Diagnostic accuracy of endoscopic ultrasonography-guided tissue acquisition prior to resection of pancreatic carcinoma: a nationwide analysis.

INTRODUCTION: Endoscopic ultrasonography guided tissue acquisition (EUS + TA) is used to provide a tissue diagnosis in patients with suspected pancreatic cancer. Key performance indicators (KPI) for these procedures are rate of adequate sample (RAS) and sensitivity for malignancy (SFM). AIM: assess practice variation regarding KPI of EUS + TA prior to resection of pancreatic carcinoma in the Netherlands. PATIENTS AND METHODS: Results of all EUS + TA prior to resection of pancreatic carcinoma from 2014-2018, were extracted from the national Dutch Pathology Registry (PALGA). Pathology reports were classified as: insufficient for analysis (b1), benign (b2), atypia (b3), neoplastic other (b4), suspected malignant (b5), and malignant (b6). RAS was defined as the proportion of EUS procedures yielding specimen sufficient for analysis. SFM was calculated using a strict definition (malignant only, SFM-b6), and a broader definition (SFM-b5+6). RESULTS: 691 out of 1638 resected patients (42%) underwent preoperative EUS + TA. RAS was 95% (range 89-100%), SFM-b6 was 44% (20-77%), and SFM-b5+6 was 65% (53-90%). All centers met the performance target RAS>85%. Only 9 out of 17 met the performance target SFM-b5+6 > 85%. CONCLUSION: This nationwide study detected significant practice variation regarding KPI of EUS + TA procedures prior to surgical resection of pancreatic carcinoma. Therefore, quality improvement of EUS + TA is indicated.

Cumulative sum learning curves guiding multicenter multidisciplinary quality improvement of EUS-guided tissue acquisition of solid pancreatic lesions.

Background and study aims In this study, we evaluated the performance of community hospitals involved in the Dutch quality in endosonography team regarding yield of endoscopic ultrasound (EUS)-guided tissue acquisition (TA) of solid pancreatic lesions using cumulative sum (CUSUM) learning curves. The aims were to assess trends in quality over time and explore potential benefits of CUSUM as a feedback-tool. Patients and methods All consecutive EUS-guided TA procedures for solid pancreatic lesions were registered in five community hospitals between 2015 and  2018. CUSUM learning curves were plotted for overall performance and for performance per center. The American Society of Gastrointestinal Endoscopy-defined key performance indicators, rate of adequate sample (RAS), and diagnostic yield of malignancy (DYM) were used for this purpose. Feedback regarding performance was provided on multiple occasions at regional interest group meetings during the study period. Results A total of 431 EUS-guided TA procedures in 403 patients were included in this study. The overall and per center CUSUM curves for RAS improved over time. CUSUM curves for DYM revealed gradual improvement, reaching the predefined performance target (70 %) overall, and in three of five contributing centers in 2018. Analysis of a sudden downslope development in the CUSUM curve of DYM in one center revealed temporary absence of a senior cytopathologist to have had a temporary negative impact on performance. Conclusions CUSUM-derived learning curves allow for assessment of best practices by comparison among peers in a multidisciplinary multicenter quality improvement initiative and proved to be a valuable and easy-to-interpret means to evaluate EUS performance over time.

Do endosonographers agree on the presence of bile duct sludge and the subsequent need for intervention?

Background and study aims Endoscopic ultrasonography (EUS) is a tool widely used to diagnose bile duct lithiasis. In approximately one out of five patients with positive findings at EUS, sludge is detected in the bile duct instead of stones. The objective of this study was to establish the agreement among endosonographers regarding: 1. presence of common bile duct (CBD) stones, microlithiasis and sludge; and 2. the need for subsequent treatment. Patients and methods 30 EUS videos of patients with an intermediate probability of CBD stones were evaluated by 41 endosonographers. Experience in EUS and endoscopic retrograde cholangiopancreatography, and the endosonographers' type of practices were recorded. Fleiss' kappa statistics were used to quantify the agreement. Associations between levels of experience and both EUS ratings and treatment decisions were investigated using mixed effects models. Results A total of 1230 ratings and treatment decisions were evaluated. The overall agreement on EUS findings was fair (Fleiss' κ 0.32). The agreement on presence of stones was moderate (κ 0.46). For microlithiasis it was fair (κ 0.25) and for sludge it was slight (κ 0.16). In cases with CBD stones there was an almost perfect agreement for the decision to subsequently perform an ERC + ES. In case of presumed microlithiasis or sludge an ERC was opted for in 78 % and 51 % of cases, respectively. Differences in experience and types of practice appear unrelated to the agreement on both EUS findings and the decision for subsequent treatment. Conclusions There is only slight agreement among endosonographers regarding the presence of bile duct sludge. Regarding the need for subsequent treatment of bile duct sludge there is no consensus.

Optimizing cytological specimens of EUS-FNA of solid pancreatic lesions: A pilot study to the effect of a smear preparation training for endoscopy personnel on sample quality and accuracy.

BACKGROUND: In the absence of rapid on-side pathological evaluation, endoscopy staff generally "smears" endoscopic ultrasound guided fine needle aspiration (EUS-FNA) specimens on a glass slide. As this technique is vulnerable to preparation artifacts, we assessed if its quality could be improved through a smear-preparation-training for endoscopy staff. METHODS: In this prospective pilot study, 10 endosonographers and 12 endoscopy nurses from seven regional EUS-centers in the Netherlands were invited to participate in a EUS-FNA smear-preparation-training. Subsequently, post training slides derived from solid pancreatic lesions were compared to pre-training "control" slides. Primary outcome was to assess if the training positively affects smear quality and, consequently, diagnostic accuracy of EUS-FNA of solid pancreatic lesions. RESULTS: Participants collected and prepared 71 cases, mostly pancreatic head lesions (48%). Sixty-eight controls were selected from the pretraining period. The presence of artifacts was comparable for smears performed before and after training (76% vs 82%, P = .36). Likewise, smear cellularity (≥50% target cells) before and after training did not differ (44% (30/68) vs 49% (35/71), P = .48). Similar, no difference in diagnostic accuracy for malignancy was detected (P = .10). CONCLUSION: In this pilot EUS-FNA smear-preparation-training for endoscopy personnel, smear quality and diagnostic accuracy were not improved after the training. Based on these results, we plan to further study other training programs and possibilities.

Diagnostic yield and agreement on fine-needle specimens from solid pancreatic lesions : comparing the smear technique to liquid-based cytology.

Background and study aims The traditional "smear technique" for processing and assessing endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is sensitive to artifacts. Processing and evaluation of specimens collected in a liquid medium, liquid-based cytology (LBC) may be a solution. We compared the diagnostic value of EUS-FNA smears to LBC in pancreatic solid lesions in the absence of rapid on-site evaluation (ROSE). Patients and methods Consecutive patients who required EUS-FNA of a solid pancreatic lesion were included in seven hospitals in the Netherlands and followed for at least 12 months. Specimens from the first pass were split into two smears and a vial for LBC (using ThinPrep and/or Cell block). Smear and LBC were compared in terms of diagnostic accuracy for malignancy, sample quality, and diagnostic agreement between three cytopathologists. Results Diagnostic accuracy for malignancy was higher for LBC (82 % (58/71)) than for smear (66 % (47/71), P  = 0.04), but did not differ when smears were compared to ThinPrep (71 % (30/42), P  = 0.56) or Cell block (62 % (39/63), P  = 0.61) individually. Artifacts were less often present in ThinPrep (57 % (24/42), P  = 0.02) or Cell block samples (40 % (25/63), P  < 0.001) than smears (76 % (54/71)). Agreement on malignancy was equally good for smears and LBC (ĸ = 0.71 versus ĸ = 0.70, P  = 0.98), but lower for ThinPrep (ĸ = 0.26, P  = 0.01) than smears. Conclusion After a single pass, LBC provides higher diagnostic accuracy than the conventional smear technique for EUS-FNA of solid pancreatic lesions in the absence of ROSE. Therefore, LBC, may be an alternative to the conventional smear technique, especially in centers lacking ROSE.

Collaboration of community hospital endosonographers improves diagnostic yield of endoscopic ultrasonography guided tissue acquisition of solid pancreatic lesions.

Background and study aims Endoscopic ultrasound (EUS)-guided tissue acquisition (TA) is the method of choice for establishing a pathological diagnosis of solid pancreatic lesions. Data on quality and yield of EUS-guided TA performed in community hospitals are lacking. A study was performed to determine and improve the diagnostic yield of EUS-guided TA in a group of community hospitals. Methods Following analysis of the last 20 EUS-guided TA procedures of solid pancreatic lesions performed in each of four community hospitals, a collaborative EUS interest group was formed and a prospective registry was started. During meetings of the interest group, feedback on results per center were provided and strategies for improvement were discussed. Results In the BEFORE team formation cohort, 80 procedures were performed in 66 patients. In the AFTER team formation cohort, 133 procedures were performed in 125 patients. After team formation, the rate of adequate sample increased from 80 % (95 %CI [0.7 - 0.9]) to 95 % (95 %CI [0.9 - 1.0]) , diagnostic yield of malignancy improved from 28 % (95 %CI [0.2 - 0.4]) to 64 % (95 % CI [0.6 - 0.7]), and sensitivity of malignancy improved from 63 % (95 %CI [0.4 - 0.8]) to 84 % (95 %CI [0.8 - 0.9]). Multivariate regression analysis revealed team formation to be the only variable significantly associated with an increased rate of adequate sample. Conclusions Formation of a regional EUS interest group with regular feedback on results per center, and discussions on methods and techniques used, significantly improved the outcome of EUS-guided TA procedures in patients with solid pancreatic lesions in community hospitals.

Association of dietary macronutrient composition and non-alcoholic fatty liver disease in an ageing population: the Rotterdam Study.

OBJECTIVE: A healthy lifestyle is the first-line treatment in non-alcoholic fatty liver disease (NAFLD), but specific dietary recommendations are lacking. Therefore, we aimed to determine whether dietary macronutrient composition is associated with NAFLD. DESIGN: Participants from the Rotterdam Study were assessed on (1) average intake of macronutrients (protein, carbohydrate, fat, fibre) using a Food Frequency Questionnaire and (2) NAFLD presence using ultrasonography, in absence of excessive alcohol, steatogenic drugs and viral hepatitis. Macronutrients were analysed using the nutrient density method and ranked (Q1-Q4). Logistic regression analyses were adjusted for sociodemographic, lifestyle and metabolic covariates. Moreover, analyses were adjusted for and stratified by body mass index (BMI) (25 kg/m2). Also, substitution models were built. RESULTS: In total, 3882 participants were included (age 70±9, 58% female). NAFLD was present in 1337 (34%) participants of whom 132 were lean and 1205 overweight. Total protein was associated with overweight NAFLD after adjustment for sociodemographic and lifestyle covariates (ORQ4vsQ1 1.40; 95% CI 1.11 to 1.77). This association was driven by animal protein (ORQ4vsQ1 1.54; 95% CI 1.20 to 1.98). After adjustment for metabolic covariates, only animal protein remained associated with overweight NAFLD (ORQ4vsQ1 1.36; 95% CI 1.05 to 1.77). Monosaccharides and disaccharides were associated with lower overall NAFLD prevalence (ORQ4vsQ1 0.66; 95% CI 0.52 to 0.83) but this effect diminished after adjustment for metabolic covariates and BMI. No consistent associations were observed for fat subtypes or fibre. There were no substitution effects. CONCLUSION: This large population-based study shows that high animal protein intake is associated with NAFLD in overweight, predominantly aged Caucasians, independently of well-known risk factors. Contrary to previous literature, our results do not support a harmful association of monosaccharides and disaccharides with NAFLD.

Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. METHODS: Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. RESULTS: Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). CONCLUSIONS: Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. LAY SUMMARY: Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.

The utility and yield of endoscopic ultrasonography for suspected choledocholithiasis in common gastroenterology practice.

BACKGROUND AND STUDY AIM: Endoscopic ultrasonography (EUS) is an established diagnostic modality for diagnosing common bile duct (CBD) stones. Its use has led to a reduction in the number of endoscopic retrograde cholangiopancreatography (ERCP) procedures performed for suspected choledocholithiasis. We aimed to explore the role of EUS in detecting CBD stones and/or sludge in common gastroenterology practice. PATIENTS AND METHODS: We reviewed case records of 268 consecutive patients who underwent (EUS) procedures performed to confirm or rule out the presence of CBD stones and/or sludge between November 2006 and January 2011 in the Reinier de Graaf Hospital, Delft, The Netherlands, which is a nonacademic community hospital. RESULTS: On the basis of EUS findings, 169 of 268 (63%) patients did not undergo ERCP and were therefore not exposed to its risk of complications. Patients with positive findings on EUS (n=99) all underwent ERCP and endoscopic sphincterotomy. Only 57 of 99 (58%) had positive findings at ERCP. The main contributing factors to this finding seem to be time interval between EUS and ERCP and the type of CBD content (i.e. sludge, one CBD stone or more than one CBD stone) described. CONCLUSION: In our common gastroenterology practice, EUS plays an important role in selecting patients suspected to have CBD stones or sludge for ERCP. Much is to be learned about the probability of spontaneous passage of CBD stones and sludge into the duodenum.

Real-world medical costs of antiviral therapy among patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND AND AIMS: Very potent direct acting antivirals for the treatment of chronic hepatitis C virus infection were recently introduced into daily clinical practice. Currently, treatment uptake is hampered by their high costs, eliciting prioritization of treatment. We aimed to evaluate the direct medical costs during interferon (IFN)-based antiviral treatment and the costs per sustained virological response (SVR) among patients with advanced hepatic fibrosis. METHODS: This retrospective cohort study included all consecutive patients with chronic hepatitis C virus infection and biopsy-proven bridging fibrosis or cirrhosis (Ishak 4-6) treated with IFN-based regimens in five hepatology units of tertiary care centers in Europe and Canada. Direct medical costs, expressed in 2013 Euros, during therapy were assessed. The components of care were quantified by three distinct categories: treatment, safety/ monitoring, and complications. Cost per SVR was calculated by dividing the mean cost by the SVR rate. RESULTS: In total, 672 interferon-based treatments administered to 455 patients were included. Total medical costs per patient were averaged to €14 559 (95% confidence interval [CI], €13 323-€15 836). The mean cost per SVR was €38 514 (95% CI, €35 244-€41 892). The costs per SVR were €26 105 (95% CI, €23 068-€29 296) for patients with a normal platelet count and €50 907 (95% CI, €44 151-€59 612) for patients with thrombocytopenia, with the costs per SVR of €74 961 (95% CI, €55 463-€103 541) among those patients with a platelet count below 100 * 109 /L. CONCLUSIONS: Because of the lower SVR rates, the cost per SVR of IFN-based treatment increased when patients with more advanced liver disease were treated. Additional costs of IFN-free therapy could be limited among these patients.

Epidemiological trends among the population with chronic HCV infection in the Netherlands.

BACKGROUND: As the field of antiviral therapy for chronic HCV infection is rapidly evolving, this study aimed to assess the epidemiological changes in patient and disease characteristics among individuals with chronic HCV infection. METHODS: This study included all consecutive patients with chronic HCV monoinfection who were referred between 1990 and 2013 to the Erasmus MC University Medical Center Rotterdam, a large tertiary centre in the Netherlands. To identify trends over time, the study population was divided into six equal eras based on date of first visit to the outpatient clinic. RESULTS: A total of 1,779 patients were diagnosed with chronic HCV infection. Mean age increased over time from 43.6 (sd 13.8) years to 51.7 (sd 11.2) years (P<0.001). The number of patients who were referred with cirrhosis increased over time, from 31 (25%) patients in Era 1 to 118 (42%) patients in Era 6 (P<0.001), respectively. More patients were referred with HCV genotype 1a and 3 in the last era, with 27 (48.2%) and 15 (14.0%) patients in Era 1 and 58 (54.2%) and 60 (21.8%) patients in Era 6 (P<0.001 both), respectively. The vast majority of patients (69.5%) were born between 1950 to 1975, with 62.5% of the patients being born between 1945 and 1965. CONCLUSIONS: The HCV-infected population is ageing and is more often referred with severe liver disease. This study stresses the importance of urgently implementing national HCV screening programmes in order to be able to decrease the future burden of chronic HCV infection in the Netherlands.

Improvement of platelets after SVR among patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND AND AIMS: Patients with chronic hepatitis C virus (HCV) infection may develop cirrhosis with portal hypertension, reflected by decreased platelet count and splenomegaly. This retrospective cohort study aimed to assess changes in platelet counts after antiviral therapy among chronic HCV-infected patients with advanced fibrosis. METHODS: Platelet counts and spleen sizes were recorded in an international cohort of patients with Ishak 4-6 fibrosis who started antiviral therapy between 1990 and 2003. Last measured platelet counts and spleen sizes were compared with their pre-treatment values (within 6 months prior to the start of therapy). All registered platelet count measurements from 24-week following cessation of antiviral therapy were included in repeated measurement analyses. RESULTS: This study included 464 patients; 353 (76%) had cirrhosis and 187 (40%) attained sustained virological response (SVR). Among patients with SVR, median platelet count, increased by 35 × 10(9) /L (IQR 7-62, P < 0.001). In comparison, patients without SVR showed a median decline of 17 × 10(9) /L (IQR -5-47, P < 0.001). In a subgroup of 209 patients, median decrease in spleen size was 1.0 cm (IQR 0.3-2.0) for patients with SVR, while median spleen size increased with 0.6 cm (IQR -0.1-2.0, P < 0.001) among those without SVR. The changes in spleen size and platelet count were significantly correlated (R = -0.41, P < 0.001). CONCLUSIONS: Among chronic HCV-infected patients with advanced hepatic fibrosis, the platelet counts improved following SVR and the change in platelets correlated with the change in spleen size following antiviral therapy. These results suggest that HCV eradication leads to reduced portal pressure.

Management of Thrombocytopenia in Chronic Liver Disease: Focus on Pharmacotherapeutic Strategies.

Thrombocytopenia (platelet count <150 × 10(9)/L) often complicates chronic liver disease, impeding optimal management of these patients. The prevalence of this manifestation ranges from 6% among non-cirrhotic patients with chronic liver disease to 70% among patients with liver cirrhosis. It has also been shown that the severity of liver disease is associated with both prevalence and level of thrombocytopenia. Its development is often multifactorial, although thrombopoietin is thought to be a major factor. The discovery of and ability to clone thrombopoietin led to new treatment opportunities for this clinical manifestation. This review discusses data on the three most important thrombopoietin receptor agonists: eltrombopag, avatrombopag, and romiplostim. Currently, only eltrombopag is approved for usage among patients with thrombocytopenia and chronic hepatitis C virus infection in order to initiate and maintain interferon-based antiviral treatment. Nevertheless, the optimal management of hematologic abnormalities among patients with chronic liver disease, and its risk for bleeding complications, is still a matter of discussion. Thrombocytopenia definitely contributes to hemostatic defects but is often counterbalanced by the enhanced presence of procoagulant factors. Therefore, a thorough assessment of the patient's risk for thrombotic events is essential when the use of thrombopoietin receptor agonists is considered among patients with chronic liver disease and thrombocytopenia.

ITPA Polymorphisms Are Associated with Hematological Side Effects during Antiviral Therapy for Chronic HCV Infection.

BACKGROUND/OBJECTIVE: Genetic polymorphisms in the inosine triphosphatase (ITPA) gene have been associated with the protection from early ribavirin(RBV)-induced hemolytic anemia among patients with chronic hepatitis C virus (HCV) infection. The aim of the present study was to investigate the association between the functional ITPA variants and hematological side effects during antiviral therapy with pegylated interferon (PegIFN) and RBV. PATIENTS AND METHODS: This cohort study included all consecutive Caucasian patients treated for chronic HCV infection with PegIFN and RBV between 2000 and 2009 for whom a serum sample was available for genetic testing. The predicted inosine triphosphate pyrophosphatase (ITPase) activity was based on the genotypes of the SNPs rs1127354 and rs7270101. Decline in hemoglobin (Hb) during antiviral therapy, as well as dose reductions, blood transfusions and use of erythropoietin were assessed. RESULTS: In total, 213 patients were included. The predicted ITPase activity was normal among 152 (71%) patients; 61 (29%) patients had ITPase deficiency. By multivariable linear regression, RBV dose in mg per kilogram (Beta 0.09, 95%CI 0.04-0.13, p<0.001) and normal ITPase activity (Beta 0.89, 95%CI 0.64-1.14, p<0.001) were associated with more Hb decline at week 4 of treatment. Patients with normal ITPase activity underwent more dose adjustments of RBV than patients with ITPase deficiency (19(13%) vs 1(2%),p = 0.014) and received erythropoietin more frequently (12 (8%) vs 0 (0%),p = 0.024). CONCLUSION: Genetic variants in the ITPA gene protected against RBV treatment-induced anemia among Caucasian patients with chronic HCV infection. Patients with normal ITPase activity underwent more dose reductions of RBV and received erythropoietin more frequently.

Risk of infections during interferon-based treatment in patients with chronic hepatitis C virus infection and advanced hepatic fibrosis.

BACKGROUND & AIM: Pegylated interferon-based treatment is still the backbone of current hepatitis C therapy and is associated with bone marrow suppression and an increased risk of infections. The aim of this retrospective cohort study was to assess the risk of infections during interferon-based treatment among patients with chronic hepatitis C virus (HCV) infection and advanced hepatic fibrosis and its relation to treatment-induced neutropenia. METHODS: This cohort study included all consecutive patients with chronic HCV infection and biopsy-proven bridging fibrosis or cirrhosis (Ishak 4-6) who started treatment between 1990 and 2003 in five large hepatology units in Europe and Canada. Neutrophil counts between 500-749/µL and below 500/µL were considered as moderate and severe neutropenia, respectively. RESULTS: This study included 723 interferon-based treatments, administered to 490 patients. In total, 113 infections were reported during 88 (12%) treatments, of which 24 (21%) were considered severe. Only one patient was found to have moderate neutropenia and three patients were found to have severe neutropenia at the visit before the infection. Three hundred and twelve (99.7%) visits with moderate neutropenia and 44 (93.6%) visits with severe neutropenia were not followed by an infection. Multivariable analysis showed that cirrhosis (odds ratio [OR] 2.85, 95% confidence interval [CI] 1.38-5.90, P=0.005) and severe neutropenia at the previous visit (OR 5.42, 95% CI 1.34-22.0, P=0.018) were associated with the occurrence of infection, while moderate neutropenia was not. Among a subgroup of patients treated with pegylated interferon, severe neutropenia was not significantly associated (OR 1.63, 95% CI 0.19-14.2, P=0.660). CONCLUSIONS: In this large cohort of patients with bridging fibrosis and cirrhosis, infections during interferon-based therapy were generally mild. Severe interferon-induced neutropenia rarely occurred, but was associated with on-treatment infection. Moderate neutropenia was not associated with infection, suggesting that current dose reduction guidelines might be too strict.

Reliable prediction of clinical outcome in patients with chronic HCV infection and compensated advanced hepatic fibrosis: a validated model using objective and readily available clinical parameters.

OBJECTIVE: Reliable tools to predict long-term outcome among patients with well compensated advanced liver disease due to chronic HCV infection are lacking. DESIGN: Risk scores for mortality and for cirrhosis-related complications were constructed with Cox regression analysis in a derivation cohort and evaluated in a validation cohort, both including patients with chronic HCV infection and advanced fibrosis. RESULTS: In the derivation cohort, 100/405 patients died during a median 8.1 (IQR 5.7-11.1) years of follow-up. Multivariate Cox analyses showed age (HR=1.06, 95% CI 1.04 to 1.09, p<0.001), male sex (HR=1.91, 95% CI 1.10 to 3.29, p=0.021), platelet count (HR=0.91, 95% CI 0.87 to 0.95, p<0.001) and log10 aspartate aminotransferase/alanine aminotransferase ratio (HR=1.30, 95% CI 1.12 to 1.51, p=0.001) were independently associated with mortality (C statistic=0.78, 95% CI 0.72 to 0.83). In the validation cohort, 58/296 patients with cirrhosis died during a median of 6.6 (IQR 4.4-9.0) years. Among patients with estimated 5-year mortality risks <5%, 5-10% and >10%, the observed 5-year mortality rates in the derivation cohort and validation cohort were 0.9% (95% CI 0.0 to 2.7) and 2.6% (95% CI 0.0 to 6.1), 8.1% (95% CI 1.8 to 14.4) and 8.0% (95% CI 1.3 to 14.7), 21.8% (95% CI 13.2 to 30.4) and 20.9% (95% CI 13.6 to 28.1), respectively (C statistic in validation cohort = 0.76, 95% CI 0.69 to 0.83). The risk score for cirrhosis-related complications also incorporated HCV genotype (C statistic = 0.80, 95% CI 0.76 to 0.83 in the derivation cohort; and 0.74, 95% CI 0.68 to 0.79 in the validation cohort). CONCLUSIONS: Prognosis of patients with chronic HCV infection and compensated advanced liver disease can be accurately assessed with risk scores including readily available objective clinical parameters.

Effects of escitalopram prophylaxis during antiviral treatment for chronic hepatitis C in patients with a history of intravenous drug use and depression.

OBJECTIVE: We aimed to identify those patients with hepatitis C virus who benefit most from prophylactic treatment with selective serotonin reuptake inhibitors (SSRIs) during antiviral therapy. METHOD: We performed post hoc analyses on a prospective randomized controlled trial (n = 79) of escitalopram versus placebo during antiviral therapy with pegylated interferon and ribavirin, conducted between August 2005 and June 2008. Our primary outcome measure was the association of baseline characteristics with the development of depression and/or depressive symptoms. Further, we studied effects of prophylactic escitalopram on depressive symptoms. Presence of a major depression was diagnosed using Mini-International Neuropsychiatric Interview (MINI), a short, structured interview used to diagnose DSM-IV-TR and ICD-10 disorders. Depressive symptoms were monitored during treatment by using the depression scale of Symptom Checklist-90 (SCL-90), Montgomery-Asberg Depression Rating Scale (MADRS), and Beck Depression Inventory (BDI) at baseline and weeks 4, 12, and 24 of antiviral therapy. RESULTS: Depression occurred in 14 patients receiving placebo and in 5 patients receiving escitalopram (Pearson χ², P = .01). Combination of history of depression and intravenous drug use was associated with depression (odds ratio = 12.60; 95% CI, 2.47-64.34; P < .01). Moreover, treatment with selective serotonin reuptake inhibitor compared to placebo was associated with a significant reduction in estimated mean depressive symptoms measured by SCL-90 (P = .03) and BDI (P = .048), but not with MADRS (P = .64). CONCLUSIONS: Patients infected by hepatitis C virus with a history of depression and intravenous drug use carry the highest risk to develop interferon-induced depression. In this subset of patients, prophylaxis with escitalopram results in the most substantial decrease of interferon-induced depressive symptoms on the SCL-90 depression scale and the BDI.

Effect of thrombocytopenia on treatment tolerability and outcome in patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND & AIMS: Pegylated interferon is still the backbone of hepatitis C treatment and may cause thrombocytopenia, leading to dose reductions, early discontinuation, and eventually worse clinical outcome. We assessed associations between interferon-induced thrombocytopenia and bleeding complications, interferon dose reductions, early treatment discontinuation, as well as SVR and long-term clinical outcome. METHODS: All consecutive patients with chronic HCV infection and biopsy-proven advanced hepatic fibrosis (Ishak 4-6) who initiated interferon-based therapy between 1990 and 2003 in 5 large hepatology units in Europe and Canada were included. RESULTS: Overall, 859 treatments were administered to 546 patients. Baseline platelets (in 10(9)/L) were normal (⩾150) in 394 (46%) treatments; thrombocytopenia was moderate (75-149) in 324 (38%) and severe (<75) in 53 (6%) treatments. Thrombocytopenia-induced interferon dose reductions occurred in 3 (1%); 46 (16%), and 15 (30%) treatments respectively (p<0.001); interferon was discontinued due to thrombocytopenia in 1 (<1%), 8 (3%), and in 8 (16%) treatments respectively (p<0.001). In total, 104 bleeding events were reported during 53 treatments. Only two severe bleeding complications occurred. Multivariate analysis showed that cirrhosis and a platelet count below 50 were associated with on-treatment bleeding. Within thrombocytopenic patients, patients attaining SVR had a lower occurrence of liver failure (p<0.001), hepatocellular carcinoma (p<0.001), liver related death or liver transplantation (p<0.001), and all-cause mortality (p=0.001) compared to patients without SVR. CONCLUSIONS: Even in thrombocytopenic patients with chronic HCV infection and advanced hepatic fibrosis, on-treatment bleedings are generally mild. SVR was associated with a marked reduction in cirrhosis-related morbidity and mortality, especially in patients with baseline thrombocytopenia.