Development of a long-acting direct-acting antiviral system for hepatitis C virus treatment in swine.

Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis worldwide and kills more Americans than 59 other infections, including HIV and tuberculosis, combined. While direct-acting antiviral (DAA) treatments are effective, limited uptake of therapy, particularly in high-risk groups, remains a substantial barrier to eliminating HCV. We developed a long-acting DAA system (LA-DAAS) capable of prolonged dosing and explored its cost-effectiveness. We designed a retrievable coil-shaped LA-DAAS compatible with nasogastric tube administration and the capacity to encapsulate and release gram levels of drugs while resident in the stomach. We formulated DAAs in drug-polymer pills and studied the release kinetics for 1 mo in vitro and in vivo in a swine model. The LA-DAAS was equipped with ethanol and temperature sensors linked via Bluetooth to a phone application to provide patient engagement. We then performed a cost-effectiveness analysis comparing LA-DAAS to DAA alone in various patient groups, including people who inject drugs. Tunable release kinetics of DAAs was enabled for 1 mo with drug-polymer pills in vitro, and the LA-DAAS safely and successfully provided at least month-long release of sofosbuvir in vivo. Temperature and alcohol sensors could interface with external sources for at least 1 mo. The LA-DAAS was cost-effective compared to DAA therapy alone in all groups considered (base case incremental cost-effectiveness ratio $39,800). We believe that the LA-DAA system can provide a cost-effective and patient-centric method for HCV treatment, including in high-risk populations who are currently undertreated.

Electrical-Driven Release and Migration of Herbicide Using a Gel-Based Nanocomposite.

In this work, an electrical-driven release and migration glyphosate (EDRMG) was fabricated using a nanocomposite made up of attapulgite (ATP), glyphosate (Gly), and calcium alginate (CA). Therein, ATP-CA acted as a nanonetwork-structured carrier to efficiently load plenty of Gly to form porous ATP-Gly-CA hydrogel spheres (actually EDRMG-0.5) via a cross-linking reaction. The pores in EDRMG-0.5 hydrogel spheres were enlarged under an electric field because of the Coulomb force of the anionic CA polymer, and the release of negatively charged Gly from the spheres could be driven by the electric field force. Thus, EDRMG-0.5 exhibited a great electroresponsively controlled-release property, which was confirmed by a pot experiment. Importantly, the EDRMG-0.5 hydrogel spheres had fine biocompatibility on fish and mice, displaying good biosafety. This work provides a low cost and promising approach to control Gly release, deliver Gly precisely, and improve utilization efficiency, which might have a high application value.

Cost-effectiveness of strategies preventing late-onset infection in preterm infants.

OBJECTIVE: Developing a model to analyse the cost-effectiveness of interventions preventing late-onset infection (LOI) in preterm infants and applying it to the evaluation of anti-microbial impregnated peripherally inserted central catheters (AM-PICCs) compared with standard PICCs (S-PICCs). DESIGN: Model-based cost-effectiveness analysis, using data from the Preventing infection using Antimicrobial Impregnated Long Lines (PREVAIL) randomised controlled trial linked to routine healthcare data, supplemented with published literature. The model assumes that LOI increases the risk of neurodevelopmental impairment (NDI). SETTING: Neonatal intensive care units in the UK National Health Service (NHS). PATIENTS: Infants born ≤32 weeks gestational age, requiring a 1 French gauge PICC. INTERVENTIONS: AM-PICC and S-PICC. MAIN OUTCOME MEASURES: Life expectancy, quality-adjusted life years (QALYs) and healthcare costs over the infants' expected lifetime. RESULTS: Severe NDI reduces life expectancy by 14.79 (95% CI 4.43 to 26.68; undiscounted) years, 10.63 (95% CI 7.74 to 14.02; discounted) QALYs and costs £19 057 (95% CI £14 197; £24697; discounted) to the NHS. If LOI causes NDI, the maximum acquisition price of an intervention reducing LOI risk by 5% is £120. AM-PICCs increase costs (£54.85 (95% CI £25.95 to £89.12)) but have negligible impact on health outcomes (-0.01 (95% CI -0.09 to 0.04) QALYs), compared with S-PICCs. The NHS can invest up to £2.4 million in research to confirm that AM-PICCs are not cost-effective. CONCLUSIONS: The model quantifies health losses and additional healthcare costs caused by NDI and LOI during neonatal care. Given these consequences, interventions preventing LOI, even by a small extent, can be cost-effective. AM-PICCs, being less effective and more costly than S-PICC, are not likely to be cost-effective. TRIAL REGISTRATION NUMBER: NCT03260517.

Outcomes and Costs Following Ommaya Placement with Thrombocytopenia Among U.S. Patients with Cancer.

BACKGROUND: Placement of Ommaya reservoirs for the administration of intrathecal chemotherapy may be complicated by comorbid thrombocytopenia among patients with hematologic or leptomeningeal disease. Aggregated data on risks of Ommaya placement among thrombocytopenic patients are lacking. This study assesses complications, revision rates, and costs associated with Ommaya placement among patients with thrombocytopenia in a large population sample. METHODS: Using a national administrative database, this retrospective study identifies a cohort of adult patients with cancer who underwent Ommaya placement between 2007 and 2016. Preoperative thrombocytopenia was defined as diagnosis of secondary thrombocytopenia, bleeding event, procedure to control bleeding, or platelet transfusion, within 30 days before index admission. Univariate and multivariate analyses were performed to assess costs, 30-day complications, readmissions, and revisions among patients with and without preoperative thrombocytopenia. RESULTS: The analytic cohort included 1652 patients, of whom 29.3% met criteria for preoperative thrombocytopenia. In-hospital mortality rates were 7.7% among patients thrombocytopenia with versus 1.2% among patients without thrombocytopenia (P < 0.001). Preoperative thrombocytopenia was associated with 14.5 times greater hazard of intracranial hemorrhage within 30 days following Ommaya placement, occurring in 25.6% versus 2.0% of patients with and without thrombocytopenia, respectively (P < 0.014). Revision rates did not differ significantly between patients with and without thrombocytopenia. Thrombocytopenia was associated with longer length of stay (7.4 vs. 13.9 days, P < 0.001) and additional $10,000 per patient in costs of index hospitalization (P < 0.001). CONCLUSIONS: This is the largest study to date documenting costs and complication rates of Ommaya placement in patients with and without thrombocytopenia.

Assessment of Health Care Utilization and Cost of Targeted Drug Delivery and Conventional Medical Management vs Conventional Medical Management Alone for Patients With Cancer-Related Pain.

Importance: Targeted drug delivery (TDD) has potential for cost savings compared with conventional medical management (CMM). Despite positive clinical and economic evidence, TDD remains underused to treat cancer pain. Objective: To assess the cost of TDD and CMM in treating cancer-related pain. Design, Setting, and Participants: This retrospective economic evaluation using propensity score-matched analysis was conducted using MarketScan commercial claims data on beneficiaries receiving TDD and CMM or CMM only for cancer pain from January 1, 2009, to September 30, 2015. Participants were matched on age, sex, cancer type, comorbidity score, and pre-enrollment characteristics. Data analysis was performed from June 1 to September 30, 2017. Main Outcomes and Measures: Total 2-, 6-, and 12-month costs, number of health care encounters, length of hospital stay, additional components of cost, and health care utilization. Results: A total of 376 TDD and CMM patients (mean [SD] age, 51.88 [9.98] years; 216 [57.5%] female) and 4839 CMM only patients (mean [SD] age, 51.52 [11.16] years; 3005 [62.1%] female) were identified for study inclusion. After matching, 536 patients were included in the study: 268 patients in the TDD and CMM group and 268 in the CMM only group. Compared with CMM only, TDD and CMM was associated with mean total cost savings of $15 142 (95% CI, $3690 to $26 594; P = .01) at 2 months and $63 498 (95% CI, $4620 to $122 376; P = .03) at 12 months; cost savings at 6 months were not statistically different ($19 577; 95% CI, -$12 831 to $51 984; P = .24). The TDD and CMM group had fewer inpatient visits (2-month mean difference [MD], 1.0; 95% CI, 0.8-1.2; P < .001; 6-month MD, 1.3; 95% CI, 0.8-1.7; P < .001; 12-month MD, 2.3; 95% CI, 1.2-3.4; P < .001) and shorter hospital stays (2-month MD, 6.8 days; 95% CI, 5.0-8.7 days; P < .001; 6-month MD, 6.8 days; 95% CI, 3.1-10.5 days; P < .001; 12-month MD, 10.6 days; 95% CI, 2.9-18.3 days; P = .007). Use of CMM only was associated with greater opioid use at 12 months (MD, 3.2; 95% CI, 0.4-6.0; P = .03). Conclusions and Relevance: Compared with CMM alone, TDD and CMM together were associated with significantly lower cost and health care utilization. The findings suggest that TDD is a cost-saving therapy that should be considered in patients with cancer for whom oral opioids are inadequate or produce intolerable adverse effects and should be expanded as health care systems transition to value-based models.

A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment.

Multigram drug depot systems for extended drug release could transform our capacity to effectively treat patients across a myriad of diseases. For example, tuberculosis (TB) requires multimonth courses of daily multigram doses for treatment. To address the challenge of prolonged dosing for regimens requiring multigram drug dosing, we developed a gastric resident system delivered through the nasogastric route that was capable of safely encapsulating and releasing grams of antibiotics over a period of weeks. Initial preclinical safety and drug release were demonstrated in a swine model with a panel of TB antibiotics. We anticipate multiple applications in the field of infectious diseases, as well as for other indications where multigram depots could impart meaningful benefits to patients, helping maximize adherence to their medication.

Clinical and economic considerations based on persistency with a novel insulin delivery device versus conventional insulin delivery in patients with type 2 diabetes: A retrospective analysis.

OBJECTIVE: Insulin is one of the most efficacious treatments for hyperglycemia; however, adherence to insulin therapy is poor, impacting its efficacy. Thus, the objectives of this study were to determine if persistent use of a new insulin delivery option, V-Go, improved clinical outcomes and secondly compare clinical and economic outcomes between persistent use of V-Go and conventional insulin delivery (CID). METHODS: A retrospective review of an outpatient clinic's records was performed. Patients initiating V-Go with documented persistent use of V-Go or resumed persistent use of CID after short-term V-Go use were included (≥5 months of persistency). Baseline data and a total of two post-V-Go or CID initiation visits were examined for clinical and economic outcomes. Cost-effectiveness of each therapy was calculated by dividing the mean cost difference (baseline to office visit 2) by the mean change in A1c (baseline to office visit 2). RESULTS: V-Go persistent patients had a significant decrease in A1c (-1.42; p < 0.001). Between baseline and office visit two, they required less insulin units/day and units/kg and had significantly lower A1c, insulin units/day, insulin units/kg, and 30-day insulin costs than CID patients. V-Go persistent patients had a lower incremental cost by $695.61 per 1% change in A1c compared to CID persistent patients. CONCLUSIONS: Utilization of a new insulin delivery option resulted in improved clinical outcomes compared to CID and was more cost-effective. Clinicians and health plans should consider the use of new insulin delivery options for the management of patients with diabetes on insulin therapy to promote persistence.

Power-efficient controlled jet injection using a compound ampoule.

We present a new mechanism for achieving needle free jet injection that significantly reduces the power required to perform a given injection. Our 'compound ampoule' produces two phases of jet speed under a constant force input by changing the effective piston area part-way through the injection. In this paper we define the benefits associated with a compound ampoule, relative to those of the conventional single piston design, by developing expressions for the power and energy required to perform an injection. We demonstrate that a compound ampoule can reduce the maximum input power required to perform a jet injection to less than one fifth of that previously required, enabling motors of less than half the mass to perform the same injection. We then detail the development of a prototype compound ampoule injector. Results from testing of this prototype demonstrate the function of a compound ampoule and verify the expected reduction in the required power and energy. Injections into post mortem porcine tissue confirm that our compound ampoule prototype can achieve the delivery of 1 mL of liquid into post-mortem tissue at least as effectively as a conventional ampoule. This approach will advance progress toward light-weight and power-efficient needle-free jet injectors for transdermal drug delivery.

Insertion-responsive microneedles for rapid intradermal delivery of canine influenza vaccine.

In this study, we present transcutaneous influenza vaccination using a novel tip-separable microneedle system called insertion-responsive microneedles (IRMNs). IRMNs are composed of dissolvable hyaluronic acid (HA) tips and biocompatible polycaprolactone (PCL) bases, the tip of which is instantly separated from the base during microneedle insertion and retraction. Vaccine antigens derived from canine influenza virus (A/canine/VC378/2012; H3N2) were successfully coated on HA tips by rapidly freezing the tips prior to coating. An ex vivo porcine skin insertion test showed that IRMNs were capable of penetrating the skin without tip breakage and releasing the coated materials within the skin. The thermal stability of the vaccine as determined by hemagglutination assay revealed that the coated vaccine partially maintained its activity when stored at 50 °C for 3 weeks, whereas the liquid form completely lost the activity. Immunization in guinea pigs showed that hemagglutination inhibition (HI) antibodies induced by IRMNs were two times higher than those induced by intramuscular (IM) injections. When challenged with influenza A/canine/Korea/01/2007 (H3N2) wild-type virus 2 weeks after the second vaccination, viral shedding was completely eliminated at 8 days post infection in both IRMNs and IM injection groups. Our results suggest that IRMNs have great potential for rapid and convenient vaccination, which will be particularly attractive for animal vaccinations.

Economic Impact of Oral Therapies for Chronic Lymphocytic Leukemia-the Burden of Novelty.

PURPOSE OF REVIEW: Small molecule tyrosine kinase inhibitors (TKIs) and BCL2 inhibitors are oral targeted therapies that have changed the treatment approach to patients with chronic lymphocytic leukemia (CLL). The aim of this review is to summarize the relevant literature on the economic impact of oral novel therapies for the treatment of CLL and discuss the underlying factors and suggested solutions for high drug prices. RECENT FINDINGS: The cost of therapy for CLL has increased substantially since the introduction of oral therapies. This increase in cost is caused by multiple factors including cost of drug development, alternate reimbursement patterns, lack of transparency, and lack of free market competition. Oral therapies for CLL have dramatically increased costs for both patients and payers. Some solutions to overcome this include value-based pricing, transparency, and legal action that allow Medicare to negotiate drug prices with manufacturers.

The association between insurance coverage for insulin pen needles and healthcare resource utilization among insulin-dependent patients with diabetes in China.

BACKGROUND: Pen needles are an important component of insulin delivery among patients with diabetes, but are not universally covered in China. We compared clinical and economic characteristics of insulin-dependent patients in China who have some level of pen needle (PN) reimbursement to those with no PN reimbursement. METHODS: A cross-sectional study was conducted among 400 insulin users with Type 1 or Type 2 diabetes treated in outpatient endocrinology units of four large tertiary care hospitals in Nanjing, Chongqing, Beijing and Zhengzhou. Demographics, medical history, healthcare resource utilization (RU), out-of-pocket costs, insurance and PN reimbursement status were surveyed. Unit costs were assigned to healthcare RU and compared using descriptive statistics and multivariate regression models. RESULTS: A total of 400 patients were analyzed; 142 (35.5%) with some level of PN coverage/reimbursement and 258 (64.5%) without. Patients without PN reimbursement had a higher prevalence of lipohypertrophy (59.3% vs. 40.7%, p = 0.0007), greater median PN reuse (12 vs. 7 times per needle, p < 0.0001), greater 6-month insulin costs (1591 vs. 1328 Renminbi [RMB], p = 0.0025) and total unadjusted 6-month expenditures (6433 vs. 4432 RMB, p < 0.0001), respectively. After controlling for clinical and demographic characteristics, patients without PN reimbursement had 4.6 times greater odds of high costs compared to those with PN reimbursement. CONCLUSIONS: Insulin users without PN reimbursement may pose a greater economic burden to China compared to those with PN reimbursement. Expansion of insurance coverage for insulin PNs can improve the quality of care and potentially help reduce the economic burden in this population.

Novel Devices for Delivering Diabetes Medications: Their Value and Some Coverage Considerations.

Insurers should consider covering new drug-delivery devices that can improve outcomes while lowering disease-specific pharmacy and long-term overall health care costs. Managing these devices in the pharmacy benefit will consolidate volume-based purchasing and capitalize on PBM strategies for improving adherence.