http://repub.eur.nl/res/aut/7609/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39783/ 2013-05-01T00:00:00Z Objective Entecavir (ETV) is a potent inhibitor of viral replication in chronic hepatitis B and prolonged treatment may result in regression of fibrosis. The aim of this study was to investigate the effect of ETV on disease progression. Design In a multicentre cohort study, 372 ETV-treated patients were investigated. Clinical events were defined as development of hepatocellular carcinoma (HCC), hepatic decompensation or death. Virological response (VR) was defined as HBV DNA <80 IU/ml. Results Patients were classified as having chronic hepatitis B without cirrhosis (n=274), compensated cirrhosis (n=89) and decompensated cirrhosis (n=9). The probability of VR was not influenced by severity of liver disease (p=0.62). During a median follow-up of 20 months (IQR 11e32), the probability of developing clinical events was higher for patients with cirrhosis (HR 15.41 (95% CI 3.42 to 69.54), p<0.001). VR was associated with a lower probability of disease progression (HR 0.29 (95% CI 0.08 to 1.00), p=0.05) which remained after correction for established risk factors such as age. The benefit of VR was only significant in patients with cirrhosis (HR 0.22 (95% CI 0.05 to 0.99), p=0.04) and remained after excluding decompensated patients (HR 0.15 (95% CI 0.03 to 0.81), p=0.03). A higher HBV DNA threshold of 2000 IU/ml was not associated with the probability of disease progression (HR 0.20 (95% CI 0.03 to 1.10), p=0.10). Conclusion VR to ETV is associated with a lower probability of disease progression in patients with cirrhosis, even after correction for possible baseline confounders. When using a threshold of 2000 IU/ml, the association between viral replication and disease progression was reduced, suggesting that complete viral suppression is essential for nucleoside/nucleotide analogue treatment, especially in patients with cirrhosis. http://repub.eur.nl/res/pub/39922/ 2013-05-01T00:00:00Z HBeAg seroconversion in HBV patients is considered an important event. We determined precore (PC) and base core promoter (BCP) mutations in 137 HBeAg-positive nucleos(t)ide analogues (NA) treated patients by INNO-LiPA HBV PreCore assay (Innogenetics). The majority of patients with nongenotype A had PC/BCP mutants present at baseline (P = 0.02). During 29 months of therapy, 45 patients achieved HBeAg seroconversion. Probability of HBeAg seroconversion was higher in patients with PC and/or BCP mutants (P = 0.01). After HBeAg seroconversion, patients with BCP mutants had more HBeAg relapse (P = 0.07), and PC mutants less often achieved HBV DNA < 2000 IU/mL (P = 0.07). http://repub.eur.nl/res/pub/39880/ 2013-04-01T00:00:00Z Introduction: We studied the influence of a broad range of genetic variants in recipient and donor innate immunity receptors on bacterial and fungal infections and acute rejection after liver transplantation (LT). Methods: Seventy-six polymorphisms in TLR 1-10, NOD2, LBP, CD14, MD2, SIGIRR, Ficolins 1, -2, and -3, MASP 1, -2, and -3, and the complement receptor C1qR1 were determined in 188 LT recipients and 135 of their donors. Associations with clinically significant infections and acute rejection were analyzed for 50 polymorphisms. Significant associations were validated in an independent cohort of 181 recipients and 167 donors. Results: Three recipient polymorphisms and 3 donor polymorphisms were associated with infections in the identification cohort, but none of these associations were confirmed in the validation cohort. Three donor polymorphisms were associated with acute rejection in the identification cohort, but not in the validation cohort. Conclusion: In contrast to their effect in the general population, 50 common genetic variations in innate immunity receptors do not influence susceptibility to bacterial/fungal infections after LT. In addition, no reproducible associations with acute rejection after LT were observed. Likely, transplant-related factors play a superior role as risk factors for bacterial/fungal infections and acute rejection after LT. http://repub.eur.nl/res/pub/39556/ 2013-03-01T00:00:00Z Background and aims: It remains unclear when anticoagulant therapy should be given in patients with non-cirrhotic portal vein thrombosis (PVT). The aim of this study was to assess the effect of anticoagulation on recurrent thrombotic events and gastrointestinal bleeding in non-cirrhotic PVT patients. Methods: Retrospective study of all patients with non-cirrhotic PVT (n = 120), seen at our hospital from 1985 to 2009. Data were collected by systematic chart review. Results: Sixty-six of the 120 patients were treated with anticoagulants. Twenty-two recurrent thrombotic events occurred in 19 patients. The overall thrombotic risk at 1, 5 and 10 years was 4%, 8% and 27%, respectively. Seventy-four percent of all recurrent thrombotic events occurred in patients with a prothrombotic disorder. Anticoagulant therapy tended to lower the risk of recurrent thrombosis (hazard ratio [HR] 0.2, P = 0.1), yet the only significant predictor of recurrent thrombotic events was the presence of a prothrombotic disorder (HR 3.1, P = 0.03). In 37 patients, 83 gastrointestinal bleeding events occurred. The re-bleeding risk at 1, 5 and 10 years was 19%, 46% and 49%, respectively. Anticoagulation therapy (HR 2.0, P ≤ 0.01) was a significant predictor of (re)bleeding. Anticoagulation therapy had no effect on the severity of gastrointestinal bleeding. Poor survival was associated with recurrent thrombotic events (HR 3.1 P = 0.02), whereas bleeding (HR 1.6 P = 0.2) and anticoagulant treatment (HR 0.5 P = 0.2) had no significant effect on survival. Conclusions: In non-cirrhotic PVT patients recurrent thrombotic events are mainly observed in patients with underlying prothrombotic disorders. Anticoagulation therapy tends to prevent recurrent thrombosis but also significantly increases the risk of gastrointestinal bleeding. http://repub.eur.nl/res/pub/38971/ 2013-02-04T00:00:00Z Background: Data on long-term response rates after successful primary hepatitis B (HBV) vaccination in HIV-infected patients are scarce. Objective: To evaluate the durability of an effective anti-HBs titer up to 5 years after primary vaccination in a cohort of 155 HIV-infected adults. Methods: From a previous multicenter HBV vaccination trial we selected patients with an anti-HBs titer of ≥10. IU/l 28 weeks after the first vaccination. The anti-HBs titer was measured in annually stored plasma samples up to 5 years after vaccination. Patients with decreasing anti-HBs titers <10. IU/I were defined as transient responders (TR*) and with persistent anti-HBs titers ≥10. IU/I as long-term responders (LTR). Results: We included 155 patients, 87 were TR and 68 LTR. Mean age, percentage of female participants and duration of HAART use at primary vaccination were similar in LTR and TR. Anti-HBs level after primary vaccination was the strongest predictor for the durability of anti-HBs. Anti-HBs >100-1000. IU/I and >1000 resulted in an OR 8.3, 95% CI 3.38-20.16; p<0.0001 and OR 75.6, 95% CI 13.41-426.45; p<0.0001 versus anti-HBs titer of 10-100. IU/I after primary vaccination respectively. The mean time to loss of an effective anti-HBs titer was 2.0, 3.7 and 4.4 years respectively, for patients with an anti-HBs titer of 10-100. IU/I, >100-1000. IU/I and >1000. IU/I at primary vaccination. An undetectable HIV-RNA load and use of HAART during vaccination and at follow-up were, though not significantly, associated a higher long-term persistence of an effective antibody titer. Conclusion: The durability of an effective anti-HBs level appears to be significantly related to the height of the antibody titers after the primary immunization procedure. Schedules to improve the vaccination response in HIV-infected patients therefore seem to be justified. Whether a HBV booster is indicated remains to be elucidated. http://repub.eur.nl/res/pub/38699/ 2012-09-17T00:00:00Z Background: Idiopathic noncirrhotic portal hypertension (INCPH) has been reported increasingly in patients with HIV infection. Aim: To evaluate the number of nationwide diagnosed HIV-associated INCPH cases and to assess its clinical features, risk factors and outcome. Methods: All HIV centres in the Netherlands were contacted and requested to notify INCPH cases diagnosed in their population. A case-control study was performed to identify the risk factors of INCPH. The cases were group-matched for duration of follow-up after HIV diagnosis to controls. Controls were selected from a database of HIV patients with negative screening for signs of portal hypertension on abdominal ultrasound. Univariate and multivariate conditional logistic regression analyses were performed. Results: On 1st of July 2011, 18.085 individuals were infected with HIV in the Netherlands. Within this population, sixteen patients with clinically overt INCPH were identified. At the time of INCPH diagnosis, cases had a lower platelet count and a higher ALT level. In univariate and multivariate analyses, didanosine [OR: 1.9 (1.3-2.8)], concomitant didanosine and stavudine treatment [OR: 6.3 (2.1-19.1)] and concomitant didanosine and tenofovir treatment [OR: 5.1 (1.2-22.6)] were independently associated INCPH. During follow-up, 4 patients died [malignancy (n = 3), liver failure (n = 1)]. A significant decline in platelets was observed after didanosine discontinuation (P = 0.003). Conclusions: HIV-associated clinically relevant idiopathic noncirrhotic portal hypertension appears to be a rarely diagnosed disease. Long-term exposure to didanosine and short-term combination of didanosine and stavudine or tenofovir exposure are associated with idiopathic noncirrhotic portal hypertension. Mortality in HIV-associated idiopathic noncirrhotic portal hypertension is mainly related to HIV-associated disorders. Portal hypertension continues despite didanosine discontinuation. http://repub.eur.nl/res/pub/37664/ 2012-09-17T00:00:00Z Background: Idiopathic noncirrhotic portal hypertension (INCPH) has been reported increasingly in patients with HIV infection. Aim: To evaluate the number of nationwide diagnosed HIV-associated INCPH cases and to assess its clinical features, risk factors and outcome. Methods: All HIV centres in the Netherlands were contacted and requested to notify INCPH cases diagnosed in their population. A case-control study was performed to identify the risk factors of INCPH. The cases were group-matched for duration of follow-up after HIV diagnosis to controls. Controls were selected from a database of HIV patients with negative screening for signs of portal hypertension on abdominal ultrasound. Univariate and multivariate conditional logistic regression analyses were performed. Results: On 1st of July 2011, 18.085 individuals were infected with HIV in the Netherlands. Within this population, sixteen patients with clinically overt INCPH were identified. At the time of INCPH diagnosis, cases had a lower platelet count and a higher ALT level. In univariate and multivariate analyses, didanosine [OR: 1.9 (1.3-2.8)], concomitant didanosine and stavudine treatment [OR: 6.3 (2.1-19.1)] and concomitant didanosine and tenofovir treatment [OR: 5.1 (1.2-22.6)] were independently associated INCPH. During follow-up, 4 patients died [malignancy (n = 3), liver failure (n = 1)]. A significant decline in platelets was observed after didanosine discontinuation (P = 0.003). Conclusions: HIV-associated clinically relevant idiopathic noncirrhotic portal hypertension appears to be a rarely diagnosed disease. Long-term exposure to didanosine and short-term combination of didanosine and stavudine or tenofovir exposure are associated with idiopathic noncirrhotic portal hypertension. Mortality in HIV-associated idiopathic noncirrhotic portal hypertension is mainly related to HIV-associated disorders. Portal hypertension continues despite didanosine discontinuation. http://repub.eur.nl/res/pub/39042/ 2012-09-01T00:00:00Z OBJECTIVE: Peginterferon (PEG-IFN) is considered as a first-line treatment option for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We aimed to evaluate the long-term response to PEG-IFN in HBeAg-negative patients. METHODS: All patients enrolled in the PARC study who completed the treatment phase were eligible for this long-term follow-up (LTFU) study. Patients received PEG-IFN α-2a (180 μg weekly)±ribavirin (1000-1200 mg daily) for 48 weeks and had at least one additional LTFU visit after the initial follow-up period of 24 weeks (mean duration 2.1±0.2 years). Retreated patients were considered nonresponders. RESULTS: Of 117 patients who completed the treatment phase, 79 (68%) were included in this LTFU study. Among 19 patients with a combined response at 24 weeks after treatment [initial responders; hepatitis B virus DNA<10 000 copies/ml (<1714 IU/ml) and normal alanine aminotransferase], 12 (63%) sustained this response through LTFU. Three additional patients showed such a response at LTFU, resulting in a total of 15 (19%) combined responders at LTFU. A marked decrease in the serum hepatitis B surface antigen (HBsAg) levels was observed in initial responders, resulting in HBsAg clearance in 26% of the patients (6% of all LTFU participants). CONCLUSION: About one-third of HBeAg-negative patients with a response to PEG-IFN at 24 weeks after treatment subsequently had a relapse during 2 years of follow-up. Despite the limited overall efficacy of PEG-IFN, patients responding to PEG-IFN treatment showed a marked decrease in serum HBsAg, resulting in a high rate of HBsAg clearance, which indicates the need for predictors of response to PEG-IFN in HBeAg-negative disease. http://repub.eur.nl/res/pub/39057/ 2012-07-01T00:00:00Z Peginterferon (PEG-IFN) treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN±lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months posttreatment and through long-term follow-up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non-WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non-WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio [OR] 2.90, 95% confidence interval [CI]: 1.15-7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26-24.63, P = 0.013) and patients with non-A genotypes with detectable mutants had a low probability of response. Conclusion: The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG-IFN for HBeAg-positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy. http://repub.eur.nl/res/pub/39087/ 2012-06-05T00:00:00Z Background: Sustained virological response (SVR) rates in previous non-responders to pegylated interferon (PEGIFN)-α and ribavirin for chronic HCV remain low (∼10%). We hypothesize that continuous subcutaneous delivery of fully potent interferon (IFN)-α2b via an external pump will lead to stable blood concentrations and thereby prevent subtherapeutic trough levels associated with viral breakthrough. The aims of the study were to assess safety, tolerability and virological response in patients who were previous PEG-IFN-α/ribavirin non-responders. Methods: We randomized 30 HCV genotype 1 (n=24) and genotype 4 (n=6) patients to receive 6, 9 or 12 million units (MU) IFN-α2b daily by continuous subcutaneous administration using an insulin pump (MiniMed® 508; Medtronic Inc., Minneapolis, MN, USA) in combination with ribavirin (1,000-1,600 mg) for 48 weeks. Results: The magnitude of viral decline in the 12 MU group after 4 weeks of treatment was 2.67 log HCV RNA compared with 1.21 and 1.27 log HCV RNA in the 9 and 6 MU groups, respectively (P=0.001). In the intention-to-treat analysis, the SVR rate was 20% (6/30). The perprotocol SVR rate was 25% (6/24), of which four out of six patients in the high-dose arm achieved SVR. Adverse events appeared dose-dependent, were mostly mild-to-moderate and were typical of IFN therapy. Five patients developed irritation and/or abscesses at the injection site. Six serious adverse events were reported in five patients. Conclusions: Continuous delivery of IFN-α2b can induce a strong dose-dependent viral suppression. This could be an effective approach in conjunction with, or as lead-in therapy prior to, treatment with a direct antiviral agent. http://repub.eur.nl/res/pub/39205/ 2012-01-30T00:00:00Z Background: On-treatment decline of serum hepatitis B surface antigen (HBsAg) may reflect the immunomodulatory effect of pegylated interferon (PEG-IFN) for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). We compared HBsAg decline across HBV genotypes between combined responders (HBeAg loss and HBV DNA<10,000 copies/ml at week 78), HBeAg responders (HBeAg loss with HBV DNA>10,000 copies/ml) and non-responders. Methods: HBsAg was measured at baseline, on-treatment and 6 months post-treatment in 221 HBeAgpositive CHB patients treated with PEG-IFN with or without lamivudine for 52 weeks, and in a representative subgroup of 142 patients at long-term follow-up (LTFU; mean 3.0 years). Results: On-treatment HBsAg decline significantly varied according to HBV genotype (A and B more than C and D; P<0.001). On-treatment HBsAg decline also differed between patients with a combined response (n=43) and those without (n=178; 3.34 versus 0.69 log IU/ml decline at week 52; P<0.001). Among patients without a combined response, no difference was observed between HBeAg responders (n=41) versus non-responders (n=137). HBsAg decline was sustained in combined responders and progressed to 3.75 log IU/ml at LTFU. Patients with a combined response achieved pronounced HBsAg declines, irrespective of HBV genotype, and those who achieved HBsAg levels <1,000 IU/ml at week 78 had a high probability of a sustained response and HBsAg clearance through LTFU. Conclusions: On-treatment HBsAg decline during PEG-IFN therapy for HBeAg-positive CHB depends upon HBV genotype. Patients with a combined response to PEG-IFN achieve a pronounced HBsAg decline, irrespective of HBV genotype, which is sustained through 3 years of off-treatment follow-up. http://repub.eur.nl/res/pub/34822/ 2012-01-01T00:00:00Z Reflux esophagitis (RO) and Barrett's esophagus (BO) can cause esophageal adenocarcinoma (OAC). The esophageal mucosa in the RO-BO-OAC cascade is chronically exposed to gastro-esophageal reflux. Epidermal growth factor (EGF) has an important role in the protection and repair of mucosal damage, and non-physiologic levels are associated with gastrointestinal tumors. The aim is to determine the functional effect of EGF gene polymorphisms on RO, BO and OAC development. A cohort of 871 unrelated Dutch Caucasians consisted of 198 healthy controls, 298 RO patients, 246 BO patients and 129 OAC patients. The frequency of the EGF-production-associated 5′UTR A61G polymorphism was determined in these four groups. EGF immunohistochemistry was performed on BO biopsies. EGF expression was significantly lower in the G/G genotype compared with the A/G (P0.008) and A/A (P0.002) group. The G/G genotype was significantly more prevalent in RO (odds ratios (OR)2.6; 95% confidence intervals (95% CI): 1.3-5.2), BO (OR3.0; 95% CI: 1.5-6.2) and OAC (OR4.1; 95% CI: 1.8-9.7) than in controls. The G allele is associated with reduced EGF expression and increased risk for RO, BO and OAC development. This indicates that reduced mucosal protection resulting from genetically decreased EGF expression enhances esophageal tumor development. http://repub.eur.nl/res/pub/33728/ 2011-12-01T00:00:00Z Background Treatment of hepatitis C with peginterferon and ribavirin is associated with psychiatric side-effects, frequently necessitating dose reduction or therapy cessation. Aim To assess the efficacy of prophylactic escitalopram to prevent psychiatric side-effects during peginterferon and ribavirin treatment in a randomised, double-blind, placebo-controlled trial. Methods Seventy-nine hepatitis C patients were treated with peginterferon and ribavirin. Patients received escitalopram (n = 40, 10 mg) or placebo (n = 39), which was initiated together with peginterferon and ribavirin. Primary outcomes were an increase of two points or more on the items reported sadness, inner tension and impaired concentration of the Montgomery-Asberg Depression Rating Scale, and hostile feelings of the Brief Anxiety Scale. Secondary outcome was the development of depression diagnosed by the Mini-International Neuropsychiatric Interview. Measurements were performed at baseline, week 4, 12 and 24 during anti-viral treatment, and 24 weeks thereafter. Results The incidence of psychiatric side-effects was significantly lower in patients treated with escitalopram compared with placebo for all primary and secondary outcomes, except for impaired concentration: reported sadness 27.5 vs. 48.7% (P = 0.052), inner tension 17.5 vs. 38.5% (P = 0.038), impaired concentration 55.0 vs. 66.7% (P = 0.288) and hostile feelings 22.5 vs. 43.6% (P = 0.046) (escitalopram vs. placebo, Chi-squared test). The sum scores of all four endpoints showed an overall beneficial effect of escitalopram (P = 0.009, Mann-Whitney U-test). Depression occurred in 12.5% of the patients in the escitalopram-group vs. 35.9% in the placebo-group (P = 0.015, Chi-squared test). Conclusions Prophylactic treatment with escitalopram is effective in the prevention of psychiatric side-effects during interferon-based treatment of hepatitis C. http://repub.eur.nl/res/pub/30845/ 2011-11-01T00:00:00Z The aim of the present study was to compare the decline of HBV DNA during peginterferon (PEG-IFN) therapy with spontaneous HBV DNA decline in placebo-treated patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A total of 136 patients who participated in a randomized trial were treated with PEG-IFN alfa-2b for 52 weeks. These patients were compared with 167 patients who received a placebo for 48 weeks using linear mixed regression analysis. Response was defined as loss of HBeAg at the end of treatment (EOT). Overall, decline of HBV DNA at the EOT was significantly greater in the PEG-IFN group than in the placebo group (mean decline 2.3log vs. 1.0log, P<0.001) and varied according to HBV genotype. Viral suppression was greater in the PEG-IFN group from week 4 throughout the entire treatment period (P<0.001). The response rate was 32% for the PEG-IFN group and 11% for the placebo group (P<0.001). Among responders, HBV DNA decline was greater for patients treated with PEG-IFN than with a placebo: the mean difference in HBV DNA decline was 0.7log (P=0.001) at 4 weeks and 2log (P<0.001) at the EOT. ALT flares (>5 times the upper limit) were associated with a greater HBV DNA decline during PEG-IFN. In conclusion, PEG-IFN therapy resulted in a greater HBV DNA decline in positive HBeAg patients than a placebo. The decline of HBV DNA was greater in patients with HBeAg loss or who exhibited an ALT flare during PEG-IFN than in patients with spontaneous HBeAg loss or flares during placebo therapy. http://repub.eur.nl/res/pub/26635/ 2011-08-01T00:00:00Z Nucleos(t)ide analogues strongly inhibit viral replication in chronic hepatitis B (CHB) infection, but knowledge of their long-term effect on serum hepatitis B surface antigen (HBsAg) levels and HBsAg loss is lacking. Seventy-five CHB patients with virological response (VR) to ETV or TDF were included. HBsAg decline 2 years after VR was most pronounced in HBeAg-positive patients. Age, alanine aminotransferase, and HBeAg loss were associated with HBsAg decline in HBeAg-positive patients. Predicted median time to HBsAg loss was 36 years for HBeAg-positive and 39 years for HBeAg-negative patients. Thus, most patients treated with ETV and TDF will probably need decades of therapy to achieve HBsAg loss. http://repub.eur.nl/res/pub/31334/ 2011-08-01T00:00:00Z Entecavir (ETV) is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients. The aim of this study was to investigate the long term efficacy and safety of ETV in NA-naïve CHB patients, particularly in those with detectable hepatitis B virus (HBV) DNA after 48 weeks, in whom treatment adaptation is suggested by current guidelines. In a multicenter cohort study, we investigated 333 CHB patients treated with entecavir monotherapy. The NA-naïve population consisted of 243 patients, whereas 90 were NA-experienced. Virological response (VR) (HBV DNA <80 IU/mL) was achieved in 48%, 76%, and 90% of hepatitis B e antigen (HBeAg)-positive and in 89%, 98%, and 99% of HBeAg-negative NA-naïve patients at weeks 48, 96, and 144, respectively. Thirty-six of 175 (21%) NA-naïve patients with at least 48 weeks of follow-up had a detectable load at week 48 (partial virological response [PVR]). Twenty-nine (81%) patients with PVR reached VR during prolonged ETV monotherapy, and none of them developed ETV-resistance. Among 22 patients with HBV DNA <1,000 IU/mL at week 48, VR was achieved in 21 (95%) patients, compared with eight of 14 (57%) patients with HBV DNA ≥1,000 IU/mL. Continuous HBV DNA decline was observed in most patients without VR during follow-up, and in three patients adherence was suboptimal according to the treating physician. ETV was safe and did not affect renal function or cause lactic acidosis. Conclusion: ETV monotherapy can be continued in NA-naïve patients with detectable HBV DNA at week 48, particularly in those with a low viral load because long-term ETV leads to a virological response in the vast majority of patients. http://repub.eur.nl/res/pub/25899/ 2011-07-01T00:00:00Z Objective. Chronic viral hepatitis B and C cause liver fibrosis, leading to cirrhosis. Fibrosis assessment is essential to establish prognosis and treatment indication. We compared seven non-invasive tests, separately and in combination, in chronic hepatitis patients to detect early stages of fibrosis according to the Metavir score in liver biopsy. Material and methods. Galactose and methacetin breath tests (GBT and MBT), biomarkers (hyaluronic acid (HA), aspartate aminotransferase platelet ratio index (APRI), FibroTest, and Fib-4) and transient elastography (TE) were evaluated in 89 patients. Additionally, 31 healthy controls were included for evaluation of breath tests and biomarkers. Results. Serum markers (HA, APRI, FibroTest, and Fib-4) and elastography significantly distinguished non-cirrhotic (F0123) from cirrhotic (F4) patients (p < 0.001, p = 0.015, p < 0.001, p = 0.005, p = 0.006, respectively). GBT, HA, APRI, FibroTest, Fib-4, and TE detected F01 from F234 (p = 0.04, p = 0.011, p = 0.009, p < 0.001, p < 0.001, and p < 0.001, respectively). A combination of different tests (TE, HA, and FibroTest) improved the performance statistically, area under the curve (AUC) = 0.87 for F234, 0.92 for F34, and 0.90 for F4. Conclusion. HA, APRI, FibroTest, Fib-4, and TE reliably distinguish non-cirrhotic and cirrhotic patients. Except for MBT, all tests discriminate between mild and moderate fibrosis. As single tests: FibroTest, Fib-4, and TE were the most accurate for detecting early fibrosis; combining different non-invasive tests increased the accuracy for detection of liver fibrosis to such an extent and thus might be acceptable to replace liver biopsy. http://repub.eur.nl/res/pub/31396/ 2011-07-01T00:00:00Z Flares in chronic hepatitis B are often detrimental but sometimes lead to sustained immune control and disease remission. The aim of this study was to estimate the frequency of hepatitis flares which occur during and/or after cessation of nucleos(t)ide analogue (NA) therapy, and to assess their outcomes. In a single centre cohort study we investigated 227 patients who received a total of 351 NA treatment courses. NA therapy was discontinued after 149 treatment courses. In total, 27 flares were observed during 9779 on-treatment patient-months. The frequency was estimated as 3.2 per 100 person-years (95% CI 2.2-4.7). Lamivudine (LAM)-treated patients demonstrated the highest frequency (4.9/100 person-years, 95% CI 3.2-7.4). Twenty (74%) of 27 on-therapy flares were associated with development of genotypic resistance, which all occurred during LAM therapy. NA withdrawal flares occurred after a median post-treatment follow-up of 3.5 months in 17 (11%) of 149 treatment discontinuations. No flares were observed in patients who switched to another antiviral agent (n = 51). None of the on-therapy and withdrawal flares related to NA therapy were associated with sustained disease remission, and seven flares resulted in decompensated liver disease. In this study, flares related to NA therapy never led to immune control and sustained disease remission, and sometimes resulted in decompensated liver disease. http://repub.eur.nl/res/pub/34305/ 2011-07-01T00:00:00Z Background and objectives: Serum Hepatitis B surface Antigen (HBsAg) levels correlate with hepatitis B virus intrahepatic covalently closed circular DNA and may predict response to treatment. Currently, 2 commercial platforms are available for HBsAg quantification in clinical practice, the Architect HBsAg QT and the Elecsys HBsAg. We aimed to directly compare the results of these assays. Study design: HBsAg levels were measured in 1427 serum samples from HBeAg-positive chronic hepatitis B patients who participated in a randomized trial of peginterferon alfa-2b ± lamivudine. Samples were extracted from our serum bank, thawed, and subsequently analysed for HBsAg levels using both assays. Results: Of 1427 samples, 242 (17%) were taken before and 1185 during the treatment phase of the study. Distribution of HBV genotypes was 447 (31%) genotype A, 125 (9%) B, 210 (15%) C and 534 (37%) D. Correlation between Architect and Elecsys results was high (r = 0.96, p< 0.001). By Bland-Altman analysis, agreement between the two assays was close (mean difference between Architect and Elecsys: -0.01. log. IU/mL, 95% CI: -0.55-0.52. log. IU/mL), also when analysed separately for HBV genotypes A-D. Additionally, the performance of our recently published stopping rule for HBeAg-positive patients treated with peginterferon was comparable: the negative predictive values were 96% and 98% for Elecsys and Architect, respectively. Conclusions: There is a high correlation and close agreement between quantitative HBsAg measurements conducted with the Architect and the Elecsys. Clinical prediction rules derived from data from one platform can be applied on the other; both can therefore be used in clinical practice. http://repub.eur.nl/res/pub/25497/ 2011-04-01T00:00:00Z Background. In human immunodeficiency virus (HIV)-infected patients, the immunogenicity of hepatitis B vaccines is impaired. The primary and secondary aims of our study were to investigate the effectiveness and compliance of 2 different vaccination regimen in an HIV-infected population. Methods. A noninferiority trial with a 10% response margin was designed. Included were patients ≥18 years old, with negative HBsAg/anti-HBc serology, and not previously vaccinated against hepatitis B. Patients were stratified according to CD4+cell count: <200, 200-500, >500. Participants received 10 μg HBvaxPRO intramuscularly according to a 0-1-3 week schedule or the standard 0-4-24 week schedule. Anti-HBs levels were measured at week 28, considered protective ≥10 IU/L. Results. Modified intention to treat analysis in 761 patients was performed. Overall response difference was 50%(standard arm) versus 38.7% (accelerated arm) =11.3% (95% confidence interval [CI], [4.3, 18.3]), close to the 10% response margin. In CD4+cell count group 200-500 cells/mm3, the response difference was 20.8% (95% CI [10.9, 30.7]). However, the response difference in CD4+cell count group .500 cells/mm3 was -1.8% (95% CI [-13.4,19.7]). Compliance was significantly superior with the accelerated schedule, 91.8% versus 82.7% (P ≤ .001). Conclusion. In HIV-infected patients, compliance with an accelerated hepatitis B vaccination schedule is significantly better. The efficacy of an accelerated schedule proved to be non-inferior in CD4+cell count group >500 cells/mm3. http://repub.eur.nl/res/pub/23473/ 2011-02-01T00:00:00Z Aim: Short-term survival after emergency surgery for perforated diverticulitis is poor. Less is known about long-term survival. The aims of this study were to evaluate long-term survival after discharge from hospital and to identify factors associated with prognosis. Method: All patients who underwent emergency surgery for perforated diverticulitis in five hospitals in Rotterdam, the Netherlands, between 1990 and 2005, were included. The association between type of surgery (Hartmann's procedure or primary anastomosis) and long-term survival was analysed using multivariate Cox regression analysis, taking into account age American Society of Anesthesiology (ASA) classification, Hinchey score, Mannheim Peritonitis Index (MPI) and surgeon's experience. In addition, survival of the patients was compared with that of the matched general Dutch population. Results Of 340 patients included in the study, 250 were discharged alive from hospital. The overall 5-year survival was 53%. Survival was significantly impaired compared with the expected matched gender-, age- and calendar time-specific survival. Overall survival was significantly related to age and ASA classification. Hinchey score, MPI, number of re-interventions, the surgeon's experience and type of procedure did not influence long-term survival, although a trend was found for Hartmann's procedure to be a risk factor for poorer survival compared with primary anastomosis (hazard ratio for mortality: 1.88; 95% confidence interval, 0.96-3.67; P=0.07). Conclusion Long-term survival of patients after perforated diverticulitis is limited and mainly caused by the poor general condition of the patients, rather than by the severity of the primary disease or calendar-time and type of procedure. http://repub.eur.nl/res/pub/25966/ 2011-02-01T00:00:00Z Background: The diagnosis of chronic GI ischemia (CGI) remains a clinical challenge. Currently, there is no single simple test with high sensitivity available. Visible light spectroscopy (VLS) is a new technique that noninvasively measures mucosal oxygen saturation during endoscopy. Objective: To determine the diagnostic accuracy of VLS for the detection of ischemia in a large cohort of patients. Design: Prospective study, with adherence to the Standards for Reporting of Diagnostic Accuracy. Setting: Tertiary referral center. Patients: Consecutive patients referred for evaluation of possible CGI. Interventions: Patients underwent VLS along with the standard workup consisting of evaluation of symptoms, GI tonometry, and abdominal CT or magnetic resonance angiography. Main Outcome Measurements: VLS measurements and the diagnosis of CGI as established with the standard workup. Results: In 16 months, 121 patients were included: 80 in a training data set and 41 patients in a validation data set. CGI was diagnosed in 89 patients (74%). VLS cutoff values were determined based on the diagnosis of CGI and applied in the validation data set, and the results were compared with the criterion standard, resulting in a sensitivity and specificity of VLS of 90% and 60%, respectively. Repeated VLS measurements showed improvement in 80% of CGI patients after successful treatment. Limitations: Single-center study; only 43% of patients had repeated VLS measurements after treatment. Conclusions: VLS during upper endoscopy is a promising easy-to-perform and minimally invasive technique to detect mucosal hypoxemia in patients clinically suspected of having CGI, showing excellent correlation with the established ischemia workup. http://repub.eur.nl/res/pub/27843/ 2010-12-30T00:00:00Z We have developed a method to longitudinally classify subjects into two or more prognostic groups using longitudinally observed values of markers related to the prognosis. We assume the availability of a training data set where the subjects' allocation into the prognostic group is known. The proposed method proceeds in two steps as described earlier in the literature. First, multivariate linear mixed models are fitted in each prognostic group from the training data set to model the dependence of markers on time and on possibly other covariates. Second, fitted mixed models are used to develop a discrimination rule for future subjects. Our method improves upon existing approaches by relaxing the normality assumption of random effects in the underlying mixed models. Namely, we assume a heteroscedastic multivariate normal mixture for random effects. Inference is performed in the Bayesian framework using the Markov chain Monte Carlo methodology. Software has been written for the proposed method and it is freely available. The methodology is applied to data from the Dutch Primary Biliary Cirrhosis Study. Copyright http://repub.eur.nl/res/pub/22960/ 2010-12-20T00:00:00Z Background: A decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX requirements in PBC over the past 20 years in the Netherlands.Methods: Analysis of PBC transplant data of the Dutch Organ Transplant Registry during the period 1988-2008, including both absolute and proportional numbers. The indication for LTX was categorized as liver failure, hepatocellular carcinoma or poor quality of life (severe fatigue or pruritus). Data were analysed for two decades: 1.1.1988-31.12.1997 (1st) and 1.1.1998-31.12.2007 (2nd). The severity of disease was quantified using MELD scores. To fit lines which show trends over time we applied a linear regression model.Results: A total of 110 patients (87% women) was placed on the waiting list. 105 patients were transplanted (1st: 61, 2nd: 44), 5 (5%) died while listed. The absolute annual number of LTX for PBC slightly decreased during the 20 year period, the proportional number decreased significantly. At the time of LTX the mean age was 53.6 yrs. (1st: 53.4, 2nd: 53.8), the mean MELD score 13.9 (1st:14.5, 2nd:13.0). The median interval from diagnosis to LTX was 90.5 months (1st:86.5, 2nd: 93.5). 69% of patients was treated with UDCA (1st38%, 2nd82%).Conclusions: Over the past 20 years the absolute number of LTX for PBC in the Netherlands showed a tendency to decrease whereas the proportional decrease was significant. There was a trend over time toward earlier transplantation. http://repub.eur.nl/res/pub/27419/ 2010-12-01T00:00:00Z Background & Aims We investigated the long-term efficacy and renal safety of tenofovir disoproxil fumarate (TDF), administered to patients co-infected with human immunodeficiency virus and hepatitis B virus (HBV) as part of an antiretroviral therapy. Methods We performed a multicenter, prospective cohort study of 102 patients co-infected with human immunodeficiency virus and HBV who were treated with TDF. Results At baseline, 80% of patients had a detectable viral load (HBV DNA >20 IU/mL). Among patients positive for hepatitis B e antigen (HBeAg) (n = 67), 92% had a virologic response (HBV DNA <20 IU/mL) after 5 years of treatment. There was no difference between patients with or without lamivudine resistance at baseline (P = .39). Loss rates of HBeAg and hepatitis B s antigen (HBsAg) were 46% and 12%, respectively. Among HBeAg-negative patients (n = 15), 100% had a virologic response after 4 years of treatment and 2 (13%) lost HBsAg. Twenty subjects (20%, all HBeAg-negative) had undetectable HBV DNA at baseline; during a median follow-up period of 52 months (interquartile range, 4163 mo), 19 (95%) maintained a virologic response and 2 (10%) lost HBsAg. Overall, one patient acquired a combination of resistance mutations for anti-HBV drugs and experienced a virologic breakthrough. Three (3%) patients discontinued TDF because of increased serum creatinine levels. The estimated decrease in renal function after 5 years of TDF therapy was 9.8 mL/min/1.73 m2, which was most pronounced shortly after TDF therapy was initiated. Conclusions TDF, administered as part of antiretroviral therapy, is a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. Only small nonprogressive decreases in renal function were observed. http://repub.eur.nl/res/pub/21396/ 2010-11-19T00:00:00Z This thesis regards treatment effects in patients with chronic hepatitis B and C, and focuses on the tools that are used to analyse these effects. In this introduction the clinical background of hepatitis B and C along with the current treatment options are described. Clinical questions arisen from the effects of treatment are stated and the current state of art of statistical models to study these effects is provided. http://repub.eur.nl/res/pub/22163/ 2010-10-01T00:00:00Z Neutropenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C virus (HCV) infection is a common cause of dose reductions of peginterferon alfa. These reductions are performed to prevent bacterial and fungal infections, which are common during HCV treatment and can be attributed to neutropenia. The aims of this study were to investigate the occurrence of infections and their relation to neutropenia and to identify potential risk factors for infections during HCV treatment. In this single-center cohort study, 2,876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for neutropenia, infections, dose reductions, and potential risk factors for infection during HCV treatment. The baseline mean absolute neutrophil count (ANC) was 3,420 cells/μL, and 16 patients had a baseline ANC of <1,500 cells/μL. During treatment, neutropenia, which was defined as ANC <750 cells/μL, was observed in 95 patients (29.7%) and ANC <375/μL was observed in 16 patients (5%). Ninety-six infections were observed in 70 patients (21.8%). Thirteen infections (13.5%) were defined as severe. Infections were not correlated with neutropenia during treatment. Dose reductions did not lead to a decrease in infection rate. Multivariate logistic regression analysis revealed that age >55 years (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.19-3.56, P = 0.01) and baseline hyperglycemia (OR 2.17, 95% CI 1.15-4.10, P = 0.016) were associated with an increased risk of infection during HCV treatment. Cirrhosis and chronic obstructive pulmonary disease were not risk factors for infection. CONCLUSION: Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia. Older patients and patients with poorly controlled diabetes mellitus have a greater risk of developing infections during HCV treatment. http://repub.eur.nl/res/pub/20282/ 2010-09-01T00:00:00Z Background & Aims: The human liver-uPA+/+-SCID mouse is currently the best small animal model available for viral hepatitis infection studies. Methods: We identify critical factors affecting animal survival, engraftment efficacy, kinetics of liver repopulation and virological outcome by analysing the data from 400 human hepatocyte transplantations and 115 subsequent HBV and/or HCV inoculations in this mouse model. Results: Almost one third of animals succumbed during the first week after hepatocyte transplantation. Only during this critical period, liver necrosis due to embolization of donor cells in the portal vein was observed. This may have caused a fatal acute liver failure that complicated the pre-existing chronic liver disease. From the second week onwards, confluent hepatocyte clusters repopulated the liver and restored its synthetic functions as evidenced by increasing human albumin levels in plasma. Xenogenic repopulation by human cells proceeded approximately 4-times slower compared to allogenic mouse hepatocytes. All HBV inoculations were successful, even in animals with low graft take. HCV infection rate varied substantially, although every donor cell type yielded infectable animals. A reproducible 100% HCV infectivity was reached with high quality inocula in animals with human albumin plasma levels >1 mg/ml. Superior animal survival, adequate liver engraftment and a high viral infection rate were observed after transplanting cryopreserved commercial human hepatocytes. Conclusions: Our findings favour the use of commercially available, cryopreserved human hepatocytes for the humanization of the uPA+/+-SCID liver. While HBV infectivity criteria are less stringent, human albumin plasma levels exceeding 1 mg/ml are required for a consistent HCV infection in chimeric mice. http://repub.eur.nl/res/pub/21167/ 2010-09-01T00:00:00Z Background & Aims: Chronic HCV patients with baseline thrombocytopenia are often excluded from treatment with peginterferon alfa and ribavirin or undergo many dose reductions of peginterferon alfa. The aim of this study was to investigate the correlation between thrombocytopenia and the occurrence of bleedings during antiviral treatment for HCV infection. Methods: In this single center cohort study 2876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for thrombocytopenia, bleedings and dose reductions during HCV treatment. Results: Mean platelet count at baseline was 207,000/μl for non-cirrhotic patients (n = 253) and 132,000/μl for cirrhotic patients (n = 68). Mean platelet drop was 42% from 191,000 to 113,100/μl (range 8000-284,000/μl). Severe thrombocytopenia (platelet counts <50,000/μl) was observed in 30 patients (9.3%) at 166 visits and 9 patients developed platelet counts <25,000/μl at 15 visits. Forty-eight bleedings were observed in 27 patients (8.4%). Only one bleeding, due to gastrointestinal angiodysplasia, was defined as severe. However, this patient did not have severe thrombocytopenia at the time of bleeding. During visits, patients reported more minor bleedings when platelet counts were <50,000/μl compared to visits with platelet counts ≥50,000/μl (11.4% vs. 1.1%, p <0.001). In the multivariate analysis, platelet count of <50,000/μl was a significant predictor of bleeding (p <0.001). Conclusions: Severe bleedings did not occur in patients with platelet counts below 50,000/μl; based on these findings, treatment with peginterferon alfa and ribavirin appears to be safe in patients with platelet counts below 50,000/μl although platelet counts below 25,000/μl were rare. http://repub.eur.nl/res/pub/21007/ 2010-08-17T00:00:00Z Background & Aims: Inconsistencies in results and guideline recommendations regarding the durability of nucleos(t)ide analogue-induced hepatitis B e antigen (HBeAg) seroconversion require clarification. We studied the long-term durability of nucleos(t)ide analogue-induced HBeAg seroconversion in patients with chronic hepatitis B virus (HBV) infection. Methods: We performed a single-center cohort study of 132 HBeAg-positive patients who had received nucleos(t)ide analogue therapy. Results: During a median treatment duration of 26 months (range, 16-43 mo), HBeAg seroconversion occurred in 46 of 132 subjects (35%). Forty-two subjects (91%) had follow-up evaluation after HBeAg seroconversion. During a median follow-up period of 59 months (range, 28-103 mo) after HBeAg seroconversion, 13 of 42 patients (31%) showed a durable remission (defined as HBeAg negative and HBV-DNA level <10,000 copies/mL). Overall, 33 of 42 subjects (79%) continued therapy after HBeAg seroconversion; of these, 22 (67%) showed serologic and/or virologic recurrence. Nine of 42 subjects (21%) discontinued therapy after HBeAg seroconversion and at least 6 months of consolidation therapy. Only 2 patients showed a durable response in the absence of therapy. Disease recurrence in patients who continued therapy after HBeAg seroconversion was preceded by the development of resistance (80% of these patients); resistance only occurred in subjects given lamivudine monotherapy. In contrast, recurrence after treatment discontinuation or noncompliance was observed in all patients given nucleos(t)ide analogues. Conclusions: Induction of HBeAg seroconversion by nucleos(t)ide analogues is temporary in most patients with chronic HBV infection. Long-term continuation of nucleos(t)ide analogue treatment, irrespective of the occurrence of HBeAg seroconversion, appears to be necessary. http://repub.eur.nl/res/pub/19688/ 2010-08-01T00:00:00Z OBJECTIVES:Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients are at high risk of treatment relapse after any antiviral therapy. Combining peginterferon α-2a with ribavirin might improve sustained response rates.METHODS:Overall, 138 HBeAg-negative chronic hepatitis B patients were randomized to receive monotherapy (peginterferon α-2a 180 μg weekly plus placebo) or combination therapy (peginterferon α-2a weekly plus ribavirin 1,000 or 1,200 mg daily, depending on body weight) for 48 weeks. Post-treatment follow-up lasted 24 weeks. Analyses were based on the modified intention-to-treat population after exclusion of five patients.RESULTS:At the end of follow-up, 14 (20%) of 69 patients assigned to monotherapy and 10 (16%) of 64 assigned to combination therapy had a combined response (hepatitis B virus (HBV) DNA <10,000 copies/ml (<1,714 IU/ml) and a normal alanine aminotransferase level, P=0.49). At the end of treatment, more patients had a combined response (25 (36%) vs. 26 (41%) in the monotherapy and combination therapy group, respectively, P=0.60), but subsequently relapsed during follow-up. Serum HBV DNA and hepatitis B surface antigen (HBsAg) levels decreased during treatment (mean change at week 48 compared with baseline -3.9 vs. -2.6 log copies/ml, P<0.001 and -0.56 vs. -0.34 log IU/ml, P=0.23, respectively). HBV DNA levels relapsed after treatment discontinuation; HBsAg remained at end-of-treatment levels. In general, combination therapy was well tolerated, although it was associated with a higher risk of anemia and neutropenia.CONCLUSIONS:Treatment with peginterferon α-2a resulted in a limited sustained response rate in HBeAg-negative chronic hepatitis B patients. Addition of ribavirin did not improve response to therapy.Am J Gastroenterol advance online publication, 11 May 2010; doi:10.1038/ajg.2010.186. http://repub.eur.nl/res/pub/21101/ 2010-08-01T00:00:00Z Peginterferon alfa-2a results in a sustained response (SR) in a minority of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). This study investigated the role of early on-treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg-negative patients receiving peginterferon alfa-2a. HBsAg (Architect from Abbott) was quantified at the baseline and during treatment (weeks 4, 8, 12, 24, 36, and 48) and follow-up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa-2a, n = 53, versus peginterferon alfa-2a and ribavirin, n = 54). Overall, 24 patients (22%) achieved SR [serum hepatitis B virus (HBV) DNA level < 10,000 copies/mL and normal alanine aminotransferase levels at week 72]. Baseline characteristics were comparable between sustained responders and nonresponders. From week 8 onward, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in nonresponders. However, HBsAg declines alone were of limited value in the prediction of SR [area under the receiver operating characteristic curve (AUC) at weeks 4, 8, and 12 = 0.59, 0.56, and 0.69, respectively]. Combining the declines in HBsAg and HBV DNA allowed the best prediction of SR (AUC at week 12 = 0.74). None of the 20 patients (20% of the study population) in whom a decrease in serum HBsAg levels was absent and whose HBV DNA levels declined less than 2 log copies/mL exhibited an SR (negative predictive value = 100%). Conclusion: At week 12 of peginterferon alfa-2a treatment for HBeAg-negative CHB, a solid stopping rule was established with a combination of declines in serum HBV DNA and HBsAg levels from the baseline. Quantitative serum HBsAg in combination with HBV DNA enables on-treatment adjustments of peginterferon therapy for HBeAg-negative CHB. http://repub.eur.nl/res/pub/20133/ 2010-07-01T00:00:00Z The goal of this study was to determine the risk factors for de novo cancer after liver transplantation (LTx). Retrospective analyses were performed in 385 LTx patients who underwent transplantation between 1986 and 2007. In total, 50 (13.0%) recipients developed de novo malignancy. The cumulative incidence of de novo cancer at 1, 5, 10, and 15 years after LTx was 2.9% ± 0.9%, 10.5% ± 1.8%, 19.4% ± 3.0%, and 33.6% ± 6.8%, respectively. The standardized incidence ratio of malignancy in LTx patients compared to the general population was 2.2 (95% confidence interval: 1.6-2.8). After excluding posttransplant lymphoproliferative disorder and skin cancer, patients with de novo cancer had a significantly lower survival rate compared to recipients who remained cancer-free. The identified univariate risk factors for de novo cancer were cyclosporine A (CsA) treatment, time period of LTx, and recipient age. In multivariate analysis, only CsA treatment emerged as an independent risk factor for de novo cancer, which was attributed to more aggressive cancer types. A surprising finding was that CsA treatment specifically enhanced cancer risk in patients who underwent transplantation after 2004, when C2 monitoring (blood concentration at 2 hours postdose) was introduced. In addition, these patients showed a significantly lower acute rejection rate, which might reflect a more robust immunosuppressive status caused by the CsA-C2 regimen. When age was considered, only patients ≤50 years had a higher cancer rate when treated with CsA compared to treatment with tacrolimus. Our data suggest that, compared to tacrolimus treatment, CsA treatment with C2 monitoring or in younger patients of ≤50 years is associated with a higher early de novo cancer risk after LTx. http://repub.eur.nl/res/pub/20663/ 2010-07-01T00:00:00Z Peginterferon (PEG-IFN) results in HBeAg loss combined with virologic response in only a minority of patients with HBeAg positive chronic hepatitis B. Baseline predictors of response to PEG-IFN include HBV-genotype, pre-treatment HBV DNA levels, and ALT. The aims of this study were to develop a model, which improves the baseline prediction of response to PEG-IFN for individual patients by including early HBV DNA measurements during treatment and to establish an early indication for cessation of treatment. One hundred thirty-six patients treated with PEG-IFN were included in the study. Response was defined as loss of HBeAg and HBV DNA <10,000 copies/ml at 26 weeks post-treatment. Logistic regression analysis techniques were used to develop a dynamic prediction model with HBV DNA during the first 32 weeks of therapy. An early clinically useful rule for dis(continuation) of treatment was identified with a grid of cut-off values of HBV DNA decline during treatment. Adding HBV DNA decline to baseline prediction increased c-statistics from 0.846 to 0.857, 0.855 to 0.866 at weeks 4, 12, and 24. A HBV DNA decline of at least 2 log10 within 24 weeks was strongly associated with response when added to the baseline prediction model: OR 5.7 (95% CI: 1.70-20.0; P=0.004). A dynamic model including HBV DNA decline during treatment provides more accurate predictions of response to PEG-IFN. The model strongly supports individual decision making on treatment (dis)continuation in patients with HBeAg positive chronic hepatitis B. It is recommended that PEG-IFN treatment is stopped by 24 weeks if HBV DNA declined <2 log10. http://repub.eur.nl/res/pub/27769/ 2010-04-01T00:00:00Z Background & Aims: Entecavir is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B patients, but data on the efficacy in NA-experienced subjects are limited. Methods: In a multi-center cohort study we investigated 161 chronic hepatitis B patients (34% NA-experienced) treated with entecavir monotherapy. Results: During a median follow-up of 11 (3-23) months, 82 (79%) of 104 NA-naïve patients achieved virologic response (VR), defined as HBV DNA <80 IU/ml, and none of the patients (0%) developed genotypic entecavir-resistance. VR was demonstrated in 31 (54%) of 57 NA-experienced patients during a median follow-up of 12 (3-31) months. Patients with lamivudine-resistant mutations at the start of entecavir monotherapy had a reduced probability of achieving VR compared to lamivudine-naïve patients (HR 0.14; 95% CI 0.04-0.58; p = 0.007). Antiviral efficacy was not decreased by prior treatment with lamivudine when lamivudine-resistance had never developed (HR 0.81; 95% CI 0.43-1.52; p = 0.52). Prior adefovir therapy without development of adefovir-resistance (HR 0.84; 95% CI 0.43-1.64; p = 0.61) and presence of adefovir-resistance (HR 0.86; 95% CI 0.27-2.71; p = 0.80) did not influence antiviral response to entecavir. Switching to a tenofovir-containing treatment regimen resulted in viral load decline in patients with entecavir-resistance associated mutations. Conclusions: Entecavir proved to be efficacious in NA-naïve patients. The antiviral efficacy of entecavir was not influenced by prior treatment with adefovir or presence of adefovir-resistance. Entecavir should not be used in patients with previous lamivudine-resistance, yet it may still be an option in lamivudine-experienced patients in case lamivudine-resistance never developed. http://repub.eur.nl/res/pub/20608/ 2010-01-01T00:00:00Z Background: Diagnosing chronic gastrointestinal ischemia (CGI) is a challenging problem in clinical practice. Serum markers for CGI would be of great diagnostic value as a non-invasive test method. Aims: This study investigated serum markers in patients with well-defined ischemia. Furthermore, intestinal mucosal injury was also evaluated in CGI patients. Methods: Consecutive patients suspected of CGI were prospectively enrolled and underwent a diagnostic work-up consisting of gastrointestinal tonometry and either CT or MR angiography. Blood samples for analysis of intestinal fatty acid-binding protein (I-FABP), D-dimer, lactate dehydrogenase (LDH), leucocyte counts, C-reactive protein (CRP), and L-lactate were drawn before and after a standard meal. Intestinal mucosal injury was assessed with glutamine, citrulline and arginine in blood samples and compared to a sugar absorption test (SAT). Test reproducibility was validated in healthy subjects. Results: Forty patients and nine healthy subjects were included. Ischemia was diagnosed in 32 patients (80%). I-FABP, leucocyte counts, LDH, CRP, glutamine, citrulline, arginine and SAT levels did not differ between patients with and without ischemia. L-lactate concentration showed a significant elevation in ischemia patients as compared to non-ischemia patients. In ischemia patients, D-dimer levels showed a significant elevation postprandially as compared to D-dimer levels at baseline. However, these ischemia patients did not show intestinal mucosal injury. Conclusions: I-FABP, leucocyte counts, LDH and CRP levels are not clinically useful for the diagnosis of CGI. However, postprandial rises in L-lactate and D-dimer serum levels can serve as non-invasive indicators of CGI. http://repub.eur.nl/res/pub/21166/ 2010-01-01T00:00:00Z Background and aims: Ursodeoxycholic acid (UDCA) has an established effect on liver biochemistries in primary biliary cirrhosis (PBC). Few studies have evaluated long-term laboratory treatment effects and data beyond 6 years are not available. The aim of this study was to assess the long-term evolution of liver biochemistries during prolonged treatment with UDCA in biochemically non-advanced PBC. Patients and methods: Prospective multicenter cohort study of patients with PBC with pretreatment normal bilirubin and albumin, treated with UDCA 13-15 mg/kg/day. At yearly intervals, follow-up data including serum bilirubin, alkaline phosphatase (ALP), transaminases, albumin and IgM were collected. Data were analyzed with a repeated measurement model. Results: Two hundred and twenty-five patients were included and followed during a median period of 10.3 years. Following 1-year treatment with UDCA 36-100% of the total biochemical improvement was achieved, the maximum response was observed after 3 years. After initial improvements, bilirubin and AST levels increased and albumin levels significantly decreased after 6-10 years. However, these changes were of limited magnitude. The beneficial effects on ALT and ALP were maintained while IgM continued to decrease. Conclusion: In non-advanced PBC the biochemical response to UDCA is maintained up to 15 years. The long-term evolution of bilirubin, albumin and ALT differs from that of ALP and AST. The mean IgM level normalised and levels continued to decrease during the period of follow-up. http://repub.eur.nl/res/pub/21972/ 2010-01-01T00:00:00Z Background & Aims: We aimed to investigate serum hepatitis B surface antigen (HBsAg) levels in patients with chronic hepatitis B virus (HBV) infection during peginterferon (PEG-IFN) and entecavir (ETV) monotherapy. Methods: HBsAg was quantified (Abbott ARCHITECT) at baseline and during antiviral therapy (weeks 12, 24, 36, 48) in hepatitis B e antigen (HBeAg-) positive patients treated with ETV (n = 33) or PEG-IFN (n = 61) and in HBeAg-negative patients treated with ETV (n = 37) or PEG-IFN (n = 69). Results: Within the HBeAg-positive population, patients treated with PEG-IFN tended to have a steeper HBsAg decline than ETV-treated patients (mean decline 0.94 versus 0.38 log IU/ml at week 48, p = 0.07 for comparison of the slope of HBsAg decline). The HBsAg decline was larger in those patients who became HBeAg negative, irrespective of the treatment regimen. A decline in HBsAg was confined to ETV-treated patients with elevated baseline alanine aminotransferase (ALT) levels, whereas HBsAg decline was not associated with baseline ALT in patients treated with PEG-IFN. Within the HBeAg-negative population, PEG-IFN induced a significant HBsAg decline, while HBsAg did not decrease in ETV-treated patients (0.56 versus -0.10 log IU/ml, p <0.001). Both in HBeAg-positive and HBeAg-negative patients, the decline in serum HBV DNA was larger in patients who received ETV as compared with patients treated with PEG-IFN. Conclusions: In HBeAg-positive patients, the decline in serum HBsAg is mainly confined to patients who clear HBeAg, by either PEG-IFN or ETV treatment. In HBeAg-negative patients, PEG-IFN therapy resulted in a significant reduction in HBsAg levels, whereas HBsAg did not decrease in ETV-treated patients.Association for the Study of the Liver. http://repub.eur.nl/res/pub/24601/ 2009-12-01T00:00:00Z Background & Aims: Therapy with pegylated interferon (PEG-IFN)-alfa results in sustained response in a minority of patients with chronic hepatitis B virus (HBV) infection and has considerable side effects. We analyzed data from the 2 largest global trials of hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B to determine which are most likely to respond to PEG-IFN-alfa therapy. Methods: The study included 542 patients treated with PEG-IFN-alfa-2a (180 μg/wk, 48 wk) and 266 patients treated with PEG-IFN-alfa-2b (100 μg/wk, 52 wk). Eighty-seven patients were excluded, leaving 721 patients for analysis. A sustained response was defined as HBeAg loss and HBV-DNA level less than 2.0 × 103IU/mL 6 months after treatment. Logistic regression analysis was used to identify predictors of sustained response and a multivariable model was constructed. Results: HBV genotype, high levels of alanine aminotransferase (ALT; ≥2 × upper limit of normal), low levels of HBV DNA (<2.0 × 108IU/mL), female sex, older age, and absence of previous IFN therapy predicted a sustained response. Genotype A patients with high ALT and/or low HBV-DNA levels had a high predicted probability (>30%) of a sustained response. The strongest predictors of response were a high level of ALT in genotype B patients and a low level of HBV DNA in genotype C patients. Genotype D patients had a low chance of sustained response, irrespective of ALT or HBV-DNA levels. Conclusions: The best candidates for a sustained response to PEG-IFN-alfa are genotype A patients with high levels of ALT or low levels of HBV DNA, and genotypes B and C patients who have both high levels of ALT and low HBV DNA. Genotype D patients have a low chance of sustained response. http://repub.eur.nl/res/pub/24374/ 2009-11-01T00:00:00Z Background: Benign gastroesophageal anastomotic strictures are common and often refractory to treatment. Various endoscopic dilation techniques have been reported, but none of these methods has been proven to be superior. Objective: Comparison of the efficacy and safety of dilation of previously untreated anastomotic strictures by using electrocautery incision (EI) and Savary bougienage (SB). Design: Randomized, prospective study. Setting: Multicenter study. Patients: Sixty-two patients with an anastomotic stricture after esophagogastrostomy and dysphagia Atkinson grades II to IV were included. Interventions: Patients were treated with EI or SB. Main Outcome Measurements: Objective and subjective results were compared with baseline and 1, 3, and 6 months after the first treatment. Complications of both treatments were noted. Primary endpoints after 6 months were the mean number of dilation sessions and success rate (percentage of patients with ≤5 dilations in 6 months). Study participation ended after 6 months or if dysphagia grades II to IV recurred despite 5 treatment sessions. Results: No complications occurred with both treatments. There was no significant difference between the EI and SB groups in the mean number of dilations (2.9; 95% CI, 2.7-4.1 vs 3.3; 95% CI, 2.3-3.6l; P = .46) or the success rate (80.6% vs 67.7%, P = .26 and 96.2% vs 80.8%, P = .19). Limitations: In a small study with negative primary endpoints, secondary endpoints and subgroup analyses are hypothesis generating only. Conclusions: This prospective trial demonstrated that EI of gastroesophageal anastomotic strictures is a safe therapy and equivalent to SB as a primary therapy. EI can be used as an alternative or additional therapy to SB. (Registered with Current Controlled Trials, Ltd, registration number ISRCTN81239664.). http://repub.eur.nl/res/pub/24543/ 2009-10-01T00:00:00Z OBJECTIVES:Treatment with pegylated interferon (PEG-IFN) α-2b results in hepatitis B e antigen (HBeAg) loss in 36% of patients at 6 months post treatment. The aim of this study was to determine whether a long-term response to PEG-IFN is dependent on the timing of HBeAg loss.METHODS:A total of 91 patients treated with PEG-IFN α-2b alone (100 g per week) and 81 patients treated with PEG-IFN α-2b and lamivudine (100 mg/day) for 52 weeks were enrolled in this study. Patients were initially followed up at 4-week intervals and had one additional long-term follow-up (LTFU) visit (mean: 3.030.77 years 26 weeks post treatment).RESULTS:Of the 172 patients included, 78 patients (46%) did not have loss of HBeAg, 47 (27%) lost HBeAg within 32 weeks, and 47 patients (27%) had loss of HBeAg after week 32. At LTFU, patients with HBeAg loss32 weeks had hepatitis B virus DNA of 400 copies/ml significantly more often than did those who lost HBeAg after week 32 (47 vs. 21%, respectively; P0.009). Hepatitis B surface antigen (HBsAg) negativity was also observed significantly more often in patients with early HBeAg loss (36 vs. 4%, respectively, P0.001). Early HBeAg loss tended to occur more often in patients treated with PEG-IFN and lamivudine combination therapy than in those treated with PEG-IFN alone (35 vs. 21%; P0.10), as did HBsAg loss (15 vs. 8%; P0.14).CONCLUSIONS:Early PEG-IFN-induced HBeAg loss results in a high likelihood of HBsAg loss and may be associated with more profound viral suppression during the first 32 weeks of therapy in patients treated with lamivudine combinations. http://repub.eur.nl/res/pub/16575/ 2009-04-01T00:00:00Z Background & Aims: Ursodeoxycholic acid (UDCA) improves laboratory liver test results in patients with primary biliary cirrhosis (PBC). Few studies have assessed the prognostic significance of biochemical data collected following UDCA treatment. We performed a prospective multicenter study of patients with PBC treated with UDCA to compare prognosis with biochemical response. Methods: PBC was classified as early (pretreatment bilirubin and albumin levels normal), moderately advanced (one level abnormal), or advanced (both levels abnormal). Biochemical response was defined as proposed by Pares (decrease in alkaline phosphatase [ALP] level >40% of baseline level or normal level), Corpechot (ALP level <3-fold the upper limit of normal [ULN], aspartate aminotransferase level <2-fold the ULN, bilirubin level <1-fold the ULN), and our group (Rotterdam; normalization of abnormal bilirubin and/or albumin levels). Results: The study included 375 patients, and median follow-up time was 9.7 (range, 1.0-17.3) years. The prognosis for early PBC was comparable with that of the Dutch population and better than predicted by the Mayo risk score. Survival of responders was better than that of nonresponders, according to Corpechot and Rotterdam criteria (P < .001). Prognosis of early PBC was comparable for responders and nonresponders; prognosis of responders was significantly better in those with (moderately) advanced disease. Conclusions: Prognosis for UDCA-treated patients with early PBC is comparable to that of the general population. Survival of those with advanced PBC with biochemical response to UDCA is significantly better than for nonresponders. Thus, UDCA may be of benefit irrespective of the stage of disease. Prognostic information, based on bilirubin and albumin levels, is superior to that provided by ALP levels. http://repub.eur.nl/res/pub/24777/ 2009-02-01T00:00:00Z Patients with chronic hepatitis B (CHB) who will and those who will not respond to adefovir (ADV) monotherapy need to be identified at an early stage in order to adjust treatment and prevent future development of antiviral resistance. In a single-centre cohort study, we investigated 76 CHB patients [50% hepatitis B e antigen (HBeAg)-positive] treated with long-term ADV monotherapy. During a median follow-up of 122 (24-185) weeks, 42 (55%) patients achieved virologic response (VR), defined as HBV-DNA levels <103copies/mL, and 10 patients (13%) developed genotypic ADV resistance. Independent baseline predictors of VR were HBeAg negativity [hazard ratio (HR) 2.98; 95% confidence interval (CI) 1.24-7.19; P = 0.02], high alanine aminotransferase (ALT) levels (HR 1.11; 95% CI 1.05-1.18; P = 0.001), and low HBV-DNA levels (HR 0.56; 95% CI 0.41-0.75; P < 0.001). HBV-DNA at week 24 demonstrated a higher predictive value for VR than HBV-DNA at week 48. Important predictors of genotypic resistance were presence of cirrhosis (HR 6.54; 95% CI 1.39-30.9; P = 0.018), and not achieving VR during treatment (HR 6.60; 95% CI 1.35-32.4; P = 0.008). Patients without VR at week 24 already demonstrated a trend towards the emergence of ADV resistance (P = 0.07). HBV-DNA at week 24 was a better on-treatment predictor of VR than HBV-DNA at week 48, and ADV-resistant mutations developed more frequently in patients without VR at week 24. Therefore, our study suggests that virologic response to ADV therapy can be assessed at 24 weeks, instead of the generally recommended 48 weeks. http://repub.eur.nl/res/pub/29066/ 2008-08-01T00:00:00Z Background & Aims: The aim of this study was to evaluate the long-term sustainability of response in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B treated with pegylated interferon (PEG-IFN) α-2b alone or in combination with lamivudine. Methods: All 266 patients enrolled in the HBV99-01 study were offered participation in a long-term follow-up (LTFU) study. Patients were treated with PEG-IFN α-2b (100 μg/wk) alone or in combination with lamivudine (100 mg/day) for 52 weeks. Initial response was defined as HBeAg negativity at 26 weeks posttreatment. For the LTFU study, patients had one additional visit after the initial study (mean interval, 3.0 ± 0.8 years). Results: Of 266 patients enrolled in the initial study, 172 (65%) participated in the LTFU study. At LTFU, HBeAg and hepatitis B surface antigen (HBsAg) negativity were observed in 37% and 11% of 172 patients, respectively. Sixty-four patients were classified as initial responders and 108 as nonresponders. Among the initial responders, sustained HBeAg negativity and HBsAg loss were observed in 81% and 30%, respectively. Significantly higher rates of HBeAg negativity were observed in genotype A-infected initial responders compared with those with genotype non-A (96% vs 76%; P = .06) as well as HBsAg loss (58% vs 11%; P < .001). Conclusions: HBeAg loss after treatment with PEG-IFN α-2b alone or in combination with lamivudine is sustained in the majority of patients and is associated with a high likelihood of HBsAg loss, particularly in genotype A-infected patients. Therefore, PEG-IFN α-2b remains an important treatment option in this era of nucleos(t)ide analogue therapy. http://repub.eur.nl/res/pub/29562/ 2008-06-01T00:00:00Z Recent studies suggest that diabetes mellitus increases the risk of developing hepatocellular carcinoma (HCC). The aim of this study is to quantify the risk of HCC among patients with both diabetes mellitus and hepatitis C in a large cohort of patients with chronic hepatitis C and advanced fibrosis. We included 541 patients of whom 85 (16%) had diabetes mellitus. The median age at inclusion was 50 years. The prevalence of diabetes mellitus was 10.5% for patients with Ishak fibrosis score 4, 12.5% for Ishak score 5, and 19.1% for Ishak score 6. Multiple logistic regression analysis showed an increased risk of diabetes mellitus for patients with an elevated body mass index (BMI) (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.00-1.11; P = 0.060) and a decreased risk of diabetes mellitus for patients with higher serum albumin levels (OR, 0.81; 95% CI, 0.63-1.04; P = 0.095). During a median follow-up of 4.0 years (interquartile range, 2.0-6.7), 11 patients (13%) with diabetes mellitus versus 27 patients (5.9%) without diabetes mellitus developed HCC, the 5-year occurrence of HCC being 11.4% (95% CI, 3.0-19.8) and 5.0% (95% CI, 2.2-7.8), respectively (P = 0.013). Multivariate Cox regression analysis of patients with Ishak 6 cirrhosis showed that diabetes mellitus was independently associated with the development of HCC (hazard ratio, 3.28; 95% CI, 1.35-7.97; P = 0.009). Conclusion: For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC. Copyright http://repub.eur.nl/res/pub/30257/ 2008-06-01T00:00:00Z Background: Alanine aminotransferase (ALT) is one of the main indicators for inflammatory activity in chronic hepatitis B. During interferon-based therapy, approximately 25%-40% of patients exhibit an ALT flare. Objectives and study design: To analyze the relation between ALT and HBV-DNA during pegylated interferon alpha-2b (PEG-IFN) treatment and compare different patterns of on-treatment viral load decline with the occurrence of ALT flares. Results: Of the 123 patients included in this study 31 (25%) exhibited an ALT flare during treatment or follow-up. Six out of 8 (75%) host-induced flares, i.e. ALT flares which were followed by a HBV-DNA decrease associated with a favorable treatment outcome, occurred in patients with a delayed HBV-DNA decline pattern (delayed vs. non-delayed decline, p = .022); 5 of these 8 patients exhibited HBeAg loss and 4 even HBsAg loss at the end of follow-up. The prediction of ALT normalization was possible using on-treatment viral load. Based on the difference from baseline, the evolution of viral load and ALT level were strongly interrelated during treatment and follow-up. With a joint model we estimated a correlation coefficient of 0.38 (p < 0.001) during the first 4 weeks of the treatment and of 0.72 (p < 0.0001) thereafter. Conclusion: There was a strong relation between ALT and viral load in HBeAg-positive chronic hepatitis B patients treated with PEG-IFN alpha-2b, especially after 4 weeks of treatment. Patients with a delayed decline in viral load often exhibited a host-induced flare associated with a favorable outcome. http://repub.eur.nl/res/pub/29229/ 2008-05-01T00:00:00Z Background: Esophagogastric variceal bleeding is the most important complication of extrahepatic portal vein thrombosis (EPVT) and is usually treated endoscopically. Little is known about the prognosis of these patients. Objectives: To investigate the long-term clinical outcome and efficacy of endoscopic treatment in patients with esophagogastric variceal bleeding secondary to EPVT. Design: Retrospective observational study. Settings: Single university center. Patients: Twenty-seven consecutive patients with esophagogastric variceal bleeding, secondary to noncirrhotic, nonmalignant EPVT, who underwent endoscopic treatment between 1982 and 2005. Interventions: Endoscopic band ligation and/or endoscopic sclerotherapy. Main Outcome Measurements: The overall rebleeding risk, overall survival, complications of the endoscopic procedures, and predictive values of rebleeding. Analyses were performed by the Kaplan-Meier method and univariate Cox regression. Results: All patients were followed-up after the first endoscopically treated variceal bleeding. A total of 241 endoscopic procedures were performed. In all patients, initial control of bleeding was obtained. The overall rebleeding risk was 23% (95% CI, 0%-24%) at 1 year and 37% (95% CI, 43%-83%) at 5 years. Extension of thrombosis into the splenic vein and the presence of fundal varices were significant predictors of rebleeding, with a nearly 5-fold increased risk for patients with EPVT and fundal varices at the time of the first variceal hemorrhage (hazard ratio 5.07, P = .01). A portosystemic shunt procedure was performed in 5 patients: 4 for variceal bleeding and in one patient for refractory ascites. Seven patients died, none from variceal bleeding. Overall 5-year and 10-year survivals were 100% and 62% (95% CI, 38%-96%), respectively. Limitations: Retrospective design. Conclusions: In patients with variceal bleeding secondary to EPVT endoscopic treatment, in particular, band ligation appears safe and effective. EPVT-related mortality is primarily determined by other causes than variceal bleeding. http://repub.eur.nl/res/pub/30313/ 2008-02-01T00:00:00Z Background: The clinical outcome of a covered vs. uncovered transjugular intrahepatic portosystemic shunt (TIPS) for patients with Budd-Chiari syndrome (BCS) is as yet largely unknown. Objectives: To compare patency rates of bare and polytetrafluoroethylene (PTFE)-covered stents, and to investigate clinical outcome using four prognostic indices [Child-Pugh score, Rotterdam BCS index, modified Clichy score and Model for End-Stage Liver Disease (MELD)]. Methods: Consecutive patients with BCS who had undergone TIPS between January 1994 and March 2006 were evaluated in a retrospective review in a single centre. Results: Twenty-three TIPS procedures were performed on 16 patients. The primary patency rate at 2 years was 12% using bare and 56% using covered stents (P = 0.09). We found marked clinical improvement at 3 months post-TIPS as determined by a drop in median Child-Pugh score (10-7, P = 0.04), Rotterdam BCS index (1.90-0.83, P = 0.02) and modified Clichy score (7.77-2.94, P = 0.003), but not in MELD (18.91-17.42, P =0.9). Survival at 1 and 3 years post-TIPS was 80% (95% CI: 59-100%) and 72% (95% CI: 48-96%). Four patients (25%) died and one required liver transplantation. Conclusions: A transjugular intrahepatic portosystemic shunt using PTFE-covered stents shows better patency rates than bare stents in BCS. Moreover, TIPS leads to an improvement in important prognostic indicators for the survival of patients with BCS. © 2008 The Authors. Journal compilation http://repub.eur.nl/res/pub/29158/ 2008-01-15T00:00:00Z Double-dose hepatitis B virus revaccination of human immunodeficiency virus (HIV)-infected patients proved to be effective in 50.7% of 144 patients who had previously failed to respond to standard doses. In the multivariate analysis, female patients were found to have a significantly better response (P = .03). The effect of age on the response depended on the viral load at the time of revaccination. For patients with a detectable HIV RNA load, the effect of age was stronger (odds ratio [OR], 0.34 per 10 years older [95% confidence interval {CI}, 0.16-0.72]; P = .005) than for patients with an undetectable HIV RNA load (OR, 0.74 per 10 years older [95% CI, 0.50-1.09]; P = .12). http://repub.eur.nl/res/pub/35058/ 2007-12-01T00:00:00Z Background: The pre-malignant gastric lesions atrophic gastritis (AG), intestinal metaplasia (IM) and dysplasia (DYS) have long been identified as principal risk factors for gastric cancer. Objective: To evaluate epidemiological time trends of pre-malignant gastric lesions in the Netherlands. Methods: Patients with a first diagnosis of AG, IM or DYS between 1991 and 2005 were identified in the Dutch nationwide histopathology registry. The number of new diagnoses per year were evaluated relative to the total number of patients with a first gastric biopsy. Time trends were evaluated with age-period-cohort models using logistic regression analysis. Results: In total, 23 278 patients were newly diagnosed with AG, 65 937 patients with IM, and 8517 patients with DYS. The incidence of AG declined similarly in men and women with 8.2% per year [95% CI 7.9% to 8.6%], and DYS with 8.1% per year [95% CI 7.5% to 8.6%]. The proportional number of new IM cases declined with 2.9% per year [95% CI 2.7% to 3.1%] in men and 2.4% [95% CI 2.2% to 2.6%] in women. With age-period-cohort models a cohort phenomenon was demonstrated for all categories of pre-malignant gastric lesions in men and in women with IM and DYS. Period phenomena with a larger decline in number of diagnoses after 1996 were also demonstrated for AG and IM. Conclusions: The incidence of pre-malignant gastric lesions is declining. Period and cohort phenomena were demonstrated for diagnoses of AG and IM. These findings imply that a further decrease of at least 24% in the incidence of gastric cancer in the coming decade may be anticipated in Western countries without specific intervention. http://repub.eur.nl/res/pub/36861/ 2007-11-01T00:00:00Z Background: High-dose peginterferon-α (PegIFN-α) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non-responders, although a higher and a longer dosing of PegIFN-α may intensify side effects. Methods: We randomized 53 patients, who previously failed with standard IFN-α ± ribavirin, to a high-dose induction and an extended regimen with PegIFN-α-2b [3.0 μg/kg once weekly (q.w.) 12 weeks → 2.0 μg/kg q.w. 12 weeks → 1.5 μg/kg q.w. 48 weeks] or a standard regimen (1.5 μg/kg q.w. 48 weeks). All patients received daily weight-based ribavirin (800-1200 m/day). The short-form 36 health survey was used to evaluate health-related quality of life (HRQL). Results: Intention-to-treat analysis showed no significant difference in SVR rate (44% vs. 37%, P = 0.62) and relapse rate (9% vs. 31%, P = 0.17) between experimental and standard treatment. Overall, 80% of the [positive predictive value (PPV)] patients with rapid virological response (RVR, HCV-RNA negativity at week 4) achieved SVR. No significant dose-related differences in HRQL were seen between both groups. At baseline, genotype 2 or 3 [odds ratio (OR): 7.4, 95% confidence interval (CI): 1.4-33.3, P = 0.01] and γ-glutamyltransferase (GGT) levels <2 × ULN (upper limit of normal) (OR: 6.76, 95% CI: 1.5-31.3, P = 0.009) were significantly associated with SVR. Multivariate logistic regression at week 4 showed that only baseline GGT <2 × ULN (OR: 7.3, 95% CI: 1.4-38.5, P = 0.01) and RVR (OR: 15.6, 95% CI: 3.2-76.9, P < 0.001) were independently predictive for SVR. Conclusion: Retreatment with PegIFN-α-2b and ribavirin for a minimum of 48 weeks should be considered in all patients unresponsive to previous IFN-based therapies. Baseline GGT values and RVR are highly predictive for retreatment outcome. http://repub.eur.nl/res/pub/35180/ 2007-10-01T00:00:00Z http://repub.eur.nl/res/pub/35916/ 2007-09-01T00:00:00Z Background: Thiopurines are widely used for the treatment of inflammatory bowel disease, but are associated with the development of side effects. It has been suggested that the enzyme inosine triphosphate pyrophosphatase (ITPA) plays a role in the digestion of thiopurines and that defective activity resulting from polymorphisms in the inosine triphosphate pyrophosphatase encoding genes may be associated with thiopurine-induced side effects. Current studies are controversial regarding this hypothesis. Aim: To perform a meta-analysis and gain more insight into a possible correlation between thiopurine-induced side effects and ITPA polymorphisms. Methods: We explored Medline for articles on ITPA polymorphisms and thiopurine toxicity. Studies that compared ITPA polymorphism frequencies among thiopurine-tolerant and -intolerant adult inflammatory bowel disease patients were included in this meta-analysis. Results: Nine published studies investigated associations between ITPA polymorphisms and thiopurine toxicity. Six studies (with 751 patients included) met our inclusion criteria and were processed in the meta-analysis. This analysis demonstrates that the ITPA 94C→A polymorphism, is not significantly associated with any of the studied side effect parameters. Conclusions: This meta-analysis does not prove a correlation between the development of thiopurine toxicity and the ITPA 94C→A polymorphism. This implies that there is no clinical relevance to determine ITPA polymorphisms in thiopurine-treated patients. http://repub.eur.nl/res/pub/35759/ 2007-08-01T00:00:00Z The factors determining the responsiveness of different hepatitis B virus (HBV) genotypes to interferon treatment are not fully understood. We investigated the relationship between HBV genetic characteristics and the outcome of short (16 weeks) or prolonged (32 weeks) treatment with standard interferon-alpha in a prospectively followed cohort of 103 patients across Europe with HBeAg positive chronic hepatitis B. INNO-LiPA assays and HBV DNA sequencing were used to determine HBV genotypes, mutations in the core promoter and precore/core regions. After 16-weeks interferon-alpha treatment, the rate of HBeAg clearance was higher in genotype A versus all other genotypes (P = 0.014), or genotype D alone (P = 0.05). The HBV genome analysis revealed that: (i) after 16-weeks treatment, an HBV subpopulation with core promoter mutations emerged or increased (P < 0.001) only in genotype A; (ii) the core gene of genotype A has the lowest number of amino acid variations in comparison with genotypes B, C, or D. Logistic regression analysis identified genotype A as a positive predictor of short (16 weeks) treatment response (P = 0.001; odds ratio 6.19, 95 confidence interval 1.94-19.8), having a greater impact than baseline HBV DNA or alanine aminotransferase (ALT) levels. In contrast, the response to prolonged interferon-alpha treatment was not different between HBV genotypes. These results suggest that HBV genotype A responds earlier to interferon treatment than other genotypes, which is associated with its molecular characteristics. The optimal duration of interferon-based therapies in chronic hepatitis B may vary between different HBV genotypes. http://repub.eur.nl/res/pub/35929/ 2007-08-01T00:00:00Z Chronic hepatitis B (CHB) patients with advanced fibrosis are often not considered for treatment with peginterferon (PEG-IFN) because IFN therapy may precipitate immunological flares, potentially inducing hepatic decompensation. We investigated the efficacy and safety of treating hepatitis B e antigen (HBeAg)-positive CHB patients with 52 weeks of PEG-IFN-α-2b (100 μg weekly) alone or in combination with lamivudine (100 mg daily). Seventy patients with advanced fibrosis (Ishak fibrosis score 4-6) and 169 patients without advanced fibrosis, all with compensated liver disease, participated in the study. Virologic response, defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA < 10,000 copies/ml at week 78, occurred significantly more often in patients with advanced fibrosis than in those without (25% versus 12%, respectively; P = 0.02). Also patients with cirrhosis (n = 24) exhibited a virologic response more frequently than did patients without cirrhosis (30% versus 14%, respectively; P = 0.02). Improvement in liver fibrosis occurred more frequently in patients with advanced fibrosis (66% versus 26%, P < 0.001). HBV genotype A was more prevalent among patients with advanced fibrosis than among those without (57% versus 24%, P < 0.001). Most adverse events, including serious adverse events, were observed equally as frequently in patients with advanced fibrosis and those without. Fatigue, anorexia, and thrombocytopenia occurred more often in patients with advanced fibrosis than in those without (P < 0.01). Necessary dose reduction or discontinuation of therapy was comparable for both patient groups (P = 0.92 and P = 0.47, respectively). Conclusion: PEG-IFN is effective and safe for HBeAg-positive patients with advanced fibrosis. Because PEG-IFN therapy results in a high rate of sustained off-therapy response, patients with advanced fibrosis or cirrhosis but compensated liver disease should not be excluded from PEG-IFN treatment. Copyright http://repub.eur.nl/res/pub/36484/ 2007-04-01T00:00:00Z Most studies on health related quality of life (HRQoL) of chronic liver patients were done in small clinical populations or restricted to one aetiology or disease stage. There is still a need for a study in a large liver patient population with various aetiologies and disease stages, approaching a population-based study. We evaluated the impact of liver disease aetiology on generic HRQoL, disease-specific HRQoL and fatigue and we compared HRQoL and fatigue between aetiological groups and healthy Dutch controls. Members of the Dutch liver patient association completed the Liver Disease Symptom Index, Short Form-36, and Multidimensional Fatigue Index-20. We compared the HRQoL between patients with viral hepatitis, autoimmune hepatitis, cholestatic diseases, hemochromatosis and other liver diseases by linear, ordinal and logistic regression, corrected for disease stage and other significant factors. Viral hepatitis patients showed a worse mental health than other aetiological groups. Hemochromatosis patients demonstrated 17% more bodily pain than viral hepatitis patients and the strongest decrease in role emotional health with increasing age. Aetiological groups showed a worse generic HRQoL and more fatigue than controls. In conclusion, viral hepatitis and hemochromatosis patients have a more impaired HRQoL than patients of other liver disease aetiological groups. http://repub.eur.nl/res/pub/35980/ 2007-01-01T00:00:00Z http://repub.eur.nl/res/pub/13456/ 2004-07-13T00:00:00Z BACKGROUND: Fatigue is a major clinical problem in many patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). An effective treatment has not been defined. Recently, a large proportion of patients with these diseases was found to have symptoms of depression. Because fatigue is a frequent symptom of depression and there is some evidence that treatment with an antidepressant improves fatigue in patients with fibromyalgia, we hypothesised that the antidepressant fluvoxamine might improve fatigue related to PBC and PSC. METHODS: Fatigued patients were randomised to receive fluvoxamine (75 mg BID) or placebo for a six-week period. Fatigue and quality of life were quantified using a visual analogue scale, the Fisk Fatigue Severity Scale, the Multidimensional Fatigue Inventory and the SF-36. RESULTS: Seventeen and 16 patients were allocated to fluvoxamine and placebo, respectively. There was no statistically significant beneficial effect of fluvoxamine on fatigue or quality of life. The median VAS scores in the fluvoxamine and placebo groups were 7.40 and 7.45 at day 0, 6.9 and 7.15 at day 14, 7.45 and 7.65 at day 42 and 7.8 and 8.0 four weeks after treatment discontinuation. CONCLUSION: We found no evidence for a beneficial effect of fluvoxamine on fatigue in these patients with cholestatic liver disease and severe chronic fatigue. http://repub.eur.nl/res/pub/8295/ 2004-01-01T00:00:00Z BACKGROUND: The key end point for treatment efficacy in chronic hepatitis C is absence of detectable virus at six months after treatment. However, the incidence of clinical events during long term follow up of patients with sustained virological response is still poorly documented and may differ between the Eastern and Western world. AIMS: To assess clinical end points during long term follow up of European patients with a sustained virological response to interferon monotherapy. METHODS: Meta-analysis of individual patient data from eight European protocolled follow up studies of interferon treatment for chronic hepatitis C. RESULTS: A total of 286 sustained virological responders and 50 biochemical responders (detectable virus but normal alanine aminotransferase levels) were followed up for 59 months. Fifteen sustained virological responders (5.2%) had cirrhosis before treatment and 112 (39%) had genotype 1. The late virological relapse rate after five years of follow up was 4.7% (95% confidence interval (CI) 2.0-7.4) among sustained virological responders; all late relapses occurred within four years after treatment. Among sustained virological responders, the rate of decompensation after five years of follow up was 1.0% (95% CI 0.0-2.3) and none developed hepatocellular carcinoma (HCC). Survival was comparable with the general population, matched for age and sex, the standard mortality ratio being 1.4 (95% CI 0.3-2.5). Clinical outcome of patients with cirrhosis was similar to other sustained virological responders. For biochemical responders, the rates of development of decompensation and HCC during long term follow up were 9.1% (95% CI 0.5-17.7) and 7.1% (95% CI 0-15.0), respectively. CONCLUSIONS: Five year survival of European sustained virological responders was similar to the overall population, matched for age and sex. No HCCs were detected during long term follow up. http://repub.eur.nl/res/pub/13262/ 2003-11-17T00:00:00Z BACKGROUND: Studies on Health Related Quality of Life (HRQoL) of chronic liver patients were performed in clinical populations. These studies included various disease stages but small variations in aetiology and no transplanted patients. We performed a large HRQoL study in non-cirrhotic, cirrhotic and transplanted liver patients with sufficient variety in aetiology. We compared the generic HRQoL and fatigue between liver patients and healthy controls and compared the disease-specific and generic HRQoL and fatigue between non-cirrhotic, cirrhotic and transplanted liver patients, corrected for aetiology. METHODS: Members of the Dutch liver patient association received the Short Form-36, the Liver Disease Symptom Index and the Multidimensional Fatigue Index-20. Based on reported clinical characteristics we classified respondents (n = 1175) as non-cirrhotic, compensated cirrhotic, decompensated cirrhotic or transplants. We used linear, ordinal and logistic regression to compare the HRQoL between groups. RESULTS: All liver patients showed a significantly worse generic HRQoL and fatigue than healthy controls. Decompensated cirrhotic patients showed a significantly worse disease-specific and generic HRQoL and fatigue than non-cirrhotic patients, while HRQoL differences between non-cirrhotic and compensated cirrhotic patients were predominantly insignificant. Transplanted patients showed a better generic HRQoL, less fatigue and lower probabilities of severe symptoms than non-cirrhotic patients, but almost equal probabilities of symptom hindrance. CONCLUSIONS: HRQoL in chronic liver patients depends on disease stage and transplant history. Non-cirrhotic and compensated cirrhotic patients have a similar HRQoL. Decompensated patients show the worst HRQoL, while transplanted patients show a significantly better HRQoL than cirrhotic and non-cirrhotic patients. http://repub.eur.nl/res/pub/13192/ 2003-08-29T00:00:00Z BACKGROUND: Evidence based medicine depends on unbiased selection of completed randomized controlled trials. For completeness it is important to publish all trials. This report describes the first large randomised controlled trial where combination therapy was compared to placebo therapy and to ribavirin monotherapy, which has not been published until now. METHODS: One hundred and twenty one patients with chronic hepatitis C and elevated transaminases who did not respond to previous treatment with standard interferon monotherapy, were included from 16 centers in Belgium, the Netherlands and Luxembourg between 1992 and 1996. Patient poor-response characteristics were: genotype 1 (69%), HCV RNA above 2 x 10(6) copies/ml (55%) and cirrhosis (38%). Patients were randomized to 6 months combination therapy with interferon alpha-2b (3 MU tiw) and ribavirin (1000-1200 mg/day), 6 months ribavirin monotherapy (1000-1200 mg/day) or 6 months ribavirin placebo. The study was double blinded for the ribavirin/placebo component. One patient did not fit the entry criteria, and 3 did not start. All 117 patients who received at least one dose of treatment were included in the intention to treat analysis. RESULTS: At the end of treatment, HCV RNA was undetectable in 35% of patients on combination therapy and in none of the patients treated with ribavirin monotherapy or placebo. The sustained virological response rate at 6 months after therapy was 15% for patients treated with interferon and ribavirin.During the 6 months treatment period 13% of patients on interferon ribavirin combination therapy, 13% of patients on ribavirin monotherapy and 11% of patients on placebo withdrew due to side effects or noncompliance. At 24 weeks of treatment the mean Hb level was 85% of the baseline value, which means a mean decrease from 9.1 mmol/l to 7.8 mmol/l. The Hb levels at the end of treatment were not significantly different from patients treated with ribavirin monotherapy (p = 0.76). End of treatment WBC was significantly lower in patients treated with combination therapy, compared to ribavirin (p < 0.01) as well as for patients treated with ribavirin monotherapy compared to placebo (p < 0.01). DISCUSSION: This belated report on the only placebo controlled study of interferon ribavirin combination therapy in non responders to standard doses of interferon monotherapy documents the effectiveness, be it limited, of this approach as well as the dynamics of the effects on blood counts. http://repub.eur.nl/res/pub/8294/ 2003-01-01T00:00:00Z Background and aims: Interferon (IFN) induced hepatitis B e antigen (HBeAg) seroconversion is durable in 80-90% of chronic hepatitis B patients. Preliminary reports on the durability of HBeAg seroconversion following lamivudine are contradictory. We investigated the durability of response following IFN, lamivudine, or IFN-lamivudine combination therapy in a meta-analysis of individual patient data. PATIENTS AND METHODS: Twenty four centres included 130 patients in total with an HBeAg seroconversion (HBeAg negative, antibodies to hepatitis B e antigen positive) at the end of antiviral therapy: 59 with lamivudine, 49 with interferon, and 22 with combination therapy. Relapse was defined as confirmed reappearance of HBeAg. RESULTS: The three year cumulative HBeAg relapse rate by the Kaplan-Meier method was 54% for lamivudine, 32% for IFN, and 23% for combination therapy (p=0.01). Cox regression analysis identified pretreatment hepatitis B virus (HBV) DNA, alanine aminotransferase (ALT), sex, and therapy as independent predictive factors of post-treatment relapse; Asian race, previous therapy, centre, and type of study were not predictive of relapse. The relative HBeAg relapse risk of lamivudine compared with IFN therapy was 4.6 and that of combination therapy to IFN therapy 0.7 (p(overall)=0.01). CONCLUSIONS: The durability of HBeAg seroconversion following lamivudine treatment was significantly lower than that following IFN or IFN-lamivudine combination therapy. The risk of relapse after HBeAg seroconversion was also related to pretreatment levels of serum ALT and HBV DNA, but independent of Asian race. http://repub.eur.nl/res/pub/8293/ 2001-01-01T00:00:00Z BACKGROUND: Malignancy, hypercoagulability, and conditions leading to decreased portal flow have been reported to contribute to the aetiology of extrahepatic portal vein thrombosis (EPVT). Mortality of patients with EPVT may be associated with these concurrent medical conditions or with manifestations of portal hypertension, such as variceal haemorrhage. PATIENTS AND METHODS: To determine which variables have prognostic significance with respect to survival, we performed a retrospective study of 172 adult EPVT patients who were followed over the period 1984-1997 in eight university hospitals. RESULTS: Mean follow up was 3.9 years (range 0.1-13.1). Overall survival was 70% (95% confidence interval (CI) 62-76%) at one year, 61% (95% CI, 52-67%) at five years, and 54% (95% CI, 45-62%) at 10 years. The one, five, and 10 year survival rates in the absence of cancer, cirrhosis, and mesenteric vein thrombosis were 95% (95% CI 87-98%), 89% (95% CI 78-94%), and 81% (95% CI 67-89%), respectively (n=83). Variables at diagnosis associated with reduced survival according to multivariate analysis were advanced age, malignancy, cirrhosis, mesenteric vein thrombosis, absence of abdominal inflammation, and serum levels of aminotransferase and albumin. The presence of variceal haemorrhage and myeloproliferative disorders did not influence survival. Only four patients died due to variceal haemorrhage and one due to complications of a portosystemic shunt procedure. CONCLUSION: We conclude that mortality among patients with EPVT is related primarily to concurrent disorders leading to EPVT and not to complications of portal hypertension.