12.80
C:53.27 ± 13.24
T:39/57
C:34/52
Qizhu (astragalus and atractylodes) granules48 wHCV RNA, AE

Chen SQ 2017 [28]COPD60/60T:65.06 ± 5.05
C:66.08 ± 6.04
T:29/31
C:32/28
Modified Erchen decoction combined with antibiotics, bronchiectasis and oxygen uptake14 dPulmonary function, IgA, AE

Xie WY 2017 [29]COPD
stable period
COPD
acute period
60/60
60/60
T:65.05 ± 5.07
C:68.07 ± 6.15
T:68.12 ± 5.07C:68.11 ± 6.06
T:33/27
C:31/29
T:32/28
C:30/30
Modified Erchen decoction combined with antibiotics, bronchiectasis and oxygen uptake14 dPulmonary function

Shang LZ 2017 [30]COPD100/100T:69.48 ± 9. 05C:70.39 ± 8. 84T: 57/43
C: 55/45
Modified Erchen decoction combined with antibiotics, bronchiectasis and oxygen uptake14 dPulmonary function

Hu WH 2015 [31]diabetic peripheral neuropathy50/50T:54.5(43-68)
C:53.2(46-69)
T:24/26
C:22/28
Eliminating arthralgia and promoting blood circulation granules combined with methycobal and antidiabetics8 wPain, neurological function

Li M &
Yang MH [3240]
Parkinson’s
disease
60/60T:66.6 ± 1.2
C:67.3 ± 1.2
T:31/27
C:42/20
Notifying the kidney and promoting blood circulation formula combined with madopar36 wUnified Parkinson’s disease rating scale, AE

Liu J 2012 [41]depression30/30T:40.13 ± 9.72
C:41.25 ± 9.59
T:14/18
C:13/20
Relieving depression granules combined with paroxetine8 wHAMD Scale, AE

Pang LJ 2013 [42]angina pectoris35/35T:57.2 ± 9.2
C:60.13 ± 3.8
T:15/15
C:15/15
Promoting blood circulation and resolving turbidity formula combined with aspirin8 wPain, attacks, ECG, nitro-glycerine

Shuang XP 2014 [43]myasthenia
gravis
20/18T:22-60
C:20-59
T:8/12
C:7/11
Notifying Qi and dehumidification formula combined with prednisone and pyridine bromide10 wMyasthenia gravis scale

Song JK 2016 [44]herpes simplex keratitis (liver-wind and deficiency of liver-Yin)35/40
38/40
T:36.5 ± 7.3
C:38.2 ± 8.6
T:46.5 ± 8.2
C:44.2 ± 7.6
T:17 /16
C:16 /15
T:15/17
C:16 /18
Clearing or softening liver formula combined with ganciclovir7 dSymptoms, laboratory test, AE

Xie WN 2016 [45]HBV40/40T:27.43 ± 5.75
C:28.72 ± 6.42
T:30/10
C:31/9
Notifying kidney and spleen formula combined with lamivudine48 wHBV DNA, HBeAg, AE

Ye YA 2012 [46]HBV295/295--Regulating liver and blood and notifying spleen/Regulating liver, detoxification and dehumidification combined with adefovir dipivoxil48 wHBeAg

Zhan BL 2013 [47]HBV30/30T:34.26 ± 9.41
C:36.19 ± 10.29
T:21/9
C:19/11
Regulating liver and blood and notifying spleen/Regulating liver, detoxification and dehumidification combined with adefovir dipivoxil48 wHBV DNA, HBeAg, AE

Zhang PJ 2013 [48]liver cirrhotic
ascites
56/56T:42.7 ± 6.42
C:44.72 ± 5.48
T:32/24
C:30/26
Alleviating water retention formula28 dLiver function

AE: adverse event; -: undescribed.
3.3. Quality Evaluation of the Articles

Among these 40 studies, patients were randomized by random number table in 13 studies [10, 11, 13, 17, 25, 26, 31, 4145, 48], by a central randomization system in 13 studies [15, 18, 19, 28, 3241] and by using SAS software in 1 study [21]; the remaining 13 studies only mentioned “random” or “randomization” without describing the specific randomization methods [12, 14, 16, 20, 22, 24, 2730, 46, 47, 49]. 14 studies described allocation concealment with the central randomization system [15, 18, 19, 21, 23, 3241]. One study described the blinding only of participants [17] and the remaining 38 studies blinding of both participants and researchers. 28 studies described the number of participants who withdrew and were lost to follow-up and only 6 of these provided reasons [10, 13, 21, 23, 26, 31]. The number of patients in all the randomized groups and in the analysis was the same in the remaining 11 studies. The research protocol was registered before publication in only 1 study [12] and all the important outcomes were reported in 26 studies without selective outcome reporting [10, 11, 1319, 2531, 3943, 49]. The remaining 14 articles only reported part of the important outcomes [11, 2022, 24, 28, 3241]. 32 studies were supported by the Chinese government project [1214, 1623, 2528, 28, 29, 2938, 42, 4449] and the remaining 8 were unknown. The quality of the studies included in our analysis was not bad. The details of the evaluation were shown in Figure 2.

3.4. Results
3.4.1. Cure Rate

14 of the 19 studies treated by CHM formula granules only, and 6 of the 21 studies treated by CHM formula granules combined with conventional therapy described the cure rate. While the definition of “cure” differed among these studies with different conditions, the standard for clinical evaluation of therapeutic effects was described in detail as follows.

According to the outcome “cure rate”, 50.00% of the studies treated by CHM formula granules only showed a positive result, such as chronic hepatitis C, nonalcoholic fatty liver disease, depression, and fever, and another 50% studies showed a negative result, such as HBV carrier, HBV recrudescence, and migraine. Four studies treated by the notifying kidney formula evaluated the effects on HBV carriers. The pooled result of 4 studies cannot demonstrate that the notifying kidney formula granules had the superior effect with placebo on the clearance of serum HBV DNA and HBeAg in HBV carriers with a RR (and the 95% CI) of 2,97 and 1.99 , respectively. Pooled analysis of 3 studies showed that Qizhu granules had a significant effect on clearance of HCV RNA with a RR (and 95% CI) of 6.26 . The pooled result showed the heat-clearing and detoxifying formula granules were superior to placebo in resolution of cold symptom among patients with fever with a RR and 95% CI of 2.58 .

Among the 6 combination studies reporting cure rate, only 1 study treated for herpes simplex keratitis showed positive results in 2 subgroups. The pooled result demonstrated that the Regulating liver formula granules were superior to placebo on the clearance of serum HBeAg in chronic hepatitis B patients based on the conventional therapy with a RR (and the 95% CI) of 1.73 , but the formula did not work with clearance of serum HBV DNA. The negative results also were shown in the studies treated for myasthenia gravis and depression. The results of all the individual outcome and meta-analyses carried out are shown in Tables 2 and 3.


Study IDTreatmentPlaceboP value
n/N%n/N%

HBV carrier: HBV DNA negative after 48-week treatment
He JS 20121/1740.570/930.000.77
Li HZ 20123/1911.570/940.000.35
Ni W 20153/407.500/200.000.41
Xing YF 20123/1911.571/1870.530.38
Meta-analysis RR and 95% CI: 2.97 ; I2 = 0%

HBV carrier: HBeAg negative after 48-week treatment
He JS 201211/1746.323/933.230.29
Li HZ 20127/1913.663/943.190.84
Ni W 20155/4012.501/205.000.38
Zheng YJ 20126/5610.712/573.510.15
Meta-analysis RR and 95% CI: 1.99 ; I2 = 0%

HBV recrudescence: HBV DNA negative after 48-week treatment
Zhang ZE 20139/2339.131/234.350.02

HBV recrudescence: HBeAg negative after 48-week treatment
Zhang ZE 20137/2330.432/238.700.08

Chronic hepatitis C: HCV RNA negative after 48-weektreatment and 24-week follow-up
Zhao L 2014 (HCV-1b)4/449.090/510.000.11
Zhao L 2014 (HCV-other)6/1442.861/156.670.04
Zhao L 2014-110/6016.673/684.410.03
Meta-analysis RR and 95% CI: 6.26 ; I2 = 0%

Non-alcoholic fatty liver disease: Normal ALT and B-ultrasound after 12-week treatment
Cheng Y 201719/4047.5010/4025.000.04

Depression: Reduction in Edinburgh Postnatal Depression Scale (EPDS)≥80
Xu F 2013-113/5026.004/508.000.02
Xu F 201314/4531.116/4513.330.05

Fever: Normal temperature and resolution of cold symptoms
Cheng Y 201627/4165.8518/4045.000.06
Xie JH 201729/4860.4217/4835.420.02
Meta-analysis RR and 95% CI: 2.58 ; I2 = 0%

Migraine: Resolution of symptoms after 12-week treatment and at 2-month follow-up
Xu YL 20114/2416.670/240.000.12


Study IDTreatmentPlaceboP value
n/N%n/N%

Chronic Hepatitis B: HBV DNA negative after 48-week treatment
Zhan BL 201324/3080.0016/3053.330.07

Chronic Hepatitis B: HBeAg negative after 48-week treatment
Ye YA 201283/28029.6450/28017.860.001
Zhan BL 201314/3046.676/3020.000.04
Meta-analysis RR and 95% CI: 1.73 ; I2 = 0%

Chronic Hepatitis B with YMDD: HBV DNA negative after 48-week treatment
Xie WN 20167/3619.441/333.030.07

Chronic Hepatitis B with YMDD: HBeAg negative after 48-week treatment
Xie WN 20169/3625.000/310.000.05

Herpes simplex keratitis: Symptoms disappeared and normal laboratory test
Song JK 201624/3372.7314/3145.160.03
Song JK 2016a23/3467.6513/3240.630.04

Depression: The score of HAMD-17 <7
Liu J 201212/3237.508/3324.240.25

Myasthenia gravis: Reduction of the score of myasthenia gravis scale≥95
Shuang XP 20140/200.000/180.00-

3.4.2. Clinical Effectiveness Rate

12 of these 19 studies treated by CHM formula granules only, and 8 of the 21 studies treated by CHM formula granules combined with conventional therapy compared the clinical effectiveness rate. As with the “cure” rate, the definition of “clinical effectiveness” differed among studies with different conditions. Again, the standard for clinical evaluation of therapeutic effects of the different conditions is described in detail below.

According to the outcome “clinical effectiveness rate”, 75.00% of the studies treated by CHM formula granules only showed a positive result, such as HVB carrier, nonalcoholic fatty liver disease, depression, and AIDS, and another 25% studies showed a negative result, such as fever and migraine. Five studies treated by the notifying kidney formula evaluated the effects on HBV carriers. Pooled analysis showed that the granules can reduce within-group HBV DNA levels by more than 2 lgIU/ml; the RR (and 95% CI) was 4.64 . There was no significant difference between heat-clearing and detoxifying formula granules and placebo granules to improve fever and cold symptoms with a RR (and 95% CI) of 3.78 .

Among the 8 combination studies reporting effectiveness rate, 1 study treated for diabetic peripheral neuropathy showed positive results. The pooled result of 3 studies demonstrated that the EeChen decoction granules were superior to placebo in COPD patients based on the conventional therapy with a RR (and the 95% CI) of 1.13 . The negative results were shown in the studies treated for myasthenia gravis, angina pectoris, herpes simplex keratitis, and depression. The results of all the individual outcome and meta-analyses carried out are shown in Tables 4 and 5.


Study IDTreatmentPlaceboP value
n/N%n/N%

HBV carrier: Reduction of within-group HBV DNA levels by more than 2lgIU/ml
He JS 201238/17421.845/935.380.001
Li HZ 201237/19119.374/944.260.002
Ni W 20156/4015.002/2010.000.59
Peng DT 201615/4434.092/238.700.04
Xing YF 201237/19119.379/1874.81<0.001
Meta-analysis RR and 95% CI: 4.64 ; I2 = 0%

Non-alcoholic fatty liver disease: Reduction in ALT by >50% after 12-week treatment
Cheng Y 201733/4082.5021/4052.000.006

Depression: Reduction in Edinburgh Postnatal Depression Scale (EPDS)≥50
Xu F 2013-140/5080.0024/5048.000.001
Xu F 201335/4577.7818/4540.330.0004

Fever: Reduction in fever, and resolution of some cold symptoms
Cheng Y 201639/4195.1226/4065.850.003
Xie JH 201745/4893.7544/4891.670.7
Meta-analysis(random) RR and 95% CI: 3.78 ; I2 = 70%

Migraine: Reduction in frequency/duration of headaches by >50% after 12-week treatment
Fu CH 2014101/12978.2949/6476.560.79
Fu CH 201492/12971.3246/6471.880.94

AIDS: Increase in CD4 levels by >30 after 6-month treatment
Li Y 201214/3638.896/3616.670.04


Study IDTreatmentPlaceboP value
n/N%n/N%

COPD: the comprehensive improvement of pulmonary function, dyspnoea classification, 6-min walking distance and BMI
Chen SQ 2017(stable period)56/6093.3348/6080.000.04
Xie WY 2017(acute period)57/6095.0053/6088.330.19
Shang LZ 201792/10092.0080/10080.000.02
Meta-analysis RR and 95% CI: 1.13 ; I2 = 0%

Diabetic peripheral neuropathy: Pain relief and neurological function improvement
Hu WH 201542/4887.5033/4770.210.04

Depression: Reduction in HAMD Scale ≥25
Liu J 201228/3287.5025/3375.760.23

Angina pectoris: Pain relieved, attacks reduced, ECG improved, nitro-glycerine reduced by 50-80
Pang LJ 201322/2975.8616/2466.670.47

Myasthenia gravis: Reduction of the score of myasthenia gravis scale≥25
Shuang XP 201418/2090.0016/1888.890.91

Herpes simplex keratitis: Symptoms improved and almost normal laboratory test
Song JK 201633/33100.0031/31100.001.00
Song JK 2016a34/34100.0030/3293.750.23

3.4.3. Overview of Effectiveness of CHM Formula Granules

According to the studies included, we calculated the overall cure rate and effectiveness rate of the diseases. It showed that, in some disease, there was poor effectiveness even if there was significant difference between groups. The results are shown in Tables 6 and 7.


DiseasesNo. of studiesCure rateEffectiveness rate
CHM granulesPlaceboCHM granulesPlacebo

HBV carrier/recrudescence
HBV DNA (HBeAg)
53.1% (7.4%)0.5% (3.8%)20.8%5.3%
Chronic hepatitis C
HCV RNA
316.9%3.0%--
Non-alcoholic fatty liver147.5%25.0%82.5%52.5%
Depression228.4%10.5%78.9%44.2%
Fever262.9%40.0%94.4%87.5%
Migraine14.2%0.0%74.8%74.2%
AIDS1--38.9%16.7%

P<0.05 (result of individual study or meta-analysis).

DiseasesNo. of studiesCure rateEffectiveness rate
CHM granulesPlaceboCHM granulesPlacebo

Chronic Hepatitis B
HBV DNA (HBeAg)
347.0%
(30.6%)
28.0%
(16.2%)
--
Myasthenia gravis10.0%0.0%90.0%88.9%
Herpes simplex keratitis170.1%42.9%100.0%96.8%
Depression137.5%24.2%87.5%75.8%
COPD3--93.2%82.3%
Diabetic peripheral neuropathy1--87.5%70.2%
Angina pectoris1--75.9%66.7%

P<0.05 (result of individual study or meta-analysis).

Neither cure rate or effectiveness rate was not described in 10 studies; among these studies, 1 study treated by CHM granules only compared with placebo in patients with asthma showed fewer attacks in the CHM granules group (P<0.05) [17]. One study treated by CHM granules combined with conventional therapy compared with conventional therapy only in patients with liver cirrhotic ascites showed undifferentiated mortality (4/56 versus 9/56, p=0.16) and lower 1-year recurrence rate (25/56 versus 41/56, p=0.003) [48]. The other 8 studies were conducted by the same research team and each study reported the outcomes selectively. The research showed that notifying the kidney and promoting blood circulation formula combined with madopar can improve the sleep quality, motor function, muscle tension, dopamine level, and TCM syndromes in patients with Parkinson’s disease [3240].

3.4.4. Adverse Events

28 of the 40 studies reported adverse events. Among them, 8 studies [10, 11, 13, 15, 17, 21, 27, 28] reported that there was no adverse event. In the migraine study [14], nausea, abdominal pain, diarrhea, abdominal distention, and constipation appeared in 15 participants, 10 in the CHM formula granules group and 5 in the placebo group. In the 7 chronic hepatitis B studies [18, 20, 2224, 45, 47], slight abdominal distention, loss of appetite, and abdominal discomfort appeared in 28 participants, 21 in the CHM formula granules group, and 7 in the placebo group. In addition, mildly raised ALT levels were found in 8 participants in the CHM formula granules group. In the 3 depression studies, dry mouth, nausea, abdominal distention, and dizzy were found in 25 participants, 15 in the CHM formula granules group, and 10 in the placebo or conventional therapy group. In the herpes simplex keratitis study, nausea and diarrhea were found in 4 patients in the CHM granules group. In the 8 with Parkinson’s disease, pneumonia was found in 1 participant in the CHM granules group, and stomachache in 2 participants, fever in 1 participants, and slightly cerebral infarction in 1 participant in the control group [2835]. There were 51 adverse events in CHM formula granules group or combination group (n=2,483) and 26 in control group (n=2,122) totally. All adverse symptoms spontaneously resolved after completing the courses of treatment and the participants with mildly raised ALT levels, slightly cerebral infarction, and pneumonia improved after symptomatic treatment.

4. Discussion

4.1. Principal Findings

Based on the findings in this systematic review, positive result was found in studies treated by CHM granules only for patients with HBV/HCV, nonalcoholic fatty liver disease, depression, fever, asthma, and AIDS and negative result for patients with migraine. It showed significant difference in studies for patients with HBV, HCV, depression, and fever by meta-analysis. Despite this, levels of HBV DNA and HBeAg clearance for CHM formula granules were much lower than for antivirals [50] or interferon [51]. This is a similar finding for patients with HCV RNA and HCV RNA clearance levels for CHM formula granules were much lower than for antivirals [52].

Also, positive result was found in studies treated by CHM granules combined with conventional therapy for patients with HBV, herpes simplex keratitis, COPD, liver cirrhotic ascites, Parkinson’s disease, and diabetic peripheral neuropathy and negative result for patients with myasthenia gravis, angina pectoris, and depression. It showed significant difference in studies for patients with HBV and COPD by meta-analysis.

Owing to the low incidence of adverse events and high spontaneous resolution of adverse events, CHM formula granules produced by China Resources Sanjiu Pharmaceutical Co., Ltd., can be regarded as being clinically safe.

4.2. The Limitations of These Studies

The limitation of our research is that we only included studies of CHM formula granules produced by China Resources Sanjiu Pharmaceutical Co., Ltd. However, it was our view that the granules produced by different manufacturers would be of varying quality and effectiveness which would make it difficult for us to be able to reduce clinical heterogeneity. For this reason, we chose granules produced by Sanjiu which are the most widely among hospitals in China. Finally, the 40 studies included in this review evaluated 17 conditions and the pooled result of each subgroup may not be particularly reliable. Despite this limitation, our view was that producing this systematic review would enable us to map the current evidence for placebo-controlled RCTs investigating CHM formula granules.

4.3. Implications for Clinical Practice and Further Research

The results of our systematic review suggest that CHM maybe is a safe treatment. CHM formula granules alone are potentially able to benefit patients with depression and may lead to a quicker resolution of symptoms for patients with fever. However, the current evidence suggests that CHM formula granules alone are not suitable for viral clearance of HBV or HCV. CHM formula granules combined with conventional therapy can improve the symptoms of patients with COPD and help viral clearance of HBV in patients with chronic hepatitis B.

The pooled results were limited by the small number of studies for the same condition and relatively small sample sizes. We recommend that further research to evaluate the clinical effectiveness of CHM formula granules be carried out by carrying out a larger number of placebo-controlled RCTs for the same condition and which should be adequately powered. Future studies should also focus on the choice of the endpoint to ensure that clinically relevant and internationally validated outcomes are incorporated.

5. Conclusion

In this systematic review of 40 randomized placebo-controlled trials, 19 studies treated by CHM granules only showed positive result in patients with HBV, HCV, fever, depression, nonalcoholic fatty liver disease, AIDS, and asthma and negative result in migraine. 21 studies treated by combination therapy showed positive result in patients with HBV, herpes simplex keratitis, COPD, liver cirrhotic ascites, Parkinson’s disease and diabetic peripheral neuropathy and negative result in patients with myasthenia gravis, angina pectoris, and depression. And, the results of our systematic review suggest that CHM granules maybe is a safe treatment. However, it is important to consider the clinical relevance of both the absolute and relative effectiveness of CHM formula granules compared with placebo granules in order to maximize the relevance of these findings to patients, medical professionals, and commissioners.

Conflicts of Interest

The authors have declared no conflicts of interest.

Authors’ Contributions

Mei Han and Lily Lai contributed equally to this work.

Acknowledgments

We thank Xue-mei Li and Yu-Yan Pan from Beijing University of Chinese Medicine for their study selection work for this article. This work is supported by Beijing University of Chinese Medicine and China Scholarship Council.

References

  1. Y. S. Tu and X. L. Bi, “Reflection on internationalization of dispensing granules of Chinese Medicine,” Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology, vol. 9, no. 2, pp. 77–81, 2007. View at: Google Scholar
  2. H. H. Liu, S. Q. Li, R. Y. Zhan et al., “Analysis on the development status and the main problems of clinical application and popularization of Chinese medicine dispensing granules,” Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology, vol. 13, no. 1, pp. 9–17, 2011. View at: Google Scholar
  3. C. Z. Tu, G. Li, Z. Z. Zhang et al., “Traditional Chinese medicine dispensing granule and its application and development in intelligent pharmacy of Chinese Medicine,” Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology, vol. 19, no. 2, pp. 207–211, 2017. View at: Google Scholar
  4. Y. B. Liu, X. M. Zhang, F. M. Qiu et al., “Research Progress on equivalence between chemical components of traditional Chinese medicine formula granules and traditional decoction,” Zhejiang Journal of Traditional Chinese Medicine, vol. 53, no. 1, pp. 73–75, 2018. View at: Google Scholar
  5. H. Luo, Q. Li, A. Flower, G. Lewith, and J. Liu, “Comparison of effectiveness and safety between granules and decoction of Chinese herbal medicine: a systematic review of randomized clinical trials,” Journal of Ethnopharmacology, vol. 140, no. 3, pp. 555–567, 2012. View at: Publisher Site | Google Scholar
  6. C. Wu, J. Zhang, Y. Zhao et al., “Chinese herbal medicine bushen qinggan formula for blood pressure variability and endothelial injury in hypertensive patients: a randomized controlled pilot clinical trial,” Evidence-Based Complementary and Alternative Medicine, vol. 2014, Article ID 804171, 7 pages, 2014. View at: Publisher Site | Google Scholar
  7. K. Ding, Y. Wang, W. Jiang et al., “Qian Yang Yu Yin Granule-containing serum inhibits angiotensin II-induced proliferation, reactive oxygen species production, and inflammation in human mesangial cells via an NADPH oxidase 4-dependent pathway,” BMC Complementary and Alternative Medicine, vol. 15, article :81, 2015. View at: Google Scholar
  8. H. Y. Lin, Z. F. Wu, L. H. Zeng et al., “Development status of Chinese medicine dispensing granules and countermeasures for industrial upgrading,” Chinese Journal of Pharmaceuticals, vol. 49, no. 8, pp. 1161–1165, 2018. View at: Google Scholar
  9. J. P. T. Higgins and S. Green, Cochrane Handbook for Systematic Reviews of Interventions, The Cochrane Collaboration and John Wiley and Sons Ltd, 2008. View at: MathSciNet
  10. Y. Cheng, J. Y. Mai, J. H. Xue et al., “Clinical evaluation of heat clearing and detoxicating prescription in treating acute upper respiratory tract infection fever,” Journal of Shanghai University of Traditional Chinese Medicine, vol. 30, no. 4, pp. 22–25, 2016. View at: Google Scholar
  11. J. H. Xue, X. X. Wu, J. J. Chen et al., “Clinical observation of heat clearing and detoxicating protocol in treating exogenous fever,” Hebei Journal of Traditional Chinese Medicine, vol. 39, no. 7, pp. 1027–1030, 2017. View at: Google Scholar
  12. Y. Li, J. Wang, Y. L. Tang et al., “Clinical study on the influence of immunization No. 1 on immune function during incubation period of AIDS,” Chinese Journal of AIDS and STD, vol. 18, no. 6, pp. 356–359, 2012. View at: Google Scholar
  13. Y. Cheng, Y. H. Gong, Y. H. Zhang et al., “Effect of jianpi qishi formula granule on FFA, HOMA-IR and APRI in patients with non-alcoholic steatohepatitis of spleen deficiency and damp-heat type,” Chinese Journal of Experimental Traditional Medical Formulae, vol. 23, no. 17, pp. 200–204, 2017. View at: Google Scholar
  14. C. H. Fu, K. G. Cao, J. J. Zhao et al., “A placebo-controlled study on treating migraine by TCM syndrome differentiation,” China Journal of Traditional Chinese Medicine and Pharmacy, vol. 29, no. 5, pp. 1444–1447, 2014. View at: Google Scholar
  15. Y. L. Xu, Clinical Study on Treatment of Migraine, Liver Wind and Blood Stasis Syndrome by Smoothing Liver and Eliminating Wind and Removing Blood Stasis and Dredging Collaterals, Changchun University of Chinese Medicine, 2011.
  16. Y. Zhang, C. H. Fu, H. W. Liu et al., “Effect of Chuanxiong Ding Tong Yin on sleep quality of migraine patients with liver wind and blood stasis syndrome: a randomized controlled study,” Jilin Journal of Traditional Chinese Medicine, vol. 33, no. 9, pp. 904–906, 2013. View at: Google Scholar
  17. Y. Y. Geng, W. G. Wang, J. H. Zhang et al., “Clinical study on the influence of Chinese herbs on the airway resistance of 2-5-year-old children with intermittent asthma,” Journal of Traditional Chinese Medicine and Pharmacy, vol. 21, no. 21, pp. 13–16, 2015. View at: Google Scholar
  18. J. S. He, Study on Syndrome Pattern of Chronic Hepatitis B Virus Carriers and Treatment of Reinforcing Kidney and Invigorating Spleen, Guang Zhou University of Chinese Medicine, 2012.
  19. H. Z. Li, Randomized Controlled Trial of Bushen Qingtou Formula in the Treatment of Chronic Hepatitis B Virus Carriers, Guang Zhou University of Chinese Medicine, 2012.
  20. W. Ni, W. Q. Shi, Q. J. Ru et al., “Effect of Bushen Qingtou Formula on cytokines in HBeAg positive chronic HBV carriers,” Chinese archives of Traditional Chinese Medicine, vol. 33, no. 3, pp. 543–545, 2015. View at: Google Scholar
  21. D. T. Peng, Y. F. Xing, C. S. Wei et al., “Clinical study of Bushen Jiedu Formula on immune tolerance of chronic HBV carriers,” Lishizhen Medicine and Materia Medica Research, vol. 27, no. 12, pp. 2949–2951, 2016. View at: Google Scholar
  22. Y. F. Xing, G. D. Tong, J. S. He et al., “Effect of Bushen Qingdu Formula on serum immune factors in chronic HBV carriers,” Infectious Disease Information, vol. 25, no. 3, pp. 158–160, 2012. View at: Google Scholar
  23. Y. J. Zheng, J. S. He, L. Chen et al., “Effect of Bushen Jianpi formula on viral replication and Th1/Th2 cytokines in patients with chronic hepatitis B virus infection,” Journal of Nanjing University of Traditional Chinese Medicine, vol. 28, no. 3, pp. 211–215, 2012. View at: Google Scholar
  24. Z. E. Zhang and Y. L. Yang, “Clinical study on Bushen Jianpi Granule in treating chronic hepatitis B after withdrawal of lamivudine,” China Modern Doctor, vol. 51, no. 6, pp. 73–74, 78, 2013. View at: Google Scholar
  25. F. Xu, Q. S. Tang, and X. L. Li, “Randomized controlled clinical trial of Yishen Tiaoqi therapy for postpartum depression,” Beijing Journal of Traditional Chinese Medicine, vol. 32, no. 03, pp. 200–203, 2013. View at: Google Scholar
  26. F. Xu, “Xiaoyao Powder Combined with acupuncture in the treatment of postpartum depression,” Word Journal of Integrated Traditional and Western Medicine, vol. 8, no. 9, pp. 896–899, 2013. View at: Google Scholar
  27. L. Zhao, J. J. Chen, H. M. Nie et al., “Clinical study on treatment of refractory viral hepatitis C with modified Qizhu granule,” Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases, vol. 24, no. 4, pp. 197–199, 2014. View at: Google Scholar
  28. S. Q. Chen, W. Y. Xie, L. Z. Shang et al., “Effect and mechanism of modified Erchen Decoction on immune function, CCL18, CC16, IL-8 and sICAM-1 in patients at acute exacerbation stage of COPD,” Chinese Journal of Experimental Traditional Medical Formulae, vol. 23, no. 10, pp. 171–177, 2017. View at: Google Scholar
  29. W. Y. Xie, S. Ji, L. Z. Shang et al., “Effect of modified Erchen Decoction on Hif-1α and Sirtuins 1 in patients with COPD,” Chinese Journal of Experimental Traditional Medical Formulae, vol. 23, no. 10, pp. 155–162, 2017. View at: Google Scholar
  30. L. Z. Shang, S. Ji, W. Y. Xie et al., “Effect of modified Erchen Decoction on CC16, SP-D and HAT and HDAC in patients at acute exacerbation stage of COPD,” Chinese Journal of Experimental Traditional Medical Formulae, vol. 23, no. 10, pp. 163–170, 2017. View at: Google Scholar
  31. W. H. Hu and Z. M. Wu, “Clinical research of Xiaobi Tongmai medicinal granules on diabetic peripheral neuropathy,” Liaoning Journal of Traditional Chinese Medicine, vol. 42, no. 8, pp. 1447-1448, 2015. View at: Google Scholar
  32. M. Li, M. H. Yang, S. D. Li et al., “Effects of bushen huoxue granule on sleep quality in Parkinson's patients,” Journal of Chinese Medicinal Materials, vol. 34, no. 9, pp. 1473–1477, 2011. View at: Google Scholar
  33. M. Li, M. H. Yang, and Y. Liu, “Effects of 'attenuation and synergia' for bushen huoxue granule on Parkinson's patients,” Journal of Chinese Medicinal Materials, vol. 35, no. 3, pp. 503–506, 2012. View at: Google Scholar
  34. M. Li, M. H. Yang, and Y. Liu, “Randomized placebo-controlled clinical study of bushen huoxue granule in improving the quality of life of patients with Parkinson's disease,” Journal of Chinese Integrative Medicine, vol. 10, no. 3, pp. 310–317, 2012. View at: Google Scholar
  35. M. H. Yang, M. Li, Y. Q. Dou et al., “Effects of bushen huoxue granule on motor function in patients with Parkinson's disease: a multicentre, randomized, double-blind and placebo-controlled trial,” Journal of Chinese Integrative Medicine, vol. 8, no. 3, pp. 231–237, 2010. View at: Google Scholar
  36. M. Li, M. H. Yang, Y. Liu et al., “Effects of bushen huoxue granules on tension of extremity muscles of Parkinson's patients,” China Journal of Traditional Chinese Medicine and Pharmacy, vol. 27, no. 3, pp. 599–602, 2012. View at: Google Scholar
  37. M. Li and M. H. Yang, “Effects of strengthening kidney and activating circulation therapy on symptoms in TCM in Parkinson’s patients,” China Journal of Traditional Chinese Medicine and Pharmacy, vol. 25, no. 12, pp. 2346–2351., 2010. View at: Google Scholar
  38. M. Li, M. H. Yang, Y. Liu et al., “Clinical research on related motor complications in Parkinson’s patients with strengthening kidney and activating circulation of TCM,” China Journal of Traditional Chinese Medicine and Pharmacy, vol. 26, no. 6, pp. 1296–1299, 2011. View at: Google Scholar
  39. M. H. Yang, M. Li, Y. Q. Dou et al., “Effects of Bushen Huoxue granules on level of dopamine in Parkinson's disease patients,” Journal of Traditional Chinese Medicine, vol. 52, no. 4, pp. 299–302, 2011. View at: Google Scholar
  40. M. Li, H. M. Yang, D. X. Luo et al., “Multi-dimensional analysis on Parkinson's disease questionnaire-39 in Parkinson's patients treated with Bushen Huoxue Granule: a multicenter, randomized, double-blinded and placebo controlled trial,” Complementary Therapies in Medicine, vol. 29, pp. 116–120, 2016. View at: Publisher Site | Google Scholar
  41. J. Liu, “Clinical observation of Jieyu granules combined with paroxetine in treating patients with refractory depression,” in Proceedings of the 7th Annual Academic Conference of Mental Disease Specialized Committee of Chinese Academy of Integrative Medicine, vol. 4, 2012. View at: Google Scholar
  42. L. J. Pang, L. Y. Zhu, M. H. Nan et al., “Clinical efficacy of the Tongmai Huazhuo decoction treatment of phlegm and blood stasis each type of angina patients,” Chinese Archives of Traditional Chinese Medicine, vol. 31, no. 9, pp. 1875–1877, 2013. View at: Google Scholar
  43. X. P. Shuang and Z. H. Tan, “Clinical Efficacy of Yiqi Chushi formula in treating myasthenia gravis,” Research of Integrated Traditional Chinese and Western Medicine, vol. 6, no. 2, pp. 61–64, 2014. View at: Google Scholar
  44. J. K. Song, X. F. Xie, Q. M. Tian et al., “A double-blind, single-dummy and randomized controlled research on treatment of herpes simplex keratitis by regulating liver,” China Journal of Chinese Ophthalmology, vol. 26, no. 6, pp. 359–363, 2016. View at: Google Scholar
  45. W. N. Xie, L. P. Huang, Y. Y. Wu et al., “Bushen Jianpi formula combined with lamivudine for chronic hepatitis B (CHB) with YMDD mutation in 36 patients,” Fujian Journal of Traditional Chinese Medicine, vol. 47, no. 4, pp. 13–15, 2016. View at: Google Scholar
  46. Y. A. Ye, “Randomized controlled study of Chinese medicine combined with adefovir digitoxin in treating patients with chronic hepatitis B,” in Proceedings of the 20th National Conference on Integrated Traditional Chinese Medicine and Western Medicine on Liver Diseases, vol. 8, 2011. View at: Google Scholar
  47. B. L. Zhan, L. Zhang, L. Chen et al., “Clinical study of adefovir digitoxin combined with traditional Chinese medicine in treating patients with HBeAg-positive chronic hepatitis B,” Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases, vol. 23, no. 4, pp. 196–198, 2013. View at: Google Scholar
  48. P. J. Zhang and W. X. Zhao, “Clinical study of Integrated Traditional Chinese and Western Medicine in treating 112 patients with ascites induced by cirrhosis,” Journal of Basic and Clinical Medicine, vol. 19, no. 4, pp. 476–477, 481, 2013. View at: Google Scholar
  49. L. Zhao, J. J. Chen, H. M. Nie et al., “Clinical characteristics of HCV genotype in refractory hepatitis C and observation of antiviral efficacy of Qizhu granule,” Journal of Nanjing University of Traditional Chinese Medicine, vol. 30, no. 5, pp. 422–424, 2014. View at: Google Scholar
  50. Y. Xie, H. Ma, B. Feng, and L. Wei, “Efficacy of Real-world Entecavir Therapy in Treatment-naïve Chronic Hepatitis B Patients,” Chinese Medical Journal, vol. 130, no. 18, pp. 2190–2197, 2017. View at: Publisher Site | Google Scholar
  51. Z. Cao, Y. Liu, L. Ma et al., “A potent hepatitis B surface antigen response in subjects with inactive hepatitis B surface antigen carrier treated with pegylated-interferon alpha,” Hepatology, vol. 66, no. 4, pp. 1058–1066, 2017. View at: Publisher Site | Google Scholar
  52. A. Abdel-Moneim, A. Aboud, M. Abdel-Gabbar, M. Zanaty, and M. Ramadan, “Retreatment efficacy of sofosbuvir/ombitasvir/paritaprevir/ritonavir + ribavirin for hepatitis C virus genotype 4 patients,” Digestive Diseases and Sciences, vol. 63, no. 5, pp. 1341–1347, 2018. View at: Publisher Site | Google Scholar

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