Acupuncture for chronic hepatitis B

De Zhao Kong; Ning Liang; Guan Lin Yang; Zhe Zhang; Yue Liu; Ye Yang; Yu Xi Liu; Qi Ge Wang; Fan Zhang; Hui Yong Zhang; Dimitrinka Nikolova; Janus C Jakobsen; Christian Gluud; Jian Ping Liu

doi:10.1002/14651858.CD013107.pub2

. 2019 Aug 22;2019(8):CD013107. doi: 10.1002/14651858.CD013107.pub2

Acupuncture for chronic hepatitis B

De Zhao Kong ^1,^2,^3,⁴, Ning Liang ^4,⁵, Guan Lin Yang ¹, Zhe Zhang ⁶, Yue Liu ³, Ye Yang ¹, Yu Xi Liu ¹, Qi Ge Wang ¹, Fan Zhang ⁶, Hui Yong Zhang ⁶, Dimitrinka Nikolova ⁴, Janus C Jakobsen ^4,⁷, Christian Gluud ⁴, Jian Ping Liu ^5,^✉

Editor: Cochrane Hepato‐Biliary Group

PMCID: PMC6705348 PMID: 31436846

Abstract

Background

Chronic hepatitis B is a liver disease associated with high morbidity and mortality. Chronic hepatitis B requires long‐term management aiming to reduce the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, as well as to improve health‐related quality of life. Acupuncture is being used to decrease discomfort and improve immune function in people with chronic hepatitis B. However, the benefits and harms of acupuncture still need to be established in a rigorous way.

Objectives

To assess the benefits and harms of acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B.

Search methods

We undertook electronic searches of the Cochrane Hepato‐Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index ‐ Science, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), Wanfang Data, and SinoMed to 1 March 2019. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry (ChiCTR) for ongoing or unpublished trials until 1 March 2019.

Selection criteria

We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B as defined by the trialists or according to guidelines. We allowed co‐interventions when the co‐interventions were administered equally to all intervention groups.

Data collection and analysis

Review authors in pairs individually retrieved data from reports and through correspondence with investigators. Primary outcomes were all‐cause mortality, proportion of participants with one or more serious adverse events, and health‐related quality of life. Secondary outcomes were hepatitis B‐related mortality, hepatitis B‐related morbidity, and adverse events considered not to be serious. We presented the pooled results as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed the risks of bias using risk of bias domains with predefined definitions. We put more weight on the estimate closest to zero effect when results with fixed‐effect and random‐effects models differed. We evaluated the certainty of evidence using GRADE.

Main results

We included eight randomised clinical trials with 555 randomised participants. All included trials compared acupuncture versus no intervention. These trials assessed heterogeneous acupuncture interventions. All trials used heterogeneous co‐interventions applied equally in the compared groups. Seven trials included participants with chronic hepatitis B, and one trial included participants with chronic hepatitis B with comorbid tuberculosis. All trials were assessed at overall high risk of bias, and the certainty of evidence for all outcomes was very low due to high risk of bias for each outcome, imprecision of results (the confidence intervals were wide), and publication bias (small sample size of the trials, and all trials were conducted in China). Additionally, 79 trials lacked the necessary methodological information to ensure their inclusion in our review.

None of the included trials aim to assess all‐cause mortality, serious adverse events, health‐related quality of life, hepatitis B‐related mortality, and hepatitis B‐related morbidity. We are uncertain whether acupuncture, compared with no intervention, has an effect regarding adverse events considered not to be serious (RR 0.67, 95% CI 0.43 to 1.06; I² = 0%; 3 trials; 203 participants; very low‐certainty evidence) or detectable hepatitis B e‐antigen (HBeAg) (RR 0.64, 95% CI 0.11 to 3.68; I² = 98%; 2 trials; 158 participants; very low‐certainty evidence). Acupuncture showed a reduction in detectable hepatitis B virus (HBV) DNA (a non‐validated surrogate outcome; RR 0.45, 95% CI 0.27 to 0.74; 1 trial, 58 participants; very low‐certainty evidence). We are uncertain whether acupuncture has an effect regarding the remaining separately reported adverse events considered not to be serious.

Three of the eight included trials received academic funding from government or hospital. None of the remaining five trials reported information on funding.

Authors' conclusions

The clinical effects of acupuncture for chronic hepatitis B remain unknown. The included trials lacked data on all‐cause mortality, health‐related quality of life, serious adverse events, hepatitis‐B related mortality, and hepatitis‐B related morbidity. The vast number of excluded trials lacked clear descriptions of their design and conduct. Whether acupuncture influences adverse events considered not to be serious is uncertain. It remains unclear if acupuncture affects HBeAg, and if it is associated with reduction in detectable HBV DNA. Based on available data from only one or two small trials on adverse events considered not to be serious and on the surrogate outcomes HBeAg and HBV DNA, the certainty of evidence is very low. In view of the wide usage of acupuncture, any conclusion that one might try to draw in the future should be based on data on patient and clinically relevant outcomes, assessed in large, high‐quality randomised sham‐controlled trials with homogeneous groups of participants and transparent funding.

Plain language summary

Acupuncture for chronic hepatitis B

Review question  To assess the benefits and harms of acupuncture versus no intervention or sham acupuncture (not real acupuncture) in people with chronic hepatitis B.

Background  Chronic hepatitis B infection has a substantial economic, psychological, and life impact on people with chronic hepatitis B and their families. Acupuncture has been used in treating people with chronic hepatitis B, as it is believed that it decreases discomfort and improves immune function in people with this disease. However, the benefits and harms of acupuncture have never been established in systematic reviews in a rigorous way.

Search date  The review includes trials published by 1 March 2019.

Study characteristics  We included eight randomised clinical trials with 555 participants. All trials compared acupuncture versus no intervention. Seven trials included participants with chronic hepatitis B. One trial included chronic hepatitis B participants with tuberculosis and ascites. These trials assessed heterogeneous acupuncture interventions (i.e. manual needle acupuncture, acupoint herbal patching, acupoint injection, and moxibustion). Acupoint is a specifically chosen site for acupuncture manipulation. All trials used heterogeneous co‐interventions applied equally in the compared groups.

Study funding sources  Three of the eight included randomised clinical trials received academic funding. None of the remaining five trials reported information on support or funding.

Key results

None of the eight included trials reported data on clinically important outcomes such as all‐cause mortality, serious adverse events, health‐related quality of life, hepatitis B‐related mortality, or hepatitis B‐related morbidity. We are uncertain whether acupuncture compared with no intervention has a beneficial or harmful effect regarding adverse events considered not to be serious. Acupuncture compared with no intervention seems to reduce the proportion of people with detectable hepatitis B virus (HBV) DNA (a non‐validated surrogate outcome; only one trial). We are uncertain whether acupuncture compared with no intervention has an effect on the proportion of people with detectable HBeAg (a non‐validated surrogate outcome; only two trials). Caution is needed in interpreting these findings as data are provided by only one or a few trials at high risk of bias, and these surrogate outcomes have not yet been proven relevant for people with chronic hepatitis B. We are uncertain whether acupuncture compared with no intervention has an effect on the remaining separately reported adverse events considered not to be serious. We could not use data from 79 other studies, of possible interest to our review, because study authors provided highly insufficient information on their study design and methods. Accordingly, we need more information from randomised clinical trials before benefits or harms of acupuncture for chronic hepatitis B can be determined.

Certainty of the evidence

Certainty of evidence means 'the extent of one's confidence that review results are correct in supporting or rejecting a finding'. The certainty of evidence on the use of acupuncture in people with chronic hepatitis B virus infection in terms of its beneficial or harmful effects on death, health‐related quality of life, risk of dying due to HBV infection, and serious adverse events cannot be determined, as data on these outcomes were lacking. The certainty of evidence on acupuncture, when compared with no intervention, in terms of adverse events considered not to be serious, the proportion of people with detectable HBV DNA, and the proportion of people with detectable HBeAg, is very low. Whether the last two outcomes are relevant to the well‐being of people with chronic hepatitis B is still not scientifically proven. The very low certainty of the evidence is due to insufficient data ensuing from one, two, or very few trials with insufficient reporting.

Summary of findings

Summary of findings for the main comparison. Acupuncture compared with no intervention for chronic hepatitis B.

Acupuncture compared with no intervention for chronic hepatitis B
Patient or population: chronic hepatitis B  Setting: outpatients or hospitalised patients  Intervention: acupuncture  Comparison: no intervention
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with no intervention	Risk with acupuncture
All‐cause mortality	No data
Proportion of participants with 1 or more serious adverse events	No data
Health‐related quality of life	No data
Hepatitis B‐related mortality	No data
Hepatitis B‐related morbidity	No data
Proportion of participants with 1 or more adverse events considered to be 'not serious' (at maximum follow‐up: 2 to 6 months; median: 3 months)	Study population		RR 0.67  (0.43 to 1.06)	203  (3 RCTs)	⊕⊝⊝⊝  VERY LOW^a,b,c	2) The optimal information size criteria are not met and the sample is not very large (fewer than 4000 participants)
	330 per 1000	221 per 1000  (142 to 350)
Exploratory outcomes: Proportion of participants with detectable HBV DNA (at maximum follow‐up: 6 months) Proportion of participants with detectable HBeAg (at maximum follow‐up: 3 to 6 months; median 4.5 months)	Study population
	821 per 1000	370 per 1000  (222 to 608)	RR 0.45  (0.27 to 0.74)	58  (1 RCT)	⊕⊝⊝⊝  VERY LOW^a,b,c	2) The optimal information size criteria are not met and the sample is not very large (fewer than 4000 participants)
	Study population
	923 per 1000	591 per 1000  (102 to 1000)	RR 0.64  (0.11 to 3.68)	158  (2 RCTs)	⊕⊝⊝⊝  VERY LOW^a,b,c	2) The number of events was less than 300 and the CI overlaps no effect and fails to exclude important benefit (RR < 0.75) and important harm (RR > 1.25)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; HBV: hepatitis B virus; HBeAg: hepatitis B virus e‐antigen; RCT: randomised clinical trial; RR: risk ratio.
GRADE Working Group grades of evidence.  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.  Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

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^aDowngraded by one level for risk of bias because of some concerns with allocation concealment, blinding, and selective outcome reporting.  ^bDowngraded by two levels (for the proportion of participants with detectable HBeAg) or one level (for the proportion of participants with one or more adverse events considered not to be serious outcomes and the proportion of participants with detectable HBV DNA) because of imprecision of the result.  ^cDowngraded by one level because of publication bias: all included studies were small.

Background

Description of the condition

Hepatitis B is caused by the hepatitis B virus (HBV), a DNA virus enveloped by an icosahedral capsid replicated via reverse transcription (Bruss 2004). HBV belongs to the family of Hepadnaviridae and is commonly classified into 10 genotypes (A through J) (Sunbul 2014; Tong 2016). This virus is commonly spread through blood, body fluids, mother‐to‐child transmission, or sexual contact, or is induced unintentionally through medical procedures (WHO 2017). Approximately 257 million people around the world, or 3.5% of the world's population, are infected by HBV (Ott 2012; Schweitzer 2015; WHO 2017). The African and Western Pacific regions account for 68% of those infected (WHO 2017). In 2006, about 93 million people in China were carriers of HBV, accounting for 8% to 10% of the total population in China (Qi 2011). Mother‐to‐child transmission still accounts for the majority of HBV infection worldwide (Nelson 2016), and the risk of developing chronic hepatitis B infection is highest among children (Nelson 2016; WHO 2017). Annually, 650,000 people die, most often from complications of hepatitis B, including cirrhosis and hepatocellular carcinoma (WHO 2017). People with hepatitis B infection may have co‐infections, including HIV and other hepatitis viruses (hepatitis C and D) (Mallet 2017), and these co‐infections may increase the risk of all‐cause mortality (Puoti 2000; Mallet 2017). Chronic HBV infection imposes substantial economic and psychological lifelong burdens on people with this chronic infection, as well as on their families (Alizadeh 2008; Lu 2013; Keshavarz 2015; Ezbarami 2017).

The initial evaluation of people with chronic HBV infection includes a thorough history, physical examination, assessment of liver disease activity and severity (e.g. liver biopsy, abdominal hepatic ultrasound, alanine transaminase assessments), and markers of HBV infection (e.g. HBV DNA and hepatitis B e‐antigen (HBeAg)) (AASLD 2016; EASL 2017). According to guidelines (AASLD 2016; EASL 2017), chronic hepatitis B is defined as HBV surface antigen (HBsAg) positivity for longer than six months, serum HBV DNA positivity greater than 2000 IU/mL (i.e. 10⁴ copies/mL), persistent or intermittent elevation in levels of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), and liver biopsy findings showing chronic HBV with moderate or severe necroinflammation. Hence, an immunological cure has been defined as HBeAg loss and sustained HBV DNA suppression, and a virological cure may be defined as eradication of the virus, including the cccDNA form, from the blood (EASL 2017). Reducing mortality and hepatitis B‐related morbidities, such as liver cirrhosis, liver failure, and liver cancer, prolonging survival, and improving quality of life are long‐term treatment aims (WHO 2015; EASL 2017).

Description of the intervention

Acupuncture, described as an organised system of interventions, was first documented in The Yellow Emperor's Classic of Internal Medicine, which dates back to 100 B.C. (YECIM 100BC). In ancient times, acupuncture was used to treat people with symptoms such as loss of appetite, nausea, and mild right upper quadrant discomfort. These symptoms are similar to the symptoms that characterise chronic hepatitis B. Nowadays, acupuncture, including manual needle acupuncture, electroacupuncture, laser acupuncture, acupressure, acupoint injection therapy, moxibustion, and acupoint herbal patching, is used most often in China, Korea, and Japan (Robinson 2000; Woo 2014); USA (Ying 2010a); UK (Hopton 2012); and Australia (Zheng 2014). Acupuncture for chronic hepatitis B is included in the Chinese medical system (Robinson 2000; Kong 2005; Lu 2010; Han 2011; He 2012; Ding 2013; Wang 2014a; Gao 2016). Westernised medical application of acupuncture involves mainly the usage of trigger points, segmental points, and formula points (Peter 2005; Biersack 2007).

Strict sterilisation of acupuncture needles or disposable acupuncture needles must be used in acupuncture practice to avoid infection caused by inadequate sterilisation of reusable acupuncture needles, lack of local official monitoring of acupuncture practice, and lack of a clear understanding of blood‐borne disease (Sulaiman 1995; Reynolds 2008; Cheng 2015). Other adverse events such as pneumothorax, injury to the central nervous system, infection, drowsiness (severe enough to cause a traffic hazard), and localised argyrosis have been reported as likely to be associated with acupuncture (Yamashita 2001; White 2004b). Although the risk of serious adverse events with acupuncture seems to be uncommon in standard practice (estimated as 0.55 per 10,000 individual patients; Yamashita 2001; White 2004b), training acupuncturists as well as developing further non‐physical invasive acupuncture methods is important.

How the intervention might work

Traditional Chinese medicine theory describes health as a state maintained by a balance of energy within the body (Longhurst 2010; Lin 2014). Energy circulation may become abnormal when organs or physiological systems act excessively or deficiently. Classical acupuncture is based on the theory of stimulating energy pathways through specific points (acupoints) to rebalance 'qi' (vital) within body and organ systems, to adjust blood circulation, and to influence physiological system function (Longhurst 2010; Yang 2011; Wang 2013a). Stimulation could be induced by needle, heat, drugs, laser, or electricity. Each acupoint may have its own specific therapeutic functions (Longhurst 2010; Yang 2011; Wang 2013a). Acupuncture as prescribed for different diseases mainly varies in terms of acupoints and manipulation approaches (Longhurst 2010; Yang 2011). Commonly used acupoints for chronic hepatitis B are Zusanli (Leg Three Miles, ST 36), Sanyinjiao (Three Yin Intersection, SP 6), Taichong (Supreme Rushing, Liv‐3), Ganshu (Liver Transporter, B1‐18), Neiguan (Inner Pass, Pc 6), Yanglingquan (Yang Mound Spring, GB 34), Jimen (Cyclic Gate, Liv‐14), Pishu (Spleen Transporter, B1‐20), and Shenshu (Kidney Transporter, Bi‐23) (Kong 2005; Han 2011; He 2012; Wang 2014a; Gao 2016). Acupuncture is widely used in clinical practice to relieve symptoms (Zhang 2005; Jin 2011; Lu 2011; Shao 2011; Chen 2013), as well as to improve immune function to slow the progression of chronic hepatitis B (Xu 2008; Xie 2010; Ding 2013). Clinical trials have suggested that acupuncture may improve immune function by increasing blood leukocyte count (Xu 2008; Zhou 2010), along with blood natural killer cell count and activity (Zhao 2010; Cao 2011; Zhang 2011), and by improving erythrocyte immune function (Xie 2010). Clinical trials have also suggested that acupuncture may regulate immune factors by increasing cluster of differentiation 3 (CD3) level, cluster of differentiation 4 (CD4) level, and the ratio of T helper cells to cytotoxic T cells (CD4+/CD8+) in serum (Lu 2010; Ding 2013), or by reducing tumour necrosis factor alpha (TNF‐α) and interleukin 1 beta (IL‐1β) in serum (He 2011).

Why it is important to do this review

We have identified two meta‐analyses on this topic (Wang 2015; Wu 2017), as well as several randomised clinical trials (Kong 2005; Han 2011; He 2012; Chen 2014; Wang 2014a; Gao 2016). The Wang 2015 meta‐analysis has shown that acupoint injection versus non‐acupoint injection might decrease transaminase levels in serum, but these authors drew attention to the high risk of bias of the included randomised clinical trials. The Wu 2017 meta‐analysis has shown that moxibustion might improve normalisation of transaminases and total bilirubin; however, these authors included only nine small randomised clinical trials, which they assessed at low methodological quality by using the Jadad scoring system (Jadad 1996). The listed randomised clinical trials and the two meta‐analyses focused primarily on assessing the effects of acupuncture on surrogate outcomes, rather than on clinically important patient‐centred outcomes, such as hepatitis B‐related mortality and morbidity and health‐related quality of life. It becomes questionable whether the surrogate outcomes assessed by these trial investigators would lead to improvement in clinically important outcomes, as validation of any clinically important outcomes should be carried out in randomised clinical trials (Gluud 2007; Flemming 2012; Ciani 2017; Jakobsen 2017; Kemp 2017; Jakobsen 2018). Therefore, we find our attempt to meta‐analyse available data on benefits and harms of acupuncture for chronic hepatitis B, in terms of patient‐centred outcomes, of high importance. The current review sought to assess the benefits and harms of acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B.

Objectives

To assess the benefits and harms of acupuncture versus no intervention or sham acupuncture in people with chronic hepatitis B.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials irrespective of blinding, language, year, publication format, or publication status.

Types of participants

Inclusion criteria

Trial participants of any sex and age, diagnosed with chronic hepatitis B, as defined according to the trialists or according to guidelines (see Description of the condition; AASLD 2016; EASL 2017). In addition to chronic hepatitis B, trial participants could have had cirrhosis, hepatocellular carcinoma, concomitant HIV or AIDS, hepatitis C, hepatitis D, or any other concomitant disease.

Exclusion criteria

No exclusion criteria were applied.

Types of interventions

Experimental intervention

Acupuncture

Acupuncture, performed via any of the techniques below, regardless of the style used by the acupuncturist (e.g. traditional Chinese medicine; Japanese, Korean, Western medical) or the treatment regimens provided (e.g. numbers and names of acupoints, depth of insertion, stimulation retention time, times in a day).

- Manual needle acupuncture: thin needles are inserted at a specific location of the body, known as 'acupoints'. Needling is usually performed perpendicularly or with a tilt of 15 to 45 degrees to a depth of 0.5 to 1 inch, accompanied with or without needle flicking or rotation. Needle retention is commonly allowed from 20 to 30 minutes after insertion of the last one. Manual needle acupuncture is usually administered once or twice a day (Wang 2012; Bardy 2015).
- Electroacupuncture: the inserted needles are attached to an electric needle instrument (e.g. G6850‐type) that generates continuous electric pulses with small clips to adjust impulse frequency and intensity. Usually, stimulation lasts for 20 to 30 minutes under a continuous wave (e.g. 2 Hz) (NGC 2016; Xu 2018).
- Laser acupuncture: this technique allows low‐level lasers to stimulate energy and blood circulation within the body. Continuous laser light at a set wavelength (e.g. 685 nm) is used as painless laser needles. Output power may vary from 20 mW to 90 mW per laser needle, and stimulation time may usually last 10 to 40 minutes (Litscher 2007; Jiang 2017).
- Acupressure: acupressure uses a similar principle to acupuncture. Commonly, it is performed by physical pressure, which can be applied by hand, elbow, or other devices to acupoints and may last from 3 to 20 minutes, once to twice daily (Yazdanpanahi 2017; Ahmedov 2018).
- Acupoint injection: a development of acupuncture, this treatment injects drugs into acupoints. Acupoint injection is usually implemented with antiviral injections (e.g. peginterferon alfa‐2b 180 μg once a week) (Liang 2011; Lee 2012; Zhang 2012; Jing 2016), or through traditional Chinese medicine injections (e.g. Xiang Dan injection 4 mL once daily) (Zhang 2005; Li 2008; Zhang 2015).
- Moxibustion: this technique burns or places dry herb moxa (Folium Artemisia argy or mugwort) or another mixture of herbs or therapeutic materials directly or indirectly on acupoints of the body. For indirect moxibustion, an approximate 2‐cm‐long moxa stick is burned at 1 to 2 cm above the skin of the acupoint. A local warm feeling should be obtained (Wang 2017; Kuge 2018). For direct moxibustion, moxa cones are burned directly on the acupoints (Yun 2016; Schlaeger 2018).
- Acupoint herbal patching: through herbal decoction made into a paste, or grinded herbal powders mixed with water, vinegar, wine, egg white, honey, and vegetable oil, or with solidified oil (e.g. vaseline) or with yellow vinegar into a paste, or ointment, or a small pie, acupoint herbal patching directly covers the acupoint or affected area (Ashi points) from three hours to 24 hours, once daily (Zhang 1990; Hsu 2010; Lee 2016).

Control intervention

No intervention or sham acupuncture

We allowed co‐interventions in both experimental and control intervention groups only if the co‐intervention was administered equally to all intervention groups.

Types of outcome measures

Primary outcomes

All‐cause mortality
Proportion of participants with one or more serious adverse events, that is, any untoward medical occurrences that result in death, are life‐threatening, require hospitalisation or prolongation of existing hospitalisation, result in persistent or significant disability or incapacity, or present as a congenital anomaly or birth defect (ICH‐E2A 1994; ICH‐GCP E6(R2) 2016)
Health‐related quality of life: any scale used by trialists to assess participants' reporting of their quality of life

Secondary outcomes

Hepatitis B‐related mortality
Hepatitis B‐related morbidity (proportion of participants with one or more of the following events: cirrhosis, ascites, variceal bleeding, hepato‐renal syndrome, hepatocellular carcinoma, hepatic encephalopathy, or needed liver transplantation, and who have not died)
Propotion of participants with one or more adverse events considered not to be serious: any untoward medical occurrence in a participant that does not meet the above criteria for a serious adverse event is defined as an adverse event considered not to be serious (ICH‐E2A 1994; ICH‐GCP E6(R2) 2016)

Exploratory outcomes

Proportion of participants with detectable HBV DNA in serum, plasma, or HBV DNA viral load
Proportion of participants with detectable hepatitis B e‐antigen (HBeAg) in serum or plasma
Separately reported serious adverse events
Separately reported hepatitis B‐related morbidity
Separately reported adverse events considered not to be serious

We assessed all outcomes at maximum follow‐up.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Hepato‐Biliary Group Controlled Trials Register (Cochrane Hepato‐Biliary Group Module); the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE Ovid; Embase Ovid; Latin American Caribbean Health Sciences Literature (LILACS; Bireme); Science Citation Index Expanded (Web of Science); and Conference Proceedings Citation Index ‐ Science (Web of Science) (Royle 2003). We also searched four Chinese biomedical databases: China Network Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), Wanfang Data, and SinoMed.

Appendix 1 provides the search strategies used along with expected time spans.

Searching other resources

We searched reference lists of systematic reviews and meta‐analyses on this topic and of the retrieved studies. We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp), ClinicalTrials.gov (www.clinicaltrials.gov/), and the Chinese Clinical Trial Registry (chictr.org.cn), for ongoing or unpublished trials.

Data collection and analysis

We conducted our review in accordance with the recommendations provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), the Cochrane Hepato‐Biliary Group Module, and the Methodological Expectations of Cochrane Intervention Reviews (MECIR) guidelines (MECIR 2018).

We performed analyses using Review Manager 5 (Review Manager 2014), as well as Trial Sequential Analysis version 0.9.5.10 Beta (Thorlund 2011a; TSA 2011).

Selection of studies

Review authors (DZK, GLY, ZZ, YY, YXL, QGW) in pairs independently screened titles and abstracts for inclusion of potentially eligible trials. We listed multiple reports of the same trial under its main reference and ineligible studies with reasons for exclusion in the Characteristics of excluded studies table. We resolved disagreements through discussion, or we asked JPL to arbitrate. We recorded the selection process in a PRISMA flow diagram (PRISMA 2009).

Data extraction and management

Review authors (DZK, YL, FZ, HYZ) in pairs independently extracted data using a prepiloted electronic data collection form created in Microsoft Excel. In case of discrepancies, we rechecked the extracted data. When disagreements persisted, we tried to resolve disagreements through discussion. We contacted JPL to arbitrate if disagreements persisted, before proceeding with analyses.

In pairs we also extracted the following information: publication data (i.e. year, country, study authors); study characteristics and design; characteristics of trial participants; trial inclusion and exclusion criteria; interventions; outcomes; follow‐up; and types of data analyses (i.e. intention‐to‐treat, modified intention‐to‐treat, per‐protocol). We contacted trial authors to request missing information. We extracted data at maximum follow‐up.

Assessment of risk of bias in included studies

Review authors in pairs (DZK, YL, FZ, HYZ) independently assessed risk of bias in the included trials. We assessed risk of bias according to the Cochrane 'Risk of bias' tool (Higgins 2011), the Cochrane Hepato‐Biliary Group Module, and methodological studies (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a; Savović 2012b; Lundh 2017; Savović 2018), using the following definitions within domains.

Allocation sequence generation

Low risk of bias: the study authors performed sequence generation using computer random number generation or a random numbers table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if an independent person not otherwise involved in the study performed them
Unclear risk of bias: the study authors did not specify the method of sequence generation
High risk of bias: the sequence generation method was not random. We planned to include such studies only for assessment of harms

Allocation concealment

Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. A central and independent randomisation unit controlled allocation. The investigators were unaware of the allocation sequence (e.g. whether the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes)
Unclear risk of bias: the study authors did not describe the method used to conceal the allocation, so the intervention allocations may have been foreseen before, or during, enrolment
High risk of bias: it is likely that investigators who assigned the participants knew the allocation sequence. We planned to include such studies only for assessment of harms

Blinding of participants and personnel

Low risk of bias: either of the following: blinding of participants and key study personnel ensured, and it was unlikely that the blinding could have been broken; or rarely, no blinding or incomplete blinding, but the review authors judged that the outcome was not likely to be influenced by lack of blinding, such as mortality
Unclear risk of bias: either of the following: insufficient information to permit judgement of 'low risk' or 'high risk'; or the study did not address this outcome
High risk of bias: either of the following: no blinding or incomplete blinding, and the outcome was likely to be influenced by lack of blinding; or blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome was likely to be influenced by lack of blinding.

Blinding of outcome assessment

Low risk of bias: either of the following: blinding of outcome assessment ensured, and unlikely that the blinding could have been broken; or rarely, no blinding of outcome assessment, but the review authors judged that the outcome measurement was not likely to be influenced by lack of blinding such as mortality
Unclear risk of bias: either of the following: insufficient information to permit judgement of 'low risk' or 'high risk'; or the study did not address this outcome
High risk of bias: either of the following: no blinding of outcome assessment, and the outcome measurement was likely to be influenced by lack of blinding; or blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement was likely to be influenced by lack of blinding

Incomplete outcome data

Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. The study used sufficient methods, such as multiple imputation, to handle missing data
Unclear risk of bias: information was insufficient for assessment of whether missing data in combination with the method used to handle missing data were likely to induce bias on the results
High risk of bias: the results were likely to be biased due to missing data

Selective outcome reporting

Low risk of bias: the trial reported the following predefined outcomes: all‐cause mortality; serious adverse events; and health‐related quality of life outcomes. If the original trial protocol was available, the outcomes should be those called for in that protocol. If the trial protocol was obtained from a trial registry (e.g. www.clinicaltrials.gov), the outcomes sought were those enumerated in the original protocol if the trial protocol was registered before or at the time that the trial was begun. If the trial protocol was registered after the trial was begun, those outcomes were not considered to be reliable
Unclear risk of bias: not all predefined outcomes were reported fully, or it was unclear whether or not data on these outcomes were recorded
High risk of bias: one or more predefined outcomes were not reported

Other bias

Low risk of bias: the study appeared to be free of other factors that could put it at risk of bias
Unclear risk of bias: the study may or may not have been free of other factors that could put it at risk of bias
High risk of bias: other factors in the study could put it at risk of bias

Overall risk of bias

Low risk of bias: we planned to classify the outcome result at overall 'low risk of bias' only if we could classify all of the bias sources described in the above paragraphs at 'low risk of bias'
High risk of bias: we planned to classify the outcome result at 'high risk of bias' if we could classify any of the risk of bias sources described above at 'unclear risk of bias' or 'high risk of bias'

We tried to reach consensus through discussion. We planned that JPL would arbitrate in cases of disagreement.

Measures of treatment effect

We used the risk ratio (RR) for measuring dichotomous outcomes, and we intended to use the mean difference (MD) for continuous data, with 95% confidence intervals (CIs) for head‐to‐head comparison meta‐analysis. If different instruments were used to measure the same continuous outcome, we planned to calculate the standardised mean difference (SMD), with 95% CI.

Unit of analysis issues

We followed the guidelines set forth in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

The unit of analysis was participants randomised to the trial intervention groups. For trials with multiple intervention groups, we intended to include the groups in which our experimental and control interventions were compared. We intended to divide the control group into two to avoid double‐counting in case this was a common comparator.

For cluster‐randomised trials, we intended to directly extract from the analysis data that properly account for the cluster design. We intended to determine the inflated standard errors that account for clustering if there was no control of the clustering. We intended to use the inverse‐variance method in Review Manager 5 (Higgins 2011; Review Manager 2014).

For cross‐over trials, we intended to extract only data from the first period to avoid residual treatment effects (Higgins 2011).

Dealing with missing data

We attempted to contact trial authors to request missing data or clarification of unclearly presented information.

We performed our analysis using the intention‐to‐treat method whenever possible. If this was not possible, we used the data that were available to us. We planned to include participants with incomplete or missing data, for all outcomes, in sensitivity analyses by imputing them as follows.

For dichotomous outcomes.

- Best‐worst‐case scenario: we planned to assume that all participants lost to follow‐up in the experimental group had survived, had improvement in clinical symptoms, had no serious adverse event, and had no morbidity (for all dichotomous variables); and that all participants lost to follow‐up in the control group had not survived, had no improvement in clinical symptoms, had a serious adverse event, and had morbidities (for all dichotomous variables).
- Worst‐best‐case scenario: we planned to assume that all participants lost to follow‐up in the experimental group had not survived, had no improvement in clinical symptoms, had a serious adverse event, and had morbidities (for all dichotomous variables); and that all participants lost to follow‐up in the control group had survived, had improvement in clinical symptoms, had no serious adverse event, and had no morbidity (for all dichotomous variables).

For continuous outcomes.

- We planned to base the 'beneficial' outcome for the group mean plus 2 standard deviations (SDs), or 1 SD, and the 'harmful' outcome for the group mean minus 2 SDs, or 1 SD (Jakobsen 2014).

We intended to request the information from trial authors or to calculate SDs using data from the trial, if not reported.

Assessment of heterogeneity

We assessed clinical and methodological heterogeneity by carefully examining trial participant characteristics and the design of included trials. We assessed the presence of clinical heterogeneity by comparing effect estimates in trial reports in terms of participants with different diagnostic criteria, participants diagnosed with only chronic hepatitis B, and participants diagnosed with concomitant diseases; participants with acupuncture response and participants with no acupuncture response; acupuncture approaches; different duration of the intervention; co‐interventions and different control interventions; and follow‐up (please see Subgroup analysis and investigation of heterogeneity). Different study designs and risk of bias can contribute to methodological heterogeneity. We assessed statistical heterogeneity by comparing the results of the fixed‐effect model meta‐analysis and the random‐effects model meta‐analysis. We primarily used visual inspection of forest plots to look for signs of statistical heterogeneity. We also used the Chi² test with significance threshold set at P < 0.10 and measured the amount of heterogeneity using the I² statistic to assess to what extent heterogeneity was present (Higgins 2002; Higgins 2003; Higgins 2011). We interpreted I² as suggested in Higgins 2011: 0% to 40%: might not be important; 30% to 60%: might represent moderate heterogeneity; 50% to 90%: might represent substantial heterogeneity; 75% to 100%: considerable heterogeneity.

For the heterogeneity adjustment of the diversity‐adjusted required information size (DARIS) in the Trial Sequential Analysis, we used diversity (D²) because the I² statistics used for this purpose might underestimate the required information size (Wetterslev 2009).

Assessment of reporting biases

We planned to assess reporting bias using funnel plots, provided that we had obtained data from at least 10 trials per comparison. To assess risk of bias, we intended to look for symmetry or asymmetry of each funnel plot. For dichotomous outcomes, we intended to assess asymmetry using the Harbord test (Harbord 2006). For continuous outcomes, we intended to apply the regression asymmetry test (Egger 1997).

Data synthesis

Meta‐analysis

We performed the analyses according to the instructions provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), as well as the Cochrane Hepato‐Biliary Group Module. We analysed data using Review Manager 5 (Review Manager 2014).

We assessed our intervention effects via both fixed‐effect and random‐effects model meta‐analyses, and we reported results of both when results differed (e.g. one giving a significant intervention effect, the other no significant intervention effect). We put greater weight on the estimate closest to the zero effect (the highest P value) (Jakobsen 2014).

We assessed three primary outcomes with P ≤ 0.025 as significant, and three secondary outcomes with P ≤ 0.025 as significant to secure a family‐wise error rate below 0.05 (Jakobsen 2014). For exploratory outcomes, we considered P < 0.05 as significant because we view these outcomes as only hypothesis‐generating outcomes. Whether we presented our data synthesis as a meta‐analysis or in a narrative way depended on our assessment of the statistical and clinical heterogeneity of the meta‐analysed trial data per comparison.

We did not impute any missing data in our primary analysis; however, we planned to impute missing values in our sensitivity analysis of continuous and dichotomous data (see Sensitivity analysis; Jakobsen 2014).

We planned to use Fisher's exact test for dichotomous data (Fisher 1922), as well as Student's t‐test for continuous data when data from only one trial were available (Student 1908).

Trial Sequential Analysis

As cumulative meta‐analysis involves risk of producing random errors due to sparse data and repetitive testing, we performed Trial Sequential Analysis. To control random errors, we calculated the required information size (i.e. the number of participants needed in a meta‐analysis to detect or reject a certain intervention effect) (Wetterslev 2008; Thorlund 2011a; TSA 2011). The required information size calculation should also account for the diversity present in the meta‐analysis (Wetterslev 2008; Wetterslev 2009; Wetterslev 2017). A more detailed description of Trial Sequential Analysis can be found at www.ctu.dk/tsa (Thorlund 2011a; TSA 2011).

We controlled the risks of type I errors and type II errors for both dichotomous and continuous outcomes (Brok 2008; Wetterslev 2008; Brok 2009; Wetterslev 2009; Thorlund 2010; Castellini 2017; Wetterslev 2017). For dichotomous outcomes, we estimated the diversity‐adjusted required information size (DARIS) based on the event proportion in the control group, a relative risk reduction of 15%, an alpha of 2.5% for primary and secondary outcomes and 5.0% for exploratory outcomes, a beta of 10% (Castellini 2017), and diversity suggested by the trials in the meta‐analysis (Wetterslev 2009; Jakobsen 2014). We intended to include participants with different severity of chronic hepatitis B, but it happened that no participants in the control group died. Therefore, we conducted three post‐hoc Trial Sequential Analyses based on assumed proportions of participants dying being low (4%; young participants with mild disease), moderate (20%; middle‐aged participants with mild disease), and high (40%, middle‐aged participants with severe disease) within one year in the control group. For continuous outcomes, we intended to estimate the DARIS based on the SD observed in the control group, a minimal relevant difference of 50% of this SD, an alpha of 2.5%, a beta of 10% (Castellini 2017), and diversity suggested by the trials in the meta‐analysis (Wetterslev 2009; Jakobsen 2014).

We tested statistical significance using trial sequential monitoring boundaries for benefit and harm, along with futility using futility boundaries (Thorlund 2011a). If the Z‐curve crosses the trial sequential monitory boundaries for benefit or harm before reaching DARIS, the effect of the intervention is considered superior or inferior to that of the control intervention. If the Z‐curve crosses the futility monitoring boundaries before reaching the DARIS, this would mean that the intervention does not possess the postulated effect, and further randomised trials might be futile. Furthermore, if the trial sequential monitoring boundaries are not surpassed, and if the trial monitoring boundaries for futility are not crossed, it is probably necessary to continue conducting trials to detect or reject a certain intervention effect (Wetterslev 2008; Thorlund 2011b). In our cases where the monitoring boundaries were not reached, we also displayed the Trial Sequential Analysis‐adjusted CI.

Subgroup analysis and investigation of heterogeneity

In cases of available data, we planned to perform the following subgroup analyses.

Trials at low risk of bias compared to trials at high risk of bias (in terms of overall risk of bias, blinding of outcome assessment, incomplete outcome data, and selective outcome reporting).
Different control interventions stratified by no intervention or sham acupuncture (data were not available).
Different acupuncture approaches stratified by manual needle acupuncture, electroacupuncture, laser acupuncture, acupressure, acupoint injection therapy, moxibustion, or acupoint herbal patching.
Different duration of the intervention stratified according to the medians observed.
Trials with participants who had acupuncture response (e.g. de qi, muscle twitch response) compared to trials with participants who had no acupuncture response (data were not available).
Participants according to different diagnostic criteria.
Participants diagnosed only with chronic hepatitis B compared to participants diagnosed with concomitant disease (cirrhosis, hepatocellular carcinoma, HIV infection, AIDS, hepatitis C, hepatitis D, or any of these). We analysed each concomitant disease separately.

Sensitivity analysis

In addition to the sensitivity analysis described under Dealing with missing data, we compared our GRADE imprecision assessments versus those conducted via Trial Sequential Analysis (Jakobsen 2014; Castellini 2018; Gartlehner 2019). We deemed the conduct of further sensitivity analyses unnecessary.

Summary of findings

We constructed a 'Summary of findings' table to show our results and confidence in the evidence for Primary outcomes and Secondary outcomes. We displayed information on assumed control group risk, corresponding intervention group risk, relative effect, MD, CI, statistical significance of relative effect, number of participants, and quality of the evidence. We calculated the corresponding risk (and its 95% CI) using the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Using GRADEpro GDT software (community.cochrane.org/help/tools‐and‐software/gradepro‐gdt), we assessed five factors of the evidence referring to limitations in the study design and implementation that suggested the quality of evidence: within‐study risk of bias, indirectness of the evidence (population, intervention, control, outcomes), unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses), imprecision of results, and risk of publication bias (GRADEpro GDT; Balshem 2011; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h; Guyatt 2013a; Guyatt 2013b; Guyatt 2013c; Guyatt 2013d; Mustafa 2013; Guyatt 2017).

We classified the evidence as follows.

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Results

Description of studies

Results of the search

Through our electronic searches, we identified a total of 1840 references (Figure 1). We found four additional references by searching the references of publications retrieved through the searches. After excluding 1651 duplicated or clearly irrelevant references, we read the full text of 199 publications. One hundred ten studies failed to fulfil the inclusion criteria. Seventy‐three studies failed to provide a clear description of the random sequence generation method, and another six studies provided highly insufficient information for review authors to judge whether or not the described studies were randomised clinical trials (Arya 1989; HBAAC 1994; Qian 1994; Manning 2000; Zhao 2004; Yao 2005). We could not obtain missing information from study authors. This is why we created a table listing the 79 studies in need of supplementary information on their design and methods (Appendix 2). We have not included any of these studies in our meta‐analysis. We found two ongoing studies ‐ ChiCTR‐IOR‐17011957; ChiCTR‐IOR‐17011962 ‐ and no unpublished studies.

Study flow diagram: date of last search 1 March 2019.

Included studies

Eight randomised clinical trials fulfilled the inclusion criteria of our review (Wang 2002; Huang 2011; Liao 2011; Zou 2011; Wang 2013; Zhang 2014; Jing 2016; Zhu 2016). Four of these trials provided data for meta‐analyses. The remaining four trials did not study the outcomes of interest of our review, and hence, we used the provided information from these four trials only in a narrative way. All eight trials were conducted in China and were published as full paper articles in Mandarin. The eight trials seem to have been published only once, as we could not come across any other publications describing the same trials. For details on the included trials, see Characteristics of included studies.

Three of the eight trials reported that they were funded through academic projects (Zou 2011; Zhang 2014; Zhu 2016). The remaining five trials provided no information on support or sponsorship.

Characteristics of the studies

Participants

The eight included trials randomised a total of 555 participants diagnosed with chronic hepatitis B (Wang 2002; Huang 2011; Liao 2011; Zou 2011; Wang 2013; Zhang 2014; Jing 2016; Zhu 2016). The number of participants in these trials ranged from 60 to 160. The age of participants ranged between 26 and 43 years. The sex of participants was reported in seven trials, and the ratio of male to female participants was 263:131 (Huang 2011; Liao 2011; Wang 2013; Zhang 2014; Jing 2016; Zhu 2016).

Participants in seven trials were diagnosed with chronic hepatitis B according to diagnostic criteria described in guidelines (Huang 2011; Liao 2011; Zou 2011; Wang 2013; Zhang 2014; Jing 2016; Zhu 2016). The remaining trial did not report on the criteria used to establish the diagnosis of chronic hepatitis B (Wang 2002). In one trial, all 65 participants also had tuberculosis and ascites (Zhu 2016).

Participants with severe chronic hepatitis B were excluded from two trials (Liao 2011; Zou 2011); participants with liver cirrhosis were excluded from two trials (Liao 2011; Jing 2016); participants with other types of hepatitis were excluded from four trials (Liao 2011; Zou 2011; Wang 2013; Jing 2016); participants with co‐infection with other hepatitis virus or human immunodeficiency virus were excluded from six trials (Huang 2011; Liao 2011; Zou 2011; Wang 2013; Zhang 2014; Jing 2016); participants with other diseases such as cardiovascular, cerebrovascular, lung, kidney, endocrine, haematopoietic, and neural disease, as well as retinopathy, psoriasis, depression, or mental illness, were excluded from six trials (Huang 2011; Liao 2011; Wang 2013; Zhang 2014; Jing 2016; Zhu 2016); participants with liver cancer were excluded from three trials (Liao 2011; Wang 2013; Jing 2016); participants with hepatic encephalopathy or gastrointestinal bleeding were excluded from two trials (Liao 2011; Zhu 2016); participants with liver surgery were excluded from two trials (Huang 2011; Zhang 2014); participants with pregnancy or breastfeeding were excluded from two trials (Liao 2011; Jing 2016); participants with alcoholism or drug use were excluded from two trials (Jing 2016; Zhu 2016); participants who were allergic to trial drugs were excluded from three trials (Huang 2011; Liao 2011; Zhang 2014); and participants using antiviral drugs, immunomodulator drugs, or drugs that would influence the trial before enrolment were excluded from five trials (Wang 2002; Huang 2011; Liao 2011; Zhang 2014; Jing 2016).

Interventions and comparisons

All eight trials compared acupuncture plus co‐interventions versus equal co‐interventions. Two trials evaluated manual needle acupuncture (Wang 2002; Zhang 2014). Three trials evaluated acupoint herbal patching (Liao 2011; Zou 2011; Zhu 2016). Two trials evaluated acupoint Astragalus injection (Huang 2011; Jing 2016). One trial evaluated moxibustion (Wang 2013).

The same acupoints for manual needle acupuncture in the included trials were Zu San Li (ST36), San Yin Jiao (SP6), and Tai Chong (LV3) (Wang 2002; Zhang 2014), and the retention time for manual needle acupuncture was one hour (Wang 2002). The same acupoints for herbal patching in the included trials were Ji Men (SP11) and Ri Yue (GB 24) (Liao 2011; Zou 2011), and the retention time for herbal patching ranged from 3 hours to 36 hours, but the herbs used for herbal patching were different among trials. The dosage of Astragalus injection was 5 mL in each side of the acupoint Zu San Li (ST36) in one trial (Jing 2016), and 2 mL in each side of the acupoint Zu San Li (ST36) in the other trial (Huang 2011). The acupoint for moxibustion was umbilicus (Shen Que, CV 8), and the retention time was 30 minutes. Treatment duration ranged from 14 days to 12 months. Follow‐up of trial participants in four trials ranged from 1 month to 12 months after completion of treatment (Wang 2002; Huang 2011; Zou 2011; Zhu 2016), and follow‐up of trial participants in the remaining four trials ended with completion of treatment (Liao 2011; Wang 2013; Zhang 2014; Jing 2016).

Participants in eight trials received co‐interventions such as antiviral drugs, immunomodulatory drugs, antidepressants, and hepatoprotective drugs (reduced glutathione for injection and human albumin in Zhu 2016; interferon in Wang 2002, Huang 2011, and Jing 2016; and diammonium glycyrrhizinate in Liao 2011, Zou 2011, and Zhang 2014). Zhang 2014 used paroxetine for all 70 participants to relieve depressive symptoms.

Outcomes

None of the included randomised clinical trials reported data on mortality, serious adverse events, health‐related quality of life, hepatitis B‐related mortality, or hepatitis B‐related morbidity. Three trials reported adverse events considered to be 'not serious' (Wang 2002; Wang 2013; Zhu 2016); two trials reported the proportion of participants with detectable HBeAg in serum (Wang 2002; Zou 2011); and only one trial reported the proportion of participants with detectable HBV DNA in serum (Wang 2002).

Seven trials also reported other biomarkers such as aspartate transaminase (AST), alanine transaminase (ALT), and total bilirubin (TBIL) (Wang 2002; Liao 2011; Zou 2011; Wang 2013; Zhang 2014; Jing 2016; Zhu 2016). Huang 2011 also reported a composite outcome consisting of multiple surrogate outcomes.

Excluded studies

We excluded 110 studies after reading the full texts of these articles. We explained the reasons for their exclusion in Characteristics of excluded studies. Another 79 studies were listed in Appendix 2 because of insufficient information on study methods.

Risk of bias in included studies

We carried out the risk of bias assessment based on information retrieved from the publications (Figure 2; Figure 3).

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

All eight included trials reported that they used a computer or a random numbers table to generate allocation sequence. Only Liao 2011 reported that investigators had concealed the allocation information in opaque envelopes; we assessed this study as having low risk of selection bias and the remaining trials as having unclear risk of selection bias.

Blinding

None of the included trials reported blinding of participants and/or researchers. We assessed the eight included trials at high risk of performance bias. None of the included trials reported blinding of outcome assessments; therefore, these trials were at unclear risk of detection bias.

Incomplete outcome data

Six of eight trials reported having no missing outcome data and included all participants in data analyses (Liao 2011; Zou 2011; Wang 2013; Zhang 2014; Jing 2016; Zhu 2016). Therefore, we assessed these six trials as having low risk of bias. Huang 2011 excluded one of the 60 trial participants (i.e. only 1.7% proportion of participants), and Wang 2002 excluded two of the 60 trial participants from the analyses (i.e. only 3.3% proportion of participants). Therefore, we classified these two trials as having low risk of bias.

Selective reporting

All included trials may have high risk of reporting bias because of lack of prepublished trial protocols and lack of data on mortality, serious adverse events, and health‐related quality of life outcomes.

Other potential sources of bias

All included randomised clinical trials appeared to be free of other factors that could put them at risk of bias. We classified the included randomised clinical trials at low risk of other biases.

Overall risk of bias

We assessed the included randomised clinical trials as having high risk of bias.

Effects of interventions

See: Table 1

All eight included randomised clinical trials compared the effects of adding acupuncture to co‐interventions versus equally implemented co‐interventions. We could not find any trials comparing acupuncture with sham acupuncture.

Below, in accordance with our protocol (Kong 2018), all outcomes are presented with the random‐effects model meta‐analysis.

Primary outcomes

All‐cause mortality

None of the included trials reported data on all‐cause mortality.

Trial Sequential Analysis

Assuming that the proportion of participants in the control group dying within one year is low (4%), the diversity‐adjusted required information size (DARIS) obtained via Trial Sequential Analysis for all‐cause mortality is 41,599 trial participants. For calculation of DARIS, we used event proportion in the control group 4%, relative risk reduction 15%, alpha 2.5%, power 90%, and diversity 0% (Huang 2011; Jing 2016; Wang 2002; Zhang 2014). By looking at the accrued information size (247 participants) and the DARIS of 41,599 participants, we calculated the accrued proportion of participants to be 0.59%. We ignored the monitoring boundaries because only 0.59% (247/41599) of the information size was accrued.

Assuming that the proportion of participants in the control group dying within one year is moderate (20%), the DARIS obtained via Trial Sequential Analysis for all‐cause mortality is 7042 trial participants. For calculation of DARIS, we used event proportion in the control group 20%, relative risk reduction 15%, alpha 2.5%, power 90%, and diversity 0% (Liao 2011; Zou 2011). By looking at the accrued information size (160 participants) and the DARIS of 7042 participants, we calculated the accrued proportion of participants to be 2.27%. We ignored the monitoring boundaries because only 2.27% (160/7042) of the information size was accrued.

Assuming that the proportion of participants in the control group dying within one year is high (40%), the DARIS obtained via Trial Sequential Analysis for all‐cause mortality was 2722 trial participants. For calculation of DARIS, we used event proportion in the control group 40%, relative risk reduction 15%, alpha 2.5%, power 90%, and diversity 0% (Wang 2013; Zhu 2016). By looking at the accrued information size (145 participants) and the DARIS of 2722 participants, we calculated the accrued proportion of participants to be 5.32%. We ignored the monitoring boundaries because only 5.32% (145/2722) of the information size was accrued.

Proportion of participants with one or more serious adverse events

None of the included trials reported data on participants with one or more serious adverse events.

Health‐related quality of life

None of the included trials reported data on health‐related quality of life.

Secondary outcomes

Hepatitis B‐related mortality

None of the included trials reported any data on hepatitis B‐related mortality.

Hepatitis B‐related morbidity

None of the included trials reported data on hepatitis B‐related morbidity.

Proportion of participants with one or more adverse events considered not to be serious

Only three trials with 203 randomised participants provided data on the proportion of participants with one or more adverse events considered not to be serious (Wang 2002; Wang 2013; Zhu 2016). We are uncertain whether acupuncture has an effect on the proportion of participants with one or more adverse events considered not to be serious (risk ratio (RR) 0.67, 95% confidence interval (CI) 0.43 to 1.06; P = 0.09; I² = 0%; Analysis 1.1).

1.1 — Comparison 1 Acupuncture versus no intervention, Outcome 1 Proportion of participants with 1 or more adverse events considered not to be serious (overall).

Trial Sequential Analysis

The diversity‐adjusted required information size (DARIS) obtained via Trial Sequential Analysis for the proportion of participants with one or more adverse events considered not to be serious was 4297 trial participants. For calculation of DARIS, we used event proportion in the control group 33%, relative risk reduction 15%, alpha 2.5%, power 90%, and diversity 0%. We ignored the monitoring boundaries because only 4.72% (203/4297) of the information size was accrued (Wang 2002; Wang 2013; Zhu 2016). Thus, the Trial Sequential Analysis found insufficient evidence to support or refute the effects of a 15% risk reduction in acupuncture on the proportion of participants with one or more adverse events considered not to be serious.

Subgroup analysis

We could not perform all prespecified subgroup analyses because information data were insufficient (see Subgroup analysis and investigation of heterogeneity).

Comparison trials with manual needle acupuncture, acupoint herbal patching, and moxibustion (test for subgroup differences: Chi² = 1.53, P = 0.47, I² = 0%; Analysis 1.2); comparison trials with treatment duration less than 12 weeks versus treatment duration longer than 12 weeks (test for subgroup differences: Chi² = 0.06, P = 0.81, I² = 0%; Analysis 1.3); comparison trials in which participants were diagnosed by trialists with chronic hepatitis B versus participants diagnosed according to guidelines (test for subgroup differences: Chi² = 0.06, P = 0.81, I² = 0%; Analysis 1.4); and comparison trials where participants had chronic hepatitis B plus a concomitant disease versus only chronic hepatitis B (test for subgroup differences: Chi² = 0.80, P = 0.37, I² = 0%, Analysis 1.5) revealed no statistically significant subgroup differences.

1.2 — Comparison 1 Acupuncture versus no intervention, Outcome 2 Proportion of participants with 1 or more adverse events considered not to be serious (acupuncture approach).

1.3 — Comparison 1 Acupuncture versus no intervention, Outcome 3 Proportion of participants with 1 or more adverse events considered not to be serious (duration).

1.4 — Comparison 1 Acupuncture versus no intervention, Outcome 4 Proportion of participants with 1 or more adverse events considered not to be serious (diagnosis).

1.5 — Comparison 1 Acupuncture versus no intervention, Outcome 5 Proportion of participants with 1 or more adverse events considered not to be serious (chronic hepatitis B plus a comitant disease and chronic hepatitis B).

Sensitivity analysis

Wang 2002 excluded from the data analysis two participants who had quit the trial because of unrecoverable white blood cell count after two weeks of medication. Both sensitivity analyses ('best‐worst' case scenario analysis: RR 0.65, 95% CI 0.41 to 1.02; P = 0.04; 205 participants; 3 trials; Analysis 1.6; and 'worst‐best' case scenario analysis: RR 0.69, 95% CI 0.44 to 1.1; P = 0.12; 205 participants; 3 trials; Analysis 1.7) showed that the two were excluded from the final analysis, and that participants were unlikely to have influenced the results of our meta‐analysis on the proportion of participants with detectable HBV DNA.

1.6 — Comparison 1 Acupuncture versus no intervention, Outcome 6 Proportion of participants with 1 or more adverse events considered not to be serious in best‐worst case scenario.

1.7 — Comparison 1 Acupuncture versus no intervention, Outcome 7 Proportion of participants with 1 or more adverse events considered not to be serious in worst‐best case scenario.

Our assessments differed when we compared the GRADE assessment of imprecision to that conducted via Trial Sequential Analysis: we downgraded the evidence for imprecision by one level with GRADE because optimal information size criteria were not met, and the sample size was not sufficiently large (fewer than 4000 participants) (Schünemann 2016; GRADE 2013). Trial Sequential Analysis downgraded the evidence by two levels because none of the sequential boundaries for benefit, harm, or futility were crossed (Jakobsen 2014).

Exploratory outcomes

Proportion of participants with detectable HBV DNA

Only one randomised clinical trial with 58 participants provided data on the proportion of participants with detectable HBV DNA (Wang 2002). Acupuncture was associated with a lower proportion of participants with detectable HBV DNA (RR 0.45, 95% CI 0.27 to 0.74; Analysis 1.8).

1.8 — Comparison 1 Acupuncture versus no intervention, Outcome 8 Proportion of participants with detectable HBV DNA (overall).

Trial Sequential Analysis

The Trial Sequential Analysis of the one trial (event proportion in the control group 82.1%, relative risk reduction 15%, alpha 5.0%, power 90%, and diversity 0%) showed that the Z‐curve neither reached the DARIS (506 trial participants) nor crossed the statistical monitoring boundaries for benefit, harm, or futility. The Trial Sequential Analysis found insufficient evidence to support or refute a 15% risk reduction in acupuncture on the proportion of participants with detectable HBV DNA (TSA‐adjusted RR 0.45, 95% CI 0.07 to 2.95; Figure 4).

Subgroup analysis

We could not perform subgroup analyses because only one trial provided data on the proportion of participants with detectable HBV DNA (Wang 2002).

Sensitivity analysis

Wang 2002 excluded from the data analysis two participants who had quit the trial because of unrecoverable white blood cell count after two weeks of medication. Both sensitivity analyses ('best‐worst' case scenario analysis: both sensitivity analyses showed that the two participants excluded from analysis in Wang 2002 did not potentially influence the results of our meta‐analysis on the proportion of participants with detectable HBV DNA; 'best‐worst' case scenario analysis: RR 0.44, 95% CI 0.27 to 0.72; P = 0.001; 60 participants; 1 trial; Analysis 1.9; 'worst‐best' case scenario analysis: RR 0.48, 95% CI 0.29 to 0.80; P = 0.005; 60 participants; 1 trial; Analysis 1.10).

1.9 — Comparison 1 Acupuncture versus no intervention, Outcome 9 Proportion of participants with detectable HBV DNA in best‐worst case scenario.

1.10 — Comparison 1 Acupuncture versus no intervention, Outcome 10 Proportion of participants with detectable HBV DNA in worst‐best case scenario.

Our assessments differed when the GRADE assessment of imprecision was compared to that conducted via Trial Sequential Analysis for the proportion of participants with detectable HBV DNA outcome: we downgraded the evidence for imprecision by one level with GRADE because optimal information size criteria were not met and the sample size was not sufficiently large (fewer than 4000 participants) (GRADE 2013; Schünemann 2016). Trial Sequential Analysis downgraded the evidence by two levels because none of the sequential boundaries for benefit, harm, or futility were crossed (Jakobsen 2014).

Proportion of participants with detectable HBeAg

Two randomised clinical trials with 158 participants provided data on the proportion of participants with detectable HBeAg (Wang 2002; Zou 2011). The fixed‐effect meta‐analysis showed that acupuncture versus no intervention reduced the proportion of participants with detectable HBeAg (RR 0.79, 95% CI 0.69 to 0.91; P = 0.0007; I² = 98%; Analysis 1.9), but the random‐effects meta‐analysis showed no difference between acupuncture versus no intervention on detectable HBeAg (RR 0.64, 95% CI 0.11 to 3.68; P = 0.61; I² = 98%; Analysis 1.12). As previously described, we put greater weight on the estimate closest to zero effect (i.e. RR 0.64, 95% CI 0.11 to 3.68; P = 0.61), which in this case comes from the random‐effects meta‐analysis.

1.12 — Comparison 1 Acupuncture versus no intervention, Outcome 12 Proportion of participants with detectable HBeAg (random‐effects).

Trial Sequential Analysis

The Trial Sequential Analysis of two trials (event proportion in the control group 82.1%, relative risk reduction 15%, alpha 5.0%, power 90%, and diversity 99.85%) calculated the DARIS to be 332,116 trial participants. We ignored the monitoring boundary because only 0.05% (158/332,116) of the information size was accrued. Thus, the Trial Sequential Analysis found insufficient evidence to support or refute a 15% risk reduction in acupuncture on the proportion of participants with detectable HBeAg.

Subgroup analysis

We could not perform all of the prespecified subgroup analyses because information data were insufficient (see Subgroup analysis and investigation of heterogeneity). Comparison trials with manual needle acupuncture versus acupoint herbal patching (test for subgroup differences: Chi² = 10.26, P = 0.001, I² = 90.3%; Analysis 1.13); comparison trials with treatment duration less than 12 weeks versus treatment duration longer than 12 weeks (test for subgroup differences: Chi² = 10.26, P = 0.001, I² = 90.3%; Analysis 1.14); and comparison trials where participants were diagnosed with chronic hepatitis B by trialists versus participants diagnosed according to guidelines (test for subgroup differences: Chi² = 10.26, P = 0.001, I² = 90.3%; Analysis 1.15) revealed no statistically significant subgroup differences. Manual needle acupuncture with treatment duration longer than 12 weeks, performed in participants with chronic hepatitis B (as diagnosed by the trialists), was associated with a lower proportion of participants with detectable HBeAg (RR 0.41, 95% CI 0.24 to 0.69; data from only one trial).

1.13 — Comparison 1 Acupuncture versus no intervention, Outcome 13 Proportion of participants with detectable HBeAg (acupuncture approach).

1.14 — Comparison 1 Acupuncture versus no intervention, Outcome 14 Proportion of participants with detectable HBeAg (duration).

1.15 — Comparison 1 Acupuncture versus no intervention, Outcome 15 Proportion of participants with detectable HBeAg (diagnosis).

Sensitivity analysis

Wang 2002 excluded from the data analysis two participants who had quit the trial because of unrecoverable white blood cell count after two weeks of medication. Both sensitivity analyses ('best‐worst' case scenario analysis: RR 0.63, 95% CI 0.10 to 3.90; P = 0.62; 160 participants; 2 trials; Analysis 1.16; 'worst‐best' case scenario analysis: RR 0.66, 95% CI 0.13 to 3.39; P = 0.62; 160 participants; 2 trials; Analysis 1.17) showed that the two were excluded from the final analysis, and that participants were unlikely to have influenced the results of our meta‐analysis on detectable HBeAg.

1.16 — Comparison 1 Acupuncture versus no intervention, Outcome 16 Proportion of participants with detectable HBeAg in best‐worst case scenario.

1.17 — Comparison 1 Acupuncture versus no intervention, Outcome 17 Proportion of participants with detectable HBeAg in worst‐best case scenario.

Our assessments did not differ when the GRADE assessment of imprecision was compared to that conducted via Trial Sequential Analysis: we downgraded the evidence for imprecision by two levels with GRADE because the number of events was less than 300 and the CI overlaps no effect and fails to exclude important benefit (RR < 0.75) and important harm (RR > 1.25) (GRADE 2013; Schünemann 2016). Trial Sequential Analysis downgraded the evidence also by two levels because none of the sequential boundaries for benefit, harm, or futility were crossed (Jakobsen 2014).

Separately reported adverse events considered not to be serious

In accordance with our protocol, we planned to analyse dichotomous outcome data from one trial using Fisher's exact test. As the results of Fisher's exact test (not shown) did not differ from those obtained via RevMan analysis, and in view of future updates of this review, we present the analysis result obtained with RevMan only.

- Proportion of participants with fatigue: only one trial with 80 participants reported the proportion of participants with fatigue (Wang 2013). We are uncertain whether acupuncture has an effect on the proportion of participants with fatigue (RR 0.67, 95% CI 0.12 to 3.78; Analysis 1.18).
- Proportion of participants with bloating: only one trial with 80 participants reported the proportion of participants with bloating (Wang 2013). The meta‐analysis showed that acupuncture was associated with a higher proportion of participants with bloating (RR 4.50, 95% CI 1.04 to 19.54; Analysis 1.19).
- Proportion of participants with loss of appetite: only one trial with 80 participants reported the proportion of participants with loss of appetite (Wang 2013). We are uncertain whether acupuncture has an effect on the proportion of participants with loss of appetite (RR 0.60, 95% CI 0.15 to 2.34; Analysis 1.20).
- Proportion of participants with flank pain: only one trial with 80 participants reported the proportion of participants with flank pain (Wang 2013). We are uncertain whether acupuncture has an effect on the proportion of participants with flank pain (RR 0.67, 95% CI 0.26 to 1.70; Analysis 1.21).
- Proportion of participants with bradycardia: only one trial with 58 participants reported the proportion of participants with bradycardia (Wang 2002). We are uncertain whether acupuncture has an effect on the proportion of participants with bradycardia (RR 2.81, 95% CI 0.12 to 66.77; Analysis 1.22).

1.18 — Comparison 1 Acupuncture versus no intervention, Outcome 18 Proportion of participants with fatigue.

1.19 — Comparison 1 Acupuncture versus no intervention, Outcome 19 Proportion of participants with bloating.

1.20 — Comparison 1 Acupuncture versus no intervention, Outcome 20 Proportion of participants with loss of appetite.

1.21 — Comparison 1 Acupuncture versus no intervention, Outcome 21 Proportion of participants with flank pain.

1.22 — Comparison 1 Acupuncture versus no intervention, Outcome 22 Proportion of participants with bradycardia.

Sensitivity analysis

Wang 2002 excluded from the data analysis two participants who had quit the trial because of unrecoverable white blood cell count after two weeks of medication. Both sensitivity analyses ('best‐worst' case scenario analysis: RR 0.50, 95% CI 0.05 to 5.22; P = 0.56; 60 participants; 1 trial; Analysis 1.23; 'worst‐best' case scenario analysis: RR 3.00, 95% CI 0.13 to 70.83; P = 0.50; 60 participants; 1 trial; Analysis 1.24) showed that the two were excluded from the final analysis, and that participants were unlikely to have influenced the results of our meta‐analysis on the proportion of participants with bradycardia.

1.23 — Comparison 1 Acupuncture versus no intervention, Outcome 23 Proportion of participants with bradycardia in best‐worst case scenario.

1.24 — Comparison 1 Acupuncture versus no intervention, Outcome 24 Proportion of participants with bradycardia in worst‐best case scenario.

- Proportion of participants with significant changes in blood routine tests: only one trial with 58 participants reported the proportion of participants with significant changes in routine blood tests (Wang 2002). We are uncertain whether acupuncture has an effect on the proportion of participants with significant changes in routine blood tests (RR 0.62, 95% CI 0.30 to 1.29; Analysis 1.25).

1.25 — Comparison 1 Acupuncture versus no intervention, Outcome 25 Proportion of participants with significant changes in blood routine tests.

Wang 2002 excluded from the data analysis two participants who had quit the trial because of unrecoverable white blood cell count after two weeks of medication. Both sensitivity analyses ('best‐worst' case scenario analysis: RR 0.57, 95% CI 0.28 to 1.16; P = 0.12; 60 participants; 1 trial; Analysis 1.26; 'worst‐best' case scenario analysis: RR 0.67, 95% CI 0.32 to 1.39; P = 0.28; 60 participants; 1 trial; Analysis 1.27) showed that the two were excluded from the final analysis, and that participants were unlikely to have influenced the results of our meta‐analysis on the proportion of participants with significant changes in routine blood tests.

1.26 — Comparison 1 Acupuncture versus no intervention, Outcome 26 Proportion of participants with significant changes in blood routine tests in best‐worst case scenario.

1.27 — Comparison 1 Acupuncture versus no intervention, Outcome 27 Proportion of participants with significant changes in blood routine tests in worst‐best case scenario.

'Summary of findings' tables

We constructed a 'Summary of findings' table for the comparison 'acupuncture versus no intervention' with an intention to present assessments of all primary and secondary outcomes (Primary outcomes; Secondary outcomes). However, because of lack of trial data, we could present only GRADE assessments for the 'proportion of participants with one or more adverse events considered not to be serious'. The included data originate from three trials only (Wang 2002; Wang 2013; Zhu 2016; Table 1). Post hoc, we decided to present the results of our exploratory outcomes: the proportion of participants with detectable HBV DNA and the proportion of participants with detectable HBeAg, because physicians consider administration of acupuncture helpful in decreasing discomfort and preventing replication of the virus in people with chronic hepatitis B. Table 1 presents details on how we have assessed the evidence. We defined the certainty of evidence as very low because we downgraded evidence by one level for each of the following factors: risk of bias, imprecision, and publication bias.

Discussion

Summary of main results

We included eight randomised clinical trials with 555 participants. We assessed all eight trials at overall high risk of bias. For our meta‐analyses, we could gather quantitative data information from four of the eight trials with 305 participants. None of the included randomised clinical trials reported data on our three primary outcomes and our two secondary outcomes (i.e. all‐cause mortality, proportion of participants with one or more serious adverse events, health‐related quality of life, hepatitis B‐related mortality, and hepatitis B‐related morbidity). Accordingly, participants do not seem to be representative of all patients with chronic hepatitis B. We found no trial comparing acupuncture with sham acupuncture. All eight included randomised clinical trials compared the effects of acupuncture performed with co‐interventions versus equal co‐interventions. The co‐interventions were heterogeneous. Evidence assessing the proportion of participants with one or more adverse events considered not to be serious, based on only three randomised trials, was of very low quality and showed no difference in the effect of acupuncture. This result was also observed in subgroup analyses between trials with different acupuncture interventions, trials with various treatment duration, trials with different diagnostic criteria sources, and trials with clearly reported concomitant disease compared to trials without clearly reported concomitant disease. The Trial Sequential Analysis suggested that more information is needed. The 'best‐worst' and 'worst‐best' case scenario sensitivity analyses showed that incomplete outcome data bias did not potentially influence our meta‐analysis result on the proportion of participants with one or more adverse events considered not to be serious (Analysis 1.6; Analysis 1.7). A sensitivity analysis on imprecision showed that the GRADE imprecision assessment downgraded the evidence by one level, and the Trial Sequential Analysis imprecision assessment downgraded the evidence by two levels. Regarding our surrogate outcome on the proportion of participants with detectable hepatitis B virus (HBV) DNA, our meta‐analysis, based on only one trial, found evidence of a difference in the decrease in the proportion of participants with detectable HBV DNA who were administered acupuncture. The Trial Sequential Analysis result showed insufficient evidence to support or reject any effects of acupuncture on this outcome. Two sensitivity analyses on 'best‐worst' case scenario and 'worst‐best' case scenario showed that incomplete outcome data bias did not potentially influence our meta‐analysis result on the proportion of participants with detectable HBV DNA (Wang 2002; Analysis 1.9; Analysis 1.10). Regarding our surrogate outcome on the proportion of participants with detectable hepatitis B e‐antigen (HBeAg), we are uncertain whether there is a difference in the effect of acupuncture compared with the effect of no intervention. The Trial Sequential Analysis result showed insufficient evidence to support or reject any effects of acupuncture on this outcome. Remaining subgroup analyses found evidence of a difference in the beneficial effects of acupuncture on the proportion of participants with detectable HBeAg (Analysis 1.13; Analysis 1.14; Analysis 1.15). Manual needle acupuncture, with treatment duration longer than 12 weeks, was performed in participants with chronic hepatitis B (as diagnosed by trialists) and was associated with a lower proportion of participants with detectable HBeAg (risk ratio (RR) 0.41, 95% confidence interval (CI) 0.24 to 0.69; data from only one trial). Two sensitivity analyses on 'best‐worst' case scenario and 'worst‐best' case scenario showed that excluding from trial analysis two participants in the control group who quit the trial did not potentially influence our meta‐analysis result on the proportion of participants with detectable HBeAg (Wang 2002; Analysis 1.16; Analysis 1.17). Regarding our surrogate outcomes on the proportion of participants with adverse events considered not to be serious, as analysed separately (i.e. fatigue, bloating, loss of appetite, flank pain, bradycardia, significant changes in routine blood tests) meta‐analysis of only one trial with 80 participants showed that acupuncture was associated with a higher proportion of participants with bloating (RR 4.50, 95% CI 1.04 to 19.54; Wang 2013; Analysis 1.19), and we are uncertain whether there is a difference in the effects of acupuncture on the remaining separately analysed adverse events considered not to be serious. Two sensitivity analyses on 'best‐worst' case scenario and 'worst‐best' case scenario showed that incomplete outcome data bias did not potentially influence the results on the proportion of participants with bradycardia and significant changes in routine blood tests (Wang 2002; Analysis 1.23; Analysis 1.24; Analysis 1.26; Analysis 1.27).

Overall completeness and applicability of evidence

By email or by phone, we contacted the authors of the 79 studies listed in Appendix 2, as well as the authors of the eight studies included in our review, to request more information related to trial design and methods; 73 studies lacked description of the random generation method used and six lacked sufficient information for review authors to judge their relevance to our review protocol. No study author provided information related to the trial methods. In addition, none of the 79 studies contained information on patient‐centred outcomes. We found two ongoing trials comparing adding acupuncture to co‐interventions versus equally implementing co‐interventions. We found no unpublished trials comparing acupuncture with no intervention or sham acupuncture that randomised people with chronic hepatitis B.

The participants included in each of the eight trials did not fully reflect the characteristics of the general chronic hepatitis B population. None of the trials included paediatric participants. Two of the eight trials included participants with cirrhosis (Wang 2013; Zhu 2016). The remaining six trials excluded participants with cirrhosis, infection of other hepatitis viruses, and other serious complications, for example, liver cancer (Wang 2002; Huang 2011; Liao 2011; Zou 2011; Zhang 2014; Jing 2016). The included studies were focused on a properly defined population, and thus the results may not be generalised. The included trials covered manual needle acupuncture, acupuncture injection, acupoint herbal patching, and moxibustion; these trials also covered commonly used retention time of acupuncture, commonly used treatment duration, and follow‐up duration of acupuncture. We could perform meta‐analysis on only one of our predefined secondary outcomes, namely, adverse events considered not to be serious, and data were presented in only three of the eight included trials. We could find no report on patient‐centred outcomes such as all‐cause mortality, health‐related quality of life, hepatitis B‐related mortality, and hepatitis B‐related morbidity. In contrast, trials reported data on surrogate outcomes such as detectable HBV DNA and detectable HBeAg in the blood.

Quality of the evidence

Lack of clinically relevant data is a serious limitation of our review and findings. Below, we describe our assessments of each of the five GRADE factors.

Within‐study risk of bias

Risk of bias is known to be responsible for overestimation and underestimation of intervention benefits and harms in randomised clinical trials with inadequate methodological quality (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2017). Of the eight included trials, eight (100%) reported adequate generation of the randomisation sequence; only one (12.5%) reported adequate allocation concealment; eight (100%) lacked blinding of participants, and it was unclear whether outcome assessors were blinded; eight trials (100%) appeared not to be influenced by incomplete outcome data; none of the trials (0%) appeared to be free from selective reporting; and all appeared to be free from other bias. Thus, we considered all trials at high risk of bias.

Indirectness of the evidence

As all of the trials included in our review assessed acupuncture in people with chronic hepatitis B, we find our results applicable for this group of people.

Heterogeneity or inconsistency of results

We explored statistical heterogeneity with the Chi² test and quantified heterogeneity using the I² statistic (Higgins 2002). Heterogeneity was not detected when outcome data from three trials on the proportion of participants with one or more adverse events considered not to be serious were analysed (I² = 0%). We identified considerable heterogeneity in the analysis of the proportion of participants with detectable HBeAg (I² = 98%). As only two trials reported data on this outcome, we analysed the clinical characteristics in an attempt to find the reason for heterogeneity (Wang 2002 ; Zou 2011). Zou 2011 treated people diagnosed with chronic hepatitis B according to a guideline with acupoint herbal patching for 12 weeks, and Wang 2002 treated people diagnosed with chronic hepatitis B with manual needle acupuncture for 24 weeks. However, Wang 2002 does not mention how trial participants were diagnosed with chronic hepatitis B. This could be a reason for the considerable heterogeneity observed. As only one trial provided data on analysis of the proportion of participants with detectable HBV DNA, we cannot report on heterogeneity (Wang 2002).

We applied both fixed‐effect and random‐effects meta‐analysis models, and we reported both models when we found differences. In our review, neither the fixed‐effect model nor the random‐effects model identified differences in the proportion of participants with one or more adverse events considered not to be serious. We could include only one trial in the analysis of detectable HBV DNA, so inconsistency of results from different models is irrelevant. The fixed‐effect model identified statistically significant differences in the proportion of participants with detectable HBeAg, which were not identified by the random‐effects model. As planned in our protocol, we plan to put more weight on the estimate closest to the zero effect, and this is why, in this case, we consider the results from the random‐effects model.

Imprecision of results

In keeping with the GRADE criteria for assessing imprecision, we downgraded the evidence by one level for the outcome ‐ proportion of participants with one or more adverse events considered not to be serious. This was due to the fact that optimal information size criteria were not met and the sample size was not very large (fewer than 4000 participants). Regarding the outcome ‐ the proportion of participants with detectable HBV DNA ‐ we downgraded the evidence by one level because optimal information size criteria were not met and the sample size was not very large (fewer than 4000 participants). As for the outcome ‐ the proportion of participants with detectable HBeAg outcome ‐ we downgraded the evidence by two levels because the number of events was less than 300 and the CI overlapped no effect, and the CI failed to exclude important benefit (RR < 0.75) and important harm (RR > 1.25) (GRADE 2013; Schünemann 2016).

Our sensitivity analysis comparing assessment of imprecision versus the Trial Sequential Analysis showed consistent results regarding the proportion of participants with detectable HBeAg outcome. Our assessments differed when the GRADE assessment of imprecision was compared to that conducted via Trial Sequential Analysis for participants with one or more adverse events considered not to be serious outcome and the proportion of participants with detectable HBV DNA outcome.

Risk of publication bias

We could not construct funnel plots because data were derived from a maximum of three trials per outcome. We suspected publication bias because the included trials had small sample sizes ‐ GRADEpro GDT; Balshem 2011; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2011h; Guyatt 2013a; Guyatt 2013b; Guyatt 2013c; Guyatt 2013d; Mustafa 2013; Guyatt 2017 ‐ and because five trials provided no information on support or sponsorship. Undisclosed funding may influence trial results and may lead to poor trial design.

Potential biases in the review process

We performed our systematic review based on recommended Cochrane methods (Higgins 2011; Cochrane Hepato‐Biliary Group Module). We followed our peer‐reviewed and published protocol with predefined participants, interventions, comparisons, outcomes, and time to follow‐up to avoid biases during the review process (Kong 2018). We applied comprehensive search strategies, which covered published studies and registered study protocols. We searched manually the reference lists of all identified studies. We combined our electronic searches with manual data searches. We extracted all available data to perform our predefined analyses, including subgroup and sensitivity analyses.

Unpublished trials with negative results, which we did not identify during the preparation of this review, are a possible source of bias. We did not succeed in receiving replies from authors of the eight included trials and the 79 potential randomised clinical trials listed in Appendix 2 to our requests to obtain missing data of relevance to our review methods and to outcome data because we received no replies. It is not possible to differentiate between poor report and poor conduct of included trials, which may generate potential bias of this review.

All the trials we have found were carried out in China, possibly because acupuncture is most often used in Asian countries. Although we have made a broad strategy to identify all available trials, studies published in languages other than Chinese and English may not be found. If possible, Japanese and Korean medical databases should be added for the update of this review, and experts should be asked to find out if there are more studies on this topic.

Observational studies may provide information on rare late‐occurring adverse events and quality of life, which are outcomes of interest to this review. We planned to consider quasi‐randomised studies, controlled clinical studies, and other observational studies for data on harms of acupuncture, if retrieved through our searches for randomised clinical trials. The 79 studies listed in Appendix 2 could be a valuable source of data on adverse events. Our decision not to perform specific searches for observational studies and not to assess potential data on adverse events in the Characteristics of excluded studies, as well as the studies in Appendix 2, might have biased our review, causing us to overlook potential harms (late or rare harms) (Storebø 2018).

Huang 2011 and Jing 2016 were conducted to investigate whether an acupuncture intervention could improve the effects of other antiviral interventions (recombinant human interferon (IFN)‐alpha 2a and peginterferon‐alpha 2a) provided as a co‐intervention. Wang 2002, Liao 2011, Zou 2011, and Zhang 2014 were conducted to investigate the effect of acupuncture for chronic hepatitis B. Zhu 2016 was performed to investigate whether acupoint herbal patching, as a co‐intervention with tolvaptan, an aquaretic drug, could relieve refractory ascites for people with chronic hepatitis B and liver cirrhosis. Wang 2013 was conducted to investigate the effects of moxibustion for people with chronic hepatitis B and liver cirrhosis. Lack of reporting of serious adverse events and lack of conclusions in our review on patient‐centred outcomes are serious limitations of the applicability of this review to people with chronic hepatitis B who receive acupuncture. For trials reporting adverse events considered not to be serious, we selected the greatest number of events among the separately reported numbers of events that had occurred in experimental or control groups to calculate the proportion of participants with one or more adverse events considered not to be serious. This may have been problematic, as it might have led to an underestimation of the proportion of participants with one or more adverse events considered not to be serious. Furthermore, the different events of this composite outcome often have different severity, such as headache compared to hepatomegaly, so that even with a neutral result, there might be in reality a significant difference in severity between groups. Using composite outcomes increases power, but the limitations as mentioned above must be considered when results are interpreted.

We have included a substantial number of subgroup analyses and several surrogate outcomes. There could have been problems with multiplicity in terms of the seven subgroup analyses for each outcome (Imberger 2011). We did not adjust the thresholds for subgroup analyses because we considered these results only as exploratory and hypothesis‐generating.

We conducted Trial Sequential Analyses for the outcomes ‐ proportion of participants with adverse events considered not to be serious (secondary outcome), with detectable HBV DNA (exploratory outcome), and with detectable HBeAg (exploratory outcome) (Wetterslev 2008; Thorlund 2011b; TSA 2011; Wetterslev 2017). We calculated the DARIS on the basis of type I error of 2.5% for secondary outcomes, 5.0% for exploratory outcomes, type II error of 10%, and risk reduction of 15%, as well as the proportion of events in the control group (Wetterslev 2009). In the Trial Sequential Analysis, the cumulative Z‐curve did not cross trial sequential monitoring boundaries for benefit, harm, or futility, and the DARIS was not reached. Therefore, we cannot exclude the risk of random errors regarding our results on the aforementioned outcomes.

Our search was conducted on 1 March 2019. It is possible that further studies of relevance to our review could have been published since then. This must be dealt with in future updates.

Agreements and disagreements with other studies or reviews

Two non‐Cochrane meta‐analyses on acupuncture for people with chronic hepatitis B have been published (Wang 2015; Wu 2017). Wang 2015 included trials comparing acupoint injection versus non‐acupoint injection. Wu 2017 included trials comparing moxibustion plus co‐interventions versus co‐interventions, but the meta‐analysis excluded studies including participants with other types of hepatitis. Neither of the two meta‐analyses was reported to have assessed effects of acupuncture on patient‐centred outcomes such as mortality, adverse events, or health‐related quality of life. Compared with the risk of bias tool used in the three meta‐analyses identified, we found that our risk of bias assessment tool is much more rigorous. We did not use scores to assess risk of bias as the Jadad scoring system does (Jadad 1996), and we used eight predefined domains to assess the possible risk of reporting bias (Higgins 2011). We used Trial Sequential Analyses to control random errors and GRADE assessments to define the certainty of evidence.

Wang 2015 showed that acupoint injection reduced the surface antigen of the hepatitis B virus (HBsAg), the hepatitis B e‐antigen (HBeAg), and the transaminase levels in serum. Wu 2017 showed that combination therapy improved transaminase and total bilirubin levels in the serum of participants. All three meta‐analyses assessed surrogate outcomes. In our review, we found no beneficial or harmful effects of acupuncture on adverse events considered not to be serious, nor on the proportion of participants with HBV DNA or the proportion of participants with HBeAg, when we compared acupuncture with no intervention. The quality of the evidence was very low.

Authors' conclusions

Implications for practice.

Data on patient‐related outcomes such as all‐cause mortality, serious adverse events, health‐related quality of life, hepatitis B‐related mortality, and hepatitis B‐related morbidity are lacking. We found no evidence of a difference in effect between acupuncture versus no intervention for the outcomes adverse events considered not to be serious and detectable HBeAg. Furthermore, it remains unclear if acupuncture versus no intervention is associated with a reduction in detectable HBV DNA because of data provided by only one trial, at high risk of bias, and with the non‐validated surrogate outcome. As we were unable to obtain information on a large number of trials regarding their design and conduct, we were deterred from including them in our review.

Implications for research.

In view of the worldwide use of acupuncture, we need large, high‐quality, randomised sham‐controlled trials with proper design and homogeneous groups of participants, in which patient‐related outcomes are assessed. We suggest the following implications for research (Brown 2006).

Evidence (what is the current state of the evidence)?

This review includes eight randomised clinical trials with 555 participants. These trials did not provide data on patient‐centred outcomes such as all‐cause mortality, proportion of participants with one or more serious adverse events, health‐related quality of life, hepatitis B‐related mortality, and hepatitis B‐related morbidity. The diversity‐adjusted required information size (DARIS) has not been reached for any of the reported outcomes. Meta‐analysed evidence showed no beneficial or harmful effects of acupuncture on adverse events considered not to be serious nor on the proportion of participants with detectable HBeAg. Data from one trial at high risk of bias showed beneficial effects of acupuncture on the proportion of participants with detectable HBV DNA. All mentioned laboratory outcomes still need validation in randomised clinical trials before we can consider these results as helpful indicators for the treatment of people with chronic hepatitis B. The certainty of the evidence identified so far is very low. Further high‐quality trials are needed, and additional trials should explicitly state their research questions. Further randomised clinical trials ought to be designed according to the SPIRIT standards and reported according to the CONSORT standards (Chan 2013; Moher 2001).

Participants (what is the population of interest)?

Our review focused on people diagnosed with chronic hepatitis B alone or those who were having concomitant disease. Only one trial included participants with concomitant disease (Zhu 2016). This is why further trials should include people with concomitant diseases and should define in sufficient detail the diagnostic criteria used in diagnosing trial participants. When a concomitant disease is present, stratified randomisation should be employed.

Interventions (what are the interventions of interest)?

Subgroup analyses showed no difference in the effects of acupuncture on the proportion of participants with non‐serious adverse events and the proportion of participants with detectable HBeAg between trials with manual needle acupuncture and those with different treatment duration. However, because of the very few identified trials and the very low certainty of the evidence, future randomised clinical trials could be designed to look for differences in acupuncture interventions, different dosages of acupoint injection, and different treatment regimens of acupuncture. No data on follow‐up time span were reported. The duration of therapy ranged from 12 to 48 weeks, and one can assume that this might also have included the duration of follow‐up. This is too short a period for researchers to explore any effects on outcomes such as mortality. Thus, future randomised clinical trials should be designed with longer duration of follow‐up.

Comparisons (what are the comparisons of interest)?

We aimed to assess the benefits and harms of acupuncture compared with no intervention or sham acupuncture for patient‐relevant outcomes among people with chronic hepatitis B. In addition to the lack of data on patient‐centred outcomes, including all‐cause mortality, the outcomes proportion of participants with one or more serious adverse events; health‐related quality of life; hepatitis B‐related mortality; hepatitis B‐related morbidity; and beneficial, harmful, or neutral effects of acupuncture on adverse events considered not to be serious could have been influenced by lack of placebo‐controlled trials and blinding. Future randomised clinical trials should include comparisons between acupuncture and sham acupuncture with or without co‐interventions, to be later included in systematic reviews.

Outcomes (what are the outcomes of interest)?

The primary outcome measures planned to be assessed in this review (all‐cause mortality, proportion of participants with one or more serious adverse events, and health‐related quality of life) should be included as primary outcomes in all future trials. Future randomised clinical trials also need to validate the relationship between surrogate outcomes and patient‐centred outcomes.

Notes

Cochrane Reviews can be expected to have a high percentage of overlap in the methods section because of standardised methods. In addition, overlap may be observed across several of our protocols, as they share at least three common authors.

Acknowledgements

We acknowledge the great help of Sarah Louise Klingenberg, the Information Specialist for the Cochrane Hepato‐Biliary Group, for designing the search strategies. We also acknowledge Dr. L Susan Wieland of the Cochrane Complementary Medicine Field (USA), who co‐ordinated the peer review process.

Review  Peer reviewers: Zhaoxiang Bian, China; Liming Lu, China.  Contact editor: Vanja Giljaca, UK  Sign‐off editor: Agostino Colli, Italy  Cochrane Abdomen and Endocrine Network Associate Editor: Rachel Richardson, UK

Cochrane Review Group funding acknowledgement: the Danish State is the largest single funder of the Cochrane Hepato‐Biliary Group through its investment in the Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark.

Disclaimer: The views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State, the Copenhagen Trial Unit, NCCIH, and the National Institutes of Health.

This work was partially funded by Grant Number R24 AT001293 from the National Center for Complementary and Integrative Health (NCCIH).

Appendices

Appendix 1. Search strategies

Database	Time span	Search strategy
The Cochrane Hepato‐Biliary Group Controlled Trials Register	March 2019	(acupunct* or acupress* or acupoint* or electroacupunct* or auriculotherap* or auriculoacupunct* or moxibust* or meridian* or patch*) AND (hepatitis B or hep B or HBV)
Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library	March 2019	#1 MeSH descriptor: [Acupuncture] explode all trees #2 MeSH descriptor: [Acupuncture Therapy] explode all trees #3 acupunct* or acupress* or acupoint* or electroacupunct* or auriculotherap* or auriculoacupunct* or moxibust* or meridian* or patch* #4 #1 or #2 or #3 #5 MeSH descriptor: [Hepatitis B] explode all trees #6 hepatitis B or hep B or HBV #7 #5 or #6 #8 #4 and #7
MEDLINE Ovid	1946 to March 2019	1. exp ACUPUNCTURE/ 2. exp ACUPUNCTURE THERAPY/ 3. (acupunct* or acupress* or acupoint* or electroacupunct* or auriculotherap* or auriculoacupunct* or moxibust* or meridian* or patch*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 4. 1 or 2 or 3 5. exp Hepatitis B/ 6. (hepatitis B or hep B or HBV).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] 7. 5 or 6 8. 4 and 7
Embase Ovid	1974 to March 2019	1. exp acupuncture/ 2. (acupunct* or acupress* or acupoint* or electroacupunct* or auriculotherap* or auriculoacupunct* or moxibust* or meridian* or patch*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 3. 1 or 2 4. exp hepatitis B/ 5. (hepatitis B or hep B or HBV).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word] 6. 4 or 5 7. 3 and 6
LILACS (Bireme)	1982 to March 2019	acupunct$ or acupress$ or acupoint$ or electroacupunct$ or auriculotherap$ or auriculoacupunct$ or moxibust$ or meridian$ or patch$ [Words] and hepatitis B or hep B or HBV [Words]
Science Citation Index Expanded (Web of Science)	1900 to March 2019	#3 #2 AND #1 #2 TS=(hepatitis B or hep B or HBV) #1 TS=(acupunct* or acupress* or acupoint* or electroacupunct* or auriculotherap* or auriculoacupunct* or moxibust* or meridian* or patch*)
Conference Proceedings Citation Index – Science (Web of Science)	1990 to March 2019	#3 #2 AND #1 #2 TS=(hepatitis B or hep B or HBV) #1 TS=(acupunct* or acupress* or acupoint* or electroacupunct* or auriculotherap* or auriculoacupunct* or moxibust* or meridian* or patch*)
China Network Knowledge Infrastructure (CNKI)	1979 to March 2019	#1 hepatitis B in abstract #2 'acupuncture and moxibustion' or 'acupunture' or 'stimulation' or 'electroacupuncture' or 'laser acupuncture' or 'acupressure' or 'acupoint injection' or 'moxibustion' or 'patching' in abstract #3 random in abstract #4 randomly grouped in abstract #5 #3 OR #4 #6 #1 AND #2 AND #5
Chongqing VIP (CQVIP)	1989 to March 2019	#1 hepatitis B in abstract #2 'acupuncture and moxibustion' or 'acupunture' or 'stimulation' or 'electroacupuncture' or 'laser acupuncture' or 'acupressure' or 'acupoint injection' or 'moxibustion' or 'patching' in abstract #3 random in abstract #4 randomly grouped in abstract #5 #3 OR #4 #6 #1 AND #2 AND #5
Wanfang Data	1990 to March 2019	#1 hepatitis B in abstract #2 'acupuncture and moxibustion' or 'acupunture' or 'stimulation' or 'electroacupuncture' or 'laser acupuncture' or 'acupressure' or 'acupoint injection' or 'moxibustion' or 'patching' in abstract #3 random in abstract #4 randomly grouped in abstract #5 #3 OR #4 #6 #1 AND #2 AND #5
SinoMed	1860 to March 2019	#1 hepatitis B in abstract #2 'acupuncture and moxibustion' or 'acupunture' or 'stimulation' or 'electroacupuncture' or 'laser acupuncture' or 'acupressure' or 'acupoint injection' or 'moxibustion' or 'patching' in abstract #3 random in abstract #4 randomly grouped in abstract #5 #3 OR #4 #6 #1 AND #2 AND #5

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Appendix 2. Potential randomised clinical trials

Trial ID	First author	Year	English title	Journal‐English name	Volume	Issue	Pages	Contact information
Cai 2016	Cai CJ	2016	Efficacy of hepatic cirrhosis ascites treated with umbilical sticking of Zhuo Mai powder and moxibustion therapy	Chinese Archives of Tradtional Chinese Medicine	34	4	1017‐1020	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Chen 1994	Chen JF	1994	The treatment on 22 people with hepatitis B virus carriers with immunoglobulin ribonucleic acid of anti hepatitis B for injection combined with acupuncture	Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases	14	11	677‐678	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Chen 1998a	Chen JJ	1998	Effect of purulent moxibustion combined with traditional Chinese medicine on serum IL‐2 and IFN‐γ concentrations in patients with chronic hepatitis B	Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases	S1	ND	84‐85	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Chen 1998b	Chen JF	1998	Comparative observation on the effect of acupuncture on immune function of HBV carriers	Hu Nan Journal of Traditional Chinese Medicine	5	ND	20‐21	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Chen 2005	Chen L	2005	Treatment of 40 people with hepatitis B with intrahepatic cholestasis by acupuncture and moxibustion combined with western medicine: a comparison of 40 people treated with western medicine	Zhejiang Journal of Traditional Chinese Medicine	11		494	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Chen 2014	Chen JZ	2014	Clinical research of Chinese drug acupoint injection combined with PEG‐IFN a‐2a to treat chronic hepatitis B	Chinese Archives of Traditional Chinese Medicine	32	8	1965‐1967	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Chen 2015	Chen S	2015	Early curative effect observation of treatment of thymic factor injection on Guan Yuan acupoint combined with entecavir	Data compilation of the third Jiangxi provincial conference on new progress in diagnosis and treatment of integrated traditional Chinese and western medicine of common and emerging infectious diseases	ND	ND	145‐149	We contacted study authors on 10 May by phone: we received no reply. We could not find email addresses
Cheng 2000	Cheng QH	2000	The clinical observation on 32 people with hepatitis B and hypochondriac pain treated by acupuncture combined with Chinese Medicine	Summary of Papers on International Convention of Traditional Medicine	ND	ND	ND	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Cheng 2004	Cheng JJ	2004	Observation on the effect of moxibustion on hyperbilirubinaemia in hepatitis B type cirrhosis patients	World Journal of Acupuncture Moxibustion	14	4	12‐15	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Cheng 2016	Cheng YF	2016	Clinical observation on 50 people with liver cirrhosis and bloating with moxibustion at the point of moxibustion	Inner Mongolia Traditional Chinese Medicine	9	ND	123‐124	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Deng 2009	Deng LH	2009	Clinical study on severe chronic hepatitis B treated with Zusanli acupoint injection of kushenin	Chinese Medicine External Governance Magazine	18	2	9‐10	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Du 2004	Du JX	2004	Acupoint injection of oxymatrine for treatment of chronic severe hepatitis B	Chinese Journal of Primary Medicine and Pharmacy	11	4	459‐460	We tried to contact study authors on 30 April: we could not contact the people
Du 2005	Du JX	2005	To investigate the clinical effect of intra‐acupoint injection of Ganyanlin on chronic hepatitis B	Chinese Journal of the Practical Chinese Modern Medicine	18	18	947‐948	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Fang 2012	Fang H	2012	Therapeutic effect of the method of separating moxibustion and moxibustion combined with acupoint application on chronic hepatitis B	CJGMCM	27	6	1173‐1174	The study author has changed his job. We could not get his current contact information
Ge 2012	Ge Q	2012	Clinical study of dexamethasone by different administration pathways for HBV associated with (Sub) acute‐on‐chronic liver failure	Nanjing University of Traditional Chinese Medicine	ND	ND	ND	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Han 2011	Han XH	2011	Clinical research of application of moxibustion on Ganshu (BL18) and Qimen (LR14) for chronic hepatitis B	China Modern Doctor	49	19	86‐88	We contacted study authors on 23 April 2018 by phone: we received no reply. We could not find email addresses
Han 2012	Han J	2012	Treatment on 15 people with Yin Yellow (hepatitis B cirrhosis) with umbilical fire therapy	Chinese Acupuncture & Moxibustion	32	6	490	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
He 2013	He YX	2013	Therapeutic effect of α‐interferon acupoint manipulation on chronic hepatitis B	Modern Journal of Integrated Traditional Chinese and Western Medicine	22	21	2358‐2360	We contacted study authors on 23 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Hu 2014	Hu JH	2014	Clinical observation of entecavir combined with matrine acupoint injection in the treatment of HBeAg‐positive chronic hepatitis B	Chinese Journal of Medicine Guide	16	5	821‐822	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Hu 2015	Hu XJ	2015	Clinical research of the bioinformatics infrared liver disease therapy instrument combined with Gan Shu acupoint sticking application on treating chronic hepatitis B	Medical Information	28	35	173‐174	We could not find any contact information about study authors
Huang 2004	Huang F	2004	Clinical observation on 46 people with chronic hepatitis B virus carriers treated with Chinese medicine combined with interferon acupoint injection	Modern Chinese Medicine	ND	2	18‐19	We could not find any contact information about study authors
Huang 2005	Huang JQ	2005	Protective actions of acupoint magnetic medicated plaster therapy on hepatic function in the patient of cirrhosis after hepatitis	Chinese Acupuncture & Moxibustion	25	9	613‐615	We contacted study authors on 10 May 2018 by phone: we received no reply. We could not find email addresses
Ji 1999	Ji S	1999	The treatment on 46 people with chronic hepatitis B with Chinese and western medicine combined with acupuncture points	Huaihai Medicine	17	2	ND	We contacted study authors on 23 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Jiang 2010	Jiang HM	2008	Clinical study of hepatocyte growth factor and salvia miltiorrhiza combined with acupoint injection in the treatment of hepatitis liver fibrosis	Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases	18	1	18‐20	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Lei 2014	Lei RG	2014	Clinical observation on 18 people with chronic hepatitis B treated with acupuncture and interferon	Nei Mongol Journal of Traditional Chinese Medicine	ND	30	58‐59	We contacted study authors on 10 May 2018 by phone: we received no reply. We could not find email addresses
Li 2000	Li P	2000	Effect of triple therapy combined with acupoint injection of Hua Chan Su on liver function	Compilation of the twelfth national symposium on digestive diseases in the Chinese academy of integrated traditional Chinese and western medicine	ND	ND	210	The study author has changed his job. We could not get his current contact information
Li 2003	Li P	2003	Clinical study on treatment of chronic hepatitis B with Huachansu acupoint injection	Chinese Journal of Celiopathy	3	11	800‐801	The study author has changed his job. We could not get his current contact information
Li 2007	Li YC	2007	28 people with chronic severe hepatitis B jaundice treated with injection of dexamethasone in acupoint of Zusanli	Chinese Medicine External Governance Magazine	16	6	31‐32	We could not find any contact information for study authors
Li 2011b	Li Y	2011	108 people with chronic hepatitis B treated with acupoint application	ND	ND	ND	101‐103	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Li 2014	Li XY	2014	Clinical observation of treatment of liver disease with acupoint application	Contemporary Medicine Forum	12	4	140‐141	We could not get any contact information for study authors
Li 2015	Li SQ	2015	The effect observation of acupuncture combined with diammonium glycyrrhizinate injection in chronic hepatitis B	China Journal of Public Health	31	ND	277‐278	We could not find any contact information for study authors
Liu 1999	Liu SJ	1999	Clinical analysis of 35 people with chronic hepatitis B treated with Chinese medicine repellent drug combined with interferon	Chinese Medicine Technology	6	2	110‐111	We could not find any contact information for study authors
Liu 2003	Liu YL	2003	Therapeutic effect of wick moxibustion combined with thymosin on anti‐HBe positive chronic hepatitis B	JCAM	19	9	39‐40	We contacted study authors on 25 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Liu 2006	Liu WT	2006	Clinical observation of acupuncture combined with Chinese medicine in treating chronic hepatitis B	Lishizhen Medicine and Materia Medica Research	17	8	1532‐1533	We contacted study authors on 10 May 2018 by phone: we received no reply. We could not find email addresses
Liu 2011	Liu W	2011	Clinical study of acupoint application combined with Qinghua Jiedu decoction in treating damp heat syndrome of hepatitis B	Beijing Journal of Traditional Chinese Medicine	30	10	726‐730	The study author has changed his job. We could not get his current contact information
Liu 2015	Liu CG	2015	Clinical observation of acupoint application combined with interferon on treating chronic hepatitis B	Inner Mongolia Traditional Chinese Medicine	34	4	92‐93	We tried to contact study authors on 28 April 2018 by phone: we could not contact the people
Lu 2011	Lu Y	2011	Summary of 33 people with chronic hepatitis B hypochondriac pain treated with acupoint application of Shugan Huayu decoction	Hunan Journal of Traditional Chinese Medicine	27	6	21‐22	We contacted study authors on 10 May 2018 by phone: we received no reply. We could not find email addresses
Lu 2016a	Lu JP	2016	Clinical study on internal medicine combined with acupuncture and moxibustion for treatment of refractory cirrhosis ascites	Journal of Sichuan of Traditional Chinese Medicine	34	8	160‐162	We contacted study authors on 25 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Lu 2016b	Lu LQ	2016	Effect of Yongquan acupoint application on chronic hepatitis B patients with insomnia	Journal of Hunan University of Chinese Medicine	36	S2	1383	We contacted study authors on 10 May 2018 by phone: we received no reply. We could not find email addresses
Ma 2001	Ma HQ	2001	Treating chronic hepatitis‐B by massage at meridian	Chinese Journal of the Practical Chinese With Modern Medicine	1	11	2480	We contacted study authors on 30 April 2018 by phone: we received no reply. We could not find email addresses
Miao 2007	Miao AJ	2007	Lamivudine combined with thymosin injection in the treatment of chronic hepatitis B: a clinical observation of 94 people	Shandong Medical Journal	47	26	81	We contacted study authors on 30 September 2018 by phone: study authors refused to provide any further information
Peng 2002	Peng CL	2002	Clinical observation of moxibustion and medicine in treating chronic hepatitis B in 32 people	Shanghai Journal of Traditional Chinese Medicine	1	ND	27	We contacted study authors on 30 April 2018 by phone: we received no reply. We could not find email addresses
Peng 2003	Peng PS	2003	Clinical research of modified formula 'Yi Guan Jiang' combine with acupuncture in the treatment of chronic hepatitis B	Hunan University of Chinese Medicine	ND	ND	ND	We could not find any contact information for study authors
Ruan 2009	Ruan YD	2009	Clinical study on treatment of YMDD variant chronic hepatitis B by acupoint injection of hepatitis and Huangmao injection	Journal of New Chinese Medicine	41	1	28‐29	We contacted study authors on 30 April 2018 by phone: we received no reply. We could not find email addresses
Shao 2009	Shao ZL	2009	Clinical observations on reducing effect of midnight‐midday ebb flow acupuncture on chronic hepatitis B HBV‐YMDD mutation	Shanghai J Acu‐mox	28	12	694‐695	We contacted study authors on 28 April 2018 by phone: we received no reply. We could not find email addresses
Shen 2004	Shen JJ	2004	The observation of curative effect on chronic hepatitis B by point injection of thymosin	ND	ND	ND	ND	We contacted study authors on 28 April 2018 by phone: we received no reply. We could not find email addresses
Sun 2000	Sun MT	2000	Clinical observation on 84 people of asymptomatic hepatitis B virus carriers treated by acupoint injection	Journal of Nanjing TCM University	16	3	174‐175	We contacted study authors on 28 April 2018 by phone: we received no reply. We could not find email addresses
Sun 2008	Sun H	2008	Clinical research on 'Ganshu plaster' in treating hepatitis B liver cirrhosis with therapy of point sticking	Nanjing University of Chinese Medicine				We could not find any contact information for study authors
Tan 2009	Tan SZ	2009	The effect of small dose dexamethasone injection in Zusanli point on treatment of early liver failure	Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases	19	4	241‐243	We tried to contact study authors on 30 April by phone: we could not contact the people
Tang 2001	Tang JP	2001	The effect of acupoint electrical stimulation with low frequency on hepatitis B	Chinese Journal of International Medicine	1	1	74	We contacted study authors on 30 April 2018 by phone: we received no reply. We could not find email addresses
Tang 2014	Tang HL	2014	Clinical observation on 36 people with chronic hepatitis B treated by interventional interferon	Asia‐Pacific Traditional Medicine	10	24	12—14	We contacted study authors on 30 April 2018 by phone: we received no reply. We could not find email addresses
Wang 2002	Wang CJ	2002	Clinical observation on acupoint injection for chronic hepatitis B	Journal of Changchun University of Chinese Medicine	18	4	14	We contacted study authors on 30 April 2018 by phone: we received no reply. We could not find email addresses
Wang 2014	Wang YM	2014	Clinical study on treatment of chronic hepatitis B with adefovir dipivoxil combined with moxibustion and liver acupoints	China Practice of Medicine	9	15	148‐149	We contacted study authors on 23 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Wang 2015	Wang Y	2015	Effect of acupoint application of Chinese herbal medicine on hepatitis B cirrhosis with water dropsy	Clinical Practice of Combination of Chinese Traditional and Western Medicine	15	7	72‐73	We could not find any contact information for study authors
Wang 2017	Wang LX	2017	Effect evaluation and nursing of adjuvant treatment of viral hepatitis by ginger moxibustion	Today Nurse	ND	3	147‐148	We contacted study authors on 23 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Wei 2014	Wei WD	2014	Preliminary clinical observation of moxibustion combined lamivudine for chronic hepatitis B liver and spleen deficiency	Master's thesis of Shandong University of Traditional Chinese Medicine	ND	ND	ND	We could not find any contact information for study authors
Wu 2012	Wu YB	2012	Treatment of 30 people with chronic hepatitis B with acupoint injection of oxymatrine	Journal of Shanxi of Traditional Chinese Medicine	33	1	12‐14	We contacted study authors on 23 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Xue 2007	Xue YH	2007	Clinical observation on 60 people with chronic hepatitis B with liver fibrosis treated by combination therapy	Journal of Jiangsu of Traditional Chinese Medicine	39	8	35‐36	We contacted study authors on 23 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Xue 2008	Xue SK	2008	Clinical observation on 37 people with chronic hepatitis B treated with acupoint injection of oxymatrine	Shandong Medical Journal	48	25	24	We contacted study authors on 23 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Yan 2002	Yan YZ	2002	Curative effect observation of Ara‐AMP point injection in treating chronic hepatitis B	Chinese Journal of Experimental and Clinical Virology	16	3	292	We could not find any contact information for study authors
Yang 2000	Yang DQ	2000	Observation on the therapeutic effect of 'Tou tian liang' acupuncture combined with anti‐hepatitis B immunoribonucleic acid on 64 chronic HBV carriers with vertical infection	Chinese Acupuncture & Moxibustion	ND	1	31‐32	We contacted study authors on 23 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Yang 2011	Yang ZH	2011	Treatment of 64 people with HBeAg‐positive chronic hepatitis B with α‐2b interferon combined with astragalus injection	Information on Traditional Chinese Medicine	28	6	94‐95	We contacted study authors on 23 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Zhang 2005	Zhang W	2005	Clinical observation of acupoint injection of interferon α‐2b combined with oxymatrine in the treatment of chronic hepatitis B	Modern Journal of Integrated Traditional Chinese and Western Medicine	14	15	1998‐1999	We contacted study authors on 23 April and 27 April 2018 by phone: we received no reply. We could not find email addresses
Zhang 2006	Zhang B	2006	Therapeutic effect of intra‐acupoint injection of Cinobufacin on active cirrhosis	Journal of Clinical and Experimental Medicine	5	8	1077‐1078	The study author has changed his job. We could not get his current contact information
Zhang 2007	Zhang Y	2007	Effect of injecting thymosin α1 at Zusanli point on T lymphocyte subset in chronic hepatitis B patient	Chinese Journal of Microecology	19	2	189‐190	We could not get any contact information for study authors
Zhang 2010	Zhang SM	2010	Curative effect observation and nursing care on chronic hepatitis B by oxymatrine injection at Zusanli point	World Health Digest Medical Periodical	7	7	245‐246	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Zhang 2012	Zhang WW	2012	Effect of acupoint injection of interferon alpha on T lymphocyte subsets in patients with chronic hepatitis B	Modern Journal of Integrated Traditional Chinese and Western Medicine	21	21	2339‐2341	We contacted the study author on 10 May by phone: the study author refused to provide any further information
Zhang 2014	Zhang Q	2014	Effect of acupuncture combined with western medicine on cellular immune function in patients with cirrhosis after hepatitis B	ND	ND	33	29	The study author has changed his job. We could not get his current contact information
Zhang 2015	Zhang SP	2015	Influence of acupoints injection with Xiang Dan injection on clinical effects of chronic hepatitis B	Traditional Chinese Medicine of Western Region	28	11	115‐117	The study author has changed his job. We could not get his current contact information
Zhang 2016	Zhang L	2016	Curative effect observation on 23 people with chronic hepatitis B treated with acupoint injection of Polyporus polysaccharide combined with entecavir	Inner Mongolia Traditional Chinese Medicine	35	6	471‐472	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Zhou 2008	Zhou M	2008	Treatment of 50 people with chronic hepatitis B with Qinggan Jiedu paste	TCM Research	21	11	27‐29	We contacted study authors on 25 April 2018 by phone: we received no reply. We could not find email addresses
Zhu 2011	Zhu Q	2011	Clinical research of acupoint injection with Huangqi treating chronic hepatitis B and discussion of TCM external treatment	Chinese Archives of Traditional Chinese Medicine	29	12	2695‐2697	We contacted study authors on 25 April 2018 by phone: we received no reply. We could not find email addresses
Zhuo 2012	Zhuo XY	2012	Therapeutic effect of lamivudine combined with meridian flow injection on chronic hepatitis B	Nurse Training Magazine	27	11	1039‐1041	We contacted study authors on 28 April and 30 April 2018 by phone: we received no reply. We could not find email addresses
Yao 2005	Yao QY	2008	Clinical observation and nursing on Huachanshu acupoint injection therapy in treating patients with chronic hepatitis B and TAP‐positive	Conference Proceeding of the Clinic of the Second Hospital of Nanjing	6	ND	62‐3	We could not obtain the original full article
Zhao 2004	Zhao QX	2004	Observation on acupuncture point irradiation of HeNe laser for the treatment of chronic B hepatitis	China Journal of Modern Medicine	1	1	46‐7	We could not obtain the original full article
Qian 1994	Qian CF	1994	Clinical observation on increased acupoint injection for interdicting the replication of chronic hepatitis B virus	Zhejing Journal of Traditional Chinese Medicine	ND	ND	155	We could not obtain the original full article
HBBAC 1994	Anonymous	1994	Hepatitis B associated with an acupuncture clinic	Communicable disease report	CDR Weekly 2	48	219	We could not obtain the original full article
Arya 1989	Arya SC	1989	Acupuncture in epidemic HBV hepatitis: other ritual surgical procedures in Africa as well	Hepatology (Baltimore, Md)	9	3	511	We could not obtain the original full article
Manning 2000	Manning GL	2000	Hepatitis carriers and acupuncture	Acupuncture in Medicine	18	ND	70	We could not obtain the original full article

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Data and analyses

Comparison 1. Acupuncture versus no intervention.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Proportion of participants with 1 or more adverse events considered not to be serious (overall)	3	203	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.43, 1.06]
2 Proportion of participants with 1 or more adverse events considered not to be serious (acupuncture approach)	3	203	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.43, 1.06]
2.1 Participants with manual needle acupuncture	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.30, 1.29]
2.2 Participants with acupoint herbal patching	1	65	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.21, 1.14]
2.3 Participants with moxibustion	1	80	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.44, 2.26]
3 Proportion of participants with 1 or more adverse events considered not to be serious (duration)	3	203	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.43, 1.06]
3.1 Duration longer than 12 weeks	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.30, 1.29]
3.2 Duration less than 12 weeks	2	145	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.35, 1.43]
4 Proportion of participants with 1 or more adverse events considered not to be serious (diagnosis)	3	203	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.43, 1.06]
4.1 Participants with diagnostic criteria according to guideline	2	145	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.35, 1.43]
4.2 Participants with diagnosis by trialists	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.30, 1.29]
5 Proportion of participants with 1 or more adverse events considered not to be serious (chronic hepatitis B plus a comitant disease and chronic hepatitis B)	3	203	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.43, 1.06]
5.1 Participants with cirrhosis	1	65	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.21, 1.14]
5.2 Unclear information on concomitant disease	2	138	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.45, 1.33]
6 Proportion of participants with 1 or more adverse events considered not to be serious in best‐worst case scenario	3	205	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.41, 1.02]
7 Proportion of participants with 1 or more adverse events considered not to be serious in worst‐best case scenario	3	205	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.44, 1.10]
8 Proportion of participants with detectable HBV DNA (overall)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9 Proportion of participants with detectable HBV DNA in best‐worst case scenario	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
10 Proportion of participants with detectable HBV DNA in worst‐best case scenario	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
11 Proportion of participants with detectable HBeAg (fixed‐effect)	2	158	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.69, 0.91]
12 Proportion of participants with detectable HBeAg (random‐effects)	2	158	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.11, 3.68]
13 Proportion of participants with detectable HBeAg (acupuncture approach)	2	158	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.11, 3.68]
13.1 Participants with manual needle acupuncture	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.24, 0.69]
13.2 Participants with acupoint herbal patching	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.91, 1.05]
14 Proportion of participants with detectable HBeAg (duration)	2	158	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.11, 3.68]
14.1 Duration longer than 12 weeks	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.24, 0.69]
14.2 Duration less than 12 weeks	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.91, 1.05]
15 Proportion of participants with detectable HBeAg (diagnosis)	2	158	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.11, 3.68]
15.1 Participants with diagnostic criteria according to guideline	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.91, 1.05]
15.2 Participants with diagnosis by trialists	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.24, 0.69]
16 Proportion of participants with detectable HBeAg in best‐worst case scenario	2	160	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.10, 3.90]
17 Proportion of participants with detectable HBeAg in worst‐best case scenario	2	160	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.13, 3.39]
18 Proportion of participants with fatigue	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
19 Proportion of participants with bloating	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
20 Proportion of participants with loss of appetite	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
21 Proportion of participants with flank pain	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
22 Proportion of participants with bradycardia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
23 Proportion of participants with bradycardia in best‐worst case scenario	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
24 Proportion of participants with bradycardia in worst‐best case scenario	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
25 Proportion of participants with significant changes in blood routine tests	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
26 Proportion of participants with significant changes in blood routine tests in best‐worst case scenario	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
27 Proportion of participants with significant changes in blood routine tests in worst‐best case scenario	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

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1.11 — Comparison 1 Acupuncture versus no intervention, Outcome 11 Proportion of participants with detectable HBeAg (fixed‐effect).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Huang 2011.

Methods	Randomised clinical trial, China Parallel‐group design
Participants	Included participants: 60 randomised participants diagnosed with chronic hepatitis B according to "The guideline of prevention and treatment for chronic hepatitis B" (CSH‐CMA and SID‐CMA 2006); disease history of chronic hepatitis B or hepatitis B virus infection, 2 × ULN ≤ alanine aminotransferase (ALT) ≤ 10 × ULN, total bilirubin (TBil) ≤ 2 × ULN, positive HBsAg and HBeAg in serum, HBV‐DNA in serum ≥ 1 × 10⁵ copies/mL, 18 to 65 years old, and signing the informed consent form. One participant in the control group was excluded from data analysis because the participant quit the trial; study authors did not report why and when the participant quit the trial Male:Female = 47:12 Mean age: experimental group 25 years, control group 23 years Exclusion criteria: participants infected by hepatitis A virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, other hepatitis viruses, or other viral infections; participants with probable liver decompensation
Interventions	Experimental intervention: acupoint injection: Astragalus was injected into both sides of the Zu San Li (ST36) acupoints, 2 mL for each acupoint per time, once every other day, for 6 months (n = 30) Control intervention: no intervention (n = 29) Co‐intervention: recombinant human interferon (IFN)‐alpha 2a 6 million units subcutaneously, 3 times a week, for 6 months
Outcomes	Liver function bio markers, HbsAg, HbeAg, HbeAb, HbcAb, HBV‐DNA, and TC level in serum, response rate (a compound outcome measure defined by trialists)
Notes	Study dates: 2009.08 to 2009.11 We called the telephone number of the authors' hospital on 28 April 2018, but we could not contact the people. We could not obtain their email addresses or any other contact details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers table
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Except for equally implemented co‐interventions, the experimental group used acupuncture injection, and the control group used nothing, which can easily unseal the blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	There was a small proportion of participants (1.7%) with missing data. One participant in the control group was excluded from data analysis
Selective reporting (reporting bias)	High risk	We could not find any protocols for this study, and this study did not report any outcomes that were defined as primary outcomes in our protocol
Other bias	Low risk	This study appeared to be free of other factors that could put it at risk of bias

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Jing 2016.

Methods	Randomised clinical trial, China Parallel‐group design
Participants	Included participants: 60 participants diagnosed with chronic hepatitis B according to "The guideline of prevention and treatment for chronic hepatitis B: a 2010 update" (CSH‐CMA and SID‐CMA 2011): disease duration longer than 6 months; HBsAg, HBeAg, and HBV‐DNA positive in serum; ALT 80 to 200 U/L; HBV‐DNA ≥ 10⁵ copies/Ml; TBiL ≤ 34.2 U/L Male:Female = 33:27 Age: 20 to 40 years old Exclusion criteria: pregnant participants; participants with mental illness; participants with uncontrolled epilepsy; participants with unabated alcoholism and drug use; participants with uncontrolled autoimmunity disease, symptomatic heart disease, thyroid disease, retinopathy, and psoriasis; participants with depression, uncontrolled diabetes, and hypertension; participants with neutrophil < 1.0 × 10⁹/L and platelet < 50 × 10⁹/L before the trial; participants using other immunomodulators or other antiviral drugs 3 months before the trial; participants with hepatitis A, C, D, or E virus infection, alcoholic liver disease, autoimmune liver disease, and other liver diseases; participants with liver cirrhosis or suspected hepatocellular carcinoma; participants with creatinine level greater than normal level in serum; participants with human immunodeficiency virus infection
Interventions	Experimental intervention: acupoint injection: Astragalus (10 mL) was injected in the acupoint Zu San Li (ST 36), each side of 5 mL; compound Angelica injection (2 mL) in either side of the acupoint Zu San Li (ST 36); 3 times a week, once every other day, for 1 year (n = 30) Control intervention: no intervention (n = 30) Co‐intervention: peginterferon alpha‐2a 180 μg, subcutaneous injection, once a week for 1 year (n = 30)
Outcomes	Response rate (a compound outcome measure defined by the trialists) and the biomarkers CD4 level, CD8 level, and CD4/CD8
Notes	Study dates: 2013.08 to 2014.06 We called the telephone number of the study authors' hospital on 23 April 2018, but we could not contact the people. We could not obtain their email addresses or any other contact details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers table
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Except for equally implemented co‐interventions, the experimental group used acupuncture injection, and the control group used nothing, which can easily unseal the blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	The number of participants included in the analysis was equal to the number of participants randomised
Selective reporting (reporting bias)	High risk	We could not find any protocols for this study, and this study did not report any outcomes that were defined as primary outcomes in our protocol
Other bias	Low risk	This study appeared to be free of other factors that could put it at risk of bias

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Liao 2011.

Methods	Randomised clinical trial, China Parallel‐group design
Participants	Included participants: 60 participants diagnosed with chronic hepatitis B according to "The guideline of prevention and treatment for chronic hepatitis B" (CSH‐CMA and SID‐CMA 2006), in light or moderate disease degree (CSIP‐CMA and CSH‐CMA 2001): disease duration longer than 6 months, HBsAg and HBV‐DNA positive in serum, ALT persistent or repeated abnormal in serum, could not afford antiviral treatments, 18 to 65 years old, willing to participate in the trial Male:Female = 48:12 Mean age: experimental group 36.5 years, control group 35.4 years Exclusion criteria: participants who did not meet the inclusion criteria; participants with serious chronic hepatitis B (CSIP‐CMA and CSH‐CMA 2001); participants with hepatitis caused by factors such as drug poisoning and alcohol poisoning; participants with autoimmune hepatitis; participants with chronic hepatitis caused by other hepatitis viruses; participants with cirrhosis; participants with hepatocellular carcinoma, hepatic encephalopathy, and serious cardiovascular or cerebrovascular disease; participants with renal system, endocrine system, or hematopoietic system disease; pregnant, preparing for pregnancy, or lactating women; participants younger than 18 years or older than 65 years; participants with an allergic history of Yin Chen Hao (Herba artemisiae); participants taking antiviral drugs; participants unwilling to accept the intervention or who could not co‐ordinate with researchers (e.g. participants with mental disease)
Interventions	Experimental intervention: acupoint herbal patching: mixture of traditional Chinese herb Yin Chen Hao, Da Huang, Zhi Zi. Cover the acupoints Ji Men (SP 11) and Ri Yue (GB 24) on the right side, with patching for 4 hours to 8 hours, once daily, 3 weeks (n = 30) Control intervention: no intervention (n = 30) Co‐intervention: diammonium glycyrrihizinate injection 150 mg, once daily, 3 weeks (n = 30)
Outcomes	Liver biomarkers: AST, ALT, A/G, and TBIL; routine blood tests, routine urinalysis, and stool analysis; renal biomarkers
Notes	Study dates: 2010.08 to 2011.04 We called the telephone number of the study authors' hospital on 25 April 2018, but we could not contact the people. We could not obtain their email addresses or any other contact details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers table
Allocation concealment (selection bias)	Low risk	Information on random allocation was hidden in opaque envelopes
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Except for equally implemented co‐interventions, the experimental group used acupoint herbal patching, and the control group used nothing, which can easily unseal the blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	The number of participants included in the analysis was equal to the number of participants randomised
Selective reporting (reporting bias)	High risk	We could not find any protocols for this study, and this study did not report any outcomes that were defined as primary outcomes in our protocol
Other bias	Low risk	The study appeared to be free of other factors that could put it at risk of bias

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Wang 2002.

Methods	Randomised clinical trial, China Parallel‐group design
Participants	Included participants: 60 randomised participants diagnosed as people having chronic hepatitis B (detailed diagnostic criteria are not reported): 18 to 65 years old, with HBsAg, HBV DNA positive in serum longer than 6 months before enrolment, ALT persistent or repeated higher than 2 times normal level in serum, TBiL in serum less than 22 μmol/L. Two participants in the control group were excluded from data analysis because unrecoverable white blood cell count after 2 weeks medication and they had quit the trial Male:Female = unclear Mean age: experimental group 25.7 years, control group 29.5 years Exclusion criteria: participants with decompensate cirrhosis; participants with infection of other hepatitis viruses and other serious complications; pregnant and lactating women; participants with regular antiviral treatments in the 6 months before enrolment
Interventions	Experimental intervention: manual needle acupuncture: 1 hour for manipulating needles, once daily, 1 day off each week, for a total of 2 months. The main acupoints are Bai Hui (GV 20), Da Zhui (GV 14), Gan Shu (BL‐18), Shen Shu (BL 23), Zu San Li (ST 36), Yang Ling Quan (GB 34), San Yin Jiao (SP 6), and Tai Chong (LV 3). Acupoints can be added or subtracted according to the disease condition (n = 30) Control intervention: no intervention (n = 28) Co‐intervention: basic liver protective drugs: intravenous vitamin C, etc. (without detailed drugs, doses, and treatment duration). Interferon IFN‐α2b, 5 million units, intramuscular injection once a day for the first 2 weeks, followed by intramuscular injection 3 times a week for a total of 6 months
Outcomes	Lliver biomarkers: AST, etc.; negative conversion rate of biomarkers: HBsAg, HBsAb, HBeAg, HBeAb, HBcAb, and HBV DNA
Notes	We called the telephone number of the study authors' hospital on 25 April 2018, but we could not contact the people. We could not obtain their email addresses or any other contact details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers table
Allocation concealment (selection bias)	Unclear risk	No information provided; no such information
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Except for equally implemented co‐interventions, the experimental group used acupuncture, and the control group used nothing, which can easily unseal the blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	There was a small proportion of participants (3.3%) with missing data. Two participants in the control group were excluded from data analysis because they had serious adverse events and had quit the trial, but study authors did not report what the adverse events were and when the participants experienced the adverse events
Selective reporting (reporting bias)	High risk	We could not find any protocols for this study, and this study did not report any outcomes that were defined as primary outcomes in our protocol
Other bias	Low risk	The study appeared to be free of other factors that could put it at risk of bias

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Wang 2013.

Methods	Randomised clinical trial, China Parallel‐group design
Participants	Included participants: 80 participants diagnosed with chronic hepatitis B according to "Liver disease diagnosis and treatment in traditional Chinese medicine" (KSWGLD 2005): disease duration longer than 6 months, HBsAg and HBV DNA positivity in serum, persistent or repeated abnormal ALT in serum Male:Female = 58:22 Mean age: 40.3 years Exclusion criteria: participants with other liver diseases such as drug‐induced hepatitis, alcoholic hepatitis, autoimmune hepatitis, etc.; participants with other hepatitis virus infection; participants with confirmed or suspected liver cancer; participants with severe cardiovascular, renal, or endocrine disease
Interventions	Experimental intervention: moxibustion: a small pill (consists of Huang Qi, Dang Shen, Bai Zhu, Dan Shen, Rou Gui, Yi Yi Ren) was placed on the umbilicus (Shen Que, CV 8); a moxa stick was burned at 2 to 3 cm above the skin of the umbilicus, which lasts for 20 to 30 minutes, once daily, for 3 months (n = 40) Control intervention: no intervention (n = 40) Co‐intervention: routine nursing and treatment methods for liver cirrhosis (without detail description)
Outcomes	Biomarkers: TBil, ALT, AST, ALB, HA, LN, PCⅢ, and Ⅳ‐C
Notes	Study dates: no information provided We called the telephone number of the authors' hospital on 24 April 2018, but we could not contact the people. We could not obtain their email addresses or any other contact details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers table
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Except for equally implemented co‐interventions, the experimental group used moxibustion, and the control group used nothing, which can easily unseal the blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	The number of participants included in the analysis was equal to the number of participants randomised
Selective reporting (reporting bias)	High risk	We could not find any protocols for this study, and this study did not report any outcomes that were defined as primary outcomes in our protocol
Other bias	Low risk	This study appeared to be free of other factors that could put it at risk of bias

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Zhang 2014.

Methods	Randomised clinical trial, China
Participants	Included participants: 70 participants diagnosed with chronic hepatitis B according to "The guideline of prevention and treatment for chronic hepatitis B" (CSH‐CMA and SID‐CMA 2006): disease duration longer than 6 to 36 months, HBsAg and HBV‐DNA positivity in serum, persistent or repeated abnormal ALT in serum, 18 to 58 years old, without using relevant drugs in the past 30 days Male:Female = 36:34 Mean age: experimental group 34.33 years, control group 36.85 years Exclusion criteria: participants not fulfilling the diagnostic criteria; patients with hepatitis; patients with heart disease; patients with mental disease or neurological disorders such as Parkinson; participants who have had liver surgery; participants allergic to the drugs used in this trial; participants allergic to anything; participants taking drugs that may have an effect on this trial
Interventions	Experimental intervention: manual needle acupuncture: on acupoints Zu San Li (ST 36), San Yin Jiao (SP 6), Zhi Yang (GV 9), Zhi Gou (SJ 6), and Tai Chong (LV 3), once daily, 3 months. Paroxetine, 10 mg, once daily, 3 months. If necessary, it can be combined with liver protective drugs such as diammonium glycyrrihizinate (n = 35) Control intervention: no intervention (n = 35) Co‐intervention: paroxetine, 10 mg, once daily, 3 months. If necessary, it can be combined with liver protective drugs such as diammonium glycyrrihizinate
Outcomes	Liver function biomarkers; indexes for drug safe testing: routine blood tests, routine urinalysis, stool analysis, renal function biomarkers, blood pressure, blood lipids, blood sugar, and electrocardiogram
Notes	Study dates: no information provided We called the telephone number of the study authors' hospital on 25 April 2018, but we could not contact the people. We could not obtain their email addresses or any other contact details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers table
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Except for equally implemented co‐interventions, the experimental group used acupuncture, and the control group used nothing, which can easily unseal the blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	The number of participants included in the analysis was equal to the number of participants randomised
Selective reporting (reporting bias)	High risk	We could not find any protocols for this study, and this study did not report any primary outcomes in our protocol
Other bias	Low risk	The study appeared to be free of other factors that could put it at risk of bias

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Zhu 2016.

Methods	Randomised clinical trial, China Parallel‐group design
Participants	Included participants: 65 participants diagnosed with chronic hepatitis B according to the "Modern liver disease treatment" (Wang JY 1999): disease duration longer than 6 months, HBsAg and HBV DNA positivity in serum, persistent or repeated abnormal ALT in serum, and liver cirrhosis with refractory ascites according to AASLD (AASLD 2009;Moore 2003) Male:Female = 41:24 Mean age = experimental group 39.3 years, control group 42.3 years Exclusion criteria: participants with serious complications such as gastrointestinal haemorrhage, hepatic encephalopathy, or hepatorenal syndrome; patients with ascites caused by infection or malignant tumour; participants with serious disease such as cardiovascular, renal, or hematopoietic system disease; patients with mental illness; participants with total bilirubin > 50 μmol/L and severe blood coagulation disorder (PTA < 30%); alcoholics
Interventions	Experimental intervention: acupuncture herbal patching: mixture of traditional Chinese herb Huang Qi, Rou Gui, Sha Ren, etc. Cover the acupoint Shen Que (CV 8) with the patching for 3 hours, once daily, 14 days (n = 33) Control intervention: no intervention (n = 32) Co‐intervention: tolvaptan (Otsuka Co., Ltd.) 15 mg, once daily for 7 days, then 7.5 mg once daily; reduced glutathione for injection, 1.8 g, once daily, intravenous drip; furosemide 80 to 160 mg per day and spironolactone 200 to 400 mg per day according to the condition, intravenous infusion; limited sodium intake (< 6 g/d); intermittent injection of human albumin
Outcomes	Color doppler: portal vein velocity/amount, splenic venous blood flow velocity/amount, and ascites dark zone depth; liver biomarkers: ALT, AST, GGT, TBIL, ALB, A/G; sodium level in blood and urine
Notes	Study dates: 2013. 12 to 2015. 07 We called the telephone number of the study authors' hospital on 23 April 2018, but we could not contact the people. We could not obtain their email addresses or any other contact details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers table
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Except for equally implemented co‐interventions, the experimental group used acupuncture herbal patching, and the control group used nothing, which can easily unseal the blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	The number of participants included in the analysis was equal to the number of participants randomised
Selective reporting (reporting bias)	High risk	We could not find any protocols for this study, and this study reported on only one of our primary outcomes ‐ serious adverse events
Other bias	Low risk	This study may or may not have been free of other factors that could put it at risk of bias

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Zou 2011.

Methods	Randomised clinical trial, China Parallel‐group design
Participants	Included participants: 100 participants diagnosed with chronic hepatitis B according to the "Diagnosis of viral hepatitis" (CMA‐SCH and CMA‐SID 2001): disease duration longer than 6 months, HBsAg positive in serum, ALT 2 to 10 times the upper limit of normal, total bilirubin lower than 5 times the upper limit of normal, and age between 18 and 65 years Male:Female = not reported Age: 13 to 65 years Exclusion criteria: participants with other hepatitis virus infection; participants with severe chronic hepatitis B, drug‐related hepatitis, alcoholic hepatitis, autoimmune hepatitis
Interventions	Experimental intervention: acupuncture herbal patching: mixture of traditional Chinese herbs Ku Shen, Qing Hao, Huang Qin, Di Bie Chong, Lang Du, Chi Shao, Ru Xiang, Chang Pu, Bo He Nao. After cleaning and massaging local skin for 1 minute, cover the acupoints Ri Yue (GB 24), Ji Men (SP 11), and Zhang Men (LV 13), on the right side, with the patching. Gently press the patching for 3 minutes for each acupoint and then keep the patching for 36 hours, once for two days, 12 weeks (n = 50) Control intervention: no intervention (n = 50) Co‐intervention: glycyrrhizic acid diamine 100 to 150 mg, intravenous drip, once daily; Ku Huang injection 20 to 30 mL, intravenous drip, once daily, 12 weeks
Outcomes	Recovery rate of biomarkers: ALT, TBIL, ALB; negative rate of biomarkers: HBsAg, HBeAg, and HBV DNA; safety indicators (not reported in detail)
Notes	Study dates: 2008 to 2009 We called the telephone number of the study authors' hospital on 23 April 2018, but we could not contact the people. We could not obtain their email addresses or any other contact details
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random numbers table
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Except for equally implemented co‐interventions, the experimental group used acupuncture herbal patching, and the control group used nothing, which can easily unseal the blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias)   All outcomes	Low risk	The number of participants included in the analysis was equal to the number of participants randomised
Selective reporting (reporting bias)	High risk	We could not find any protocols for this study, and this study did not report any primary outcomes in our protocol
Other bias	Low risk	This study appear to be free of other factors that could put it at risk of bias

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A/G: albumin/globulin ratio.  ALT: alanine aminotransferase.  AST: aspartate aminotransferase.  CD4: cluster of differentiation 4.  CD8: cluster of differentiation 8.  GGT: gamma‐glutamyltransferase.  HA: hyaluronic acid.  HbcAb: hepatitis B core‐antibody.  HbeAb: hepatitis B virus e‐antibody.  HbeAg: hepatitis B virus e‐antigen.  HbsAg: hepatitis B virus S‐antigen.  HBV DNA: hepatitis B virus DNA.  Ⅳ‐C: type Ⅳ collagen.  LN: laminin.  PCⅢ: type Ⅲ procollagen.  PTA: plasma thromboplastin antecedent.  ULN: upper limit of normal.  TC: total cholesterol.

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Chang 1994	Does not fulfil the intervention inclusion criteria
Chen 1993	Does not fulfil the intervention inclusion criteria
Chen 1995	Does not fulfil the intervention inclusion criteria
Chen 1999	Does not fulfil the intervention inclusion criteria
Chen 2013	Does not fulfil the intervention inclusion criteria
Chen 2015	Does not fulfil the intervention inclusion criteria
Cui 2002	Does not fulfil the intervention inclusion criteria
Dai 2009	Does not fulfil the intervention inclusion criteria
Dai 2015	Does not fulfil the intervention inclusion criteria
Dong 1997	Does not fulfil the intervention inclusion criteria
Fu 1994	Does not fulfil the intervention inclusion criteria
Fu 2007	Does not fulfil the intervention inclusion criteria
Fu 2015	Does not fulfil the intervention inclusion criteria
Gao 2016	Does not fulfil the intervention inclusion criteria
Ge 2013	Does not fulfil the intervention inclusion criteria
Gu 1996	Does not fulfil the intervention inclusion criteria
Guo 2000	Does not fulfil the intervention inclusion criteria
Han 2005	Does not fulfil the intervention inclusion criteria
Han 2009	Does not fulfil the intervention inclusion criteria
Han 2012	Does not fulfil the intervention inclusion criteria
Hao 2014	Does not fulfil the intervention inclusion criteria
He 2002	Does not fulfil the intervention inclusion criteria
Huang 2005	Does not fulfil the intervention inclusion criteria
Huang 2011b	Does not fulfil the intervention inclusion criteria
Jin 2011	Does not fulfil the intervention inclusion criteria
Kong 2005	Does not fulfil the intervention inclusion criteria
Kong 2008	Does not fulfil the intervention inclusion criteria
Lan 2001	Does not fulfil the intervention inclusion criteria
Li 1990	Does not fulfil the intervention inclusion criteria
Li 1992	Does not fulfil the intervention inclusion criteria
Li 2000a	Does not fulfil the intervention inclusion criteria
Li 2000b	Not chronic hepatitis B
Li 2005	Self‐controlled clinical study
Li 2011	Not a randomised clinical trial
Li 2013	Does not fulfil the intervention inclusion criteria
Li 2014	Does not fulfil the intervention inclusion criteria
Li 2015	Does not fulfil the intervention inclusion criteria
Li 2016	Does not fulfil the intervention inclusion criteria
Lian 1990	Does not fulfil the intervention inclusion criteria
Lian 1991	Does not fulfil the intervention inclusion criteria
Lin 2003	Does not fulfil the intervention inclusion criteria
Lin 2003b	Does not fulfil the intervention inclusion criteria
Lin 2011	Does not fulfil the intervention inclusion criteria
Liu 1999	Does not fulfil the intervention inclusion criteria
Liu 2003	Does not fulfil the intervention inclusion criteria
Liu 2003b	Does not fulfil the intervention inclusion criteria
Liu 2004	Does not fulfil the intervention inclusion criteria
Liu 2004b	Does not fulfil the intervention inclusion criteria
Liu 2005	Does not fulfil the intervention inclusion criteria
Liu 2006	Does not fulfil the intervention inclusion criteria
Lu 2004	Does not fulfil the intervention inclusion criteria
Lu 2004b	Does not fulfil the intervention inclusion criteria
Lu 2011	Does not fulfil the intervention inclusion criteria
Ma 2002	Does not fulfil the intervention inclusion criteria
Ma 2014	Does not fulfil the intervention inclusion criteria
Qin 2009	Does not fulfil the intervention inclusion criteria
Qiu 2006	Does not fulfil the intervention inclusion criteria
Ruan 2004	Does not fulfil the intervention inclusion criteria
Shao 2011	Does not fulfil the intervention inclusion criteria
Shi 1997	Does not fulfil the intervention inclusion criteria
Song 2008	Does not fulfil the intervention inclusion criteria
Sun 2000	Does not fulfil the intervention inclusion criteria
Sun 2003	Does not fulfil the intervention inclusion criteria
Tang 2007	Does not fulfil the intervention inclusion criteria
Tang 2013	Does not fulfil the intervention inclusion criteria
Tao 1988	Does not fulfil the intervention inclusion criteria
Tian 1998	Does not fulfil the intervention inclusion criteria
Tian 2005	Does not fulfil the intervention inclusion criteria
Wang 1990	Does not fulfil the intervention inclusion criteria
Wang 1993	Does not fulfil the intervention inclusion criteria
Wang 2003	Does not fulfil the intervention inclusion criteria
Wang 2010	Does not fulfil the intervention inclusion criteria
Wang 2011	Does not fulfil the intervention inclusion criteria
Wang 2013b	Does not fulfil the intervention inclusion criteria
Wang 2014	Does not fulfil the intervention inclusion criteria
Wang 2015	Review
Wang 2016	Does not fulfil the intervention inclusion criteria
Wei 1989	Does not fulfil the intervention inclusion criteria
Wen 2003	Does not fulfil the intervention inclusion criteria
Wu 2002	Does not fulfil the intervention inclusion criteria
Xia 1988	Does not fulfil the intervention inclusion criteria
Xia 2015	Does not fulfil the intervention inclusion criteria
Xu 1988	Does not fulfil the intervention inclusion criteria
Xu 1994	Does not fulfil the intervention inclusion criteria
Xu 1996	Not a randomised controlled trial
Xu 1999	Does not fulfil the intervention inclusion criteria
Xu 2011	Does not fulfil the intervention inclusion criteria
Xu 2016	Does not fulfil the intervention inclusion criteria
Xue 2012	Does not fulfil the intervention inclusion criteria
Yang 1992	Does not fulfil the intervention inclusion criteria
Yang 2002	Does not fulfil the intervention inclusion criteria
Yang 2007	Does not fulfil the intervention inclusion criteria
Ying 2010	Does not fulfil the intervention inclusion criteria
Yu 2015	Does not fulfil the intervention inclusion criteria
Zeng 1994	Does not fulfil the intervention inclusion criteria
Zhang 1998	Does not fulfil the intervention inclusion criteria
Zhang 1998b	Does not fulfil the intervention inclusion criteria
Zhang 1999	Does not fulfil the intervention inclusion criteria
Zhang 2000	Does not fulfil the intervention inclusion criteria
Zhang 2003	Does not fulfil the intervention inclusion criteria
Zhang 2005	Does not fulfil the intervention inclusion criteria
Zhang 2008	Does not fulfil the intervention inclusion criteria
Zhang 2008b	Does not fulfil the intervention inclusion criteria
Zhang 2012	Does not fulfil the intervention inclusion criteria
Zhang 2016	Does not fulfil the intervention inclusion criteria
Zhao 2014	Does not fulfil the intervention inclusion criteria
Zhao 2014b	Does not fulfil the intervention inclusion criteria
Zhou 1998	Does not fulfil the intervention inclusion criteria
Zhou 2002	Does not fulfil the intervention inclusion criteria
Zhou 2015	Does not fulfil the intervention inclusion criteria

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Characteristics of ongoing studies [ordered by study ID]

ChiCTR‐IOR‐17011957.

Trial name or title	Therapeutic effect of acupoint application (Shu Gan Jian Pi plaster) combined with antiviral drugs on chronic hepatitis B with stagnation of liver qi and spleen deficiency
Methods	Randomised clinical trial, China Parallel‐group design
Participants	Inclusion criteria: participants diagnosed with chronic hepatitis B; participants with positive HBsAg and HBV DNA in serum or participants with liver biopsy ≥ G2; participants with ALT level in serum greater than 2 times the normal value; participants with chronic hepatitis B and traditional Chinese medicine syndrome of liver stagnation and spleen deficiency Exclusion criteria: participants with infection of other type of hepatitis virus; participants with chronic severe hepatitis or cirrhosis; participants with heart, kidney, lung, endocrine, blood, metabolism, or gastrointestinal serious primary disease or participants with mental disease; pregnant women or lactating women; participants with allergic constitution
Interventions	Experimental intervention: acupuncture herbal patching (Shu Gan Jian Pi herbal patching) (n = 60) Control intervention: no intervention (n = 60) Co‐intervention: basic treatment (no detailed information provided)
Outcomes	Symptoms caused by implementation of Chinese medicine, liver function test, quantitative HBV DNA, quantitative HBsAg, SF‐36 concise health scale, cirrhosis incidence, coagulation function, routine blood test, renal function, routine urine test, fecal routine
Starting date	2017.08.01
Contact information	Infectious Disease Hospital of Shanghai Pudong District of Shanghai; contact author: Jianhua Xue; email address: 61512641@qq.com or hk5771@126.com; telephone number: +86 13585980751
Notes	None

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ChiCTR‐IOR‐17011962.

Trial name or title	Observation on the quality of life of chronic hepatitis B treated with acupoint magnetotherapy combined with Chinese Medicine
Methods	Randomised clinical trial, China Parallel‐group design
Participants	Inclusion criteria: participants diagnosed with chronic hepatitis B; participants with positive HBsAg and HBV DNA in serum or participants with liver biopsy ≥ G2; participants with ALT level in serum greater than 2 times the normal value Exclusion criteria: participants with infection of other type of hepatitis virus; participants with chronic severe hepatitis or cirrhosis; participants with heart, kidney, lung, endocrine, blood, metabolism, or gastrointestinal serious primary disease or participants with mental disease; pregnant women or lactating women; participants with allergic constitution
Interventions	Experimental intervention: ear acupoint magnetotherapy (n = 36) Control intervention: no intervention (n = 36) Co‐intervention: basic treatment (no detailed information provided)
Outcomes	Symptoms caused by implementation of Chinese Medicine, SF‐36 concise health scale, Pittsburgh Sleep Scale, liver function test, coagulation function, routine blood test,  ECG examination, renal function, routine urine test, fecal routine
Starting date	2017.08.01
Contact information	Infectious Disease Hospital of Shanghai Pudong District of Shanghai; contact author: Jianhua Xue; email address: 61512641@qq.com; telephone number: +86 13585980751
Notes	None

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ALT: alanine aminotransferase.  ECG: electrocardiography.  HBsAg: hepatitis B virus S‐antigen.  HBV DNA: hepatitis B virus DNA.

Differences between protocol and review

In the protocol, we planned to look at quasi‐randomised studies, controlled clinical studies, and other observational studies for data on harm, provided that they were retrieved through our searches for randomised clinical trials. This was our plan because adverse events are rarely reported in randomised clinical trials (Storebø 2018). Moreover, observational studies may provide information on rare or late‐occurring adverse events (Storebø 2018). However, due to the large number of studies retrieved and the large number of studies with insufficient information regarding their design, we decided to perform a separate systematic review on harms of acupuncture. This is why we did not extract data on harm from the identified non‐randomised studies (see Characteristics of excluded studies, as well as Appendix 2).

We performed 'best‐worst' case and 'worst‐best' case analyses for all outcomes instead of only for primary and secondary outcomes because we had very limited evidence for primary and secondary outcomes.

In case of one trial providing outcome data, we post hoc compared the results with Fisher's exact test and RevMan analysis, and we found no differences between them. Therefore, in view of future updates of the review, we kept and presented only results obtained through RevMan analysis.

Post hoc, we decided to present the results on our exploratory outcomes: the proportion of participants with detectable HBV DNA and the proportion of participants with detectable HBeAg, because acupuncture is considered by physicians to decrease discomfort and prevent replication of the virus in people with chronic hepatitis B. We conducted three post‐hoc Trial Sequential Analyses assuming the following: proportions of participants dying was low (4%; young participants with mild disease), moderate (20%; middle‐aged participants with mild disease), and high (40%; middle‐aged participants with severe disease) within one year in the control group.

Post hoc, we decided to present the results on our surrogate outcomes: the proportion of participants with detectable HBV DNA and the proportion of participants with detectable HBeAg, in the 'Summary of findings' table, in the Abstract, and in the Plain language summary.

In keeping with Cochrane CENTRAL requirements, we have now excluded the risk of bias domain on 'for‐profit funding' from the risk of bias domains listed in the protocol part of the review, and instead, we have reported in a narrative way the information gathered from the trials. In addition, consistent with Cochrane CENTRAL requirements, we assessed imprecision via Trial Sequential Analysis in a separate assessment of imprecision with GRADE in a sensitivity analysis.

Contributions of authors

DZK: developed and drafted the protocol; selected trials for inclusion; extracted trial data; contacted study authors for missing data; performed the risk of bias assessment; interpreted data; drafted the final review.  NL: developed and co‐ordinated the protocol; interpreted data; commented on the final review.  GLY: selected trials for inclusion; commented on the final review.  ZZ: selected trials for inclusion; commented on the final review.  YY: selected trials for inclusion; commented on the final review.  YXL: selected trials for inclusion; commented on the final review.  QGW: selected trials for inclusion; commented on the final review.  YL: extracted data from trials; contacted study authors for missing data; performed the risk of bias assessment; commented on the final review.  FZ: extracted data from trials; contacted study authors for missing data; performed the risk of bias assessment; commented on the final review.  HYZ: extracted data from trials; contacted study authors for missing data; performed the risk of bias assessment; commented on the final review.  DN: developed, co‐ordinated, and advised on the protocol; advised on interpretation of data; commented on the final review.  JCJ: developed, co‐ordinated, and advised on the protocol; advised on interpretation of data; commented on the final review.  CG: developed, co‐ordinated, and advised on the protocol; advised on interpretation of data; commented on the final review.  JPL: initiated the review; advised and commented on the protocol and the final review.

All review authors approved publication of the current version.

Sources of support

Internal sources

No sources of support supplied

External sources

2017 Open‐end Fund of Education Ministry Key Laboratory for Research and Application of 'Zang Xiang' Theory in Liaoning University of Traditional Chinese Medicine (zyzx1702), China.
Science and Technology Research Project of Department of Education of Liaoning Province (L201713), China.
Grant Number R24 AT001293 from the National Center for Complementary and Integrative Health (NCCIH), USA, USA.
- This work was partially funded by Grant Number R24 AT001293 from the National Center for Complementary and Integrative Health (NCCIH). The contents of this systematic review are solely the responsibility of the authors and do not necessarily represent the official views of the NCCIH or the National Institutes of Health.

Declarations of interest

DZK: none known.  NL: none known.  GLY: none known.  ZZ: none known.  YL: none known.  YY: none known.  YXL: none known.  QGW: none known.  FZ: none known  HYZ: none known  DN: none known.  JCJ: none known.  CG: none known.  JPL: none known.

New

References

References to studies included in this review

Huang 2011 {published data only}

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Li 1990 {published data only}

Li DX, Zhu XQ, Wang BS. Treatment of 40 cases of chronic hepatitis B with acupoint application of Chinese medicine [中药穴位敷贴治疗慢性乙型肝炎40例]. Shanghai Journal of Acupuncture and Moxibustion 1990;1:6. [Google Scholar]

Li 1992 {published data only}

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Li 2000a {published data only}

Li FS. Treatment of 48 cases of chronic hepatitis B with acupoint injection of hepatitis B vaccine combined with traditional Chinese medicine [乙肝疫苗穴位注射联合中药治疗慢性乙型肝炎48例]. Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases 2000;10(4):39‐40. [Google Scholar]

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Li 2005 {published data only}

Li XP, Gao YX, Chai YF, Qiu AG. Effect of acupuncture and moxibustion combined therapy on liver histopathology in patients with chronic hepatitis B [针灸药结合疗法对慢性乙型肝炎患者肝组织病理学的影响]. Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases 2005;15(2):79‐80. [Google Scholar]

Li 2011 {published data only}

Li XJ, Liu XY. Treatment of 60 cases of chronic hepatitis B by intervention of moxibustion and interferon [督灸预防干扰素治疗慢性乙型肝炎副反应60例]. Global Traditional Chinese Medicine 2011;4(6):471‐2. [Google Scholar]

Li 2013 {published data only}

Li YS, Zhao WS. Therapeutic effect of Ling Zhi Yang Gan pill combined with liver disease treatment instrument and lamivudine for chronic hepatitis B and liver fibrosis [灵芝养肝丸联合肝病治疗仪、拉米夫定治疗慢性乙型肝炎肝纤维化的疗效探讨]. Seek Medical and Ask the Medicine 2013;11(2):530‐1. [Google Scholar]

Li 2014 {published data only}

Li YC. Clinical efficacy of traditional Chinese herbal patching in the treatment of chronic hepatitis B [中药贴敷干预治疗慢性乙型肝炎的临床疗效]. Drugs and Clinical 2014;11:69‐70. [Google Scholar]

Li 2015 {published data only}

Li YF, Xie DM, Yang ZZ, Yao LH, Qi YP. Clinical research of chronic hepatitis B with combined therapy by acupoint catgut embedding and entecavir [穴位埋线联合恩替卡韦片治疗慢性乙型肝炎临床研究]. Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases 2015;25(4):203‐5. [Google Scholar]

Li 2016 {published data only}

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Lian 1990 {published data only}

Lian WZ. Acupoint injection of water needle for treatment of chronic hepatitis B [水针穴位注射治疗慢性乙型肝炎]. Journal of Traditional Chinese Medicine 1990;9:38‐40. [Google Scholar]

Lian 1991 {published data only}

Lian WZ. Water needle in acupuncture point in treating patients with hepatitis A and B double infection [穴位水针治疗乙型甲型肝炎双重感染]. Zhejiang Journal of Traditional Chinese Medicine 1991;26(4):176‐7. [Google Scholar]

Lin 2003 {published data only}

Lin CL, Zhang FY. Treatment of 100 cases of hepatitis B with acupoint injection of water needle and oral drugs [水针穴位注射联合口服药物治疗乙型肝炎100例]. Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases 2003;S1:126‐7. [Google Scholar]

Lin 2003b {published data only}

Lin XM, Shi JP. Clinical observation on 47 cases of chronic hepatitis B treated by acupoint water needle [穴位水针治疗慢性乙型肝炎47例临床观察]. Chinese Journal of Traditional Medical Science and Technology 2003;10(1):57. [Google Scholar]

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Liu 1999 {published data only}

Liu YM, Chang XH, Han TY, Zhang LL, Zhou SF, Du ZP. Effect of acupuncture on hepatitis B serum virus markers [针刺对乙肝血清病毒标志物的影响]. Shanxi Journal of Traditional Chinese Meidicine 1999;15(1):30‐1. [Google Scholar]

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Liu YL. Observation on therapeutic effect of combined treatment of acupoint injection, burning rush moxibustion and interferon on chronic hepatitis B [穴位注射灯芯灸联合干扰素治疗慢性乙型肝炎疗效观察]. Chinese Acupuncture & Moxibustion 2003;23(10):583‐4. [Google Scholar]

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Liu CQ. Treatment of 351 cases of chronic hepatitis B with traditional Chinese medicine combined with acupoint injection, pricking, and cupping [中药结合穴位注射与刺络拔罐法治疗慢性乙肝351例]. Shanxi Journal of Traditional Chinese Medicine 2005;21(2):38‐9. [Google Scholar]

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Liu SJ, Wang X, Li XY, Liu ZF, Yao LH. Clinical study on blocking hepatitis B virus mother‐to‐child transmission by acupoint injection of hepatitis B immunoglobulin [穴位注射乙型肝炎免疫球蛋白阻断乙型肝炎病毒母婴传播的临床研究]. Chinese Journal of Practical Gynecology and Obstetrics 2006;22(1):47‐8. [Google Scholar]

Lu 2004 {published data only}

Lu MS, Guo YW, Xu LH, Chen GH, Gan JE. Clinical study on treatment of chronic hepatitis B with Huang Bai Zhu Cao mixture combined with acupoint injection therapy [黄白珠草合剂联合穴位注射疗法治疗慢性乙型肝炎的临床研究]. Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases 2004;14(2):83‐4. [Google Scholar]

Lu 2004b {published data only}

Lu HY, Wang CX, Zhou L. Clinical observation of acupoint injection of α‐1b interferon in the treatment of chronic hepatitis B [α‐1b干扰素穴位注射治疗慢性乙肝临床观察]. Chinese Medicine Study 2014;2(6):69‐70. [Google Scholar]

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Lu HY. Therapeutic effect of low‐dose interferon α‐1b acupoint injection on elderly patients with chronic hepatitis B [小剂量干扰素α‐1b穴位注射治疗老年慢性乙型肝炎疗效观察]. China Practical Medicine 2011;6(28):166‐7. [Google Scholar]

Ma 2002 {published data only}

Ma JM, Yu DD, Wang R, Ying Q. Acupoint injection for treatment of 15 cases of hepatitis B [穴位注射治疗乙型肝炎15例]. Journal of Changchun College of Traditional Chinese Medicine 2002;18(2):38. [Google Scholar]

Ma 2014 {published data only}

Ma WQ. Therapeutic effect of traditional Chinese medicine enema combined with moxibustion on cirrhosis ascites [中药灌肠配合艾灸治疗肝硬化腹水疗效观察]. China Practical Medicine 2014;9(9):171. [Google Scholar]

Qin 2009 {published data only}

Qin XL, Li SQ, Jiang YP, Zhong T, Cao Z. Treatment of 100 cases of chronic hepatitis B (liver stagnation and spleen deficiency syndrome) by acupuncture combined with medicine [针药并用治疗慢性乙型肝炎(肝郁脾虚型)100例]. Jiangxi Journal of Traditional Chinese Medicine 2009;40(322):61. [Google Scholar]

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Qiu WW, Chang J, Shen SE, Shi BB, Pan XF. Clinical study on 30 cases of chronic hepatitis B treated with electroacupuncture [电针治疗慢性乙型肝炎30例临床研究]. Jiangsu Journal of Traditional Chinese Medicine 2006;27(6):39‐40. [Google Scholar]

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Ruan YD, Mo BQ, Ning XJ, Liu P. Clinical observation on 60 cases of chronic hepatitis B treated by Gan Yan Ling injection and Huang Yin injection [肝炎灵加黄茵注射液穴注治疗慢性乙型肝炎60例临床观察]. Journal of New Chinese Medicine 2004;36(8):25‐6. [Google Scholar]

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Shao FZ, Chen XY, Cao DH, Jiang XH. Clinical observation on 30 cases of chronic hepatitis B treated by Bushen granule combined with α‐2b interferon acupoint injection [补肾冲剂联合α一2b干扰素穴位注射治疗慢性乙型肝炎30例临床观察]. The Inaugural Meeting of the Infectious Diseases Committee of the Jiangxi Association of Integrative Medicine and the Compilation of the First Academic Conference on Infectious Diseases of Integrative Medicine in Jiangxi Province. 2011.

Shi 1997 {published data only}

Shi JP, Zhang BG. Effect of acupoint self‐blood therapy combined with natural moxibustion therapy on immune function in patients with chronic hepatitis B [腧穴自血疗法结合天灸疗法对慢性乙型肝炎患者免疫功能的影响]. Chinese Journal of Integrated Traditional and Western Medicine on Liver Diseases 1997;7(1):46‐7. [Google Scholar]

Song 2008 {published data only}

Song LC, Zhang GH, Huai DG, Zhang LY, Zhao J. Treatment of 46 cases of chronic hepatitis B by acupoint injection of oxymatrine injection [苦参素注射液穴位注射治疗慢性乙型肝炎46例]. China Foreign Medical Treatment 2008;23:66‐7. [Google Scholar]

Sun 2000 {published data only}

Sun HX, Fan EX, Song XW, Yao S, Hu ML. Effect of autologous frozen blood acupoint injection on serological markers in patients with hepatitis B [自体冷冻血液穴位注射对乙肝病人血清学标志的影响]. Journal of Norman Bethune University of Medical Science 2000;26(2):181‐2. [Google Scholar]

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Tang RG. Clinical observation on treatment of chronic hepatitis B with acupoint injection of Ku Shen Su combined with peginterferon α‐2a [苦参素穴位注射联合聚乙二醇干扰素α‐2a治疗慢性乙型肝炎的临床观察]. Compilation of the 16th National Conference on Viral Hepatitis and Liver Diseases of the Chinese Medical Association. 2013.

Tao 1988 {published data only}

Tao MZ, Zhang BS, Wang TY, Qiu ML. Efficacy evaluation of acupuncture treatment for asymptomatic hepatitis B virus carriers [针灸治疗无症状乙型肝炎病毒携带者疗效评价]. Acta Medica Sinica 1988;8(6):18‐20. [Google Scholar]

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Wang 2016 {published data only}

Wang AN, Li M, Dai Y, Gao J. Shugan Jianpi ointment acupoint sticking in the treatment of chronic hepatitis B (syndrome of stagnation of liver qi and spleen deficiency) for 30 cases [疏肝健脾膏穴位贴敷治疗慢性乙型肝炎(肝郁脾虚证)30例]. Chinese Medicine Modern Distance Education of China 2016;14(10):74‐6. [Google Scholar]

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Zhang WW, Han ZY. Expression of P‐glycoprotein and its significance in metastatic lymph nodes and primary lesions of gastric carcinoma [穴位注射α‐干扰素治疗慢性乙型肝炎临床疗效观察]. China Health Care & Nutrition 2012;7:1767‐8. [Google Scholar]

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Zhou L, Wang CJ, Liu YQ. Clinical observation on treatment of chronic hepatitis B by acupoint injection of polyporus polysaccharide [猪等多糖穴位注射治疗慢性乙型肝炎的临床观察]. Journal of Changchun College of Traditional Chinese Medicine 1998;14(72):13. [Google Scholar]

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Zhou Y, Xie RH, Du J. Therapeutic effect of acupoint injection of hepatitis A vaccine on 456 patients with chronic hepatitis B [甲肝疫苗穴位注射治疗456例慢性乙型肝炎患者疗效研究]. Infectious Disease Information 2002;15(2):91‐2. [Google Scholar]

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Zhou ZM, Li QY, Zhang JY, Lei HQ, Huang ZG. Randomized controlled study of traditional Chinese medicine fumigation combined with acupuncture on hepatitis B with jaundice [中药熏蒸联合针刺治疗黄疸型乙型肝炎随机平行对照研究]. Journal of Practical Traditional Chinese Internal Medicine 2015;29(8):147‐8. [Google Scholar]

References to ongoing studies

ChiCTR‐IOR‐17011957 {published data only}

ChiCTR‐IOR‐17011957. Therapeutic effect of acupoint application (Shugan Jianpi plaster) combined with antiviral drugs on chronic hepatitis B with stagnation of liver qi and spleen deficiency [穴位敷贴（疏肝健脾贴）联合抗病毒药物治疗肝郁脾虚型慢性乙型肝炎的疗效观察]. www.chictr.org.cn/showproj.aspx?proj=20420 (first received 12 July 2017).

ChiCTR‐IOR‐17011962 {published data only}

ChiCTR‐IOR‐17011962. Observation on the quality of life of chronic hepatitis B treated with acupoint magnetotherapy combined with Chinese Medicine [耳穴磁疗联合中药塌渍治疗慢性乙型肝炎生存质量观察]. www.chictr.org.cn/showproj.aspx?proj=20433 (first received 12 July 2017).

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PERMALINK

Acupuncture for chronic hepatitis B

De Zhao Kong

Ning Liang

Guan Lin Yang

Zhe Zhang

Yue Liu

Ye Yang

Yu Xi Liu

Qi Ge Wang

Fan Zhang

Hui Yong Zhang

Dimitrinka Nikolova

Janus C Jakobsen

Christian Gluud

Jian Ping Liu

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings for the main comparison. Acupuncture compared with no intervention for chronic hepatitis B.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Experimental intervention

Control intervention

Types of outcome measures

Primary outcomes

Secondary outcomes

Exploratory outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Allocation sequence generation

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessment

Incomplete outcome data

Selective outcome reporting

Other bias

Overall risk of bias

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Meta‐analysis

Trial Sequential Analysis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings

Results

Description of studies

Results of the search

1.

Included studies

Characteristics of the studies

Participants

Interventions and comparisons