A longitudinal study evaluating the effects of interferon-alpha therapy on cognitive and psychiatric function in adults with chronic hepatitis C
Introduction
Approximately 2.2% of adults world-wide are chronically infected with the hepatitis C virus (HCV) [1], and approximately 10–15% of these cases progress to advanced liver disease resulting in decompensated liver cirrhosis, hepatocellular carcinoma, liver transplantation, or death [2]. Until recently, standard of care for HCV was combination therapy including both PEGylated interferon-alpha and ribavirin. For HCV genotype 1, combination therapy is typically for 48 weeks, while for genotype 2/3, treatment is typically for 24 weeks. In 2011, the Food and Drug Administration (FDA) approved two protease inhibitors, telaprevir and boceprevir, for the treatment of HCV [3]. Thus, current antiviral therapy for HCV can either entail combination therapy or triple drug therapy with pegylated interferon-alpha, ribavirin, and a protease inhibitor. Following combination therapy, sustained viral response (SVR) (i.e., viral clearance for at least six months following treatment termination) is achieved in approximately 40–50% of those with HCV genotype 1, and 75–80% of those with genotype 2/3 [4]. Recent clinical trials suggest that triple drug therapy significantly increases SVR rates among individuals with HCV genotype 1 to above 65% [5], [6], [7].
Interferon-alpha is an endogenous cytokine that can also be administered exogenously for the treatment of malignancies such as malignant melanoma as well as chronic viral diseases including hepatitis B and HCV. Interferon-alpha based antiviral therapy for HCV (IFN) is associated with significant side effects, the most commonly reported ones including flu-like symptoms (e.g., fever, chills, myalgia, nausea, fatigue), psychiatric symptoms (e.g., depressed mood, anxiety, irritability, emotional lability, agitation, apathy, anhedonia, anorexia, psychomotor retardation, sleep disturbance, sexual dysfunction) and cognitive complaints [8].
Although cognitive complaints are frequently reported during IFN, relatively few studies have attempted to longitudinally characterize neuropsychological function before, during and after IFN using objective neuropsychological tests. Objective neuropsychological testing is important because people do not typically assess their cognitive skills accurately, and subjective cognitive complaints poorly correlate with objective neuropsychological performance [9]. Perhaps due in part to widely varying methodology, results from available cognitive studies are mixed, showing no clear pattern of whether objective cognitive performance declines during IFN, whether impairments abate following treatment termination, nor which cognitive domains are most sensitive to IFN effects [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24]. In terms of psychiatric side effects, there is a relatively large literature documenting high rates of psychiatric symptoms during IFN administration but significantly less information regarding the possible persistence of these side effects following IFN termination. A recent community survey of 200 patients treated with IFN for HCV found that 84.5% reported psychiatric side effects during IFN, and 42.5% reported psychiatric side effects that persisted up to six months following IFN termination [25]. IFN induced depression is the most prevalent and well-studied IFN induced psychiatric side effect. The most recent meta-analysis on this topic [26] evaluated 26 prospective observational studies that reported on the incidence of IFN induced major depressive disorder in patients treated for HCV; overall cumulative incidence of depression was 25% following 24 weeks of IFN, and 28% following 48 weeks of IFN. Although the depressive symptoms associated with IFN are generally considered to be transient and remit following termination of therapy [8], a handful of case reports have described worsening depression, and at times increased suicidality, following IFN termination [27], [28], [29], [30]. In a case series of five patients treated with IFN, suicide was attempted in four cases after IFN termination and was responsible for two deaths [30]. In another report, two attempted suicides and one successful suicide during or shortly after IFN were described [28]. The rates and time course of other IFN induced psychiatric symptoms have been less rigorously studied. However, an expert panel convened by the European Liver Patient's Organization (ELPA) recently published a consensus statement regarding treatment recommendations for the management of mental health problems among HCV infected patients [31]. Based on their review of the available literature on HCV, IFN, and mental health, this consensus statement reports prevalence rates of IFN induced psychiatric side effects ranging from 30 to 70% for depression, 39–80% for fatigue, 18–45% for sleep disturbances, 16–50% for irritability, 11–45% for anxiety, 0–3.2% for mania, 0–0.6% for psychosis, 3.5–10% for suicidal ideation, and 0–0.2% for suicidal attempts.
In light of the inconsistent findings within the cognitive literature, additional well-designed longitudinal studies are warranted to better characterize the trajectory of potential IFN induced cognitive effects both during IFN and following IFN termination. The present study, therefore, utilizes a comprehensive battery of widely used, well-validated, and adequately normed neuropsychological assessment instruments to prospectively evaluate neuropsychological functioning in patients before, during, and after IFN, and also includes a demographically similar (i.e., age, race/ethnicity, gender, education, baseline estimated IQ) control group of untreated HCV patients to control for possible confounding factors such as practice effects. This study additionally adds to the literature on the psychiatric side effects of IFN by simultaneously including well-validated symptom questionnaires to evaluate the severity and persistence of symptoms of IFN induced depression, anxiety, fatigue and pain.
Section snippets
Participants
A total of 64 adults were recruited from the Portland, Oregon area and assigned to one of two groups: 1) adults with chronic HCV (> 5 years) who were about to initiate IFN (IFN +, n = 33), 2) a control group of adults with chronic HCV (> 5 years) who were not planning to initiate IFN (IFN −, n = 31). Participants were recruited from Portland area hepatology clinics through referral by the hepatologists, announcements at hepatology clinic HCV education classes, mailings to patients who had previously
Baseline characteristics
As summarized in Table 1, groups were similar in terms of age, gender, ethnicity, Veteran status, education, estimated baseline cognitive ability (i.e., WTAR scores), and body mass index, as well as rates of lifetime psychiatric disorders and medical conditions. Although rates of past alcohol use disorders were similar across groups, the IFN − group had significantly higher rates of past drug use disorders. There were no significant differences across groups in terms of HCV viral load [i.e., HCV
Discussion
Overall, our results indicate that adults undergoing IFN treatment for HCV report significantly increased psychiatric symptoms, including depression, anxiety, fatigue and pain that interferes with daily life during treatment, but that these symptoms remit or are markedly reduced six months following treatment termination. Although many studies have documented increased rates of depression during IFN therapy [8], [26], our data reveals that while the somatic symptoms of depression, including
Conflict of interest statement
The authors have no competing interests to declare.
Acknowledgments
This work was supported by career development awards to M.H. (Staff Psychologist and Neuropsychologist) and J.M.L. (Research Scientist) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Clinical Sciences Research and Development. This material is the result of work supported with resources and the use of facilities at the Portland Veterans Affairs Medical Center, Portland, Oregon. The authors thank the study participants and staff at
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