Costs to Medicare of Nonrecommended Bone-Modifying Agent Use for Castration-Sensitive Prostate Cancer.

PURPOSE: Bone-modifying agents (BMAs) do not prevent skeletal-related events among patients with castration-sensitive prostate cancer (CSPC), but many patients receive BMAs unnecessarily. The costs to Medicare from overuse have not been assessed. METHODS: We used linked SEER-Medicare data 2011-2015 to measure the frequency and number of doses of zoledronic acid (ZA) and denosumab received during CSPC (between diagnosis and initiation of metastatic, castration resistant prostate cancer therapy). We estimated excess BMA among patients who received BMA therapy for CSPC and did not have an indication for osteoporosis fracture prevention. We used the Medicare fee schedule for drug prices and peer-reviewed sources to estimate adverse event frequencies and costs. RESULTS: Median CSPC duration was 387 days (IQR, 253-573), during which time 42% of patients received ≥one dose of denosumab (mean doses, 7) and 18% received ≥one dose of ZA (mean doses, 7). Thirty-eight percent of those receiving denosumab and 47% of those receiving ZA had a history of osteoporosis, osteopenia, spine or hip fracture, or hypercalcemia. The estimated, annual excess BMA cost to Medicare was $44,105,041 in US dollars (USD), composed of $43,303,078 USD and $45,512 USD in drug costs for denosumab and ZA, respectively, and $682,865 USD and $75,585 USD in adverse event costs, respectively. In one-way sensitivity analysis, the estimate was most sensitive to denosumab dosing frequency (estimate range, $28,469,237 USD-$98,830,351 USD) and duration of CSPC (estimate range, $36,823,311 USD-$99,015,908 USD). CONCLUSION: BMA overuse in CSPC incurs substantial cost to Medicare, largely because of denosumab drug costs. Excess costs may be reduced by greater adherence to guideline-concordant BMA use.

Cognitive assessment in patients with Hepatitis C submitted to treatment with Sofosbuvir and Simeprevir or Daclatasvir.

BACKGROUND: Hepatitis C can be defined as an infectious disease that develops an inflammatory activity, which may cause an impairment in the central nervous system, may cause cognitive impairments and symptoms of depression. OBJECTIVE: The objective of this study was to verify the cognitive performance of patients with chronic hepatitis C before and after treatment with simeprevir, sofosbuvir, and daclatasvir. METHODS: A prospective study was carried out in three stages: before, right after treatment, and six months after. Fifty-eight patients under clinical follow-up were evaluated at the Emílio Ribas Infectology Institute, in São Paulo, Brazil. The following instruments were used: sociodemographic questionnaire, Lawton's Scale, Beck's Depression Inventory, and a battery of neuropsychological tests that evaluated: intellectual function, memory, attention, executive function, and motor and processing speed). For statistical analysis, the analyses described (mean, frequency, and standard deviation), chi-square, and ANOVA were used. RESULTS: Most of the participants were male (n=30, 51.7%), with a mean of 58.23±8.79 years, mean schooling of 9.75±4.43 years. Comparing the results of neuropsychological evaluations (before, just after completion of drugs, and six months), a significant improvement was observed in relation to the acquisition of new knowledge (p=0.03), late visual memory (p=0.01), and tendency towards alternate attention (p=0.07). CONCLUSION: The treatment of the hepatitis C virus improved cognitive performance, especially in relation to memory.

Assessment of Drug Interaction Potential Between the Hepatitis C Virus Direct-Acting Antiviral Agents Elbasvir/Grazoprevir and the Nucleotide Analog Reverse-Transcriptase Inhibitor Tenofovir Disoproxil Fumarate.

Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug-drug interactions. We evaluated the pharmacokinetic interaction of the direct-acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open-label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration-time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV-coinfected people.

Assessment of Azeliragon QTc Liability Through Integrated, Model-Based Concentration QTc Analysis.

Azeliragon is an inhibitor of the receptor for advanced glycation end products being developed for the treatment of Alzheimer's disease. The objective of the current analysis was to evaluate the relationship between plasma azeliragon concentrations and QT interval. Simultaneous QT values and plasma concentrations were available from 711 subjects (6236 records), pooled from 5 studies in healthy volunteers, 2 studies in patients with mild to moderate Alzheimer's disease, and 1 study in patients with type 2 diabetes and persistent albuminuria. Nonlinear mixed-effects modeling was conducted to describe azeliragon concentration-related changes in QT interval, after correcting for heart rate, using Fridericia's criteria (QTcF) and sex-related differences in baseline QTcF. Azeliragon-related changes in QTcF were predicted using 2 methods: simulation and bias-corrected 90% confidence interval approaches. A small positive relationship between azeliragon plasma concentration and QTcF was noted with a slope of 0.059 ms/ng/mL. Simulations predicted mean (90% prediction interval) changes in QTcF of 0.733 milliseconds (0.32-1.66 milliseconds) with the phase 3 dose (5 mg once daily steady state) and 4.32 milliseconds (1.7-8.74 milliseconds) at supratherapeutic doses (20 mg once daily steady state or 60 mg once daily × 6 days). Bias-corrected upper 90% confidence intervals for therapeutic and supratherapeutic doses were 0.88 and 5.01 milliseconds, respectively. Model-based analysis showed a small, nonclinically meaningful, positive relationship between azeliragon plasma concentration and QTcF with a slope close to zero. Neither the prediction interval nor the upper bound of the 90% confidence interval reached 10 milliseconds, demonstrating no clinically meaningful drug-related effect on QTcF at expected therapeutic and supratherapeutic doses of azeliragon.

Assessment of drug interaction potential between the HCV direct-acting antiviral agents elbasvir/grazoprevir and the HIV integrase inhibitors raltegravir and dolutegravir.

BACKGROUND: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection. OBJECTIVES: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir. METHODS: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg. RESULTS: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir. CONCLUSIONS: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people.

Comparative efficacy and safety of tyrosine kinase inhibitors for chronic myeloid leukaemia: A systematic review and network meta-analysis.

BACKGROUND: The pharmacotherapy of chronic myeloid leukaemia (CML) is mainly based on tyrosine kinase inhibitors (TKIs). The aim of this study was to compare the efficacy and safety of all TKIs in CML patients. METHODS: We conducted a systematic review with network meta-analysis (NMA) of randomised controlled trials (RCTs), including imatinib, nilotinib, dasatinib, bosutinib, radotinib and ponatinib. Searches were performed in PubMed, Scopus, Web of Science and SciELo (March 2018). The NMAs were built for six outcomes at 12 months: complete cytogenetic response (CCyR), major cytogenetic response (MCyR), deep molecular response, major molecular response (MMR), complete haematologic response and incidence of serious adverse events. We conducted rank order and surface under the cumulative ranking curve (SUCRA) analyses. RESULTS: Thirteen RCTs were included (n = 5079 patients). Statistical differences were observed for some comparisons in all outcomes. Imatinib 400 mg was considered the safest drug (SUCRA values of 10.3%) but presented low efficacy. Overall, nilotinib 600 mg was superior to the other TKI in efficacy (SUCRA values of 61.1% for CCyR, 81.0% for MMR, 90.0% for MCyR); however, no data on its safety profile at 12 months were reported. INTERPRETATION: Our results suggest that nilotinib should be upgraded to first-line therapy for CML, although further cost-effectiveness analyses, including the new TKI (i.e., ponatinib, radotinib), are needed.

A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America.

OBJECTIVE: A large, pivotal, phase 3 trial in patients with newly diagnosed multiple myeloma (MM) demonstrated that denosumab, compared with zoledronic acid, was non-inferior for the prevention of skeletal-related events (SREs), extended the observed median progression-free survival (PFS) by 10.7 months, and showed significantly less renal toxicity. The cost-effectiveness of denosumab vs zoledronic acid in MM in the US was assessed from societal and payer perspectives. METHODS: The XGEVA Global Economic Model was developed by integrating data from the phase 3 trial comparing the efficacy of denosumab with zoledronic acid for the prevention of SREs in MM. SRE rates were adjusted to reflect the real-world incidence. The model included utility decrements for SREs, administration, serious adverse events (SAEs), and disease progression. Drug, administration, SRE management, SAEs, and anti-MM treatment costs were based on data from published studies. For the societal perspective, the model additionally included SRE-related direct non-medical costs and indirect costs. The net monetary benefit (NMB) was calculated using a willingness-to-pay threshold of US$150,000. One-way deterministic and probabilistic sensitivity analyses were conducted. RESULTS: From a societal perspective, compared with zoledronic acid, the use of denosumab resulted in an incremental cost of US$26,329 and an incremental quality-adjusted life-year (QALY) of 0.2439, translating into a cost per QALY gained of US$107,939 and a NMB of US$10,259 in favor of denosumab. Results were sensitive to SRE rates and PFS parameters. LIMITATIONS: Costs were estimated from multiple sources, which varied by tumor type, patient population, country, and other parameters. PFS and overall survival were extrapolated beyond the follow-up of the primary analysis using fitted parametric curves. CONCLUSION: Denosumab's efficacy in delaying or preventing SREs, potential to improve PFS, and lack of renal toxicity make it a cost-effective option for the prevention of SREs in MM compared with zoledronic acid.

Improving Adherence to Treatment and Reducing Economic Costs of Hypertension: The Role of Olmesartan-Based Treatment.

Poor adherence to antihypertensive treatment is the single most important factor of unsatisfactory blood pressure (BP) control. This review focuses on therapy-related factors affecting adherence and suggests how to improve it with a wise choice of treatment schedule. Complex drug treatment schemes, poor tolerability and drug substitutions are frequent causes of poor adherence which, in turn, causes insufficient BP control, greater incidence of cardiovascular events and, finally, higher global health costs. The effects of prescribing generic drugs and of drug substitutions on adherence is also discussed. In terms of adherence, generic drugs do not seem to be better than branded drugs, unless patients have to bear very high "out of pocket" expenses to buy original drugs, suggesting no advantages in switching drug with the mere goal of reducing the cost of therapy. An important role in improving adherence (and thus cardiovascular events and health expenditure) is also played by the availability of fixed-dose combinations; among antihypertensive drugs, angiotensin receptor blockers (ARBs) are those associated with higher levels of adherence and persistence. Among ARBs, olmesartan stands out for a wide choice of effective fixed-dose combinations.

Daclatasvir Plus Asunaprevir Dual Therapy for Chronic HCV Genotype 1b Infection: Results of Turkish Early Access Program

Abstract: Background. Daclatasvir and asunaprevir dual therapy is approved for the treatment of HCV genotype 1b infection in several countries. Aim. To evaluate the efficacy and safety of daclatasvir and asunaprevir dual therapy in Turkish patients. Material and methods. Sixty-one patients with HCV genotype 1b were enrolled in the Turkish early access program. Most of the patients were in difficult-to-treat category. Patients were visited at each 4 week throughout the follow-up period. Laboratory findings and adverse events were recorded at each visit. Results. Fifty-seven of 61 enrolled patients completed 24 weeks of treatment. Two patients died as a result of underlying diseases at 12-14th weeks of treatment. Two patients stopped the treatment early as a consequence of virological breakthrough, and 2 patients had viral relapse at the post-treatment follow-up. Overall SVR12 rates were 90% (55/61) and 93.2% (55/59) according to intention-to-treat (ITT) and per protocol (PP) analysis respectively. In ITT analysis, SVR12 was achieved by 93% (13/14) in relapsers, 80% (12/15) in interferon-ineligible patients and 91% (20/22) in previous nonresponder patients. SVR12 rates were 86.5% and 91.4% in patients with cirrhosis according to ITT and PP analysis respectively. SVR12 was 95.8% in non-cirrhosis group in both analysis. Patients with previous protease inhibitor experience had an SVR12 of 87.5%. Common adverse events developed in 28.8% of patients. There were no treatment related severe adverse event or grade-4 laboratory abnormality. Conclusions. Daclatasvir and asunaprevir dual therapy is found to be effective and safe in difficult-to-treat Turkish patients with HCV genotype 1b infection.

Daclatasvir plus asunaprevir dual therapy for chronic HCV genotype 1b infection: results of Turkish early access program.

 Background. Daclatasvir and asunaprevir dual therapy is approved for the treatment of HCV genotype 1b infection in several countries. AIM: To evaluate the efficacy and safety of daclatasvir and asunaprevir dual therapy in Turkish patients. MATERIAL AND METHODS: Sixty-one patients with HCV genotype 1b were enrolled in the Turkish early access program. Most of the patients were in difficult-to-treat category. Patients were visited at each 4 week throughout the follow-up period. Laboratory findings and adverse events were recorded at each visit. RESULTS: Fifty-seven of 61 enrolled patients completed 24 weeks of treatment. Two patients died as a result of underlying diseases at 12-14th weeks of treatment. Two patients stopped the treatment early as a consequence of virological breakthrough, and 2 patients had viral relapse at the post-treatment follow-up. Overall SVR12 rates were 90% (55/61) and 93.2% (55/59) according to intention-to-treat (ITT) and per protocol (PP) analysis respectively. In ITT analysis, SVR12 was achieved by 93% (13/14) in relapsers, 80% (12/15) in interferon-ineligible patients and 91% (20/22) in previous nonresponder patients. SVR12 rates were 86.5% and 91.4% in patients with cirrhosis according to ITT and PP analysis respectively. SVR12 was 95.8% in non-cirrhosis group in both analysis. Patients with previous protease inhibitor experience had an SVR12 of 87.5%. Common adverse events developed in 28.8% of patients. There were no treatment related severe adverse event or grade-4 laboratory abnormality. CONCLUSIONS: Daclatasvir and asunaprevir dual therapy is found to be effective and safe in difficult-to-treat Turkish patients with HCV genotype 1b infection.

The cost-effectiveness of testing for NS5a resistance-associated polymorphisms at baseline in genotype 1a-infected (treatment-naïve and treatment-experienced) subjects treated with all-oral elbasvir/grazoprevir regimens in the United States.

BACKGROUND: The presence of baseline NS5A resistance-associated variants (RAVs) impacted treatment response in HCV genotype 1a (GT1a)-infected patients treated with elbasvir/grazoprevir (EBR/GZR) for 12 weeks, but not patients treated with EBR/GZR and ribavirin (RBV) for 16 weeks. AIMS: To assess the cost-effectiveness of baseline testing for NS5A RAVs in EBR/GZR-treated patients compared without testing, and with current treatments for GT1a patients. METHODS: We simulated the course of treatment with EBR/GZR, ledipasvir/sofosbuvir (LDV/SOF) and ombitasvir/paritaprevir/ritonavir+dasabuvir (3D) with or without RBV and natural history of disease of GT1a patients. Treatment-related data from clinical trials were used in a state-transition model of the natural history of chronic HCV GT1a infection and liver disease to project lifetime costs (US$2015) and quality-adjusted life years (QALY). Other clinical and economic inputs were estimated from published sources. We conducted base case and sensitivity analyses. RESULTS: RAVs testing-guided treatment with EBR/GZR resulted in more QALYs than EBR/GZR without testing, 3D+RBV, or LDV/SOF8. This strategy was cost-saving relative to 3D+RBV or LDV/SOF8 and was cost-effective compared with EBR/GZR without testing. LDV/SOF12 was not cost-effective compared with the EBR/GZR RAVs testing-based strategy. Treatment with EBR/GZR guided by RAVs testing is the most effective regimen among treatment-experienced patients without cirrhosis and cirrhotic patients. In sensitivity analysis, RAVs testing was cost-effective in 48-55% and 63-85% among noncirrhotic and cirrhotic patients respectively. CONCLUSIONS: RAVs testing before treatment with EBR/GZR is likely to be a cost-effective alternative to the use of EBR/GZR without testing, LDV/SOF, or 3D among GT1a treatment-naïve or treatment-experienced patients.

Assessment of Efficacy, Safety, and Quality of Life of 124 Patients Treated With Axitinib as Second-Line Therapy for Metastatic Renal-Cell Carcinoma: Experience in Real-World Clinical Practice in Japan.

PURPOSE: To comprehensively analyze the efficacy of axitinib for metastatic renal-cell carcinoma (mRCC) patients. PATIENTS AND METHODS: This study included 124 consecutive Japanese patients treated with axitinib as second-line systemic therapy for mRCC in a routine clinical setting. RESULTS: In addition to 4 indeterminate patients (3.2%), 0 (0%), 21 (16.9%), 87 (70.2%), and 12 (9.7%) were judged to show complete response, partial response, stable disease, and progressive disease, respectively, as the best responses to axitinib. The median progression-free survival (PFS) and overall survival (OS) after initiating treatment with axitinib were 9.3 and 27.0 months, respectively. Multivariate analyses of several parameters identified the following independent predictors of PFS and OS: Memorial Sloan Kettering Cancer Center (MSKCC) classification and C-reactive protein level for PFS; and MSKCC classification, C-reactive protein level, bone metastasis, and liver metastasis for OS. Common grade 3 or higher adverse events associated with axitinib were hypertension in 41 (33.1%), proteinuria in 14 (11.3%), and hand-foot syndrome in 14 (11.3%). Quality-of-life analysis using the Medical Outcomes Study 36-Item Short Form showed that 2 scores were significantly improved 12 weeks after the administration of axitinib, while there were no significant differences in the remaining 6 scores between surveys administered before and 12 weeks after the treatment with axitinib. CONCLUSION: Favorable disease control could be achieved with acceptable tolerability by introducing axitinib as second-line systemic therapy, resulting in improvement of the prognosis and quality of life of Japanese patients with mRCC.

Retrospective Audit: Does Prior Assessment by Oral and Maxillofacial Surgeons Reduce the Risk of Osteonecrosis of The Jaw in Patients Receiving Bone-Targeted Therapies for Metastatic Cancers to the Skeleton?--Part II.

Men who receive bone-targeted therapy for metastatic prostate cancer are at increased risk of osteonecrosis of the jaw (ONJ). Development of ONJ has been associated with the administration of bone-targeted therapies in association with other risk factors. ONJ can be distressing for a patient because it can cause pain, risk of jaw fracture, body image disturbance, difficultly eating, and difficulty maintaining good oral hygiene. The aim of this article is to report results of an audit of prior assessment by oral and maxillofacial surgeons (OMFS) before initiation of bone-targeted therapies and whether it may reduce the risk of ONJ in patients receiving bone-targeted therapies for advanced cancers.

[Tyrosine kinase inhibiting the VEGF pathway and elderly people: Tolerance, pre-treatment assessment and side effects management]. / Inhibiteurs de tyrosine kinase ciblant l'angiogenèse et sujets âgés : tolérance, évaluation pré-thérapeutique et gestion des effets indésirables.

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (>70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

Severe intestinal malabsorption associated with olmesartan: a French nationwide observational cohort study.

OBJECTIVES: Severe sprue-like enteropathy associated with olmesartan has been reported, but there has been no demonstration of an increased risk by epidemiological studies. AIM: To assess, in a nationwide patient cohort, the risk of hospitalisation for intestinal malabsorption associated with olmesartan compared with other angiotensin receptor blockers (ARB) and ACE inhibitors (ACEIs). DESIGN: From the French National Health Insurance claim database, all adult patients initiating ARB or ACEI between 1 January 2007 and 31 December 2012 with no prior hospitalisation for intestinal malabsorption, no serology testing for coeliac disease and no prescription for a gluten-free diet product were included. Incidence of hospitalisation with a discharge diagnosis of intestinal malabsorption was the primary endpoint. RESULTS: 4 546 680 patients (9 010 303 person-years) were included, and 218 events observed. Compared with ACEI, the adjusted rate ratio of hospitalisation with a discharge diagnosis of intestinal malabsorption was 2.49 (95% CI 1.73 to 3.57, p<0.0001) in olmesartan users. This adjusted rate ratio was 0.76 (95% CI 0.39 to 1.49, p=0.43) for treatment duration shorter than 1 year, 3.66 (95% CI 1.84 to 7.29, p<0.001) between 1 and 2 years and 10.65 (95% CI 5.05 to 22.46, p<0.0001) beyond 2 years of exposure. Median length of hospital stay for intestinal malabsorption was longer in the olmesartan group than in the other groups (p=0.02). Compared with ACEI, the adjusted rate ratio of hospitalisation for coeliac disease was 4.39 (95% CI 2.77 to 6.96, p<0.0001) in olmesartan users and increased with treatment duration. CONCLUSIONS: Olmesartan is associated with an increased risk of hospitalisation for intestinal malabsorption and coeliac disease.

The cost-effectiveness of daclatasvir-based regimens for the treatment of hepatitis C virus genotypes 1 and 4 in the UK.

OBJECTIVE: This study aimed to determine the cost-effectiveness of daclatasvir in combination with other medicinal products for the treatment of patients with hepatitis C virus genotypes 1 and 4 and advanced liver disease in the UK. METHODS: A published and validated Markov model designed to simulate the natural history of chronic hepatitis C was used to compare daclatasvir with relevant treatment options for patients with hepatitis C virus genotypes 1 and 4 and a METAVIR score of F3-F4. Patients were defined according to their treatment status; that is, naive, experienced or interferon ineligible/intolerant. Data inputs for the analysis were derived from published sources, UK-specific where possible. A lifetime horizon was used, with costs and benefits discounted at 3.5%. RESULTS: Daclatasvir-based regimens are estimated to be cost-effective versus no treatment and established standard-of-care regimens, including telaprevir in combination with pegylated interferon-α+ribavirin (PR), boceprevir in combination with PR and PR alone (incremental cost-effectiveness ratio range: £3715-£15,408). The cost-effectiveness of daclatasvir-based regimens versus emerging regimens (sofosbuvir or simeprevir based) is less consistent, but was dominant or cost-effective (incremental cost-effectiveness ratio range: £1394-£28,393) in all except two scenarios. CONCLUSION: Daclatasvir-based regimens are expected to be highly cost-effective for the majority patients with advanced disease versus relevant comparator regimens, including newer direct-acting antiviral regimens.

Tyrosine Kinase Inhibitors Early in the Disease Course: Lessons From Chronic Myelogenous Leukemia.

The landscape of chronic myeloid leukemia (CML) management has changed with the advent of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 oncoprotein. Imatinib mesylate, followed by nilotinib and dasatinib, has been approved for newly diagnosed patients. Since none of these TKIs show survival superiority, the drug choice is a challenge. Even so, the rate of deeper and earlier responses is higher with second-generation TKIs than it is with imatinib, and, in general, better response is associated with a survival advantage, regardless of TKI type being used. Patients should be monitored carefully for response, and treatment failure should prompt a timely switch to another TKI. Side effect profile and drug cost are other important considerations in therapy choice. In several clinical studies, achieving undetectable and durable disease status allowed some patients to discontinue the TKI and enjoy long-term treatment-free remission. Cure for CML may be possible with TKIs alone or TKIs in combination with other investigational therapies. However, due to lack of long-term outcome data and absence of consensus for the definition of optimal response and time to stop TKIs, discontinuation is discouraged outside of a clinical trial.

Nitrogen-containing bisphosphonate therapy: assessment of the alveolar bone structure in rats - a blind randomized controlled trial.

This study aimed to assess the effect of zoledronic acid exposure on structures of the alveolar bone of rats. The sample was composed of 42 male Wistar rats. Animals in the T1 and T2 groups received weekly doses of 0.2 mg/kg intraperitoneal zoledronic acid for 3 weeks, while animals in the T3 group received the same treatment for 8 weeks. The control groups C1, C2 and C3 received equivalent doses of saline. The first upper molars of Wistar rats in the C2, T2, C3 and T3 groups were extracted. Cone-beam computerized tomography scans were performed, and the image density was analysed by grey levels. The presence and type of inflammatory infiltrate, vascularization and bone necrosis were assigned by histological qualitative scores. Histomorphometric analysis of bone density was performed in the groups without extraction. No significant differences were found in the bone grey density estimated by grey-level value and histomorphometric analysis between the C1 and T1 groups (P > 0.05). The grey levels in the T3 group were lower (P < 0.05) than in the C3 group, corresponding to the bone defect. Histological assessments showed the presence of bone necrosis in the T3 group and lower levels of bone remodelling in the test groups (T2 and T3) compared to the control groups (C2 and C3). The results of qualitative analyses did not differ significantly between the groups (P > 0.05). Zoledronic acid-exposed animals showed maxillary changes including reduced grey levels, the presence of bone necrosis and a higher prevalence of inflammatory signs.