IFN-alpha Treatment Research Articles

Role of Tumor Necrosis Factor alpha promoter polymorphisms in interferon related side effects in chronic hepatitis B patients under interferon alpha 2b treatment

Objective(s). Interferon alpha therapy is associated with series of adverse effects leading premature discontinuation of treatment. Here we aimed to determine the effects of Tumor necrosis alpha promoter polymorphisms on interferon related side effects during interferon alpha 2b treatment in chronic hepatitis B patients
 Material and Method(s). This observational study enrolled 50 chronic hepatitis B patients, who were treated with interferon alpha 2b 10 tiw plus lamivudine 100mg/day at Selçuk University Meram Medical Faculty Department of Infectious Diseases and Clinical Bacteriology between 2006-2007. Patients were followed-up with complete blood count, transaminases and amylase monthly at out patient clinics of our department. All patients were asked to fill a questionnaire to evaluate the interferon related side effects at every visit. Tumor necrosis factor alpha -238 and -308 polymorphisms were investigated with PCR-Restriction fragment length polymorphisms.
 Result(s) and Conclusion Arthralgia was present in 93.8% of patients. Exhaustion, loss of appetite, mount dryness and fever are the leading complaints of the patients. Median complaint scores were 9, 9.5, 11 and 5 at 4th, 12th, 24th and 48th week visits, respectively. Thrombocytopenia and leucopenia were detected in 8 (16%) and 5 (10%) patients, respectively. One-third of the patients reported depressive mood however, depression was diagnosed in 5 (10%) patients. TNF alpha promoter 238GG and 308GG allele was present in 42/50 and 43/50 patients, respectively. No association was found between TNF promoter allele and certain patient-reported side effect, complaint score, hematological and psychological adverse effects. TNF alpha promoter polymorphisms do not contribute to occurrence of IFN alpha treatment related side effects.

West Nile virus infection and interferon alpha treatment alter the spectrum and the levels of coding and noncoding host RNAs secreted in extracellular vesicles

BackgroundExtracellular vesicles (EVs) are small membrane vesicles secreted by the cells that mediate intercellular transfer of molecules and contribute to transduction of various signals. Viral infection and action of pro-inflammatory cytokines has been shown to alter molecular composition of EV content. Transfer of antiviral proteins by EVs is thought to contribute to the development of inflammation and antiviral state. Altered incorporation of selected host RNAs into EVs in response to infection has also been demonstrated for several viruses, but not for WNV. Considering the medical significance of flaviviruses and the importance of deeper knowledge about the mechanisms of flavivirus-host interactions we assessed the ability of West Nile virus (WNV) and type I interferon (IFN), the main cytokine regulating antiviral response to WNV, to alter the composition of EV RNA cargo.ResultsWe employed next generation sequencing to perform transcriptome-wide profiling of RNA cargo in EVs produced by cells infected with WNV or exposed to IFN-alpha. RNA profile of EVs secreted by uninfected cells was also determined and used as a reference. We found that WNV infection significantly changed the levels of certain host microRNAs (miRNAs), small noncoding RNAs (sncRNAs) and mRNAs incorporated into EVs. Treatment with IFN-alpha also altered miRNA and mRNA profiles in EV but had less profound effect on sncRNAs. Functional classification of RNAs differentially incorporated into EVs upon infection and in response to IFN-alpha treatment demonstrated association of enriched in EVs mRNAs and miRNAs with viral processes and pro-inflammatory pathways. Further analysis revealed that WNV infection and IFN-alpha treatment changed the levels of common and unique mRNAs and miRNAs in EVs and that IFN-dependent and IFN-independent processes are involved in regulation of RNA sorting into EVs during infection.ConclusionsWNV infection and IFN-alpha treatment alter the spectrum and the levels of mRNAs, miRNAs and sncRNAs in EVs. Differentially incorporated mRNAs and miRNAs in EVs produced in response to WNV infection and to IFN-alpha treatment are associated with viral processes and host response to infection. WNV infection affects composition of RNA cargo in EVs via IFN-dependent and IFN-independent mechanisms.

STUDY THE EXPRESSION OF TETRASPANIN (CD81) ON B CELLS IN RESPONSE TO INTERFERON THERAPY IN CHRONIC HCV PATIENTS

ABSTRACT Hepatitis C virus (HCV) infection causes life threatening disease due to its persistence in the liver, over time leading to cirrhosis and hepatocellular carcinoma. Therapeutic intervention with interferon (INF) - alpha combined with ribavirin is aimed at viral clearance, Interferon and ribavirin might discontinue the virus induced hepatocytes damage, thus slowing down the progress to end- stage liver disease. It has been demonstrated that HCV virion, via major structure envelop (E) protein 2 or EIE2 complex could specifically bind to human CD81 molecule, thereby altering the cellular activities in B cells, T cells and natural killer (NK) cells. CD81, a surface protein belonging to the tetraspanin family, facilitates B–T cell interaction in the process of antigen presentation Evidence has revealed that CD81 on B and T cells substantially enhanced T helper IL-4 secretion and NK-cell CD81 enabled E2-mediated reduction of the IFN-gamma levels Those data suggest that CD81 might activate the pathway leading to a predominant type-2 immune response, and as such be prone to cause a strong antibody production but weak or insufficient cytotoxic activities to clear the.The aim of this work was to investigate the clinical relevance and the possible mechanism of CD81 down-regulation under IFN-alpha treatment to detect possible role of CD 81in response to INF therapy of chronic HCV patients. Subjects and Methods: The study included: Group I: 10 healthy subjects. And 60 HCV patients classified into 3 groups: Group II: 20 chronic HCV patients have not received treatment Group IIIa: 20 chronic HCV patients have received treatment responsive to treatment Group IIIb: 20 chronic HCV patients have received treatment not responsive to treatment .the patients were subjected to: (CBC) .liver and kidney function tests and special investigation CD 81, CD19, CD 22. Results: TLC and PLT higher in group I while ALT and AST were significantly higher in group II, while T. bilirubin was significantly higher in group IIIb, Direct bilirubin was significantly higher in group II ,and Alb was significantly higher in group I ,ASMA and ANA more higher in group IIIb, AFP and TSH were significantly higher in group IIIb , there was negative correlation between CD81 and TLC positive correlation between ALT, AST and CD81 were positively correlated to T Bilirubin , D Bilirubin and CD81.There was also significant negative correlation between Albumin and CD81. CD81, CD19, CD22 and Lymphocytes were significantly higher in group IIIb. Conclusion: In conclusion, CD81 down-regulation is a primary host response to interferon-alpha-based therapy and an immunophenotype associated with anti-HCV sustained virological response (SVR) Key words:HCV,CD81 ,interferone

Abstract B49: Sustained IFNalpha treatment inhibits metastasis in 4T1 mammary carcinoma and correlates with decreasing myeloid-derived suppressor cells

Abstract In order to model pharmacokinetics and pharmacodynamics of pegylated IFNalpha, we utilized hydrodynamic delivery technology using minicircle DNA vectors encoding universal IFNalpha as a rapid and cost-effective method to obtain sustained levels of serum IFNalpha2alpha1. This approach is particularly useful for delivering secreted molecules, such as cytokines, as transfected hepatocytes secrete the transgene product in a paracrine manner providing a serum exposure profile resembling that reported in PEG-intron-treated patients. We found that sustained exposure of IFNalpha2alpha1 induced inhibition of metastasis. Primary 4T1 tumor growth was partially inhibited, while significant decreases in pulmonary metastatic burden were consistently observed. Further evidence that the observed inhibition of metastasis was independent of potential effects on the primary tumor was tested by resecting the primary tumor prior to treatment, which did not alter the outcome. Importantly, sustained IFNalpha2alpha1 treatment correlated with a significant increase in the survival of tumor-bearing animals. IFNalpha effects are plieotropic resulting in potential activation of numerous immune cell types associated with both innate and adaptive immunity. However, the mechanisms associated with IFNalpha-induced inhibition of lung metastasis were largely engendered by innate immune cells since treatment in BALB/c mice deficient for T and B cells did not affect the capacity of IFNalpha to inhibit pulmonary metastasis when compared to wild-type animals. The importance of NK cells has recently been reported as an important innate component for IFNalpha induced reduction of metastatic burden. However, little is known about IFNalpha-regulation of other innate cell types that may contribute to the inhibition of tumor metastasis. Here we report IFNalpha2alpha1 treatment induced marked decreases in 4T1-induced expansion and activation of immature CD11b+ Gr-1+ myeloid cells (aka: MDSC), which have been reported to contribute to metastatic potential. These results correlated with similar decreases in metastatic burden in mice following chlodronate-liposome depletion of CD11b+ Gr-1+ myeloid cells. Citation Format: Christina Kochel, Kalyan Pande, Roanna Ueda, Dan Gorman, Drake Laface. Sustained IFNalpha treatment inhibits metastasis in 4T1 mammary carcinoma and correlates with decreasing myeloid-derived suppressor cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B49.

Liver Gene Expression Profiles Correlate with Virus Infection and Response to Interferon Therapy in Chronic Hepatitis B Patients

The natural course of chronic hepatitis B (CHB) infection and treatment response are determined mainly by the genomic characteristics of the individual. We investigated liver gene expression profiles to reveal the molecular basis associated with chronic hepatitis B and IFN-alpha (IFNα) treatment response in CHB patients. Expression profiles were compared between seven paired liver biopsy samples taken before and 6 months after successful IFNα treatment or between pretreatment biopsy samples of 11 IFNα responders and 11 non-responders. A total of 132 differentially up-regulated and 39 down-regulated genes were identified in the pretreated livers of CHB patients. The up-regulated genes were mainly related to cell proliferation and immune response, with IFNγ and B cell signatures significantly enriched. Lower intrahepatic HBV pregenomic RNA levels and 25 predictive genes were identified in IFNα responders. The predictive gene set in responders significantly overlapped with the up-regulated genes associated with the pretreated livers of CHB patients. The mechanisms responsible for IFNα treatment responses are different between HBV and HCV patients. HBV infection evokes significant immune responses even in chronic infection. The up-regulated genes are predictive of responsiveness to IFNα therapy, as are lower intrahepatic levels of HBV pregenomic RNA and pre-activated host immune responses.

Psychological experiences reported in regarding hepatitis C and use of interferon: A clinical-qualitative study in a Brazilian university outpatient service considering its possible side effects

Relevant emotional and behavioural reactions are associated with diagnosis and treatment of hepatitis C that can impair adherence to medical management. Hepatitis C accounts for significant number of both – liver transplants and deaths. Treatment has as major component the interferon alpha, and many of patients can experience side effects that often lead to non-adherence to drug treatment and dose modification.ObjectiveTo discuss psychological meanings attributed to IFN alpha treatment's side effects and its symbolic relation with adherence or not to treatment, on viewpoint of interviewed outpatients at a Hepatitis Service.MethodData collection was conducted using the Clinical-Qualitative Method, utilizing semi-directed interviews with open-ended questions in depth, fully transcribed. Qualitative Content Analysis employed for processing data, emerging meaning cores, with categorization into discussion topics. Sample closed by information saturation.ResultsNine interviews. The analysis revealed:– coping attitude - handling the disease to have willpower; a moral feeling regarding the need to overcome the disease and treatment side effects to demonstrate “strength”, as well as to deny psychologically the occurrence of side effects;– disruptive attitude: reports of anxiety regarding to patients presenting neuropsychiatric symptoms by medication;– realistic attitude: speeches show perception of natural evolution and treatment real function.ConclusionGuilt feelings emerged regarding to difficulties of being loyal to treatment, a strongly valorative speech on being ill what must lead to “overcome the evils of life”. Health teams must understand these meanings to talk openly about human feelings on illness and treatment, promoting an adequate adherence.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced Depression.

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.

Elimination of HCV via a non-ISG-mediated mechanism by vaniprevir and BMS-788329 combination therapy in human hepatocyte chimeric mice

We previously reported that interferon (IFN)-free direct-acting antiviral combination treatment succeeded in eradicating genotype 1b hepatitis C virus (HCV) in human hepatocyte chimeric mice. In this study, we examined the effect of vaniprevir (MK7009, NS3/4A protease inhibitor) and BMS-788329 (NS5A inhibitor) combination treatment on HCV genotype 1b and the expression of IFN-stimulated genes (ISGs) using a subgenomic replicon system and the same animal model. Combination treatment with vaniprevir and BMS-788329 significantly reduced HCV replication compared to vaniprevir monotherapy in HCV replicon cells (Huh7/Rep-Feo cells). HCV genotype 1b-infected human hepatocyte chimeric mice were treated with vaniprevir alone or in combination with BMS-788329 for four weeks. Vaniprevir monotherapy reduced serum HCV RNA titers in mice, but viral breakthrough was observed in mice with high HCV titers. Ultra-deep sequence analysis revealed a predominant replacement by drug-resistant substitutions at 168 in HCV NS3 region in these mice. Conversely, in mice with low HCV titers, HCV was eradicated by vaniprevir monotherapy without viral breakthrough. In contrast to monotherapy, combination treatment with vaniprevir and BMS-788329 succeeded in completely eradicating HCV regardless of serum viral titer. IFN-alpha treatment significantly increased ISG expression; however, vaniprevir and BMS-788329 combination treatment caused no increase in ISG expression both in cultured cells and in mouse livers. Therefore, combination treatment with vaniprevir and BMS-788329 eliminated HCV via a non-ISG-mediated mechanism. This oral treatment might offer an alternative DAA combination therapy for patients with chronic hepatitis C.

Brief Report: Reduced Cell-Associated HTLV-2 DNA in Antiretroviral Treated HIV-1-HCV-Coinfected Patients Who Either Received Interferon-α/Ribavirin-Based Hepatitis C Therapy or Had Spontaneous HCV RNA Clearance.

We analyzed the effect of interferon α (IFN-α) and ribavirin (RBV) therapy on cell-associated human T-lymphotropic virus type 2 (HTLV-2) DNA in HIV-1-coinfected patients receiving antiretroviral therapy. Sixty-one patients under suppressive antiretroviral therapy were included: 37 with hepatitis C virus (HCV) infection, 15 with sustained virologic response (N = 10), relapse (N = 2), or with nonresponse (N = 3) after IFN-α/RBV treatment, and 9 with spontaneous HCV RNA clearance. Patients who were treated with IFN-α/RBV or had spontaneous HCV clearance had lower level of cell-associated HTLV-2 DNA (P = 0.022 and P = 0.040, respectively). Both IFN-alpha treatment and the ability to spontaneously clear HCV infection seem to reduce cell-associated HTLV-2 DNA in HIV-1-coinfected patients.

Age-related increases in basal ganglia glutamate are associated with TNF, reduced motivation and decreased psychomotor speed during IFN-alpha treatment: Preliminary findings

Inflammation-induced alterations in central nervous system (CNS) metabolism have focused on glutamate. At excessive concentrations, glutamate is toxic to glia and neurons, and inflammatory cytokines have been shown to influence glutamate turnover by blocking glutamate reuptake and increasing glutamate release. Increased glutamate has also been found in depression, a disorder associated with increased inflammation. Data by our group have shown increased glutamate as measured by magnetic resonance spectroscopy (MRS) in basal ganglia and dorsal anterior cingulate cortex of patients administered the inflammatory cytokine interferon (IFN)-alpha. Given data that increasing age is associated with an exaggerated CNS inflammatory response, we examined whether older age (>55years) would be associated with a greater IFN-alpha-induced increase in CNS glutamate. Using a longitudinal design, 31 patients with hepatitis C virus (HCV) underwent MRS, blood sampling for inflammatory markers, and behavioral assessments before (Visit 1) and after 4weeks (Visit 2) of either IFN-alpha (n=17) or no treatment (n=14). Older patients treated with IFN-alpha exhibited a significantly greater increase in glutamate from Visit 1 to Visit 2 as reflected by the glutamate/creatine ratio (Glu/Cr) in left basal ganglia compared to older controls and younger IFN-alpha-treated and untreated subjects. In addition, increased Glu/Cr in older but not younger IFN-alpha-treated and untreated patients was associated with increased tumor necrosis factor, reduced motivation as measured by the Multidimensional Fatigue Inventory and increased choice movement time on the Cambridge Neuropsychological Test Automated Battery. Taken together, these preliminary data support the notion that older age may interact with inflammation to exaggerate the effects of inflammatory stimuli on CNS glutamate and behavior.

Distinct DC subsets are not equally susceptible to HTLV-1 infection

Beside lymphocytes, HTLV-1 can infect monocytes, blood- or monocytes-derived dendritic cells (DCs) and plasmacytoid DCs in vitro. Considering that DCs might be the first cells to be infected during primo infection, we hypothesize that they may constitute viral reservoirs and eventually spread the virus to surrounding lymphocytes. Interestingly, ATL and HAM/TSP diseases display opposite immunological features, i.e. an impaired CTL response versus a chronic inflammation respectively. Since DCs are major effectors of both innate and adaptative immune responses, infection of specific DC subsets and the subsequent alteration of their functions might also lead to the orientation of the adaptive immune response towards either viral tolerance associated with impaired CTL responses or chronic inflammation, and thus directly participate to the determination of the infection outcome. Using various cytokines cocktails, we therefore generated distinct monocytes-derived DC (MDDC) subsets and infected these cells with HTLV-1 biofilm. We first show that the different MDDC subsets are not equally susceptible to HTLV-1 infection, as measured by FACS analyses and real time PCR assays. We then show that following infection, DC activation or IFN alpha production are not affected by infection in the MDDC subtypes tested. However, while DC maturation alters their susceptibility to the virus, we demonstrate that IFN alpha treatment does not. Finally, the ability of MDDC subsets to transmit HTLV-1 to T-cells will be discussed. Taken together, our results suggest that differential susceptibility of various DC subsets to HTLV-1 infection could differently shape immune responses and therefore affect viral pathogenesis.

A selective defect in Fas-mediated apoptosis in HAM/TSP: An ex vivo, in vitro and in silico study

Fas/FasL-mediated apoptosis is crucial for a functional immune response, with deficient Fas/FasL expression being linked to several autoimmune diseases. In addition, a FAS-670 polymorphism in an interferon (IFN)-regulated STAT1-binding site has been associated to both ATL (Farre et al., 2008) and HAM/TSP (Vallinotto et al., 2012) susceptibility. Recently, Fas has also been identified as part of an IFN-regulated gene signature in HAM/TSP (Tattermusch et al., 2012). Therefore, we examined Fas expression and function in lymphocyte activation, apoptosis, lymphoproliferation and gene expression profiling, using polychromatic flow cytometry, thymidine incorporation and microarray analysis (Affymetrix) respectively, in PBMCs from 20 HAM/TSP patients, 30 asymptomatic HTLV-1-infected individuals and 34 healthy controls (Salvador-Bahia, Brazil). Fas expression was increased in both asymptomatic HTLV-1-infected individuals and HAM/TSP patients, as compared to uninfected controls. In HAM/TSP, Fas expression correlated positively to lymphocyte activation markers (HLA-DR, CD86), but negatively to disease duration, suggesting that Fas-mediated pro-apoptotic capacity decreases over time in patients. Likewise, increased Fas expression in HAM/TSP did not lead to increased apoptosis upon in vitro culture. However, in HAM/TSP patients, IFN-alpha-induced Fas expression was paralleled by decreased lymphoproliferation, suggesting a link between defective Fas-mediated apoptosis and excessive lymphoproliferation, a hallmark of HTLV-1 infection, which can be restored by IFN-alpha treatment. Taken together, our results suggest defective Fas-mediated apoptosis might be an additional factor of HAM/TSP pathogenesis, besides its recently identified IFN gene signature.

Disturbances of Tryptophan Metabolism and Risk of Depression in HCV Patients Treated with IFN-Alpha.

Depression is a common side-effect of interferon (IFN)-alpha treatment of hepatitis C virus (HCV) infection and melanoma. Disturbances of tryptophan (TRP) metabolism might contribute to development of IFN-alpha–associated depression due to IFN-alpha-induced activation of indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme of TRP–kynurenine (KYN) metabolism. The increased frequency of high producer (T) allele of IFN-gamma (IFNG) (+874) gene, that encodes IFNG production, in depressed patients suggested that increased IDO activity might be a risk factor for depression. The present study assessed KYN/TRP ratio (KTR) as a marker of IDO activity in American Caucasian HCV patients awaiting IFN-alpha treatment. KTR did not differ between 43 patients who did and 37 patients who did not develop depression. TRP concentrations were higher in patients who experienced depression. Odds of development of depression increased with elevation of serum TRP levels from 33% (TRP levels <12000 pmol/ml) to 68% (TRP levels > 16000 pmol/ml). Elevated serum TRP may reflect the impairment of TRP conversion into serotonin in agreement with suggested link between serotonin deficiency and depression. Up-regulation of IDO might be an additional risk factor of IFN-alpha–associated depression. Future studies shall explore the causes of elevated serum TRP in relation to IFN-alpha–associated depression.

114. Inflammation induced changes in Anterior Cingulate Cortex Glutamate is associated with Depression and Fatigue

Behavioral symptoms including depression and fatigue are well-known consequences of activated peripheral immunity. Increased glutamate turnover in mood-regulating brain regions targeted by inflammatory mediators such as cytokines might mediate this relationship. We used single voxel proton magnetic resonance spectroscopy (MRS) to quantify glutamate concentrations in the anterior cingulate cortex (ACC) before and after four weeks of exposure to interferon (IFN)-alpha. IFN-alpha is an inflammatory cytokine used in the treatment of hepatitis C virus (HCV) infection that is known to cause depression and fatigue up to 50% of patients depending on the dose. Sixteen HCV patients underwent MRS scans, behavior ratings and immune marker assessments before and after 4 weeks of IFN-alpha treatment. Fourteen HCV control patients awaiting IFN-alpha therapy were studied in parallel. IFN-alpha administration was associated with significant increases in glutamate concentrations measured as glutamate/creatine (Glu/Cr) ratios in the ACC. Increases in the Glu/Cr ratio in the ACC was in turn correlated with increases in plasma soluble tumor necrosis factor 2 receptor (r = 0.54, p < 0.002), depression (r = 0.53, p < 0.003) and fatigue (r = 0.41, p < 0.03). The above findings are consistent with previously reported changes in ACC function among HCV patients following IFN-alpha treatment and among healthy volunteers administered immune stimuli including typhoid vaccination. These data suggest that altered glutamate metabolism as a result of impaired glial function may contribute to ACC changes following immune activation.

1267 – Functional polymorphism in the interleukin-6 gene (IL-6 rs1800795), and depression induced by interferon-alpha and ribavirin during the HCV treatment

The inflammatory response system is important in the pathophysiology of depressive symptoms that are frequent side effects of interferon-alpha (IFN-alpha) treatment. The functional rs1800795 IL-6 promoter SNP [-174 IL-6 (G > C)] has been described, with ‘CC’ genotype associated with lower synthesis of IL-6. The present study was carried out to determine whether rs1800795 IL-6 polymorphism is associated with severity of depression developed during IFN-alpha and ribavirin treatment. We included 54 Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus infection in the prospective cohort study. Symptoms of depression (Montgomery - Åsberg Depression Rating Scale, MADRS, Beck Depression Inventory, BDI) and neuroticism (Eysenck Personality Questionnaire - Revised, EPQ-R/N) were assessed before treatment, just after treatment and 24 weeks after treatment. The mean MADRS ratings were higher in subjects with genotype ‘CC’ (p> 0.1). On the other hand, the BDI and EPQR/ N ratings were higher, and more stable in patients with ‘GG’ genotype (p> 0.1). Higher changes and the lowest values 24 weeks after the end of treatment were associated with ‘CC’ genotype (p< 0.05). The mean values were as follows (begin, end of treatment, 24 weeks after treatment): MADRS ‘CC’ (8.7, 11.3, 4.8), ‘GG’ (6.9, 11.1, 6.0); BDI ‘CC’ (6.9, 8.9, 3.2), ‘GG’ (8.4, 11.3, 6.2); EPQ-R/N ‘CC’ (8.3, 10.1, 7.3), ‘GG’ (10.4, 10.9, 9.2). Genotype ‘CC’ of IL-6 rs1800795 polymorphism is associated with bigger differences in BDI and EPQ-R/N ratings during IFN-alpha and ribavirin treatment, and lower ratings after treatment.

Association between genetic mutations and the development of autoimmune thyroiditis in patients with chronic hepatitis C treated with interferon alpha

BackgroundConsiderable progress was made by the introduction of interferon to the treatment of chronic hepatitis C virus infection. This treatment, however, is associated with the risk of developing or exacerbating autoimmune diseases, with chronic autoimmune thyroiditis being one of them. The aim of our study was to evaluate the predisposition to autoimmune thyroiditis in patients with chronic hepatitis C virus during IFN-alpha therapy, depending on the presence of polymorphisms in the promoter region of CTLA-4C (−318)T gene and in exon 1 of A49G gene as well as C1858T transition of PTPN22 gene.MethodsThe study was conducted in 149 patients aged between 18 and 70 years (mean of 43.9 years), including 82 men and 67 women. Control group for the assessment of the distribution of analyzed polymorphism of genotypes consisted of 200 neonates, from whom umbilical blood was drawn for the tests. The patients were divided into three groups: group 1 consisted of 114 patients without thyroid impairment before and during IFN-alpha therapy, group 2 contained 9 patients with AT with the onset prior to IFN-alpha treatment, and group 3 comprised 26 patients with AT starting after the beginning of IFN-alpha therapy.ResultsThe frequency of C1858Tand C(−318)T genotypes observed in the study group did not differ significantly from control group. A significant difference, however, was found for A49G polymorphism.ConclusionsNo association was demonstrated between the occurrence of autoimmune thyroiditis with the onset during IFN-alpha therapy and the presence of polymorphisms within CTLA-4 C(−318)T gene in the promoter region and A49G in exon 1, as well as C1858T transition of PTPN22 gene.

Role of Interferon-gamma and Immune Response Biomarkers in Predicting IFN-alpha Responsiveness and Treatment Outcome in Patients with Hepatitis C Virus

Role of Interferon-gamma and Immune Response Biomarkers in Predicting IFN-alpha Responsiveness and Treatment Outcome in Patients with Hepatitis C Virus

178. Interferon-alpha-induced fatigue is associated with alterations in CNS glutamate metabolism as measured by magnetic resonance spectroscopy

Peripheral inflammatory states and their behavioral consequences including fatigue have been well-documented. One mechanism that may contribute to inflammation-induced behavioral changes is alterations in central nervous system (CNS) glutamate metabolism. To examine the role of CNS glutamate in inflammation-induced fatigue, proton magnetic resonance spectroscopy ( MRS ) was conducted in 12 patients with hepatitis C (HCV) before and after 4 weeks of treatment with interferon ( IFN )- alpha compared to 12 HCV patients awaiting IFN-alpha therapy. IFN-alpha is an inflammatory cytokine well-known to induce symptoms of fatigue in a high percentage of patients. Compared to controls, the glutamate /creatine ratio in the left basal ganglia significantly increased following 4 weeks of IFN-alpha administration ( p < 0.05). This increase in the glutamate /creatine ratio was in turn significantly correlated with increases in fatigue severity ( r = 0.435, p = 0.034). Increased glutamate concentrations in the left basal ganglia are consistent with previously reported alterations in basal ganglia function following IFN-alpha treatment in cancer patients and patients with HCV. The data are also consistent with changes in basal ganglia function in healthy volunteers administered immune stimuli including endotoxin or typhoid vaccination. These data suggest that altered glutamate metabolism possibly as a result of altered glial function may contribute to basal ganglia changes following acute and chronic immune activation.

Sustained efficacy of α-interferon therapy combined with yixuesheng capsule in treatment of chronic Hepatitis B

To observe the difference between the combination therapy of alpha-interferon (IFN-alpha) therapy Yixuesheng Capsule and the monotherapy of IFN-alpha in treatment of chronic hepatitis B. A total of 288 patients with HBeAg-positive chronic hepatitis B proven by liver biopsy were included in this study. During the individualized therapy, they received hypodermic injection of IFN-alpha 1b, with 5 MU x time(-1) and three times x w(-1). Of them, 125 patients received combination therapy with Yixuesheng Capsule for three months, with 1.0 g/time and three times/d; and 163 patients received only IFN-alpha 1b (the IFN-alpha monotherapy group). After the course of therapy, all patients were followed up for at least 24 months. The intention-to-treat analysis was adopted for statistic analysis. The two groups showed no statistical significance by gender, age, liver necroinflammation grading, liver fibrosis staging, serum ALT levels, serum HBV DNA levels and IFN-alpha therapy course. The whole course and the 24-month follow-up visit cover all of 112 patients in the combination treatment group and 141 cases in the IFN-alpha monotherapy group. The response rates of the combination treatment group and the IFN-alpha monotherapy group were 48.0% (60/125) and 35.0% (57/163) (x = 4.980, P = 0.026) at the end of treatment, respectively, 45.6% (57/125) and 33.1% (54/163) (x2 = 4.645, P =0.031) at the end of 12-month-follow-up period, respectively, and 38.4% (48/125) and 32.5% (53/163) (x2 = 1.076, P = 0.300) at the end of 24-month follow-up period, respectively. The combination treatment with IFN-alpha and Yixuesheng Capsule shows a slightly better sustained efficacy on HBeAg-positive chronic hepatitis B patients compared with IFN-alpha monotherapy.

Exogenous IFN-alpha Administration Reduces Influenza A Virus Replication in the Lower Respiratory Tract of Rhesus Macaques

To determine the role of innate immune responses in controlling influenza A virus replication, rhesus macaques (RM) were administered pegylated IFN-alpha prior to virus challenge. Systemic and mucosal pegylated IFN-alpha administration induced expression of the interferon-stimulated genes (ISG) MxA and OAS in the airways. RM treated with IFN-alpha 24 hours prior to influenza virus challenge had significantly lower peak vRNA levels in the trachea compared to untreated animals. In addition to blunting viral replication, IFN-alpha treatment minimized the weight loss and spike in body temperature after influenza infection of RM. These results confirm the importance of IFN-alpha induced innate immune responses in the rapid control of influenza A virus replication in primates.