High rates of sustained virological response despite premature discontinuation of directly acting antivirals in HCV-infected patients treated in a real-life setting.

In routine clinical practice, hepatitis C virus-infected patients can prematurely discontinue the prescribed regimen for several reasons. The aim of our study was to investigate sustained virological response (SVR12) rates in patients who prematurely discontinued directly acting antiviral (DAA) regimens and to assess the shortest effective duration of DAA able to lead to SVR12. We retrospectively collected the SVR rates of patients, registered in the NAVIGATORE-Lombardia Network database from January 2015, who discontinued DAAs before the predefined end of treatment. Overall, we included 365 patients, males were the majority (213, 58.4%), mean age was 60.5 years, and 53 (14.5%) patients were HIV-co-infected. Liver cirrhosis was observed in 251 (68.8%) subjects, and the most represented genotypes were 1b (n = 168, 46%) and 3 (n = 59, 16.2%). DAA was discontinued a median of 1 (IQR 1-4) weeks before the predefined EOT, with 164 (44.9%) patients stopping DAAs at least 2 weeks before the planned schedule. In patients with F0-F3 liver fibrosis, lower rates of SVR12 were observed in patients treated for <4 weeks: 50% (n = 2/4) vs. 99.1% (n = 109/110) for ≥4 weeks, p = 0.003. In patients with liver cirrhosis, lower rates of SVR12 were observed in patients treated <8 weeks: 83.3% (n = 25/30) vs. 94.6% (n = 209/221) for ≥8 weeks, p = 0.038. Despite premature discontinuation of DAA, high SVR12 rates were observed in a real-life setting for treatment lasting at least 4 weeks in patients with liver fibrosis F0-F3 and 8 weeks in those with liver cirrhosis. On this basis, feasibility of reducing DAA treatment duration should be explored in randomized clinical trials.

Liver function following hepatitis C virus eradication by direct acting antivirals in patients with liver cirrhosis: data from the PITER cohort.

BACKGROUND: The development of direct-acting antivirals (DAA) for HCV has revolutionized the treatment of HCV, including its treatment in patients with HIV coinfection. The aim of this study was to compare the changes in liver function between coinfected and monoinfected patients with cirrhosis who achieved HCV eradication by DAA. METHODS: Patients with pre-treatment diagnosis of HCV liver cirrhosis, consecutively enrolled in the multicenter PITER cohort, who achieved a sustained virological response 12 weeks after treatment cessation (SVR12) were analysed. Changes in Child-Pugh (C-P) class and the occurrence of a decompensating event was prospectively evaluated after the end of DAA treatment. Cox regression analysis was used to evaluate factors independently associated with changes in liver function following viral eradication. RESULTS: We evaluated 1350 patients, of whom 1242 HCV monoinfected (median follow-up 24.7, range 6.8-47.5 months after viral eradication) and 108 (8%) HCV/HIV coinfected (median follow-up 27.1, range 6.0-44.6). After adjusting for age, sex, HCV-genotype, HBsAg positivity and alcohol use, HIV was independently associated with a more advanced liver disease before treatment (C-P class B/C vs A) (OR: 3.73, 95% CI:2.00-6.98). Following HCV eradication, C-P class improved in 17/20 (85%) coinfected patients (from B to A and from C to B) and in 53/82 (64.6%) monoinfected patients (from B to A) (p = 0.08). C-P class worsened in 3/56 coinfected (5.3%) (from A to B) and in 84/1024 (8.2%) monoinfected patients (p = 0.45) (from A to B or C and from B to C). Baseline factors independently associated with C-P class worsening were male sex (HR = 2.00; 95% CI = 1.18-3.36), platelet count < 100,000/µl (HR = 1.75; 95% CI 1.08-2.85) and increased INR (HR = 2.41; 95% CI 1.51-3.84). Following viral eradication, in 7 of 15 coinfected (46.6%) and in 61 of 133 (45.8%) monoinfected patients with previous history of decompensation, a new decompensating event occurred. A first decompensating event was recorded in 4 of 93 (4.3%) coinfected and in 53 of 1109 (4.8%) monoinfected patients (p = 0.83). CONCLUSIONS: Improvement of liver function was observed following HCV eradication in the majority of patients with cirrhosis; however viral eradication did not always mean cure of liver disease in both monoinfected and coinfected patients with advanced liver disease.

Comparison of three therapeutic regimens for genotype-3 hepatitis C virus infection in a large real-life multicentre cohort.

BACKGROUND & AIMS: In the direct-acting antiviral era, treatment of genotype-3 HCV (HCV-GT3) is still challenging. Real-life comparisons between recommended regimens, sofosbuvir (SOF)+daclatasvir (DAC), SOF/velpatasvir (VEL), glecaprevir/pibrentasvir (GLE/PIB), are scarce. We aimed at filling this data gap. METHODS: Sustained virological response 12 weeks after treatment completion (SVR12) was assessed for all HCV-GT3 patients consecutively treated within the Lombardia web-based Navigatore HCV-Network; differences in SVR12 across regimens were evaluated by logistic regression. RESULTS: Of the 2082 subjects with HCV-GT3, 1544 were evaluable for comparisons between regimens: SOF + DAC (1023, 66.2%), SOF/VEL (369, 23.9%), GLE/PIB (152, 9.8%). Patients treated with former regimens were more frequently male, cirrhotic, HIV-positive, pretreated, used ribavirin in their regimen, and had lower baseline HCV-RNA. SVR12 was similar across groups: 94.8% in SOF + DAC, 97.6% in SOF/VEL, 96.7% in GLE/PIB (P = .065). At univariate analysis, SVR12 was associated with female gender (97.9% vs 94.8%, P = .007) and lower median pretreatment Log10 HCV-RNA (5.87 vs 6.20, P = .001). At multivariate logistic regression analysis, treatment with SOF/VEL was associated with a higher likelihood of SVR12 than SOF + DAC, but only in the absence of ribavirin (98% vs 90.3%). Female gender and lower pretreatment HCV-RNA were independently associated with SVR12. CONCLUSIONS: In a large real-life setting of HCV-GT3-infected patients with a high proportion of cirrhosis, the success rate was remarkable. The slight advantage of SOF/VEL on SOF + DAC was significant only without ribavirin. The current prescription shift towards novel regimens (ie SOF/VEL and GLE/PIB) in easier-to-treat patients allows ribavirin-free and shorter schedules without mining SVR12 in this <> genotype.

Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure.

BACKGROUND & AIMS: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. METHODS: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. RESULTS: A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). CONCLUSIONS: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. LAY SUMMARY: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.

Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C.

BACKGROUND AND AIMS: The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting. METHODS: All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment. RESULTS: A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m2, and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x103/mm3 and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes. CONCLUSIONS: In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks. LAY SUMMARY: A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles.

Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real-Life Cohort Study.

The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real-life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE-Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow-up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2 , 1.03-1.09) and diabetes (OR 2.01 [1.65-2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35-0.60]; P < 0.0001 for all). The impact of BMI was greater in those without diabetes (P = 0.003). Diabetes was independently associated with less pronounced LSM improvement after viral eradication (P = 0.001) and in patients with advanced fibrosis was an independent predictor of the most frequent clinical events, namely de novo hepatocellular carcinoma (HCC; hazard ratio [HR] 2.09 [1.20-3.63]; P = 0.009) and cardiovascular events (HR 2.73 [1.16-6.43]; P = 0.021). Metformin showed a protective association against HCC (HR 0.32 [0.11-0.96]; P = 0.043), which was confirmed after adjustment for propensity score (P = 0.038). Diabetes diagnosis further refined HCC prediction in patients with compensated advanced chronic liver disease at high baseline risk (P = 0.024). Conclusion: Metabolic comorbidities were associated with advanced liver fibrosis at baseline, whereas statins were protective. In patients with advanced fibrosis, diabetes increased the risk of de novo HCC and of cardiovascular events. Optimization of metabolic comorbidities treatment by a multi-disciplinary management approach may improve cardiovascular and possibly liver-related outcomes.

Directly acting antivirals are safe and effective in HCV positive patients aged 80 years and older: a multicenter real-life study.

Background: Treatment of chronic Hepatitis C with directly acting antivirals (DAAs) can bring to sustained virologic response (SVR) in approximately 95% of patients. Efficacy and safety of DAAs in aging patients has not been widely analyzed. We aimed to determine safety and efficacy of DAA-based regimens in a cohort of elderly patients in a real-life setting.Research Design and Methods: We retrospectively investigated safety and efficacy of DAAs in HCV patients of 80 years or older treated in three Hepatology Units.Results and Expert opinion: During the study period, 170 patients older than 80 years received DAAs. Their mean age was 82,3 years. The predominant HCV genotype was 1 (100 patients, 59%). Among the 93 cirrhotic patients (54,7%), 18 had CPT score > A5. Different DAAs regimens were used. Concomitant drugs were common: 163 patients (95,8%) taking at least one drug. In 11 patients, usual therapy had to be changed to start antiviral treatment. Two serious adverse events occurred. Four patients terminated treatment prematurely. In total, 45 patients (26,5%) testified mild side effects. HCV-RNA undetectability at week 12 of treatment follow-up was achieved in 168/170 patients. DAA treatment in HCV patients of 80 years or older is efficacious and safe. Drug-drug interaction should be judiciously evaluated before starting therapy.

SARS-CoV-2-related ARDS in a maintenance hemodialysis patient: case report on tailored approach by daily hemodialysis, noninvasive ventilation, tocilizumab, anxiolytics, and point-of-care ultrasound.

Without rescue drugs approved, holistic approach by daily hemodialysis, noninvasive ventilation, anti-inflammatory medications, fluid assessment by bedside ultrasound, and anxiolytics improved outcomes of a maintenance hemodialysis patient affected by severe COVID-19.

Clinical features and comorbidity pattern of HCV infected migrants compared to native patients in care in Italy: A real-life evaluation of the PITER cohort.

BACKGROUND: Direct-acting antivirals are highly effective for the treatment of hepatitis C virus (HCV) infection, regardless race/ethnicity. We aimed to evaluate demographic, virological and clinical data of HCV-infected migrants vs. natives consecutively enrolled in the PITER cohort. METHODS: Migrants were defined by country of birth and nationality that was different from Italy. Mann-Whitney U test, Chi-squared test and multiple logistic regression were used. RESULTS: Of 10,669 enrolled patients, 301 (2.8%) were migrants: median age 47 vs. 62 years, (p < 0.001), females 56.5% vs. 45.3%, (p < 0.001), HBsAg positivity 3.8% vs. 1.4%, (p < 0.05). Genotype 1b was prevalent in both groups, whereas genotype 4 was more prevalent in migrants (p < 0.05). Liver disease severity and sustained virologic response (SVR) were similar. A higher prevalence of comorbidities was reported for natives compared to migrants (p < 0.05). Liver disease progression cofactors (HBsAg, HIV coinfection, alcohol abuse, potential metabolic syndrome) were present in 39.1% and 47.1% (p > 0.05) of migrants and natives who eradicated HCV, respectively. CONCLUSION: Compared to natives, HCV-infected migrants in care have different demographics, HCV genotypes, viral coinfections and comorbidities and similar disease severity, SVR and cofactors for disease progression after HCV eradication. A periodic clinical assessment after HCV eradication in Italians and migrants with cofactors for disease progression is warranted.

Effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients: Results of the Italian cohort of a post-marketing observational study.

BACKGROUND AND AIMS: The MARS post-marketing, observational study evaluates glecaprevir/pibrentasvir in a large population of Italian patients who are infected with HCV. PATIENTS AND METHODS: Achievement of SVR12 was the primary endpoint in the overall population and by subpopulations of interest (treatment-naïve and treatment-experienced patients, subjects infected with different HCV genotype/sub-genotype, cirrhotic and non-cirrhotic patients, patients with different severity of fibrosis, patients with an APRI score ≥1, subjects with comorbidities, HIV-coinfected patients, elderly patients and people who use drugs). Safety and quality of life (assessed by SF-36 and Work Productivity and Activity Impairment) were also evaluated. RESULTS: The SVR12 rate was 99.4% (319/321; 95% CI: 97.8-99.8%) in the core population with sufficient follow-up (n = 321), 99.7% (289/290) in 8-week treated patients, and high (>96%) across subgroups. Only three patients (0.9%) had treatment-related adverse events that led to treatment discontinuation. In total, 30.1% of patients showed an improvement of ≥2.5 points in the Physical Component Summary of the SF-36 from baseline to the end of treatment, and this figure raised to 37.5% with the achievement of SVR12. Corresponding values for MCS were 42.2% and 42.8%, respectively. CONCLUSION: Glecaprevir/pibrentasvir is safe and effective across subpopulations who are underserved in clinical trials.

Liver alterations in anorexia nervosa are not caused by insulin resistance.

BACKGROUND: Liver dysfunction has been widely reported in connection with anorexia nervosa (AN) but the pathogenesis of these alterations has never been fully understood despite reported theories about the presence of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). The aim of this study is to investigate if hypertransaminasemia in AN is linked to IR and NAFLD. METHODS: Anthropometric data and laboratory exams of 34 patients and 34 controls were analyzed, including alanine-aminotransferase, aspartate-aminotransferase and homeostatic model assessment of insulin resistance (HOMA-IR) index. All subjects also underwent magnetic resonance imaging (MRI), ultrasonography (US), and transient elastography (TE). RESULTS: Evidence of increased alanine aminotransferase in AN patients was confirmed in our sample together with a lower HOMA-IR index compared to controls. Positive results in US appeared in 16 patients vs none in controls (p = 0.0007); patients with liver parenchyma abnormalities in US were not different than normal-US patients in any of the studied variables. Only one patient showed non-alcoholic fatty liver disease in MRI while abnormal TE was found in four patients and never in controls. CONCLUSIONS: Liver damage suggested by increased serum liver enzymes cannot be due to liver steatosis but potentially to a different liver disease (not identified by MRI) or to an early liver fibrosis not associated with an insulin-resistant status.

Renal safety in 3264 HCV patients treated with DAA-based regimens: Results from a large Italian real-life study.

BACKGROUND: Sofosbuvir (SOF)-based regimens have been associated with renal function worsening in HCV patients with estimated glomerular filtration rate (eGFR) ≤ 45 ml/min, but further investigations are lacking. AIM: To assess renal safety in a large cohort of DAA-treated HCV patients with any chronic kidney disease (CKD). METHODS: All HCV patients treated with DAA in Lombardy (December 2014-November 2017) with available kidney function tests during and off-treatment were included. RESULTS: Among 3264 patients [65% males, 67% cirrhotics, eGFR 88 (9-264) ml/min], CKD stage was 3 in 9.5% and 4/5 in 0.7%. 79% and 73% patients received SOF and RBV, respectively. During DAA, eGFR declined in CKD-1 (p < 0.0001) and CKD-2 (p = 0.0002) patients, with corresponding rates of CKD stage reduction of 25% and 8%. Conversely, eGFR improved in lower CKD stages (p < 0.0001 in CKD-3a, p = 0.0007 in CKD-3b, p = 0.024 in CKD-4/5), with 33-45% rates of CKD improvement. Changes in eGFR and CKD distribution persisted at SVR. Baseline independent predictors of CKD worsening at EOT and SVR were age (p < 0.0001), higher baseline CKD stages (p < 0.0001) and AH (p = 0.010 and p < 0.0001, respectively). CONCLUSIONS: During DAA, eGFR significantly declined in patients with preserved renal function and improved in those with lower CKD stages, without reverting upon drug discontinuation.

Effectiveness and safety of simeprevir-based regimens for hepatitis C in Italy: The STIly observational study.

The combination of the direct-acting antivirals, simeprevir (SMV) and sofosbuvir (SOF), was the first highly efficacious interferon-free combination for treating patients with hepatitis C virus (HCV), and was widely used in Italy as a result.The aim of this study was to evaluate effectiveness and safety of SMV in Italian patients with HCV genotype (GT) 1 and 4 overall, by treatment regimen [SMV/SOF and SMV/SOF+ribavirin (RBV)], cirrhosis status, and GT (GT1a, GT1b, and GT4).An observational multicenter cohort study was conducted in 46 centers across Italy. Adult HCV + GT1 or GT4 patients, naive or treatment-experienced, with or without cirrhosis, who underwent treatment with a SMV-containing regimen from May to September 2015 were included. The primary endpoint was sustained virologic response (SVR), defined as undetectable serum HCV RNA levels 12 weeks after treatment end (SVR12). The secondary endpoints included duration of treatment, safety and tolerability of each treatment regimen, and SVR by treatment and according to response to previous treatment and fibrosis stage. The association between SVR and a subset of the most clinically relevant variables was investigated by a multivariate logistic regression analysis.A total of 349 HCV-positive patients treated with an SMV-based regimen were enrolled, of whom 342 received SMV/SOF ±â€ŠRBV and were included in this analysis. Most patients (59.4%) were treatment-experienced and had cirrhosis (78.1%). In the group receiving SMV/SOF + RBV, most (63.1%) were treatment-experienced and 82.9% had cirrhosis. Three patients were lost to follow-up; 330 patients receiving SMV/SOF ±â€ŠRBV (96.5%) were treated for 12 weeks. Overall, SVR12 was achieved by 324 patients [94.2%, 95% confidence interval (95% CI) 92-97]. When stratified by treatment and clinical and virologic characteristics, SVR12 was achieved by 77 of 79 [97.5% (95% CI 94.0-100.0)] and 247 of 263 [93.9% (95% CI 91.0-96.8)] patients receiving SMV/SOF and SMV/SOF + RBV, respectively; 132 of 139 (95.0%) naive versus 192/203 (94.6%) treatment-experienced patients; 250 of 267 (93.6%) cirrhotic and 56 of 62 (90.3%) HIV coinfected patients. SMV-based regimens were generally well tolerated. Adverse events leading to treatment discontinuations were not observed.A high proportion of patients treated with SMV/SOF-based regimens achieved SVR12 in this study. A high SVR12 rate was also achieved in patients with cirrhosis, treatment experience, and HUV coinfected patients.

Helicobacter pylori infection in hepatic encephalopathy: Relationship to plasma endotoxins and blood ammonia.

BACKGROUND/AIM: Hepatic encephalopathy (HE) is frequently observed in patients with advanced liver disease and manifests a wide variety of neuropsychiatric signs and symptoms. Ammonia toxicity and bacterial endotoxins have been suggested as key determinants of HE onset whereas a role for Helicobacter pylori infection has not been established. We investigated the correlation between H. pylori infection and HE severity (evaluated through functional tests) in 60 outpatients with established liver cirrhosis and 20 non-cirrhotic controls. METHODS: Fasting arterial blood ammonia, plasma endotoxins, and H. pylori infection status were investigated in all subjects. RESULTS: H. pylori infection was documented in 35/60 (58%) patients and in 6/20 (30%) controls (P = 0.039). Significant differences were observed between patients with and withoutHE for age, presence of ascites, fasting arterial blood ammonia, plasma endotoxin, and H. pylori infection. Further, a significant increase in fasting arterial blood ammonia and plasma endotoxin was associated with H. pylori infection in cirrhotic patients. Last, medical treatment of H. pylori infection led to a significant decrease in HE severity and fasting arterial blood ammonia levels. CONCLUSION: In conclusion, we submit that H. pylori infection might, in fact, play a role in increasing the circulating levels of ammonia and endotoxins in cirrhotic patients, thus facilitating the onset of HE.

Primary biliary cirrhosis: solving the enigma.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease, most commonly affecting female patients between 40 and 60 years of age. Patient sera present autoantibodies against mitochondrial antigens (AMA) and elevated serum IgM. Histologic studies demonstrate progressive destruction of small- and medium-sized intrahepatic bile ducts and, ultimately, liver cirrhosis. The precise mechanisms leading to selective destruction of such biliary epithelial cells are still unknown, although a number of immunomediated pathways have been proposed. Genetic background is critical in determining susceptibility to the disease, although no clear association with haplotypes of the major histocompatibility complex has been identified. Molecular mimicry by either infectious agents or xenobiotics has been proposed as a means of breaking tolerance in genetically predisposed individuals, thus leading to the onset of PBC. In this review, available data and current theories regarding the immunomediated pathogenesis of PBC will be described.

Treatment with PEG-interferon and ribavirin for chronic hepatitis C increases neutrophil and monocyte chemotaxis.

The incidence of infections increases during treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV) for chronic hepatitis C (CHC). Despite a reduction in neutrophil count, there is no clear relationship between infection occurrence and neutropenia. In the present study we investigated whether HCV treatment alters leukocyte function. We studied cell chemotaxis, reactive oxygen species, neutrophil phagocytosis, CR3 expression, and plasma colony stimulating factors (CSF) in 20 healthy subjects and 20 patients with CHC (10 with cirrhosis) at baseline, during antiviral treatment (at 4, 12, 24 weeks), and 12 weeks after discontinuation. Our results demonstrate that neutrophil chemotaxis and oxidative burst significantly increased during treatment and returned to baseline at the end of therapy. CR3 neutrophil expression was enhanced in baseline CHC compared to controls but did not change during antiviral treatment. Chemotaxis, oxidative burst, phagocytosis, and CSF levels did not differ significantly between patients before treatment and control subjects or among CHC cases according to the presence of cirrhosis in either cell subpopulation. In conclusion, the innate immune cell activity is enhanced in patients with CHC during antiviral treatment and returns to normal after its discontinuation thus possibly playing a role in their susceptibility to infections.