Interferon Formulations Research Articles

The Topical Novel Formulations of Interferon α-2в Effectively Inhibit HSV-1 Keratitis in the Rabbit Eye Model and HSV-2 Genital Herpes in Mice.

Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) are widespread human pathogens that establish chronic latent infections leading to recurrent episodes. Current treatments are limited, necessitating the development of novel antiviral strategies. This study aimed to assess the antiviral efficacy of novel topical formulations containing interferon alpha-2b (IFN α-2b) against HSV-1 and HSV-2. The formulations, Oftalmoferon® forte (eye drops) and Interferon Vaginal Tablets, demonstrated potent antiviral effects against HSV-1 and HSV-2 in Vero cells, respectively, with concentration-dependent inhibition of viral replication. Subsequently, their efficacy was tested in animal models: HSV-1 keratitis in the rabbit eye model and HSV-2 genital herpes in mice. Oftalmoferon® forte effectively treated HSV-1 keratitis, reducing clinical symptoms and ulcerations compared to virus control. Interferon Vaginal Tablets showed promising results in controlling HSV-2 genital herpes in mice, improving survival rates, reducing clinical signs, weight loss and viral replication. The novel IFN α-2b formulations exhibited significant antiviral activity against HSV infections in cell culture and animal models. These findings suggest the potential of these formulations as alternative treatments for HSV infections, particularly in cases resistant to current therapies. Further studies are warranted to optimize treatment regimens and assess clinical efficacy in humans.

Ruxolitinib Treatment in Polycythemia Vera Results in Reduction in JAK2 Allele Burden in Addition to Improvement in Hematocrit Control and Symptom Burden

Introduction:In the pivotal RESPONSE and RESPONSE 2 trials, the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib was superior to best available therapy (BAT) at providing hematocrit control and complete hematologic response, as well as in improving disease-related symptoms, in patients with polycythemia vera (PV). Here we report the results of a post hoc pooled efficacy analysis using data from the RESPONSE studies. Methods:RESPONSE and RESPONSE 2 were randomized, open-label, multicenter phase 3 trials that assessed efficacy and safety of ruxolitinib in adults with PV who had resistance or intolerance to hydroxyurea. Splenomegaly was required for enrollment into RESPONSE but not for RESPONSE 2; patients in both studies were randomized 1:1 to ruxolitinib (starting dose, 10 mg twice daily) or BAT (most commonly hydroxyurea [59%, 49%] or interferon formulations [12%, 13%] in RESPONSE and RESPONSE 2, respectively). Patients in either trial who were randomized to BAT could cross over to ruxolitinib at the time of primary analysis (Week 32 in RESPONSE; Week 28 in RESPONSE 2) or later for efficacy or safety reasons. In this pooled analysis, hematocrit control was assessed in the pooled population at Weeks 28 and 80 and was defined as hematocrit <45% that was maintained since Week 16 with ≤1 phlebotomy occurring postrandomization and before Week 4. Symptom control (using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score [MPN-SAF TSS]) and changes over time in JAK2V617F allele burden were also assessed. Response rate 95% CIs were calculated using the Clopper-Pearson exact method, and the odds ratio (OR) and 95% CI for comparisons of the proportion of patients achieving ≥50% reduction from baseline in MPN-SAF TSS were calculated by the Mantel-Haenszel method. Results:Overall, 371 patients were randomized in RESPONSE and RESPONSE 2 (ruxolitinib, n=184; BAT, n=187). Patient baseline characteristics were similar across trials and treatment groups and have been previously published. Mean (SD) age in the overall pooled analysis population was 61.8 (11.0) years; most patients were male (62.5%) and White (88.1%). At Week 28, 62.0% (95% CI, 54.5%-69.0%) of ruxolitinib patients achieved hematocrit control compared with 18.2% (12.9%-24.5%) of BAT patients (Figure 1). Durable hematocrit control was maintained to Week 80 by 47.3% (95% CI, 39.9%-54.8%) of patients randomized to ruxolitinib (nearly all patients in the BAT arm crossed over to ruxolitinib). The percentage of patients achieving ≥50% reduction from baseline in MPN-SAF TSS at Week 16 (the only common timepoint in both studies) was higher for ruxolitinib vs BAT (48.7% [95% CI, 40.7%-56.8%] vs 18.0% [95% CI, 12.5%-24.6%]; OR, 4.3 [95% CI, 2.6-7.2]). Mean (SD) change from baseline to Week 16 in MPN-SAF TSS was −4.4 (10.0) for ruxolitinib patients and 0.6 (6.9) for BAT patients. JAK2V617F allele burden decreased consistently from baseline to Week 208 in patients randomized to ruxolitinib. Mean JAK2V617F allele burden decreased from 66.1% to 41.4% at 4 years. Best change from baseline in JAK2V617F allele burden is shown in Figure 2, with a decrease of ≥25% in 57.1% of patients randomized to ruxolitinib and ≥50% decrease in 38.9%. Similar reductions in JAK2V617F allele burden were observed following crossover from BAT to ruxolitinib (Figure 2), with a best decrease of ≥25% and ≥50% in 48.7% and 35.3% of patients, respectively. Analysis of the BAT group is limited by small patient numbers after Week 32, as most patients crossed over to ruxolitinib, with a best decrease of ≥25% and ≥50% in 7.2% and 2.6% of patients respectively. Conclusions:In this pooled analysis of RESPONSE and RESPONSE 2, patients with PV treated with ruxolitinib achieved durable hematocrit control through Week 80 and had better symptom control at Week 16 than those who received BAT. Reductions in JAK2V617F allele burden were consistently observed through Week 208 in patients treated with ruxolitinib, including those who crossed over from BAT. Taken together, these results provide further evidence of the patient benefit of ruxolitinib in patients with PV with or without splenomegaly.

Tre-P-14 - The use of pegylated interferon a-2a in a cohort of Greek patients with mycosis fungoides

<h3>Introduction:</h3> IFN a with its cytotoxic and immunological effects on tumorous T cells has been introduced in the treatment of cutaneous T-cell lymphoma since the 1980s. The reported experience (average response rates 45–80%, further improved with combination schemes) is mostly based on the use of the recombinant IFN a-2a or IFN a-2b. However, these interferon formulations are no longer commercially available in Europe and therefore, the pegylated analogue (pegylated IFN a-2a, Pegasys; Hoffmann-La Roche) has been currently used to treat CTCLs. The purpose of the current study was to evaluate the efficacy and safety profile of pegylated IFN a-2a in the treatment of mycosis fungoides (MF). <h3>Methods:</h3> We collected data from three referral Cutaneous Lymphoma Units in Greece, covering a 2-year period, before COVID -19 pandemic restrictions. The primary endpoint was to determine the effectiveness of peg IFN as measured by the overall response rate (RR) in this cohort. Secondary endpoints were difference in RRs with respect to gender, disease stage, presence of folliculotropism and treatment features, time to best response, duration of response, drug survival, reasons for drug discontinuation and safety profile. Statistical analysis of the data was performed using the Statistical Package for Social Sciences (SPSS), version 15.0 (SPSS, Inc., Chicago, IL, USA). <h3>Results:</h3> Overall, 31 patients were included. Most patients (n=12; 38.7%) had ΙΒ-stage disease at peg IFN initiation. In all, 11 (35.5%) patients received PegIFN monotherapy, while 20 (64.5%) subjects on peg IFN concomitantly received bexarotene, acitretin, methotrexate or topical chemotherapy. PegIFN was administered in the majority of patients as third or fourth line therapy (21/31). A 54.8% (17/31) overall response rate was noted: 9.7% and 45.2% for CR and PR, respectively. In our cohort, no differences in RRs with respect to gender (p=0.427), disease stage (p=0.179) or presence of folliculotropism (p=0.532) was observed. Peg IFN was not more effective as monotherapy than as a subsequent agent with respect to overall response (p=0.680). Mean time to best response was 7.29±4.99 months. Treatment dose was reduced in 8 (25.8%) cases due to drug intolerance. Adverse effects were recorded in 21 (67.7%) cases with leukopenia (n=16; 76.1%), fatigue (n=9; 42.8%) and anemia (n=4; 19.0%) being the most recorded. <h3>Discussion:</h3> Overall, peg IFN may be considered an effective additional regimen in the treatment of MF, stage IB or higher, with a rather good tolerance and safety profile.

Polymeric nanoencapsulation of alpha interferon increases drug bioavailability and induces a sustained antiviral response in vivo.

Polymeric nanoparticulate systems allow the encapsulation of bio-active substances, giving them protection against external agents and increasing the drug's bioavailability. The use of biocompatible and biodegradable polymers usually guarantees the harmless character of the formulation, and a controlled drug release is also assured. A relatively easy procedure to obtain polymeric formulations of bioactive agents is ionotropic gelation, which allows the synthesis of chitosan (CS) - sodium tri-polyphosphate nanoparticles (NPs) loading encapsulated proteins. In this work, Bovine serum albumin (BSA) model protein and a recombinant porcine alpha interferon variant were used to obtain nanoparticulate formulations. The internalization of the encapsulated material by cells was studied using a BSA-fluorescein system; the fluorescent conjugate was observable inside the cells after 20h of incubation. The therapeutic CS-alpha interferon formulation showed a maximum of protein released in vitro at around 90h. This system was found to be safe in a cytotoxicity assay, while biological activity experiments in vitro showed antiviral protection of cells in the presence of encapsulated porcine alpha interferon. In vivo experiments in pigs revealed a significant and sustained antiviral response through overexpression of the antiviral markers OAS2 and PKR. This proves the preservation of porcine alpha interferon biological activity, and also that a lasting response was obtained. This procedure is an effective and safe method to formulate drugs in nanoparticulate systems, representing a significant contribution to the search for more effective drug delivery strategies.

Interferon Therapy in Myelofibrosis: Systematic Review and Meta-analysis

BackgroundMyelofibrosis (MF) is a Philadelphia chromosome–negative myeloproliferative neoplasm characterized by progressive bone marrow failure, increased risk of progression to acute myeloid leukemia, and constitutional symptoms. For over 3 decades, various formulations of interferon (IFN) have been used for the treatment of MF, with variable results, and the role of IFN in the treatment of MF is evolving. Patients and MethodsFor this systematic review and meta-analysis, Medline and Embase via Ovid, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched from inception through March 2019 for studies of pegylated IFN (peg-IFN) and non–peg-IFN in MF patients. The primary outcome of overall response rate was defined as a composite of complete response, partial response, complete hematologic response, and partial hematologic response. Random-effects models were used to pool overall response rate, and metaregression analyses were performed to compare peg-IFN and non-–peg-IFN formulations. ResultsAmong the 10 studies with 141 MF patients included, the overall response rate was 49.9% (95% confidence interval [CI], 30.4-69.3), and there was no statistically significant difference (P = .99) between peg-IFN (50.0%; 95% CI, 26.2-73.9; I2 = 76.9%) and non–peg-IFN (49.6%; 95% CI, 20.5-79.0; I2 = 56.7%). Treatment discontinuation resulting from adverse events was common with non–peg-IFN at 35.8% (95% CI, 3.5-68.1) per year, and less in the one study on peg-IFN (0.5% per year). ConclusionIFN can lead to hematologic improvements in a subset of MF patients, but study quality is limited and heterogenous. Biomarkers predicting response to IFN and formulations with improved tolerability are needed.

Development of an anti-hepatitis B virus (HBV) agent through the structure-activity relationship of the interferon-like small compound CDM-3008.

Hepatitis B, a viral infectious disease caused by hepatitis B virus (HBV), is a life-threatening disease that leads liver cirrhosis and liver cancer. Because the current treatments for HBV, such as an interferon (IFN) formulation or nucleoside/nucleotide analogues, are not sufficient, the development of a more effective agent for HBV is urgent required. CDM-3008 (1, 2-(2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole) (RO8191)) is a small molecule with an imidazo[1,2-a][1,8]naphthyridine scaffold that shows anti-HCV activity with an IFN-like effect. Here, we report that 1 was also effective for HBV, although the solubility and metabolic stability were insufficient for clinical use. Through the structure-activity relationship (SAR), we discovered that CDM-3032 (11, N-(piperidine-4-yl)-2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxamide hydrochloride) was more soluble than 1 (>30 mg/mL for 11 versus 0.92 mg/mL for 1). In addition, the half-life period of 11 was dramatically improved in both mouse and human hepatic microsomes (T1/2, >120 min versus 58.2 min in mouse, and >120 min versus 34.1 min in human, for 11 and 1, respectively).

Nebulized Mannitol, Particle Distribution, and Cough in Idiopathic Pulmonary Fibrosis.

Inhaled interferon, a potential treatment for idiopathic pulmonary fibrosis, must be formulated with mannitol, which can cause bronchospasm and cough. Coughing during drug inhalation can be affected by many factors, but some factors are fixed by the needs of the formulation and inflammatory disease in the airways. A component of the cough response may be related to sites of deposition, particularly upper and central airways. If deposition sites are important, then manipulating the particle distribution of the aerosol may mitigate coughing. To design a therapeutic formulation and delivery system for formulations that contain mannitol, we tested the effect of particle distribution on cough during mannitol inhalation in volunteers with idiopathic pulmonary fibrosis. A solution of mannitol was formulated to match requirements for future interferon formulations (40 mg/mL, 220 mOsm/L). Mannitol aerosols were generated by using different nebulizers providing particle distributions that were expected to vary upper airway deposition. The nebulizer fill volume was adjusted to correct for differences in nebulizer efficiency with a target inhaled mass of 20 mg. Particle distributions were measured by cascade impaction (mass median aerodynamic diameters, 1.2 and 6.5 μm). Seven subjects with idiopathic pulmonary fibrosis participated in the study. To maximize deposition, the subjects were trained to inhale slowly and deeply (6 s inspiration). Spirometry was measured before and after inhalation. The study was carried out on separate days (day 1: 1.2 μm; day 2: 6.5 μm), and the pattern of coughing was observed. Coughing was often spontaneous and provoked by spirometry. When inhaling the 1.2-μm distribution, no subject coughed during inhalation. Six of the seven subjects coughed when inhaling the 6.5-μm particles. Spirometry was unaffected. In subjects with idiopathic pulmonary fibrosis, nebulized mannitol can cause coughing. Modifying the aerosol distribution prevents coughing during mannitol inhalation. Mannitol aerosols can be inhaled safely without bronchospasm. These data serve to inform future formulation and/or device combinations for planned interferon therapy.

How We Treat Patients With Polycythemia Vera

How We Treat Patients With Polycythemia Vera

Drug Development Pipeline for Myeloproliferative Neoplasms: Potential Future Impact on Guidelines and Management

The unprecedented success of ruxolitinib in myelofibrosis (MF) has paved the way for the development of other Janus kinase (JAK) inhibitors and other agents representing diverse drug classes and mechanisms of action in myeloproliferative neoplasms (MPNs). In particular, the symptomatic benefits afforded by ruxolitinib have led to the recognition of "clinical improvement" in symptoms and the spleen in international consensus response criteria for MF. Ruxolitinib is also approved for the second-line treatment of polycythemia vera and is being developed for essential thrombocythemia. Appreciation of the universal role of activated JAK/signal transducer and activator of transcription (STAT) signaling in MPNs and improved understanding of the canonical and noncanonical actions of JAK2 have yielded a number of drug targets beyond JAK2 in MPNs, which form the basis for a number of ruxolitinib-based rational combinations that are being explored in MF. Other JAK inhibitors with the potential for significantly less myelosuppression or even improvement of anemia continue to be tested. Finally, agents with very distinct mechanisms of action, such as novel interferon formulations, antifibrotic agents, and telomerase inhibitors, are being pursued in polycythemia vera and MF, respectively. This article reviews the current landscape of clinical drug development in MPNs, focusing on the most promising agents and combinations.

The cross-reactivity of binding antibodies with different interferon beta formulations used as disease-modifying drugs in multiple sclerosis patients

Interferon beta (IFNb) preparations are commonly used as first-line therapy in relapsing-remitting multiple sclerosis (RRMS). They are, however, characterized by limited efficacy, partly due to the formation of anti-IFNb antibodies in patients.In this pilot study, we assessed with the ELISA method the presence of the binding antibodies (BAbs) against interferon beta after 2 years of therapy with subcutaneous interferon beta 1a (Rebif) in 49 RRMS patients. Antibody levels were established again within 1 year after treatment withdrawal. We used 3 interferons that are commercially available for MS therapy, namely Avonex (Biogen Idec Limited), Rebif (Merck Serono), and Betaferon (Bayer Pharma AG), as antigens.BAbs reacting with Rebif were found in 24.4% to 55% of patients, depending on the units of their expression. The levels of anti-Rebif antibodies remained high in 8 patients and in 4 patients they dropped significantly. Strong correlations were obtained in all assays (anti-Rebif-anti-Avonex, anti-Rebif-anti-Betaferon, and anti-Betaferon-anti-Avonex) and the existence of cross-reactivity in the formation of antibodies against all the tested formulations of interferon beta was confirmed. The levels of BAbs remain significant in the clinical context, and their assessment is the first choice screening; however, methods of BAbs evaluation can be crucial for further decisions. More studies are needed to confirm our results; specifically it would be of interest to evaluate methods of neutralizing antibodies identification, as we only assessed the binding antibodies. Nevertheless, our results support the concept that in interferon nonresponders, that are positive for binding antibodies, switching the therapy to alternative disease-modifying agent (for example glatiramer acetate, fingolimod, or natalizumab) is justified, whereas the switch to another interferon formulation will probably be of no benefit.

Early Relapsing Multiple Sclerosis.

This article provides an evidence-based approach to the management of patients with early relapsing multiple sclerosis (MS). Numerous clinical trials have shown the role of disease-modifying therapies in reducing relapses and new MRI lesions in patients with relapsing MS. Many of these trials also show the ability of these agents to delay disability progression, and a few suggest that disease-modifying therapies may slow brain atrophy in relapsing MS; however, very few suggest that disease-modifying therapies can improve symptoms or disability. The therapeutic armamentarium of disease-modifying therapies includes five interferon formulations, two versions of glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, and alemtuzumab. Although multiple disease-modifying therapies exist, the risks of these vary markedly, head-to-head comparator trials are limited, and no prospective biomarkers for treatment efficacy exist; therefore, choosing a disease-modifying therapy for an individual patient with MS is a difficult decision. This difficulty is compounded by limitations in predicting a patient's disease course, and the risk tolerance of the patient and opinions of the care partner need to be factored into the decision analysis as well. After a disease-modifying therapy is chosen, vigilance for clinical or radiographic breakthrough disease is very important, as this may suggest a suboptimal response to the chosen therapy. Furthermore, the role of symptom management and wellness should always remain part of the approach to the patient with MS.

Beyond interferon: rationale and prospects for newer treatment paradigms for chronic hepatitis C

Hepatitis C virus (HCV) infection results in a chronic carrier state in 80% of individuals infected with the virus and presently affects over 170 million people worldwide. Approximately 20% of those chronically infected will ultimately progress to develop cirrhosis and death due to end-stage liver disease or hepatocellular carcinoma (HCC). Unlike many other chronic viral infections, effective treatments for HCV are available. Cure from the infection is known as a sustained virologic response (SVR). SVR is associated with reversal of the long-term outcomes of chronic liver disease, decrease in incidence of HCC, and decrease HCV attributable mortality. The current FDA approved therapies for hepatitis C virus genotype 1 (GT-1) include pegylated interferon (PEG-IFN) and ribavirin (RBV) in combination with a directly acting antiviral agent (DAA). New therapeutic advances are being made aiming to simplify management, improve the tolerability of treatment, and shorten the duration of therapy. Moreover, treatment regimens that will effectively eradicate hepatitis C without the use of interferon formulations (IFN) are being developed. In this review, we report the transition of HCV therapeutics from an interferon-α based combination therapy to an all-oral, directly acting antiviral therapy.

Interferon stimulated exonuclease gene 20 kDa links psychiatric events to distinct hepatitis C virus responses in human immunodeficiency virus positive patients.

Hepatitis C Virus (HCV) infection occurs frequently in patients with preexisting mental illness. Treatment for chronic hepatitis C using interferon formulations often increases risk for neuro-psychiatric symptoms. Pegylated-Interferon-α (PegIFN-α) remains crucial for attaining sustained virologic response (SVR); however, PegIFN-α based treatment is associated with psychiatric adverse effects, which require dose reduction and/or interruption. This study's main objective was to identify genes induced by PegIFN-α and expressed in the central nervous system and immune system, which could mediate the development of psychiatric toxicity in association with antiviral outcome. Using peripheral blood mononuclear cells from Human Immunodeficiency Virus (HIV)/HCV co-infected donors (N = 28), DNA microarray analysis was performed and 21 differentially regulated genes were identified in patients with psychiatric toxicity versus those without. Using these 21 expression profiles a two-way-ANOVA was performed to select genes based on antiviral outcome and occurrence of neuro-psychiatric adverse events. Microarray analysis demonstrated that Interferon-stimulated-exonuclease-gene 20 kDa (ISG20) and Interferon-alpha-inducible-protein 27 (IFI27) were the most regulated genes (P < 0.05) between three groups that were built by combining antiviral outcome and neuro-psychiatric toxicity. Validation by bDNA assay confirmed that ISG20 expression levels were significantly associated with these outcomes (P < 0.035). Baseline levels and induction of ISG20 correlated independently with no occurrence of psychiatric adverse events and non-response to therapy (P < 0.001). Among the 21 genes that were associated with psychiatric adverse events and 20 Interferon-inducible genes (IFIGs) used as controls, only ISG20 expression was able to link PegIFN-α related neuro-psychiatric toxicity to distinct HCV-responses in patients co-infected with HIV and HCV in vivo.

Predictive factors for adverse dermatological events during pegylated/interferon alpha and ribavirin treatment for hepatitis C

BackgroundTreatment of chronic hepatitis C (CHC) with pegylated interferon-alpha/ribavirin is associated with well-characterized dermatological adverse events (AEs), which can lead to premature discontinuation of treatment. ObjectiveTo investigate the incidence and spectrum of dermatological AEs during CHC treatment with interferon-alpha plus ribavirin and analyzed factors predisposing patients to such reactions. Study designBetween January 2008 and December 2012, 152 CHC patients who had received interferon/pegylated interferon plus ribavirin therapy were enrolled in this retrospective study. To determine which factors were associated with dermatological AE development, a Cox proportional-hazards regression analysis was performed. ResultsThirty dermatological AEs were recorded in 28 (18.4%) patients. These reactions included 14 (9.2%) patients with eczematous reactions, four (2.6%) patients with xerosis, three (2.0%) patients with new-onset or exacerbation of psoriasis, two (1.3%) patients with lichenoid eruption, two (1.3%) patients with diffuse folliculitis and one patient with lichen planus, alopecia areata, hypermelanosis, and necrosis of the skin and toenails. Application of the Cox proportional-hazards model revealed that age older than 60 years (HR=1.070; 95% CI: 1.043–1.096), pre-existing anaphylaxis/skin disease (HR=2.612; 95% CI: 1.593–3.324), cirrhosis (HR=1.863; 95% CI: 1.047–3.013), and treatment with pegylated interferon formulations (HR=1.930; 95% CI: 1.052–3.687) were associated with occurrence of dermatologic AEs. Twenty-seven (90%) skin conditions were classified as mild to moderate, while one case (3.3%) warranted premature discontinuation of treatment. ConclusionDermatological AEs resulting from interferon-alpha/ribavirin treatment of CHC contribute to a wide spectrum involve the skin, mucous membrane, hair, and nails. These dermatological AEs correlated with older age, previous skin condition, cirrhosis, and use of pegylated interferon formulations.

Patient subgroup analyses of the treatment effect of subcutaneous interferon β-1a on development of multiple sclerosis in the randomized controlled REFLEX study

The REFLEX study (NCT00404352) established that subcutaneous (sc) interferon (IFN) β-1a reduced the risks of McDonald MS (2005 criteria) and clinically definite multiple sclerosis (CDMS) in patients with a first clinical demyelinating event suggestive of MS. The aim of this subgroup analysis was to assess the treatment effect of sc IFN β-1a in patient subgroups defined by baseline disease and demographic characteristics (age, sex, use of steroids at the first event, classification of first event as mono- or multifocal, presence/absence of gadolinium-enhancing lesions, count of <9 or ≥9 T2 lesions), and by diagnosis of MS using the revised McDonald 2010 MS criteria. Patients were randomized to the serum-free formulation of IFN β-1a, 44 μg sc three times weekly or once weekly, or placebo, for 24 months or until diagnosis of CDMS. Treatment effects of sc IFN β-1a on McDonald 2005 MS and CDMS in the predefined subgroups were similar to effects found in the intent-to-treat population. McDonald 2010 MS was retrospectively diagnosed in 37.7 % of patients at baseline. Both regimens of sc IFN β-1a significantly reduced the risk versus placebo of McDonald 2005 MS and CDMS, irrespective of McDonald 2010 status at baseline (risk reductions between 29 and 51 %). The effect of sc IFN β-1a was not substantially influenced by baseline patient demographic and disease characteristics, or baseline presence/absence of McDonald 2010 MS.

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Comparative efficacy, pharmacokinetic, pharmacodynamic activity, and interferon stimulated gene expression of different interferon formulations in HIV/HCV genotype‐1 infected patients

The effect of different formulations of interferon on therapeutic response in patients coinfected with HIV and HCV is unclear. In this study, the safety, tolerability, viral kinetics (VK) modeling and host responses among HIV/HCV coinfected patients treated with pegylated-IFN or albinterferon alfa-2b (AlbIFN) with weight-based ribavirin were compared. Three trials treated 57 HIV/HCV coinfected genotype-1 patients with PegIFN alfa-2b (1.5 µg/kg/week) (n = 30), PegIFN alfa-2a (180 µg/week) (n = 10), and AlbIFN (900 µg/q2week) (n = 17) in combination with weight-based ribavirin (RBV). HCV RNA, safety labs, and interferon stimulated gene expression (ISG) was evaluated. Adverse events were documented at all study visits. HCV viral kinetics using a full pharmacokinetic/pharmacodynamic model was also evaluated. Baseline patient characteristics were similar across the three studies. All three formulations exhibited comparable safety and tolerability profiles and efficacy. VK/PK/PD parameters for all three studies as measured by mean efficiency and rate of infected cell loss were similar between the three groups. Host responses (ISG expression and immune activation markers) were similar among the three groups. All three regimens induced significant ISG at week 4 (P < 0.05) and ISG expression strongly correlated with therapeutic response (r = 0.65; P < 0.01). In summary, a comprehensive analysis of responses to three different interferon formulations in HIV/HCV coinfected patients demonstrated similar effects. Notably, interferon-based therapy results in a blunted host response followed by modest antiviral effect in HIV/HCV coinfected patients. This suggests that future treatment options that do not rely on host immune responses such as direct antiviral agents would be particularly beneficial in these difficult to treat patients.

CPC-033 Comparing Effectiveness of First-Line Disease Modifying Drugs in Relapsing-Remitting Multiple Sclerosis Patients

BackgroundImmunomodulatory drugs represent the best therapeutic option in first-line treatment of relapsing-remitting multiple sclerosis (RRMS). This group includes glatiramer acetate (GA) and three formulations of Interferon β (IFNβ): subcutaneous IFNβ1a...

Real-life Experience With Pegylated Interferon and Conventional Interferon in Adjuvant Melanoma Therapy

Interferon (IFN) is the most studied and the only approved adjuvant therapy for melanoma. There are 2 formulations of IFN, conventional IFN and pegylated IFN (peg-IFN), which have been investigated in multiple randomized clinical trials. We have compared the feasibility and tolerability of low-dose conventional IFN and peg-IFN in real life, outside the controlled settings of clinical trials. In this study, we analyzed 99 patients with resected melanoma, who were treated with either conventional IFN (n=48) or with peg-IFN (n=51), retrospectively. The median treatment duration in conventional IFN group was 13.3 versus 16.5 months in peg-IFN (P=0.52). Moreover, patients with peg-IFN tended to have dose reduction or treatment discontinuation due to adverse events (AE) significantly more often. In addition, neutropenia occurred significantly more often in peg-IFN group versus IFN group (n=2; 5% conventional vs. n=16; 36.4% peg-IFN, P=0.00). More than 90% of these patients developed only grade 2 neutropenia and there were no reported infections. We conclude that the 100 µg flat dose peg-IFN, which is commonly referred to as "low-dose," actually represents a higher dose of IFN, which consequently results in more frequent dose reductions and discontinuation of treatment. The use of peg-IFN is certainly more convenient for the patient in terms of application, thus close monitoring, early medical interventions, and dose adjustments to avoid treatment discontinuation are crucial for compliance.

Management of Patients Coinfected With HCV and HIV: A Close Look at the Role for Direct-Acting Antivirals

With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients.