Procedure-related bleeding risk in patients with cirrhosis and severe thrombocytopenia.

BACKGROUND: Gaps of knowledge still exist about the potential association between severe thrombocytopenia and increased risk of procedure-associated bleeding in patients with liver disease. METHODS: In this narrative review, we aimed at examining the association between procedure-related bleeding risk and platelet count in patients with cirrhosis and severe thrombocytopenia in various settings. We updated to 2020 a previously conducted literature search using MEDLINE/PubMed and EMBASE. The search string included clinical studies, adult patients with chronic liver disease and thrombocytopenia undergoing invasive procedures, any interventions and comparators, and haemorrhagic events of any severity as outcome. RESULTS: The literature search identified 1276 unique publications, and 15 studies met the inclusion criteria and were analysed together with those identified by the previous search. Most of the new studies included in our analysis did not assess the association between post-procedural bleeding risk and platelet count alone in patients with chronic liver disease. Furthermore, some results could have been biased by prophylactic platelet transfusions. A few studies found that severe thrombocytopenia may be predictive of bleeding following percutaneous liver biopsy, dental extractions, percutaneous ablation of liver tumours and endoscopic polypectomy. CONCLUSIONS: Currently available literature cannot support definitive conclusions about the appropriate target platelet counts to improve the risk of bleeding in cirrhotic patients who underwent invasive procedures; moreover, it showed enormous variability in the use of prophylactic platelet transfusions.

Vitamin D level and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C: a systematic review and meta-analysis.

BACKGROUND & AIMS: The baseline 25-hydroxyvitamin D (25[OH]D) level has recently been reported to be an independent predictor of sustained virologic response (SVR) to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C virus (HCV) infection. However, studies have yielded inconsistent results. Thus, we conducted a systematic review and meta-analysis to clarify any association between baseline 25(OH)D level and SVR in HCV therapy. METHODS: Two reviewers searched four electronic databases (Medline, Embase, PubMed, and Cochrane trials register) and relevant international conference proceedings up to March 2014 for studies treating chronic HCV infection with PEG-IFN plus RBV where baseline 25(OH)D level was tested. Studies involving patients with HIV co-infection, previous liver transplantation or those receiving vitamin D supplementation were excluded. The mean baseline 25(OH)D level was compared between those who achieved and those who failed to achieve SVR. Pooled standard difference in mean 25(OH)D level, odds ratios (OR) and 95% confidence intervals (CI) were calculated with the Comprehensive Meta-Analysis software (version 2.0) using a random effects model. RESULTS: 11 studies comprising 2605 patients were included in the meta-analysis. There was no significant association between the baseline mean 25(OH)D level and SVR (OR 1.44, 95% CI 0.92-2.26; p=0.11), either in patients infected with genotypes 1/4/5 (OR 1.48, 95% CI 0.94-2.34; p=0.09) or genotypes 2/3 (OR 1.51, 95% CI 0.26-8.87; p=0.65). CONCLUSIONS: The baseline 25(OH)D level is not associated with SVR to PEG-IFN plus RBV therapy in chronic HCV infection, regardless of genotype. Any effect of vitamin D supplementation on SVR is yet to be definitively determined.

Vitamin A deficiency is associated with hepatitis C virus chronic infection and with unresponsiveness to interferon-based antiviral therapy.

UNLABELLED: Recent data suggest that vitamin A modulates the expression of type I interferon receptor enhancing the antireplication effect of interferon-α on hepatitis C virus (HCV). This study aimed to investigate the prevalence of vitamin A deficiency among patients with chronic HCV infection and to assess whether vitamin A deficiency could be associated with unresponsiveness to interferon-based antiviral therapy. The analysis included 199 consecutive treatment-naïve chronic HCV patients in whom pretreatment serum vitamin A and 25-OH vitamin D were measured; 119 healthy blood donors were used as controls. Median (interquartile range) serum vitamin A in HCV-positive patients was significantly lower than in controls: 256 ng/mL (128-440) versus 742 (624-942, P<0.0001). Overall sustained viral response was achieved in 122/199 patients, 46/109 infected by difficult to treat HCV genotypes. In these latter, 39/104 (37.5%) were nonresponders. At multivariate analysis, nonresponse to antiviral therapy was predicted by carriage of interleukin (IL)-28B T/* genotypes, baseline serum levels of γGT>60 IU/mL, of HCV RNA>600,000 IU/mL, of vitamin A≤100 ng/mL, and a cumulative dose of ribavirin≤80%. Seventeen patients (9.0%) had both serum levels of vitamin A≤100 ng/mL and of vitamin D≤20 ng/mL; the presence of a combined vitamin A and D deficiency was found to be a strong independent predictor of nonresponse to antiviral therapy. CONCLUSION: A high percentage of patients with chronic HCV infection have serum vitamin A deficiency. This condition is associated with nonresponse to antiviral therapy.

Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C.

UNLABELLED: Vitamin D deficiency seems to predict the unsuccessful achievement of sustained viral response (SVR) after antiviral treatment in hepatitis C virus (HCV) difficult-to-treat genotypes. Vitamin D binding protein (GC) gene polymorphisms are known to influence vitamin D levels. This study was performed to assess whether the interaction between basal circulating vitamin D and the GC polymorphism plays a role in influencing the rate of antiviral responses in patients affected by chronic hepatitis C. In all, 206 HCV patients treated with a combination therapy of pegylated (PEG)-interferon plus ribavirin were retrospectively evaluated. GC rs7041 G>T, GC rs4588 C>A, and IL-28B rs12979860 C>T polymorphisms were genotyped. Frequencies of GC rs7041 G>T and rs4588 C>A polymorphisms were: G/G = 64 (31.1%), G/T = 100 (48.5%), T/T = 42 (20.4%) and C/C = 108 (52.4%), C/A = 84 (40.8%), A/A = 14 (6.8%). Patients were divided into those carrying ≥3 major alleles (wildtype [WT]+: G-C/G-C, G-C/T-C, G-C/G-A, N = 100) and the remaining (WT-: G-C/T-A, T-A/T-C, T-A/T-A, T-C/T-C, N = 106). Four groups were identified: vitamin D ≤20 ng/mL and WT-, vitamin D ≤20 and WT+, vitamin D >20 and WT-, vitamin D >20 and WT+. In difficult-to-treat HCV genotypes the proportion of patients achieving SVR significantly increased with a linear trend from the first to the last group: 6/25 (24.0%), 9/24 (37.5%), 12/29 (41.4%), 19/29 (65.5%) (P = 0.003). At multivariate analysis, having basal vitamin D >20 ng/mL plus the carriage of GC WT+ was found to be an independent predictor of SVR (odds ratio 4.52, P = 0.015). CONCLUSION: In difficult-to-treat HCV genotypes, simultaneous pretreatment normal serum vitamin D levels and the carriage of GC-globulin WT isoform strongly predicts the achievement of SVR after PEG-interferon plus ribavirin antiviral therapy.

Treatment of genotype-1 hepatitis C recurrence after liver transplant improves survival in both sustained responders and relapsers.

The aim of this study was to evaluate the factors affecting the response to treatment and how it could affect survival in a large series of genotype-1 HCV-transplanted patients. Three-hundred and twenty six genotype-1 HCV patients were enrolled. One hundred and ninety-six patients (60.1%) were nonresponders and 130 (39.9%) showed negative HCV-RNA at the end of treatment. Eighty-four of them (25.8%) achieved sustained virological response, while 46 (14.1%) showed viral relapse. Five-year cumulative survival was significantly worse in nonresponders (76.4%) compared with sustained viral response (93.2) or relapsers (94.9%). Sustained responders and relapsers were therefore considered as a single 'response group' in further analysis. Pretreatment variables significantly associated with virological response at multivariate regression analysis were the absence of ineffective pretransplant antiviral therapy, the recurrence of HCV-hepatitis more than 1 year after transplant, an histological grading ≥4 at pretreatment liver biopsy, a pretreatment HCV-RNA level <1.2 × 10(6 ) IU/ml, and the absence of diabetes. As expected, also on-treatment variables (rapid and early virological response) were significantly associated to the response to antiviral treatment. In conclusion, this study shows that postliver transplant antiviral treatment results in beneficial effect on survival not only in sustained responders but also in relapsers.

Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C.

UNLABELLED: The widely accepted interleukin-28B (IL-28B) rs12979860 C/T polymorphism and the more recently proposed vitamin D serum concentration are two novel predictors of the response to antiviral treatment in chronic hepatitis C virus (HCV) infection. This study aimed to verify whether the IL-28B rs12979860 C/T polymorphism and pretreatment serum vitamin D levels have independent or complementary roles in predicting the rates of sustained viral response (SVR). The present study included 211 consecutive, treatment-naïve chronic HCV patients who had their pretreatment serum 25-OH vitamin D level and IL-28B rs12979860 C/T genotype determined. Overall, SVR was achieved by 134/211 (63.5%) patients and by 47/110 (42.7%) patients infected with difficult-to-treat HCV genotypes. On multivariate analysis, SVR was predicted by the HCV genotype, the IL-28B rs12979860 C/T polymorphism, and gamma-glutamyl transpeptidase, HCV RNA, cholesterol, and 25-OH vitamin D serum levels, with an area under the receiver operating characteristic (ROC) curve of 0.827. When difficult-to-treat HCV genotypes were analyzed separately, the SVR was predicted by the IL-28B rs12979860 C/T polymorphism, viral load, and serum vitamin D level, with an area under the ROC curve of 0.836. Moreover, by categorizing these latter patients into four groups-C/C homozygotes with vitamin D levels >20 ng/mL (group A) or ≤20 ng/mL (group B) and C/T heterozygotes or T/T homozygotes with vitamin D levels >20 ng/mL (group C) or ≤20 ng/mL (group D)-a significant linear trend was observed, with SVR rates in the following descending order: group A, 18/21 (85.7%); group B, 6/11 (54.5%); group C, 14/38 (36.8%); and group D, 9/40 (22.5%) (P < 0.0001). CONCLUSION: Vitamin D serum levels are complementary to the IL-28B rs12979860 C/T polymorphism in enhancing the correct prediction of the SVR in treatment-naïve chronic hepatitis C.

Treatment of hepatitis C recurrence is less successful in female than in male liver transplant recipients.

It has been recently suggested that the risk of graft loss after liver transplantation (LT) may increase in female HCV patients. The aim of the study was to examine gender differences in HCV therapy tolerance and outcome in LT patients treated for HCV recurrence. A retrospective study was conducted on liver recipients with HCV recurrence, who were given antiviral therapy from 2001 to 2009 in 12 transplant centers in Italy. Sustained virological response (SVR), adherence-to-therapy, and side effects were evaluated. A multivariate logistic regression model was used after adjusting for possible confounders. The data regarding 342 treated patients were analyzed. SVR was reported in 38.8% of patients. At baseline, male and female did not differ in HCV viral load, histology, or rate of diabetes. SVR was lower in females than in males (29.5% vs. 42.1%; P=0.03). Adherence-to-therapy was also lower in females than in males 43.4% vs. 23.8%; P=0.001); anemia was the main reason for lower adherence. In a multivariate analysis in patients Genotype1, female gender (P<0.04), early virological response (P<0.0001), and adherence to therapy (P<0.0001) were independent predictors for SVR. In conclusion, female gender represents an independent negative prognostic factor for the outcome of HCV antiviral therapy after LT.

Treatment of recurrent genotype 4 hepatitis C after liver transplantation: early virological response is predictive of sustained virological response. An AISF RECOLT-C group study.

INTRODUCTION: Hepatitis C virus genotype 4 is predominant in the Middle East and Northern Africa, even if it has recently spread to Southern Europe. Data about the treatment of post-liver transplantation (LT) genotype 4 hepatitis C recurrence are scarce. We report a retrospective analysis of post-LT genotype 4 hepatitis C treatment in 9 Italian transplant centres, focusing on the overall survival rates and treatment outcome. RESULTS: Among 452 recipients, we identified 17 HCV genotype 4 patients (16 males, 1 female) transplanted between 1998 and 2007. All patients received combined antiviral treatment with conventional doses of interferon (recombinant or pegylated) and ribavirin after histological diagnosis of hepatitis C recurrence. The observed overall survival after LT was 100% at 1 year and 83.3% at 5 years. More than 1/3 (35.3%) of patients achieved a sustained virological response (SVR) and 40% (data available in 15 subjects) an early virological response (EVR), which was significantly associated with the achievement of SVR (overall accuracy: 85.7%; predictive values of EVR absence/presence 80/88.8%; chi-square p < 0.05). CONCLUSION: In conclusion, in post-LT genotype 4 hepatitis C treatment, SVR rates are similar to genotype 1. Patients who don't show an EVR are not likely to achieve a SVR.

Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C.

OBJECTIVES: Antiviral treatment in chronic hepatitis C (CHC) involves ribavirin, a hemolytic agent. We planned a prospective study to evaluate whether drug-induced iron perturbation is clinically relevant as it relates to therapeutic outcome. METHODS: Iron variables were sequentially assessed in 206 CHC patients undergoing antiviral therapy and were correlated with pretreatment iron status and histology, hemolysis, and therapeutic outcome. RESULTS: At week 1 of therapy, serum iron (SI), transferrin saturation (TS), and serum ferritin (SF) increased markedly in all patients. All iron parameters correlated with hemolysis up to week 4; this correlation was lost for SF at later time points. SF rise during treatment was inversely related to baseline SF and iron deposits in hepatic mesenchymal/Kupffer cells. Both baseline SF and mesenchymal iron significantly correlated with fibrosis at multivariate analysis (P=0.015 and 0.008, respectively). Interestingly, baseline SF, despite good specificity (89%), had low sensitivity in predicting siderosis (25%). During therapy, SI, TS, and hemolysis parameters did not correlate with sustained virological response (SVR), whereas SF rise became an independent predictor of therapeutic response: a 2.5-fold increase of SF at week 12 associated with higher likelihood of SVR (odds ratio 1.91, P=0.032). Accordingly, lack of mesenchymal iron deposits at the baseline biopsy correlated with SVR (odds ratio 3.02, P=0.043). CONCLUSIONS: In CHC, SF is a useful marker for assessing disease duration and progression before starting treatment and for predicting therapeutic response while on therapy. SF rise during antiviral therapy is largely independent of hemolysis and likely indicates activation of macrophages in response to antivirals.

Consensus conference on TIPS management: Techniques, indications, contraindications.

The trans jugular intrahepatic Porto systemic shunt (TIPS) is no longer viewed as a salvage therapy or a bridge to liver transplantation and is currently indicated for a number of conditions related to portal hypertension with positive results in survival. Moreover, the availability of self-expandable polytetrafluoroethylene (PTFE)-covered endoprostheses has dramatically improved the long-term patency of TIPS. However, since the last updated International guidelines have been published (year 2009) new evidence have come, which have open the field to new indications and solved areas of uncertainty. On this basis, the Italian Association of the Study of the Liver (AISF), the Italian College of Interventional Radiology-Italian Society of Medical Radiology (ICIR-SIRM), and the Italian Society of Anesthesia, Analgesia and Intensive Care (SIAARTI) promoted a Consensus Conference on TIPS. Under the auspices of the three scientific societies, the consensus process started with the review of the literature by a scientific board of experts and ended with a formal consensus meeting in Bergamo on June 4th and 5th, 2015. The final statements presented here were graded according to quality of evidence and strength of recommendations and were approved by an independent jury. By highlighting strengths and weaknesses of current indications to TIPS, the recommendations of AISF-ICIR-SIRM-SIAARTI may represent the starting point for further studies.

Long-term maintenance of sustained virological response in liver transplant recipients treated for recurrent hepatitis C.

BACKGROUND: The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients' survival. AIM: To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis C recurrence. METHODS: 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis C recurrence were retrospectively evaluated. RESULTS: The overall sustained virological response rate was 40% (173/436 patients), and the mean follow-up after liver transplantation was 11±3.5 years (range, 5-24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p=0.007), treatment duration >80% of the scheduled period (p=0.027), and early virological response (p=0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p=0.008). CONCLUSIONS: Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival.

Interaction between calcineurin inhibitors and IL-28B rs12979860 C>T polymorphism and response to treatment for post-transplant recurrent hepatitis C.

BACKGROUND: The impact of calcineurin inhibitors on achievement of sustained virological response to antiviral therapy for post-transplant recurrent hepatitis C is controversial. This study aimed at investigating the interactions between calcineurin inhibitors and interleukin-28B (IL-28B) gene polymorphisms and sustained virological response. METHODS: Retrospective study of 147 liver transplant recipients with recurrent hepatitis C, who received 48 weeks of peg-interferon-α (N=113) or standard interferon (N=34), in association with ribavirin. Cyclosporine and tacrolimus were administered in 68 and 79 patients, respectively. IL-28B rs12979860 allele frequency was assessed in both donors and recipients. RESULTS: Overall, 57 patients (38.8%) obtained sustained virological response; no difference was found between cyclosporine and tacrolimus-treated patients (42.6% vs. 35.4%, p=0.371). Recipient and donor IL-28B genotypic frequencies were C/C=30.6%, C/T=51.7%, T/T=17.7% and C/C=44.9%, C/T=50.3%, T/T=4.8%, respectively. Combining donor and recipient alleles, response rates decreased from cyclosporine-treated patients carrying ≤ 1 T allele (56.1%) to tacrolimus-treated patients carrying ≤ 1 T allele (44.7%) to patients carrying ≥ 2 T alleles (25.0%, p=0.0009). CONCLUSIONS: Donor and recipient rs12979860 alleles synergistically influence sustained virological response rate to antiviral treatment for recurrent hepatitis C. In patients carrying <2 T alleles cyclosporine favours a better response than tacrolimus, while no difference was found in the presence of ≥ 2 T alleles.

Antiviral treatment of hepatitis C.

Therapy of hepatitis C virus (HCV) infection may prevent progression to cirrhosis, hepatocellular carcinoma and end-stage liver disease. The cornerstone of treatment has long been standard IFN-alpha, the use of which was associated with a sustained biochemical and viral response in only a small proportion of patients. More recently, the success of interferon-based regimens has substantially improved due to the combination with the guanosine analogue ribavirin and to the advent of pegylated interferon formulations. However, even the most up-to-date regimens fail to cure the infection in many cases and are limited by side effects and high costs. A better understanding of the HCV genomic organisation, the elucidation of the three-dimensional structures of virally encoded enzymes and the recent development of a HCV-replicon system in human hepatoma (Huh-7) cells have led to significant advances in the development of new antiviral compounds, many of which are under evaluation in clinical trials. The aim of this review is to trace a brief overview of the progress made by interferon-based treatments for hepatitis C since their introduction in the early 1990s, and to highlight the results of recent clinical studies concerning new and emerging drugs.

Pegylated versus standard interferon-alpha in antiviral regimens for post-transplant recurrent hepatitis C: Comparison of tolerability and efficacy.

BACKGROUND: In the treatment of hepatitis C virus (HCV) infection, regimens including pegylated interferon-alpha are superior to those including standard interferon; the present retrospective study was performed to verify whether the same is applicable to biopsy-proven recurrent hepatitis C (genotype 1b) after liver transplantation (OLT). METHODS: Twenty-four patients (16 male) were studied. Twelve had received interferon-alpha(2b) (IFN), 9 MU weekly and 12 received pegylated interferon-alpha(2b) (PEG-IFN), 0.5 microg/kg weekly. All had received oral ribavirin 600-800 mg/day. Treatment duration was intended for 12 months. A repeat liver biopsy, with evaluation of the Ishak grading and staging scores, was obtained at 1 year. RESULTS: Only 12/24 patients (50%) completed a full year of therapy; 17 (71%) experienced side-effects requiring a 50% dosage reduction or discontinuation of the IFN, PEG-IFN and/or ribavirin. This was observed in 6/12 patients (50%) treated with IFN in comparison to 11/12 patients (92%) treated with PEG-IFN (P < 0.05). The difference was mainly accounted for by anemia and leukopenia that were reported in 4/12 IFN patients (33%) versus 9/12 PEG-IFN patients (75%; P < 0.05), respectively. End-of-treatment viral response (ETVR) and histological response were always associated and occurred in 4/24 patients (17%), two in each treatment arm. Patients with ETVR were younger, had always completed 1 year of therapy, had had recurrent hepatitis later after transplantation and presented a higher baseline grading score. CONCLUSIONS: In the OLT setting, the potential benefits of antiviral treatments including PEG-IFN may be limited by the poor tolerability of the adopted drugs.