Maternal and Neonatal Outcomes in Intrahepatic Cholestasis of Pregnancy.

The aims of our study were to evaluate the maternal and fetal outcomes of intrahepatic cholestasis of pregnancy (ICP). In this observational, retrospective case-control study, we included all pregnant women who gave birth with a diagnosis of ICP between January 2010 and December 2020 at the Unit of Obstetrics and Gynecology, University Hospital of Messina. The data were compared with those from a control group of pregnant women who did not have ICP. One hundred twenty-nine and eighty-five patients were included, respectively, in the study and in the control group. There was a significant difference between the two groups in the incidence of hypothyroidism, thrombophilia, gestational diabetes, gestational hypertension, postpartum hemorrhage, and preterm delivery, which were more frequent in the ICP patients. No neonatal adverse events were recorded, although a significant difference in the meconium-stained amniotic fluid condition was noted. After a 24-month follow-up, 48/129 patients with ICP accepted to be reassessed by liver ultrasound, elastographic examination, and liver function blood tests. No patient showed signs of chronic liver disease. This study confirmed a higher probability of adverse short-term maternal outcomes in ICP pregnant patients, but a lower probability of adverse short-term fetal outcomes and the absence of a long-term maternal risk of chronic liver disease.

Hypergammaglobulinemia before Starting DAA Therapy Is A Strong Predictor of Disease Progression in Cirrhotic Patients Even after HCV Clearance.

The predictive factors of long-term clinical benefits in patients with hepatitis C virus (HCV)­related liver cirrhosis after Direct Antiviral Agents (DAA) treatment are still undefined. The aim of this study was to identify any predictors of liver failure, hepatocellular carcinoma (HCC) and/or death in patients with compensated liver cirrhosis who achieved the sustained virological response (SVR). To this purpose, 324 consecutive cirrhotic patients who started DAA treatment from 1 April 2015 to 31 December 2016 were retrospectively analyzed. All patients were followed up for a median time of 63 months (range 19−77) through clinical/biochemical/instrumental examinations performed at baseline and after stopping the DAA treatment. At the end of the evaluation, 230 (71%) individuals showed stable clinical liver disease over time, 43 (13.3%) developed HCC, and 24 (7.4%) developed hepatic decompensation without HCC. Overall, 49 (15,1%) patients died. Multivariate regression analysis showed that hepatic decompensation was significantly associated with at baseline older age, higher liver stiffness, higher spleen longitudinal size values and hypergammaglobulinemia (p = 0.003, p = 0.005, p = 0.001, p = 0.029, respectively). HCC development was significantly associated with hypergammaglobulinemia (p < 0.001). Death was associated with older age and hypergammaglobulinemia (p < 0.001 and p = 0.007, respectively). Finally, survival analysis confirmed that patients with gamma globulin levels ≥ 1.8 gr/dl had a significantly higher risk of death compared to those with gamma globulin levels < 1.8 gr/dl (p < 0.001). In conclusion, hypergammaglobulinemia before starting DAA therapy represents a strong predictor of hepatic decompensation, HCC and death in cirrhotic patients even after HCV clearance.

RESIST-HCV Criteria to Monitor Progression of Low-Risk Esophageal Varices in Patients With Compensated Cirrhosis After HCV Eradication: The SIMPLE Study: SIMPLE: Scoring Index to Monitor Progression of Low-risk Esophageal varices.

INTRODUCTION: Noninvasive criteria to predict the progression of low-risk esophageal varices (EV) in patients with compensated hepatitis C virus (HCV) cirrhosis after sustained virological response (SVR) by direct-acting antivirals (DAAs) are lacking. Our aim was to assess the diagnostic performance of Rete Sicilia Selezione Terapia-HCV (RESIST-HCV) criteria for EV progression compared with elastography-based criteria (Baveno VI, Expanded Baveno VI, and Baveno VII-HCV criteria). METHODS: All consecutive patients observed at 3 referral centers with compensated HCV cirrhosis with or without F1 EV who achieved sustained virological response by DAAs were classified at last esophagogastroduodenoscopy (EGDS) as RESIST-HCV low risk (i.e., low probability of high-risk varices [HRV]) if platelets were >120 × 10 9 /L and serum albumin >3.6 g/dL or RESIST-HCV high risk (i.e., high probability of HRV) if platelets were <120 × 10 9 /L or serum albumin <3.6 g/dL. The primary outcome was the progression to HRV. The area under the receiver operating characteristic curve and decision curve analysis of noninvasive criteria were calculated. RESULTS: The cohort consisted of 353 patients in Child-Pugh class A (mean age 67.2 years, 53.8% males). During a mean follow-up of 44.2 months, 34 patients (9.6%, 95% CI 6.7%-13.5%) developed HRV. At the last EGDS, 178 patients (50.4%) were RESIST-low risk, and 175 (49.6%) were RESIST-high risk. RESIST-HCV criteria showed the highest area under the receiver operating characteristic curve (0.70, 95% confidence interval 0.65-0.75), correctly sparing the highest number of EGDS (54.3%), with the lowest false-positive rate (45.7%), compared with elastography-based criteria. Decision curve analysis showed that RESIST-HCV had higher clinical utility than elastography-based criteria. DISCUSSION: Biochemical-based RESIST-HCV criteria are useful to easily predict HRV development after HCV eradication by DAAs in patients with compensated cirrhosis and low-risk EV.

Antibody to hepatitis B virus core antigen positivity is a predictor of non-alcoholic fatty liver disease severity.

Insufficient information is available about co-factors favoring the progression of non-alcoholic fatty liver disease (NAFLD) toward cirrhosis. We aimed to evaluate the impact of a limited alcohol intake and of occult hepatitis B virus (HBV) infection (OBI) on the severity of NAFLD. Three-hundred-seventy-four alcohol non-abusers and HBV surface antigen negative NAFLD patients (223 males; mean age 55.4 years), consecutively admitted to the outpatients clinic of a referral liver unit from January 1st, 2018 to December 31st, 2019, were studied. Anti-HBV core antigen antibody [(anti-HBc), a surrogate marker of OBI] was assessed in all patients. Patients were distinguished between teetotal and moderate alcohol consumers (intake of less than 30 g and 20 g if males or females, respectively). Liver fibrosis was non-invasively assessed by FIB-4 and transient elastography. Uni- and multivariate analyses were performed to identify predictors of advanced fibrosis. Patients had a mean BMI of 28.5 kg/m2, and the majority presented metabolic and cardio-vascular comorbidities [258 patients (69%) had insulin resistance/diabetes, 249 (66.6%) dyslipidemia, 200 (53.5%) arterial hypertension]. Multivariate analysis showed that anti-HBc positivity (p = 0.046, OR 2.153) was a factor associated with advanced fibrosis at FIB-4 score testing, whereas moderate alcohol intake was not associated with severe NAFLD both at FIB-4 and transient elastography evaluations. The study showed that a moderate alcohol intake has no impact on NAFLD severity and suggested that OBI might negatively affect the NAFLD outcome.

Cirrhotic Patients with Bacterial Infection and Negative Cultures Have a More Advanced Disease and an Increased Short-Term Mortality Rate.

BACKGROUND: The negative clinical impact of bacterial infections (BI) in patients with cirrhosis is well documented. In cirrhotic patients, failure to isolate the pathogen is a frequent event, occurring in 30-40% of cases. AIM: The aim of this study was to compare the clinical characteristics, early (30-day) and short-term (90-day) mortality rates, in a cohort of cirrhotic patients with BI, between those with positive (C-pos) and those with negative (C-neg) microbiological cultures. METHODS: We retrospectively enrolled 279 consecutive hospitalized cirrhotic patients with BI. Survival and predictors of 30-day and 90-day mortality were assessed by Kaplan-Meier curves and logistic regression analysis, respectively. RESULTS: Cultures tested negative in 108/279 (38.7%) patients. C-neg patients were more frequently males (p = 0.035), had higher Child-Pugh-Turcotte (CPT; p = 0.007) and model for end-stage liver disease-sodium (MELD-Na; p = 0.043) scores, and had more frequently decompensated liver disease (p = 0.04). Mortality rate was higher in C-neg than in C-pos patients, both at 30 days (22.2% versus 11.7%, p = 0.024) and 90 days (46.3% versus 33.3%, p = 0.030). MELD-Na score and non-selective beta-blockers (NSBBs) were independent risk factors for 30-day and 90-day mortality. In particular, the use of NSBBs was independently associated with a lower 30-day and 90-day mortality risk (OR 0.41, CI95% 0.17-0.94, p = 0.040; and OR 0.43, CI95% 0.25-0.75, p = 0.003, respectively). CONCLUSIONS: Cirrhotic patients with BI and negative microbiological cultures have significantly higher mortality compared to those with positive cultures. Early mortality and short-term mortality are mainly influenced by the underlying severity of liver disease. In this contest, therapy with NSBBs has a positive impact on short-term survival.

A prospective study of direct-acting antiviral effectiveness and relapse risk in HCV cryoglobulinemic vasculitis by the Italian PITER cohort.

BACKGROUND AND AIMS: Mixed cryoglobulinemia is the most common HCV extrahepatic manifestation. We aimed to prospectively evaluate the cryoglobulinemic vasculitis (CV) clinical profile after a sustained virologic response (SVR) over a medium-term to long-term period. APPROACH AND RESULTS: Direct-acting antiviral-treated cryoglobulinemic patients, consecutively enrolled in the multicentric Italian Platform for the Study of Viral Hepatitis Therapy cohort, were prospectively evaluated. Cumulative incidence Kaplan-Meier curves were reported for response, clinical deterioration, relapse and relapse-free survival rates. Cox regression analysis evaluated factors associated with different outcomes. A clinical response was reported in at least one follow-up point for 373 of 423 (88%) patients with CV who achieved SVR. Clinical response increased over time with a 76% improvement rate at month 12 after the end of treatment. A full complete response (FCR) was reached by 164 (38.8%) patients in at least one follow-up point. CV clinical response fluctuated, with some deterioration of the initial response in 49.6% of patients (median time of deterioration, 19 months). In patients who achieved FCR and had an available follow-up (137 patients) a relapse was observed in 13% and it was transient in 66.7% of patients. The rate of patients without any deterioration was 58% and 41% at 12 and 24 months, respectively. After achieving SVR, a clinical nonresponse was associated with older age and renal involvement; a clinical deterioration/relapse was associated with high pretreatment rheumatoid factor values, and FCR was inversely associated with age, neuropathy, and high cryocrit levels. CONCLUSION: In patients with CV, HCV eradication may not correspond to a persistent clinical improvement, and clinical response may fluctuate. This implies an attentive approach to post-SVR evaluation through prognostic factors and tailored treatment.

Over time evaluation of glycaemic control in direct-acting antiviral-treated hepatitis C virus/diabetic individuals with chronic hepatitis or with cirrhosis.

BACKGROUND: Data concerning the impact of hepatitis C virus (HCV) cure on type 2 diabetes mellitus (T2DM) are controversial. The aim of the study was to evaluate the effects of anti-HCV direct-acting antiviral (DAA) treatments on long-term glucose control in HCV/T2DM patients with chronic hepatitis C (CHC) or with cirrhosis. METHODS: One hundred and eighty-two consecutive HCV/T2DM patients who achieved a viral clearance by DAA treatment were enrolled. Seventy or 182 of them had CHC, and 112 had cirrhosis. Clinical, biochemical and instrumental parameters were recorded at baseline and at 48, 96 and 120 weeks (48w, 96w and 120w, respectively) after stopping DAA therapy. RESULTS: At baseline, the overall study population had a mean of glycated haemoglobin (HbA1c) value of 7.2% (ranging from 5 to 11.2), without any significant differences between CHC and cirrhosis [7.1 and 7.2, respectively]. Evaluation over time of HbA1c variations showed a significant improvement of glucose control at all post-treatment time points compared with baseline in CHC patients (P = .001). In cirrhotic patients, a significant decrease of HbA1c levels was only found when comparing HbA1c values between baseline and 48w time-point (P = .001), whereas this improvement disappeared at both 98w and 120w (P = .8 and P = .3, respectively). Multivariate logistic regression analysis showed that patients with chronic hepatitis have a 2.5 (CI 1.066-5.945) times greater chance of achieving an improvement of glycaemic values than patients with liver cirrhosis (P = .035). CONCLUSION: DAA-based HCV cure induces a significant and persistent amelioration of glycaemic control in HCV/diabetic patients with chronic hepatitis, whereas cirrhotic HCV/diabetic subjects have only a transient benefit from the virus elimination.

Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis.

BACKGROUND & AIM: An unexpected early increase in incidence, recurrence and clinical aggressiveness of hepatocellular carcinoma (HCC) has been reported (and refuted) in patients with HCV-related cirrhosis following direct-acting antiviral (DAA) treatment. To address this controversy, we performed a prospective multicenter study on consecutively enrolled cirrhotic patients, with or without a history of HCC, undergoing DAA therapy. PATIENTS AND METHODS: A total of 1,161 HCC-free cirrhotics (group 1) and 124 cirrhotics who had received a curative treatment for an HCC (group 2) were enrolled. Clinical features, including presence of undefined/non-malignant liver nodules (UNMNs), were analyzed with respect to HCC incidence and recurrence. RESULTS: During a median study time of 17 months in group 1 and 16 months in group 2, de novo HCC developed in 48 patients (yearly incidence 3.1/100 patient-years, 75% BCLC 0-A) and recurred in 40 (mean yearly incidence 29.9/100 patient-years, 83% BCLC 0-A). A peak of HCC instant incidence was observed at 4.2 months in group 1 patients with UNMNs, and at 7.7 months in group 2. By multivariable Cox regression models, UNMNs (hazard ratio [HR] 3.11; 95% CI 1.47-6.57: p = 0.003), ascites detected any time before enrolment (HR 3.04; 95% CI 1.23-7.51; p = 0.02), and alpha-fetoprotein log-value (HR 1.90; 95% CI 1.05-3.44; p = 0.03) were the variables independently associated with the incidence of de novo HCC, while history of alcohol abuse (HR 2.10; 95% CI 1.08-4.09; p = 0.03) and history of recurrence of HCC (HR 2.87; 95% CI 1.35-6.09; p = 0.006) were associated with HCC recurrence. CONCLUSION: An early high incidence of both de novo HCC, in patients with UNMNs, and recurrent HCC was observed in DAA-treated patients; this was not accompanied by increased tumor aggressiveness. LAY SUMMARY: This prospective study focuses on the risk of developing de novo or recurrent hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment in patients with hepatitis C-related cirrhosis. We found that DAA treatment was associated with an early high HCC incidence in patients with undefined or non-malignant nodules, as well as in those with a history of complete response to HCC treatment. Whether this is related to the presence of clinically undetectable nests of cancer cells or to precancerous lesions that may progress to overt HCC upon DAA treatment remains unanswered. No evidence of increased clinical aggressiveness was reported in de novo or recurrent HCC.

Real-life use of elbasvir/grazoprevir in adults and elderly patients: a prospective evaluation of comedications used in the PITER cohort.

BACKGROUND: In patients treated for HCV infection, potential drug-drug interactions (DDIs) can occur among direct-acting antiviral drugs (DAAs) and comedications used. The real-life effectiveness and safety of elbasvir/grazoprevir (ELB/GZR) among co-medicated HCV patients was evaluated. METHODS: We prospectively evaluated consecutive patients from 15 clinical centres participating in PITER who were treated with ELB/GZR and had been followed for at least 12 weeks after treatment. Data were prospectively collected on the use of comedications (including discontinuation, dose modification and addition of drugs) and potential DDIs with DAAs. RESULTS: Of the 356 patients with at least 12-week post-treatment follow-up (median age 67, range 50-88 years), 338 (95%) achieved sustained virological response. Of these, 219 (60%) had at least one comorbidity (median 2, range 1-6); information on comedication was available for 212 of them. Of 190 comedications used, 15 (8%) drugs were modified during ELB/GZR therapy, specifically in 9 (4%) patients they were interrupted, in 2 (1%) of whom, the comedication was interrupted before the DAA therapy because of potential DDI (that is, patients treated with carbamazepine); in 12 (6%) patients the comedications were modified in terms of dosage. In 29 (14%) patients, the comedications required monitoring when used with ELB/GZR, as well as with all available DAAs. Of the 190 drugs, 27 (14%) used in 67% of patients were free of DDIs when used with ELB/GZR, whereas they required monitoring if used with other DAA regimens. CONCLUSIONS: The results of this prospective study support findings that ELB/GZR is effective and safe in most treated patients.

Advanced liver disease outcomes after hepatitis C eradication by human immunodeficiency virus infection in PITER cohort.

BACKGROUND: Liver disease progression after Hepatitis C Virus (HCV) eradication following direct-acting antiviral (DAA) treatment in the real-life setting according to Human Immunodeficiency Virus (HIV) coinfection was evaluated. METHODS: Patients consecutively enrolled in PITER between April 2014 and June 2019 and with at least 12-weeks follow-up following treatment were analysed. Cox regression analysis were used to evaluate HIV coinfection and factors independently associated with liver disease outcomes following viral eradication in DAA treated patients with pre-treatment liver cirrhosis. RESULTS: 93 HIV/HCV coinfected and 1109 HCV monoinfected patients were evaluated during a median follow-up of 26.7 (range 6-44.6) and 24.6 (range 6.8-47.3) months, respectively. No difference in the cumulative HCC incidence and hepatic decompensation was observed between coinfected and monoinfected patients. Age (Hazard Ratio [HR] = 1.08; 95% CI 1.04-1.13), male sex (HR = 2.76; 95% CI 1.28-5.96), lower albumin levels (HR = 3.94; 95% CI 1.81-8.58), genotype 3 (HR = 5.05; 95% CI 1.75-14.57) and serum anti-HBc positivity (HR = 1.99, 95% CI 1.01-3.95) were independently associated with HCC incidence. Older age (HR = 1.03; 95% CI 1.00-1.07), male sex (HR = 2.13; 95% CI 1.06-4.26) and lower albumin levels (HR = 3.75; 95% CI 1.89-7.46) were independently associated with the appearance of a decompensating event after viral eradication. CONCLUSION: Different demographic, clinical and genotype distribution between HIV coinfected vs those monoinfected, was observed in a representative cohort of HCV infected patients in Italy. Once liver cirrhosis is established the disease progression is decreased, but still persists regardless of viral eradication in both coinfected and monoinfected patients. In patients with cirrhosis, HIV coinfection was not associated with a higher probability of liver complications, after viral eradication.

Outcome of cutaneous psoriasis in hepatitis C virus-infected patients treated with Direct-Acting Antiviral therapy.

Apart from chronic liver disease, hepatitis C virus (HCV) may be responsible for several extra-hepatic manifestations. Its involvement in psoriasis development is still controversial. The aim of this study was to evaluate the possible effect of anti-HCV direct-acting antiviral (DAA) treatment on cutaneous psoriasis. Thirty-seven consecutive HCV patients with cutaneous psoriasis underwent efficacious DAA treatment, and all of them were efficiently cured as shown by HCV RNA negativity 24 weeks after stopping therapy (PT24W). An expert dermatologist evaluated the skin lesions at baseline, end of treatment (EOT) and PT24W using the psoriasis area severity index (PASI) scoring system. The impact on quality of life was measured with the Dermatologic Quality of Life Index (DLQI). Six patients had a stable disease throughout the study period, whereas 31/37 patients (83.8%) showed a significant improvement of the skin lesions at EOT (P < .0001). However, 24 of these 31 patients (77.4%) had a dramatic worsening of the psoriatic lesions at PT24W compared with EOT (P < .001), with lesion severity comparable to baseline. The outcome of psoriasis during and after treatment was independent of baseline PASI score, age, sex, HCV genotype, liver disease stage and of the presence of arterial hypertension, diabetes and autoimmune diseases. In conclusion, DAA-based HCV cure has only a transient effect on skin lesions of patients with concomitant cutaneous psoriasis.

Erectile dysfunction in compensated liver cirrhosis.

BACKGROUND: Data on erectile dysfunction (ED) in cirrhotic patients are limited as yet. Aim of this study was to investigate the prevalence of ED and the factors potentially involved in its development in compensated cirrhosis. METHODS: We prospectively enrolled 102 male (mean age 63 ±â€¯10 years) affected by cirrhosis in Child-Pugh Class A. The following questionnaires were used: simplified International Index of Erectile Function (IIEF-5) Questionnaire, Centre of Epidemiologic Studies Depression Scale and ANDROTEST. RESULTS: ED was found in 57/102(55.9%) patients, and was mild, moderate and severe in 21(36.8%), 6(10.5%) and 30(52.6%) subjects, respectively. ED patients were significantly older than those without (66 ±â€¯10 vs 60 ±â€¯10,p = 0.006); ED prevalence gradually increased with age. There was no statistically significant difference between patients with and without ED concerning the coexistence of diabetes, hypertension, and cardiovascular disease. Age(p = 0.040) and serum haemoglobin(p = 0.027) were identified as predictors of ED on multivariate analysis. Liver-related factors and pharmacological treatment, including ß-blockers, were not associated with the presence of ED. CONCLUSIONS: In patients with compensated liver cirrhosis, even in concomitance with other chronic comorbidities, the prevalence of ED is not markedly different from the general population. Compensated cirrhosis per se is not a risk factor for ED occurrence. Older age and low haemoglobin values are significantly associated with ED in cirrhotics.

Predictors of Re-bleeding and Mortality Among Patients with Refractory Variceal Bleeding Undergoing Salvage Transjugular Intrahepatic Portosystemic Shunt (TIPS).

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) has proven clinical efficacy as rescue therapy for cirrhotic patients with acute portal hypertensive bleeding who fail endoscopic treatment. AIMS: To investigate predictive factors of 6-week and 1-year mortality in patients undergoing salvage TIPS for refractory portal hypertensive bleeding. METHODS: A total of 144 consecutive patients were retrospectively evaluated. Three logistic regression multivariate models were estimated to individualize prognostic factors for 6-week and 12-month mortality. Log-rank test was used to evaluate survival according to Child-Pugh classes and Bureau's criteria. RESULTS: Mean age 51 ± 10 years, 66% male, mean MELD 18.5 ± 8.3, Child-Pugh A/B/C 8%/38%/54%. TIPS failure occurred in 23(16%) patients and was associated with pre-TIPS portal pressure gradient and pre-TIPS intensive care unit stay. Six-week and 12-month mortality was 36% and 42%, respectively. Pre-TIPS intensive care unit stay, MELD, and Child-Pugh score were independently associated with mortality at 6 weeks. Independent predictors of mortality at 12 months were pre-TIPS intensive care unit stay and Child-Pugh score. CONCLUSIONS: In this large cohort of patients undergoing salvage TIPS, MELD and Child-Pugh scores were predictive of short- and long-term mortality, respectively. Pre-TIPS intensive care unit stay was independently associated with TIPS failure and mortality at 6 weeks and 12 months. Salvage TIPS is futile in patients with Child-Pugh score of 14-15.

NS3 Variability in Hepatitis C Virus Genotype 1A Isolates from Liver Tissue and Serum Samples of Treatment-Naïve Patients with Chronic Hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) NS3 resistance-associated substitutions (RASs) reduce HCV susceptibility to protease inhibitors. Little is known about NS3 RASs in viral isolates from the liver of chronic hepatitis C (CHC) patients infected with HCV genotype-1a (G1a). AIM: The objective of this work was to study NS3 variability in isolates from the serum and liver of HCV-G1a-infected patients naïve to direct-acting antivirals (DAAs). METHODS: NS3 variability of HCV-G1a isolates from the serum and liver of 11 naïve CHC patients, and from sera of an additional 20 naïve CHC patients, was investigated by next-generation sequencing. RESULTS: At a cutoff of 1%, NS3 RASs were detected in all the samples examined. At a cutoff of 15%, they were found in 54.5% (6/11) and 27.3% (3/11) of the paired liver and serum samples, respectively, and in 22.5% (7/31) of the overall serum samples examined. Twenty-six out of thirty-one (84%) patients showed NS3 variants with multiple RASs. Phylogenetic analysis showed that NS3 sequences clustered within 2 clades, with 10/31 (32.2%) patients infected by clade I, 15/31 (48.8%) by clade II, and 6/31 (19.3%) by both clades. CONCLUSIONS: Though the number of patients examined was limited, NS3 variants with RASs appear to be major components of both intrahepatic and circulating viral quasispecies populations in DAA-naïve patients.

Correction: Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study.

[This corrects the article DOI: 10.1371/journal.pone.0172159.].

Elective endoscopic variceal ligation is not a risk factor for bacterial infection in patients with liver cirrhosis.

BACKGROUND: Patients with cirrhosis are at high risk of bacterial infections. Invasive procedures are generally believed to increase this susceptibility. AIMS: We investigated the incidence of bacterial infections in cirrhotic patients undergoing elective endoscopic variceal ligation (EVL). METHODS: We enrolled 60 consecutive cirrhotic patients who underwent a total number of 112 elective EVL procedures. One to seven bands were applied at each session until variceal eradication. Markers of inflammation/infection and blood cultures were obtained before and 24 h after EVL. RESULTS: Aetiology of liver disease was metabolic in 27 (45%), viral in 21 (35%), alcoholic in 12 (20%) patients. Child-Pugh class A/B/C distribution was 29/26/5, respectively, 23 (38%) patients had ascites and 15 (25%) had hepatocellular carcinoma. Blood cultures were negative in all samples before EVL, whereas 3/112 (2.7%) cultures tested positive after endoscopy. Streptococcus mitis and Staphylococcus epidermidis were isolated in 1 and 2 cases, respectively. None of these three patients developed any features of clinically relevant infection, suggesting that the positive cultures were an expression of a transient bacteraemia with no clinical sequelae. CONCLUSIONS: Bacterial infection is an uncommon occurrence after elective EVL in cirrhotic patients, and antibiotic prophylaxis is not necessary in this clinical setting.

Hypergammaglobulinemia is a strong predictor of disease progression, hepatocellular carcinoma, and death in patients with compensated cirrhosis.

BACKGROUND & AIMS: The outcome of compensated cirrhosis may vary considerably and cannot be predicted by routinely performed tests at present. The aim of this study was to evaluate possible predictors of clinical evolution in patients with Child-Pugh (C-P) class A cirrhosis because of untreatable causes by analysing clinical/biochemical/instrumental parameters evaluated at the time of diagnosis and during the subsequent long-lasting follow-up. METHODS: Two hundred and seventy-two consecutive C-P class A cirrhotic patients (155 males; median age 63 years, range 34-81) were analysed. All patients were followed up for a median time of 96 months (range 21-144) through periodically performed clinical/biochemical/ultrasonographic and esophagogastroduodenoscopic examinations. RESULTS: During the follow-up, 97 individuals (36%) were clinically stable, 104 (38%) developed hepatocellular carcinoma (HCC) and 71 (26%) progressed towards C-P class B/C without developing cancer. One hundred and thirty-one patients (48%) died or underwent liver transplantation. Multivariate regression analysis showed that clinical stability was significantly associated with older age (P < .001), the absence of diabetes (P = .04) and of oesophageal varices (P < .001), serum albumin >3.5 gr/dL (P = .01) and gamma globulin <1.8 gr/dL (P = .01). HCC development was significantly associated with younger age (P = .01) and serum gamma globulin values ≥1.8 gr/dL (P < .001). C-P score progression was associated with oesophageal varices (P < .001), lower serum albumin (P = .03) and cholesterol (P = .01) values, and hypergammaglobulinemia (P = .02). Death was associated with younger age (P < .001) and hypergammaglobulinemia (P = .01). Multivariate Cox regression analysis and Kaplan-Meier's survival test confirmed that gammaglobulinemia ≥1.8 g/dL was a significant predictor of death (P < .02, and P < .01 respectively). CONCLUSIONS: Hypergammaglobulinemia identifies C-P class A cirrhotic patients at higher risk of disease progression, HCC development and death.

Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network.

BACKGROUND: Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure. AIM: To evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage. METHODS: Data on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers. RESULTS: Among 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvir±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs ±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5-14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3-12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and worsened in 2 (2.8%) patients. Of patients who were retreated, 3 (4%) had undergone OLT before retreatment (all reached SVR12 following retreatment) and 2 (2.8%) underwent OLT after having achieved retreatment SVR12. Two (70%) of the 3 patients who failed to achieve SVR12 after retreatment, and 2 (2.8%) of the 69 patients who achieved retreatment SVR12 died from liver failure (Child-Pugh class deteriorated from B to C) or HCC complications. CONCLUSIONS: Failure rate following the first DAA regimen in patients with advanced disease is similar to or lower than that reported in clinical trials, although the majority of patients were treated with suboptimal regimens. Interim findings showed that worsening of liver function after failure, in terms of Child Pugh class deterioration, was improved by successful retreatment in about one third of retreated patients within a short follow-up period; however, in some advanced liver disease patients, clinical outcomes (Child Pugh class, HCC development, liver failure and death) were independent of viral eradication.

Low prevalence of hepatitis B and hepatitis C virus serum markers in a cohort of pregnant women from Southern Italy.

BACKGROUND: Mother-to-child transmission is still considered a major factor in the spread of hepatitis viruses. Nevertheless, epidemiological data on hepatitis B virus (HBV) and hepatitis C virus (HCV) in reproductive-age women are limited even in areas like the South of Italy where both viruses had been widespread. AIM: The aim of this study was to investigate the prevalence of HBV and HCV serum markers in a large cohort of pregnant women from Southern Italy. METHODS: Data concerning 7558 pregnant women consecutively admitted to an Obstetric Division of a Sicilian University Hospital over a six-year period (January 2010-December 2015) were retrospectively collected from clinical notes. RESULTS: Positivity for both HBV s-antigen (HBsAg) and antibodies to HCV (anti- HCV) was very low (0.5% and 0.2%, respectively). HBsAg prevalence was significantly higher in non-Italian than in Italian women (p<0.001). On the contrary, all the anti-HCV positive cases were of Italian origin. Age was not significantly different between positive and negative women. CONCLUSION: These results confirm the dramatic decline of HBV and HCV prevalence that recently occurred in Southern Italy, and highlight the importance and cost-effectiveness of systematic HBV and HCV screening in childbearing age women in order to properly apply the available preventive measures and definitively eliminate the risk of vertical transmission for both viruses.

Real-life data on potential drug-drug interactions in patients with chronic hepatitis C viral infection undergoing antiviral therapy with interferon-free DAAs in the PITER Cohort Study.

BACKGROUND: There are few real-life data on the potential drug-drug interactions (DDIs) between anti-HCV direct-acting antivirals (DAAs) and the comedications used. AIM: To assess the potential DDIs of DAAs in HCV-infected outpatients, according to the severity of liver disease and comedication used in a prospective multicentric study. METHODS: Data from patients in 15 clinical centers who had started a DAA regimen and were receiving comedications during March 2015 to March 2016 were prospectively evaluated. The DDIs for each regimen and comedication were assigned according to HepC Drug Interactions (www.hep-druginteractions.org). RESULTS: Of the 449 patients evaluated, 86 had mild liver disease and 363 had moderate-to-severe disease. The use of a single comedication was more frequent among patients with mild liver disease (p = 0.03), whereas utilization of more than three drugs among those with moderate-to-severe disease (p = 0.05). Of the 142 comedications used in 86 patients with mild disease, 27 (20%) may require dose adjustment/closer monitoring, none was contraindicated. Of the 322 comedications used in 363 patients with moderate-to-severe liver disease, 82 (25%) were classified with potential DDIs that required only monitoring and dose adjustments; 10 (3%) were contraindicated in severe liver disease. In patients with mild liver disease 30% (26/86) used at least one drug with a potential DDI whereas of the 363 patients with moderate-to-severe liver disease, 161 (44%) were at risk for one or more DDI. CONCLUSIONS: Based on these results, we can estimate that 30-44% of patients undergoing DAA and taking comedications are at risk of a clinically significant DDI. This data indicates the need for increased awareness of potential DDI during DAA therapy, especially in patients with moderate-to-severe liver disease. For several drugs, the recommendation related to the DDI changes from "dose adjustment/closer monitoring", in mild to moderate liver disease, to "the use is contraindicated" in severe liver disease.