Interferon Alfa Research Articles

The use of sofosbuvir for the treatment of recurrent hepatitis C after liver transplantation

The article presents the experience of direct-acting antiviral (DAA) drug treatment for hepatitis C in the patients after liver transplantation. The end-stage liver disease caused by hepatitis C is the main indication for orthotopic liver transplantation (OLT). In 2013, the first agent in the class of antiviral drugs directly acting on hepatitis C virus (HCV) was introduced into clinical practice. That was sofosbuvir, a HCV polymerase inhibitor, that could be used without interferon alfa. Materials and methods . The study enrolled 33 liver transplant recipients with recurrent hepatitis C. Thirty-five courses of antiviral therapy (AT) were conducted with sofosbuvir being one of AT components. Results. By the time of analysis, 21 patients had completed the antiviral therapy. All the patients showed an initial response to the antiviral therapy, HCV aviremia was achieved. In 3 patients, with the evaluable sustained virologic response (SVR), a renewed HCV replication was observed in the first weeks after the AT completion. Conclusion. The new direct-acting antiviral drugs offer an effective antiviral therapy to all liver graft recipients with recurrent HCV.

Phase 3 trial of first generation protease inhibitor therapy for hepatitis C virus/human immunodeficiency virus coinfection.

AIMTo evaluate efficacy/safety of hepatitis C virus (HCV) protease inhibitor boceprevir with pegylated interferon (PEG-IFN) alfa and weight-based ribavirin (RBV) in a phase 3 trial.METHODSA prospective, multicenter, phase 3, open-label, single-arm study of PEG-IFN alfa, weight-based RBV, and boceprevir, with a PEG-IFN/RBV lead-in phase was performed. The HCV/human immunodeficiency virus coinfected study population included treatment naïve (TN) and treatment experienced (TE) patients. Treatment duration ranged from 28 to 48 wk dependent upon response-guided criteria. All patients had HCV Genotype 1 with a viral load > 10000 IU/mL. Compensated cirrhosis was allowed. Sample size was determined to establish superiority to historical (PEG-IFN plus RBV) rates in sustained viral response (SVR).RESULTSA total of 257 enrolled participants were analyzed (135 TN and 122 TE). In the TN group, 81.5% were male and 54.1% were black. In the TE group, 76.2% were male and 47.5% were white. Overall SVR12 rates (HCV RNA < lower limit of quantification, target not detected, target not detected) were 35.6% in TN and 30.3% in TE. Response rates at SVR24 were 28% in TN and 10% in TE, and exceeded those in historical controls. The highest rate was observed in TN non-cirrhotic participants (36.8% and the lowest in TE cirrhotics (26.3%). Cirrhotic TN participants had a 27.8% SVR12 rate and 32.1% of TE non-cirrhotics achieved SVR12. Significantly lower response rates were observed among black participants; in the TE, SVR12 was 39.7% in white participants but only 13.2% of black subjects (P = 0.002). Among the TN, SVR12 was 42.1% among whites and 27.4% among blacks (P = 0.09).CONCLUSIONThe trial met its hypothesis of improved SVR compared to historical controls but overall SVR rates were low. All-oral HCV treatments will mitigate these difficulties.

The influence of hepatic steatosis on the success of antiviral therapy for chronic hepatitis C

Background/Aim. Chronic hepatitis C and liver steatosis often appear simultaneously in the same person, and steatosis can lead to worsening of liver disease and reducing the success of the treatment of chronic hepatitis C. Treatment of one disease can influence and cause favorable impact on treatment of other diseases. The aim of this study was to determine the incidence of liver steatosis in patients with chronic hepatitis C and to examine the impact of steatosis of the liver and other predictors on the success of antiviral therapy for chronic hepatitis C. Methods. The study included 123 patients with chronic hepatitis C treated with pegylated interferon alfa 2a in combination with ribavirin. The patients were divided into two groups based on the presence of cirrhosis: the group I consisted of 43 (34.9%) patients with steatosis and the group II consisted of 80 (65.1%) patients without liver steatosis. The success of the treatment was evaluated on the basis of the stable virological response. Results. The presence of steatosis was determined in 34.96% of the patients. The overall success of antiviral therapy was found in 74.79% of the patients. The success of antiviral therapy was present in 62.79% of the patients with hepatic steatosis, and in 81.25% the patients without steatosis (p &lt; 0.05). The success of antiviral treatments was seen in 80.95% of the patients with hepatic steatosis and the genotype of hepatitis C virus 3. The predictors of antiviral therapy success for chronic hepatitis C in our study were patient's age, duration of infection, genotype 3, steatosis and severe fibrosis or cirrhosis. Conclusion. Liver steatosis is often present in patients with chronic hepatitis C. It has negative impact on the efficacy of antiviral therapy in patients with infection with genotype non-3 hepatitis C virus. Therefore, hepatic steatosis in these patients must be eliminated or treated prior to application of antiviral therapy.

Enhancement of interferon treatment for large basaliomas

Background: Treatment of large basaliomas may be problematic, because relapses after the use of various treatment modalities are frequent. Aim : To assess the efficacy of interferon therapy for primary solitary T2N0M0 basalioma. Materials and methods : We retrospectively analyzed the results of treatment of 72 patients with primary solitary basalioma T2N0M0. The patients from the main group (n = 35) were treated with injections of recombinant interferon alfa 2b into the lesion at a dose of 2 to 3 Mio IU (total dose for the treatment course from 18 to 27 Mio IU). The reference group included 37 patients treated by cryodestruction. The results were assessed at 8 weeks after the end of interferon therapy and at 3 months after cryotherapy. The cure was confirmed cytologically at 3 months after clinical reconvalescence (formation of the scarring atrophy area or re-epithelization). Results : The treatment was effective in 100% (35/35) of the patients from the main group. Twenty nine (82.9%) cases of basalioma required two courses of interferon therapy, 5 (14.3%) cases 3 courses, and one case (2.8%) 4 courses. In the reference group, 94.6% (35/37) of patients were cured. The difference between the proportions of the cured patients between the two groups was 5.4% (confidence interval (CI) -5.2–17.7%). Within the next 3 years of the follow-up there were no relapses in the main group, whereas the relapses were diagnosed in 9 (24.3%) of the patients from the reference group. The difference of the proportions between the two groups was 24.3% (CI 9.6–40%). Conclusion : Based on the short- and long-term results, the efficacy of intralesional interferon administration in basalioma T2N0M0 was 100%. For tumors of more than 2 cm², an increase of the single and the total cumulative dose of recombinant interferon alfa 2b is necessary, as well as several courses of interferon treatment. Interferon therapy is more effective than cryodestruction based on the 3-year relapse-free survival.

A Case of Bowen's Disease Successfully Treated with Ingenol Mebutate Gel.

Bowen’s disease represents a form of squamous cellcarcinoma in situ and usually appears as a sharply demarcated erythematous plaque. It can be treated by surgery, curettage and cautery, cryotherapy, 5-fluorouracil (5-FU), laser therapy, radiotherapy, photodynamic therapy, or local or systemic injections of interferon alfa or gamma. Ingenol mebutate is a novel agent extracted from the sap of the plant Euphorbia peplus, which is known to have therapeutic effects on cancerous lesions. A 82-year-old woman visited to our clinic with 1 year history of walnut sized annular erythemaotus plaque on her right ankle. Skin biopsy was done and we could observe irregularly thickened epidermis and throughout the epidermis, the cells lie in disarray resulting in a “windblown” appearance with atypical mitoses. We applied ingenol mebutate 0.05% gel 3 consecutive days once daily to a 9cm2 contiguous field containing the affected area. The local skin reactions (erythema, vesiculation and scales) occurred as we expected. However, symptoms were transient and resolved spontaneously within 2 weeks after discontinuation. The lesion had disappeared almost completely with a mild pigmentation after 1 month. And also, she had not experienced any other adverse effects or recurrence over 2 months of follow-up. Herein we describe a case of Bowen’s disease successfully treated with ingenol mebutate gel.

Cost-effectiveness of antiviral therapy in treatment-naive patients with chronic hepatitis C (genotype 1)

Interferon-free therapy for genotype 1 hepatitis C are preferable from the point of view of clinical effectiveness and safety. The purpose of work was the assessment of costs and costeffectiveness of regimens for the treatment of HCV (1 genotype) at the treatment-naive patients. Methods. The assessment was carried out from the payer perspective. In base case the analysis of costs of the drugs included and recommended for inclusion in the List of VED was carried out on the basis of a median of the registered prices including VAT and the average wholesale extra charge taking into account population in the Russian Federation. Besides, the scenario with the assessment on the basis of the prices of all drugs (which both are included, and not included in the List by VED) revealed in auctions for 2016 is analysed. Results. In the base case cost of paritaprevir/ombitasvir/ dasabuvir/ritonavir (PTV/OBV/DSV/r) therapy in patients without cirrhose is 12,2-26,6% less compared with simeprevir with pegylated interferon alfa and ribavirin (PegIFN/RBV/ SMV) at a full course of the last (12 weeks) at all patients. In scenario with refusal of inefficient therapy with PegIFN/ RBV/SMV after 4 weeks, PTV/OBV/DSV/r is characterized by the comparable volume of expenses – from decrease by 15,5% to increase by 3,2%. The analysis on the basis of the prices of auctions has shown that in comparison with the PegIFN/RBV/SMV (without refusal of inefficient therapy with PegIFN/RBV/SMV after 4 weeks) and daclatasvir and asunaprevir, economy at therapy by a PTV/OBV/DSV/r will make 4,1-19,8% and 28,3%, respectively. In comparison with PegIFN/RBV/SMV (with refusal of therapy in the absence of effect in 4 weeks) PTV/OBV/DSV/r is characterized by the comparable volume of expenses (from decrease by 7,5% to increase by 12,8%). In genotype 1b costs of PTV/OBV/DSV/r are 24,6% higher compared with narlaprevir in a combination with ritonavir, peginterferon and ribavirin. Cost-effectiveness of PTV/OBV/DSV/r is higher at patients without cirrhosis in comparison with all analysed alternatives, except for a narlaprevir in a combination with ritonavir, peginterferon and ribavirin (genotype 1b). At patients with cirrhosis the analysis on the basis of the registered prices has shown that at a full cycle of therapy decrease in costs of a PTV/OBV/DSV/r ± RBV will make 8,4% in comparison with the PegIFN/RBV/SMV, but at refusal of PegIFN/RBV/SMV in 4 weeks in the absence of the response, additional expenses on PTV/OBV/DSV/r ± RBV will make 5,6%. In the analysis on the basis of the prices of auctions PTV/ OBV/DSV/r ± RBV will allow to lower expenses at patients with cirrhosis on average by 11,9% in comparison with the daclatasvir and asunaprevir. In comparison with PegIFN/ RBV/SMV PTV/OBV/DSV/r ± RBV or it doesn’t influence expenses (at a full course of a simeprevir at all patients), or it increases them by 15,2% (at refusal of therapy in the absence of the response in 4 weeks). The cost-effectiveness of PTV/ OBV/DSV/r ± RBV surpasses all comparators at patients with cirrhosis, as well as at patients without cirrhosis. The sensitivity analysis has shown high reliability of the received results. Conclusions. Costs of PTV/OBV/DSV/r ± RBV at treatment-naive patients with HCV (1 genotype) without cirrhosis and with the compensated cirrhosis, are comparable to costs of a PegIFN/RBV/SMV at higher clinical and economic effectiveness. Taking into account the need for repeated courses of therapy to treatment-naive patients with the compensated cirrhosis, now purpose of a PTV/OBV/DSV/r ± RBV in the first line of therapy is the most preferable economically.

Effect of Chronic Hepatitis C Virus Treatment by Combination Therapy on Cardiovascular System.

BACKGROUNDThe prevalence of hepatitis C virus (HCV) in Egypt is quite high, and the combined oral direct-acting antiviral agents (DAAs) may have impressive results.OBJECTIVETo assess the cardiovascular effects of DAAs in patients with HCV.METHODSA total of 170 patients with HCV were divided into 2 groups: first group (100 patients) received triple combination therapy (pegylated interferon alfa, sofosbuvir, and ribavirin, whereas the second group (70 patients) received dual combination therapy (sofosbuvir and simeprevir). Group 1 patients were followed up for 1 year more than 3 visits, whereas group 2 patients were followed up for 6 months more than 2 visits; and the end point of the study was the development of a major cardiovascular event (eg, congestive heart failure, echocardiographic evidence of left ventricular dysfunction, occurrence of significant arrhythmias, or acute coronary syndrome). The following parameters were accomplished: medical history and clinical examination, electrocardiogram, echo-Doppler study, and laboratory investigations.RESULTSNo significant differences were found between the 2 study groups regarding demographic criteria. None of the both group patients had developed any major cardiac event. No significant changes were observed regarding ST-T wave abnormalities, arrhythmias, or QT interval. None of the both group patients developed echocardiographic regional wall motion abnormalities at baseline or at study end. Systolic function parameters showed minute nonsignificant changes over study visits. Diastolic function parameters showed nonsignificant changes between baseline and 6-month and 12-month visits.CONCLUSIONSThe DAAs used in combination regimen with interferon or used orally in combination do not significantly affect the cardio-vascular system.

Maintenance Therapy for Patients with Mantle Cell Lymphoma (MCL) - a Systematic Review and Meta-Analysis of Randomized Controlled Trials (RCTs)

Background:MCL is characterized by a dismal long term prognosis with a median overall survival of 3-5 years. Rituximab maintenance treatment (MR) improves survival of patients with follicular lymphoma, and its effect was assessed for MCL patients in several trials with inconsistent results. Other agents as bortezomib were also evaluated as maintenance therapy for MCL.Aims:We performed a systematic review and meta-analysis of RCTs in order to assess the effect of maintenance therapy on clinical outcomes of patients with MCL.Methods:We included RCTs that compared any type of maintenance to no maintenance or a different maintenance for patients with MCL, either in first line or relapsed disease. In July 2016 we searched The CochraneLibrary, MEDLINE, conference proceedings, and databases of ongoing trials. Two reviewers independently assessed the qualityof the trials and extracted data. The primary outcome wasall cause mortality. Secondary outcomes included progression free survival (PFS) and infectious adverse events. Relative risk (RR) for dichotomous data and hazard ratio (HR) for time to event datawere estimated and pooled using random-effects model.ResultsWe identified 6 trials that reported relevant outcomes, conducted between the years 1998 to 2012 and randomizing 857 patients with MCL. Most patients were males, with a median age ranging from 57 to 70 years, and predominantly good performance status. Ninety-six percent of the patients received their first line of treatment. MIPI score was reported in three trials: 20 to 42 percent of patients had a high MIPI score. Induction therapy included rituximab in all trials. In five trials chemotherapy induction was applied and consisted of fludarabine, cyclophosphamide (FC) and mitoxantrone (Forstpointner, Blood 2006), cyclophosphamide, vincristine, adriamycin, prednisone (CHOP) or FC in one trial (Kluin-Nelemans et al.), bendamustine (Rummel et al.), DHAP followed by autologous stem cell transplantation (ASCT) (Le Gouill et al.), and CHOP/cytarabine followed by ASCT (Doorduijn et al.); in one trial rituximab was given alone (Ghielmini et al.). Maintenance consisted of rituximab in five trials and bortezomib in one trial (Doorduijn et al.). The control group received no maintenance in two trials and interferon alfa in one trial. All included trials were judged at low risk of selection bias, none were blinded.No statistically significant effect on mortality rate was shown with rituximab maintenance therapy compared to no maintenance or interferon alfa RR 0.72, 95% CI 0.50 to 1.04, I2 of heterogeneity 57%, 751 patients. The RR of mortality with bortezomib maintenance was 0.67, 95% CI 0.12 to 3.71, but that is based on only 60 patients.PFS improved with rituximab maintenance compared to no maintenance or interferon alfa: HR 0.59, 95% CI 0.46 to 0.75. With bortezomib maintenance vs. no maintenance the HR of event free survival was 0.84, 95% CI 0.32 to 2.20.There was no statistically significant difference in infection rate with or without maintenance (RR 0.80, 95% CI 0.37 to 1.69, 419 patients).ConclusionsMaintenance therapy improved PFS of patients with MCL, but no survival benefit could be shown. The pooled analysis is based mainly on the results of rituximab maintenance as data of the effect of bortezomib maintenance is scarce. The absence of significant increase of infection rate as opposed to maintenance rituximab in follicular lymphoma might be attributed to the small sample size. Based on these results patients treated for both first line and relapsed/refractory MCL should receive rituximab maintenance after achieving response to induction. [Display omitted] DisclosuresDreyling:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Final Results from PROUD-PV a Randomized Controlled Phase 3 Trial Comparing Ropeginterferon Alfa-2b to Hydroxyurea in Polycythemia Vera Patients

▪Background: Interferon alfa (IFNa) based therapies have been successfully applied in myeloproliferative neoplasms (MPN) for over thirty years. Several uncontrolled phase II trials have independently shown high rates of hematologic, splenic and sustained mutant JAK2 molecular responses in Polycythemia vera (PV) patients. However, a head-to-head assessment versus other treatment options in confirmatory trials has been lacking so far. Here we report 12 month data from a randomized controlled phase III trial comparing the novel, long-acting Ropeginterferon alfa-2b (AOP2014) with hydroxyurea (HU) in PV patients.Study design: Randomized, controlled, parallel group multicenter phase III trial assessing efficacy, safety and tolerability in patients diagnosed with PV according to WHO2008 criteria, either naïve to cytoreduction or HU experienced (but neither intolerant nor complete responders, cumulative HU exposure max. 3 years). The primary endpoint was non-inferiority of AOP2014 vs. HU at 12 months of therapy in terms of complete hematological response (CHR) rate. CHR was defined as normal hematocrit, leukocyte and platelet counts, spleen size and absence of phlebotomy in the preceding 3 months. As important secondary endpoint the effect of treatment on mutant JAK2 allele burden was assessed as rate of complete and partial molecular response (C/PMR) rate according to modified ELN criteria. Both cohorts are followed up further maintaining the original randomization for assessing effects of prolonged therapy.Results: 257 patients were randomized in 48 sites in 13 European countries and treated with response-driven escalating doses of either AOP2014, or HU. 62% of patients were naïve to cytoreduction, 38% HU experienced; 19% had a previous thrombotic event. Response-driven dose escalation was done in both treatment arms applying up to 10 dose levels (50-500µg AOP2014 every other week, or 250-3000 mg HU daily). Both treatments were well tolerated. The drop-out rate after 12 months was low with ~15% in both arms, the majority of drop-outs were due to administrative reasons (bi-weekly hospital visits).This presentation will provide the detailed analysis of primary and secondary endpoints of the trial, which is still blinded as of 4th Aug 2016. Preliminary pooled analysis revealed that at 12 months 45% of patients had a hematologic response: mean Hct values dropped from 48% to 42%, leukocyte counts from 12 to 6 *109/L and platelets from 530 to 260 *109/L. Need for phlebotomy within 3 months dropped from 86% to 6%. 37% of patients achieved a JAK2 molecular response (PMR or CMR), mean mutant JAK2 allele burden went from 42,5% to 28,7%.Conclusions: This is the first phase III trial formally assessing efficacy, safety and tolerability of Ropeginterferon alfa-2b versus HU. Both cohorts are followed-up for prolonged treatment duration, and it is expected that the currently available and emerging data will establish the role of Ropeginterferon alfa-2b as first-line treatment for PV. DisclosuresGisslinger:AOP Orphan Pharmaceuticals AG, Novartis, Celgene, Baxalta: Consultancy, Honoraria, Research Funding. Klade:AOP Orphan: Employment. Georgiev:Alnylam Pharmaceuticals: Consultancy. Illes:University of Debrecen faculty of medicine department of hematology: Employment. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Research Funding; AOP Orphan: Research Funding.

Peginterferon Lambda-1a, a New Therapeutic for Hepatitis C Infection, from Bench to Clinic.

Chronic infection with hepatitis C virus (HCV) is estimated to affect approximately 3% of the world's population and cause 350,000 deaths each year. For a number of years, the standard of care has been combination therapy with recombinant alfa interferons—originally as native proteins but more recently as polyethyleneglycol-modified derivatives—and ribavirin, with the recent addition of an NS3 protease inhibitor for HCV genotype 1. However, therapeutic alfa interferons are associated with a significant burden of treatment-limiting adverse events, including musculoskeletal and influenza-like symptoms, hematologic cytopenias, autoimmune disease, fatigue, and other neurologic events. In 2003, a team at ZymoGenetics (now a fully owned subsidiary of Bristol-Myers Squibb) and a second, independent group simultaneously identified a new class of interferons—the type III lambda interferons—with near-identical activity to the type I alfa interferons in hepatocytes but with an unrelated and less ubiquitous receptor. Subsequent evaluation of the type III interferon system demonstrated antiviral activity against HCV in vitro with limited activity in peripheral blood mononuclear cells and other nonhepatocyte cell types, supporting its development as a potentially better-tolerated therapy for viral hepatitis. Peginterferon lambda-1a (Lambda) is an investigational type III therapeutic agent originally developed at ZymoGenetics that is currently in Phase 3 studies for the treatment of HCV. In this review, we describe the selection of the Lambda molecule and its preclinical and early clinical development, and how the resulting data have helped to establish the differentiated safety profile for Lambda—with fewer influenza-like and musculoskeletal symptoms and less hematologic toxicity than the alfa interferons—that was seen in later studies.

JAK-inhibitor tofacitinib suppresses interferon alfa production by plasmacytoid dendritic cells and inhibits arthrogenic and antiviral effects of interferon alfa

Tofacitinib is an oral Janus kinase inhibitor that is effective for the treatment of rheumatoid arthritis and shows encouraging therapeutic effects in several other autoimmune diseases. A prominent adverse effect of tofacitinib therapy is the increased risk of viral infections. Despite its advanced stage of clinical development, the modes of action that mediate the beneficial and adverse effects of tofacitinib in autoimmune diseases remain unclear. Interferon alfa (IFNα) produced by plasmacytoid dendritic cells (PDCs) is critically involved in the pathogenesis of many systemic autoimmune diseases and in immunity to viral infections. Using invitro culture models with human cells, we studied the effects of tofacitinib on PDC survival and IFNα production, and on arthrogenic and antiviral effects of IFNα. Tofacitinib inhibited the expression of antiapoptotic BCL-A1 and BCL-XL in human PDC and induced PDC apoptosis. TLR7 stimulation upregulated the levels of antiapoptotic Bcl-2 family members and prevented the induction of PDC apoptosis by tofacitinib. However, tofacitinib robustly inhibited the production of IFNα by toll like receptor-stimulated PDC. In addition, tofacitinib profoundly suppressed IFNα-induced upregulation of TLR3 on synovial fibroblasts, thereby inhibiting their cytokine and protease production in response to TLR3 ligation. Finally, tofacitinib counteracted the suppressive effects of IFNα on viral replication. Tofacitinib inhibits PDC survival and IFNα production and suppresses arthrogenic and antiviral effects of IFNα signaling. Inhibition of the IFNα pathway at 2 levels may contribute to the beneficial effects of tofacitinib in autoimmune diseases and explain the increased viral infection rates observed during tofacitinib treatment.

Ledipasvir plus sofosbuvir fixed-dose combination for 6 weeks in patients with acute hepatitis C virus genotype 1 monoinfection (HepNet Acute HCV IV): an open-label, single-arm, phase 2 study

Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa is highly effective, but can be associated with frequent side-effects. We investigated the safety and efficacy of an interferon-free regimen for treatment of acute HCV infection. In this prospective, open-label, multicentre, single-arm pilot study, we enrolled adults (≥18 years) with acute HCV genotype 1 monoinfection from ten centres in Germany. Patients were given ledipasvir (90 mg) plus sofosbuvir (400 mg) as a fixed-dose combination tablet once daily for 6 weeks. The primary efficacy outcome was the proportion of patients with sustained virological response (defined as undetectable HCV RNA 12 weeks after the end of treatment; other primary outcomes were safety and tolerability of ledipasvir plus sofosbuvir. The primary analysis population consisted of all patients who received at least one dose of study drug. Safety was also assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02309918. Between Nov 19, 2014, and Nov 10, 2015, we enrolled 20 patients. Median HCV RNA viral load at baseline was 4·04 log10 IU/mL (1·71-7·20); 11 patients were infected with HCV genotype 1a and nine patients with genotype 1b. All patients achieved a sustained virological response 12 weeks after the end of treatment (20 [100%] of 20 patients). Treatment was well tolerated; there were no drug-related serious adverse events. Up to 12 weeks after treatment, 22 possible or probable drug-related adverse events were reported. There was one serious adverse event, which was judged unrelated to the study drug; one patient was admitted to hospital for surgery of a ruptured cruciate ligament. Treatment for 6 weeks with ledipasvir plus sofosbuvir was well tolerated and highly effective in patients with acute HCV genotype 1 monoinfection. Short-duration treatment of acute hepatitis C might prevent the spread of HCV in high-risk populations. Gilead Sciences, HepNet Study-House/German Liver Foundation, and German Centre for Infection Research (DZIF).

Differential Dynamics of CALR Mutant Allele Burden in Myeloproliferative Neoplasms during Interferon Alfa Treatment.

Discovery of somatic mutations in the calreticulin gene (CALR) has identified a subgroup of Philadelphia-negative chronic myeloproliferative neoplasms (MPN) with separate haematological characteristics and prognosis. CALR mutations serve as novel markers both of diagnostic value and as targets for monitoring molecular responses during therapy. Interferon-α (IFN) selectively targets the malignant clone in a subset of MPN patients and can induce both haematological and molecular remissions in CALR mutated essential thrombocythemia (ET) patients. We investigated the response to IFN in a cohort of 21 CALR mutated MPN patients including ET, prefibrotic primary myelofibrosis (pre-PMF), and primary myelofibrosis (PMF) with a median follow-up of 31 months. For evaluation of a molecular response, we developed highly sensitive quantitative PCR (qPCR) assays for monitoring the mutant allele burden of the two most prevalent CALR mutations (type 1 and type 2). Thirteen patients (62%) experienced a decrease in the mutant allele burden with a median decline of 29% from baseline. However, only four patients, including patients with ET, pre-PMF, and PMF diagnosis, achieved molecular responder (MR) status with >50% reduction in mutant allele burden according to European LeukemiaNet (ELN) guidelines. MR patients displayed significant differences in the dynamics of the CALR mutant load with regard to time to response and dynamics in mutant allele burden after discontinuation of IFN treatment. Furthermore, we highlight the prognostic value of the CALR mutant allele burden by showing a close association with leucocyte- and platelet counts, hemoglobin concentration, in addition to plasma lactate dehydrogenase (LDH) irrespective of molecular response and treatment status.

Hepatitis B virus and its sexually transmitted infection - an update.

Epidemiology: incidence and prevalence: About 5% of the world’s population has chronic hepatitis B virus (HBV) infection, and nearly 25% of carriers develop chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The prevalence of chronic HBV infection in human immunodeficiency virus (HIV)-infected individuals is 5%-15%; HIV/HBV coinfected individuals have a higher level of HBV replication, with higher rates of chronicity, reactivation, occult infection, and HCC than individuals with HBV only. The prevalence of HBV genotype A is significantly higher among men who have sex with men (MSM), compared with the rest of the population. Molecular mechanisms of infection, pathology, and symptomatology: HBV replication begins with entry into the hepatocyte. Sodium taurocholate cotransporting polypeptide was identified in 2012 as the entry receptor of HBV. Although chronic hepatitis B develops slowly, HIV/HBV coinfected individuals show more rapid progression to cirrhosis and HCC. Transmission and protection: The most common sources of HBV infection are body fluids. Hepatitis B (HB) vaccination is recommended for all children and adolescents, and all unvaccinated adults at risk for HBV infection (sexually active individuals such as MSM, individuals with occupational risk, and immunosuppressed individuals). Although HB vaccination can prevent clinical infections (hepatitis), it cannot prevent 100% of subclinical infections. Treatment and curability: The goal of treatment is reducing the risk of complications (cirrhosis and HCC). Pegylated interferon alfa and nucleos(t)ide analogues (NAs) are the current treatments for chronic HBV infection. NAs have improved the outcomes of patients with cirrhosis and HCC, and decreased the incidence of acute liver failure.

Second malignancies in hydroxyurea and interferon-treated Philadelphia-negative myeloproliferative neoplasms.

In an era of controversy in regard to 'hydroxyurea-leukaemogenicity' and when interferon-alfa2 (IFN) is being revived in the treatment of Philadelphia-negative myeloproliferative neoplasms (MPNs), we aim in this single-centre observational study to describe the frequencies of second malignancies in a cohort of MPN patients treated with hydroxyurea (HU) or IFN monotherapy or the combination of these agents. Records of a MPN cohort of 196 patients were reviewed, and a retrospective analysis was performed on 90 patients treated with HU, 38 patients treated with IFN and 68 patients treated with both IFN and HU. Logistic regression was used to compare frequencies in second malignancies. Patients treated with HU had a significantly higher risk of developing all second malignancies compared with patients treated with IFN [HU vs. IFN: OR of 4.01 (95%CI: 1.12-14.27, P-value: 0.023) and HU-IFN vs. IFN: OR 5.58 (95%CI: 1.55-20.15, P-value: 0.004)]. We have found an increased risk of second malignancies in MPN patients treated with HU compared with patients treated with IFN.

A randomized, controlled study of peginterferon lambda-1a/ribavirin ± daclatasvir for hepatitis C virus genotype 2 or 3

Background and purpose Peginterferon Lambda was being developed as an alternative to alfa interferon for the treatment of chronic hepatitis C virus (HCV) infection. We compared peginterferon Lambda-1a plus ribavirin (Lambda/RBV) and Lambda/RBV plus daclatasvir (DCV; pangenotypic NS5A inhibitor) with peginterferon alfa-2a plus RBV (alfa/RBV) in treatment-naive patients with HCV genotype 2 or 3 infection.Methods In this multicenter, double-blind, phase 3 randomized controlled trial, patients were assigned 2:2:1 to receive 24 weeks of Lambda/RBV, 12 weeks of Lambda/RBV + DCV, or 24 weeks of alfa/RBV. The primary outcome measure was sustained virologic response at post-treatment Week 12 (SVR12).Results Overall, 874 patients were treated: Lambda/RBV, n = 353; Lambda/RBV + DCV, n = 349; alfa/RBV, n = 172. Patients were 65 % white and 33 % Asian, 57 % male, with a mean age of 47 years; 52 % were infected with genotype 2 (6 % cirrhotic) and 48 % with genotype 3 (9 % cirrhotic). In the Lambda/RBV + DCV group, 83 % (95 % confidence interval [CI] 78.5, 86.5) achieved SVR12 (90 % genotype 2, 75 % genotype 3) whereas SVR12 was achieved by 68 % (95 % CI 63.1, 72.9) with Lambda/RBV (72 % genotype 2, 64 % genotype 3) and 73 % (95 % CI 66.6, 79.9) with peginterferon alfa/RBV (74 % genotype 2, 73 % genotype 3). Lambda/RBV + DCV was associated with lower incidences of flu-like symptoms, hematological abnormalities, and discontinuations due to adverse events compared with alfa/RBV.ConclusionThe 12-week regimen of Lambda/RBV + DCV was superior to peginterferon alfa/RBV in the combined population of treatment-naive patients with genotype 2 or 3 infection, with an improved tolerability and safety profile compared with alfa/RBV.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2920-z) contains supplementary material, which is available to authorized users.

Six weeks of sofosbuvir/ledipasvir (SOF/LDV) are sufficient to treat acute hepatitis C virus genotype 1 monoinfection: The HepNet Acute HCV IV Study

Background: Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa monotherapy for 12 – 24 weeks is highly effective but is associated with frequent unfavorable side effects. There is no fully published study yet exploring the safety, efficacy and required treatment duration of interferon-free treatment of acute hepatitis C virus monoinfection.

Chikungunya Virus: In Vitro Response to Combination Therapy With Ribavirin and Interferon Alfa 2a.

We evaluated the antiviral activities of ribavirin (RBV) and interferon (IFN) alfa as monotherapy and combination therapy against chikungunya virus (CHIKV). Vero cells were infected with CHIKV in the presence of RBV and/or IFN alfa, and viral production was quantified by plaque assay. A mathematical model was fit to the data to identify drug interactions for effect. We ran simulations using the best-fit model parameters to predict the antiviral activity associated with clinically relevant regimens of RBV and IFN alfa as combination therapy. The model predictions were validated using the hollow fiber infection model (HFIM) system. RBV and IFN alfa were effective against CHIKV as monotherapy at supraphysiological concentrations. However, RBV and IFN alfa were highly synergistic for antiviral effect when administered as combination therapy. Simulations with our mathematical model predicted that a standard clinical regimen of RBV plus IFN alfa would inhibit CHIKV burden by 2.5 log10 following 24 hours of treatment. In the HFIM system, RBV plus IFN alfa at clinical exposures resulted in a 2.1-log10 decrease in the CHIKV burden following 24 hours of therapy. These findings validate the prediction made by the mathematical model. These studies illustrate the promise of RBV plus IFN alfa as a potential therapeutic strategy for the treatment of CHIKV infections.

Case report of a renal cell carcinoma patient with acute pancreatitis under both sunitinib and axitinib treatment

Abstract Sunitinib and axitinib are oral tyrosine kinase inhibitors (TKI) that is commonly used in the treatment of metastatic renal cell carcinoma (RCC) as it has been shown to improve the progression-free survival of patients compared with sorafenib. Hypertension, palmar-plantar erythrodysesthesia, diarrhea, decreased appetite, nausea, and fatigue are common adverse events associated with them. We declared the first case report of a RCC patient with acute pancreatitis both under sunitinib and axitinib treatment. A 63-year-old male RCC patient who had been previously treated with interferon alfa 2b, sunitinib, everolimus and axitinib was hospitalized for acute pancreatitis four months after the onset of sunitinib therapy and five months after the onset of axitinib treatment. Symptoms and levels of serum lipase were normalized within one week after drug was withheld. Acute pancreatitis is a rare side effect of TKI and because of this, in patients under TKI treatment abdominal pain should be considered as a possible symptom of acute pancreatitis.

Editorial Comment

Surgical cytoreduction has been an integral component of multimodal therapy for metastatic renal cell carcinoma (mRCC) since the seminal reports supporting cytoreductive nephrectomy (CN) were published. 1 Mickisch G.H. Garin A. van Poppel H. et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomized trial. Lancet. 2001; 358: 966-970 Abstract Full Text Full Text PDF PubMed Scopus (1183) Google Scholar , 2 Flanigan R.C. Salmon S.E. Blumenstein B.A. et al. Nephrectomy followed by interferon Alfa-2b compared to interferon Alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001; 345: 1655-1659 Crossref PubMed Scopus (1415) Google Scholar With the introduction and adoption of targeted therapies and increasing enthusiasm for checkpoint inhibition, the role and sequential timing of CN are now the source of considerable debate. Given the emerging data associating CN with significant perioperative morbidity, critical consideration of optimal patient selection remains paramount.