Factors Enhancing Treatment of Hepatitis C Virus-Infected Italian People Who Use Drugs: The CLEO-GRECAS Experience.

INTRODUCTION: We assessed the performance of direct-acting antivirals (DAAs) in hepatitis C virus (HCV)-infected people who use drugs (PWUDs) in terms of sustained virological response (SVR) and adherence rates in comparison to a location-matched cohort of non-PWUD HCV patients. METHODS: All consecutive HCV RNA-positive PWUDs were enrolled between 2015 and 2019. All subjects underwent DAA treatment according to international guidelines and then followed, at least, up to 12 weeks after the end of treatment (SVR12). The SVR and adherence to treatment was compared with that of non-PWUD HCV patients observed at hepatological units of the CLEO platform. Intention-to-treat analysis was performed. RESULTS: A total of 1,786 PWUDs who were followed up were available for assessment. Most PWUDs (85.4%) were managed inside the specialized outpatient addiction clinics (SerDs). The overall SVR rate was 95.4%. The SerDs group achieved an SVR rate of 96.2% compared with 91.6% of the non-SerDs group (P < 0.001). Comparison with the non-SerDs group and the control HCV group showed a significant difference in the dropout rate (0.6% in the SerDs group versus 2.8% in the non-SerDs group and 1.2% in the control group; P < 0.001). At multivariate analysis, factors independently associated with SVR were use of the most recent regimens (elbasvir/grazoprevir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir; odds ratio: 3.126; P = 0.000) and belonging to the SerDs group (odds ratio: 2.356; P = 0.002). DISCUSSION: The performance of DAAs in PWUD is excellent, if 2 conditions are met: (i) that the latest generation drugs are used and (ii) that the patients are managed within the SerDs.

Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial.

BACKGROUND: Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue. METHODS: We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008-000625-19, and ClinicalTrials.gov, number NCT01288794. FINDINGS: From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40-0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3-4 non-liver related adverse events. INTERPRETATION: In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis. FUNDING: Italian Medicine Agency.

Treatment of hepatitis C virus carriers with persistently normal alanine aminotransferase levels with peginterferon alpha-2a and ribavirin: a multicentric study.

BACKGROUND/AIMS: To evaluate, in clinical practice, the efficacy and safety of combined antiviral treatment in hepatitis C virus (HCV) carriers with normal alanine aminotransferase (ALT) levels. METHODS: Eighty-eight HCV carriers with persistently normal ALT levels were enrolled. All patients received peginterferon (PEG-IFN) alpha-2a 180 microg once weekly plus ribavirin (RBV) 800 mg/day for 24 weeks (HCV-2 and -3) or 1000-1200 mg/day for 48 weeks (HCV-1). RESULTS: Rapid virological response (RVR) was seen in 66/88 patients (75%): 19/32 HCV-1 (59%), 40/46 HCV-2 (87%) and 7/10 HCV-3 patients. Younger patients, leaner subjects and patients with non-1 genotype or lower baseline HCV RNA levels were more likely to achieve an RVR. Sustained virological response (SVR) was seen in 69/88 patients (78%): 20/32 HCV-1 patients (62%), 41/46 HCV-2 patients (89%) and 8/10 (80%) HCV-3 patients. The overall SVR rate was 88% in patients with RVR (58/66) and 50% in those without RVR. CONCLUSIONS: The combination of PEG-IFN alpha-2a and RBV produces, in patients with normal ALT, virological response rates that are comparable or even higher than those obtained in patients with elevated ALT levels. Thus, we suggest that in selected cases immediate therapy might be preferred to a 'wait-and-see' policy.

Quantitation of tissue polypeptide antigen (TPA) in hepatic and systemic circulation in patients with chronic liver diseases.

BACKGROUND AND AIM: Abnormal serum tissue polypeptide antigen (TPA) values are commonly found in patients with chronic liver damage and liver cirrhosis even in the absence of malignancies. The aim of this study was to compare serum TPA levels in patients with cirrhosis, to examine correlations between TPA levels and the degree of portal hypertension, and to evaluate TPA concentrations in paired hepatic and peripheral blood samples. METHODS: A total of 128 patients with chronic liver disease of various severity were studied prospectively. TPA concentrations in hepatic vein and peripheral blood were determined, and Hepatic Vein Pressure Gradient (HVPG) was measured. RESULTS: TPA levels were significantly higher in patients with cirrhosis than in those with chronic hepatitis, and in systemic circulation than in hepatic vein blood. Peripheral but not hepatic TPA levels did correlate with the HVPG. Subjects with clinically significant portal hypertension (HVPG > 10 mmHg) showed significantly higher peripheral TPA levels than those with HVPG < 10 mmHg. CONCLUSIONS: Our data suggest that the increased TPA levels observed in cirrhotic patients and the high systemic-to-hepatic blood TPA gradient are probably due to the presence of portal-systemic shunts rather than to hepatic necro-inflammatory activity. In clinical practice, TPA determination could help us to identify and to follow up cirrhotic patients with more severe portal hypertension.

Antiviral treatment of HCV carriers with persistently normal ALT levels.

Approximately 30% of patients with chronic HCV infection show persistently normal alanine aminotransferase levels (PNAL). The prevalence of HCV carriers with normal liver seems to be very low (less than 15-20%). Liver disease is usually minimal/mild and fibrosis is generally absent or minimal, although the association of normal alanine aminotransferase (ALT) with cirrhosis or with liver cancer has been reported. In all studies, liver histology was, on average, significantly less severe in subjects with PNAL than with abnormal ALT. Although the majority of data seem to show that HCV carriers with normal ALT have mild and stable disease, with a favourable prognosis, several studies reported a significant progression of fibrosis in approximately 20-30% of the patients with ALT normality, and the development of HCC in some cases has been described, despite persistent ALT normality. Sudden worsening of disease with ALT increase and histological deterioration has been described after up to 15 years of follow-up, in particular in patients harboring genotype 2. As to antiviral treatment, it has been clearly stated that it no longer seems reasonable to affirm that sustained response rates for patients with normal ALT levels are any different than those for patients with elevated ALT levels when the combination of pegylated interferon (IFN) and ribavirin is used. The issue at hand is whether or not patients with mild disease should be treated. There are numerous other factors which impact on this decision, including genotype, histology, patients motivation, symptoms, co-morbid illness, and the age of the patient.

Surveillance of patients with chronic hepatitis C not on antiviral therapy: a practical approach.

Surveillance of patients with HCV-related chronic liver disease (CHC) not on antiviral therapy is mandatory, because of the risk of worsening of the disease and progression to cirrhosis and its lethal complications. Unfortunately, data from the literature are scarce, and sometimes there are differences among experts and discrepancies between recommendations. Furthermore, the wide range of diagnostic tests and the continuous development of new diagnostic tools not rarely results in expensive, redundant and not justified surveillance programs. The identification of the optimal frequency of follow-ups constitutes another source of difficulties for the physicians. The purpose of this article is to provide practicing physicians with published criteria for performing a cost-effective and adequate surveillance program for patients with CHC not on antiviral treatment. On the basis of randomized controlled trials (RCTs), metanalysis, and international guide-lines and Consensus Conference statements we have attempted to outline a cost-effective surveillance program for HCV carriers with normal aminotransferases (ALT), for responders to previous interferon (IFN) treatment and for patients with CHC non-eligible for antiviral therapy. This surveillance strategy relies upon the judicious use of un-expensive and widely available tests.

HCV carriers with normal alanine aminotransferase levels: healthy persons or severely ill patients? Dealing with an everyday clinical problem.

Approximately 30% of patients with chronic HCV infection show persistently normal ALT levels. Although formerly referred to as 'healthy' or 'asymptomatic' HCV carriers, and thus historically excluded from antiviral treatment, it has now become clear that the majority of these patients have some degree of histological liver damage that may be significant in up to 20% of patients and might progress toward a more severe degree of liver fibrosis. A significant proportion of patients (> or =20%) experience periods of increased serum ALT (flare) associated with enhanced disease progression. However, controversies still exist in clinical practice regarding the definition of 'persistent' ALT normality, the virological and histological features of these subjects, the need for liver biopsy, the role of non invasive tools for the assessment of liver fibrosis (transient hepatic elastography, fibroscan), and the natural history and optimal management of chronic hepatitis C with normal ALT. The advent of new therapeutic options (pegylated interferons plus ribavirin) has shifted treatment targets toward eradication of underlying infection, with therapy decision based on age, severity of disease and likelihood of response rather than on aminotransferase levels. This review does approach the main unresolved issues on this topic in the form of a dialog between a hepatologist and a patient with HCV infection but normal alanine aminotransferase levels, trying to give evidence-based answers to the more frequently asked questions from patients and their physicians.

Extrahepatic manifestations of chronic HCV infection.

Several extrahepatic manifestations have been reported in the natural history of hepatitis C virus infection (HCV). Up to 40-74% of patients infected with HCV might develop at least one extrahepatic manifestation during the course of their disease. Mixed Cryoglobulinemia (MC) is the most known and studied syndrome associated with HCV infection. It is a systemic vasculitis that may involve the skin, kidney and nervous system. A frequent reported association is that between HCV infection and non-Hodgkin lymphoma. The cryoglobulinemia may be the intermediary disorder, in fact some persistent forms of cyoglobulinemia can switch over to a more aggressive haematologic disorder. As compared to cutaneous vasculitis described in MC, HCV infection has been associated with dermatological disorders such as porphyria cutanea tarda and lichen planus. Thyroid disease (usually hypothyroidism) is commonly seen in people with HCV. Up to 25% have thyroid antibodies. Several studies described a correlation between HCV and lympho-cytic sialoadenitis, similar to sialoadenitis associated with idiopathic Sjögren syndrome, but we can define as "pseudo- Sjögren syndrome" the one associated with HCV infection, because it shows several differences in the idiopathic form. In the course of chronic HCV infection, a common obser-vation are rheumatological symptoms such as polyarthritis. The clinical pattern of joint involvement in the course of HCV infection varies from a rheumatoid arthritis-like form (very rare), to a non erosive oligoarthritis involving the large-sized and middle joints.

Hepatic venous pressure gradient does not correlate with the presence and the severity of portal hypertensive gastropathy in patients with liver cirrhosis.

BACKGROUND AND AIMS: To evaluate whether the hepatic venous pressure gradient (HVPG) differs between cirrhotic patients with severe portal hypertensive gastropathy (PHG) and those with mild or absent PHG. METHODS: 59 cirrhotic patients with portal hypertension underwent hepatic vein catheterisation. 44 patients (76%) had PHG (16 mild and 28 severe). SETTING: tertiary care setting (Liver Unit, Internal Medicine). RESULTS: HVPG values did not differ between the patients without PHG (21.6 +/- 10.1 mmHg) and those with PHG (18.6 +/- 9.1 mmHg), nor between those with mild (19.3 +/- 4.3 mmHg) or severe PHG (17.7 +/- 4.6 mmHg; p = 0.26). The overall prevalence of PHG and the proportion of patients with severe PHG did not differ regarding the Child Pugh classification. The etiology of the cirrhosis did not influence the HVPG. No correlations were found between HVPG values and Child Pugh score, age, platelet count, prothrombin time, bilirubin levels and ALT values. The HVPG did not differ between patients with small, medium or large esophageal varices, nor between subjects with or without gastric varices. CONCLUSIONS: Our data show that PHG does not correlate with the degree of portal pressure, and that the prevalence and the severity of this condition are not influenced by the severity of underlying liver disease or by the size of varices.