Quantifying Physician Preferences for Systemic Atopic Dermatitis Treatments Using a Discrete-Choice Experiment.

INTRODUCTION: As research continues, new drugs will no doubt be added to the current pool of treatments for moderate-to-severe atopic dermatitis (AD). This raises the need for studies to determine prescriber preferences for different pharmacological options and the factors that influence their choice of treatment. Here we aim to explore physician preferences in the systemic treatment of moderate-to-severe AD, identify the sociodemographic characteristics that can influence physician preferences, and evaluate their satisfaction with current AD therapies. METHODS: A discrete-choice experiment (DCE) survey was administered to physicians treating patients with AD in Spain. Results were analyzed using a conditional logit model to estimate the relative importance of each attribute and the maximum risk accepted to achieve therapeutic benefit. RESULTS: A total of 28 respondents completed the DCE survey (67.9% female, mean age 45.9 years). Participants identified objective clinical efficacy and risk of severe adverse events (AEs) as the most important attributes, followed by improvement in sleep and pruritus and faster onset of action from the start of the treatment. Respondents gave less importance to mode of administration and therapeutic benefit in other atopic conditions. Respondents were willing to accept an increased risk of severe AEs and mild-to-moderate AEs leading to treatment discontinuation due to intolerance in order to obtain improvements in efficacy, sleep, and pruritus, and long-term clinical benefit. CONCLUSION: Our findings can help prescribers choose the most appropriate systemic AD therapy.

Cost-effectiveness of Ruxolitinib vs Best Available Therapy in the Treatment of Myelofibrosis in Spain.

Introduction: Primary myelofibrosis (MF) is a rare hematologic disease belonging to the group of Philadelphia-negative chronic myeloproliferative neoplasms. Identification of the Janus Kinase (JAK) gene mutations inaugurated a new era in the targeted therapy of myeloproliferative diseases. Ruxolitinib is the first JAK1/JAK2 inhibitor specifically approved for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis. The objective of this study was to assess the cost-effectiveness of ruxolitinib vs best available therapy (BAT) in MF patients in Spain. Methods: A decision-tree and Markov model were adapted to the Spanish setting to assess the cost-effectiveness of ruxolitinib vs. BAT on a lifetime horizon (≤15 years) from the societal perspective, while healthcare system perspective was included in the one-way sensitivity analysis. The population was assumed to be similar to that of the COMFORT-II clinical trial (CT), which was also the source of treatment efficacy data. BAT composition was derived from the same CT and validated with Spanish experts. Utilities were derived from the COMFORT-I CT. Costs included treatment, management, hospitalizations, emergency and outpatient visits, as well as adverse events and end-of-life costs. Additionally, costs associated to productivity loss were taken into account. Resource use was validated with experts and costs were extracted from Spanish sources. A probabilistic sensitivity analysis was also performed to evaluate the consistency of the results under the uncertainty or variability of the input data. Results: Patients on ruxolitinib accumulated 6.1 life years gained (LYGs), resulting in 73% extra life-years compared to patients treated with BAT (3.5LYs gained). Ruxolitinib provided 4.4 quality-adjusted life years (QALYs), with a 99% improvement compared to BAT (2.2 QALYs). This analysis gave an incremental cost of €47 199 per LYG and an incremental cost of €55 616 per QALY gained from the societal perspective. Conclusions: Ruxolitinib would be cost-effective in Spain according to the end-of-life criteria defined by the NICE and commonly referred for Spain (cost-effectiveness threshold of €61 500/QALY), in line with results published for other European countries.

Liraglutide vs. sitagliptin add-on to metformin treatment for type 2 diabetes mellitus: Short-term cost-per-controlled patient in Italy.

AIM: To estimate the short-term cost-per-controlled-patient with type 2 diabetes mellitus with liraglutide 1.2mg/day vs. sitagliptin 100mg/day as add-on treatment to metformin in Italy. METHODS: The percentage of controlled patients, i.e. with "HbA1c<7% without hypoglycemia and weight gain", at 26 and 52 weeks with liraglutide and sitagliptin, as well as at 78 weeks for patients switching at 52 weeks from sitagliptin to liraglutide or hypothetically continuing on sitagliptin were obtained from randomized clinical trials (RCT) and a meta-analysis. The treatment cost-per-controlled-patient was calculated from the perspective of the National Health System over a 26, 52- and 78-week time horizon. RESULTS: Despite the higher acquisition cost of liraglutide vs. sitagliptin, at 26 weeks liraglutide resulted in a lower cost-per-controlled-patient (€1460 vs. €1820 - with efficacy from RCT - and €1593 vs. €2234 - with efficacy from a meta-analysis), as well as at 52 weeks (€2627 vs. €2649). At 78 weeks, in patients who have switched from sitagliptin to liraglutide at 52 weeks, the cost-per-controlled-patient is also lower than that of patients continuing sitagliptin for 78 weeks (€2889 vs. €3970). CONCLUSIONS: Due to higher efficacy, liraglutide is associated with better cost-benefit than sitagliptin at 26, 52 and 78 weeks.

Cost-Effectiveness Analysis of Insulin Detemir Compared to Neutral Protamine Hagedorn (NPH) in Patients with Type 1 and Type 2 Diabetes Mellitus in Spain.

INTRODUCTION: An Excel® (Microsoft Corporation) model was adapted to estimate the short-term (1-year) cost effectiveness of insulin detemir (IDet) versus neutral protamine Hagedorn (NPH) insulin in patients initiating insulin treatment with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in Spain. METHODS: Clinical benefits included the non-severe hypoglycemia rate for T1DM and T2DM, and weight change for T2DM. Three scenarios were included with different hypoglycemia rates estimated on the basis of clinical trials and observational studies. Costs, estimated from perspective of the Spanish Public Healthcare System (Euros 2014), included insulin treatment and non-severe hypoglycemia management costs. Non-severe hypoglycemia, defined as a self-managed event, implied the use of extra glucose testing strips and a general practitioner visit during the week following the event for 25% of patients. An average disutility value was associated to non-severe hypoglycemia events and, for T2DM, to one body mass index unit gain to calculate quality-adjusted life years (QALYs). RESULTS: For the three scenarios a range of 0.025-0.076 QALYs for T1DM and 0.014-0.051 QALYs for T2DM were gained for IDet versus NPH due to non-severe hypoglycemia and weight gain avoidance, in return of an incremental cost of €145-192 for T1DM and €128-206 for T2DM. This resulted in the IDet versus NPH incremental cost-effectiveness ratio (ICER) ranging between €1910/QALY and €7682/QALY for T1DM and €2522/QALY and €15,009/QALY for T2DM. CONCLUSION: IDet was a cost-effective alternative to NPH insulin in the first year of treatment of patients with T1DM and patients with T2DM in Spain, with ICERs under the threshold value commonly accepted in Spain (€30,000/QALY). FUNDING: Novo Nordisk.

[Cost-effectiveness of rosuvastatin versus simvastatin, atorvastatin and pitavastatin in patients with high and very high cardiovascular risk in Spain]. / Coste-efectividad de rosuvastatina frente a simvastatina, atorvastatina y pitavastatina en pacientes con riesgo cardiovascular alto y muy alto en España.

INTRODUCTION AND OBJECTIVES: To estimate the cost-effectiveness of rosuvastatin versus simvastatin, atorvastatin and pitavastatin in Spain, according to the European guidelines for the treatment of dyslipidemias in patients with high and very high cardiovascular risk. METHODS: A Markov long-term cost-effectiveness model of rosuvastatin versus simvastatin, atorvastatin and pitavastatin in patients with high and very high cardiovascular risk defined according to 5 factors (sex, age, smoking habit, baseline cholesterol level, and systolic blood pressure) using the SCORE system. The incremental cost-effectiveness ratio is expressed in euros per quality adjusted life years and is calculated according to the perspective of the Spanish National Health System. RESULTS: Rosuvastatin is associated with a greater health benefit than the other statins across the considered profiles. Rosuvastatin is cost-effective compared to simvastatin in patients with SCORE risk ≥8% in females and ≥6% in males, while between 5% and the indicated values its cost-effectiveness is conditional to the patient baseline c-LDL level. Rosuvastatin is more cost-effective versus atorvastatin in female profiles associated with a SCORE risk≥11% and male profiles with SCORE risk ≥10%. Rosuvastatin is superior versus pitavastatin in both female and male profiles with high and very high cardiovascular risk. CONCLUSIONS: Rosuvastatin is a cost-effective therapy in the treatment of hypercholesterolemia versus simvastatin, atorvastatin and pitavastatin, especially in specific profiles of patients with high and very high cardiovascular risk factors, according to the SCORE system, in Spain.

Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins.

E6 viral oncoproteins are key players in epithelial tumors induced by papillomaviruses in vertebrates, including cervical cancer in humans. E6 proteins target many host proteins by specifically interacting with acidic LxxLL motifs. We solved the crystal structures of bovine (BPV1) and human (HPV16) papillomavirus E6 proteins bound to LxxLL peptides from the focal adhesion protein paxillin and the ubiquitin ligase E6AP, respectively. In both E6 proteins, two zinc domains and a linker helix form a basic-hydrophobic pocket, which captures helical LxxLL motifs in a way compatible with other interaction modes. Mutational inactivation of the LxxLL binding pocket disrupts the oncogenic activities of both E6 proteins. This work reveals the structural basis of both the multifunctionality and the oncogenicity of E6 proteins.