Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis B in the UK: systematic review and economic evaluation.

We compared the cost-effectiveness of various noninvasive tests (NITs) in patients with chronic hepatitis B and elevated transaminases and/or viral load who would normally undergo liver biopsy to inform treatment decisions. We searched various databases until April 2012. 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 decision-making strategies: testing with NITs and treating patients with fibrosis stage ≥F2, testing with liver biopsy and treating patients with ≥F2, treat none (watchful waiting) and treat all irrespective of fibrosis. Treating all patients without prior fibrosis assessment had an incremental cost-effectiveness ratio (ICER) of £28,137 per additional QALY gained for HBeAg-negative patients. For HBeAg-positive patients, using Fibroscan was the most cost-effective option with an ICER of £23,345. The base case results remained robust in the majority of sensitivity analyses, but were sensitive to changes in the ≥ F2 prevalence and the benefit of treatment in patients with F0-F1. For HBeAg-negative patients, strategies excluding NITs were the most cost-effective: treating all patients regardless of fibrosis level if the high cost-effectiveness threshold of £30,000 is accepted; watchful waiting if not. For HBeAg-positive patients, using Fibroscan to identify and treat those with ≥F2 was the most cost-effective option.

Effects of donor/recipient human leukocyte antigen mismatch on human cytomegalovirus replication following liver transplantation.

BACKGROUND: Natural immunity against cytomegalovirus (CMV) can control virus replication after solid organ transplantation; however, it is not known which components of the adaptive immune system mediate this protection. We investigated whether this protection requires human leukocyte antigen (HLA) matching between donor and recipient by exploiting the fact that, unlike transplantation of other solid organs, liver transplantation does not require HLA matching, but some donor and recipient pairs may nevertheless be matched by chance. METHODS: To further investigate this immune control, we determined whether chance HLA matching between donor (D) and recipient (R) in liver transplants affected a range of viral replication parameters. RESULTS: In total, 274 liver transplant recipients were stratified according to matches at the HLA A, HLA B, and HLA DR loci. The incidence of CMV viremia, kinetics of replication, and peak viral load were similar between the HLA matched and mismatched patients in the D+/R+ and D-/R+ transplant groups. D+/R- transplants with 1 or 2 mismatches at the HLA DR locus had a higher incidence of CMV viremia >3000 genomes/mL blood compared to patients matched at this locus (78% vs. 17%; P = 0.01). Evidence was seen that matching at the HLA A locus had a small effect on peak viral loads in D+/R- patients, with median peak loads of 3540 and 14,706 genomes/mL in the 0 and combined (1 and 2) mismatch groups, respectively (P = 0.03). CONCLUSION: Overall, our data indicate that, in the setting of liver transplantation, prevention of CMV infection and control of CMV replication by adaptive immunity is minimally influenced by HLA matching of the donor and recipient. Our data raise questions about immune control of CMV in the liver and also about the cells in which the virus is amplified to give rise to CMV viremia.

De novo use of generic tacrolimus in liver transplantation - a single center experience with one-yr follow-up.

UNLABELLED: Use of generic tacrolimus in liver transplantation (LT) could result in cost savings. Generic tacrolimus has been shown to be bioequivalent to innovator tacrolimus in healthy volunteers and renal transplant patients. There are limited data on the de novo use of generic tacrolimus in LT. This study aimed to determine whether the de novo use of generic tacrolimus (Adoport, Sandoz,UK) was associated with differences in outcomes, safety, and cost compared with innovator tacrolimus (Prograf, Astellas, Japan). METHODS: Patients were studied before and after a programmatic change from de novo IS with Prograf to Adoport. Outcomes, tacrolimus levels, doses, and costs were compared for the first-yr post-LT. RESULTS: Ninety-four patients were studied, 46 Prograf, 48 Adoport. No significant differences in rejection, cytomegalovirus infection, acute kidney injury, sepsis, or graft loss were observed between groups. Tacrolimus costs were significantly reduced with the de novo use of Adoport. Day 14 dose normalized levels in Adoport patients showed significant variation but at the day 30 and one yr, there were no significant differences in the doses or levels of tacrolimus between groups. CONCLUSIONS: Adoport is safe and effective compared to Prograf when used de novo in LT patients. Tacrolimus costs were significantly reduced by the use of Adoport.

A randomised phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation vs embolisation alone for hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolisation (TACE) has not been shown to be superior to bland embolisation (TAE) for treatment of hepatocellular carcinoma (HCC). METHODS: We conducted a randomised phase II/III trial in patients with untreated HCC. Patients were randomised to TAE with polyvinyl alcohol (PVA) particles alone or sequential TACE (sTACE) in which cisplatin 50 mg was administered intrarterially 4-6 h before PVA embolisation. Treatment was repeated 3-weekly for up to three treatments. The primary endpoint was overall survival and secondary endpoints were progression-free survival, toxicity and response. Target sample sizes for phase II and III were 80 and 322. RESULTS: The trial was terminated at phase II after 86 patients had been randomised. Patients were well matched for prognostic criteria. All three planned treatments were given to 57.1% (TAE) and 56.8% (TACE) patients. Grade 3/4 toxicity occurred in 63.5% and 83.7%, respectively (P=0.019). End-of-treatment RECIST response (CR+PR) was 13.2 and 32.6% (P=0.04) (mRECIST 47.3% and 67.4) and median overall survival and progression-free survival was 17.3 vs 16.3 (P=0.74) months and 7.2 vs 7.5 (P=0.59), respectively. CONCLUSION: Transarterial chemoembolisation according this novel schedule is feasible and associated with a higher response rate than TAE alone. The survival benefit of TACE over TAE remains unproven.

A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer.

BACKGROUND: The prognosis for patients with hepatocellular cancer (HCC) undergoing transarterial therapy (TACE/TAE) is variable. METHODS: We carried out Cox regression analysis of prognostic factors using a training dataset of 114 patients treated with TACE/TAE. A simple prognostic score (PS) was developed, validated using an independent dataset of 167 patients and compared with Child-Pugh, CLIP, Okuda, Barcelona Clinic Liver Cancer (BCLC) and MELD. RESULTS: Low albumin, high bilirubin or α-fetoprotein (AFP) and large tumour size were associated with a two- to threefold increase in the risk of death. Patients were assigned one point if albumin <36 g/dl, bilirubin >17 µmol/l, AFP >400 ng/ml or size of dominant tumour >7 cm. The Hepatoma arterial-embolisation prognostic (HAP) score was calculated by summing these points. Patients were divided into four risk groups based on their HAP scores; HAP A, B, C and D (scores 0, 1, 2 and >2, respectively). The median survival for the groups A, B, C and D was 27.6, 18.5, 9.0 and 3.6 months, respectively. The HAP score validated well with the independent dataset and performed better than other scoring systems in differentiating high- and low-risk groups. CONCLUSIONS: The HAP score predicts outcomes in patients with HCC undergoing TACE/TAE and may help guide treatment selection, allow stratification in clinical trials and facilitate meaningful comparisons across reported series.

Tacrolimus trough levels, rejection and renal impairment in liver transplantation: a systematic review and meta-analysis.

We hypothesized that current trough concentrations of tacrolimus after liver transplantation are set too high, considering that clinical consequences of rejection are not severe while side effects are increased.We systematically reviewed 64 studies (32 randomized controlled trials and 32 observational studies) to determine how lower tacrolimus trough concentrations than currently recommended affect acute rejection rates and renal impairment. Among randomized trials the mean of tacrolimus trough concentration during the first month was positively correlated with renal impairment within 1 year (r = 0.73; p = 0.003), but not with acute rejection, either defined using protocol biopsies (r = -0.37; p = 0.32) or not (r = 0.11; p = 0.49). A meta-analysis of randomized trials directly comparing tacrolimus trough concentrations (five trials for acute rejection [n = 957] and two trials for renal impairment [n = 712]) showed that "reduced tacrolimus" trough concentrations (<10 ng/mL) within the first month after liver transplantation were associated with less renal impairment at 1 year (RR = 0.51 [0.38-0.69]), with no significant influence on acute rejection (RR = 0.92 [0.65-1.31]) compared to "conventional tacrolimus" trough levels (>10 ng/mL). Lower trough concentrations of tacrolimus (6-10 ng/mL during the first month) would be more appropriate after liver transplantation. Regulatory authorities and the pharmaceutical industry should allow changes of regulatory drug information.

The Eurotransplant donor risk index in liver transplantation: ET-DRI.

Recently we validated the donor risk index (DRI) as conducted by Feng et al. for the Eurotransplant region. Although this scoring system is a valid tool for scoring donor liver quality, for allocation purposes a scoring system tailored for the Eurotransplant region may be more appropriate. Objective of our study was to investigate various donor and transplant risk factors and design a risk model for the Eurotransplant region. This study is a database analysis of all 5939 liver transplantations from deceased donors into adult recipients from the 1st of January 2003 until the 31st of December 2007 in Eurotransplant. Data were analyzed with Kaplan-Meier and Cox regression models. From 5723 patients follow-up data were available with a mean of 2.5 years. After multivariate analysis the DRI (p < 0.0001), latest lab GGT (p = 0.005) and rescue allocation (p = 0.007) remained significant. These factors were used to create the Eurotransplant Donor Risk Index (ET-DRI). Concordance-index calculation shows this ET-DRI to have high predictive value for outcome after liver transplantation. Therefore, we advise the use of this ET-DRI for risk indication and possibly for allocation purposes within the Eurotrans-plant region.

Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy.

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission.

Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?

Patients with cirrhosis can have abnormalities in laboratory tests reflecting changes in primary haemostasis, including bleeding time, platelet function tests, markers of platelet activation, and platelet count. Such changes have been considered particularly relevant in the bleeding complications that occur in cirrhosis. However, several studies have shown that routine diagnostic tests, such as platelet count, bleeding time, PFA-100, thromboelastography are not clinically useful to stratify bleeding risk in patients with cirrhosis. Moreover, treatments used to increase platelet count or to modulate platelet function could potentially do harm. Consequently the optimal management of bleeding complications is still a matter of discussion. Moreover, in the last two decades there has been an increased recognition that not only bleeding but also thrombosis complicates the clinical course of cirrhosis. Thus, we performed a literature search looking at publications studying both qualitative and quantitative aspects of platelet function to verify which primary haemostasis defects occur in cirrhosis. In addition, we evaluated the contribution of qualitative and quantitative aspects of platelet function to the clinical outcome in cirrhosis and their therapeutic management according to the data available in the literature. From the detailed analysis of the literature, it appears clear that primary haemostasis may not be defective in cirrhosis, and a low platelet count should not necessarily be considered as an automatic index of an increased risk of bleeding. Conversely, caution should be observed in patients with severe thrombocytopenia where its correction is advised if bleeding occurs and before invasive diagnostic and therapeutic procedures.

Elastography for the diagnosis of severity of fibrosis in chronic liver disease: a meta-analysis of diagnostic accuracy.

BACKGROUND & AIMS: Transient elastography is a non-invasive method, for the assessment of hepatic fibrosis, developed as an alternative to liver biopsy. We studied the performance of elastography for diagnosis of fibrosis using meta-analysis. METHODS: MEDLINE, EMBASE, SCI, Cochrane Library, conference abstracts books, and article references were searched. We included studies using biopsy as a reference standard, with the data necessary to calculate the true and false positive, true and false negative diagnostic results of elastography for a fibrosis stage, and with a 3-month maximum interval between tests. The quality of the studies was rated with the QUADAS tool. RESULTS: We identified 40 eligible studies. Summary sensitivity and specificity was 0.79 (95% CI 0.74-0.82) and 0.78 (95% CI 0.72-0.83) for F2 stage and 0.83 (95% CI 0.79-0.86) and 0.89 (95% CI 0.87-0.91) for cirrhosis. After an elastography result at/over the threshold value for F2 or cirrhosis ("positive" result), the corresponding post-test probability for their presence (if pre-test probability was 50%) was 78%, and 88% respectively, while, if values were below these thresholds ("negative" result), the post-test probability was 21% and 16%, respectively. No optimal stiffness cut-offs for individual fibrosis stages were validated in independent cohorts and cut-offs had a wide range and overlap within and between stages. CONCLUSIONS: Elastography theoretically has good sensitivity and specificity for cirrhosis (and less for lesser degrees of fibrosis); however, it should be cautiously applied to everyday clinical practice because there is no validation of the stiffness cut-offs for the various stages. Such validation is required before elastography is considered sufficiently accurate for non-invasive staging of fibrosis.

Systematic review and meta-analysis of intraoperative versus preoperative endoscopic sphincterotomy in patients with gallbladder and suspected common bile duct stones.

BACKGROUND: Most patients with gallbladder and common bile duct stones are treated by preoperative endoscopic sphincterotomy (POES) followed by laparoscopic cholecystectomy. Recently, intraoperative endoscopic sphincterotomy (IOES) during laparoscopic cholecystectomy has been suggested as an alternative treatment. METHODS: Data from randomized clinical trials related to safety and effectiveness of IOES versus POES were extracted by two independent reviewers. Risk ratios (RRs) or mean differences were calculated with 95 per cent confidence intervals based on intention-to-treat analysis whenever possible. RESULTS: Four trials with 532 patients comparing IOES with POES were included. There were no deaths. There was no significant difference in rates of ampullary cannulation (RR 1·01, 0·97 to 1·04; P = 0·70) or stone clearance by ES (RR 0·99, 0·96 to 1·02; P = 0·58) between the groups. The proportion of patients with at least one post-ES complication, including pancreatitis, bleeding, perforation, cholangitis, cholecystitis or gastric ulcer, was significantly lower in the IOES group (RR 0·37, 0·18 to 0·78; P = 0·009). There was no significant difference in morbidity after laparoscopic cholecystectomy or requirement for open operation between the groups. Mean hospital stay was 3 days shorter in the IOES group: mean difference - 2·83 (-3·66 to - 2·00) days (P < 0·001). CONCLUSION: In patients with gallbladder and common bile duct stones, IOES is as effective and safe as POES and results in a significantly shorter hospital stay.

Long-term outcomes of liver transplantation in type 1 Gaucher disease.

Gaucher disease (GD) is the most prevalent lysosomal storage disorder. Enzyme replacement therapy (ERT) has demonstrable efficacy in reversing clinical and pathological manifestations of GD. We report four patients with GD and severe hepatic impairment who were successfully treated by orthotopic liver transplantation. Liver failure resulted from GD in two patients and due to a comorbidity in two others (HCV and autoimmune chronic active hepatitis). Following successful liver transplantation, patients received long-term ERT. Liver transplantation is a life-saving treatment for end-stage liver disease in patients with Gaucher disease. All four patients have had excellent outcomes from liver transplantation for up to 10 years postprocedure with no evidence of Gaucher-related pathology in the graft.

Fibrosis staging in chronic hepatitis C: analysis of discordance between transient elastography and liver biopsy.

In chronic hepatitis C, transient elastography (TE) accurately identifies cirrhosis, but its ability to assess significant fibrosis (Metavir > or = F2) is variable. Constitutional and liver disease-related factors may influence TE and here we examined the variables associated with differences. Three hundred consecutive hepatitis C virus (HCV)-RNA positive patients had biochemical tests, TE and a biopsy performed on the same day. The Dale model was used to identify the variables associated with discordance between biopsy and elastography results. In 97 patients (34.2%), TE and histological assessment were discordant. Seventy-six of 286 (26.6%) had stage > or =F2 and TE < 7.1 kPa (false negative); 21 of 286 (7.3%) had stage or = 7.1 kPa (false positive). No patient with discordant results had cirrhosis. By Dale model, aspartate aminotransferase (AST) was found to be the unique variable significantly related (P = 0.046) with discordance between biopsy and TE. Discordance rate was 43.4% (82 patients) with AST < 1.5 x UNL vs 25.8% (25 patients) with AST > or = 1.5 x UNL (P = 0.004). False negative rate was 43.4 (82 patients) with AST < 1.5 x UNL vs 17.1% (13 patients) with AST > or = 1.5 x UNL (P < 0.001). Areas under the receiver operating characteristic (AUROC) for F > or = 2, according to AST < 1.5 x UNL vs > or = 1.5 x UNL were 0.738 (95% CI: 0.683-0.812) and 0.854(95% CI: 0.754-0.907). Transient elastography is not adequate on its own to rule out or to rule in significant fibrosis, as it is influenced by major variations in biochemical activity of liver disease. Liver stiffness, at low levels of AST, can underestimate fibrosis.

Prospective comparison of Fibroscan, King's score and liver biopsy for the assessment of cirrhosis in chronic hepatitis C infection.

Historically, liver biopsy (LB) was the sole method to evaluate the severity of hepatic fibrosis in patients with chronic hepatitis C infection. However, LB is expensive and associated with a risk of severe complications. Therefore, noninvasive tests have been developed to assess the severity of liver fibrosis. The accuracy of Fibroscan (FS) and King's score (KS) was evaluated individually and in combination using liver histology as the reference standard. One hundred and eighty-seven patients were identified who had undergone a biopsy with a diagnosis of chronic hepatitis C virus (HCV) mono-infection (HCV RNA-positive by RT-PCR), attending King's College Hospital (n = 88) or the Royal Free Hospital (n = 99) (London) between May 2006 and December 2007. Liver fibrosis was scored using the Ishak method; significant fibrosis was defined as Ishak fibrosis stage F3-F6, and cirrhosis defined as Ishak fibrosis F5-F6. The diagnostic accuracy of each test was assessed by area under receiver operator characteristic curves (AUROC). Median age was 49 years (43-54) and 115 (61%) were male. The AUROC for FS, KS and FS + KS for the diagnosis of Ishak F3-F6 were 0.83, 0.82 and 0.85, respectively and for the diagnosis of cirrhosis (>or=F5) were 0.96, 0.89 and 0.93, respectively. The negative predictive values for the diagnosis of cirrhosis using the optimal cut-off results for fibrsocan (10.05 kPa), KS (24.3) and the two combined (26.1) were 98%, 91% and 94%, respectively. The noninvasive markers and, particularly, FS were effective tests for the prediction of cirrhosis in chronic hepatitis C. Both KS and FS also had clinical utility for the prediction of Ishak fibrosis stages F3-F6.

A simple, noninvasive test for the diagnosis of liver fibrosis in patients with hepatitis C recurrence after liver transplantation.

Recurrent hepatitis C is a common cause of graft loss in patients undergoing liver transplantation, and serial protocol liver biopsies have been used to identify patients at risk of graft loss from rapid fibrosis progression. The aim of this study was to derive a simple noninvasive index to predict fibrosis in patients with recurrent hepatitis C post-transplant. A retrospective study was performed assessing serial liver biopsies for post-transplant chronic hepatitis C infection. One hundred eighty-five patients were included in the analysis; median age 53 years (interquartile range 48-59) and 140 (76%) were male. Liver histology showed 53 (29%) had Ishak fibrosis stages F0/F1, 31 (17%) had F2, 29 (16%) had F3, 19 (10%) had F4 and 53 (29%) had F5/F6. The London Transplant Centres' (LTC) score was derived combining aspartate aminotransferase (AST IU/L), time from liver transplant (TFLT months), international normalized ratio and platelets. Diagnostic accuracy of the LTC score was assessed using area under receiver-operating characteristic (ROC) curves. The area under the ROC curve for moderate fibrosis (F >or= 2) was 0.78 (95% CI, 0.70-0.86; P < 0.0001), for advanced fibrosis (F4-6) was 0.80 (95% CI, 0.72-0.87; P < 0.0001) and for cirrhosis was 0.80 (95% CI, 0.72-0.88; P < 0.0001). An optimal cut-off value of 6.3 distinguished patients with no or mild fibrosis (F

Azathioprine in liver transplantation: a reevaluation of its use and a comparison with mycophenolate mofetil.

Calcineurin inhibitors (CNIs) combined with steroids with or without azathioprine (AZA), have been a standard immunosuppression regimen after liver transplantation (LT). Since 2000 many centers have substituted AZA by mycophenolate mofetil (MMF). However, in LT the superiority of MMF over AZA is not clearly demonstrated. Therefore, we questioned the benefit of MMF versus AZA in LT with regard to rejection, renal dysfunction and hepatitis C virus (HCV) recurrence and survival. Using a literature search, relevant randomized controlled trials (RCT) and cohort studies were identified: two RCTs compared MMF to AZA only for acute rejection. Treated rejection was less with MMF in only one RCT (38.5% vs. 47.7%; p = 0.025), with no difference in patient and graft survival. No RCTs compared MMF and AZA in patients with CNI-related chronic renal dysfunction. Among two studies evaluating MMF, with substitution of AZA, one was stopped due to severe rejection. Recurrent HCV was less severe in 5/9 studies with AZA compared with 2/17 using MMF, six of which documented worse recurrence. Published data in LT show little, if any, clinical benefit of MMF versus AZA. RCTs should reevaluate AZA in LT. Evaluation of HCV replication and recurrence will be particularly important as AZA may have advantages over MMF.

Coagulation and fibrosis in chronic liver disease.

In the hepatic tissue repair mechanism, hepatic stellate cells (HSCs) are recruited at the site of injury and their changes reflect paracrine stimulation by all neighbouring cell types, including sinusoidal endothelial cells, Kupffer cells, hepatocytes, platelets and leucocytes. Thrombin converts circulating fibrinogen to fibrin, promotes platelet aggregation, is a potent activator of endothelial cells, acts as a chemoattractant for inflammatory cells and is a mitogen and chemoattractant for fibroblasts and vascular smooth muscle cells. Most of the cellular effects elicited by thrombin are mediated via a family of widely expressed G-protein-coupled receptors termed protease activated receptors (PARs). All known members of the PAR family stimulate cell proliferation/activation in a rat HSC line. Thrombin receptors are constitutively expressed in the liver, and their expression increases in parallel with the severity and/or the duration of liver disease. In human studies, thrombotic risk factors were found to be independently associated with the extent of fibrosis; severity of hepatitis C virus (HCV)-associated liver disease appears to be less in patients with haemophilia when compared with those with HCV alone. Several studies, based mostly on rat models, demonstrate that anticoagulants or antiplatelet agents prevent hepatic necrosis and fibrosis by acting on HSCs. These drugs could be therapeutic agents in patients with chronic liver disease and specific studies should be initiated.

Autoimmune disease and molecular mimicry: an hypothesis.

Helper T lymphocytes are normally only stimulated to initiate an immune reaction through the recognition of peptides bound to class II major histocompatibility complex (MHC) molecules. Class II MHC molecules are constitutively expressed on antigen-presenting cells which play a critical role in the initiation of immune responses. In disease states, however, other cells often express class II MHC molecules inappropriately. This article suggests an hypothesis for the pathogenesis of autoimmune diseases based on molecular mimicry. The mimicry described is between microbial or viral peptides presented by antigen-presenting cells and self peptides presented inappropriately on a target tissue. This leads to helper T cells, stimulated by peptides derived from infectious organisms, initiating an autoimmune attack on the target tissue.