Gene therapy for people with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is the most common type of liver cancer, accounting for 70% to 85% of individuals with primary liver cancer. Gene therapy, which uses genes to treat or prevent diseases, holds potential for treatment, especially for tumours. Trials on the effects of gene therapy in people with hepatocellular carcinoma have been published or are ongoing. OBJECTIVES: To evaluate the benefits and harms of gene therapy in people with hepatocellular carcinoma, irrespective of sex, administered dose, and type of formulation. SEARCH METHODS: We identified randomised clinical trials through electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We searched five online clinical trial registries to identify unpublished or ongoing trials. We checked reference lists of the retrieved studies for further trials. The date of last search was 20 January 2023. SELECTION CRITERIA: We aimed to include randomised clinical trials assessing any type of gene therapy in people diagnosed with hepatocellular carcinoma, irrespective of year, language of publication, format, or outcomes reported. DATA COLLECTION AND ANALYSIS: We followed Cochrane methodology and used Review Manager to prepare the review. The primary outcomes were all-cause mortality/overall survival (whatever data were provided), serious adverse events during treatment, and health-related quality of life. The secondary outcomes were proportion of people with disease progression, adverse events considered non-serious, and proportion of people without improvement in liver function tests. We assessed risk of bias of the included trials using RoB 2 and the certainty of evidence using GRADE. We presented the results of time-to-event outcomes as hazard ratios (HR), dichotomous outcomes as risk ratios (RR), and continuous outcomes as mean difference (MD) with their 95% confidence intervals (CI). Our primary analyses were based on intention-to-treat and outcome data at the longest follow-up. MAIN RESULTS: We included six randomised clinical trials with 364 participants. The participants had unresectable (i.e. advanced inoperable) hepatocellular carcinoma. We found no trials assessing the effects of gene therapy in people with operable hepatocellular carcinoma. Four trials were conducted in China, one in several countries (from North America, Asia, and Europe), and one in Egypt. The number of participants in the six trials ranged from 10 to 129 (median 47), median age was 55.2 years, and the mean proportion of males was 72.7%. The follow-up duration ranged from six months to five years. As the trials compared different types of gene therapy and had different controls, we could not perform meta-analyses. Five of the six trials administered co-interventions equally to the experimental and control groups. All trials assessed one or more outcomes of interest in this review. The certainty of evidence was very low in five of the six comparisons and low in the double-dose gene therapy comparison. Below, we reported the results of the primary outcomes only. Pexastimogene devacirepvec (Pexa-Vec) plus best supportive care versus best supportive care alone There is uncertainty about whether there may be little to no difference between the effect of Pexa-Vec plus best supportive care compared with best supportive care alone on overall survival (HR 1.19, 95% CI 0.78 to 1.82; 1 trial (censored observation at 20-month follow-up), 129 participants; very low-certainty evidence) and on serious adverse events (RR 1.42, 95% CI 0.60 to 3.33; 1 trial at 20 months after treatment, 129 participants; very low-certainty evidence). The trial reported quality of life narratively as "assessment of quality of life and time to symptomatic progression was confounded by the high patient dropout rate." Adenovirus-thymidine kinase with ganciclovir (ADV-TK/GCV) plus liver transplantation versus liver transplantation alone There is uncertainty about whether ADV-TK/GCV plus liver transplantation may benefit all-cause mortality at the two-year follow-up (RR 0.39, 95% CI 0.20 to 0.76; 1 trial, 45 participants; very low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation alone There is uncertainty about whether double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation may benefit all-cause mortality at five-year follow-up (RR 0.40, 95% CI 0.22 to 0.73; 1 trial, 86 participants; low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Recombinant human adenovirus-p53 with hydroxycamptothecin (rAd-p53/HCT) versus hydroxycamptothecin alone There is uncertainty about whether there may be little to no difference between the effect of rAd-p53/HCT versus hydroxycamptothecin alone on the overall survival at 12-month follow-up (RR 3.06, 95% CI 0.16 to 60.47; 1 trial, 48 participants; very low-certainty evidence). The trial did not report serious adverse events or quality of life. rAd-p53/5-Fu (5-fluorouracil) plus transarterial chemoembolisation versus transarterial chemoembolisation alone The trial included 46 participants. We had insufficient data to assess overall survival. The trial did not report serious adverse events or quality of life. E1B-deleted (dl1520) adenovirus versus percutaneous ethanol injection The trial included 10 participants. It did not report data on overall survival, serious adverse events, or health-related quality of life. One trial did not provide any information on sponsorship; one trial received a national research grant, one trial by the Pedersen foundation, and three were industry-funded trials. We found five ongoing randomised clinical trials. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effects of gene therapy on the studied outcomes because of high risk of bias and imprecision of outcome results. The trials were underpowered and lacked trial data on clinically important outcomes. There was only one trial per comparison, and we could not perform meta-analyses. Therefore, we do not know if gene therapy may reduce, increase, or have little to no effect on all-cause mortality or overall survival, or serious adverse events in adults with unresectable hepatocellular carcinoma. The impact of gene therapy on adverse events needs to be investigated further. Evidence on the effect of gene therapy on health-related quality of life is lacking.

Effects of primary or secondary prevention with vitamin A supplementation on clinically important outcomes: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis.

OBJECTIVES: This systematic review with meta-analyses of randomised trials evaluated the preventive effects of vitamin A supplements versus placebo or no intervention on clinically important outcomes, in people of any age. METHODS: We searched different electronic databases and other resources for randomised clinical trials that had compared vitamin A supplements versus placebo or no intervention (last search 16 April 2024). We used Cochrane methodology. We used the random-effects model to calculate risk ratios (RRs), with 95% CIs. We analysed individually and cluster randomised trials separately. Our primary outcomes were mortality, adverse events and quality of life. We assessed risks of bias in the trials and used Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) to assess the certainty of the evidence. RESULTS: We included 120 randomised trials (1 671 672 participants); 105 trials allocated individuals and 15 allocated clusters. 92 trials included children (78 individually; 14 cluster randomised) and 28 adults (27 individually; 1 cluster randomised). 14/105 individually randomised trials (13%) and none of the cluster randomised trials were at overall low risk of bias. Vitamin A did not reduce mortality in individually randomised trials (RR 0.99, 95% CI 0.93 to 1.05; I²=32%; p=0.19; 105 trials; moderate certainty), and this effect was not affected by the risk of bias. In individually randomised trials, vitamin A had no effect on mortality in children (RR 0.96, 95% CI 0.88 to 1.04; I²=24%; p=0.28; 78 trials, 178 094 participants) nor in adults (RR 1.04, 95% CI 0.97 to 1.13; I²=24%; p=0.27; 27 trials, 61 880 participants). Vitamin A reduced mortality in the cluster randomised trials (0.84, 95% CI 0.76 to 0.93; I²=66%; p=0.0008; 15 trials, 14 in children and 1 in adults; 364 343 participants; very low certainty). No trial reported serious adverse events or quality of life. Vitamin A slightly increased bulging fontanelle of neonates and infants. We are uncertain whether vitamin A influences blindness under the conditions examined. CONCLUSIONS: Based on moderate certainty of evidence, vitamin A had no effect on mortality in the individually randomised trials. Very low certainty evidence obtained from cluster randomised trials suggested a beneficial effect of vitamin A on mortality. If preventive vitamin A programmes are to be continued, supporting evidence should come from randomised trials allocating individuals and assessing patient-meaningful outcomes. PROSPERO REGISTRATION NUMBER: CRD42018104347.

Environmentally Benign pSOFC for Emissions-Free Energy: Assessment of Nickel Network Resistance in Anodic Ni/BCY15 Nanocatalyst.

Yttrium-doped barium cerate (BCY15) was used as ceramic matrix to obtain Ni/BCY15 anode cermet for application in proton-conducting solid oxide fuel cells (pSOFC). Ni/BCY15 cermets were prepared in two different types of medium, namely deionized water (W) and anhydrous ethylene glycol (EG) using wet chemical synthesis by hydrazine. An in-depth analysis of anodic nickel catalyst was made aiming to elucidate the effect of anode tablets' preparation by high temperature treatment on the resistance of metallic Ni in Ni/BCY15-W and Ni/BCY15-EG anode catalysts. On purpose reoxidation upon high-temperature treatment (1100 °C for 1 h) in air ambience was accomplished. Detailed characterization of reoxidized Ni/BCY15-W-1100 and Ni/BCY15-EG-1100 anode catalysts by means of surface and bulk analysis was performed. XPS, HRTEM, TPR, and impedance spectroscopy measurements experimentally confirmed the presence of residual metallic Ni in the anode catalyst prepared in ethylene glycol medium. These findings were evidence of strong metal Ni network resistance to oxidation in anodic Ni/BCY15-EG. Enhanced resistance of the metal Ni phase contributed to a new microstructure of the Ni/BCY15-EG-1100 anode cermet getting more stable to changes that cause degradation during operation.

New Insights on the Nickel State Deposited by Hydrazine Wet-Chemical Synthesis Route in the Ni/BCY15 Proton-Conducting SOFC Anode.

Yttrium-doped barium cerate (BCY15) was used as an anode ceramic matrix for synthesis of the Ni-based cermet anode with application in proton-conducting solid oxide fuel cells (pSOFC). The hydrazine wet-chemical synthesis was developed as an alternative low-cost energy-efficient route that promotes 'in situ' introduction of metallic Ni particles in the BCY15 matrix. The focus of this study is a detailed comparative characterization of the nickel state in the Ni/BCY15 cermets obtained in two types of medium, aqueous and anhydrous ethylene glycol environment, performed by a combination of XRD, N2 physisorption, SEM, EPR, XPS, and electrochemical impedance spectroscopy. Obtained results on the effect of the working medium show that ethylene glycol ensures active Ni cermet preparation with well-dispersed nanoscale metal Ni particles and provides a strong interaction between hydrazine-originating metallic Ni and cerium from the BCY15 matrix. The metallic Ni phase in the pSOFC anode is more stable during reoxidation compared to the Ni cermet prepared by the commercial mechanical mixing procedure. These factors contribute toward improvement of the anode's electrochemical performance in pSOFC, enhanced stability, and a lower degradation rate during operation.

Vitamin D supplementation for chronic liver diseases in adults.

BACKGROUND: Vitamin D deficiency is often reported in people with chronic liver diseases. Improving vitamin D status could therefore be beneficial for people with chronic liver diseases. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D supplementation in adults with chronic liver diseases. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We also searched ClinicalTrials.gov  and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and enquired experts and pharmaceutical companies as to additional trials. All searches were up to November 2020. SELECTION CRITERIA: Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 27 randomised clinical trials with 1979 adult participants. This review update added 12 trials with 945 participants. We assessed all trials as at high risk of bias. All trials had a parallel-group design. Eleven trials were conducted in high-income countries and 16 trials in middle-income countries. Ten trials included participants with chronic hepatitis C, five trials participants with liver cirrhosis, 11 trials participants with non-alcoholic fatty liver disease, and one trial liver transplant recipients. All of the included trials reported the baseline vitamin D status of participants. Participants in nine trials had baseline serum 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), whilst participants in the remaining 18 trials were vitamin D insufficient (less than 20 ng/mL). Twenty-four trials administered vitamin D orally, two trials intramuscularly, and one trial intramuscularly and orally. In all 27 trials, the mean duration of vitamin D supplementation was 6 months, and the mean follow-up of participants from randomisation was 7 months. Twenty trials (1592 participants; 44% women; mean age 48 years) tested vitamin D3 (cholecalciferol); three trials (156 participants; 28% women; mean age 54 years) tested vitamin D2; four trials (291 participants; 60% women; mean age 52 years) tested 1,25-dihydroxyvitamin D; and one trial (18 participants; 0% women; mean age 52 years) tested 25-hydroxyvitamin D. One trial did not report the form of vitamin D. Twelve trials used a placebo, whilst the other 15 trials used no intervention in the control group. Fourteen trials appeared to be free of vested interest. Eleven trials did not provide any information on clinical trial support or sponsorship. Two trials were funded by industry. We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on all-cause mortality (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.51 to 1.45; 27 trials; 1979 participants). The mean follow-up was 7 months (range 1 to 18 months). We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) (follow-up: 12 months); serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants); myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants); thyroiditis (RR 0.33, 95% CI 0.01 to 7.91; 1 trial; 68 participants); circular haemorrhoidal prolapse (RR 3.00, 95% CI 0.14 to 65.9; 1 trial; 20 participants); bronchopneumonia (RR 0.33, 95% CI 0.02 to 7.32; 1 trial 20 participants); and non-serious adverse events. The certainty of evidence for all outcomes is very low. We found no data on liver-related morbidity such as gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, ascites, or liver cancer. There were also no data on health-related quality of life. The evidence is also very uncertain regarding the effect of vitamin D versus placebo or no intervention on rapid, early, and sustained virological response in people with chronic hepatitis C. AUTHORS' CONCLUSIONS: Given the high risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, vitamin D supplementation versus placebo or no intervention may increase or reduce all-cause mortality, liver-related mortality, serious adverse events, or non-serious adverse events in adults with chronic liver diseases. There is a lack of data on liver-related morbidity and health-related quality of life. Further evidence on clinically important outcomes analysed in this review is needed.

Improved Water-Gas Shift Performance of Au/NiAl LDHs Nanostructured Catalysts via CeO2 Addition.

Supported gold on co-precipitated nanosized NiAl layered double hydroxides (LDHs) was studied as an effective catalyst for medium-temperature water-gas shift (WGS) reaction, an industrial catalytic process traditionally applied for the reduction in the amount of CO in the synthesis gas and production of pure hydrogen. The motivation of the present study was to improve the performance of the Au/NiAl catalyst via modification by CeO2. An innovative approach for the direct deposition of ceria (1, 3 or 5 wt.%) on NiAl-LDH, based on the precipitation of Ce3+ ions with 1M NaOH, was developed. The proposed method allows us to obtain the CeO2 phase and to preserve the NiAl layered structure by avoiding the calcination treatment. The synthesis of Au-containing samples was performed through the deposition-precipitation method. The as-prepared and WGS-tested samples were characterized by X-ray powder diffraction, N2-physisorption and X-ray photoelectron spectroscopy in order to clarify the effects of Au and CeO2 loading on the structure, phase composition, textural and electronic properties and activity of the catalysts. The reduction behavior of the studied samples was evaluated by temperature-programmed reduction. The WGS performance of Au/NiAl catalysts was significantly affected by the addition of CeO2. A favorable role of ceria was revealed by comparison of CO conversion degree at 220 °C reached by 3 wt.% CeO2-modified and ceria-free Au/NiAl samples (98.8 and 83.4%, respectively). It can be stated that tuning the properties of Au/NiAl LDH via CeO2 addition offers catalysts with possibilities for practical application owing to innovative synthesis and improved WGS performance.

Xiao Chai Hu Tang, a herbal medicine, for chronic hepatitis B.

BACKGROUND: Chronic hepatitis B is associated with high morbidity and mortality. Chronic hepatitis B requires long-term management aiming at reduction of the risks of hepatocellular inflammatory necrosis, liver fibrosis, decompensated liver cirrhosis, liver failure, and liver cancer, and improving health-related quality of life. The Chinese herbal medicine formula Xiao Chai Hu Tang has been used to decrease discomfort and replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Xiao Chai Hu Tang formula have never been established with rigorous review methodology. OBJECTIVES: To assess the benefits and harms of Xiao Chai Hu Tang formula versus placebo or no intervention in people with chronic hepatitis B. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, and seven other databases 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 for ongoing or unpublished trials to 1 March 2019. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, and blinding, comparing Xiao Chai Hu Tang formula versus no intervention or placebo in people with chronic hepatitis B. We included participants of any sex and age, diagnosed with chronic hepatitis B according to guidelines or as defined by the trialists. We allowed co-interventions when the co-interventions were administered equally to all the intervention groups. DATA COLLECTION AND ANALYSIS: Review authors independently retrieved data from reports and after correspondence with investigators. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered 'not to be serious'. We presented the meta-analysed results as risk ratios (RR) with 95% confidence intervals (CI). We assessed the risks of bias using risk of bias domains with predefined definitions. We used GRADE methodology to evaluate our certainty in the evidence. MAIN RESULTS: We included 10 randomised clinical trials with 934 participants, but only five trials with 490 participants provided data for analysis. All the trials compared Xiao Chai Hu Tang formula with no intervention. All trials appeared to have been conducted and published only in China. The included trials assessed heterogeneous forms of Xiao Chai Hu Tang formula, administered for three to eight months. One trial included participants with hepatitis B and comorbid tuberculosis, and one trial included participants with hepatitis B and liver cirrhosis. The remaining trials included participants with hepatitis B only. All the trials were at high risk of bias, and the certainty of evidence for all outcomes that provided data for analyses was very low. We downgraded the evidence by one or two levels because of outcome risk of bias, inconsistency or heterogeneity of results (opposite direction of effect), indirectness of evidence (use of surrogate outcomes instead of clinically relevant outcomes), imprecision of results (the CIs were wide), and publication bias (small sample size of the trials). Additionally, 47 trials lacked the necessary methodological information needed to ensure the inclusion of these trials in our review. None of the included trials aimed to assess clinically relevant outcomes such as all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, or hepatitis B-related morbidity. The effects of Xiao Chai Hu Tang formula on the proportion of participants with adverse events considered 'not to be serious' is uncertain (RR 0.43, 95% CI 0.02 to 11.98; I2 = 69%; very low-certainty evidence). Only three trials with 222 participants reported the proportion of people with detectable hepatitis B virus DNA (HBV-DNA), but the evidence that Xiao Chai Hu Tang formula reduces the presence of HBV-DNA in the blood (a surrogate outcome) is uncertain (RR 0.62, 95% CI 0.45 to 0.85; I2 = 0%; very low-certainty evidence). Only two trials with 160 participants reported the proportion of people with detectable hepatitis B virus e-antigen (HBeAg; a surrogate outcome) (RR 0.72, 95% CI 0.50 to 1.02; I2 = 38%; very low-certainty evidence) and the evidence is uncertain. The evidence is also uncertain for separately reported adverse events considered 'not to be serious'. FUNDING: two of the 10 included trials received academic funding from government or hospital. None of the remaining eight trials reported information on funding. AUTHORS' CONCLUSIONS: The clinical effects of Xiao Chai Hu Tang formula for chronic hepatitis B remain unclear. The included trials were small and of low methodological quality. Despite the wide use of Xiao Chai Hu Tang formula, we lack data on all-cause mortality, serious adverse events, health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. The evidence in this systematic review comes from data obtained from a maximum three trials. We graded the certainty of evidence as very low for adverse events considered not to be serious and the surrogate outcomes HBeAg and HBV-DNA. We found a large number of trials which lacked clear description of their design and conduct, and hence, these trials are not included in the present review. As all identified trials were conducted in China, there might be a concern about the applicability of this review outside China. Large-sized, high-quality randomised sham-controlled trials with homogeneous groups of participants and transparent funding are lacking.

Acupuncture for chronic hepatitis B.

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.

Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disorder, possibly associated with an increased risk of severe fetal adverse events. Total serum bile acids (TSBA) concentration, alone or in combination with serum aminotransferases, have been the most often used biomarkers for the diagnosis of intrahepatic cholestasis of pregnancy in clinical practice. Serum bile acid profile, composed of primary or secondary, conjugated or non-conjugated bile acids, may provide more specific disease information. OBJECTIVES: To assess and compare, independently or in combination, the diagnostic accuracy of total serum bile acids or serum bile acids profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women, presenting with pruritus. To define the optimal cut-off values for components of serum bile acid profile; to investigate possible sources of heterogeneity. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE Ovid, Embase Ovid, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, BIOSIS, CINAHL, two Chinese databases (CKNI, VIP), Latin American and Caribbean Health Sciences Literature (LILACS), Scientific Electronic Library Online (SciELO), Evidence Search: Health and Social Care by the National Institute for Health and Care Excellence (NICE), the World Health Organization (WHO) Reproductive Health Library (RHL), and the Turning Research into Practice database (TRIP). The most recent date of search was 6 May 2019. We identified additional references by handsearching the references of articles, meta-analyses, and evidence-based guidelines retrieved from the computerised databases, on-line trial registries, and grey literature through OpenSIGLE, National Technical Information Service (NTIS), ProQuest Dissertations & Thesis Database, and Index to Theses in Great Britain and Ireland. SELECTION CRITERIA: Prospective or retrospective diagnostic case-control or cross-sectional studies, irrespective of publication date, format, and language, which evaluated the diagnostic accuracy of total serum bile acids (TSBA) or components of serum bile acid profile for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women of any age or ethnicity, in any clinical setting, symptomatic for pruritus. DATA COLLECTION AND ANALYSIS: We selected studies by reading titles, abstracts, or full texts, and assessing their fulfilment of our inclusion criteria. We emailed primary authors to request missing data or individual participant data. Having extracted data from each included study, we built the two-by-two tables for each primary study and for all the index tests considered. We estimated sensitivity and specificity with their 95% confidence intervals (CI). We presented data in coupled forest plots, showing sensitivities and specificities of each study, and we plotted the studies in the Receiver Operating Characteristic (ROC) space. We performed meta-analyses adopting the hierarchical summary ROC model (HSROC) or the bivariate model to meta-analyse the data. We made indirect comparisons of the considered index tests by adding the index tests as covariates to the bivariate or HSROC models. We performed heterogeneity analysis and sensitivity analysis on studies assessing TSBA accuracy. We used Review Manager 5 (RevMan 5) and SAS statistical software, release 9.4 (SAS Institute Inc., Cary, NC, USA), to perform all statistical analyses. We used QUADAS-2 domains to assess the risk of bias of the included studies. MAIN RESULTS: Our search yielded 5073 references, but at the end of our selection process, only 16 studies fulfilled the review inclusion criteria. Nine of these provided individual participant data. We analysed only data concerning TSBA, cholic acid (CA), glycocholic acid (GCA), chenodeoxycholic acid (CDCA), and CA/CDCA because the remaining planned index tests were assessed in few studies. Only one study had low risk of bias in all four QUADAS-2 domains. The most biased domains were the patient sampling and the reference standard domains. When considering all studies with a cut-off of 10 µmol/L, TSBA overall sensitivity ranged from 0.72 to 0.98 and specificity ranged from 0.81 to 0.97. After a sensitivity analysis excluding case-control studies, TSBA sensitivity ranged from 0.48 to 0.66 and specificity from 0.52 to 0.99. After a sensitivity analysis excluding studies in which TSBA was part of the reference standard, TSBA sensitivity ranged from 0.49 to 0.65 and specificity from 0.53 to 0.99. We found the estimates of the overall accuracy for some serum bile acid components (CA, GCA, CDCA, and CA/CDCA) to be imprecise, with the CI for sensitivity and specificity very wide or impossible to calculate. Indirect comparisons between serum bile acid profile components and TSBA were not statistically significant. None of the heterogeneity analysis performed was statistically significant, except for the timing of assessment of TSBA (onset of symptoms, peak value among multiple assessments, delivery) but without clinically relevant results. We could not analyse the diagnostic accuracy of combinations of index tests because none of the included studies carried them out, and because of the small number of included studies. AUTHORS' CONCLUSIONS: The overall high risk of bias, the existing concern regarding applicability of the results in clinical practice, and the great heterogeneity of the results in the included studies prevents us from making recommendations and reaching definitive conclusions at the present time. Thus, we do not find any compelling evidence to recommend or refute the routine use of any of these tests in clinical practice. So far, the diagnostic accuracy of TSBA for intrahepatic cholestasis of pregnancy might have been overestimated. There were too few studies to permit a precise estimate of the accuracy of serum bile acid profile components. Further primary clinical research is mandatory. We need both further phase II and phase III diagnostic studies.

Radix Sophorae flavescentis versus other drugs or herbs for chronic hepatitis B.

BACKGROUND: Hepatitis B virus (HBV) infection is a liver disease caused by hepatitis B virus, which may lead to serious complications such as cirrhosis and hepatocellular carcinoma. People with HBV infection may also have coinfections including HIV and other hepatitis viruses (hepatitis C or D), and coinfections may increase the risk of all-cause mortality. Chronic HBV infection increases morbidity, psychological stress, and it is an economic burden on people with chronic hepatitis B and their families. Radix Sophorae flavescentis, a herbal medicine, is administered mostly in combination with other drugs or herbs. It is believed that it decreases discomfort and prevents the replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Radix Sophorae flavescentis on patient-centred outcomes are unknown, and its wide usage has never been established with rigorous review methodology. OBJECTIVES: To assess the benefits and harms of Radix Sophorae flavescentis versus other drugs or herbs in people with chronic hepatitis B. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, and seven other databases to December 2018. 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 for ongoing or unpublished trials to December 2018. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, or blinding, comparing Radix Sophorae flavescentis versus other drugs or herbs for people with chronic hepatitis B. In addition to chronic hepatitis B, participants could also have had cirrhosis, hepatocellular carcinoma, or any other concomitant disease. We excluded polyherbal blends containing Radix Sophorae flavescentis. We allowed cointerventions when the cointerventions were administered equally to all intervention groups. DATA COLLECTION AND ANALYSIS: Review authors in pairs individually retrieved data from published reports and after correspondence with investigators. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered 'not to be serious'. We presented the meta-analysed results as risk ratios (RR) with 95% confidence intervals (CI). We assessed the risk of bias using domains with predefined definitions. We conducted Trial Sequential Analyses to control the risks of random errors. We used GRADE methodology to evaluate our certainty in the evidence (i.e. "the extent of our confidence that the estimates of the effect are correct or are adequate to support a particular decision or recommendation"). MAIN RESULTS: We included 10 randomised clinical trials with 898 participants. We judged all trials at high risk of bias. The trials covered oral capsules, intravenous infusion, intramuscular injection, and acupoint (a specifically chosen site of acupuncture) injection of Radix Sophorae flavescentis with a follow-up period from 1 to 12 months. The drugs being used as a comparator were lamivudine, adefovir, interferon, tiopronin, thymosin, or other Chinese herbs. Two trials included children up to 14 years old. Participants in one trial had cirrhosis in chronic hepatitis B. None of the trials reported all-cause mortality, health-related quality of life, serious adverse events, hepatitis B-related mortality, or morbidity. We are uncertain as to whether Radix Sophorae flavescentis has a beneficial or harmful effect on adverse events considered 'not to be serious' (RR 0.86, 95% CI 0.42 to 1.75; I2 = 0%; 2 trials, 163 participants; very low-certainty evidence), as well as if it decreases or increases the proportion of participants with detectable HBV-DNA (RR 1.14, 95% CI 0.81 to 1.63; I2 = 92%; 8 trials, 719 participants; very low-certainty evidence). Radix Sophorae flavescentis showed a reduction in the proportion of participants with detectable hepatitis B virus e-antigen (HBeAg) (RR 0.86, 95% CI 0.75 to 0.98; I2 = 43%; 7 trials, 588 participants; very low-certainty evidence).Two of the 10 trials were not funded, and one received academic funding. The remaining seven trials provided no information on funding.The randomisation process in another 109 trials was insufficiently reported to ensure the inclusion of any of these studies in our review. AUTHORS' CONCLUSIONS: 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 evidence on the effect of Radix Sophorae flavescentis on the proportion of participants with adverse events considered 'not to be serious' and on the proportion of participants with detectable HBV-DNA is still unclear. We advise caution regarding the results of Radix Sophorae flavescentis showing a reduction in the proportion of people with detectable HBeAg because the trials were at high risk of bias, because it is a non-validated surrogate outcome, and because of the very low certainty in the evidence. As we were unable to obtain information on a large number of studies regarding their trial design, we were deterred from including them in our review. Undisclosed funding may have influence on trial results and lead to poor design of the trial. In view of the wide usage of Radix Sophorae flavescentis, we need large, unbiased, high-quality placebo-controlled randomised trials assessing patient-centred outcomes.

Plasma expanders for people with cirrhosis and large ascites treated with abdominal paracentesis.

BACKGROUND: Plasma volume expanders are used in connection to paracentesis in people with cirrhosis to prevent reduction of effective plasma volume, which may trigger deleterious effect on haemodynamic balance, and increase morbidity and mortality. Albumin is considered the standard product against which no plasma expansion or other plasma expanders, e.g. other colloids (polygeline , dextrans, hydroxyethyl starch solutions, fresh frozen plasma), intravenous infusion of ascitic fluid, crystalloids, or mannitol have been compared. However, the benefits and harms of these plasma expanders are not fully clear. OBJECTIVES: To assess the benefits and harms of any plasma volume expanders such as albumin, other colloids (polygeline, dextrans, hydroxyethyl starch solutions, fresh frozen plasma), intravenous infusion of ascitic fluid, crystalloids, or mannitol versus no plasma volume expander or versus another plasma volume expander for paracentesis in people with cirrhosis and large ascites. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, CNKI, VIP, Wanfang, Science Citation Index Expanded, and Conference Proceedings Citation Index until January 2019. Furthermore, we searched FDA, EMA, WHO (last search January 2019), www.clinicaltrials.gov/, and www.controlled-trials.com/ for ongoing trials. SELECTION CRITERIA: Randomised clinical trials, no matter their design or year of publication, publication status, and language, assessing the use of any type of plasma expander versus placebo, no intervention, or a different plasma expander in connection with paracentesis for ascites in people with cirrhosis. We considered quasi-randomised, retrieved with the searches for randomised clinical trials only, for reports on harms. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We calculated the risk ratio (RR) or mean difference (MD) using the fixed-effect model and the random-effects model meta-analyses, based on the intention-to-treat principle, whenever possible. If the fixed-effect and random-effects models showed different results, then we made our conclusions based on the analysis with the highest P value (the more conservative result). We assessed risks of bias of the individual trials using predefined bias risk domains. We assessed the certainty of the evidence at an outcome level, using GRADE, and constructed 'Summary of Findings' tables for seven of our review outcomes. MAIN RESULTS: We identified 27 randomised clinical trials for inclusion in this review (24 published as full-text articles and 3 as abstracts). Five of the trials, with 271 participants, assessed plasma expanders (albumin in four trials and ascitic fluid in one trial) versus no plasma expander. The remaining 22 trials, with 1321 participants, assessed one type of plasma expander, i.e. dextran, hydroxyethyl starch, polygeline, intravenous infusion of ascitic fluid, crystalloids, or mannitol versus another type of plasma expander, i.e. albumin in 20 of these trials and polygeline in one trial. Twenty-five trials provided data for quantitative meta-analysis. According to the Child-Pugh classification, most participants were at an intermediate to advanced stage of liver disease in the absence of hepatocellular carcinoma, recent gastrointestinal bleeding, infections, and hepatic encephalopathy. All trials were assessed as at overall high risk of bias. Ten trials seemed not to have been funded by industry; twelve trials were considered unclear about funding; and five trials were considered funded by industry or a for-profit institution.We found no evidence of a difference in effect between plasma expansion versus no plasma expansion on mortality (RR 0.52, 95% CI 0.06 to 4.83; 248 participants; 4 trials; very low certainty); renal impairment (RR 0.32, 95% CI 0.02 to 5.88; 181 participants; 4 trials; very low certainty); other liver-related complications (RR 1.61, 95% CI 0.79 to 3.27; 248 participants; 4 trials; very low certainty); and non-serious adverse events (RR 1.04, 95% CI 0.32 to 3.40; 158 participants; 3 trials; very low certainty). Two of the trials stated that no serious adverse events occurred while the remaining trials did not report on this outcome. No trial reported data on health-related quality of life.We found no evidence of a difference in effect between experimental plasma expanders versus albumin on mortality (RR 1.03, 95% CI 0.82 to 1.30; 1014 participants; 14 trials; very low certainty); serious adverse events (RR 0.89, 95% CI 0.10 to 8.30; 118 participants; 2 trials; very low certainty); renal impairment (RR 1.17, 95% CI 0.71 to 1.91; 1107 participants; 17 trials; very low certainty); other liver-related complications (RR 1.10, 95% CI 0.82 to 1.48; 1083 participants; 16 trials; very low certainty); and non-serious adverse events (RR 1.37, 95% CI 0.66 to 2.85; 977 participants; 14 trials; very low certainty). We found no data on heath-related quality of life and refractory ascites. AUTHORS' CONCLUSIONS: Our systematic review and meta-analysis did not find any benefits or harms of plasma expanders versus no plasma expander or of one plasma expander such as polygeline, dextrans, hydroxyethyl starch, intravenous infusion of ascitic fluid, crystalloids, or mannitol versus albumin on primary or secondary outcomes. The data originated from few, small, mostly short-term trials at high risks of systematic errors (bias) and high risks of random errors (play of chance). GRADE assessments concluded that the evidence was of very low certainty. Therefore, we can neither demonstrate or discard any benefit of plasma expansion versus no plasma expansion, and differences between one plasma expander versus another plasma expander.Larger trials at low risks of bias are needed to assess the role of plasma expanders in connection with paracentesis. Such trials should be conducted according to the SPIRIT guidelines and reported according to the CONSORT guidelines.

Glucocorticosteroids for people with alcoholic hepatitis.

BACKGROUND: Alcoholic hepatitis is a form of alcoholic liver disease characterised by steatosis, necroinflammation, fibrosis, and complications to the liver. Typically, alcoholic hepatitis presents in people between 40 and 50 years of age. Alcoholic hepatitis can be resolved if people abstain from drinking, but the risk of death will depend on the severity of the liver damage and abstinence from alcohol. Glucocorticosteroids have been studied extensively in randomised clinical trials to assess their benefits and harms. However, the results have been contradictory. OBJECTIVES: To assess the benefits and harms of glucocorticosteroids in people with alcoholic hepatitis. SEARCH METHODS: We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We looked for ongoing or unpublished trials in clinical trials registers and pharmaceutical company sources. We also scanned reference lists of the studies retrieved. The last search was 18 January 2019. SELECTION CRITERIA: Randomised clinical trials assessing glucocorticosteroids versus placebo or no intervention in people with alcoholic hepatitis, irrespective of year, language of publication, or format. We considered trials with adults diagnosed with alcoholic hepatitis, which could have been established through clinical or biochemical diagnostic criteria or both. We defined alcoholic hepatitis as mild (Maddrey's score less than 32) and severe (Maddrey's score 32 or more). We allowed cointerventions in the trial groups, provided they were similar. DATA COLLECTION AND ANALYSIS: We followed Cochrane methodology, performing the meta-analyses using Review Manager 5. We presented the results of dichotomous outcomes as risk ratios (RR) and of continuous outcomes as mean difference (MD), with 95% confidence intervals (CI). We used both the fixed-effect and the random-effects models for meta-analyses. Whenever there were significant discrepancies in the results, we reported the more conservative point estimate of the two. We considered a P value of 0.01 or less, two-tailed, as statistically significant if the required information size was reached for our three primary outcomes (all-cause mortality, health-related quality of life, and serious adverse events during treatment) and our post hoc decision to include analyses of mortality at more time points. We presented heterogeneity using the I² statistic. If trialists used intention-to-treat analysis to deal with missing data, we used these data in our primary analysis; otherwise, we used the available data. We assessed the bias risk of the trials using bias risk domains and the certainty of the evidence using GRADE. MAIN RESULTS: Sixteen trials fulfilled our inclusion criteria. All trials but one were at overall high risk of bias. Fifteen trials (one of which was an abstract) provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention). Glucocorticosteroids were administered orally or parenterally for a median 28 days (range 3 days to 12 weeks). The participants were between 25 and 70 years old, had different stages of alcoholic liver disease, and 65% were men. Follow-up, when reported, was up to the moment of discharge from the hospital, until they died (median of 63 days), or for at least one year. There was no evidence of effect of glucocorticosteroids on all-cause mortality up to three months following randomisation (random-effects RR 0.90, 95% CI 0.70 to 1.15; participants = 1861; trials = 15; very low-certainty evidence) or on health-related quality of life up to three months, measured with the European Quality of Life - 5 Dimensions - 3 Levels scale (MD -0.04 points, 95% CI -0.11 to 0.03; participants = 377; trial = 1; low-certainty evidence). There was no evidence of effect on the occurrence of serious adverse events during treatment (random-effects RR 1.05, 95% CI 0.85 to 1.29; participants = 1861; trials = 15; very low-certainty evidence), liver-related mortality up to three months following randomisation (random-effects RR 0.89, 95% CI 0.69 to 1.14; participants = 1861; trials = 15; very low-certainty evidence), number of participants with any complications up to three months following randomisation (random-effects RR 1.04, 95% CI 0.86 to 1.27; participants = 1861; very low-certainty evidence), and number of participants of non-serious adverse events up to three months' follow-up after end of treatment (random-effects RR 1.99, 95% CI 0.72 to 5.48; participants = 160; trials = 4; very low-certainty evidence). Based on the information that we collected from the published trial reports, only one of the trials seems not to be industry-funded, and the remaining 15 trials did not report clearly whether they were partly or completely funded by the industry. AUTHORS' CONCLUSIONS: We are very uncertain about the effect estimate of no difference between glucocorticosteroids and placebo or no intervention on all-cause mortality and serious adverse events during treatment because the certainty of evidence was very low, and low for health-related quality of life. Due to inadequate reporting, we cannot exclude increases in adverse events. As the CIs were wide, we cannot rule out significant benefits or harms of glucocorticosteroids. Therefore, we need placebo-controlled randomised clinical trials, designed according to the SPIRIT guidelines and reported according to the CONSORT guidelines. Future trials ought to report depersonalised individual participant data, so that proper individual participant data meta-analyses of the effects of glucocorticosteroids in subgroups can be conducted.

Radix Sophorae flavescentis versus no intervention or placebo for chronic hepatitis B.

BACKGROUND: Hepatitis B virus (HBV) infection, a liver disease caused by hepatitis B virus, may lead to serious complications such as cirrhosis and hepatocellular carcinoma. People with HBV infection may have co-infections including HIV and other hepatitis viruses (hepatitis C or D), and co-infection may increase the risk of all-cause mortality. Chronic HBV infection increases morbidity and psychological stress and is an economic burden on people with chronic hepatitis B and their families. Radix Sophorae flavescentis, an herbal medicine, is administered most often in combination with other drugs or herbs. It is believed that it decreases discomfort and prevents replication of the virus in people with chronic hepatitis B. However, the benefits and harms of Radix Sophorae flavescentis for patient-centred outcomes are not known, and its wide usage has never been established with rigorous review methodology. OBJECTIVES: To assess the benefits and harms of Radix Sophorae flavescentis versus placebo or no intervention in people with chronic hepatitis B. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), Wanfang Data, and SinoMed. 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 for ongoing or unpublished trials. We conducted the last search in December 2018. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, or blinding, comparing Radix Sophorae flavescentis versus no intervention or placebo in people with chronic hepatitis B. We excluded polyherbal blends containing Radix Sophorae flavescentis. We allowed co-interventions when the co-interventions were administered equally to all intervention groups. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Review authors in pairs retrieved data from individual published reports and after correspondence with investigators. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. Our secondary outcomes were hepatitis B-related mortality, hepatitis B-related morbidity, and adverse events considered 'not to be serious'. We presented meta-analysed results as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed risk of bias using domains with pre-defined definitions. We conducted Trial Sequential Analyses to control the risk of random errors. We used GRADE methodology to evaluate our certainty in the evidence (i.e. "the extent of our confidence that the estimates of the effect are correct or are adequate to support a particular decision or recommendation"). MAIN RESULTS: We included 35 randomised clinical trials with 3556 participants. One trial compared Radix Sophorae flavescentis with placebo; the remaining 34 trials compared effects of Radix Sophorae flavescentis in addition to a co-intervention versus the same co-intervention. The included trials assessed heterogenous forms and ways of administering Radix Sophorae flavescentis (e.g. oral capsules, oral tablets, intravenous infusion, intramuscular injection, acupoint (a specifically chosen site of acupuncture) injection) with treatment duration of 1 to 24 months. Two of the trials included children up to 14 years old. Participants in two trials had cirrhosis in addition to chronic hepatitis B. All trials were assessed at high risk of bias, and certainty of the evidence for all outcomes was very low.Only one of the 35 trials assessed mortality; no deaths occurred. Ten trials assessed serious adverse events; no serious adverse events occurred. None of the trials reported health-related quality of life, hepatitis B-related mortality, or morbidity. Adverse events considered 'not to be serious' was an outcome in 19 trials; nine of these trials had zero events in both groups. Radix Sophorae flavescentis versus placebo or no intervention showed no difference in effects on adverse events considered 'not to be serious' (RR 1.10, 95% CI 0.76 to 1.59; I² = 49%; 10 trials, 1050 participants). Radix Sophorae flavescentis showed a reduction in the proportion of participants with detectable HBV-DNA (RR 0.61, 95% CI 0.55 to 0.68; I² = 56%; 29 trials, 2914 participants) and in the proportion of participants with detectable HBeAg (hepatitis B e-antigen) (RR 0.71, 95% CI 0.66 to 0.76; I² = 19%; 20 trials, 2129 participants).Seven of the 35 randomised clinical trials received academic funding from government or hospital. Four trials received no funding. The remaining 24 trials provided no information on funding.Additionally, 432 trials lacked the methodological information needed to ensure inclusion of these trials in our review. AUTHORS' CONCLUSIONS: The included trials lacked data on health-related quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity. The effects of Radix Sophorae flavescentis on all-cause mortality and on the proportion of participants with serious adverse events and adverse events considered 'not to be serious' remain unclear. We advise caution in interpreting results showing that Radix Sophorae flavescentis reduced the proportion of people with detectable HBV-DNA and detectable HBeAg because the trials reporting on these outcomes are at high risk of bias and both outcomes are non-validated surrogate outcomes. We were unable to obtain information on the design and conduct of a large number of trials; therefore, we were deterred from including them in our review. Undisclosed funding may influence trial results and may lead to poor trial design. Given the wide usage of Radix Sophorae flavescentis, we need large, unbiased, high-quality placebo-controlled randomised trials in which patient-centred outcomes are assessed.

Letter to Editor: Response to AASLD Editorial/Message from the President.

A commentary [1] criticized our systematic review regarding the use of direct-acting agents (DAAs) in chronic hepatitis C [2]. The following represents our major disagreements. Sustained virological response (SVR) is a non-validated surrogate outcome. The principles of evidence-based medicine require that it be validated in randomized clinical trials (RCTs) by showing parallel benefits in clinical outcomes [3]. This article is protected by copyright. All rights reserved.

Surgical portosystemic shunts versus devascularisation procedures for prevention of variceal rebleeding in people with hepatosplenic schistosomiasis.

BACKGROUND: Hepatosplenic schistosomiasis is an important cause of variceal bleeding in low-income countries. Randomised clinical trials have evaluated the outcomes of two categories of surgical interventions, shunts and devascularisation procedures, for the prevention of variceal rebleeding in people with hepatosplenic schistosomiasis. The comparative overall benefits and harms of these two interventions are unclear. OBJECTIVES: To assess the benefits and harms of surgical portosystemic shunts versus oesophagogastric devascularisation procedures for the prevention of variceal rebleeding in people with hepatosplenic schistosomiasis. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, reference lists of articles, and proceedings of relevant associations for trials that met the inclusion criteria (date of search 11 January 2018). SELECTION CRITERIA: Randomised clinical trials comparing surgical portosystemic shunts versus oesophagogastric devascularisation procedures for the prevention of variceal rebleeding in people with hepatosplenic schistosomiasis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the trials and extracted data using methodological standards expected by Cochrane. We assessed risk of bias according to domains and risk of random errors with GRADE and Trial Sequential Analysis. We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: We found two randomised clinical trials including 154 adult participants, aged between 18 years and 65 years, diagnosed with hepatosplenic schistosomiasis. One of the trials randomised participants to proximal splenorenal shunt versus distal splenorenal shunt versus oesophagogastric devascularisation with splenectomy, and the other randomised participants to distal splenorenal shunt versus oesophagogastric devascularisation with splenectomy. In both trials the diagnosis of hepatosplenic schistosomiasis was made based on clinical and biochemical assessments. The trials were conducted in Brazil and Egypt. Both trials were at high risk of bias.We are uncertain as to whether surgical portosystemic shunts improved all-cause mortality compared with oesophagogastric devascularisation with splenectomy due to imprecision in the trials (risk ratio (RR) 2.35, 95% confidence interval (CI) 0.55 to 9.92; participants = 154; studies = 2). We are uncertain whether serious adverse events differed between surgical portosystemic shunts and oesophagogastric devascularisation with splenectomy (RR 2.26, 95% CI 0.44 to 11.70; participants = 154; studies = 2). None of the trials reported on health-related quality of life. We are uncertain whether variceal rebleeding differed between surgical portosystemic shunts and oesophagogastric devascularisation with splenectomy (RR 0.39, 95% CI 0.13 to 1.23; participants = 154; studies = 2). We found evidence suggesting an increase in encephalopathy in the shunts group versus the devascularisation with splenectomy group (RR 7.51, 95% CI 1.45 to 38.89; participants = 154; studies = 2). We are uncertain whether ascites and re-interventions differed between surgical portosystemic shunts and oesophagogastric devascularisation with splenectomy. We computed Trial Sequential Analysis for all outcomes, but the trial sequential monitoring boundaries could not be drawn because of insufficient sample size and events. We downgraded the overall certainty of the body of evidence for all outcomes to very low due to risk of bias and imprecision. AUTHORS' CONCLUSIONS: Given the very low certainty of the available body of evidence and the low number of clinical trials, we could not determine an overall benefit or harm of surgical portosystemic shunts compared with oesophagogastric devascularisation with splenectomy. Future randomised clinical trials should be designed with sufficient statistical power to assess the benefits and harms of surgical portosystemic shunts versus oesophagogastric devascularisations with or without splenectomy and with or without oesophageal transection.

Vitamin D supplementation for chronic liver diseases in adults.

BACKGROUND: Vitamin D deficiency is often reported in people with chronic liver diseases. Therefore, improving vitamin D status could have a beneficial effect on people with chronic liver diseases. OBJECTIVES: To assess the beneficial and harmful effects of vitamin D supplementation in people with chronic liver diseases. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science. We also searched databases of ongoing trials and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. All searches were up to January 2017. SELECTION CRITERIA: Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. We contacted authors of the trials to ask for missing information. We conducted random-effects and fixed-effect meta-analyses. For dichotomous outcomes, we calculated risk ratios (RRs), and for continuous outcomes, we calculated mean differences (MD), both with 95% confidence intervals (CI) and Trial Sequential Analyses-adjusted CIs. We calculated Peto odds ratio (OR) for rare events. We considered risk of bias in domains to assess the risk of systematic errors. We conducted Trial Sequential Analyses to control the risk of random errors. We assessed the quality of the evidence with GRADE. MAIN RESULTS: We included 15 randomised clinical trials with 1034 participants randomised. All trials had a parallel group design. Nine trials were conducted in high-income countries and six trials in middle-income countries. All trials were at high risk of bias. Six trials included participants with chronic hepatitis C, four trials included participants with liver cirrhosis, four trials included participants with non-alcoholic fatty liver disease, and one trial included liver transplant recipients. All included trials reported the baseline vitamin D status of participants. Participants in six trials had baseline 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), while participants in the remaining nine trials were vitamin D insufficient (less than 20 ng/mL). All trials administered vitamin D orally. Mean duration of vitamin D supplementation was 0.5 years and follow-up was 0.6 years. Eleven trials (831 participants; 40% women; mean age 52 years) tested vitamin D3, one trial (18 men; mean age 61 years) with three intervention groups tested vitamin D2 and 25-dihydroxyvitamin D in separate groups, and three trials (185 participants; 55% women; mean age 55 years) tested 1,25-dihydroxyvitamin D. Seven trials used placebo, and eight trials used no intervention in the control group.The effect of vitamin D on all-cause mortality at the end of follow-up is uncertain because the results were imprecise (Peto OR 0.70, 95% CI 0.09 to 5.38; I2 = 32%; 15 trials; 1034 participants; very low quality evidence). Trial Sequential Analysis on all-cause mortality was performed based on a mortality rate in the control group of 10%, a relative risk reduction of 28% in the experimental intervention group, a type I error of 2.5%, and type II error of 10% (90% power). There was no diversity. The required information size was 6396 participants. The cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit or harm after the 15th trial, and the Trial Sequential Analyses-adjusted CI was 0.00 to 2534.The effect of vitamin D on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) and on serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants), myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants), and thyroiditis (RR 0.33 95% CI 0.01 to 7.91; 1 trial; 68 participants) is uncertain because the results were imprecise. The evidence on all these outcomes is of very low quality. The effect of vitamin D3 on non-serious adverse events such as glossitis (RR 3.70, 95% CI 0.16 to 87.6; 1 trial; 65 participants; very low quality of evidence) is uncertain because the result was imprecise.Due to few data, we did not conduct Trial Sequential Analysis on liver-related mortality, and serious and non-serious adverse events.We found no data on liver-related morbidity and health-related quality of life in the randomised trials included in this review. AUTHORS' CONCLUSIONS: We are uncertain as to whether vitamin D supplements in the form of vitamin D3, vitamin D2, 1,25-dihydroxyvitamin D, or 25-dihydroxyvitamin D have important effect on all-cause mortality, liver-related mortality, or on serious or non-serious adverse events because the results were imprecise. There is no evidence on the effect of vitamin D supplementation on liver-related morbidity and health-related quality of life. Our conclusions are based on few trials with an insufficient number of participants and on lack of data on clinically important outcomes. In addition, the analysed trials are at high risk of bias with significant intertrial heterogeneity. The overall quality of evidence is very low.

Glucocorticosteroids for people with alcoholic hepatitis.

BACKGROUND: Alcoholic hepatitis is a form of alcoholic liver disease, characterised by steatosis, necroinflammation, fibrosis, and potential complications to the liver disease. Typically, alcoholic hepatitis presents in people between 40 and 50 years of age. Alcoholic hepatitis can be resolved if people abstain from drinking, but the risk of death will depend on the severity of the liver damage and abstinence from alcohol. Glucocorticosteroids are used as anti-inflammatory drugs for people with alcoholic hepatitis. Glucocorticosteroids have been studied extensively in randomised clinical trials in order to assess their benefits and harms. However, the results have been contradictory. OBJECTIVES: To assess the benefits and harms of glucocorticosteroids in people with alcoholic hepatitis. SEARCH METHODS: We identified trials through electronic searches in Cochrane Hepato-Biliary's (CHB) Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, and Science Citation Index Expanded. We looked for ongoing or unpublished trials in clinical trials registers and pharmaceutical company sources. We also scanned reference lists of the studies retrieved. The last search was 20 October 2016. SELECTION CRITERIA: Randomised clinical trials assessing glucocorticosteroids versus placebo or no intervention in people with alcoholic hepatitis, irrespective of year, language of publication, or format. We considered trials with adult participants diagnosed with alcoholic hepatitis, which could have been established through clinical or biochemical diagnostic criteria or both. We defined alcoholic hepatitis as mild (Maddrey's score less than 32) and severe (Maddrey's score 32 or more). We allowed co-interventions in the trial groups, provided they were similar. DATA COLLECTION AND ANALYSIS: We followed Cochrane and CHB methodology, performing the meta-analyses using Review Manager 5 and Trial Sequential Analysis. We presented the results of dichotomous outcomes as risk ratios (RR) and those of the continuous outcomes as mean difference (MD). We applied both the fixed-effect model and the random-effects model meta-analyses. Whenever there were significant discrepancies in the results, we reported the more conservative point estimate of the two. We considered a P value of 0.01 or less, two-tailed, as statistically significant if the required information size was reached due to our three primary outcomes (all-cause mortality, health-related quality of life, and serious adverse events during treatment) and our post hoc decision to include analyses of mortality at more time points. We presented heterogeneity using the I² statistic. If trialists used intention-to-treat analysis to deal with missing data, we used these data in our primary analysis; otherwise, we used the available data. We assessed the bias risk of the trials using bias risk domains and the quality of the evidence using GRADE. MAIN RESULTS: Sixteen trials fulfilled the inclusion criteria. All trials were at high risk of bias. Fifteen trials provided data for analysis (927 participants received glucocorticosteroids and 934 participants received placebo or no intervention). The glucocorticosteroids were administered orally or parenterally for a median of 28 days (range 3 days to 12 weeks). The participants were between 25 and 70 years old, had different stages of alcoholic liver disease, and 65% were men. The follow-up of trial participants, when it was reported, was up to the moment of discharge from the hospital, until they died (a median of 63 days), or for at least a year. There was no evidence of effect of glucocorticosteroids on all-cause mortality up to three months following randomisation neither with traditional meta-analysis (random-effects RR 0.90, 95% CI 0.70 to 1.15; participants = 1861; trials = 15; I² = 45% (moderate heterogeneity) nor with Trial Sequential Analysis. Meta-analysis showed no evidence of effect on health-related quality of life up to three months (MD -0.04 points; 95% CI -0.11 to 0.03; participants = 377; trial = 1; low-quality evidence), measured with the European Quality of Life - 5 Dimensions-3 Levels (EQ- 5D-3L) scale. There was no evidence of effect on the occurrence of serious adverse events during treatment, neither with traditional meta-analysis (random-effects RR 1.05, 95% CI 0.85 to 1.29; participants = 1861; trials = 15; I² = 36% (moderate heterogeneity), liver-related mortality up to three months following randomisation (random-effects RR 0.89, 95% CI 0.69 to 1.14; participants = 1861; trials = 15; I² = 46% (moderate heterogeneity), frequency of any complications up to three months following randomisation (random-effects RR 1.04, 95% CI 0.86 to 1.27; participants = 1861; I² = 42% (moderate heterogeneity), and frequency of non-serious adverse events up to three months' follow-up after end of treatment (random-effects RR 1.99, 95% CI 0.72 to 5.48; participants = 160; trials = 4; I² = 0% (no heterogeneity) nor with Trial Sequential Analysis. Nine of the trials were industry-funded. AUTHORS' CONCLUSIONS: We found no evidence of a difference between glucocorticosteroids and placebo or no intervention on all-cause mortality, health-related quality of life, and serious adverse events during treatment. The risk of bias was high and the quality of evidence was very low or low. Therefore, we are very uncertain about this effect estimate. Due to inadequate reporting, we cannot exclude increases in adverse events. As the confidence intervals were wide, we cannot rule out significant benefits and harms of glucocorticosteroids. Therefore, we need placebo-controlled, randomised clinical trials, designed according to the SPIRIT guidelines and reported according to the CONSORT guidelines. Future trials ought to report depersonalised individual participant data, so that proper individual participant data meta-analyses of the effects of glucocorticosteroids in subgroups can be conducted.

Direct-acting antivirals for chronic hepatitis C.

BACKGROUND: Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs), e.g. sofosbuvir, are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). Sustained virological response (SVR) is used by investigators and regulatory agencies as a surrogate outcome for morbidity and mortality, based solely on observational evidence. However, there have been no randomised trials that have validated that usage. OBJECTIVES: To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS: We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA: Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and health-related quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and SVR. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. We evaluated the overall quality of the evidence, using GRADE. MAIN RESULTS: We included a total of 138 trials randomising a total of 25,232 participants. The trials were generally short-term trials and designed primarily to assess the effect of treatment on SVR. The trials evaluated 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered DAAs that were discontinued or withdrawn from the market. Study populations were treatment-naive in 95 trials, had been exposed to treatment in 17 trials, and comprised both treatment-naive and treatment-experienced individuals in 24 trials. The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.We could not reliably determine the effect of DAAs on the market or under development on our primary outcome of hepatitis C-related morbidity or all-cause mortality. There were no data on hepatitis C-related morbidity and only limited data on mortality from 11 trials (DAA 15/2377 (0.63%) versus control 1/617 (0.16%); OR 3.72, 95% CI 0.53 to 26.18, very low-quality evidence). We did not perform Trial Sequential Analysis on this outcome.There is very low quality evidence that DAAs on the market or under development do not influence serious adverse events (DAA 5.2% versus control 5.6%; OR 0.93, 95% CI 0.75 to 1.15 , 15,817 participants, 43 trials). The Trial Sequential Analysis showed that there was sufficient information to rule out that DAAs reduce the relative risk of a serious adverse event by 20% when compared with placebo. The only DAA that showed a lower risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, the meta-analysis result showed no evidence of a difference.DAAs on the market or under development may reduce the risk of no SVR from 54.1% in untreated people to 23.8% in people treated with DAA (RR 0.44, 95% CI 0.37 to 0.52, 6886 participants, 32 trials, low quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).There was insufficient evidence from trials on withdrawn or discontinued DAAs to determine their effect on hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79; 5 trials, very low-quality evidence). However, these DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73; 29 trials, very low-quality evidence). Trial Sequential Analysis confirmed this meta-analysis result.None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS: The evidence for our main outcomes of interest come from short-term trials, and we are unable to determine the effect of long-term treatment with DAAs. The rates of hepatitis C morbidity and mortality observed in the trials are relatively low and we are uncertain as to how DAAs affect this outcome. Overall, there is very low quality evidence that DAAs on the market or under development do not influence serious adverse events. There is insufficient evidence to judge if DAAs have beneficial or harmful effects on other clinical outcomes for chronic HCV. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs may reduce the number of people with detectable virus in their blood, but we do not have sufficient evidence from randomised trials that enables us to understand how SVR affects long-term clinical outcomes. SVR is still an outcome that needs proper validation in randomised clinical trials.

Direct-acting antivirals for chronic hepatitis C.

BACKGROUND: Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs) are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). However, it is still questionable if eradication of hepatitis C virus in the blood eliminates hepatitis C in the body, and improves survival and leads to fewer complications. OBJECTIVES: To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS: We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA: Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and sustained virological response. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. The overall quality of the evidence was evaluated using GRADE. MAIN RESULTS: We included a total of 138 trials randomising a total of 25,232 participants. The 138 trials assessed the effects of 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered withdrawn or discontinued DAAs. Trial participants were treatment-naive (95 trials), treatment-experienced (17 trials), or both treatment-naive and treatment-experienced (24 trials). The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.Meta-analysis of the effects of all DAAs on the market or under development showed no evidence of a difference when assessing hepatitis C-related morbidity or all-cause mortality (OR 3.72, 95% CI 0.53 to 26.18, P = 0.19, I² = 0%, 2,996 participants, 11 trials, very low-quality evidence). As there were no data on hepatitis C-related morbidity and very few data on mortality (DAA 15/2377 (0.63%) versus control 1/617 (0.16%)), it was not possible to perform Trial Sequential Analysis on hepatitis C-related morbidity or all-cause mortality.Meta-analysis of all DAAs on the market or under development showed no evidence of a difference when assessing serious adverse events (OR 0.93, 95% CI 0.75 to 1.15, P = 0.52, I² = 0%, 15,817 participants, 43 trials, very low-quality evidence). The Trial Sequential Analysis showed that the cumulative Z-score crossed the trial sequential boundary for futility, showing that there was sufficient information to rule out that DAAs compared with placebo reduced the relative risk of a serious adverse event by 20%. The only DAA that showed a significant difference on risk of serious adverse events when meta-analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, then the meta-analysis result showed no evidence of a difference.DAAs on the market or under development seemed to reduce the risk of no sustained virological response (RR 0.44, 95% CI 0.37 to 0.52, P < 0.00001, I² = 77%, 6886 participants, 32 trials, very low-quality evidence) and Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).Withdrawn or discontinued DAAs had no evidence of a difference when assessing hepatitis C-related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79, P = 0.40, I² = 0%; 5 trials, very low-quality evidence). However, withdrawn DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73, P = 0.001, I² = 0%, 29 trials, very low-quality evidence), and Trial Sequential Analysis confirmed this meta-analysis result.Most of all outcome results were short-term results; therefore, we could neither confirm nor reject any long-term effects of DAAs. None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS: Overall, DAAs on the market or under development do not seem to have any effects on risk of serious adverse events. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low.