Impact on QoL and Cognitive Functioning of New Antiviral Therapies in Subjects With Chronic Hepatitis HCV-related
Impact on QoL and Cognitive Functioning of New Antiviral Therapies in Subjects With Chronic Hepatitis HCV-related
Chronic hepatitis HCV-related is the most common cause of chronic liver disease in Italy.
 Patients with chronic hepatitis C present a prevalence of depressive disorders higher than
 that of the general population; moreover, it has been repeatedly demonstrated the presence of
 cognitive deficits and poor quality of life. Chronic hepatitis C therapy was based on the
 combined use of pegylated alpha-interferons (PEG-INF), and ribavirin. Recently, new
 therapeutic protocols have been introduced, and while some antiviral drugs, including the
 first-generation ones, were used only in combination with PEG-IFN and ribavirin, the second
 and third generation antiviral drugs protocols are interferon-free. However, because of the
 high cost, the access to interferon-free protocols is only for patients with advanced fibrous
 stages, or with concomitant extra-hepatic HCV-related diseases, or for transplanted patients.
 Many side effects, such as flu-like symptoms, and psychiatric symptoms (depression, anxiety,
 irritability, insomnia) are common during antiviral therapy with IFN. However, in patients
 with chronic hepatitis C, a high lifetime prevalence of major depressive disorder, panic
 disorder, and brief recurrent depression have been observed, irrespective of IFN treatment
 and the use of alcohol and narcotics; such associations between mood and anxiety disorders
 and chronic hepatitis C may reflect a high prevalence of bipolar spectrum disorders. The
 presence of severe psychopathological symptoms requires the reduction of posology and causes
 high rates of discontinuation of antiviral therapy.

 This project represents an innovative psychiatric and neuropsychological screening program
 for patients with chronic hepatitis C, eligible for antiviral therapy.

 1. Primary objectives:

 1. to verify the medium-term impact of new antiviral therapies on quality of life,
 psychological well-being and cognitive function in subjects with chronic hepatitis
 C;

 2. to verify the predictability of specific psychopathological components and specific
 determinants on compliance with new antiviral therapies.

 2. Main secondary objectives:

 1. to verify the evidence of association between various psychiatric disorders and
 cognitive deficits and chronic hepatitis C;

 2. to evaluate the relative weight of psychopathological and/or cognitive disorders on
 the efficacy of antiviral therapy and on quality of life.
Background HCV-related chronic hepatitis represents the most common cause of chronic liver
 disease in Italy, with an estimated prevalence of 1-1.1% in the general population, reaching
 about 15% in subjects over 50 years of age. Chronic HCV infection is the cause of 27% of
 cases of cirrhosis and 25% of cases of hepatocarcinoma. Persons with chronic hepatitis C
 present a prevalence of depressive disorders higher than that of the general population (59%
 vs. 21%). Moreover, there has been repeatedly demonstrated the presence of cognitive
 deficits, mainly concerning attentive, executive, and verbal comprehension, also in the
 absence of liver cirrhosis and comorbidities due to the use of substances, and a reduced
 quality of life. Chronic hepatitis C therapy was based on the combined use of pegylated alpha
 interferons (PEG-INF) and ribavirin, with SVR (sustained virological response, defined as
 HCV-RNA undetectable in serum at six months after the end of therapy), normalization of
 transaminases and improvement of liver histology, altogether in 60% of cases. Recently, new
 antiviral drugs with direct activity (e.g. antiprotease and antipolymer activity) have been
 introduced into hepatitis C therapeutic protocols, with the development of PEG-INF-free
 therapeutic schemes. Unfortunately, because of the excessive cost, in many Countries,
 including Italy, the access to PEG-INF-free schemas is only for patients with advanced
 fibrous stages, or who have concomitant extra-hepatic viral diseases HCV-related, or those
 already transplanted, while others are still expected to be treated with PEG-INF and
 ribavirin.

 There are frequent side effects of antiviral therapy, often of minor magnitude, but sometimes
 incompatible with the continuation of therapy or life threatening. The most common adverse
 effects are influenza-like symptoms, occurring in more than half of the patients, especially
 during the first treatment period, and psychiatric symptoms (depression, anxiety,
 irritability, insomnia), which occur around the third month of treatment from 12 to 41% of
 patients. However, in persons with chronic hepatitis C, a high lifetime prevalence of major
 depressive disorder and panic disorder, and brief recurrent depression have been observed,
 irrespective of PEG-INF treatment and the use of alcohol and narcotic drugs; such
 associations between mood and anxiety disorders and chronic hepatitis C may reflect a high
 prevalence of bipolar disorder, which is more difficult to diagnose using non-dedicated
 screening tools. Some symptoms before treatment start, such as lack of pleasure or interest,
 asthenia, loss of appetite, social withdrawal, reduced work function, and hostility, are
 highly predictive of the onset of depressive disorders during antiviral therapy. Poor
 cognitive performance prior to antiviral therapy, coupled with the only depressive symptom of
 sadness, is predictive of more severe depressive disorders during antiviral treatment.
 However, cognitive deficits found before therapy appear potentially reversible and tend to
 completely recede when there is a virological response sustained by antiviral therapy. The
 presence of severe psychopathological symptoms leads to a reduction in posology and high
 rates of discontinuation of antiviral therapy.

 Careful psychiatric and neuropsychological evaluation before, during and after antiviral
 treatment should therefore be an indispensable part of screening and HCV-related chronic
 hepatitis therapy. This project represents an innovative psychiatric and neuropsychological
 screening program for persons with chronic hepatitis C, eligible for antiviral therapy. This
 program aims:

 -  to determine which psychopathological symptoms and cognitive deficits are more frequent
 in persons with chronic hepatitis C;

 -  to verify the impact of antiviral therapy on persons' reported quality of life, and on
 the onset, aggravation, maintenance of psychopathological symptoms and/or cognitive
 deficits;

 -  to determine which psychopathological and neuropsychological symptoms are predictive to
 high compliance and the effectiveness of antiviral therapy;

 -  to verify the existence of specific psychopathological and neuropsychological patterns
 in persons with chronic hepatitis C before, during and after antiviral therapy;

 -  to produce a standard procedure for psychiatric and neuropsychological screening in
 patients with HCV-related chronic hepatitis.

 Early identification of subjects at risk of psychiatric and cognitive disorders during
 antiviral therapy will effectively treat individuals at risk of discontinuing the antiviral
 therapy itself, improving the quality of the treatment and the effectiveness of the
 treatments.

 Design Observational study on a sample of persons with chronic hepatitis C. The experimental
 cohort will consist of participants who will be admitted to new antiviral treatments. The
 control cohort will consist of subjects recruited later, for which there is no immediate
 possibility of access to new treatments (wait-list).

 Selection of the sample

 The study will be conducted at the Center for the Study of Liver Diseases at the University
 Hospital of Monserrato, Cagliari. It is intended for subjects with chronic hepatitis C
 consecutively afferent to the facility, eligible for antiviral therapy. From the whole sample
 of cases will be drawn two cohorts:

 1. approximately 50 subjects with chronic hepatitis C, selected to receive new antiviral
 therapy immediately;

 2. approximately 50 subjects with chronic hepatitis C, who are eligible to receive new
 antiviral therapy, but are on a waiting list for non-availability of the treatment.

 Statistical analysis The data analysis will be carried out after the end of the study and in
 the next 3 months, by setting up a complete database for each participant, including in an
 anonymous form the socio-demographic and anamnestic data, and the data from the assessments
 performed at baseline and in subsequent times. The sample will be analyzed for frequency of
 lifetime and current psychiatric disorders, current cognitive deficits, subjectively
 perceived Quality of Life, depressive, hypomanic and manic symptoms, and patterns of
 biological rhythms. Data analysis will be done with multivariate techniques, for evaluating
 the effect and interaction of the various factors. The presence of psychiatric disorders and
 cognitive deficits will be considered dependent variables. The psychopathological specificity
 of symptoms related to antiviral treatment will also be measured in terms of different
 frequencies of specific psychiatric/neuropsychological symptoms and specific profiles of
 response to antiviral therapy. The whole sample will be compared at the baseline with a
 normative sample extracted with a computerized matching technique (4 controls each case) by
 gender and age from the database of a Italian population study. Through matchings 1: 4 it
 will be possible to increase the sample size and increase the statistical power of the study.
 The data analyses will be performed through SPSS (Statistical Package for Social Science)
 software.

 Funding This project is a spontaneous study, without any source of funding. Ethical Aspects
 The study will be conducted in accordance with the ethical principles contained in the
 Helsinki Declaration. The final study protocol was approved by the Ethics Independent
 Committee of the Azienda Ospedaliero Universitaria di Cagliari (approval record N.
 PG/2015/16964).

 Informed consent The interviewer will give clear and comprehensive information about the
 nature and the assumptions of the study to the respondents. Participants will also be
 informed of the possibility of interrupting the interview and withdrawing the consent to the
 study at any time. Interviewees will be required to sign an informed consent form.

 Data protection The subjects enrolled in the study will be given information about data
 protection and the privacy law. The interviewer will explain that the study data will be
 placed in a database with anonymous codes to maintain confidentiality, in accordance with
 local data protection laws.
Inclusion Criteria:

 -  diagnosis of chronic hepatitis HCV-related, eligible to new antiviral drugs treatments

 -  understanding Italian language

 -  signed informed consent

 Exclusion Criteria:

 -  severe cognitive deficits