Sergio Neri

Hepatitis C infection, antiviral treatment and mental health: A European expert consensus statement

Mental health problems frequently occur in chronic infection with the hepatitis C virus (HCV) and during antiviral treatment with pegylated interferon-alpha (PegIFNα) and ribavirin. Depression is one of the most important complications during antiviral treatment of chronic hepatitis C infection. However, an increased prevalence of depression, fatigue, and cognitive disturbances has also been reported in untreated HCV-positive patients. Patients with psychiatric disorders or drug addiction also have an increased risk of HCV infection. Furthermore, because of possible drug-drug interactions, new antivirals administered together with PegIFNα and ribavirin may complicate psychiatric side effect management, even if no specific psychiatric adverse events are known so far for these new drugs. The European liver patients organization (ELPA) organised a European expert conference to review the literature and develop expert recommendations for the management of mental health problems in HCV infected patients. This paper results from the output of the 2011 EASL meeting and subsequent dialogue with patient groups and relevant experts in Europe. It summarises the current knowledge of HCV infection and the brain; prevalence, course, and neurobiology of IFN-α associated psychiatric side effects; possible risk factors for IFN-α associated depression and suicide attempts; psychiatric management of HCV infected patients before and during antiviral treatment; prevention of IFN- α associated psychiatric side effects; and psychiatric aspects of the new antivirals. The summarised current knowledge about mental health changes before and during antiviral treatment should improve interdisciplinary management of HCV infected patients.

Meeting ReportHepatitis C infection, antiviral treatment and mental health: A European expert consensus statement

Mental health problems frequently occur in chronic infection with the hepatitis C virus (HCV) and during antiviral treatment with pegylated interferon-alpha (PegIFNα) and ribavirin. Depression is one of the most important complications during antiviral treatment of chronic hepatitis C infection. However, an increased prevalence of depression, fatigue, and cognitive disturbances has also been reported in untreated HCV-positive patients. Patients with psychiatric disorders or drug addiction also have an increased risk of HCV infection. Furthermore, because of possible drug-drug interactions, new antivirals administered together with PegIFNα and ribavirin may complicate psychiatric side effect management, even if no specific psychiatric adverse events are known so far for these new drugs. The European liver patients organization (ELPA) organised a European expert conference to review the literature and develop expert recommendations for the management of mental health problems in HCV infected patients. This paper results from the output of the 2011 EASL meeting and subsequent dialogue with patient groups and relevant experts in Europe. It summarises the current knowledge of HCV infection and the brain; prevalence, course, and neurobiology of IFN-α associated psychiatric side effects; possible risk factors for IFN-α associated depression and suicide attempts; psychiatric management of HCV infected patients before and during antiviral treatment; prevention of IFN- α associated psychiatric side effects; and psychiatric aspects of the new antivirals. The summarised current knowledge about mental health changes before and during antiviral treatment should improve interdisciplinary management of HCV infected patients.

Ultrasound imaging in diagnosis of superior mesenteric artery syndrome

Objectives.  We screened a cohort of subjects affected by various degree of dyspepsia to reveal if they presented a reduction of the aorto‐mesenteric angle and to diagnose suspected cases of superior mesenteric artery (SMA) syndrome.

Controlled clinical trial to assess the response of recent heroin abusers with Chronic hepatitis C virus infection to treatment with interferon alpha-n2b

BACKGROUND Chronic infection with hepatitis C virus (HCV) is the most common infectious disease among heroin abusers, but it is recommended that specific treatment with interferon be delayed until at least 6 to 12 months after the end of drug addiction. OBJECTIVE We investigated the response of heroin abusers to interferon treatment shortly after the end of detoxification treatment with methadone. METHODS We studied 2 homogeneous groups of white Italian patients with chronic HCV infection: former male heroin abusers and males without a history of drug addiction. Tumor necrosis factor, interleukin-1beta, interleukin-2, activated monocytes, anti-HCV antibodies, HCV RNA, and alanine aminotransferase levels were assessed. Standard treatment was initiated with 5 MU interferon alpha-n2b administered subcutaneously once daily for 8 weeks. Patients with negative HCV-RNA findings at the end of 8 weeks received further treatment with 5 MU TIW subcutaneously for an additional 48 weeks. RESULTS Thirty of 47 patients in group A (former heroin abusers) and 30 of 30 patients in group B (controls) completed the study. Heroin abusers presented a significantly enhanced response to treatment compared with the controls. After 8 weeks, HCV-RNA test results were negative in 27 of 30 patients in group A (90.0%) and in 25 of 30 in group B (83.3%) (P = NS). Onset of relapse occurred significantly later in heroin abusers (mean [SD], 53 [3] weeks) than in controls (26 [2] weeks) (P < 0.05). Cytokine levels and activated CD11 antigen-expressing monocytes were significantly (P < 0.001) higher in heroin abusers than controls. CONCLUSION Heroin abusers with chronic HCV infection were successfully treated with interferon alpha-n2b soon after the end of detoxification treatment.

Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor

BACKGROUND Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS We conducted an international, prospective, multicenter, randomized, double‐blind, placebo‐controlled, dose‐ranging, phase 3 trial to evaluate the efficacy and safety of self‐administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2‐month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16‐week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, –2.42 attacks per month; 95% confidence interval [CI], –3.38 to –1.46; and mean difference with 60 IU, –3.51 attacks per month; 95% CI, –4.21 to –2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40‐IU group and 90% (95% CI, 77 to 96) in the 60‐IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40‐IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60‐IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013‐000916‐10, and ClinicalTrials.gov number, NCT01912456.)

Duration of menopause and behavior of malondialdehyde, lipids, lipoproteins and carotid wall artery intima-media thickness

AIM our study assessed whether minor or major hormonal deficiency influenced oxidative status and vascular wall structure in menopausal women. METHODS the study series was made up of 62 non hypertensive non diabetic menopausal women (mean age 52.3+/-4.7 years) divided into two groups depending on duration of menopause (group 1 duration 0-5 years; group 2 duration over 5 years). Total cholesterol (TC), LDL cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides (TG), malondialdehyde (MDA) and common carotid artery wall intima-media thickness (IMT) were determined in the entire series. RESULTS mean TC, LDL-C, TG, MDA and IMT values were higher in group 2 than group 1. The intergroup difference between MDA (P<0.007) and IMT values (P<0.006) values was statistically significant. CONCLUSIONS the study revealed a close temporal correlation between plasma oxidative stress and carotid wall IMT, jeopardizes vascular wall status as menopause proceeds.

Current Status of Implementation of Self-Administration Training in Various Regions of Europe, Canada and the USA in the Management of Hereditary Angioedema

Results from a 16-question survey about self-administration of hereditary angioedema (HAE) therapy, administered in Europe, Canada and the USA, were used to guide discussion at an international HAE expert meeting. The aim was to capture information about current practice in self-administered HAE therapy in these countries, including self-administration training, the key benefits of switching to self-administration, the barriers to self-administration and trends in self-administration. Overall, switching to self-administration therapy is looked upon favourably from both patient and clinician perspectives by virtue of the potential improvement in quality of life arising from optimisation of therapy and early intervention. The recent changes to product licences allowing self-administration provide additional options for the management of HAE.

Psychiatric Symptoms Induced by Antiviral Therapy in Chronic Hepatitis C

AbstractBackground and objective: Interferon-α treatment is associated with a large number of adverse effects. Depressive symptoms are not unexpected, and potentially dangerous psychiatric adverse effects can induce life-threatening conditions. We compared the incidence of depressive symptoms in patients with chronic hepatitis C during treatment with pegylated interferon-α-2a (IFNα-2a) and pegylated interferon-α-2b (IFNα-2b). Patients and design: We randomly divided 186 subjects with chronic hepatitis C into two treatment groups: group A, treated with IFNα-2a, and group B, treated with IFNα-2b. Treatment was continued for up to 48 weeks. Liver biopsy and hepatitis C virus RNA assay were carried out in all patients. Depressive symptoms and the prevalence of psychiatric adverse effects during treatment with IFN were evaluated using the Hamilton Depression Rating Scale, the Zung Self-Rating Depression Scale, and the Structured Clinical Interview for Diagnostic and Statistic Manual-IV axis disorders. Results: At baseline 53% of subjects in group A and 57% of subjects in group B presented with depressive symptoms; at 12 weeks we found a high incidence of depressive symptoms in both groups (group A 61% and group B 65%) and three cases of life-threatening psychiatric symptoms (i.e. psychosis and delirium requiring discontinuation of antiviral therapy and admission to a psychiatric unit) in group A. Conclusions: Long-term administration of IFN can be associated with serious psychiatric adverse effects. It is very important that psychiatric symptoms are diagnosed early in IFN treatment so to improve treatment compliance and prevent fatal and/or life-threatening adverse events, as were documented in some subjects treated with IFNα-2a in our study.

L-Carnitine Decreases Severity and Type of Fatigue Induced by Interferon-α in the Treatment of Patients with Hepatitis C

Background: Hepatitis C virus (HCV) is one of the major agents of chronic hepatitis and liver disease worldwide. Infection with HCV leads to chronic hepatitis in about 80% of the cases. The most used treatment is based on interferon (IFN)-α, which is effective in less than 50% of patients; however, a high proportion of responders may relapse after interferon withdrawal. Fatigue is a common complaint in patients with liver disease. The aim of our study was to evaluate the efficacy of carnitine on IFN-induced fatigue in subjects with chronic hepatitis C. Patients and Methods: We studied 50 patients (30 males and 20 females) with chronic hepatitis C. Chronic hepatitis was diagnosed by determination of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (at least 2-fold upper normal values for 1 year). Our study series was divided into two groups and matched as to number, age, sex, as well as grade and duration of disease. Group 1, composed of 25 patients, was treated with leucocytic IFN-α at a dosage of 3 million IU thrice a week; group 2 (25 patients) was treated with the same protocol as group 1, but was also administered carnitine 2 g per os daily. Patients’ response was evaluated on the basis of serum levels of AST and ALT as well as liver functions; fatigue was evaluated by Wessely and Powell scores. All patients studied were tested before treatment and then 1, 3 and 6 months after the beginning of IFN administration. Results: The difference of physical fatigue between the two groups after 1 month of therapy was significant (p < 0.01) for patients treated with carnitine. This significance continued at the end of month 3 (p < 0.01). With reference to mental fatigue, the comparison between the two groups showed a significant difference for group 2 after 1 month (p < 0.01). Finally, with respect to the fatigue severity, the comparison between the two groups showed that after 1 and 3 months of therapy, fatigue was significantly less severe in group 2 than group 1 (p < 0.0005). Conclusions: If we take into account baseline values of mental and physical fatigue as well as the severity of this symptom in our study series, one observes that therapy with IFN alone induces fatigue in the majority of cases after 1 and 3 months, while at month 6, the values decrease. In contrast, patients treated with IFN + carnitine show a marked and early significant reduction of fatigue levels. These data suggest that the greater energetic substrate utilised by group 2 patients may in some way provide a better response of the patients to this side-effect. Abnormalities of neurotransmission concerning serotonine seem involved in the genesis of depression and fatigue. In addition, depression and fatigue commonly occur together, and the former is the most commonly observed symptom in patients with chronic fatigue syndrome.

A randomised, controlled clinical trial evaluating changes in therapeutic efficacy and oxidative parameters after treatment with propionyl L-carnitine in patients with peripheral arterial disease requiring haemodialysis.

ObjectiveWe explored the efficacy of intravenous therapy with propionyl L-carnitine in patients with both peripheral arterial disease (PAD) and chronic renal insufficiency requiring haemodialysis.MethodsThe trial was a randomised, double-blind, placebo-controlled trial. Sixty-four patients on haemodialysis (32 per treatment arm) with chronic renal insufficiency and PAD were assigned to receive either intravenous propionyl L-carnitine 600mg or placebo 3 times weekly for 12 months. The main outcome measures were the ankle/brachial index (ABI), plasma malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations, and the plasma nitrite/nitrate ratio (NO2/NO3); these were measured at baseline and at 6 and 12 months.ResultsSignificant increases in ABI were observed in the propionyl L-carnitine group, whereas in the placebo group the reverse trend was seen. In patients treated with propionyl L-carnitine, significant progressive decreases were seen in plasma MDA, 4-HNE and the NO2/NO3 ratio from baseline. In the placebo-treated group, only weakly significant or no differences were seen.ConclusionIntravenous administration of propionyl L-carnitine to haemodialysis patients with PAD improves both haemodynamic flow and the oxidative profile.