Interferon-alpha Therapy Research Articles

Induction of Vogt-Koyanagi-Harada Disease by Interferon-Alpha and Ribavirin Treatment in Patients with Hepatitis C: A Case Report and Review of the Literature

ABSTRACTPurpose: To describe a case of Vogt-Koyanagi-Harada disease (VKH) presenting in a hepatitis C patient after interferon-alpha (IFN-α) and ribavirin treatment.Methods: A retrospective review of our patient and a review of the published literature.Results: A 59 year-old man developed VKH after the four months of IFN-α and ribavirin therapy for hepatitis C. The patient’s VKH was controlled by systemic corticosteroids. The relationship between VKH and IFN-α is discussed based on the published literature.Conclusions: VKH is a rare autoimmune complication triggered by interferon-alpha therapy; the T-cell modulatory properties of IFN-α possibly contribute to this association. Early diagnosis of VKH and aggressive systemic corticosteroid intervention are essential for this type of IFN-α -related autoimmune complication.

Tocilizumab for the Treatment of Behçet Uveitis that Failed Interferon Alpha and Anti-Tumor Necrosis Factor-Alpha Therapy

ABSTRACTPurpose: To report the results of tocilizumab (TCZ) treatment in patients with Behçet uveitis (BU) who had failed conventional, interferon alpha, and anti-Tumor necrosis factor-alpha therapy.Methods: We reviewed the records of five patients with BU treated with monthly infusions of TCZ 8 mg/kg. Outcome measures were visual acuity, anterior chamber cells, laser flare meter (LFM) readings, vitreous haze, central macular thickness (CMT), and fluorescein angiography (FA) score.Results: The clinical inactivity of BU and 20/50 or better vision were achieved in three female and two male patients treated with TCZ for 5–19 months. The mean LFM reading was reduced from 15.4 ± 2.7 to 5.0 ± 0.9 ph/ms; the mean CMT from 324.7 ± 36.6 µm to 280.2 ± 34.1 µm; and the mean FA score from 20.6 ± 5.4 to 9.3 ± 4.5 µm at the last visit. The only side effect was a slight elevation of the total cholesterol level in one patient.Conclusions: Tocilizumab may be a safe and effective therapeutic option for refractory BU.

Abstract 3971: MTA-mediated inhibition of human T cells: Mechanism and MTAP overexpression as putative overcoming strategy

Abstract Metabolic changes of malignant cells lead to the secretion of tumor metabolites which contribute to the shaping of a favorable milieu for tumor immune escape facilitating cancer development and resistance to anti-tumor immunotherapy. Recently, disrupted methylthioadenosine metabolism drew interest as further putative immunoinhibitory metabolic dysregulation. A broad spectrum of tumor entities was reported to lack methylthioadenosine phosphorylase (MTAP) expression leading to elevated levels of its substrate 5’-deoxy-5’-methylthioadenosine (MTA). MTAP deficiency is reported to correlate with worse response to adjuvant interferon-alpha therapy and a higher risk for metastatic disease in malignant melanoma providing evidence for immunobiological relevance. We therefore examined the effect of the tumor metabolite MTA on human T cell responses. We could show that MTA has a strong inhibitory impact on human T cell function regarding proliferation, viability, activation, differentiation, tumor antigen-specific expansion and cytotoxicity. We therefore aimed to overexpress MTAP in human T cells by retroviral transduction as a putative strategy to overcome MTA-mediated inhibition of T cells. In addition, we investigated the effect of MTA on T cell metabolism and maturation of human monocyte derived mDC. We successfully generated stable MTAP-overexpressing primary human T cells. First studies were performed to examine the resistance to MTA after equipping the T cells with higher levels of its metabolizing enzyme MTAP. MTAPhigh T cells revealed less sensitivity against inhibitory effects of MTA on proliferation, viability or cytotoxicity compared to mock transduced controls suggesting a promising approach to strengthen the performance of T cells facing the MTA-rich milieu of MTAP-deficient tumors. Mechanistically, we found MTA to interfere with several signaling pathways. Of most importance, MTA impaired Akt phosphorylation as well as intracellular protein methylation, both crucial processes for proper T cell function. In addition, we studied the combined effect of MTA and PRMT5 inhibition on T cells. Several metabolic studies focusing on glycolysis and fatty acid metabolism could confirm our findings that MTA keeps T cells in a rather inactive, naïve state. Finally, we found MTA to interfere with DC maturation and their potential to induce cytokine secretion of T cells. Our data emphasizes the crucial role of tumor metabolites such as MTA in the tumor milieu for tumor immune escape. Additionally, the identification of potential molecular mechanisms of MTA-induced immunosuppression offer the opportunity to pharmacologically tackle MTA-mediated immunoinhibition and will help to develop more effective immune-based therapies against MTAP-deficient tumors. Citation Format: Carolin D. Strobl, Frederik Henrich, Katrin Singer, Katrin Peter, Marina Kreutz, Anita Kremer, Andreas Mackensen, Michael Aigner. MTA-mediated inhibition of human T cells: Mechanism and MTAP overexpression as putative overcoming strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3971. doi:10.1158/1538-7445.AM2017-3971

Metastasis of renal cell carcinoma to the thyroid gland 9 years after nephrectomy: A case report and literature review

We report a case presenting with thyroid and lung metastases of renal cell carcinoma that was treated with molecular targeted therapy followed metastasectomy. A 52-year-old female underwent radical nephrectomy of right renal cell carcinoma in 2007. The patient presented 9 years after nephrectomy at the age of 61 years with sudden loss of vision on the left side and a mass on the neck. On magnetic resonance imagining, there was a mass on the midline of the neck, extending to the left, measuring 46 x 31 mm and containing central cystic-necrotic areas. Fine-needle aspiration biopsy was performed. The histopathological examination of the biopsy specimen revealed a lesion composed of malignant epithelial cells compatible with metastasis of renal carcinoma. Computed tomography showed multiple metastases in bilateral lungs. Metastasectomy and total tiroidectomy were performed. Thyroid and lung metastasis of renal cell carcinoma were pathologically confirmed. But on the first computed tomography after metastasectomy, there was residual tumor in the thyroid. Interferon-alpha therapy was given for 8 weeks. After that, pazopanib therapy started. Three months later, on computed tomography, residual metastatic foci were regressed. The patient was followed up for 1 year after metastasectomy. The patient is currently receiving a single dose of pazopanib per day (400 mg/day) and the general condition is good. Thyroid metastasis should be considered in patients with a thyroid nodule and positive history for renal cell carcinoma. Successful results can be obtained with metastasectomy and systemic targeted therapy.

Increased serum level of soluble interleukin-2 receptor is associated with a worse response of metastatic clear cell renal cell carcinoma to interferon alpha and sequential VEGF-targeting therapy

BackgroundRenal cell carcinoma (RCC) is a tumor with immunogenic properties. Soluble interleukin-2 receptor (sIL-2R) has a role in T cell activation and may be important for immune regulation in various conditions, including infections, transplantation rejection, autoimmune inflammatory states, and cancer. We investigated the prognostic value of the serum sIL-2R level in patients with metastatic RCC receiving IFN-alpha and vascular endothelial growth factor (VEGF)-targeting therapy.MethodsWe monitored the serum level of sIL-2R over time and examined phosphorylated Akt expression by the primary tumor in 47 patients with metastatic clear cell RCC (ccRCC) undergoing cytoreductive nephrectomy followed by first-line adjuvant therapy with IFN-alpha plus sequential VEGF-targeting therapy as second- or third-line adjuvant therapy.ResultsA preoperative increase of the serum level of sIL-2R was correlated with a higher preoperative serum level of programmed cell death 1 (PD-1)-ligand 1 (PD-L1), increased expression of phosphorylated Akt by the primary tumor, and a worse response to IFN-alpha/sequential VEGF-targeting therapy, as well as being an independent prognostic factor for a shorter overall survival time by multivariate analysis. Over time, the serum sIL-2R level largely reflected the tumor response to therapy.ConclusionsMonitoring the serum level of sIL-2R may help to predict the biological behavior of ccRCC, its response to IFN-alpha/sequential VEGF-targeting therapy, and the prognosis.

Patterns of persistent HPV infection after treatment for cervical intraepithelial neoplasia (CIN): A systematic review.

A systematic review of the literature was conducted to determine the estimates of and definitions for human papillomavirus (HPV) persistence in women following treatment of cervical intra-epithelial neoplasia (CIN). A total of 45 studies presented data on post-treatment HPV persistence among 6,106 women. Most studies assessed HPV persistence after loop excision (42%), followed by conization (7%), cryotherapy (11%), laser treatment (4%), interferon-alpha, therapeutic vaccination, and photodynamic therapy (2% each) and mixed treatment (38%). Baseline HPV testing was conducted before or at treatment for most studies (96%). Follow-up HPV testing ranged from 1.5 to 80 months after baseline. Median HPV persistence tended to decrease with increasing follow-up time, declining from 27% at 3 months after treatment to 21% at 6 months, 15% at 12 months, and 10% at 24 months. Post-treatment HPV persistence estimates varied widely and were influenced by patient age, HPV-type, detection method, treatment method, and minimum HPV post-treatment testing interval. Loop excision and conization appeared to outperform cryotherapy procedures in terms of their ability to clear HPV infection. This systematic review provides evidence for the substantial heterogeneity in post-treatment HPV DNA testing practices and persistence estimates.

18F]Fluorodeoxyglucose Positron Emission Tomography Reveals a Complete Remission of Refractory Metastatic Melanoma after Therapy with Ipilimumab.

Ipilimumab (YERVOY) is a monoclonal CTLA-4-antibody with anti-tumor-immunogenic effect and is used to treat malignant melanoma. In this case study, we present [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) images of a 37-year-old woman with metastatic melanoma, who was previously treated with interferon-alpha therapy and dacarbazine and still progressed. After four cycles of ipilimumab, there was a complete remission of the disease with no evidence of vital, FDG-positive tumor tissue. The follow-up for a total of 1 year confirmed the therapeutic success. This report demonstrates that FDG-PET/CT is a reliable imaging method for response monitoring in metastatic melanoma treated with ipilimumab.

Outcomes of Patients with Myeloproliferative Neoplasms (MPN) after Interferon-Alpha (IFN) Therapy Discontinuation

▪Background:We and others have shown that IFN therapy provides several benefits to MPN patients (pts) including molecular responses and possible long-term remissions off cytoreductive therapy (CRT). However, little is known about outcomes after IFN discontinuation, and the clinical relevance of achievement of molecular response is disputed.Methods:We collected all cases of MPN pts followed in our institution who received IFN therapy since 2000, and who discontinued treatment. Cumulative incidences of relapse, hematological transformation and thrombosis were based on competing risks estimator. Survival curves and event free survival (EFS, i.e. time to first event including transformation, thrombosis and death) curves from IFN start were plotted based on the Kaplan Meier method. Univariate logistic models were used to predict complete hematological response (CHR) without any CRT; Cox models were used to predict EFS, and cause-specific hazard of relapse. Multivariable models were then fitted, with a stepwise selection procedure. All tests were two-sided with p-values ≤0.05 denoting statistical significance.Results:A total of 149 out of 333 IFN treated MPN pts had discontinued therapy at time of analysis. 78 had polycythemia vera (PV), 61 essential thrombocythemia (ET), and 10 myelofibrosis (MF). Reasons for choosing IFN in these 149 pts were young age in 75 (50%), resistance / intolerance to previous therapies in 40 (27%), pregnancy in 4 and other in 30. Median age at IFN start was 49.5 years [interquartile range, IQR: 39-60] and median [IQR] time since diagnosis of MPN was 2 years [0.6-6.8]. 64 pts had a history of vascular event.123 pts were JAK2V617F+, 15 had CALR, 5 MPL and 1 JAK2 exon 12 mutations, and 5 were triple-neg. Among 47 pts tested by NGS, 15 had additional mutations.Best response to IFN was CHR in 123 (83%), partial response (PR) in 16, and failure in 10 pts. Reasons for IFN discontinuation were toxicity in 79 (53%), prolonged hematological CHR in 52 (35%), and other in 18. Median IFN treatment duration was 28.3 months (mos) [10-45]. At discontinuation, 114 (77%) pts were in CHR, 17 (11%) in PR, and IFN failed in 18 (12%).At IFN start, median mutant allele burdenwere 25% [IQR: 15-48] and 38% [34-43] for JAK2 and CALR resp. At IFN discontinuation, median %JAK2 and %CALR had decreased to 10% [3-25], and 13.5% [6-43], resp.At last follow up, 109 (73%) pts were alive in CHR for a median time after IFN discontinuation of 42 mos [23-58], including 46 (42%) without CRT after 33 mos [19-53]. Based on a multivariable logistic model, the CHR without CRT was associated with mutant allele burden at IFN discontinuation (OR=0.95, 95%CI, 0.95-0.96, P=0.034), stopping for toxicity reason (OR= 0.82, 95%CI, 0.75-0.89, P= 0.009), and cumulative dose of IFN (OR=1.01/mg, 95%CI, 1.003-1.02, P= 0.012).Hematological relapse occurred in 49 pts. IFN was restarted in 25 of them and all achieved hematological response, including 72% CHR. Based on a multivariable Cox model, the cause-specific hazard of relapse was decreased in ET (HR= 0.4, 95%CI, 0.2-0.8; P= 0.013) while increased with the baseline WBC count (HR= 1.07, 95%CI, 1.02-1.14, P= 0.011).Ten pts had a thrombotic event after IFN, with a 5 year cumulative incidence of 10% (95%CI, 4-16%). A total of 11 pts transformed to MF, 3 to MDS / AML, and 2 from ET to PV; the 5-year cumulative incidence of transformation was 3.8% (95%CI, 0.4-7.2%). Six patients had died (4 after transformation). Overall, 25 patients developed a thrombosis, transformation or death. The 5- and 10-year EFS were 92% (95%CI, 87-97) and 72% (95%CI, 62-84), resp. In multivariate model, only time between diagnosis and IFN start (HR=1., 95%CI, 1.002-1.016, P=0.011) and mutant allele burden at IFN discontinuation (HR=1.03, 95%CI, 1.016-1.048, P<0.0001) remained jointly associated with the outcome. Pts with an allele burden ≥ 25% at discontinuation had a higher hazard of event (HR= 3.4, 95%CI, 1.3-9.3, P=0.0145).Conclusion: This study allowed for the first time identification or several parameters associated with major outcomes after IFN therapy. In particular, a lower mutant allele burden at IFN discontinuation was associated with persistent complete hematologic response without therapy and longer event-free survival, indicating a clinical relevance in obtaining a deeper molecular response. Our results also show that late onset of IFN therapy after MPN diagnosis is associated with poorer outcome. DisclosuresKiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Influence of JAK2V617F Allele Burden on Hematological Response in the Treatment of Polycythemia Vera

Background. The presence of the JAK2V617F mutation is a major criterion in diagnostic of Polycythemia Vera (PV). The role of JAK2V617F allele burden in the progression of PV is not completely understood. The significance of this variable for the progression of the disease, complications development and response to therapy are still a big question mark.Aim. To estimate the significance of the level of JAK2V617F allele burden in the treatment of PV.Methods. Seventy-nine patients (pts), 48 females and 31 males, were included in the study. PV was diagnosed from 1980 to 2016. Median age was 61 years (range, 28 - 85), median of the observation period was 4.9 year (0,2 - 35 years). JAK2V617F allele burden was studied in all pts. Patients received therapy with phlebotomy (erythrocytapheresis), hydroxyurea, interferon-alpha or combined therapy. Hematological response to the therapy was evaluated according to ELN criteria[1]. Differences between the groups were assessed with the Mann-Whitney U test.Results. Out of the 79 patients, complete hematological response (CHR) was achieved in 8 (10%) pts, partial response (PHR) in 48 (60.8%) pts, and no response was achieved (no response - NR) in 23 (29,2%) pts. The mean level of allele burden in the group of patients with PHR was 68%(CI 57%-79%), in that without response - 65%(CI 43%-86%), and in the group with CHR was 35% (CI 19%-50%). The JAK2V617F allele burden was significantly different between the groups with CHR and PHR (p<0,03). We also observed statistical trends (p<0,09) regarding differences between the groups with CHR and NR. The JAK2V617F allele burden by groups is shown in Figure 1. Consequently, patients who achieved CHR on treatment, had lower JAK2V617F allele burden compared to patients with PHR or NR to the therapy.Conclusion. The level of JAK2V617F allele burden can be a predictive marker of a response to treatment of PV. An individual approach to each patient, including a detailed study of molecular factors, is the key to successful prevention of complications and ensuring positive outcomes.[1] Barosi G, Birgegard G, Finazzi G, et al. Response Criteria for EssentialThrombocythemia and Polycythemia Vera: Result of a European LeukemiaNet(ELN) Consensus Conference. Blood. 2009 Mar 10 [Display omitted] DisclosuresShuvaev:Novartis pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Fominykh:Novartis Pharma: Honoraria; BMS: Honoraria.

Monitoring Molecular Response, Minimal Residual Disease and Clonal Structures in Polycythemia Vera Patients Treated with Interferon Alpha

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) primarily characterized by an elevated red blood cell count, consequently to clonal expansion of myeloid progenitor cells driven almost exclusively by a mutation of a specific single nucleotide in JAK2 exon 14 (JAK2-V617F). JAK2-V617F mutational burden therefore represents a surrogate measure for the size of the "liquid tumor" underlying PV, i.e. the amount of malignant cells in the peripheral blood. We previously reported on sustained molecular responses (MR) in PV patients on interferon alpha (IFNa) based therapies. Monitoring MR is crucial for understanding the therapeutic potential of IFNa and can be an important parameter in future PV patient care. Thus, highly sensitive laboratory techniques providing most accurate quantification at lowest limit of detection (LOD) are required. Here we evaluate four different methods for JAK2-V617F mutational burden monitoring, which are digital droplet PCR (ddPCR), next-generation sequencing (NGS), quantitative PCR (qPCR) and allele-specific PCR (AS-PCR). Moreover, using an NGS-based approach we investigate the patients' clonal composition by targeted re-sequencing involving 54 genes in longitudinal patient samples.To determine the characteristics of the different methods for burden quantification, we benchmarked a ddPCR assay (Assay ID dHsaCP2000061/dHsaCP2000062, Bio-Rad, Hercules, CA) using serial dilutions of JAK2-V617F positive in JAK2-V617F negative gDNA. The assay showed an LOD of 0.01% JAK2-V617F with a false positivity rate of 0 mutation-positive droplets in 8 independent measurements of healthy donor gDNA. Next we quantified the JAK2-V617F burden in baseline and follow-up (FU) gDNAs from a PV patient cohort on IFNa-based therapy (n=51) using ddPCR, a qPCR-based assay (ipsogen MutaQuant, Qiagen, Hilden, Germany), an NGS-based approach (TruSight Myeloid Sequencing Panel, Illumina, San Diego, CA) and an AS-PCR assay described previously (Kralovics et al, Blood, 2006). Covering the full spectrum of allelic burden values, correlations with ddPCR-derived values were best for NGS (R2=0.998) followed by qPCR (R2=0.976) and AS-PCR (R2=0.951). While mutational burden values >10% JAK2-V617F showed high concordance between methods, JAK2-V617F burdens <10% exhibited significant deviations from the benchmarked ddPCR assay, suggesting that ddPCR is most suitable for monitoring residual disease in PV. Therefore, applying ddPCR, we next re-evaluated two PV patients with baseline JAK2-V617F burdens of 46% and 28%, respectively, both previously classified as complete MR based on JAK2-V617F undetectable by AS-PCR. For those two patients, ddPCR revealed an actual residual disease of 3.02% and 2.39% mutant allele burden at 138 and 68 weeks post initiation of IFNa therapy, respectively. Further monitoring of these patients showed a sustained decrease in mutant allele burden to 1.53% and 0.20% at weeks 217 and 171, respectively.In addition to JAK2-V617F burden quantification, our NGS approach allowed for quantitative evaluation of mutations in 54 genes implicated in myeloid diseases. After somatic variant calling, paired analysis of baseline and FU samples (n=96) from 48 PV patients revealed an average of 2.8 variants per patient in a total of 17 genes. Besides JAK2, recurrently affected genes were TET2, PHF6, ASXL1 and CEBPA. The paired analysis allowed for tracking changes in clonal structures upon therapy. Most notably, TET2-JAK2 double-positive clones present in two patients showed mutant burden decreases of 13% and 59% respectively, arguing against an implication of TET2 mutations in IFNa resistance. Furthermore, PHF6 positive clones present in three patients showed ambiguity upon therapy, shrinking concordantly with the JAK2 positive clone in two patients while expanding as a JAK2-independent clone in the third patient.In summary, while larger studies will be required to assign statistical significance to mutations implicated in IFNa-based therapies, targeted re-sequencing of serial samples in MPN patient cohorts has the potential to deconvolute the impact of the patients' clonal architecture on therapeutic success. Moreover, as medications such as IFNa-based drugs have been shown to induce deep MR in a substantial fraction of PV patients, the use of highly accurate assays such as ddPCR will be crucial for monitoring minimal residual disease. DisclosuresKlade:AOP Orphan: Employment. Gisslinger:Baxalta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria. Hoermann:Novartis: Honoraria; Ariad: Honoraria; Gilead: Research Funding; Amgen: Honoraria. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees.

Interleukin 10 gene single nucleotide polymorphisms in Polish patients with chronic hepatitis C: Analysis of association with severity of disease and treatment outcome

It is suggested that interleukin 10 (IL-10), as a modulator of immune response, is likely to influence the elimination of hepatitis C virus (HCV), the progression of chronic hepatitis C (CHC) and the response to interferon-based therapy in CHC patients. The aim of the study was to analyze the association of single nucleotide polymorphisms (SNPs) of IL-10 gene with severity of liver disease (degree of inflammation and stage of fibrosis) and outcome of pegylated interferon alpha and ribavirin combined therapy (sustained virological response (SVR) and relapse) in 196 Polish CHC patients infected with HCV genotype 1. The analysis included IL-10 promoter SNPs: −1082(A/G) rs1800896, −819(C/T) rs1800871, −592(C/A) rs1800872 and SNP in the 3′ UTR of IL-10 gene: +4529(A/G) rs3024498. Genotyping was performed using PCR-RFLP and HRM analysis. It was demonstrated that the −592C allele is associated with mild hepatic inflammation. Moreover, it was found that the −819C allele might be associated with SVR and that the ACCA haplotype and intermediate IL-10 producer ACC haplotype are associated with SVR and non-relapse. It can be concluded that IL-10 SNPs are associated with severity of disease and response to therapy and may be considered as potential prognostic and predictive markers in CHC.

Depression and anxiety in patients receiving interferon-alpha: The role of illness perceptions.

Development of psychiatric symptoms during interferon-alpha therapy may be influenced by psychological factors. We examined illness perceptions using the Revised Illness Perceptions Questionnaire in 55 patients with chronic hepatitis C virus infection, due to receive interferon-alpha. The Hospital Anxiety and Depression Scale was used to assess the development of symptoms. Negative identity, consequences and emotional representation beliefs were significantly associated with both higher depression and anxiety scores. Negative illness perceptions play a predictive role in the development of interferon-alpha-induced psychiatric symptoms.

Liver-specific mono-unsaturated fatty acid synthase-1 inhibitor for anti-hepatitis C treatment

Recently, direct antiviral agents against hepatitis C virus (HCV) infection have been developed as highly effective anti-HCV drugs. However, the appearance of resistant viruses against direct anti-viral agents is an unsolved problem. One of the strategies considered to suppress the emergence of the drug-resistant viruses is to use drugs inhibiting the host factor, which contributes to HCV proliferation, in combination with direct anti-viral agents. The replication complex was reported to be present in the membranous compartment in the cells. Thus, lipid metabolism modulators are good candidates to regulate virus assembly and HCV replication. Recent studies have shown that stearoyl-CoA desaturase (SCD), an enzyme for long-chain mono-unsaturated fatty acid (LCMUFA) synthesis, is a key factor that defines HCV replication efficiency. Systemic exposure to SCD-1 inhibor induces some side effects in the eyes and skin. Thus, systemic SCD-1 inhibitors are considered inappropriate for HCV therapy. To avoid the side effects of systemic SCD-1 inhibitors, the liver-specific SCD-1 inhibitor, MK8245, was synthesized; it showed antidiabetic effects in diabetic model mice with no side effects. In the phase 1 clinical study on measurement of MK8245 tolerability, no significant side effects were reported (ClinicalTrials.gov Identifier: NCT00790556). Therefore, we thought liver-specific SCD-1 inhibitors would be suitable agents for HCV-infected patients. MK8245 was evaluated using recombinant HCV culture systems. Considering current HCV treatments, to avoid the emergence of direct anti-viral agents-resistant viruses, combination therapy with direct anti-viral agents and host-targeted agents would be optimal. With this viewpoint, we confirmed MK8245’s additive or synergistic anti-HCV effects on current direct anti-viral agents and interferon-alpha therapy. The results suggest that MK8245 is an option for anti-HCV multi-drug therapy with a low risk of emergence of drug-resistant HCV without significant side effects.

Effect of interferon alpha therapy on chronic hepatitis C patients with croglobulinemia (clinical &amp; laboratory)

Effect of interferon alpha therapy on chronic hepatitis C patients with croglobulinemia (clinical &amp; laboratory)

Treatment Response of Chronic Hepatitis C Patients and Health-Related Quality of Life

Objective(s): The objectives of present study were to investigate the response of chronic hepatitis C (CHC) patients to pegylated interferon alpha plus ribavirin (PEG-INF/RBV) combination therapy, to identify factors that could predict their response to treatment and to assess their health-related quality of life (HRQOL) before, during and after PEG-INF/RBV combination therapy. Methods: An intervention study (one group pre-test - post-test design) was used. Data were collected from 300 CHC patients who attended the Hepatology and Interferon Therapy Unit at Gamal Abd El Naser Insurance Hospital using a pre-designed structured interviewing questionnaire and viral hepatitis C quality of life questionnaire. Review of the patients’ medical records and their laboratory investigations was also carried out. Results: The cumulative seronegativity rate of treated patients was 74%. The proportion of CHC patients who survived seronegativity was 0.270 at the 12 th week, 0.261 at the 24 th week and 0.250 at the 48 th week of treatment. Patients’ age and viral load significantly affected seronegativity. Significant univariate main effects for age were statistically associated with poor HRQOL in the domains of physical functioning, role limitations due to physical health, emotional problems and pain. Presence of chronic diseases and HC viral load had a significant effect on physical functioning, role limitations due to physical health problems, emotional problems and pain. All domains of the HRQOL short form (SF36) decreased by the end of the 4 th week and started to increase at the 24 th and 48 th weeks of the follow up period. Conclusion: The proportion of CHC patients who survived seronegativity was 0.250 at the 48 th week of treatment. Factors associated with seroconversion were age and hepatitis C virus (HCV) load. CHC patients aged 55 years and above, those with chronic diseases and those with HC viral load of ≥ 900,000 IU/ml were found to be statistically associated with poor HRQOL. All the domains of the SF36 decreased by the end of the 4 th week and started to increase at the 24 th and 48 th weeks of follow up period. Keywords: hepatitis C, treatment, quality of life.

KIR2DS2 as predictor of thrombocytopenia secondary to pegylated interferon-alpha therapy.

Our aim was to evaluate the killer cell immunoglobulin-like receptors (KIRs) as a marker for the development of thrombocytopenia secondary to Peg-interferon (IFN) therapy in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients. Patients were naive to HCV treatment, receiving a first course of Peg-IFN/Ribavirin combination therapy. Total platelet count (cells ml-1) was determined at each visit, determining platelet decline from baseline to weeks 1, 2, 4, 8 and 12 after starting therapy. The end point of the study was development of thrombocytopenia, defined as a platelet count of <1 50 000 cells ml-1. Fifty-eight HIV/HCV co-infected patients were included in the study, of whom 20 (34.4%) developed thrombocytopenia. The absence of KIR2DS2 was associated with higher and faster rate of thrombocytopenia (54.2% vs 22.5%; P=0.012; 6.6 vs 10.3 weeks; P=0.008). The absence of KIR2DS2 was associated with a greater decline in platelet count and development of thrombocytopenia during Peg-IFN treatment in HIV/HCV co-infected patients.

Manic episode associated with interferon alpha therapy: A case report

Interferon alpha is a cytokine with antiviral and antineoplastic action, which is commonly used for treatment of Hepatitis C and B, malignant melanoma, Kaposi's sarcoma, kidney cancer and certain hematologic diseases. It is well-known some of its neuropsychiatric symptoms such as depressive symptoms, cognitive impairment, chronic fatigue, dysphoria and anxiety, but there are also other less common like mania, psychotic symptoms and suicide risk that have been reported. These symptoms interfere in the quality of life very significantly, which at the end can affect treatment adherence.We report a case of a 33-year-old man who was taken to the emergency department by his family referring nervousness, irritability, verbose, and insomnia during the last 5 days. The patient had not psychiatric history. He was diagnosed with a malignant melanoma stage III A a year ago which required to start interferon alpha treatment.Patient and family tell that symptoms began after forgetting last interferon dose. In the psychopathology exploration, we could observe mood lability, delusion ideas of prosecution, which includes his entire family and autorreferentiality. In the emergency room the blood test, urine drug test and CT were normal.During the admission, and in collaboration with the Oncology service, it was agreed the reintroduction and maintenance of interferon combined with olanzapine up to 30 mg/day and clonazepam up to 6 mg/day, which resulted in the resolution of symptoms in two weeks.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Sex differences in depressive symptomatology in patients with chronic hepatitis C during pegylated interferon alpha therapy: A 72-week prospective study

IntroductionTreatment with pegylated interferon alpha (PEG-IFN-α) is associated with depression more frequently in chronic hepatitis C (CHC) patients than with other inflammatory diseases.ObjectivesTo prospectively asses sex differences in the prevalence of depression in CHC patients during the PEG-IFN-α, as well as in the CHC group with no therapy.MethodsSample consisted of 103 subjects with CHC on the PEG-IFN-α and 103 subjects with CHC without interferon therapy. The diagnosis of depressive disorder was established by using Structured Clinical Interview and Criteria of International Classification Disorder. The severity of depression was assessed by using Hamilton Depression Rating Scale (HAMD ≥ 8) prior to PEG-IFN-α (baseline) and at the follow-up visits (4th, 12th, 24th, 48th, 72nd week).ResultsDuring the course of PEG-IFN-α, 49.5% of subjects showed depressive symptomatology (HAMD ≥ 8). Except at baseline and in the 72nd week, on the all other follow-up visits the prevalence of depression was significantly higher in female subjects (*all Ps &lt; 0.05). The strongest difference was observed in the 12th week: of all the subjects with HAMD ≥ 8, 68.8% were female and 32.7% were male (P &lt; 0.001). The multivariate logistic regression model showed that female sex is a very strong predictor for the development of depression during the interferon treatment [Exp (B) = 6.729]. There were no significant sex differences in the prevalence of depression in the control group.ConclusionsOur study (the longest study in this area) indicate that the prevalence of depression is significantly higher in female subjects with CHC during antiviral treatment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

MicroRNA expression in chronic Hepatitis C patients treated with combined pegylated interferon alpha and ribavirin therapy

The role of microRNAs (miRNA) in many diseases, including chronic hepatitis, represents an interesting research field. The current work aimed to study the effect of combination therapy (pegylated interferon alpha-2b plus ribavirin) on microRNA-128 (miR-128) and microRNA-296 (miR-296-5p) expression in patients with chronic hepatitis C. Also, we aimed to investigate the potential value of both types of microRNAs in differentiation between responders and non-responders either in the pre-treatment or post-treatment groups. Sixteen patients with chronic hepatitis C were compared to 10 healthy, age and sex matched controls. Venous blood samples were withdrawn before initiation of combination therapy and 12 weeks later and qPCR was used for gene expression assays. Comparison of pre-treatment group to the control group showed significant miR-128 down-regulation, while miR-296-5p showed a non-significant downregulation. Regarding post-treatment group, there was non-significant upregulation of miR-128, while miR-296-5p was significantly downregulated compared to either pre-treatment group or the control group. Comparative studies of miR-128 and miR-296-5p in responders versus non-responders showed non-significant fold change either in the pre- or post-treatment groups. It could be concluded that chronic hepatitis C as well as the combination therapy modulate miR-128/296 expression. Until now, miRNAs studied were not useful indicators to differentiate between responders and non-responders to combination therapy either in pre- or post-treatment group.

Prevalence of thyroid disorders in hepatitis C virus positive patients on interferon and antiviral therapy.

Background:Hepatitis C virus (HCV) infection is common worldwide. The treatment typically involves a combination of interferon-alpha (IFN-α) and ribavirin (RBV) therapy; however, the use of IFN-α is well documented to be associated with thyroid disease, the most common autoimmune disorder associated with IFN-α.Aim:The aim of the present study was to know the prevalence of thyroid abnormality in the HCV-positive patients on IFN and antiviral therapy.Materials and Methods:Fifty known HCV positive patients were enrolled for the study. All the patients were on IFN (3 million unit subcutaneously 3 times/week) and antiviral therapy (oral RBV 1000–1200 mg/day). Thyroid function tests were performed first at the start of treatment and then after 12 weeks of treatment.Results:13 (26%) of the patients were found to develop hypothyroidism, and 1 (2%) patient developed hyperthyroidism in the course of 12 weeks therapy.Conclusion:HCV patients on IFN and antiviral therapy have an effect on the thyroid gland, so these patients should be regularly screened for thyroid disorders and appropriately treated to maintain euthyroid status.