Non-alcoholic fatty liver disease(NAFLD)is the most common liver disease in the world.Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis(NASH).NAFLD is a ...hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components.Up to80%of patients with NAFLD are obese,defined as a body mass index(BMI)>30 kg/m2.However,the distribution of fat tissue plays a greater role in insulin resistance than the BMI.The large amount of visceral adipose tissue(VAT)in morbidly obese(BMI>40 kg/m2)individuals contributes to a high prevalence of NAFLD.Free fatty acids derived from VAT tissue,as well as from dietary sources and de novo lipogenesis,are released to the portal venous system.Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD.In addition,secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways,which are also activated by free fatty acids,and contribute to insulin resistance.Most NAFLD patients are asymptomatic on clinical presentation,even though some may present with fatigue,dyspepsia,dull pain in the liver and hepatosplenomegaly.Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications,anti-obesity medication and bariatric surgery.This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease.The relative contribution of visceral and liver fat to insulin resistance is discussed,and recommendations for clinical evaluation of affected individuals is provided.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic hepatic disorder in Western countries, with a prevalence of 20-30%. NAFLD comprises 'silent liver disease', in which simple ...steatosis is the only histological finding and which is benign in course, and nonalcoholic steatohepatitis, which is characterized by hepatocellular injury and inflammation with or without fibrosis. NAFLD is clinically important, because even benign fatty liver can progress to steatohepatitis in many patients, which can lead to liver cirrhosis and its complications and hepatocellular carcinoma. NAFLD is a hepatic manifestation of metabolic syndrome; it is closely related to other clinical features of metabolic syndrome, and thus to cardiovascular morbidity. There are several different noninvasive techniques for formal diagnosis and follow-up, but liver biopsy remains the gold standard. The most important therapeutic strategies include lifestyle changes, including changes in dietary habits aimed at weight loss and blood pressure regulation, with a consequent decrease in insulin resistance. For some patients with NAFLD/nonalcoholic steatohepatitis, pharmacological treatment is the best option, although further studies are needed to confirm its efficacy and tolerability.
Background
Acute pancreatitis is a common and potentially lethal disease with increasing incidence. Severe cases are characterised by high mortality, and despite improvements in intensive care ...management, no specific treatment relevantly improves clinical outcomes of the disease. Meta‐analyses suggest that enteral nutrition is more effective than conventional treatment consisting of discontinuation of oral intake with use of total parenteral nutrition. However, no systematic review has compared different enteral nutrition formulations for the treatment of patients with acute pancreatitis.
Objectives
To assess the beneficial and harmful effects of different enteral nutrition formulations in patients with acute pancreatitis.
Search methods
We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Specialised Register of Clinical Trials, the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 7), MEDLINE (from inception to 20 August 2013), EMBASE (from inception to 2013, week 33) and Science Citation Index–Expanded (from 1990 to August 2013); we conducted full‐text searches and applied no restrictions by language or publication status.
Selection criteria
We considered randomised clinical trials assessing enteral nutrition in patients with acute pancreatitis. We allowed concomitant interventions if they were received equally by all treatment groups within a trial.
Data collection and analysis
Two review authors independently assessed trials for inclusion and extracted data. We performed the analysis using Review Manager 5 (Review Manager 2013) and both fixed‐effect and random‐effects models. We expressed results as risk ratios (RRs) for dichotomous data, and as mean differences (MDs) for continuous data, both with 95% confidence intervals (CIs). Analysis was based on an intention‐to‐treat principle.
Main results
We included 15 trials (1376 participants) in this review. We downgraded the quality of evidence for many of our outcomes on the basis of high risk of bias. Low‐quality evidence suggests that immunonutrition decreases all‐cause mortality (RR 0.49, 95% CI 0.29 to 0.80). The effect of immunonutrition on other outcomes from a subset of the included trials was uncertain. Subgrouping trials by type of enteral nutrition did not explain any variation in effect. We found mainly very low‐quality evidence for the effects of probiotics on the main outcomes. One eligible trial in this comparison reported a higher rate of serious adverse events leading to increased organ failure and mortality due to low numbers of events and low risk of bias. When we excluded this study as a post hoc sensitivity analysis, risks of mortality (RR 0.30, 95% CI 0.10 to 0.84), organ failure (RR 0.74, 95% CI 0.59 to 0.92) and local septic complications (RR 0.40, 95% CI 0.22 to 0.72) were lower with probiotics. In one trial assessing immunonutrition with probiotics and fibres, no deaths occurred, but hospital stay was shorter with immunonutrition (MD ‐5.20 days, 95% CI ‐8.73 to ‐1.67). No deaths were reported following semi‐elemental enteral nutrition (EN), and the effect on length of hospital stay was small (MD 0.30 days, 95% CI ‐0.82 to 1.42). Fibre‐enriched formulations reduced the number of other local complications (RR 0.52, 95% CI 0.32 to 0.87) and length of hospital stay (MD ‐9.28 days, 95% CI ‐13.21 to ‐5.35) but did not significantly affect all‐cause mortality (RR 0.23, 95% CI 0.03 to 1.84) and other outcomes. Very low‐quality evidence from the subgroup of trials comparing EN versus no intervention showed a decrease in all‐cause mortality with EN (RR 0.50, 95% CI 0.29 to 0.86).
Authors' conclusions
We found evidence of low or very low quality for the effects of immunonutrition on efficacy and safety outcomes. The role of supplementation of enteral nutrition with potential immunomodulatory agents remains in question, and further research is required in this area. Studies assessing probiotics yielded inconsistent and almost contrary results, especially regarding safety and adverse events, and their findings do not support the routine use of EN enriched with probiotics in routine clinical practice. However, further research should be carried out to try to determine the potential efficacy or harms of probiotics. Lack of trials reporting on other types of EN assessed and lack of firm evidence regarding their effects suggest that additional randomised clinical trials are needed. The quality of evidence for the effects of any kind of EN on mortality was low, and further studies are likely to have an impact on the finding of improved survival with EN versus no nutritional support. Evidence remains insufficient to support the use of a specific EN formulation.
Background
Hepatocellular carcinoma occurs mostly in people with chronic liver disease and ranks sixth in terms of global incidence of cancer, and fourth in terms of cancer deaths. In clinical ...practice, computed tomography (CT) is used as a second‐line diagnostic imaging modality to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma on prior diagnostic test such as abdominal ultrasound or alpha‐foetoprotein, or both, either in surveillance programmes or in clinical settings. According to current guidelines, a single contrast‐enhanced imaging study CT or magnetic resonance imaging (MRI) showing typical hallmarks of hepatocellular carcinoma in people with cirrhosis is valid to diagnose hepatocellular carcinoma. However, a significant number of hepatocellular carcinomas do not show typical hallmarks on imaging modalities, and hepatocellular carcinoma is, therefore, missed. There is no clear evidence of the benefit of surveillance programmes in terms of overall survival: the conflicting results can be a consequence of inaccurate detection, ineffective treatment, or both. Assessing the diagnostic accuracy of CT may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of CT in people with chronic liver disease, who are not included in surveillance programmes is needed for either ruling out or diagnosing hepatocellular carcinoma.
Objectives
Primary: to assess the diagnostic accuracy of multidetector, multiphasic contrast‐enhanced CT for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease, either in a surveillance programme or in a clinical setting.
Secondary: to assess the diagnostic accuracy of CT for the diagnosis of resectable hepatocellular carcinoma in adults with chronic liver disease.
Search methods
We searched the Cochrane Hepato‐Biliary Trials Register, Cochrane Hepato‐Biliary Diagnostic‐Test‐Accuracy Studies Register, the Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index – Science until 4 May 2021. We applied no language or document‐type restrictions.
Selection criteria
Studies assessing the diagnostic accuracy of CT for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, with cross‐sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver and histology of resected or biopsied focal liver lesion with at least a six‐month follow‐up.
Data collection and analysis
At least two review authors independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS‐2 checklist. We presented the results of sensitivity and specificity, using paired forest plots, and tabulated the results. We used a hierarchical meta‐analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double‐checked all data extractions and analyses.
Main results
We included 21 studies, with a total of 3101 participants. We judged all studies to be at high risk of bias in at least one domain because most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time‐interval between the index test and the reference standard was rarely defined. Regarding applicability in the patient selection domain, we judged 14% (3/21) of studies to be at low concern and 86% (18/21) of studies to be at high concern owing to characteristics of the participants who were on waiting lists for orthotopic liver transplantation.
CT for hepatocellular carcinoma of any size and stage: sensitivity 77.5% (95% CI 70.9% to 82.9%) and specificity 91.3% (95% CI 86.5% to 94.5%) (21 studies, 3101 participants; low‐certainty evidence).
CT for resectable hepatocellular carcinoma: sensitivity 71.4% (95% CI 60.3% to 80.4%) and specificity 92.0% (95% CI 86.3% to 95.5%) (10 studies, 1854 participants; low‐certainty evidence).
In the three studies at low concern for applicability (861 participants), we found sensitivity 76.9% (95% CI 50.8% to 91.5%) and specificity 89.2% (95% CI 57.0% to 98.1%).
The observed heterogeneity in the results remains mostly unexplained. The sensitivity analyses, which included only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted without knowledge of the results of the index test, showed no variation in the results.
Authors' conclusions
In the clinical pathway for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, CT has roles as a confirmatory test for hepatocellular carcinoma lesions, and for staging assessment. We found that using CT in detecting hepatocellular carcinoma of any size and stage, 22.5% of people with hepatocellular carcinoma would be missed, and 8.7% of people without hepatocellular carcinoma would be unnecessarily treated. For resectable hepatocellular carcinoma, we found that 28.6% of people with resectable hepatocellular carcinoma would improperly not be resected, while 8% of people without hepatocellular carcinoma would undergo inappropriate surgery. The uncertainty resulting from the high risk of bias in the included studies and concerns regarding their applicability limit our ability to confidently draw conclusions based on our results.
Background
Hepatocellular carcinoma occurs mostly in people with chronic liver disease. Worldwide, it ranks sixth in terms of incidence of cancer, and fourth in terms of cancer‐related deaths. ...Contrast‐enhanced ultrasound (CEUS) is used as an add‐on test to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma after prior diagnostic tests such as abdominal ultrasound or measurement of alpha‐foetoprotein, or both. According to guidelines, a single contrast‐enhanced imaging investigation, with either computed tomography (CT) or magnetic resonance imaging (MRI), may show the typical hepatocellular carcinoma hallmarks in people with cirrhosis, which will be sufficient to diagnose hepatocellular carcinoma. However, a significant number of hepatocellular carcinomas show atypical imaging features, and therefore, are missed at imaging.
Dynamic CEUS images are obtained similarly to CT and MRI images. CEUS differentiates between arterial and portal venous phases, in which sonographic hepatocellular carcinoma hallmarks, such as arterial hyperenhancement and subsequent washout appearance, are investigated. The advantages of CEUS over CT and MRI include real‐time imaging, use of contrast agents that do not contain iodine and are not nephrotoxic, and quick image acquisition. Despite the advantages, the use of CEUS in the diagnostic algorithm for HCC remains controversial, with disagreement on relevant guidelines.
There is no clear evidence of the benefit of surveillance programmes in terms of overall survival as the conflicting results can be a consequence of an inaccurate detection, ineffective treatment, or both. Therefore, assessing the diagnostic accuracy of CEUS may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of CEUS for the diagnosis of hepatocellular carcinoma is needed for either diagnosing hepatocellular carcinoma or ruling it out in people with chronic liver disease who are not included in surveillance programmes.
Objectives
1. To assess the diagnostic accuracy of contrast‐enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease, in a surveillance programme or in a clinical setting.
2. To assess the diagnostic accuracy of CEUS for the diagnosis of resectable hepatocellular carcinoma in people with chronic liver disease and identify potential sources of heterogeneity in the results.
Search methods
We used standard, extensive Cochrane search methods. The last date of search was 5 November 2021.
Selection criteria
We included studies assessing the diagnostic accuracy of CEUS for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, with cross‐sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver, and histology of resected or biopsied focal liver lesion with at least a six‐month follow‐up.
Data collection and analysis
We used standard Cochrane methods to screen studies, extract data, and assess the risk of bias and applicability concerns, using the QUADAS‐2 checklist. We used the bivariate model and provided estimates of summary sensitivity and specificity. We assessed the certainty of the evidence using GRADE. We presented uncertainty‐of‐the‐accuracy estimates using 95% confidence intervals (CIs).
Main results
We included 23 studies with 6546 participants. Studies were published between 2001 and 2021. We judged all 23 studies at high‐risk of bias in at least one domain, and 13/23 studies at high concern for applicability. Most studies used different reference standards to exclude the presence of the target condition. The time interval between the index test and the reference standard was rarely defined. We also had major concerns on their applicability due to the characteristics of the participants.
– CEUS for hepatocellular carcinoma of any size and stage: sensitivity 77.8% (95% CI 69.4% to 84.4%) and specificity 93.8% (95% CI 89.1% to 96.6%) (23 studies, 6546 participants; very low‐certainty evidence).
– CEUS for resectable hepatocellular carcinoma: sensitivity 77.5% (95% CI 62.9% to 87.6%) and specificity 92.7% (95% CI 86.8% to 96.1%) (13 studies, 1257 participants; low‐certainty evidence).
The observed heterogeneity in the results remains unexplained. The sensitivity analyses, including only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted with no knowledge of the results about the index test, showed no differences in the results.
Authors' conclusions
We found that by using CEUS, as an add‐on test following abdominal ultrasound, to diagnose hepatocellular carcinoma of any size and stage, 22% of people with hepatocellular carcinoma would be missed, and 6% of people without hepatocellular carcinoma would unnecessarily undergo further testing or inappropriate treatment. As to resectable hepatocellular carcinoma, we found that 23% of people with resectable hepatocellular carcinoma would incorrectly be unresected, while 8% of people without hepatocellular carcinoma would undergo further inappropriate testing or treatment. The uncertainty resulting from the high risk of bias of the included studies, heterogeneity, and imprecision of the results and concerns on their applicability limit our ability to draw confident conclusions.
Background
Hepatocellular carcinoma occurs mostly in people with chronic liver disease and ranks sixth in terms of global incidence of cancer, and third in terms of cancer deaths. In clinical ...practice, magnetic resonance imaging (MRI) is used as a second‐line diagnostic imaging modality to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma on prior diagnostic test such as abdominal ultrasound or alpha‐fetoprotein, or both, either in surveillance programmes or in clinical settings. According to current guidelines, a single contrast‐enhanced imaging study (computed tomography (CT) or MRI) showing typical hallmarks of hepatocellular carcinoma in people with cirrhosis is considered valid to diagnose hepatocellular carcinoma. The detection of hepatocellular carcinoma amenable to surgical resection could improve the prognosis. However, a significant number of hepatocellular carcinomas do not show typical hallmarks on imaging modalities, and hepatocellular carcinoma may, therefore, be missed. There is no clear evidence of the benefit of surveillance programmes in terms of overall survival: the conflicting results can be a consequence of inaccurate detection, ineffective treatment, or both. Assessing the diagnostic accuracy of MRI may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of MRI in people with chronic liver disease who are not included in surveillance programmes is needed for either ruling out or diagnosing hepatocellular carcinoma.
Objectives
Primary: to assess the diagnostic accuracy of MRI for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease.
Secondary: to assess the diagnostic accuracy of MRI for the diagnosis of resectable hepatocellular carcinoma in adults with chronic liver disease, and to identify potential sources of heterogeneity in the results.
Search methods
We searched the Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Hepato‐Biliary Group Diagnostic Test of Accuracy Studies Register, the Cochrane Library, MEDLINE, Embase, and three other databases to 9 November 2021. We manually searched articles retrieved, contacted experts, handsearched books from meetings held during the last 10 years, and searched for literature in OpenGrey (9 November 2021). Further information was requested by e‐mails, but no additional information was provided. No data was obtained through correspondence with investigators. We applied no language or document‐type restrictions.
Selection criteria
Studies assessing the diagnostic accuracy of MRI for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, with cross‐sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver and histology of resected or biopsied focal liver lesion with at least a six‐month follow‐up.
Data collection and analysis
At least two review authors independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS‐2 checklist. We presented the results of sensitivity and specificity, using paired forest plots, and we tabulated the results. We used a hierarchical meta‐analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double‐checked all data extractions and analyses.
Main results
We included 34 studies, with 4841 participants. We judged all studies to be at high risk of bias in at least one domain because most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time interval between the index test and the reference standard was rarely defined. Regarding applicability, we judged 15% (5/34) of studies to be at low concern and 85% (29/34) of studies to be at high concern mostly owing to characteristics of the participants, most of whom were on waiting lists for orthotopic liver transplantation, and due to pathology of the explanted liver being the only reference standard.
MRI for hepatocellular carcinoma of any size and stage: sensitivity 84.4% (95% CI 80.1% to 87.9%) and specificity 93.8% (95% CI 90.1% to 96.1%) (34 studies, 4841 participants; low‐certainty evidence).
MRI for resectable hepatocellular carcinoma: sensitivity 84.3% (95% CI 77.6% to 89.3%) and specificity 92.9% (95% CI 88.3% to 95.9%) (16 studies, 2150 participants; low‐certainty evidence).
The observed heterogeneity in the results remains mostly unexplained. The sensitivity analyses, which included only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted without knowledge of the results of the index test, showed no variation in the results.
Authors' conclusions
We found that using MRI as a second‐line imaging modality to diagnose hepatocellular carcinoma of any size and stage, 16% of people with hepatocellular carcinoma would be missed, and 6% of people without hepatocellular carcinoma would be unnecessarily treated. For resectable hepatocellular carcinoma, we found that 16% of people with resectable hepatocellular carcinoma would improperly not be resected, while 7% of people without hepatocellular carcinoma would undergo inappropriate surgery. The uncertainty resulting from the high risk of bias in the included studies and concerns regarding their applicability limit our ability to confidently draw conclusions based on our results.
Kliničke smjernice donose preporuke za rad kliničara koje proizlaze iz sustavnog pregleda dokaza. Cilj rada je opisati njihov povijesni razvoj, ukazati na prednosti koje donose, ali i potencijalne ...nedostatke. Prve smjernice objavljene su u šezdesetim godinama prošlog stoljeća, a zbog primjenjivosti njihov broj nastavlja rasti. Prednosti koje donose uključuju ujednačavanje zdravstvene skrbi, što rezultira poboljšanjem kliničkih ishoda. Samim time napuštaju se neučinkovite metode. Također, bolesnici u smjernicama nalaze informacije o tome što je za njih
optimalno te su smjernice način osnaživanja položaja bolesnika. Navedeno može rezultirati boljom učinkovitosti zdravstvenog sustava. Kliničke smjernice imaju i svoje nedostatke. Neka pitanja nemaju odgovore u rezultatima istraživanja koji se nalaze visoko u hijerarhiji dokaza, već su rezultat mišljenja stručnjaka, koji mogu biti u krivu. Ponekad zbog inkonkluzivnih rezultata istraživanja preporuke isto tako mogu biti dvosmislene. Zbog brzog priljeva novih dokaza preporuke u smjernicama mogu biti zastarjele. Premda su razvijeni protokoli, ostavlja se
mogućnost sukoba interesa autora kao i pristranosti zbog izvora financiranja istraživanja. Kliničke smjernice unaprijedile su zdravstvenu skrb i zaslužne su za poboljšanje ishoda bolesnika. No, prilikom donošenja konačne odluke o pristupu pojedinom bolesniku valja uzeti u obzir i vrijednosti bolesnika kao i procjenu kliničara, što je u skladu s načelima medicine temeljene na dokazima.
Barrett's esophagus (BE) requires surveillance to identify potential neoplasia at an early stage. The standard surveillance regimen includes random 4-quadrant biopsies by Seattle protocol. Main ...limitations of random biopsies are high risk of sampling error, difficulties in histology interpretation, common inadequate classification of pathohistological changes, increased risk of bleeding, and time necessary to acquire the final diagnosis. Probe-based confocal laser endomicroscopy (pCLE) has emerged as a potential tool with an aim to overcome these obvious limitations.
pCLE represents a real-time microscopic imaging method that offers evaluation of epithelial and subepithelial structures with 1,000-fold magnification. In theory, pCLE has potential to eliminate the need for biopsy in BE patients. The main advantages would be real-time diagnosis and decision-making, greater diagnostic accuracy, and evaluation of larger area compared to random biopsies. Clinical pCLE studies in the esophagus show high diagnostic accuracy, and its high negative predictive value offers high reliability and confidence to exclude dysplastic and neoplastic lesions. However, it still cannot replace histopathology due to lower positive predictive value and sensitivity. Key Messages: Despite promising results, its role in routine use in patients with BE remains questionable primarily due to lack of well-organized double-blind randomized trials.
Background
Pegylated interferon (peginterferon) plus ribavirin is the recommended treatment for patients with chronic hepatitis C, but systematic assessment of the effect of this treatment compared ...with interferon plus ribavirin is needed.
Objectives
To systematically evaluate the benefits and harms of peginterferon plus ribavirin versus interferon plus ribavirin for patients with chronic hepatitis C.
Search methods
We searched the Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index‐Expanded, and LILACS. We also searched conference s, journals, and grey literature. The last searches were conducted in September 2013.
Selection criteria
We included randomised clinical trials comparing peginterferon plus ribavirin versus interferon plus ribavirin with or without co‐intervention(s) (e.g., other antiviral drugs) for chronic hepatitis C. Quasi‐randomised and observational studies retrieved through the searches for randomised clinical trials were also considered for reports of harms. Our primary outcomes were liver‐related morbidity, all‐cause mortality, serious adverse events, adverse events leading to treatment discontinuation, other adverse events, and quality of life. Our secondary outcome was sustained virological response in serum, that is, undetectable hepatitis C virus RNA in serum by sensitive tests six months after the end of treatment.
Data collection and analysis
Two review authors independently used a standardised data collection form. We meta‐analysed data with both fixed‐effect and random‐effects models. For each outcome, we calculated the odds ratio (OR) (for liver‐related morbidity or all‐cause mortality) or the risk ratio (RR) along with 95% confidence interval (CI) based on intention‐to‐treat analysis. We used domains of the trials to assess the risk of systematic errors (bias) and trial sequential analyses to assess the risk of random errors (play of chance).
For each outcome, we calculated the RR with 95% CI based on intention‐to‐treat analysis. Effects of interventions on outcomes were assessed according to GRADE.
Main results
We included 27 randomised trials with 5938 participants. All trials had high risk of bias. We considered that the risk of bias did not impact on the quality of evidence for liver‐related mortality and adverse event outcomes, but it did for virological response. All trials compared peginterferon alpha‐2a or peginterferon alpha‐2b plus ribavirin versus interferon plus ribavirin for participants with chronic hepatitis C. Three trials administered co‐interventions (amantadine hydrochloride 200 mg daily to both intervention groups), and 24 trials were conducted without co‐interventions. The effect observed between the two intervention groups regarding liver‐related morbidity plus all‐cause mortality (5/907 (0.55%) versus 4/882 (0.45%) was imprecise: OR 1.14 ( 95% CI 0.38 to 3.42; five trials; low quality of evidence), as was the risk of adverse events leading to treatment discontinuation (332/2692 (12.3%) versus 409/2176 (18.8%); RR 0.86, 95% CI 0.68 to 1.09; 15 trials; low quality of evidence) or regarding adverse events leading to treatment discontinuation (332/2692 (12.3%) versus 409/2176 (18.8%); RR 0.86, 95% CI 0.66 to 1.12; 17 trials; low quality of evidence). However, peginterferon plus ribavirin versus interferon plus ribavirin significantly increased the risk of neutropenia (332/2202 (15.1%) versus 117/1653 (7.1%); RR 2.15, 95% CI 1.76 to 2.61; 13 trials), thrombocytopenia (65/1113 (5.8%) versus 23/1082 (2.1%); RR 2.63, 95% CI 1.68 to 4.11; 10 trials), arthralgia (517/1740 (29.7%) versus 282/1194 (23.6%); RR 1.19, 95% CI 1.05 to 1.35; four trials), injection site reaction (627/1168 (53.7%) versus 186/649 (28.7%); RR 1.71, 95% CI 1.50 to 1.93; four trials), and nausea (606/1784 (34.0%) versus 354/1239 (28.6%); RR 1.13, 95% CI 1.01 to 1.26; four trials). The most frequent adverse event was fatigue, which occurred in 57% of participants (2024/3608). No significant difference was noted between peginterferon plus ribavirin versus interferon plus ribavirin in terms of fatigue (1177/2062 (57.1%) versus 847/1546 (54.8%); RR 1.01, 95% CI 0.96 to 1.07; 12 trials). No significant differences were reported between the two treatment groups regarding anaemia, headache, rigours, myalgia, pyrexia, weight loss, asthenia, depression, insomnia, irritability, alopecia, pruritus, skin rash, thyroid malfunction, decreased appetite, or diarrhoea. We were unable to identify any data on quality of life. Peginterferon plus ribavirin versus interferon plus ribavirin seemed to significantly increase the number of participants achieving sustained virological response (1673/3300 participants (50.7%) versus 1081/2804 patients (36.7%); RR 1.39, 95% CI 1.25 to 1.56; I2 = 64%; 27 trials; very low quality of evidence). However, the risk of bias in the 13/27 (48.1%) trials reporting on this outcome was high and was considered only 'lower' in the remainder. Because the conventional meta‐analysis did not reach its required information size (n = 14,486 participants), we used trial sequential analysis to control for risks of random errors. Again, in this analysis, the estimated effect was statistically significant in favour of peginterferon. Subgroup analyses according to risk of bias, viral genotype, baseline viral load, past treatment history, and type of intervention yielded similarly significant results favouring peginterferon over interferon on the outcome of sustained virological response.
Authors' conclusions
Peginterferon plus ribavirin versus interferon plus ribavirin seems to significantly increase the proportion of patients with sustained virological response, as well as the risk of certain adverse events. However, we have insufficient evidence to recommend or reject peginterferon plus ribavirin for liver‐related morbidity plus all‐cause mortality compared with interferon plus ribavirin. The clinical consequences of achieved sustained virological response are unknown, as sustained virological response is still an unvalidated surrogate outcome. We found no evidence of the potential benefits on quality of life in patients with achieved sustained virological response. Further high‐quality research is likely to have an important impact on our confidence in the estimate of patient‐relevant outcomes and is likely to change our estimates.There is very low quality evidence that peginterferon plus ribavirin increases the proportion of patients with sustained virological response in comparison with interferon plus ribavirin. There is evidence that it also increases the risk of certain adverse events.
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