BACKGROUND:Sickness behavioral changes elicited by inflammation may become prolonged and dysfunctional in patients with chronic disease, such as chronic hepatitis C (CHC). Neuroimaging studies show that the basal ganglia and insula are sensitive to systemic inflammation. AIM:To elucidate the clinical and neurobiological aspects of prolonged illnesses in patients with CHC. METHODS:Thirty-five CHC patients not treated with interferon-α or other antiviral therapy, and 30 control subjects matched for age and sex, were evaluated for perceived stress (perceived stress scale; PSS), depression (PHQ-9), fatigue and irritability through a visual analog scale (VAS), as well as serum levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2) and oxidative stress markers. Functional MRI was performed, measuring resting-state functional connectivity using a region-of-interest (seed)-based approach focusing on the bilateral insula, subgenual anterior cingulate cortex and bilateral putamen. Between-group differences in functional connectivity patterns were assessed with two-sample t-tests, while the associations between symptoms, inflammatory markers and functional connectivity patterns were analyzed with multiple regression analyses. RESULTS:CHC patients had higher PSS, PHQ-9 and VAS scores for fatigue and irritability, as well as increased IL-6 levels, PGE2 concentrations and antioxidant system activation compared to controls. PSS scores positively correlated with functional connectivity between the right anterior insula and right putamen, whereas PHQ-9 scores correlated with functional connectivity between most of the seeds and the right anterior insula. PGE2 (positively) and IL-6 (negatively) correlated with functional connectivity between the right anterior insula and right caudate nucleus and between the right ventral putamen and right putamen/globus pallidus. PGE2 and PSS scores accounted for 46% of the variance in functional connectivity between the anterior insula and putamen. CONCLUSIONS:CHC patients exhibited increased perceived stress and depressive symptoms, which were associated with changes in inflammatory marker levels and in functional connectivity between the insula and putamen, areas involved in interoceptive integration, emotional awareness, and orientation of motivational state.

Abstract INTRODUCTION Chemotherapy-induced hepatitis B virus (HBV) reactivation is a well-recognized complication and is a potentially life-threatening condition in cancer patients with chronic HBV (hepatitis B surface antigen [HBsAg]-positive). Rituximab has been associated with an increase in HBV reactivation in chronic HBV patients (45%) and even in patients with resolved infection (HBsAg negative and hepatitis B core antibody [anti-HBc]-positive (22%); however, the reported frequency varies among different studies. Current guidelines for management of chronic HBV recommend routine antiviral HBV prophylaxis with lymphoma before starting chemotherapy. In contrast, there is little evidence-based consensus regarding patients with resolved HBV infection. Aim: To analyze the incidence of HBV reactivation and the role of antiviral HBV prophylaxis in lymphoma patients with chronic HBV or resolved HBV treated with chemotherapy, immunotherapy or immunochemotherapy managed according to our institutional HBV guidelines. Secondary endpoints were to analyze the incidence of HBV in this population and HBV guidelines adherence. PATIENTS AND METHODS Lymphoma patients with chronic HBV or resolved HBV in a single center. HBV viral status definitions: Active Chronic HBV infection: HBsAg positive, anti-HBc positive and HBV DNA >2000 IU/mL; Inactive Carriers: HBsAg positive, Anti-HBc positive, HBV DNA undetectable or <2000 IU/mL with normal transaminases; Resolved HBV: HBsAg negative, anti-HBc positive, HBV DNA undetectable. HBV reactivation was defined as increased serum HBV DNA (≥1 log10), regardless of liver biochemistry or HBsAg status. Institutional HBV guidelines: serum samples were collected at baseline for HBsAg and anti-HBc testing in all lymphoma patients. Patients were evaluated by a hepatologist if any of them fulfilled HBV viral status definition. Baseline at screening and monitoring every 3 months during therapy and up to 24 months after completing therapy (assessment of liver biochemistry, serum HBV DNA, HBsAg and anti-HBs levels). Specific prophylaxis strategies according to HBV status: Group A (Active chronic HBV): treatment for HBV; Group B (Inactive carriers): antiviral HBV prophylaxis; Group C (Resolved HBV): antiviral HBV prophylaxis if rituximab containing-therapy or follow-up only if rituximab-free therapy. HBV antiviral prophylaxis was started before therapy and finished 12 months after completing therapy. RESULTS From January 2012 to January 2015, 227 lymphoma patients received chemotherapy or immunochemotherapy. 142 (63%) patients received rituximab-containing therapy. 43 (19%) patients were anti-HBc positive. Group A: 2 (1%) patients; Group B: 2 (1%) patients; Group C: 39 (17%) patients. 14 (6%) patients have coinfection with hepatitis C virus and 12 (5%) patients co-infection with human immunodeficiency virus (HIV). Adherence to HBV guidelines was 90%. Patients in Group A (n=2) and B (n=2) received antiviral treatment/prophylaxis before starting therapy. In the Group C, 16 (41%) patients underwent only follow-up and 23 (59%) patients received HBV antiviral prophylaxis (lamivudine in 4, entecavir in 8 and tenofovir in 11). Median duration of HBV prophylaxis was 18 months (95% CI: 16-19 months). After a median follow-up of 21 months, 2 patients developed HBV reactivation during lymphoma treatment: 1 from group B (reactivation rate of 50%) and 1 from group C (reactivation rate of 3%). Both patients had received rituximab-containing treatment and both developed HBV reactivation (without hepatitis flare) within the first 6 months after finishing antiviral HBV prophylaxis (delayed HBV reactivation). Outcome was favorable in both patients. Characteristics of HBV reactivation patients are shown in table I. Cumulative incidence of HBV reactivation at 12 and 24 months were 0% and 8%, respectively. CONCLUSION Our strategy of close monitoring patients with chronic HBV or resolved HBV that receive chemotherapy and adding antiviral HBV prophylaxis only in selected patients clearly decrease HBV reactivation. Nevertheless, this strategy may not fully protect patients from late HBV reactivations. Larger validation studies are needed to confirm our data and to establish the best cost-effective strategy in this lymphoma population, especially in the new era of inmunomodulatory drugs of their real involvement in HBV reactivation is unknown. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

Background: The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression. Methods: We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis. Results: The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1.14), disorderliness (p = 0.0339, HR = 1.11), and low scores on extravagance (p = 0.0040, HR = 0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR = 3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR = 3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p = 0.0436, HR = 1.88) and BDNF genes (Val/Val genotype: p = 0.0453, HR = 0.55) were associated with depression. Conclusions: The results of the study support the theory that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders.

Background: Cytokines and serotonin neurotransmission may play an important role on the development of psychopathological symptoms during interferon (IFN) treatment. The aim of the present study was to investigate the association between IFN-induced depression, anxiety and fatigue and functional genetic variants at the interleukin-6 gene (IL-6) and serotonin transporter gene (SERT).Methods: 385 consecutive Caucasian outpatients with chronic hepatitis C initiating treatment with IFN-alpha and ribavirin were included. All patients were interviewed at baseline using the Structured Clinical Interview for DSM-IV (SCID-I) and those with a current major depressive disorder or anxiety disorder before starting treatment were excluded. Depression and anxiety were assessed at baseline during the treatment (at 4, 12, 24 and 48 weeks) using the Hospital Anxiety and Depression Scale and fatigue was evaluated using a visual analogue scale. The 5-HTTLPR region of SERT gene and the functional polymorphism located at the promoter region of IL-6 gene (rs1800795) were genotyped.Results: Genotypic distribution was in the Hardy-Weinberg equilibrium for SERT (p = 0.41) and for IL-6 (p = 0.72) polymorphisms. At baseline we found only a significant effect of IL-6 polymorphism on fatigue symptoms. During antiviral treatment we reported that subjects with CC genotype (1-6) presented significantly lower changes from baseline in IFM-induced depression (p = 0.005) and IFN-induced anxiety (p = 0.004). We did not find statistically significant differences on depression (p = 0.21) or anxiety (p = 0.15) between SS/SL and LL genotypes of SERT.Conclusions: Genetic variations in the IL-6 gene increase the risk of IN-induced depression and anxiety. The IL-6 polymorphism was associated with fatigue rates in patients with chronic hepatitis C before treatment. Our study confirms the role of inflammatory mechanisms in IFN-induced psychopathological symptoms. (C) 2013 Elsevier Ltd. All rights reserved.

Depression and anxiety in patients with hepatitis C virus (HCV) infection influence their health-related quality of life and their adherence to antiviral treatment.Objective: To study the psychometric properties of the Patient Health Questionnaire (PHQ) as a screening instrument for depression and anxiety in HCV patients.Methods: Criterion validity, using the structured clinical interview for DSM-IV-Axis I (SCID-I) to diagnose depression and anxiety disorders as diagnostic standard, was evaluated for both summed and algorithm-based PHQ in 500 HCV patients. Correlations with quality of life (Short-Form-36 Health Survey; SF-36) and severity of illness (Hospital Anxiety and Depression Scale; HADS) were calculated to assess construct validity. Test-retest reliability and patients' reaction to the PHQ were assessed in 120 HCV patients.Results: Twenty-three percent of patients (N = 114) had a psychiatric disorder (any depressive disorder = 18.2%; major depressive disorder = 6.4%; generalized anxiety disorder = 7.0% and panic disorder = 5.8%). The questionnaire demonstrated good test-retest reliability for any depressive disorder (k = .847), major depressive disorder (k = .784), generalized anxiety disorder (k = .787), panic disorder (k = .848), and for any psychiatric disorder (k = .847). There was good agreement between PHQ and SCID-I diagnoses (for any PHQ disorder. k = .821; overall accuracy = 90.43%. sensitivity = 83.84%; specificity = 97.01%). Patients with any PHQ disorder had higher impairment on the SF-36 (p<.001). HADS depression and anxiety scores showed high correlations with PHQ depression (p<.001) and anxiety (p<.001) scores respectively. PHQ administration was well accepted by 97% of patients.Conclusions: The Spanish version of the PHQ is a reliable, valid, and useful screening instrument to detect depression, generalized anxiety and panic disorders in HCV patients. (C) 2012 Elsevier B.V. All rights reserved.

Chronic hepatitis C infection (CHC) represents a public health problem that affects around 3% of population worldwide. Pegylated Interferon-alpha (PegIFN-α) and Ribavirin (RBV) is the recommended treatment reaching about 40–80% of sustained virological response. However, a common treatment side-effect is induced-depression that impairs patient's quality of life and treatment adherence (1,2). This paper showed polymorphisms in HTR1A, NCR1, TPH2 genes as predictive variables of IFN-induced depression. 396 consecutive, euthymic, CHC outpatients treated with PegIFN-α/RBV were included. Patients were assessed at baseline, 4, 12, 24 and 48 weeks of treatment using PHQ and MINI-DSM-IV-R interview to diagnose depression. Survival analysis was performed. In the univariated analysis functions were compared using logrank test. Significative variables (0.1 level) were extracted for the multivariated model, using a Weibull regression model. The incidence of induced-depression along the treatment was 39.4%. Polimorphisms on HTR1A (P = 0.0104), TPH2 (P = 0.0231) and NRC1 (P = 0.0702) genes predicted IFN-induced depression. Genes related with serotonine and inflamation system may play an important role in the pathogenesis of IFN-induced depression. Knowledge of predictive variables for IFN-induced depression may help to better manage patients at risk.

IntroductionThe hepatitis C virus infection (HVC) represents a public health problem that affects the 3% of world population. The currently recommended treatment is Pegylated Interferon (PegIFN) alpha and Ribavirin (RBV) during 24 or 48 weeks. This treatment has been associated with high rates of neuropsychiatric side effects, mainly depression. Recent studies have documented impairment in health related quality of life (SF-36) in these patients.AimsTo study the induced depression and quality of life of chronic HVC patients under antiviral treatment.MethodsThree hundred seventeen consecutive HCV patients, who received PegIFN alpha and RBV, were assessed using the SCID interview for DSM-IV. Moreover, the PHQ, the HADS and the SF-36 were administered at baseline, 4, 12, 24, and/or 48 weeks of treatment.ResultsTwo hundred twenty-four (64.7%) of patients were men, the mean (SD) age was 43.6 (10.6), and 130 (40.1%) had history of mood disorder. One-hundred eleven (41%) of the sample had a depressive disorder during the treatment. There was a significant difference in the total SF-36 score and in all subscales (p < 0.001). HADS subscale of depression was highly correlated with SF-36 total score (p < 0.001).ConclusionsDuring the antiviral treatment, HVC patients had a higher incidence of induced depression. Both physical and mental component scores of SF-36 in induced depressed patients were significantly worse.This study has been supported in part by Spanish grants: FIS E08/00268, Dra. Martín-Santos, and Dr. Solà.

BACKGROUND:Depression is one of the main reasons for treatment withdrawal and failure in chronic hepatitis C patients treated with interferon. Antidepressants are useful for its treatment, but whether they can also be used for prevention has yet to be established.METHOD:To evaluate the efficacy and safety of escitalopram for preventing interferon alfa-2a-induced depression, we conducted an investigator-initiated multicenter, randomized, double-blind, placebo-controlled trial in 133 chronic hepatitis C patients without baseline mental disorders who were randomly assigned to receive escitalopram or placebo during the first 12 weeks of treatment. Primary efficacy outcomes were the development of DSM-IV major depression and scores on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hospital Anxiety and Depression Scale (HADS). Primary safety end points were biochemical and virological responses. Patients were recruited between March 2005 and July 2006.RESULTS:Rates of major depression were low (5.4%) and did not differ between placebo (3.2%) and escitalopram (7.6%). MADRS and HADS scores significantly increased during treatment (P < .001 and P = .028, respectively), but there were no differences between treatment groups. Sustained virological response was achieved by 69.2% of patients, 70.4% in the placebo group and 67.9% in the escitalopram group.CONCLUSIONS:Findings do not support the use of an antidepressant to prevent interferon-induced depression during the first 12 weeks of treatment in chronic hepatitis C patients at low psychiatric risk. Future studies should be directed to subpopulations of patients at high psychiatric risk.TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00166296.

Quantitative sensory testing (QST) allows researchers to evaluate associations between noxious stimuli and acute pain in clinical populations and healthy participants. Despite its widespread use, our understanding of QST's reliability is limited, as reliability studies have used small samples and restricted time windows. We examined the reliability of pain ratings in response to noxious thermal stimulation in 171 healthy volunteers (n = 99 female, n = 72 male) who completed QST on multiple visits ranging from 1 day to 952 days between visits. On each visit, participants underwent an adaptive pain calibration in which they experienced 24 heat trials and rated pain intensity after stimulus offset on a 0 to 10 Visual Analog Scale. We used linear regression to determine pain threshold, pain tolerance, and the correlation between temperature and pain for each session and examined the reliability of these measures. Threshold and tolerance were moderately reliable (Intra-class correlation = .66 and .67, respectively; P < .001), whereas temperature-pain correlations had low reliability (Intra-class correlation = .23). In addition, pain tolerance was significantly more reliable in female participants than male participants, and we observed similar trends for other pain sensitive measures. Our findings indicate that threshold and tolerance are largely consistent across visits, whereas sensitivity to changes in temperature vary over time and may be influenced by contextual factors.This article assesses the reliability of an adaptive thermal pain calibration procedure. We find that pain threshold and tolerance are moderately reliable whereas the correlation between pain rating and stimulus temperature has low reliability. Female participants were more reliable than male participants on all pain sensitivity measures.

Background Suboptimal doses of ribavirin have been suggested to explain the diminished efficacy of pegylated interferon (PEG-IFN) plus ribavirin in hepatitis C virus (HCV)–HIV-coinfected patients. Methods A cohort of 104 coinfected patients and an age-, sex- and genotype-matched cohort of HCV-monoinfected patients ( n=104) were compared. All patients received PEG-IFN-α2a 180 μg/week plus ribavirin 800–1,200 mg daily (HCV genotype 2/3 patients received 800 mg daily and those with genotype 1/4 received 1,000–1,200 mg daily) for 48 weeks (24 weeks for monoinfected patients with genotypes 2/3). HCV RNA levels were determined qualitatively at weeks 4, 12, 24, 48 and 72 and quantified monthly until week 12. Results The coinfected cohort had more advanced liver disease and lower body weight. HCV genotype 1 patients coinfected with HIV showed higher levels of HCV RNA than monoinfected patients. A significantly higher proportion of coinfected patients interrupted the prescribed treatment period prematurely (84% versus 98%). During the first 12 weeks, smaller decreases in HCV RNA levels were observed in coinfected patients. Among patients with HCV genotype 1, coinfected patients achieved lower rates of early virological response (64% versus 87%), end-of-treatment response (47.3% versus 80%) and sustained virological response (SVR; 27.3% versus 56.4%), but not rapid virological response (RVR). HCV–HIV-coinfected patients with HCV genotype 2/3 achieved significantly lower rates of RVR (52% versus 88%). Multivariate analysis identified RVR, gender and liver fibrosis as independent predictors of SVR. Conclusions Differences in efficacy of PEG-IFN-α2a plus ribavirin treatment between HCV–HIV-coinfected and HCV-monoinfected patients were maintained despite optimized ribavirin dose.

Background: Treatment of recurrent HCV after liver transplant (LT) with interferon (PEG) and ribavirin (RBV) is complicated by poor tolerance, risk of rejection, low SVR (15-35%), and high relapse (18-50%).Ability to predict relapse may prompt extended therapy.Tissue PCR may be useful in identifying residual hepatic HCV RNA when unable to detect in serum.We postulated that negative tissue PCR during PEG/RBV would predict low risk of relapse.Methods: Patients with recurrent HCV following LT were given PEG/RBV for a minimum 48 weeks.In 14 patients that achieved serum PCR negativity, treatment was extended until serum TMA negative, tissue PCR negative, and absence of moderate necroinflammation on biopsy.Tissue PCR (NGI, Los Angeles, CA) was performed on liver biopsy specimens frozen in liquid nitrogen at bedside.Results: 11/14 patients eventually achieved SVR (79%) while 3/14 patients had relapse or breakthrough on treatment.One patient required 2 treatment courses for SVR (initially relapsed), and another patient received 2 treatment courses, with one relapse and one breakthrough, for a total of 16 treatment courses for 14 patients.SVR was noted in 11/16 courses; relapse or breakthrough were noted in 5/16 courses.The baseline viral load, HAI, stage, duration of PEG, and duration of PCR or TMA negativity on treatment were no different between the groups.The Delta HAI trended toward more improved in those with SVR (p = 0.07).20 biopsies for tissue PCR from 14 patients were obtained.18/20 biopsy PCRs were negative while 2 were positive.All patients with negative serum PCR/TMA at time of biopsy also had negative tissue PCR, including the 3 patients that relapsed.The only 2 positive tissue PCRs had viremia (breakthrough) at time of biopsy.Positive tissue PCR identified breakthrough, but not relapse.Conclusions: Treatment of HCV recurrence following LT appears to require protracted treatment courses with prolonged negative molecular testing and a decrease in necroinflammation before sustained response is likely.Tissue PCR does not appear to add additional information regarding risk of relapse in post-transplant patients undergoing treatment for HCV.