Pharmacological interventions for acute hepatitis B infection: an attempted network meta-analysis.

BACKGROUND: Infection with hepatitis B virus (HBV) can be symptomatic or asymptomatic. Apart from chronic HBV infection, the complications related to acute HBV infection are severe acute viral hepatitis and fulminant hepatitis characterised by liver failure. The optimal pharmacological treatment of acute HBV infection remains controversial. OBJECTIVES: To assess the benefits and harms of pharmacological interventions in the treatment of acute HBV infection through a network meta-analysis and to generate rankings of the available treatments according to their safety and efficacy. As it was not possible to assess whether the potential effect modifiers were similar across different comparisons, we did not perform the network meta-analysis, and instead, assessed the benefits and harms of different interventions using standard Cochrane methodological procedures. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, WHO International Clinical Trials Registry Platform, and randomised clinical trials (RCTs) registers to August 2016 to identify RCTs on pharmacological interventions for acute HBV infection. SELECTION CRITERIA: RCTs, irrespective of language, blinding, or publication status in participants with acute HBV infection. We excluded trials if participants had previously undergone liver transplantation and had other coexisting viral diseases such as hepatitis C virus and HIV. We considered any of the various pharmacological interventions compared with each other or with placebo, or no intervention. DATA COLLECTION AND ANALYSIS: We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS: Seven trials (597 participants) met our review inclusion criteria. All trials provided information for one or more outcomes; however, five participants were excluded from analysis by study authors. All the trials were at high risk of bias. Overall, all the evidence was low or very low quality evidence because of risk of bias (downgraded one level for risk of bias), small sample size (downgraded one level for imprecision), and wide CIs (downgraded one more level for imprecision in some comparisons). Of the seven trials, six were two-armed trials, while one trial was a three-armed trial. The comparisons included hepatitis B immunoglobulin (HBIG) versus placebo (one trial; 55 participants); interferon versus placebo (two trials; 200 participants); lamivudine versus placebo or no intervention (four trials; 316 participants); lamivudine versus entecavir (one trial; 90 participants); and entecavir versus no intervention (one trial; 131 participants). One trial included only people with acute HBV with hepatic encephalopathy (i.e. people with fulminant liver failure); one trial included only people with severe acute HBV, but it did not state whether any of the people also had fulminant HBV infection; three trials excluded fulminant HBV infection; and two trials did not report the severity of acute HBV infection. The mean or median follow-up period in the trials ranged from three to 12 months in the trials that provided this information.There was no evidence of any differences in short-term mortality (less than one year) in any of the comparisons: HBIG versus placebo (OR 1.13, 95% CI 0.36 to 3.54; participants = 55; 1 trial), lamivudine versus placebo or no intervention (OR 1.29, 95% CI 0.33 to 4.99; participants = 250; 2 trials); lamivudine versus entecavir (OR 1.23, 95% CI 0.13 to 11.65; participants = 90; 1 trial), or entecavir versus no intervention (OR 1.05, 95% CI 0.12 to 9.47; participants = 131; 1 trial). The proportion of people who progressed to chronic HBV infection was higher in the lamivudine group than the placebo or no intervention group (OR 1.99, 95% CI 1.05 to 3.77; participants = 285; 3 trials) and in the lamivudine group versus entecavir group (OR 3.64, 95% CI 1.31 to 10.13; participants = 90; 1 trial). There was no evidence of a difference in the proportion of people who progressed to chronic HBV infection between the entecavir and the no intervention groups (OR 0.58, 95% CI 0.23 to 1.49; participants = 131; 1 trial). None of the trials reported progression to fulminant HBV infection. Three trials with 371 participants reported serious adverse events. There were no serious adverse events in any of the groups (no intervention: 0/183 (0%), interferon: 0/67 (0%), lamivudine: 0/100 (0%), and entecavir: 0/21 (0%)). The proportion of people with adverse events was higher in the interferon group than the placebo group (OR 348.16, 95% CI 45.39 to 2670.26; participants = 200; 2 trials). There was no evidence of a difference in the proportion of people with adverse events between the lamivudine group and the placebo or no intervention group (OR 1.42, 95% CI 0.34 to 5.94; participants = 35; 1 trial) or number of adverse events between the lamivudine group and the placebo or no intervention group (rate ratio 1.72, 95% CI 1.01 to 2.91; participants = 35; 1 trial). One trial with 100 participants reported quality of life at one week. The scale used to report the health-related quality of life was not stated and lacked information on whether higher score meant better or worse, making it difficult to interpret the results. None of the trials reported quality of life beyond one week or other clinical outcomes such as mortality beyond one year, liver transplantation, cirrhosis, decompensated cirrhosis, or hepatocellular carcinoma.Two trials received funding from pharmaceutical companies; three trials were funded by parties without any vested interest in the results or did not receive any special funding; the source of funding was not available in the remaining two trials. AUTHORS' CONCLUSIONS: Low or very low quality evidence suggests that progression to chronic HBV infection was higher in people receiving lamivudine compared with placebo, no intervention, or entecavir. Low quality evidence suggests that interferon may increase the adverse events after treatment for acute HBV infection. Based on a very low quality evidence, there is currently no evidence of benefit of any intervention in acute HBV infection. There is significant uncertainty in the results and further RCTs are required.

Does Intragastric Balloon Treatment for Obesity in Chronic Kidney Disease Heighten Acute Kidney Injury Risk?

BACKGROUND: The outcomes of intragastric balloon (IGB) placement to achieve weight loss in obese patients with chronic kidney disease (CKD) have not been reported to date. This study aimed to assess the safety and efficacy of the IGB as a weight-loss treatment among this patient population. METHODS: A prospective, single-arm, 'first in CKD' interventional study was conducted in patients with a body mass index >35 kg/m2 and CKD stages 3-4, referred for weight loss. After clinical assessment, the IGB was endoscopically inserted into the stomach and kept in place for 6 months. Complications, adverse events, acceptability, weight loss and metabolic responses were monitored over 6 months. RESULTS: Eleven participants were recruited over 18 months. Two patients withdrew (1 prior to IGB insertion and 1 early removal after 3 days due to persistent vomiting) from the study; 9 patients completed the study. There were 5 episodes of acute kidney injury (AKI), occurring in 3 patients. After 6 months, the mean body mass decreased by 9.6% (SD ±6.8). Median waist circumference and total cholesterol decreased significantly (-7.7 cm; interquartile range (IQR) -15.3 to -3.9; and -0.2 mmol/l; IQR -0.6 to -0.05, respectively), with no changes in estimated glomerular filtration rate, blood pressure, triglycerides, adipokines, inflammation, or arterial stiffness measured by carotid-femoral pulse wave velocity. At IGB removal, there was 1 new case each of gastritis and esophagitis. CONCLUSIONS: Treatment with IGB has only moderate efficacy on weight loss; yet it results in a high rate of complications in obese patients with established CKD. The risk of AKI may be raised due to increased risk of dehydration secondary to gastrointestinal symptoms associated with IGB placement and reduced baseline kidney function.

Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis C.

UNLABELLED: The cost-effectiveness of noninvasive tests (NITs) as alternatives to liver biopsy is unknown. We compared the cost-effectiveness of using NITs to inform treatment decisions in adult patients with chronic hepatitis C (CHC). We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes (quality-adjusted life-years; QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four treatment strategies: testing with NITs and treating patients with fibrosis stage≥F2; testing with liver biopsy and treating patients with ≥F2; treat none; and treat all irrespective of fibrosis. We compared all NITs and tested the cost-effectiveness using current triple therapy with boceprevir or telaprevir, but also modeled new, more-potent antivirals. Treating all patients without any previous NIT was the most effective strategy and had an incremental cost-effectiveness ratio (ICER) of £9,204 per additional QALY gained. The exploratory analysis of currently licensed sofosbuvir treatment regimens found that treat all was cost-effective, compared to using an NIT to decide on treatment, with an ICER of £16,028 per QALY gained. The exploratory analysis to assess the possible effect on results of new treatments, found that if SVR rates increased to >90% for genotypes 1-4, the incremental treatment cost threshold for the "treat all" strategy to remain the most cost-effective strategy would be £37,500. Above this threshold, the most cost-effective option would be noninvasive testing with magnetic resonance elastography (ICER=£9,189). CONCLUSIONS: Treating all adult patients with CHC, irrespective of fibrosis stage, is the most cost-effective strategy with currently available drugs in developed countries.

Foxp3 expression in liver correlates with the degree but not the cause of inflammation.

Patients with chronic viral hepatitis display increased expression of Foxp3 in liver, suggesting that Tregs expansion contributes to persistent infection. The purpose of this study was to elucidate whether the expression of Foxp3 relates not to the viral infection but to the resulting liver inflammation. Liver biopsies obtained from 69 individuals (26 chronic HBV hepatitis, 14 chronic HCV hepatitis, 11 nonalcoholic fatty liver disease, 8 autoimmune diseases, 2 methotrexate-related toxicity, and 8 controls) were examined, by qRT-PCR, for the mRNA expression of Foxp3, IL-10, TGF-ß1, Fas, FasL, TRAIL, caspase-3, TNF-α, IFN-γ, and IL-1ß. Significant increase of Foxp3 was observed in all disease groups compared to controls, which was positively correlated with the intensity of inflammation. The expression of the apoptosis mediators Fas, FasL, and TRAIL, but not of IL-10 and TGF-ß1, was also significantly elevated. Our findings indicate that, independently of the initial inducer, liver inflammation is correlated with elevated expression of apoptosis mediators and is followed by local Treg accumulation. Further research towards the elucidation of the underlying casual relationships is required, in order to clarify whether our results signify the existence of a uniform Treg-mediated regulatory mechanism of apoptosis-induced inflammation.

Malnutrition and sarcopenia predict post-liver transplantation outcomes independently of the Model for End-stage Liver Disease score.

BACKGROUND: Although malnutrition and sarcopenia are prevalent in cirrhosis, their impact on outcomes following liver transplantation is not well documented. METHODS: The associations of nutritional status and sarcopenia with post-transplant infections, requirement for mechanical ventilation, intensive care (ICU) and hospital stay, and 1 year mortality were assessed in 232 consecutive transplant recipients. Nutritional status and sarcopenia were assessed using the Royal Free Hospital-Global Assessment (RFH-GA) tool and the L3-psoas muscle index (L3-PMI) on CT, respectively. RESULTS: A wide range of RFH-SGA and L3-PMI were observed within similar Model for End-stage Liver Disease (MELD) sub-categories. Malnutrition and sarcopenia were independent predictors of all outcomes. Post-transplant infections were associated with MELD (OR = 1.055, 95%CI = 1.002-1.11) and severe malnutrition (OR = 6.55, 95%CI = 1.99-21.5); ventilation > 24 h with MELD (OR = 1.1, 95%CI = 1.036-1.168), severe malnutrition (OR = 8.5, 95%CI = 1.48-48.87) and suboptimal donor liver (OR = 2.326, 95%CI = 1.056-5.12); ICU stay > 5 days, with age (OR = 1.054, 95%CI = 1.004-1.106), MELD (OR = 1.137, 95%CI = 1.057-1.223) and severe malnutrition (OR = 7.46, 95%CI = 1.57-35.43); hospital stay > 20 days with male sex (OR = 2.107, 95%CI = 1.004-4.419) and L3-PMI (OR = 0.996, 95%CI = 0.994-0.999); 1 year mortality with L3-PMI (OR = 0.996, 95%CI = 0.992-0.999). Patients at the lowest L3-PMI receiving suboptimal grafts had longer ICU/hospital stay and higher incidence of infections. CONCLUSIONS: Malnutrition and sarcopenia are associated with early post-liver transplant morbidity/mortality. Allocation indices do not include nutritional status and may jeopardize outcomes in nutritionally compromised individuals.

Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation.

BACKGROUND: Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. OBJECTIVE: To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. DATA SOURCES: We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. METHODS: We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. RESULTS: Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of £9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of £28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (£30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a £20,000 threshold (ICER: £19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of £822. LIMITATIONS: A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. CONCLUSIONS: Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001561. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Can non-invasive measurements aid clinical assessment of volume in patients with cirrhosis?

AIM: To evaluate the non-invasive assessments of volume status in patients with cirrhosis. METHODS: Echocardiography and multifrequency bioimpedance analysis measurements and short synacthen tests were made in 20 stable and 25 acutely decompensated patients with cirrhosis. RESULTS: Both groups had similar clinical assessments, cortisol response and total body water (TBW), however the ratio of extracellular water (ECW)/TBW was significantly greater in the trunk (0.420 ± 0.004 vs 0.404 ± 0.005), and limbs (R leg 0.41 ± 0.003 vs 0.398 ± 0.003, P < 0.05, and L leg 0.412 ± 0.003 vs 0.399 ± 0.003) with decompensated cirrhosis compared to stable cirrhotics, P < 0.05). Echocardiogram derived right atrial and ventricular filling and end diastolic pressures and presence of increased left ventricular end diastolic volume and diastolic dysfunction were similar in both groups. The decompensated group had lower systemic blood pressure, mean systolic 101.8 ± 4.3 vs 122.4 ± 5.3 and diastolic 58.4 ± 4.1 mmHg vs 68.8 ± 3.1 mmHg respectively, P < 0.01, and serum albumin 30 (27-33) vs 32 (31-40.5) g/L, P < 0.01. CONCLUSION: Decompensated cirrhotics had greater leg and truncal ECW expansion with lower serum albumin levels consistent with intravascular volume depletion and increased vascular permeability.

Confronting gastrocutaneous fistulas.

A gastrocutaneous fistula (GCF) represents a fistula connecting the stomach with the skin. The aim of the present review is to clarify the entity of a GCF and to discuss the various treating strategies employed. In order to elucidate GCFs as an entity etiology was pointed out and relative pathogenetic mechanisms were explored. Moreover, diagnostic modalities are discussed with a special focus on GCFs following bariatric operations. Finally, the treating strategies currently employed when confronting GCFs are presented, as well as their effectiveness.

Complicated hepatic hydatid cyst with simultaneous biliary tree and intraperitoneal rupture: can we treat it in a minimally invasive way?

We report a case of complicated liver hydatid cyst with biliary system communication, cholangitis, and having at the same time simultaneous free intraperitoneal rupture. This very rare case was treated successfully by a minimally invasive method, namely ERCP, large sphincterotomy and bile duct decompression by cysts and membranes, percutaneous radiologic subdiaphragmatic drainage and prolonged medical treatment with albendazole. Our patient, an 87-year-old lady, was considered unfit for open or laparoscopic surgery because of her poor general condition, although surgery represents the common practice in such cases.

Endoscopic closure of an iatrogenic rupture of upper esophagus (Lannier's triangle) with the use of endoclips - case report and review of the literature.

We present a case report regarding a 74-year-old male with iatrogenic esophageal perforation, after an attempt to remove a food bolus impaction at Lannier's triangle (proximal esophagus). The perforation was treated endoscopically (flexible EGD) by clip application in two sessions, with excellent outcome. Esophageal perforations occur rarely, usually following a medical procedure. The clinical manifestations are often insidious with potentially catastrophic complications. Although the majority of cases have been treated conservatively and/or operatively over the years, there is a rising tendency for non-operative endoscopic interventions due to the high morbidity and mortality rates seen even in specialized units. For this reason self-expandable stents, endoclips, tissue sealants and suturing devices have been used. A high degree of clinical suspicion is essential for successful management of esophageal perforations, as is early decision to intervene and respect for basic surgical principles such as prevention and limitation of extraesophageal contamination, prevention of reflux of gastric contents and restoration of gastrointestinal tract integrity. The published reports on the use of endoclips for repairing perforations of the proximal esophagus are rare. To our knowledge, this is the first case report regarding the endoscopic application of endoclips for the successful closure of an iatrogenic perforation at Lannier's triangle.