Immunogenicity and Vaccine Shedding After 1 or 2 Doses of rVSVΔG-ZEBOV-GP Ebola Vaccine (ERVEBO®): Results From a Phase 2, Randomized, Placebo-controlled Trial in Children and Adults.

BACKGROUND: The rVSVΔG-ZEBOV-GP vaccine (ERVEBO®) is a single-dose, live-attenuated, recombinant vesicular stomatitis virus vaccine indicated for the prevention of Ebola virus disease (EVD) caused by Zaire ebolavirus in individuals 12 months of age and older. METHODS: The Partnership for Research on Ebola VACcination (PREVAC) is a multicenter, phase 2, randomized, double-blind, placebo-controlled trial of 3 vaccine strategies in healthy children (ages 1-17) and adults, with projected 5 years of follow-up (NCT02876328). Using validated assays (GP-ELISA and PRNT), we measured antibody responses after 1-dose rVSVΔG-ZEBOV-GP, 2-dose rVSVΔG-ZEBOV-GP (given on Day 0 and Day 56), or placebo. Furthermore, we quantified vaccine virus shedding in a subset of children's saliva using RT-PCR. RESULTS: In total, 819 children and 783 adults were randomized to receive rVSVΔG-ZEBOV-GP (1 or 2 doses) or placebo. A single dose of rVSVΔG-ZEBOV-GP increased antibody responses by Day 28 that were sustained through Month 12. A second dose of rVSVΔG-ZEBOV-GP given on Day 56 transiently boosted antibody concentrations. In vaccinated children, GP-ELISA titers were superior to placebo and non-inferior to vaccinated adults. Vaccine virus shedding was observed in 31.7% of children, peaking by Day 7, with no shedding observed after Day 28 post-dose 1 or any time post-dose 2. CONCLUSIONS: A single dose of rVSVΔG-ZEBOV-GP induced robust antibody responses in children that was non-inferior to the responses induced in vaccinated adults. Vaccine virus shedding in children was time-limited and only observed after the first dose. Overall, these data support the use of rVSVΔG-ZEBOV-GP for the prevention of EVD in at-risk children. Clinical Trials Registration. The study is registered at ClinicalTrials.gov (NCT02876328), the Pan African Clinical Trials Registry (PACTR201712002760250), and the European Clinical Trials Register (EudraCT number: 2017-001798-18).

Statin use and the risk of developing diabetes: a network meta-analysis.

PURPOSE: Randomized controlled trials have shown mixed findings regarding the association of statins and diabetes. This systematic literature review and network meta-analysis (NMA) was performed to update evidence on this association to possibly assist clinicians in making more informed treatment choices. METHODS: We identified studies relevant to our NMA by performing study searches in databases like Embase, Cochrane, and PubMed, published between August 2010 and June 2014. Pre-2010 studies were identified from bibliography of previously published meta-analyses. Unpublished study data were found from clinicaltrial.gov. Data synthesis was performed by pairwise meta-analysis and NMA within a Frequentist framework. RESULTS: Twenty nine trials in which 1 63 039 participants had been randomized were included in this review; among these 1 41 863 were non-diabetic patients. The direct meta-analysis showed that statins, as a class, significantly increased the likelihood of developing diabetes by 12% (pooled OR 1.12; 95%CI 1.05-1.21; I2 36%; p = 0.002; 18 RCTs). In the NMA, atorvastatin 80 mg was associated with a highest risk of diabetes, with OR of 1.34 (95%CI 1.14-1.57) followed by rosuvastatin (OR: 1.17; 95%CI: 1.02-1.35). The ORs (95%CIs) for simvastatin 80 mg, simvastatin, atorvastatin, pravastatin, lovastatin and pitavastatin were 1.21 (0.99-1.49), 1.13 (0.99-1.29), 1.13 (0.94-1.34), 1.04 (0.93-1.16), 0.98 (0.69-1.38) and 0.74 (0.31-1.77), respectively. High-dose atorvastatin increased the odds of developing diabetes even when compared with pravastatin, simvastatin and low-dose atorvastatin in the NMA. CONCLUSIONS: Based on the results, statins, as a class, increased the risk of diabetes significantly in the pairwise meta-analysis. Overall, there appears to be a small increased risk of incident diabetes, particularly with more intensive statin therapy, although more data would be valuable to increase the robustness of this interpretation, given that the lower confidence intervals of our study analyses are close to, or just crossing one. Copyright © 2016 John Wiley & Sons, Ltd.

A Systematic Review of Time and Resource Use Costs of Subcutaneous Versus Intravenous Administration of Oncology Biologics in a Hospital Setting.

BACKGROUND: The introduction of human epidermal growth factor receptor 2 (HER2)-targeted treatment options, including dual HER2 blockade, has improved the prognosis for patients with HER2-positive breast cancer (BC) substantially. However, most of these treatments are administered via the intravenous (IV) route, which can present many challenges, such as long infusion and observation times, issues associated with repeated IV access, and increased strain on time and resources of medical centers and healthcare professionals. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous (SC) injection (pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO®, F. Hoffmann-La Roche Ltd, Basel, Switzerland; PH FDC SC)) has been approved for use alongside chemotherapy for early-stage and metastatic HER2-positive BC. OBJECTIVES: This systematic literature review was performed to identify evidence relating to time/resource use and resulting cost differences between SC and IV administration of oncology biologics in a hospital setting, and, ultimately, to inform economic modeling and associated health technology assessment of PH FDC SC. METHODS: Electronic databases (Embase, MEDLINE, and EconLit) were searched on 9 April 2020. Additional hand searches were performed to identify publications not captured in the electronic database search. Publication screening and data extraction (study characteristics, participants, interventions, costs, and time/resource use) were carried out per the standard Cochrane review methodology. The quality of economic evidence of cost analyses was assessed using the 36-item checklist of the National Institute for Health and Care Excellence Single Technology Appraisal Specification for submission of evidence (January 2015). RESULTS: The database search identified 2,740 records, of which 237 underwent full text screening. Full text screening, prioritization of publications about patients with a cancer diagnosis, and the addition of four citations identified during the hand search resulted in 72 final included publications, relating to 71 unique studies. This included 40 publications that described the time/resource use and/or costs associated with SC versus IV trastuzumab administration for the treatment of HER2-positive BC, and 28 publications that described time/resource use and/or costs associated with rituximab SC versus IV administration for the treatment of non-Hodgkin's lymphoma/follicular lymphoma and diffuse large B-cell lymphoma. The majority of publications showed substantial time savings for preparation and administration of SC versus IV therapy, and cost savings associated with reductions in healthcare professional time and resource use for SC administration. LIMITATIONS: There was a lack of consensus between publications regarding time and cost measurements. In addition, the search was limited to publications related to anticancer drugs; the majority of the studies included were performed in European countries. CONCLUSIONS AND IMPLICATIONS: This review indicated a substantial body of evidence showing time/resource and cost savings of SC versus IV administration of oncology biologics in a hospital setting, which can be used to inform economic evaluations of PH FDC SC.

The Economic Burden of Non-Alcoholic Steatohepatitis: A Systematic Review.

BACKGROUND: The global prevalence of non-alcoholic steatohepatitis (NASH) is increasing, such that NASH is predicted to become the leading cause of liver transplantation (LT) in the US by 2025. Despite this, data on the economic burden of NASH are limited. OBJECTIVES: This systematic literature review aimed to summarise and critically evaluate studies reporting on the economic burden of NASH and identify evidence gaps for subsequent research. METHODS: Medline, EMBASE, the Cochrane Library and EconLit were searched up to 6 January 2021 for English language articles published from January 2010 to January 2021 inclusive that reported economic outcomes of a NASH population or subpopulation. Evidence was presented and synthesised using narrative data analysis, and quality was assessed by two reviewers using an 11-item checklist developed for economic evaluations and adapted to cost of illness. RESULTS: Fourteen studies were included, of which five presented data on costs and resource use, four on costs only and five on resource use only. Overall, NASH is associated with a significant and increasing economic burden in terms of healthcare resource utilisation (HCRU) and direct and indirect costs. This burden was higher among NASH patients with advanced (fibrosis stage 3-4) versus early (fibrosis stage 0-2) disease, symptomatic versus asymptomatic disease and for patients with complications or comorbidities versus those without. In LT patients, those with NASH as the primary indication had greater HCRU and higher costs compared with non-NASH indications such as hepatitis B and C viruses. Considerable variability in HCRU and costs was seen across the US and Europe, with the highest costs seen in the US. The quality of the included studies was variable, and the studies themselves were heterogeneous in terms of study methodology, patient populations, comorbidities, follow-up time and outcomes measured. CONCLUSIONS: This review highlights a general scarcity of NASH-specific economic outcomes data. Despite this, the identified studies show that NASH is associated with a significant economic burden in terms of increased HCRU, and high direct medical and non-medical costs and societal burden that increases with disease severity or when patients have complications or comorbidity. More national-level NASH prevalence data are needed to generate accurate forecasts of HCRU and costs in the coming decades. FUNDING: Novo Nordisk A/S, Søborg, Denmark.

It is important to know the cost of treating different diseases because this helps to guide how healthcare resources and funds are used. Non-alcoholic steatohepatitis (NASH) is a serious liver disease that can lead to liver scarring (cirrhosis), liver transplantation and early death, and the number of people with NASH is growing around the world. Fourteen studies published over the past 10 years have investigated the costs of treating patients with NASH. Patients with NASH generally use more healthcare services with a higher cost than the general population or patients with type 2 diabetes. In people with more serious liver disease, such as liver transplant patients, NASH tends to be more expensive and use more healthcare services than other serious liver diseases such as hepatitis. Costs and use of health services are particularly high in patients with more severe NASH, or those who have other diseases or complications in addition to NASH (such as type 2 diabetes or kidney failure).

The burden of non-alcoholic steatohepatitis: A systematic review of health-related quality of life and patient-reported outcomes.

Background & Aims: Non-alcoholic steatohepatitis (NASH) is associated with increased mortality and a high clinical burden. NASH adversely impacts patients' health-related quality of life (HRQoL), but published data on the humanistic burden of disease are limited. This review aimed to summarise and critically evaluate studies reporting HRQoL or patient-reported outcomes (PROs) in populations with NASH and identify key gaps for further research. Methods: Medline, EMBASE, the Cochrane Library and PsycINFO were searched for English-language publications published from 2010 to 2021 that reported HRQoL/PRO outcomes of a population or subpopulation with NASH. Results: Twenty-five publications covering 23 unique studies were identified. Overall, the data showed a substantial impact of NASH on HRQoL, particularly in terms of physical functioning and fatigue, with deterioration of physical and mental health as NASH progresses. Prevalent symptoms, including fatigue, abdominal pain, anxiety/depression, cognition problems, and poor sleep quality, adversely impact patients' ability to work and perform activities of daily living and the quality of relationships. However, some patients fail to attribute symptoms to their disease because of a lack of patient awareness and education. NASH is associated with high rates of comorbidities such as obesity and type 2 diabetes, which contribute to reduced HRQoL. Studies were heterogeneous in terms of diagnostic methods, population, outcomes, follow-up time, and measures of HRQoL/utility. Most studies were rated 'moderate' at quality assessment, and all evaluable studies had inadequate control of confounders. Conclusions: NASH is associated with a significant HRQoL burden that begins early in the disease course and increases with disease progression. More robust studies are needed to better understand the humanistic burden of NASH, with adequate adjustment for confounders that could influence outcomes. Lay summary: Non-alcoholic steatohepatitis (NASH) has a significant impact on quality of life, with individuals experiencing worse physical and mental health compared with the general population. NASH and its symptoms, which include tiredness, stomach pain, anxiety, depression, poor focus and memory, and impaired sleep, affect individuals' relationships and ability to work and perform day-to-day tasks. However, not all patients are aware that their symptoms may be related to NASH. Patients would benefit from more education on their disease, and the importance of good social networks for patient health and well-being should be reinforced. More studies are needed to better understand the patient burden of NASH.

The Burden of Nonalcoholic Steatohepatitis: A Systematic Review of Epidemiology Studies.

Background and Aims: Nonalcoholic steatohepatitis (NASH) is associated with increased mortality and risk of complications but is often asymptomatic and under-recognized. A systematic review of NASH epidemiology was conducted to provide information on the burden of NASH and highlight important evidence gaps for future research. Methods: Medline, EMBASE, and Cochrane Library databases were searched for English-language publications published from 2010 to January 2022 that reported on natural history, risk factors, comorbidities, and complications of a NASH population or subpopulation. Results: Overall, 173 publications were included. NASH was shown to have a variable disease course and high prevalence of comorbid disease. Although many patients progressed to cirrhosis and end-stage liver disease, disease regression or resolution was reported in up to half of patients in some studies. Reported risk factors for disease progression or resolution included levels of (or changes in) serum fibrosis markers, liver enzymes, and platelets. The presence of NASH increased the risk of liver cirrhosis and other serious diseases such as hepatocellular carcinoma, colorectal cancer, chronic kidney disease, and cardiovascular disease. In 2017, NASH was responsible for ∼118,000 cirrhosis deaths globally, and an increasing proportion of patients are receiving liver transplantation for NASH in Europe and the United States. Consolidation of data was hampered by heterogeneity across the studies in terms of patient populations, follow-up time, and outcomes measured. Conclusion: NASH is associated with significant morbidity and mortality, an increased risk of comorbidities, and imposes an increasing burden among liver transplantation recipients. Longer studies with harmonized study criteria are required to better understand the impact of NASH on patient outcomes.

Further evidence for the association of MMP9 with nephropathy in type 2 diabetes and application of DNA pooling technology to candidate gene screening.

BACKGROUND: Diabetic nephropathy is characterised by extracellular matrix (ECM) expansion, a key modulator of which is TGF-b1. Glucose-stimulated transcriptional activation of the TGF-b1 gene is an important component of the pathogenesis of nephropathy, following which latent TGF-b1 protein is synthesised. Matrix metalloproteinase 9 (MMP9) remodels the ECM and has been implicated in TGF-b1 activation. The ECM glycosaminoglycan hyaluronan (HA) influences TGF-b1 generation and can modulate its signal transduction activity; renal HA is synthesised by HA synthases HAS2 and HAS3. METHODS: We report the first screening of the genes encoding HAS2 and HAS3 for sequence variants predisposing to nephropathy in UK type 2 diabetes patients, together with the MMP9 and TGF-b1 genes. Also for the first time, we used validated DNA pools to carry out association analyses of single nucleotide polymorphisms on nephropathic and non-nephropathic cohorts from a total of 199 type 2 diabetes patients, to increase the throughput and decrease the cost of genotype analysis. RESULTS: None of the 23 single nucleotide polymorphisms analysed in DNA pools were found to be associated with diabetic nephropathy. However, genotyping of alleles at the MMP9 promoter microsatellite locus D20S838 in individual genomic DNA samples supported previous evidence of association between this locus and diabetic nephropathy. CONCLUSIONS: The use of DNA pooling technology increased the throughput and decreased the cost of our association analysis of nephropathy in our type 2 diabetes sample, which demonstrated sufficient sensitivity to support previous positive findings of association with a microsatellite in the MMP9 promoter region.

Systematic literature review to evaluate and characterize the health economics and outcomes research studies in India.

AIM: This systematic literature review was conducted to identify, evaluate, and characterize the variety, quality, and intent of the health economics and outcomes research studies being conducted in India. MATERIALS AND METHODS: Studies published in English language between 1999 and 2012 were retrieved from Embase and PubMed databases using relevant search strategies. Two researchers independently reviewed the studies as per Cochrane methodology; information on the type of research and the outcomes were extracted. Quality of reporting was assessed for model-based health economic studies using a published 100-point Quality of Health Economic Studies (QHES) instrument. RESULTS: Of 546 studies screened, 132 were included in the review. The broad study categories were cost-effectiveness analyses [(CEA) 54 studies], cost analyses (19 studies), and burden of illness [(BOI) 18 studies]. The outcomes evaluated were direct and indirect costs, and incremental cost-effectiveness ratio (ICER), quality-adjusted life years (QALYs), and disability-adjusted life years (DALYs). Direct medical costs assessed cost of medicines, monitoring costs, consultation and hospital charges, along with direct non-medical costs (travel and food for patients and care givers). Loss of productivity and loss of income of patients and care givers were identified as the components of indirect cost. Overall, 33 studies assessed the quality of life (QoL), and the WHO Quality of Life-BREF (WHOQOL-BREF) was the most commonly used instrument. Quality assessment for modeling studies showed that most studies were of high quality [mean (range) QHES score to be 75.5 (34-93)]. CONCLUSIONS: This review identified various patterns of pharmacoeconomic studies and good-quality CEA studies. However, there is a need for better assessment of utilization of healthcare resources in India.

Personalized medicine: Striding from genes to medicines.

Personalized medicine has the potential of revolutionizing patient care. This treatment modality prescribes therapies specific to individual patients based on pharmacogenetic and pharmacogenomic information. The mapping of the human genome has been an important milestone in understanding the interindividual differences in response to therapy. These differences are attributed to genotypic differences, with consequent phenotypic expression. It is important to note that targeted therapies should ideally be accompanied by a diagnostic marker. However, most efforts are being directed toward developing both these separately; the former by pharmaceutical companies and the later by diagnostic companies. Further, this companion strategy will be successful only when the biomarkers assayed are differentiated on a value-based approach rather than a cost-based approach, especially in countries that reimburse disease management costs. The advantages of using personalized therapies are manifold: targeted patient population; avoidance of drug-related toxicities and optimization of costs in nonresponder patients; reduction in drug development costs, and fewer patients to be tested in clinical trials. The success of personalized therapy in future will depend on a better understanding of pharmacogenomics and the extension of these scientific advances to all countries.

Gene polymorphism and coronary risk factors in Indian population.

Asian Indians who have settled overseas and those in urban India have increased risk of coronary events. Reasons for this increased risk are thought to be genetic but are yet unclear. Advances in molecular cardiology have revealed a number of single nucleotide polymorphisms associated with atherosclerosis. In this review, gene polymorphisms that have been associated with coronary diseases among Indians are discussed. Topics include the genes involved in hyperlipidemia, hypertension, and homocysteine. Mutations in the low-density lipoprotein receptor (LDLR) gene resulting in familial hypercholesterolemia have strong association with premature atherosclerosis. Common polymorphism of the apolipoproteins (apo) B-100 and E genes have been associated with variation in lipid and lipoprotein levels. Recently identified polymorphisms in the apoC3 (T-455C, C-482T), and cholesteryl ester transfer protein (CETP) (B1/B2 allele) genes are associated with increased triglycerides and reduced high-density lipoprotein (HDL)-levels, a feature now also common among Asian Indians. Angiotensin-converting enzyme-deletion (DD) polymorphism has been shown to influence beta-blocker therapy in heart failure. Mutations in methylenetetrahydrofolate reductase (C667T), cystathionine beta-synthase (T833C), and methionine synthase (A2756G) genes cause hyperhomocysteinemia, an independent risk factor for atherothrombosis. As the genetics of atherosclerosis continues to evolve, these factors along with the newer emerging factors may become a part of the routine assessment, aiding prediction of future coronary events.