A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma.

BACKGROUND: This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC). METHODS: Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomised 2:1 to nintedanib (MTD) or sorafenib (400-mg bid) in 28-day cycles until intolerance or disease progression. Time-to-progression (TTP, primary endpoint), overall survival (OS) and progression-free survival (PFS) were determined. RESULTS: Phase-I: no DLTs observed; nintedanib MTD in both groups was 200 mg bid. Phase-II: patients (N = 93) were randomised to nintedanib (n = 62) or sorafenib (n = 31); TTP was 5.5 vs. 4.6 months (HR = 1.44 [95% CI, 0.81-2.57]), OS was 11.9 vs. 11.4 months (HR = 0.88 [95% CI, 0.52-1.47]), PFS was 5.3 vs. 3.9 months (HR = 1.35 [95% CI, 0.78-2.34]), respectively (all medians). Dose intensity and tolerability favoured nintedanib. Fewer patients on nintedanib (87.1%) vs. sorafenib (96.8%) had drug-related adverse events (AEs) or grade ≥ 3 AEs (67.7% vs. 90.3%), but more patients on nintedanib (28 [45.2%]) had AEs leading to drug discontinuation than did those on sorafenib (7 [22.6%]). CONCLUSIONS: Nintedanib may have similar efficacy to sorafenib in aHCC.

Hepatitis C: The beginning of the end-key elements for successful European and national strategies to eliminate HCV in Europe.

Hepatitis C virus (HCV) infection is a major public health problem in the European Union (EU). An estimated 5.6 million Europeans are chronically infected with a wide range of variation in prevalence across European Union countries. Although HCV continues to spread as a largely "silent pandemic," its elimination is made possible through the availability of the new antiviral drugs and the implementation of prevention practices. On 17 February 2016, the Hepatitis B & C Public Policy Association held the first EU HCV Policy Summit in Brussels. This summit was an historic event as it was the first high-level conference focusing on the elimination of HCV at the European Union level. The meeting brought together the main stakeholders in the field of HCV: clinicians, patient advocacy groups, representatives of key institutions and regional bodies from across European Union; it served as a platform for one of the most significant disease elimination campaigns in Europe and culminated in the presentation of the HCV Elimination Manifesto, calling for the elimination of HCV in Europe by 2030. The launch of the Elimination Manifesto provides a starting point for action in order to make HCV and its elimination in Europe an explicit public health priority, to ensure that patients, civil society groups and other relevant stakeholders will be directly involved in developing and implementing HCV elimination strategies, to pay particular attention to the links between hepatitis C and social marginalization and to introduce a European Hepatitis Awareness Week.

Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29).

BACKGROUND: Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S. PATIENTS AND METHODS: Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments. RESULTS: A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% [95% confidence interval (CI) 54-83] and 68% (95% CI 53-81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E. CONCLUSIONS: No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted. CLINICALTRIALSGOV: NCT01005199.

Revisiting predictors of virologic response to PEGIFN + RBV therapy in HIV-/HCV-coinfected patients: the role of metabolic factors and elevated GGT levels.

Evaluation of metabolic factors and elevated γ-glutamyltransferase (GGT) levels as independent predictors of treatment failure in a thoroughly documented cohort of HIV-/HCV-coinfected patients (HIV/HCV). Sixty-four HIV/HCV patients treated with pegylated interferon-α-2a plus ribavirin (PEGIFN + RBV) at the Medical University of Vienna within a prospective trial were included in this study. In addition, 124 patients with HIV/HCV from the AIFA-HIV and AHIVCOS cohorts were included as a validation cohort. Advanced liver fibrosis, GGT elevation, insulin resistance (IR) and low CD4+ nadir were defined as METAVIR F3/F4, GGT levels >1.5× sex-specific upper limit of normal, homoeostasis model assessment of insulin resistance >2 and CD4+ nadir <350 cells/µL, respectively. HCV-genotype 1/4 (OR26.3; P = 0.006), advanced liver fibrosis (OR20.2; P = 0.009), interleukin 28B rs12979860 non-C/C SNP (OR8.27; P = 0.02) and GGT elevation (OR7.97; P = 0.012) were independent predictors of treatment failure, while both IR (OR3.51; P = 0.106) and low CD4 + nadir (OR2.64; P = 0.263) were not independently associated with treatment failure. A statistically significant correlation between GGT elevation and prior alcohol abuse (r = 0.259; P = 0.039), liver steatosis (r = 0.301; P = 0.034) and low-density lipoprotein-cholesterol (r = -0.256; P = 0.041) was observed. The importance of GGT elevation as an independent predictor of treatment failure was confirmed in a validation cohort (OR2.76; P = 0.026). While GGT elevation emerged as an independent predictor of treatment failure in both the derivation and the validation cohort, no independent associations between metabolic factors and treatment failure were observed. Thus, our findings suggest that GGT elevation is an independent predictor of treatment failure in HIV/HCV that can easily be incorporated into predictive algorithms.

Viral determinants predicting hepatitis B surface antigen (HBsAg) seroclearance in HIV-/HBV-coinfected patients.

The aim of this retrospective study was the identification of clinically useful viral determinants for the prediction of hepatitis B surface antigen (HBsAg) seroclearance and sustained virological response in hepatitis B virus/human immunodeficiency virus (HBV-/HIV)-coinfected patients receiving HBV-active combined antiretroviral therapy (cART). Quantification of HBsAg, HBeAg and HBV DNA before and after initiation of HBV-active cART in a cohort of 59 HIV-/HBV-coinfected patients was performed. Calculations of receiver operating characteristics (ROC) and Kaplan-Meier analysis were used for the identification of predictors of HBsAg seroclearance for HBeAg-positive [HBeAg(+); n = 36] and HBeAg-negative [HBeAg(-);n = 23] patients. HBeAg(+) patients with an HBsAg on-treatment decline ≥ 1 log IU/mL per year achieved higher HBsAg loss rates (P = 0.0294), whereas the quantification of HBeAg had no predictive value for HBsAg seroclearance. Among HBeAg(-) patients, a pretreatment baseline cut-off level of HBsAg ≤ 100 IU/mL was highly predictive for HBsAg seroclearance. No significant influence of the HBV genotype on HBsAg seroclearance was observed among the entire cohort. Quantitative determination of HBsAg provides a clinically useful viral parameter for the prediction of HBsAg seroclearance both in HBeAg(+) and HBeAg(-) HIV-/HBV-coinfected patients receiving HBV-active cART.

Diagnostic workup of primary sclerosing cholangitis: the benefit of adding gadoxetic acid-enhanced T1-weighted magnetic resonance cholangiography to conventional T2-weighted magnetic resonance cholangiography.

AIM: To evaluate the value of gadoxetic acid-enhanced T1-weighted (T1W) magnetic resonance cholangiography (MRC) versus conventional T2-weighted (T2W) MRC compared to endoscopic retrograde cholangiopancreatography (ERCP) in patients with primary sclerosing cholangitis (PSC). MATERIALS AND METHODS: Based on T1W MRC, PSC patients were classified into a regular (RG) and a delayed (DG) excreting group, with an absence of gadoxetic acid in the common bile duct at 20 min. Beading, pruning, and gradation of central bile duct stenosis, evaluated by T1W and T2W MRC, were compared to ERCP. Liver parenchymal enhancement was measured in both study groups and compared to a reference group (n = 20) without a history of liver disease. Two readers performed all measurements. RESULTS: Based on beading and pruning of the peripheral bile ducts, sensitivities, specificities, and accuracies for reader 1 were 0.17/0.43, 0/0.17, and 0.15/0.31 for T1W MRC, and 0.83/0.86, 1/0.83, and 0.85/0.85 for T2W MRC (p = 0.004). For reader 2 sensitivities, specificities, and accuracies were 0.25/0.57, 0/0.33, and 0.23/0.46 for T1W MRC, and 0.92/1, 1/0.83, and 0.92/0.92 for T2W MRC (p = 0.012). Compared to ERCP, central bile duct stenoses were significantly overestimated (p < 0.001) by T2W MRC. A significantly lower parenchymal enhancement was found in the DG (n = 7) compared to the RG (n = 13), and compared to the reference group (p < 0.001). CONCLUSION: The combined performance of T2W and T1W MRC may provide a comprehensive imaging workup of PSC, including morphological and functional information resulting in optimal management.

Evaluation of portal hypertension and varices by acoustic radiation force impulse imaging of the liver compared to transient elastography and AST to platelet ratio index.

BACKGROUND: Acoustic radiation force impulse imaging (ARFI) is a new method of liver stiffness measurement (LSM). The aim was to compare ARFI, transient elastography (TE) and AST to platelet ratio index (APRI) for the noninvasive diagnosis of clinically significant portal hypertension (CSPH, hepatic venous pressure gradient; HVPG ≥ 10 mmHg) and esophageal varices (EV). MATERIALS AND METHODS: LSM via ARFI and TE was performed in 88 consecutive patients with cirrhosis prior to HVPG measurement. The mean liver stiffness for ARFI was calculated out of 5 measurements for each lobe. RESULTS: LSM by TE and ARFI was not successful in 22 (25%) patients and 1 (1 %) patient, respectively, due to ascites or obesity. Both TE (r = 0.765; p < 0.001) and ARFI (r = 0.646; p < 0.001) correlated significantly with HVPG. At the optimal cut-off (16.8 kPa), TE (area under the curve, AUC 0.870) yielded a sensitivity and specificity of 89.7% and 75%, respectively, for predicting CSPH. At the optimal cut-off (2.58 m/s), the sensitivity and specificity for ARFI (AUC 0.855) were 71.4% and 87.5%, respectively. Using an APRI (AUC 0.838), the sensitivity and specificity were 69% and 87.5%, respectively. The AUC for the diagnosis of EV was 0.802 for TE (cut-off: 27.9 kPa), 0.743 for ARFI (cut-off: 2.74 m/s), and 0.805 for APRI (cut-off: 1.90). CONCLUSION: ARFI shows a higher applicability particularly in obese and ascitic patients. All three investigated methods show a high diagnostic accuracy for CSPH. Notably, APRI performed not significantly different compared to ARFI for the diagnosis of CSPH.

Non-invasive evaluation of patients with viral hepatitis.

Liver fibrosis evaluation is essential in patients with chronic viral liver disease with major impact on treatment decisions. Liver biopsy is still considered the "gold-standard", but it is an invasive method, non-totally risk free, not very well accepted by patients, and unsuitable for regular follow-up examinations. In the last 10-15 years, several non-invasive methods for liver fibrosis assessment were developed: serological tests (simple or complex), ultrasound based elastographic methods (which can be classified in shear wave elastography methods and strain elastography methods) and magnetic resonance elastography. Today in clinical practice, ultrasound based elastographic methods are mostly used. From this category of methods, the oldest and more used is transient elastography, which was included also in several guidelines for assessing liver fibrosis in chronic hepatitis B and C patients. Each method has his advantages and weakness and today there is no consensus regarding which method should be considered the best "surrogate" for liver biopsy. Here we will try to give a comprehensive overview about the different techniques and depict the advantages and disadvantages of each of these methods.

Five-year on-treatment efficacy of lamivudine-, tenofovir- and tenofovir + emtricitabine-based HAART in HBV-HIV-coinfected patients.

Data on the efficacy of lamivudine (LAM)-, tenofovir (TDF)- and emtricitabine (FTC)-based antiretroviral therapy (HAART) in HBV-HIV coinfection are limited. We completed a retrospective analysis of HBV-HIV-coinfected patients treated at the Medical University of Vienna. One-hundred and ten coinfected patients were included, with 57% being initially HBV e-Antigen (HBeAg) positive. Baseline HBV load was significantly higher in HBeAg+ than in HBeAg- patients (5962 ± 3663 vs 20 ± 19 × 10(6) IU/mL; P < 0.0001). Over a median observation period of 83 month (range: 26-183), 87% received HAART and 91% showed a suppression of HBV replication. After 5 years of continuous treatment, HBeAg seroconversion was achieved in 21% of LAM-, 50% of TDF- (P = 0.042 vs LAM) and in 57% of TDF + FTC (P = 0.008 vs LAM)-treated patients, respectively. HBsAg loss after 5 years was found in 8% (LAM), 25% (TDF; P = 0.085 vs LAM) and 29% (TDF + FTC; P = 0.037 vs LAM) of HBeAg+ patients. In HBeAg- patients, HBsAg loss was achieved in 11% (LAM), 27% (TDF; P = 0.263 vs LAM) and 36% (TDF + FTC; P = 0.05 vs LAM), respectively. Pretreatment CD4+ counts did not influence rates of HBeAg seroconversion and of HBsAg loss. Patients with HBsAg loss had lower baseline HBV-DNA levels and higher AST/ALT levels than patients without HBsAg loss. Transient HAART-related hepatotoxicity was found in 32% (Grade I: 21%; II:7%; III:2%; IV:0%). Most HBV-HIV-coinfected patients achieve complete suppression of HBV replication despite high baseline viremia. TDF-based HAART leads to high rates of HBeAg seroconversion and HBsAg loss after 5 years of continuous exposure. One-third of HBV-HIV-coinfected patients may experience transient HAART-related hepatotoxicity.

[Expert opinion on boceprevir- and telaprevir-based triple therapies of chronic hepatitis C]. / Expertenempfehlungen zur Triple-Therapie der HCV-Infektion mit Boceprevir und Telaprevir.

With the approval of boceprevir and telaprevir the standard treatment of chronic hepatitis C virus (HCV) genotype 1 infection will be the triple therapy of a HCV protease inhibitor together with pegylated interferon alfa and ribavirin. In clinical studies a significant increase of sustained virological response rates from 38 - 44 % to 63 - 75 % for treatment-naïve and from 17 - 21 % to 59 - 66 % in treatment-experienced patients in comparison to the dual combination therapy with pegylated interferon alfa and ribavirin alone has been demonstrated. In addition, a large number of treatment-naïve patients and relapsers benefit from shorten treatment durations to 24 - 28 weeks. However, important differences exist between the administration of boceprevir and telaprevir in terms of a pegylated interferon alfa/ribavirin lead-in phase, the duration of dosing of the protease inhibitor, the overall treatment duration, HCV RNA measurements for response guided treatment durations and stopping rules. Furthermore, triple therapies with boceprevir and telaprevir may be associated with selection of resistant viral variants, new adverse events and clinically relevant drug-drug interactions. The present review gives an overview on the results of underlying clinical studies together with a guideline for the practical management of boceprevir- and telaprevir-based triple therapies.

Concomitant highly active antiretroviral therapy leads to smaller decline and faster recovery of CD4+ cell counts during and after pegylated interferon plus ribavirin therapy in HIV-hepatitis C virus coinfected patients.

INTRODUCTION: The impact of highly active antiretroviral therapy (HAART) on CD4+ cell course during treatment with pegylated interferon plus ribavirin (PegIFN-RBV) in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is unknown. METHODS: We determined CD4(+) cell count in 94 HIV-HCV coinfected patients undergoing treatment with pegylated interferon plus RBV at baseline, treatment weeks 4-48 (W4-W48), and months 1, 3, and 6 of follow-up. Of the 94 patients, 70 underwent concomitant HAART (group A) and 24 did not (group B). RESULTS: Group A showed smaller CD4(+) cell decreases from W24-W48 (P = .027) and greater CD4(+) cell increases after cessation of pegylated interferon plus ribavirin therapy (P = .002) than group B showed. CONCLUSIONS: Concomitant HAART leads to smaller decreases and faster recovery of CD4(+) cells during and after pegylated interferon plus RBV therapy.

Imaging and early diagnosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cancer worldwide. Effective treatment to allow long-term survival requires early diagnosis, which can only be achieved by regular surveillance by ultrasound. As soon as a suspicious lesion is detected, more sophisticated imaging has to be employed in order to definitely establish the diagnosis of HCC. Imaging should be done by either contrast-enhanced multidetector computed tomography (MDCT) or by dynamic contrast-enhanced magnetic resonance imaging (dynamic MRI). Most tumors, especially the ones larger than 2 cm in diameter, can be diagnosed non-invasively by a typical pattern of early arterial enhancement on contrast-enhanced imaging and venous or delayed-phase wash-out. In some instances, in particular in tumors between 10 and 20 mm, a definitive diagnosis cannot be reached by non-invasive imaging and biopsy has to be used for histologic diagnosis. While it might become possible in the future to develop serologic surveillance tests for early diagnosis of HCC, currently regular ultrasound at 6 to 12 months interval is the method of choice for this purpose.

HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension.

Patients co-infected with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) are fraught with a rapid fibrosis progression rate and with complications of portal hypertension (PHT) We aimed to assess the influence of immune function [Centers of Disease Control and Prevention (CDC) stage] on development of PHT and disease progression in HIV-HCV co-infection. Data of 74 interferon-naïve HIV-HCV co-infected patients undergoing liver biopsy, measurement of portal pressure and of liver stiffness and routine laboratory tests (including CD4+ cell count, HIV and HCV viral load) were analysed. Time of initial exposure (risk behaviour) was used to assess fibrosis progression. Fibrosis progression, time to cirrhosis and portal pressure were correlated with HIV status (CDC stage). HIV-HCV patients had rapid progression of fibrosis [0.201 +/- 0.088 METAVIR fibrosis units/year (FU/y)] and accelerated time to cirrhosis (24 +/- 13 years), high HCV viral loads (4.83 x 10(6) IU/mL) and a mean HVPG at the upper limit of normal (5 mmHg). With moderate or severe immunodeficiency, fibrosis progression was even higher (CDC-2 = 0.177 FU/y; CDC-3 = 0.248 FU/y) compared with patients with higher CD4+ nadirs (CDC-1 = 0.120 FU/y; P = 0.0001). An indirect correlation between CD4+ cell count and rate of fibrosis progression (R = -0.6654; P < 0.001) could be demonstrated. Hepatic venous pressure gradient (HVPG) showed early elevation of portal pressure with median values of 4, 8 and 12 mmHg after 10, 15 and 20 years of HCV infection for CDC-3 patients. Patients treated with highly active anti-retroviral therapy (HAART) had similar rates of progression and portal pressure values than patients without HAART. Progression of HCV disease is accelerated in HIV-HCV co-infection, being more pronounced in patients with low CD4+ cell count. A history of a CD4+ cell nadir <200/microL is a risk factor for rapid development of cirrhosis and PHT. Thus, HCV treatment should be considered early in patients with HIV-HCV co-infection and largely preserved CD4+ cell counts.

Aetiology of cirrhosis of the liver has an impact on survival predicted by the Model of End-stage Liver Disease score.

BACKGROUND: Originally, aetiology of liver disease has been incorporated into the computation of the Model of End-stage Liver Disease (MELD) score. Clinical observations prompted us to hypothesize that patients with viral and alcoholic cirrhosis may differ in predicted survival rates. Until now, no large representative studies evaluated the impact of aetiology on long-term survival predicted by the Child-Pugh and MELD scores. MATERIALS AND METHODS: Four hundred and ninety-three patients who underwent transjugular intrahepatic portosystemic shunt implantation in Vienna, Austria, and Palermo, Italy, were included in this retrospective study. The main analyses were a logistic regression model and a Cox proportional hazards regression model calculating the interaction of the aetiology with the scores. RESULTS: Both groups had similar survival rates (median 1377 and 1721 days for viral and alcoholic cirrhosis, respectively; P = 0.58), but patients with viral cirrhosis had significantly lower MELD scores (P = 0.002). In the Cox analysis, aetiology had a significant impact on the prediction of overall survival by MELD score. For 3-month survival, MELD score was adequately predictive for both groups. For 1-year survival, aetiology had a significant impact on survival, indicating that patients with identical scores but different aetiologies differed in survival rates. When stratifying patients into high- and low-risk patients (MELD < 16 vs. MELD >or= 16), aetiology of cirrhosis had no impact on the predictive value for low-risk patients; high-risk-patients (MELD >or= 16) with viral cirrhosis had significantly lower survival rates than patients with alcoholic cirrhosis and identical scores. With regard to Child-Pugh Score, no significant differences between the two patient groups and in the prediction of 3-month and 1-year survival could be observed. CONCLUSIONS: Our study suggests that aetiology of cirrhosis has an impact on 1-year survival predicted by the MELD score. This becomes more apparent in patients with advanced stage of liver disease (MELD >or= 16). Since MELD score is used for ranking patients for liver transplantation and waiting times are regularly longer than 3 months, our observations suggest that with increasing time on the waiting list and severity of disease, patients with viral cirrhosis may have a disadvantage in the current allocation policy.

Efficacy of interferon in immunocompromised HCV patients after liver transplantation or with HIV co-infection.

BACKGROUND: Interferon (IFN)-based antiviral therapy is increasingly used in immunocompromised patients with chronic hepatitis C after orthotopic liver transplantation (OLT) and HIV-HCV co-infection. Differences in early viral kinetics have not been compared in these patients. MATERIALS AND METHODS: We retrospectively analysed 76 patients (31 OLT, 20 HIV-HCV and 25 HCV control patients) undergoing IFN sensitivity testing before starting antiviral therapy with pegylated IFN-alpha 2a (180 microg week(-1)) plus ribavirin (0.8-1.2 g day(-1)) for 48 weeks. We compared baseline parameters, response to IFN and treatment outcome between the groups and assessed the influence of specific calcineurin inhibitors in OLT patients and immune status in HIV-HCV patients on treatment response. RESULTS: Viral loads pretherapy were higher in OLT compared to nontransplanted HCV controls (P = 0.003). The same trend was present in HIV-HCV (P = 0.09). The log-drop after test dose was less in OLT compared to HCV (P = 0.02), while no significant difference was found between HIV-HCV and HCV. In HIV-HCV patients viral load log-drop correlated significantly with CD4(+) cell counts (P = 0.001). No difference in viral load pretherapy, log-drop and treatment outcome was noted between different calcineurin inhibitors in OLT patients. Sustained virological response rates were 28% in OLT, 50% in HIV-HCV and 56% in HCV patients. CONCLUSIONS: Immunosuppression results in high HCV viral loads. Initial efficacy of IFN is significantly impaired in OLT patients, but not in HIV-HCV with largely preserved CD4(+) cell counts. Sustained virological response rates of 28% in OLT patients are suboptimal, but encouraging results are shown for HIV-HCV patients with relatively high CD4(+) cell counts.

Carvedilol for reducing portal pressure in primary prophylaxis of variceal bleeding: a dose-response study.

BACKGROUND: Sequential measurements of hepatic venous pressure gradient (HVPG) are used to assess the haemodynamic response to nonselective betablockers (NSBBs) in patients with portal hypertension. AIMS: To assess the rates of HVPG response to different doses of carvedilol. METHODS: Consecutive patients with cirrhosis undergoing HVPG-guided carvedilol therapy for primary prophylaxis of variceal bleeding between 08/2010 and 05/2015 were retrospectively included. After baseline HVPG measurement, carvedilol 6.25 mg/d was administered and HVPG response (HVPG-decrease ≥20% or to ≤12 mm Hg) was assessed after 3-4 weeks. In case of nonresponse, carvedilol dose was increased to 12.5 mg/d and a third HVPG-measurement was performed after 3-4 weeks. We also assessed HVPG-response rates according to the Baveno VI consensus (HVPG decrease ≥10% or to ≤12 mm Hg) and changes in systolic arterial pressure (SAP). RESULTS: Seventy-two patients (Child A, 37%; B, 35%; C, 28%) were included. 28 (39%) patients achieved a HVPG-decrease ≥ 20% with carvedilol 6.25 mg/d and another 10 (14%) with carvedilol 12.5 mg/d. Forty (56%) patients had a HVPG decrease ≥10% with carvedilol 6.25 mg/d and 24 (33%) with carvedilol 12.5 mg/d. Thus, in total, a HVPG-response of ≥20% and ≥10% and was achieved in 38 (53%) and 55 (76%) and of patients respectively. Notably, 6 patients (n = 4 with ascites) did not tolerate an increase to 12.5 mg/d due to hypotension/bradycardia. However, none of the other patients had a SAP < 90 mm Hg at the final HVPG measurement. CONCLUSION: Carvedilol 12.5 mg/d was more effective than 6.25 mg/d in decreasing HVPG in primary prophylaxis. A total of 76% of patients achieved a HVPG-response of ≥ 10% to carvedilol 12.5 mg/d, however, arterial hypotension might occur, especially in patients with ascites.

Von Willebrand factor indicates bacterial translocation, inflammation, and procoagulant imbalance and predicts complications independently of portal hypertension severity.

BACKGROUND: Elevated plasma von Willebrand factor antigen (vWF) has been shown to indicate the presence of clinically significant portal hypertension, and thus, predicts the development of clinical events in patients with cirrhosis. AIM: To investigate the impact of bacterial translocation and inflammation on vWF, as well as the association between vWF and procoagulant imbalance. Moreover, we assessed whether vWF predicts complications of cirrhosis, independent of the severity of portal hypertension. METHODS: Our study population comprised 225 patients with hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg without active bacterial infections or hepatocellular carcinoma. RESULTS: vWF correlated with markers of bacterial translocation (lipopolysaccharide-binding protein [LBP; ρ = 0.201; P = 0.021]), inflammation (interleukin 6 [IL-6; ρ = 0.426; P < 0.001] and C-reactive protein [CRP; ρ = 0.249; P < 0.001]), and procoagulant imbalance (factor VIII/protein C ratio; ρ = 0.507; P < 0.001). Importantly, the associations between vWF and these parameters were independent of HVPG. Moreover, vWF (per 10%) independently predicted variceal bleeding (hazard ratio [HR]: 1.08 [95% confidence interval (95% CI): 1.01-1.16]; P = 0.023), requirement of paracentesis (HR: 1.05 [95% CI: 1.01-1.1]; P = 0.023) and bacterial infections (HR: 1.04 [95% CI: 1-1.09]; P = 0.04) including spontaneous bacterial peritonitis (HR: 1.09 [95% CI: 0.999-1.18]; P = 0.053) on a trend-wise level. After backward elimination, vWF (HR: 1.05 [95% CI: 1.02-1.08]; P = 0.003) and CRP (per 10 mg/L; HR: 1.53 [95% CI: 1.14-2.05]; P = 0.005) remained in the final model for transplant-free mortality. Finally, the independent prognostic value of vWF/CRP groups for mortality was confirmed by competing risk analysis. CONCLUSION: Our results demonstrate that vWF is not only a marker of portal hypertension but also independently linked to bacterial translocation, inflammation and procoagulant imbalance, which might explain its HVPG-independent association with most clinical events. Prognostic groups based on vWF/CRP efficiently discriminate between patients with a poor 5-year survival and patients with a favourable prognosis.

Randomised clinical study: the effects of oral taurine 6g/day vs placebo on portal hypertension.

BACKGROUND: The amino sulphonic acid taurine reduces oxidative endoplasmatic reticulum stress and inhibits hepatic stellate cell activation, which might lead to reduction of portal pressure in cirrhosis. AIM: To assess the haemodynamic effects of taurine supplementation in patients with cirrhosis and varices. METHODS: Patients with hepatic venous pressure gradient (HVPG) ≥12 mm Hg were included in this prospective proof of concept study. Concomitant nonselective beta-blockers therapy was not allowed. Patients received either 4 weeks of oral taurine (6 g/day), or placebo, prior to evaluation of HVPG response. RESULTS: Thirty patients were screened and 22 included in the efficacy analysis (12 taurine/10 placebo; 64% male, mean age: 52 ± 11 years, Child A: 9%, B:64%, C:27%, ascites:68%). In the taurine group, mean HVPG dropped from 20 mm Hg (±4) at baseline to 18 mm Hg (±4) on day 28 (mean relative change: -12%, P = .0093). In the placebo group, mean HVPG increased from 20 mm Hg (±5) at baseline to 21 mm Hg (±5) on day 28 (mean relative change:+2%, P = .4945). Taurine had no significant effects on systemic haemodynamics. Seven of 12 patients (58%) on taurine achieved a HVPG response >10%, compared to none in the placebo group (P = .0053). In a multivariate linear model, HVPG reduction was significantly larger in the taurine group compared to placebo group (P = .0091 and P = .0109 for absolute and relative change respectively). Treatment-related adverse events included gastrointestinal discomfort and fatigue, and were usually mild and comparable between treatment groups. CONCLUSION: Taurine is safe and may reduce portal pressure in cirrhotic patients. More studies on the underlying mechanisms of action and long-term effects of taurine supplementation are warranted.

Impact of patatin-like phospholipase domain containing 3 rs738409 G/G genotype on hepatic decompensation and mortality in patients with portal hypertension.

BACKGROUND: The rs738409 C>G p.I148M variant in the patatin-like phospholipase domain containing 3 (PNPLA3)-gene promotes triglyceride accumulation in hepatocytes and hepatic stellate cell activation and has previously been linked to hepatic steatosis/liver fibrosis. AIM: To investigate its impact on hepatic decompensation and (liver-related) mortality in patients who had already developed portal hypertension. Moreover, we assessed its link with hepatic steatosis as evaluated by controlled attenuation parameter. METHODS: We performed a retrospective analysis in prospectively characterised patients with viral hepatitis/fatty liver disease-induced portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) diagnosed at the Medical University of Vienna who underwent HVPG measurement (until 2013; n = 372; longitudinal study) or simultaneous HVPG and controlled attenuation parameter measurement (2014-2017; n = 153; cross-sectional study). RESULTS: While survival was similar between PNPLA3-C/C and -C/G patients, we observed substantially increased mortality in PNPLA3-G/G patients. PNPLA3-G/G had no impact on mortality in the subgroup of patients with viral hepatitis; however, we observed a strong independent association between PNPLA3-G/G and hepatic decompensation (adjusted subdistribution hazard ratio [aSHR]: 2.1, 95% confidence interval [95% CI]: 1.1-4; P = 0.024) as well as mortality (overall: aSHR: 2.2, 95% CI: 1.22-3.98; P = 0.009; liver-related: aSHR: 2.2, 95% CI: 1.08-4.46; P = 0.029) in patients with fatty liver disease. Interestingly, even in the subgroup of patients who had already progressed to clinically significant portal hypertension (HVPG ≥ 10 mm Hg), PNPLA3-G/G substantially increased mortality (aSHR: 2.33, 95% CI: 1.27-4.29; P = 0.006). PNPLA3-genotype had no influence on controlled attenuation parameter or the prevalence of values ≥248 dB/m. CONCLUSION: PNPLA3-G/G-genotype seems to double the risks of hepatic decompensation and (liver-related) mortality in patients with portal hypertension due to fatty liver disease. Further studies are warranted to investigate potential underlying pathophysiological mechanisms unrelated to hepatic steatosis.