FIB-4 and APRI as Predictive Factors for Short- and Long-Term Survival in Patients with Transjugular Intrahepatic Portosystemic Stent Shunts.

(1) Background: Transjugular intrahepatic portosystemic shunt (TIPS) is a standard therapy for portal hypertension. We aimed to explore the association of established baseline scores with TIPS outcomes. (2) Methods: In total, 136 liver cirrhosis patients underwent TIPS insertion, mainly to treat refractory ascites (86%), between January 2016 and December 2019. An external validation cohort of 187 patients was chosen. (3) Results: The majority of the patients were male (62%); the median follow-up was 715 days. The baseline Child­Turcotte−Pugh stage was A in 14%, B in 75% and C in 11%. The patients' liver-transplant-free (LTF) survival rates after 3, 12 and 24 months were 87%, 72% and 61%, respectively. In the univariate analysis, neither bilirubin, nor the international normalized ratio (INR), nor liver enzymes were associated with survival. However, both the APRI (AST-to-platelet ratio index) and the FIB-4 (fibrosis-4 score) were associated with LTF survival. For patients with FIB-4 > 3.25, the hazard ratio for mortality after 2 years was 3.952 (p < 0.0001). Liver-related clinical events were monitored for 24 months. High FIB-4 scores were predictive of liver-related events (HR = 2.404, p = 0.001). Similarly, in our validation cohort, LTF survival was correlated with the APRI and FIB-4 scores. (4) Conclusions: Well-established scores that reflect portal hypertension and biochemical disease activity predict long-term outcomes after TIPS and support clinical decisions over TIPS insertion.

Whipple's disease - a rare and challenging complication in a patient with Crohn's disease.

INTRODUCTION: Whipple's disease (WD) is a rare and infectious condition leading to multi-organ impairment caused by Tropheryma whipplei (TW), a ubiquitously occurring bacterium. TW can be detected in tissues by histological detection of PAS ("periodic acid-ship reaction")-positive macrophages and by polymerase-chain-reaction (PCR). Clinically, WD is often characterized by diarrhea, abdominal pain, and weight loss. These symptoms are also typical for a flare in Crohn's disease (CD) and, therefore, can lead to fatal misdiagnosis and wrong treatment by using biologics (e.g., anti-TNF-α). CASE REPORT: We here report a young male patient with pre-existing CD. The patient's symptoms were misinterpreted as a flare of CD and illustrate the multifaceted nature of WD. After intensifying immunosuppressive therapy, the patient developed therapy-refractory diarrhea with several opportunistic infections with a final, fatal outcome. CONCLUSION: Patients with inflammatory bowel disease (IBD) are not only at risk from infectious complications known with clostridium difficile or cytomegalovirus (CMV); infection with WD should also be ruled out by endoscopy and biopsy before the escalation of the immunosuppressive regime.

Low Serum Cholinesterase Identifies Patients With Worse Outcome and Increased Mortality After TIPS.

Transjugular intrahepatic portosystemic shunt (TIPS) is an effective treatment for portal hypertension-related complications. However, careful selection of patients is crucial. The aim of this study was to evaluate the prognostic value of serum cholinesterase (CHE) for outcomes and mortality after TIPS insertion. In this multicenter study, 389 consecutive patients with cirrhosis receiving a TIPS at Hannover Medical School, University Hospital Essen, or Medical University of Vienna were included. The Hannover cohort (n = 200) was used to initially explore the role of CHE, whereas patients from Essen and Vienna served as a validation cohort (n = 189). Median age of the patients was 58 years and median Model for End-Stage Liver Disease (MELD) score was 12. Multivariable analysis identified MELD score (hazard ratio [HR]: 1.16; P < 0.001) and CHE (HR: 0.61; P = 0.008) as independent predictors for 1-year survival. Using the Youden Index, a CHE of 2.5 kU/L was identified as optimal threshold to predict post-TIPS survival in the Hannover cohort (P < 0.001), which was confirmed in the validation cohort (P = 0.010). CHE < 2.5 kU/L was significantly associated with development of acute-on-chronic liver failure (P < 0.001) and hepatic encephalopathy (P = 0.006). Of note, CHE was also significantly linked to mortality in the subgroup of patients with refractory ascites (P = 0.001) as well as in patients with high MELD scores (P = 0.012) and with high-risk FIPS scores (P = 0.004). After propensity score matching, mortality was similar in patients with ascites and CHE < 2.5 kU/L if treated by TIPS or by paracentesis. Contrarily, in patients with CHE ≥ 2.5 kU/L survival was significantly improved by TIPS as compared to treatment with paracentesis (P < 0.001). Conclusion: CHE is significantly associated with mortality and complications after TIPS insertion. Therefore, we suggest that CHE should be evaluated as an additional parameter for selecting patients for TIPS implantation.

Liver stiffness across different chronic liver disease under therapy with statin in a real life cohort.

INTRODUCTION: Statins have been associated with improved clinical outcomes in patients with viral hepatitis and after variceal bleeding. Still, the clinical benefit of statins is not well defined for different liver diseases. Moreover, associations between statin use and liver stiffness as well as event free survival have not been established. METHODS: Liver stiffness was evaluated in 6490 patients with liver disease (January 2012 till December 2016). Two hundred thirty-four of those received statin therapy, 468 controls without statins were selected by a 1:2 case by case matching using age, sex, underlying liver disease and BMI. RESULTS: Statins were given to 234 patients with chronic virus hepatitis (n = 104), nonalcoholic fatty liver disease (n = 52), autoimmune liver disease including autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis (n = 31) and hepatitis of unknown origin (n = 47). Follow-up data were available for 96 and 119 pairs (mean follow-up 2 years). Statin users showed reduced inflammatory activity. Elevated liver enzymes were reported in 57% of statin-treated compared with 70% of controls (mean alanine aminotransferase level 53 vs. 74 U/l; P < 0.001). Statin use was well tolerated in this cohort. Mean liver stiffness values were 10.7 kPa (SEM 0.7) and 15.5 kPa (SEM 0.7) accordingly (P < 0.0001). Decompensation was less likely to occur in the statin group, both groups do not defer in the incidence of liver tumor occurrence, transplantation or death (odds ratio = 1, P = nonsignificant). CONCLUSIONS: Use of statins was well tolerated irrespective of liver disease. Statin users showed reduced hepatic inflammatory activity, less severe markers of liver stiffness and portal hypertension. There might be a beneficial effect of statin on the risk to experience hepatic decompensation.

Altered effector functions of NK cells in chronic hepatitis C are associated with IFNL3 polymorphism.

Interferon α-mediated effector functions of NK cells may contribute to the control of HCV replication and the pathogenesis of liver disease. The single-nucleotide polymorphism rs12979860 near IFNL3 (previously known as IL28B) is important in response to IFN-α treatment and in spontaneous resolution of acute hepatitis C. The role of the IFNL3 polymorphism in NK cell function is unclear. Thus, we investigated the role of IFNL3 polymorphism in type I IFN-dependent regulation of NK cell functions in patients with cHC and healthy control subjects. We demonstrated a marked polarization of NK cells toward cytotoxicity in response to IFN-α stimulation in patients with hepatitis C. That TRAIL up-regulation was present, particularly in patients with the IFNL3-TT allele, was supported by a shift in the pSTAT-1:pSTAT-4 ratios toward pSTAT-1. In patients bearing the IFNL3-TT allele, NK cell effector function correlated with liver disease activity. In contrast, higher cytokine production of NK cells was observed in healthy individuals with the IFNL3-CC genotype, which may support spontaneous HCV clearance in acute infection. Overall, these findings show that the role of NK cells may differ in chronic infection vs. early antiviral defense and that the IFNL3 genotype differentially influences NK cell function.

Limited effectiveness and safety profile of protease inhibitor-based triple therapy against chronic hepatitis C in a real-world cohort with a high proportion of advanced liver disease.

BACKGROUND/OBJECTIVE: Triple therapy with pegylated-interferon-α, ribavirin, and a protease inhibitor (PI), boceprevir or telaprevir, is the standard of care for the treatment of chronic hepatitis C genotype 1 in several countries. Pivotal studies showed reasonable results for safety and efficacy. However, it remains uncertain to what extent this can be transferred to the real world.Here, we aimed to analyze the effectiveness and safety of pegylated-interferon-α/ribavirin/PI triple therapy in a real-world cohort of a tertiary referral center. PATIENTS AND METHODS: Between June 2011 and November 2011, a total of 208 consecutive patients with chronic hepatitis C genotype 1 were evaluated for the initiation of a triple-therapy regimen and included in this study. Eighty-six patients (86% F3/F4) started a triple-therapy regimen and were followed until 12 weeks after the end of treatment. RESULTS: Overall, 36 out of the 86 treated patients (42%) achieved a sustained virological response. However, only 17% of the initially screened 208 patients were cured with triple therapy at our center. A high rate of serious adverse events (28%) was documented during treatment. The risk/benefit ratio was poor for patients with signs of advanced liver cirrhosis (n=33, 38%), indicated by increased bilirubin, low albumin, and/or low platelet count at baseline. CONCLUSION: The effectiveness and safety of PI-based triple therapy can be limited in real-world cohorts including large numbers of patients with advanced liver disease. Future therapies can only overcome these limitations if interferon-free regimens are established.

PEG-IFN alpha but not ribavirin alters NK cell phenotype and function in patients with chronic hepatitis C.

BACKGROUND: Ribavirin (RBV) remains part of several interferon-free treatment strategies even though its mechanisms of action are still not fully understood. One hypothesis is that RBV increases responsiveness to type I interferons. Pegylated Interferon alpha (PEG-IFNa) has recently been shown to alter natural killer (NK) cell function possibly contributing to control of hepatitis C virus (HCV) infection. However, the effects of ribavirin alone or in combination with IFNa on NK cells are unknown. METHODS: Extensive ex vivo phenotyping and functional analysis of NK cells from hepatitis C patients was performed during antiviral therapy. Patients were treated for 6 weeks with RBV monotherapy (n = 11), placebo (n = 13) or PEG-IFNa-2a alone (n = 6) followed by PEG-IFNa/RBV combination therapy. The effects of RBV and PEG-IFNa-2a on NK cells were also studied in vitro after co-culture with K562 or Huh7.5 cells. RESULTS: Ribavirin monotherapy had no obvious effects on NK cell phenotype or function, neither ex vivo in patients nor in vitro. In contrast, PEG-IFNa-2a therapy was associated with an increase of CD56bright cells and distinct changes in expression profiles leading to an activated NK cell phenotype, increased functionality and decline of terminally differentiated NK cells. Ribavirin combination therapy reduced some of the IFN effects. An activated NK cell phenotype during therapy was inversely correlated with HCV viral load. CONCLUSIONS: PEG-IFNa activates NK cells possibly contributing to virological responses independently of RBV. The role of NK cells during future IFN-free combination therapies including RBV remains to be determined.

Compromised function of natural killer cells in acute and chronic viral hepatitis.

BACKGROUND: Natural killer (NK) cells are an integral part of the innate immune system. They have been suggested to play an important role in both defense against viral hepatitis and the pathogenesis of other liver diseases. METHODS: NK cells from 134 individuals including patients with acute hepatitis B and C as well as chronic hepatitis B, C, and delta (D) patients were studied. RESULTS: Infection with viral hepatitis was associated with increased frequencies of NK cells in the peripheral blood; that NK cells showed a less activated phenotype and were compromised in cytolotytic function and cytokine production in all viral hepatitis infections: Hepatitis virus infections did not alter NK cell differentiation, and the activity and severity of liver disease were reflected by alterations of NK cell surface receptors as demonstrated by principal component analysis. CONCLUSION: NK cell phenotypic and functional alterations can equally be observed in HBV, HCV, and HDV infections. Instead, patterns of NK cell alterations differ in acute and chronic infections. Thus, our data suggest a common mechanism in the alteration of NK cell phenotype and function with unique variations that depend on disease activity rather than virus-specific factors.

Eligibility and safety of triple therapy for hepatitis C: lessons learned from the first experience in a real world setting.

BACKGROUND: HCV protease inhibitors (PIs) boceprevir and telaprevir in combination with PEG-Interferon alfa and Ribavirin (P/R) is the new standard of care in the treatment of chronic HCV genotype 1 (GT1) infection. However, not every HCV GT1 infected patient is eligible for P/R/PI therapy. Furthermore phase III studies did not necessarily reflect real world as patients with advanced liver disease or comorbidities were underrepresented. The aim of our study was to analyze the eligibility and safety of P/R/PI treatment in a real world setting of a tertiary referral center. METHODS: All consecutive HCV GT1 infected patients who were referred to our hepatitis treatment unit between June and November 2011 were included. Patients were evaluated for P/R/PI according to their individual risk/benefit ratio based on 4 factors: Treatment-associated safety concerns, chance for SVR, treatment urgency and nonmedical patient related reasons. On treatment data were analyzed until week 12. RESULTS: 208 patients were included (F3/F4 64%, mean platelet count 169/nl, 40% treatment-naïve). Treatment was not initiated in 103 patients most frequently due to safety concerns. 19 patients were treated in phase II/III trials or by local centers and a triple therapy concept was initiated at our unit in 86 patients. Hospitalization was required in 16 patients; one patient died due to a gastrointestinal infection possibly related to treatment. A platelet count of <110/nl was associated with hospitalization as well as treatment failure. Overall, 128 patients were either not eligible for therapy or experienced a treatment failure at week 12. CONCLUSIONS: P/R/PI therapies are complex, time-consuming and sometimes dangerous in a real world setting, especially in patients with advanced liver disease. A careful patient selection plays a crucial role to improve safety of PI based therapies. A significant number of patients are not eligible for P/R/PI, emphasizing the need for alternative therapeutic options.

Phase III results of Boceprevir in treatment naïve patients with chronic hepatitis C genotype 1.

INTRODUCTION: Chronic hepatitis C virus infection affects approximately 2% of the world population and can result in cirrhosis and hepatocellular carcinoma. Until 2011, the standard of care (SOC) has been therapy with pegylated interferon alfa and ribavirin (PEG-IFN/RBV). Sustained virologic response rates (SVR) after SOC in patients infected with genotype 1 have been 40-50%. The development of new direct antiviral agents (DAA) is vital. The first drugs that specifically target the HCV protease have been approved in 2011. This review summarizes the results of SPRINT-2, a phase III double blind, placebo controlled study in which the efficacy and safety of Boceprevir, a new HCV protease inhibitor, was compared to SOC. DESIGN: A total of 1097 treatment-naïve, genotype 1, chronic hepatitis C patients were randomized into three different groups. All patients received a 4-week lead in phase with peginterferon alfa-2b and ribavirin. A total of 363 patients were randomized to the control group and received 44 additional weeks of PEG-IFN/RBV; of the 368 patients randomized to group 2, the response-guided treatment regimen (RGT), patients with undetectable HCV RNA through week 8 and 24 received 24 weeks of triple therapy (PEG-IFN/RBV/Boceprevir); patients whose HCV-RNA was detectable between weeks 8 and 24 but undetectable at week 24 received subsequently 20 weeks of (PEG-IFN/RBV); 366 patients in group 3 were treated with lead-in followed by triple therapy through week 48. RESULTS: Treatment with Boceprevir triple therapy increased SVR to 63-66% compared to 38% receiving PEG-IFN/RBV therapy. Non-Black patients achieved higher SVR rates compared to Black patients. Responsiveness to interferon in the lead-in phase was predictive for SVR. SVR rates did not differ between patients randomized to RGT with Boceprevir and those treated with a fixed duration. Anaemia was the most important adverse event leading to dose reduction of RBV in 13% of controls and 21% of Boceprevir recipients. CONCLUSION: Triple therapy of Boceprevir in combination with PEG-IFN 2b/RBV is more effective than SOC alone. RGT is possible without reducing the SVR rates. Management of anaemia has to be considered.

Hepatitis E virus (HEV)-specific T-cell responses are associated with control of HEV infection.

Hepatitis E virus (HEV) infection is usually self-limited but may lead to acute hepatitis and rarely to fulminant hepatic failure. Persistent HEV infections have recently been described in organ transplant recipients receiving immunosuppressive medications, suggesting that HEV is controlled by adaptive immune responses. However, only few studies have investigated HEV-specific T-cell responses and immune correlates for the failure to clear HEV infection have not been established so far. We investigated T-cell responses against HEV in 38 subjects including anti-HEV-positive (exposed, n = 9) and anti-HEV-negative (n = 10) healthy controls, 12 anti-HEV-positive but HEV RNA-negative organ transplant recipients, and seven transplant recipients with chronic hepatitis E. Proliferation as well as cytokine production of CD4+ and CD8+ T cells was studied after stimulation with overlapping peptides spanning all proteins encoded by HEV-open reading frame (ORF)2 and HEV-ORF3. We show that (1) strong and multispecific HEV-specific T-cell responses are present in exposed healthy controls, and to a lesser extent also in recovered patients after transplantation; (2) that these responses are absent in patients with chronic hepatitis E but become detectable after viral clearance; and (3) that HEV-specific T-cell responses can be restored in vitro by blocking the PD-1 or CTLA-4 pathways. However, a combination of PD-1 and CTLA-4 blockade had no synergistic effects. We conclude that chronic hepatitis E is associated with impaired HEV-specific T-cell responses and suggest that enhancing adaptive cellular immunity against HEV might prevent persistent HEV infections.

Hepatitis B surface antigen (HBsAg) decrease and serum interferon-inducible protein-10 levels as predictive markers for HBsAg loss during treatment with nucleoside/nucleotide analogues.

BACKGROUND: Hepatitis B surface antigen (HBsAg) loss is the ultimate goal of antiviral therapy and its prediction may be important for treatment individualization. Quantitative HBsAg (qHBsAg) has been shown to predict response to interferon-α, but few studies have analysed qHBsAg during treatment with nucleoside/nucleotide analogues (NAs). Serum interferon-inducible protein-10 (IP-10) has been associated with treatment response in hepatitis C, but data in chronic hepatitis B are lacking. Here, we aimed to investigate potential factors predictive for HBsAg loss. METHODS: HBsAg was quantified at multiple time points in 126 patients with chronic HBV infection; 95 received NA treatment for 6-107 months. At an early time point (first 6 months of therapy) and late time point after virological response (VR; HBV DNA<100 IU/ml), we distinguished three patterns of HBsAg decrease: strong decrease (>0.5 log(10)), moderate decrease (10% to 0.5 log(10)) and no decrease (<10%). In addition to conventional biochemical and virological parameters, we analysed serum IP-10 levels in 55 patients. RESULTS: Early and late HBsAg kinetics did not correlate. Overall, 42% of patients with a strong HBsAg decrease 2 years after VR cleared HBsAg. Importantly, no patient without a late HBsAg decrease >0.5 log(10) cleared HBsAg. By contrast, early HBsAg decrease after 6 months of NA therapy was not associated with HBsAg loss. Baseline serum IP-10 levels were associated with late but not early HBsAg kinetics and were highest in patients with HBsAg loss. CONCLUSIONS: Monitoring qHBsAg after successful HBV DNA suppression might be useful to identify patients who clear HBsAg, implicating finite NA treatment. The role of IP-10 as predictive marker for HBsAg loss should be further evaluated.