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1.  Long-term efficacy and safety of omalizumab in patients with persistent uncontrolled allergic asthma: a systematic review and meta-analysis 
Scientific Reports  2015;5:8191.
Currently, limited information is available to clinicians regarding the long-term efficacy of omalizumab treatment for allergic asthma. In this report, we aimed to (i) systematically review the evidence regarding the long-term efficacy of omalizumab in patients with persistent uncontrolled allergic asthma, and to (ii) discuss the cost-effectiveness evidence published for omalizumab in this patient population. A comprehensive search for randomized controlled trials (RCTs; ≥52 weeks) was performed, and six studies met our final inclusion criteria (n = 2,749). Omalizumab was associated with significant improvements in quality of life and the Global Evaluation of Treatment Effectiveness. Omalizumab also allowed patients to completely withdraw from inhaled corticosteroid therapy and did not increase the overall incidence of adverse events. However, there was insufficient evidence that omalizumab reduced the incidence of exacerbations, and the cost-effectiveness of omalizumab varied across studies. Our data indicated that omalizumab use for at least 52 weeks in patients with persistent uncontrolled allergic asthma was accompanied by an acceptable safety profile, but it lacked effect on the asthma exacerbations. Use of omalizumab was associated with a higher cost than conventional therapy, but these increases may be cost-effective if the medication is used in patients with severe allergic asthma.
doi:10.1038/srep08191
PMCID: PMC4314644  PMID: 25645133
2.  Omalizumab in the management of patients with allergic (IgE-mediated) asthma 
Immunoglobulin E (IgE) is central to the pathophysiology of allergic asthma. Omalizumab, an anti-IgE monoclonal antibody, binds to the FcɛRI binding site on free IgE. As a result, circulating free IgE is reduced, IgE is prevented from attaching to mast cells and basophils, and FcɛRI receptor expression is down-regulated. The inflammatory response to allergens and the acute and chronic effector phases of allergic inflammation are thereby attenuated. In clinical trials in adults and adolescents, omalizumab reduced asthma exacerbations, severe asthma exacerbations, inhaled corticosteroid requirements, and emergency visits, as well as significantly improving asthma-related quality of life, morning peak expiratory flow and asthma symptom scores in patients with severe allergic (IgE-mediated) asthma. Results from clinical trials in children (<12 years) are consistent with those in the adult population. It is difficult to predict which patients will respond to omalizumab. Responders to omalizumab should be identified after a 16-week trial of therapy using the physician’s overall assessment. When treatment is targeted to these responders, omalizumab provides a cost-effective therapy for inadequately controlled severe allergic (IgE-mediated) asthma. Long-term therapy with omalizumab shows the potential for disease-modification in asthma. Ongoing studies are also evaluating the use of omalizumab in other non-asthma IgE-mediated conditions.
PMCID: PMC3048609  PMID: 21437144
omalizumab; IgE; allergic asthma
3.  Safety of anti-immunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection 
Background
Although the role of immunoglobulin E (IgE) in immunity against helminth parasites is unclear, there is concern that therapeutic antibodies that neutralize IgE (anti-IgE) may be unsafe in subjects at risk of helminth infection.
Objective
We conducted an exploratory study to investigate the safety of omalizumab (anti-IgE) in subjects with allergic asthma and/or perennial allergic rhinitis at high risk of intestinal helminth infection. The primary safety outcome was risk of infections with intestinal helminths during anti-IgE therapy.
Methods
A randomized, double-blind, placebo-controlled trial was conducted in 137 subjects (12–30 years) at high risk of geohelminth infection. All subjects received pre-study anthelmintic treatment, followed by 52 weeks' treatment with omalizumab or placebo.
Results
Of the omalizumab subjects 50% (34/68) experienced at least one intestinal geohelminth infection compared with 41% (28/69) of placebo subjects [odds ratio (OR) 1.47, 95% confidence interval (CI) 0.74–2.95, one-sided P = 0.14; OR (adjusted for study visit, baseline infection status, gender and age) 2.2 (0.94–5.15); one-sided P = 0.035], providing some evidence for a potential increased incidence of geohelminth infection in subjects receiving omalizumab. Omalizumab therapy was well tolerated, and did not appear to be associated with increased morbidity attributable to intestinal helminths as assessed by clinical and laboratory adverse events, maximal helminth infection intensities and additional anthelmintic requirements. Time to first infection (OR 1.30, 95% CI 0.79–2.15, one-sided P = 0.15) was similar between treatment groups. Infection severity and response to anthelmintics appeared to be unaffected by omalizumab therapy.
Conclusions
In this exploratory study of allergic subjects at high risk of helminth infections, omalizumab therapy appeared to be safe and well tolerated, but may be associated with a modest increase in the incidence of geohelminth infection.
doi:10.1111/j.1365-2222.2007.02650.x
PMCID: PMC1859973  PMID: 17250692
allergic rhinitis; asthma; geohelminth infections; immunoglobulin E; monoclonal antibody; omalizumab
4.  Economic Appraisal of Ontario's Universal Influenza Immunization Program: A Cost-Utility Analysis 
PLoS Medicine  2010;7(4):e1000256.
Beate Sander and colleagues assess the cost-effectiveness of the program that provides free seasonal influenza vaccines to the entire population of Ontario, Canada.
Background
In July 2000, the province of Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free seasonal influenza vaccines for the entire population. This is the first large-scale program of its kind worldwide. The objective of this study was to conduct an economic appraisal of Ontario's UIIP compared to a targeted influenza immunization program (TIIP).
Methods and Findings
A cost-utility analysis using Ontario health administrative data was performed. The study was informed by a companion ecological study comparing physician visits, emergency department visits, hospitalizations, and deaths between 1997 and 2004 in Ontario and nine other Canadian provinces offering targeted immunization programs. The relative change estimates from pre-2000 to post-2000 as observed in other provinces were applied to pre-UIIP Ontario event rates to calculate the expected number of events had Ontario continued to offer targeted immunization. Main outcome measures were quality-adjusted life years (QALYs), costs in 2006 Canadian dollars, and incremental cost-utility ratios (incremental cost per QALY gained). Program and other costs were drawn from Ontario sources. Utility weights were obtained from the literature. The incremental cost of the program per QALY gained was calculated from the health care payer perspective. Ontario's UIIP costs approximately twice as much as a targeted program but reduces influenza cases by 61% and mortality by 28%, saving an estimated 1,134 QALYs per season overall. Reducing influenza cases decreases health care services cost by 52%. Most cost savings can be attributed to hospitalizations avoided. The incremental cost-effectiveness ratio is Can$10,797/QALY gained. Results are most sensitive to immunization cost and number of deaths averted.
Conclusions
Universal immunization against seasonal influenza was estimated to be an economically attractive intervention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Annual outbreaks (epidemics) of influenza—a viral disease of the nose, throat, and airways—make millions of people ill and kill about 500,000 individuals every year. In doing so, they impose a considerable economic burden on society in terms of health care costs and lost productivity. Influenza epidemics occur because small but frequent changes in the viral proteins to which the immune system responds mean that an immune response produced one year by exposure to an influenza virus provides only partial protection against influenza the next year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains can boost this natural immunity and greatly reduce a person's chances of catching influenza. Consequently, many countries run seasonal influenza vaccine programs. These programs usually target people at high risk of complications from influenza and individuals likely to come into close contact with them, and people who provide essential community services. So, for example, in most Canadian provinces, targeted influenza immunization programs (TIIPs) offer free influenza vaccinations to people aged 65 years or older, to people with chronic medical conditions, and to health care workers.
Why Was This Study Done?
Some experts argue, however, that universal vaccination might provide populations with better protection from influenza. In 2000, the province of Ontario in Canada decided, therefore, to introduce a universal influenza immunization program (UIIP) to provide free influenza vaccination to everyone older than 6 months, the first large program of this kind in the world. A study published in 2008 showed that, following the introduction of the UIIP, vaccination rates in Ontario increased more than in other Canadian provinces. In addition, deaths from influenza and influenza-related use of health care facilities decreased more in Ontario than in provinces that continued to offer a TIIP. But is universal influenza vaccination good value for money? In this study, the researchers evaluate the cost-effectiveness of the Ontario UIIP by comparing the health outcomes and costs associated with its introduction with the health outcomes and costs associated with a hypothetical continuation of targeted influenza immunization.
What Did the Researchers Do and Find?
The researchers used data on TIIP and UIIP vaccine uptake, physician visits, emergency department visits, hospitalizations for influenza, and deaths from influenza between 1997 and 2004 in Ontario and in nine Canadian states offering TIIPs, and Ontario cost data, in their “cost-utility” analysis. This type of analysis estimates the additional cost required to generate a year of perfect health (a quality-adjusted life-year or QALY) through the introduction of an intervention. QALYs are calculated by multiplying the time spent in a certain health state by a measure of the quality of that health state. The researchers report that the cost of Ontario's UIIP was about twice as much as the cost of a TIIP for the province. However, the introduction of the UIIP reduced the number of influenza cases by nearly two-thirds and reduced deaths from influenza by more than a quarter compared with what would have been expected had the province continued to offer a TIIP, an overall saving of 1,134 QALYs. Furthermore, the reduction in influenza cases halved influenza-related health care costs, mainly because of reductions in hospitalization. Overall, this means that the additional cost to Ontario of saving one QALY through the introduction of the UIIP was Can$10,797, an “incremental cost-effectiveness ratio” of $10,797 per QALY gained.
What Do These Findings Mean?
In Canada, an intervention is considered cost-effective from the point of view of a health care purchaser if it costs less than Canadian $50,000 to gain one QALY. These findings indicate, therefore, that for Ontario the introduction of the UIIP is economically attractive. Indeed, the researchers calculate that even if the costs of the UIIP were to double, the additional cost of saving one QALY by introducing universal immunization would remain below $50,000. Other “sensitivity” analyses undertaken by the researchers also indicate that universal immunization is likely to be effective and cost-effective in Ontario if other key assumptions and/or data included in the calculations are varied within reasonable limits. Given these findings, the researchers suggest that a UIIP might be an appealing intervention in other Canadian provinces and in other high-income countries where influenza transmission and health-care costs are broadly similar to those in Ontario.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000256.
A PLoS Medicine Research Article by Kwong and colleagues describes how the introduction of universal influenza immunization in Ontario altered influenza-related health care use and deaths in the province
Wikipedia pages are available on QALYs and on cost-utility analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Bandolier, an independent online journal about evidence-based health-care, provides information about QALYs and their use in cost-utility analysis
The UK National Institute for Health and Clinical Excellence has a webpage on Measuring effectiveness and cost-effectiveness: the QALY
doi:10.1371/journal.pmed.1000256
PMCID: PMC2850382  PMID: 20386727
5.  Omalizumab: Clinical Use for the Management of Asthma 
Omalizumab, a humanized monoclonal antibody that binds circulating IgE antibody, is a treatment option for patients with moderate to severe allergic asthma whose asthma is poorly controlled with inhaled corticosteroids and inhaled long-acting β2 agonist bronchodilators. This review considers the mechanism of action, pharmacokinetics, efficacy, safety and place in management of omalizumab in asthma and focuses particularly on key articles published over the last three years. Omalizumab reduces IgE mediated airway inflammation and its effect on airway remodeling is under investigation. Recent long-term clinical trials confirm the benefits of omalizumab in reducing exacerbations and symptoms in adults and in children with moderate to severe allergic asthma. No clinical or immunological factor consistently predicts a good therapeutic response to omalizumab in allergic asthma. In responders, the duration of treatment is unclear. The main adverse effect of omalizumab is anaphylaxis, although this occurs infrequently. Preliminary data from a five-year safety study has raised concerns about increased cardiovascular events and a final report is awaited. Clinical trials are in progress to determine whether omalizumab has efficacy in the treatment of non-allergic asthma.
doi:10.4137/CCRPM.S7793
PMCID: PMC3382304  PMID: 22745565
IgE; severe asthma; allergic asthma; omalizumab
6.  Omalizumab: the evidence for its place in the treatment of allergic asthma 
Core Evidence  2008;3(1):55-66.
Introduction:
Asthma is a chronic inflammatory airways disease associated with reversible airflow obstruction and bronchial hyperresponsiveness. Asthma is prevalent worldwide and results in significant morbidity, mortality, and healthcare costs, the majority of which arise from those with severe disease. Omalizumab is a monoclonal antibody to immunoglobulin E (IgE) that has been developed for the treatment of severe persistent allergic (IgE mediated) asthma.
Aims:
The aim of this review is to evaluate the available clinical evidence on omalizumab to determine the role it has to play in the treatment of persistent allergic asthma.
Evidence review:
There is clear evidence to show that omalizumab is effective in reducing the rate of asthma exacerbations, inhaled corticosteroid dose, and the need for rescue medication in patients with allergic asthma. Clinical data indicate beneficial effects on patient-reported symptoms and perceived quality of life, as well as a reduction in unscheduled healthcare visits. There is little evidence to suggest omalizumab may enhance lung function or reduce the requirement for oral corticosteroids. Omalizumab has a favorable safety profile, although anaphylaxis has occurred. A study in children showed similar results to those achieved in adults and adolescents, with fewer asthma exacerbations and school days missed. Omalizumab may be cost effective in patients when used as add-on therapy to inhaled corticosteroids and long-acting beta2 agonists (LABA).
Place in therapy:
Omalizumab is an effective add-on therapy to inhaled corticosteroids and LABAs in adults and adolescents with severe persistent allergic asthma. Currently there is insufficient evidence to support the use of omalizumab in children.
doi:10.3355/ce.2008.012
PMCID: PMC2899803  PMID: 20694084
allergic asthma; omalizumab; immunoglobulin E; evidence
7.  A review of anti-IgE monoclonal antibody (omalizumab) as add on therapy for severe allergic (IgE-mediated) asthma 
Bronchial asthma is recognized as a highly prevalent health problem in the developed and developing world with significant social and economic consequences. Increased asthma severity is not only associated with enhanced recurrent hospitalization and mortality but also with higher social costs. The pathogenetic background of allergic-atopic bronchial asthma is characterized by airway inflammation with infiltration of several cells (mast cells, basophils, eosinophils, monocytes, and T-helper (Th)2 lymphocytes). However, in atopic asthma the trigger factors for acute attacks and chronic worsening of bronchial inflammation are aeroallergens released by pollens, dermatophagoides, and pets, which are able to induce an immune response by interaction with IgE antibodies. Currently anti-inflammatory treatments are effective for most asthma patients, but there are asthmatic subjects whose disease is not completely controlled by inhaled or systemic corticosteroids and who account for a significant portion of the healthcare costs of asthma. A novel therapeutic approach to asthma and other allergic respiratory diseases involves interference in the action of IgE, and this antibody has been viewed as a target for novel immunological drug development in asthma. Omalizumab is a humanized recombinant monoclonal anti-IgE antibody approved for treatment of moderate to severe IgE-mediated (allergic) asthma. This non-anaphylactogenic anti-IgE antibody inhibits IgE functions, blocking free serum IgE and inhibiting their binding to cellular receptors. By reducing serum IgE levels and IgE receptor expression on inflammatory cells in the context of allergic cascade, omalizumab represents a new class of mast cells stabilizing drugs; it is a novel approach to the treatment of atopic asthma. Omalizumab therapy is well tolerated and significantly improves symptoms and disease control, reducing asthma exacerbations and the need to use high dosage of inhaled corticosteroids. Moreover, omalizumab improves quality of life of patients with severe persistent allergic asthma which is inadequately controlled by currently available asthma medications. In conclusion omalizumab may fulfil an important need in patients with moderate to severe asthma.
PMCID: PMC2374942  PMID: 18472983
airway hyper-reactivity; asthma; allergic respiratory diseases; atopic respiratory diseases; anti-IgE therapy; hypersensitivity; monoclonal anti-IgE antibody; omalizumab
8.  Cryptococcal Meningitis Treatment Strategies in Resource-Limited Settings: A Cost-Effectiveness Analysis 
PLoS Medicine  2012;9(9):e1001316.
David Boulware and colleagues assess the cost effectiveness of different treatment strategies in low- and middle-income countries for cryptococcal meningitis, one of the most common opportunistic infections of people with HIV.
Background
Cryptococcal meningitis (CM) is the most common form of meningitis in Africa. World Health Organization guidelines recommend 14-d amphotericin-based induction therapy; however, this is impractical for many resource-limited settings due to cost and intensive monitoring needs. A cost-effectiveness analysis was performed to guide stakeholders with respect to optimal CM treatment within resource limitations.
Methods and Findings:
We conducted a decision analysis to estimate the incremental cost-effectiveness ratio (ICER) of six CM induction regimens: fluconazole (800–1,200 mg/d) monotherapy, fluconazole + flucytosine (5FC), short-course amphotericin (7-d) + fluconazole, 14-d of amphotericin alone, amphotericin + fluconazole, and amphotericin + 5FC. We computed actual 2012 healthcare costs in Uganda for medications, supplies, and personnel, and average laboratory costs for three African countries. A systematic review of cryptococcal treatment trials in resource-limited areas summarized 10-wk survival outcomes. We modeled one-year survival based on South African, Ugandan, and Thai CM outcome data, and survival beyond one-year on Ugandan and Thai data. Quality-adjusted life years (QALYs) were determined and used to calculate the cost-effectiveness ratio and ICER. The cost of hospital care ranged from $154 for fluconazole monotherapy to $467 for 14 d of amphotericin + 5FC. Based on 18 studies investigating outcomes for HIV-infected individuals with CM in resource-limited settings, the estimated mean one-year survival was lowest for fluconazole monotherapy, at 40%. The cost-effectiveness ratio ranged from $20 to $44 per QALY. Overall, amphotericin-based regimens had higher costs but better survival. Short-course amphotericin (1 mg/kg/d for 7 d) with fluconazole (1,200 mg/d for14 d) had the best one-year survival (66%) and the most favorable cost-effectiveness ratio, at $20.24/QALY, with an ICER of $15.11 per additional QALY over fluconazole monotherapy. The main limitation of this study is the pooled nature of a systematic review, with a paucity of outcome data with direct comparisons between regimens.
Conclusions
Short-course (7-d) amphotericin induction therapy coupled with high-dose (1,200 mg/d) fluconazole is “very cost effective” per World Health Organization criteria and may be a worthy investment for policy-makers seeking cost-effective clinical outcomes. More head-to-head clinical trials are needed on treatments for this neglected tropical disease.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Cryptococcal meningitis, a fungal infection of the membranes around the brain and spinal cord, affects about a million people every year (most of them living in sub-Saharan Africa and Southeast Asia) and kills about 640,000 people annually. People become infected with Cryptococcus neoformans, the fungus that causes cryptococcal meningitis and which is found in soil and dirt, by breathing it in. In healthy individuals, infection rarely causes disease. But in people living with AIDS, whose immune system has been damaged by HIV infection, and in people whose immune system is compromised for other reasons, the fungus can invade and damage many organs, including the brain. Cryptococcal meningitis, the symptoms of which include fever, stiff neck, headache, and vomiting, is diagnosed by looking for the fungus in fluid taken from the spinal cord in a procedure called a lumbar puncture. Cryptococcal meningitis is treated with antifungal drugs such as amphotericin, fluconazole, and flucytosine (induction therapy); recurrence of the infection is prevented by taking fluconazole daily for life or until the immune system recovers.
Why Was This Study Done?
The World Health Organization (WHO) recommends a 14-day regimen of intravenous (injected) amphotericin and oral flucytosine or fluconazole for induction therapy of cryptococcal meningitis. Unfortunately, this regimen is impractical in many resource-limited settings because of the cost of the drugs and hospital care and the need for intensive monitoring—amphotericin is extremely toxic. Consequently, high-dose fluconazole monotherapy is the usual treatment for cryptococcal meningitis in resource-limited countries, although this regimen is much less effective. Another regimen that has improved survival in trials is flucytosine with fluconazole for two weeks. However, flucytosine is very expensive and is not licensed in most sub-Saharan African countries. Stakeholders in developing countries badly need guidance, therefore, on which induction treatment for cryptococcal meningitis they should recommend to optimize outcomes in their particular countries. In this cost-effectiveness analysis (a study that compares the costs and health effects of different interventions), the researchers use costs in Uganda to estimate the survival, cost, and cost per benefit associated with various induction treatments for cryptococcal meningitis in HIV-infected patients.
What Did the Researchers Do and Find?
The researchers calculated the overall cost of six induction treatments using 2012 healthcare costs in Uganda for medications, supplies, and hospital care, and average laboratory costs for monitoring treatment from three African countries. They used data from published trials of cryptococcal meningitis treatment in resource-limited areas to estimate ten-week and one-year survival, life expectancy, and quality-adjusted life years (QALYs, the number of years of life added by an intervention, adjusted for the quality of life) for each intervention. Finally, they calculated the cost-effectiveness ratio (cost per QALY gained) and the incremental cost effectiveness ratio (ICER, the additional cost of a treatment strategy compared to fluconazole monotherapy divided by the incremental improvement in QALYs) for each intervention. The estimated costs per person for each induction treatment strategy ranged from US$154 for 14 days of fluconazole monotherapy to US$467 for 14 days of amphotericin plus flucytosine. Estimated average one-year survival was lowest for fluconazole (40%) and highest for short-course (seven days) amphotericin plus 14 days of fluconazole (66%), similar to other amphotericin-based treatments. Cost-effectiveness ratios ranged from US$20 per QALY for short-course amphotericin plus fluconazole to US$44 per QALY for 14 days of amphotericin plus flucytosine. Short-course amphotericin plus fluconazole had the lowest ICER (US$15.11 per additional QALY over fluconazole monotherapy).
What Do These Findings Mean?
These findings suggest that, among the treatments investigated, a seven-day course of amphotericin with high-dose fluconazole for at least two weeks is the most cost-effective induction treatment for cryptococcal meningitis in Uganda. Although this result should be generalizable to other African countries, it needs to be treated with caution because very few trials have actually looked at the clinical effectiveness of this particular regimen. While short short-course amphotericin appears to be substantially more effective than fluconazole monotherapy, large-scale trials comparing short-course amphotericin regimens with more traditional 14-day regimens in resource-limited countries must be undertaken before short-course amphotericin-based treatments are adopted. Notably, however, if these trials confirm that survival with short-course amphotericin with fluconazole is about 30% better than with fluconazole alone, the researchers calculate that moving to short-course amphotericin could save about 150,000 lives every year in sub-Saharan Africa at a cost of US$220 per life saved.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001316.
This study is further discussed in a PLOS Medicine Perspective by Andrew Farlow
Preventcrypto.org provides a clearinghouse for updated guidelines for cryptococcal diagnosis and treatment.
The US Centers for Disease Control and Prevention provides information on Cryptococcus neoformans and a training manual called the Cryptococcal Screening Program Training Manual for Healthcare Providers
NAM/aidsmap provides information about all aspects of infection with Cryptococcus neoformans, including a personal story about cryptococcal meningitis
AIDS InfoNet has a fact sheet on cryptococcal meningitis (in several languages)
The not-for-profit organization Project Inform, which provides information, inspiration, and advocacy for people with HIV/AIDS and hepatitis C (in English and Spanish), has a fact sheet on cryptococcal meningitis
The MedlinePlus encyclopedia has a page on cryptococcal meningitis (in English and Spanish)
doi:10.1371/journal.pmed.1001316
PMCID: PMC3463510  PMID: 23055838
9.  Omalizumab vs. placebo in the management of chronic idiopathic urticaria: a systematic review 
Objectives
To examine the evidence derived from randomized controlled clinical trials on the efficacy and safety of omalizumab compared to placebo in controlling symptoms of chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU).
Data source
The electronic databases PubMed, Medline, EMBASE, Biomed Central, The Cochrane Central Register of Controlled Trials (CENTRAL), Wiley, OVID, and HighwirePress were reviewed. The date limit was set to May 31th, but it was extended to September 30th of 2014 due to a new publication. No language restriction was used. The articles included were randomized trials controlled with placebo in individuals older than 12 years diagnosed with CIU/CSU refractory to conventional treatment, the intervention being, omalizumab at different doses, and the comparison, placebo. The primary outcome was symptom improvement according to the weekly score of urticaria severity (UAS7), the itch severity score (ISS), the weekly score of number of urticarial lesions, the dermatology life quality index, and the chronic urticaria quality of life questionnaire (CU-QoL). Databases were searched using the following Mesh or EMTREE key words including as intervention “omalizumab” or “humanized monoclonal antibody,” compared to placebo and the disease of interest “urticaria” or “angioedema”. The title, abstract and article were reviewed by two independent investigators, according to the selection criteria in each of the databases. An assessment of the quality of the articles was performed according to the bias tool from the studies of the Cochrane Collaboration. Information such as author data, date of study, number of participants, interventions, dose and frequency of administration, comparison, time of follow-up, measurements of weekly score of urticaria activity, pruritus severity score, weekly urticarial lesions, percentage of angioedema and post-treatment change were extracted. Frequency of adverse events and the ones suspected to be caused by the intervention drug were included.
Results
770 records were identified in all databases described. 720 were eliminated for failing to meet the inclusion criteria in the first review or for duplicate records. 24 articles were reviewed by abstract, 18 additional articles were further removed, leaving 6 records for inclusion. An experimental study was excluded because it wasn’t randomized. Five studies were finally included, with 1117 patients, of these 831 received a dose of omalizumab of 75 mg (183 patients, 16.38%), 150 mg (163 patients, 14.59%), 300 mg (437 patients, 39.12%) or 600 mg (21 patients, 1.8%), as a single dose, or every 4 weeks until 24 weeks maximum. The average age was 42.07 years, predominantly female gender and white ethnicity. It was observed that the use of omalizumab 300 mg lowered the weekly scores of urticarial activity in 19.9 vs. 6.9 on placebo (p <0.01), 19 vs 8.5 and 20.7 vs 8.01 in three studies, the weekly ISS (−9.2 vs. - 3.5, p <0.001, −9.8 vs −5.1 p < 0.01, −8.6 vs −4.0 and −9.4 vs −3.63 p <0.001 in four studies), and the percentage of angioedema-free days (omalizumab 95.5% vs. placebo 89.2% p <0.001, and 91.95% vs. 88.1% p <0.001 in two of the studies respectively).
Limitations
The different doses used throughout the study, time of administration and follow-up periods ranged from single dose to monthly dose for 24 weeks. Therefore no meta-analysis of the review was conducted.
Conclusions and implications of the main findings
Despite the limitations, it is considered that omalizumab 300 mg is effective in treating chronic idiopathic urticaria refractory to H1 antihistamines. Further studies are required to determine the duration of effective treatment.
Registration number of the systematic review
CRD42014010029 (PROSPERO. International Prospective Register of Systematic Reviews).
doi:10.1186/s40413-014-0050-z
PMCID: PMC4280746  PMID: 25566332
Antibodies; Monoclonal; Humanized; Urticaria; Angioedema
10.  Reduction in oral corticosteroid use in patients receiving omalizumab for allergic asthma in the real-world setting 
Background
Oral corticosteroids (OCS) are commonly administered in patients with severe persistent allergic asthma. Despite their efficacy, they are associated with a wide variety of adverse events. The eXpeRience registry was set up to investigate real-world outcomes among patients receiving omalizumab for the treatment of uncontrolled allergic asthma. Here, we present the effect of omalizumab treatment on OCS use.
Methods
eXpeRience was a 2-year, multinational, non-interventional, observational registry of patients receiving omalizumab for uncontrolled allergic asthma. OCS use (proportion of patients on maintenance OCS, mean total daily OCS dose and change in status of OCS therapy) was assessed at baseline, 16 weeks, and 8, 12, 18, and 24 months after the initiation of omalizumab. Response to omalizumab was assessed using the physician’s Global Evaluation of Treatment Effectiveness (GETE) at approximately Week 16. Safety data were also recorded.
Results
A total of 943 patients (mean age, 45 years; female, 64.9%) were enrolled in the registry, 263 of whom were receiving maintenance OCS at baseline. The proportion of patients taking maintenance OCS was markedly lower at Months 12 (16.1%) and 24 (14.2%) than at baseline (28.6%; intent-to-treat population). GETE status was determined in 915 patients receiving omalizumab: 64.2% were responders (excellent or good response), 30.7% were non-responders (moderate, poor or worsening response); 5.1% had no assessment. The frequency of serious adverse events was comparable to that seen in controlled trials of omalizumab.
Conclusions
Omalizumab use is associated with an OCS-sparing effect in patients with uncontrolled persistent allergic asthma in the real-world setting.
doi:10.1186/1710-1492-9-47
PMCID: PMC3879326  PMID: 24305549
Anti-immunoglobulin E; Oral corticosteroid use; Omalizumab; Registry; Uncontrolled persistent allergic asthma
11.  The effect of omalizumab on ventilation and perfusion in adults with allergic asthma 
Omalizumab promotes clinical improvement in patients with allergic asthma, but its effect on pulmonary function is unclear. One possibility is that omalizumab improves asthma symptoms through effects on the regional distributions of ventilation, perfusion, and ventilation/perfusion matching, metrics which can be assessed with Nitrogen-13-saline Position Emission Tomography (PET). Four adults with moderate to severe uncontrolled allergic asthma underwent symptom assessment, spirometry and functional pulmonary imaging with Nitrogen-13-saline PET before and after 4-5 months of treatment with omalizumab. PET imaging was used to determine ventilation/perfusion ratios, the heterogeneity (coefficient of variation, COV) of ventilation and perfusion, and lung regions with ventilation defects. There were no significant changes in spirometry values after omalizumab treatment, but there was a trend towards an improvement in symptom scores. There was little change in the matching of ventilation and perfusion. The COV of perfusion was similar before and after omalizumab treatment. The COV of ventilation was also similar before (0.57 (0.28)) and after (0.66 (0.13)) treatment, and it was similar to previously published values for healthy subjects. There was a non-significant trend towards an increase in the extent of ventilation defects after omalizumab treatment, from 5 (15)% to 12.8 (14.7)%. Treatment of moderate to severe uncontrolled allergic asthma with omalizumab did not result in a significant improvement in ventilation and perfusion metrics assessed with functional PET imaging. The normal COV of ventilation which was unaffected by treatment supports the hypothesis that omalizumab exerts its clinical effect on lung function during allergen exposure rather than in between exacerbations.
PMCID: PMC3715779  PMID: 23901360
PET functional imaging; omalizumab; Xolair; asthma; V/Q ratios
12.  Reassessment of Omalizumab-Dosing Strategies and Pharmacodynamics in Inner-City Children and Adolescents 
BACKGROUND
Treatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and adolescents or subgroups that most benefit from treatment.
OBJECTIVES
Post hoc analyses were conducted to (1) examine patient characteristics of those eligible and ineligible for omalizumab, (2) describe onset of effect after initiation of omalizumab and offset of treatment effect after stopping therapy, and (3) determine whether the efficacy differs by age, asthma severity, dosing regimen, and prespecified biomarkers.
METHODS
Inner-city children and adolescents with persistent allergic asthma were enrolled in the Inner-City Anti-IgE Therapy for Asthma trial that compared omalizumab with placebo added to guidelines-based therapy for 60 weeks.
RESULTS
Two hundred ninety-three of 889 participants (33%) clinically suitable for omalizumab were ineligible for dosing according to a modified dosing table specifying IgE level and body weight criteria. Baseline symptoms were comparable among those eligible and ineligible to receive omalizumab, but other characteristics (rate of health care utilization and skin test results) differed. The time of onset of omalizumab effect was <30 days and time of offset was between 30 and 120 days. No difference in efficacy was noted by age or asthma severity, but high exhaled nitric oxide, blood eosinophils, and body mass index predicted efficacy.
CONCLUSIONS
A significant portion of children and adolescents particularly suited for omalizumab because of asthma severity status may be ineligible due to IgE >1300 IU/mL. Omalizumab reduced asthma symptoms and exacerbations rapidly; features associated with efficacy can be identified to guide patient selection.
doi:10.1016/j.jaip.2013.01.011
PMCID: PMC4254887  PMID: 24565455
Asthma exacerbations; Biomarkers; Dosing regimens; Inhaled corticosteroids; Omalizumab; Pharmacodynamics; Response predictors
13.  Improvement of quality of life in patients with concomitant allergic asthma and atopic dermatitis: one year follow-up of omalizumab therapy 
Objective
Anti IgE treatment with omalizumab is efficacious in the treatment of patients suffering from allergic asthma, improving asthma control and improving quality of life. Furthermore, this approach could be beneficial for patients with concomitant atopic dermatitis. We assessed quality of life and asthma control in atopic patients with allergic asthma and concomitant atopic dermatitis versus those with asthma and without atopic dermatitis treated with omalizumab.
Methods
A total of 22 patients with severe allergic asthma were treated with omalizumab for 12 months. 13 patients with allergic asthma without concomitant atopic dermatitis (IgE 212 ± 224 IU/ml) and 9 patients with concomitant allergic asthma and atopic dermatitis (IgE 3,528 ± 2,723 IU/ml) were included. Asthma-related quality of life (AQLQ), atopic dermatitis related quality of life (DLQI), and asthma-related treatment were compared between both groups at baseline and after initiating omalizumab treatment.
Results
DLQI was significantly in favor of omalizumab after 2 months in the atopic dermatitis/asthma group (P = 0.01); AQLQ was improved after 6 months in the asthma group (P = 0.01), while no change was seen in AQLQ in the atopic dermatitis/asthma group (P = 0.12). Omalizumab controlled oral corticosteroid use more effective (P < 0.01) in patients with asthma and atopic dermatitis (in 9/9 cases) compared to patients with asthma alone (9/13). Baseline IgE as well as other factors do not predict response to omalizumab.
Conclusions
Omalizumab is effective in improving atopic dermatitis-related quality of life scores and modulates oral corticosteroid use in patients with concomitant asthma and atopic dermatitis in a positive fashion.
doi:10.1186/2047-783X-16-9-407
PMCID: PMC3352146  PMID: 22024441
allergic asthma; anti-IgE; atopic dermatitis; omalizumab; quality of life
14.  Patient-Centered Research 
>PURPOSE
Antiviral treatment of herpes zoster is controversial due to uncertain benefits and relatively high costs. We reviewed the literature on the costs and benefits of antiviral therapy and used that data to test its cost-effectiveness.
METHODS
We used a Markov decision model to estimate the incremental cost-effectiveness of antiviral treatment compared to no treatment in immunocompetent 40, 60, and 70 year old patients with either mildly or severely symptomatic acute zoster. We were specifically interested in the cost-effectiveness of treating severely symptomatic acute zoster in all patients and milder zoster in patients older than 50 (the current clinical recommendations). A societal perspective was taken, using reference case recommendations of the Panel on Cost-Effectiveness in Health and Medicine. Parameter values and assumptions in the baseline analysis were consistently biased against antiviral use. Effectiveness was measured in quality adjusted life years (QALY). We assumed that antivirals did not change postherpetic neuralgia (PHN) risk, but decreased PHN duration in patients older than 50. PHN risk increased with age and with acute zoster severity as seen in published data. Mild acute zoster was assumed to have a utility value of 0.9 and severe acute zoster a value of 0.7 on a scale where 0 = death and 1 = perfect health.
RESULTS
Treating mildly symptomatic acute herpes zoster cost $89,000/QALY gained in 40 year olds, $47,700/QALY in 60 year olds and $40,700/QALY in 70 year olds. Results are most sensitive to variation of antiviral costs (baseline $134), but charges in acute symptom relief, PHN risk, PHN duration, PHN costs, PHN utility, and antiviral effect on PHN duration increase costs/QALY above $50,000 in 60 and 70 year olds in extremes of parameter ranges. However no variation causes treatment of mild illness in 40 year olds to fall below $50,000/QALY gained. Treatment of severe acute zoster cost $29,700, $18,000, $16,500/QALY gained in 40, 60, and 70 year olds respectively. Results are sensitive to variation of antiviral costs (>$225) and acute symptom relief (<21%) in 40 year olds.
CONCLUSION
Antiviral therapy of herpes zoster is cost-effective by conventional criteria for mild zoster in patients 50 years and older and for severe acute zoster in all adults.
doi:10.1046/j.1525-1497.2000.15200-15.x
PMCID: PMC1495753
15.  272 Gender and Different Prevalence in Asthma Treatment With Anti-IGE (Omalizumab) 
Background
General opinion on pathogenesis and prevalence of bronchial asthma indicates that age and sex are the major risk factors. Detailed physiological mechanisms of the changing sex ratio are not fully known.
Aims and objectives
Investigate the influence the asthmatic patients treated with anti-IgE with different gender.
Methods
Here, we pooled data from ten published studies from 1999 with more of our unpublished data of patients with severe persistent asthma treated with omalizumab, an anti-immunoglobulin E (IgE) monoclonal antibody. Static analysis was used to find gender risk factors as the ratio of treatment effect (omalizumab: control) on the standardized exacerbation rate per year.
Results
The studies included 3270 patients (treated with omalizumab), whose had severe persistent asthma according to the Global Initiative for Asthma (GINA) classification. Analysis of 2 groups male versus female showed that the efficacy of omalizumab on asthma exacerbations was unaffected by patient age, gender, baseline serum IgE (split by median) or by 2- or 4-weekly dosing schedule, although a more large number of women were treated (1921/1349; 59 % women vs 41% men; P < 0.001) and benefit in absolute terms appeared to be greatest in women patients which had a more severe asthma, defined by a lower value of percentage predicted forced expiratory volume in 1 second (FEV1) at baseline, this subgroup showed odds of being a responder (composite definition) 1.25 times higher (95% CI, 1.18-3.01) than men.
Conclusions
These results suggest that in population of asthmatics treated with anti-IgE the number of women is shown higher than men, it confirms that asthma should be considered with different approach by the gender for being adequately controlled on current therapy.
doi:10.1097/01.WOX.0000412029.54630.1c
PMCID: PMC3512610
16.  275 Efficacy of Omalizumab in the Treatment of Urticaria-Vasculitis Associated to Churg-Strauss Syndrome: A Case Report 
The World Allergy Organization Journal  2012;5(Suppl 2):S106-S107.
Background
Churg-Strauss Syndrome (CCS) is a rare systemic necrotizing small vessel vasculitis associated with bronchial asthma, peripheral blood eosinophilia and eosinophilic lung infiltration. Skin changes compatible with vasculitis are present in about 75% of patients. Previous reports suggest that patients with CSS can be treated with anti-IgE (omalizumab) in addition to conventional therapy to achieve asthma control. Here we report the efficacy of a 6-month treatment with omalizumab in a patient with CSS characterized by severe asthma and urticarial vasculitis.
Methods
A 44 year old Caucasian female with a 5 year history of severe asthma, chronic urticaria and mild eosinophilia (1100/μL) was evaluated for possible CSS. Total serum IgE was 662 KU/l with positive skin prick tests for dust mites. Bronchial asthma was not controlled and FEV1 was 60% despite treatment with budesonide (640 mcg/die) and formoterol (18 mcg/die). Diffuse and confluent urticarial rash occurred in the last 6 months before evaluation and responded neither to prednisone (10 mg/die) and rupatadin (10 mg/die) nor to immunosuppressive agents (cyclosporin 200 mg/die or azathioprin 100 mg/die). The patient was treated, as add-on therapy, with omalizumab (300 mg s.c. every 2 weeks) accordingly to total IgE and weight parameters reported in the drug information leaflet.
Results
After 6 months of treatment the patient reported a significant improvement in asthma control with 50% reduction of nocturnal awakenings and asthma exacerbations and a major FEV1 improvement (101% at 16 weeks and 103% at 24 weeks). Eosinophil count was reduced to 600/μL. A 75% reduction of oral prednisone was registered after 8 weeks of treatment. Importantly, urticarial lesions disappeared after the first injection of omalizumab. Omalizumab injections were well tolerated and no adverse event was recorded.
Conclusions
This case suggests that omalizumab can be beneficial and safe in patients affected by CSS with severe asthma and urticarial vasculitis. In addition to its effect on serum IgE, efficacy of omalizumab in CSS may be related to an inhibitory effect on blood eosinophilia.
doi:10.1097/01.WOX.0000412032.39383.49
PMCID: PMC3513125
17.  Omalizumab: Practical considerations regarding the risk of anaphylaxis 
Omalizumab has demonstrated efficacy among patients with moderate to severe persistent allergic asthma, whose symptoms are inadequately controlled with other controller agents. This therapy is generally well tolerated, but there are some safety considerations, the most important of which is the rare, but potentially life-threatening, occurrence of omalizumab-associated anaphylaxis.
In Canada, data from the manufacturer of omalizumab indicate that the frequency of anaphylaxis attributed to Xolair in post-marketing use is approximately 0.2%. Other researchers, including the American Omalizumab Joint Task Force (OJTF), have suggested a lower overall frequency of 0.09%.
This paper provides a summary of the epidemiologic research carried out to date and presents a concise, practical set of recommendations for the prevention, monitoring and management of omalizumab-associated anaphylaxis. Prevention tips include advice on patient education measures, concomitant medications and optimal administration. For the first three injections, the recommendation is to monitor in clinic for two hours after the omalizumab injection; for subsequent injections, the monitoring period should be 30 minutes or an appropriate time agreed upon by the individual patient and healthcare professional.
In the event that a patient does experience omalizumab-associated anaphylaxis, the paper provides recommendations for handling the situation in-clinic and recommendations on how to counsel patients to recognize the potential signs and symptoms in the community and react appropriately.
doi:10.1186/1710-1492-6-32
PMCID: PMC3006370  PMID: 21129189
18.  Economic effects of interventions to reduce obesity in Israel 
Background
Obesity is a major risk factor for many diseases. The paper calculates the economic impact and the cost per Quality-Adjusted Life Year (QALY) resulting from the adoption of eight interventions comprising the clinical and part of the community components of the National Prevention and Health Promotion Program (NPHPP) of the Israeli Ministry of Health (MOH) which represents the obesity control implementation arm of the MOH Healthy Israel 2020 Initiative.
Methods
Health care costs per person were calculated by body mass index (BMI) by applying Israeli cost data to aggregated results from international studies. These were applied to BMI changes from eight intervention programmes in order to calculate reductions in direct treatment costs. Indirect cost savings were also estimated as were additional costs due to increased longevity of program participants. Data on costs and QALYs gained from Israeli and International dietary interventions were combined to provide cost-utility estimates of an intervention program to reduce obesity in Israel over a range of recidivism rates.
Results
On average, persons who were overweight (25 ≤ BMI < 30)had health care costs that were 12.2% above the average health care costs of persons with normal or sub-normal weight to height ratios (BMI < 25). This differential in costs rose to 31.4% and 73.0% for obese and severely obese persons, respectively.
For overweight (25 ≤ BMI < 30) and obese persons (30 ≤ BMI < 40), costs per person for the interventions (including the screening overhead) ranged from 35 NIS for a community intervention to 860 NIS, reflecting the intensity of the clinical setting intervention and the unit costs of the professionals carrying out the intervention [e.g., dietician]. Expected average BMI decreases ranged from 0.05 to 0.90. Higher intervention costs and larger BMI decreases characterized the two clinical lifestyle interventions for the severely obese (BMI ≥ 40).
A program directed at the entire Israeli population aged 20 and over, using a variety of eight different interventions would cost 2.07 billion NIS overall. In the baseline scenario (with an assumed recidivism rate of 50% per annum), approximately 620,000,000 NIS would be recouped in the form of decreased treatment costs and indirect costs, increased productivity and decreased absenteeism. After discounting the 89,000,000 NIS additional health costs attributable to these extra life years, it is estimated that the total net costs to society would be 1.55 billion NIS. This total net cost was relatively stable to increases in the program's recidivism rates, but highly sensitive to reductions in recidivism rates.
Under baseline assumptions, implementation of the cluster of interventions would save 32,671 discounted QALYs at a cost of only 47,559 NIS per QALY, less than half of the Israeli per capita GNP (104,000 NIS). Thus implementation of these components of the NPHPP should be considered very cost-effective.
Conclusion
Despite the large costs of such a large national program to control obesity, cost-utility analysis strongly supports its introduction.
doi:10.1186/2045-4015-1-17
PMCID: PMC3424853  PMID: 22913803
19.  Cost-Effectiveness of Pooled Nucleic Acid Amplification Testing for Acute HIV Infection after Third-Generation HIV Antibody Screening and Rapid Testing in the United States: A Comparison of Three Public Health Settings 
PLoS Medicine  2010;7(9):e1000342.
Angela Hutchinson and colleagues conducted a cost-effectiveness analysis of pooled nucleic acid amplification testing following HIV testing and show that it is not cost-effective at recommended antibody testing intervals for high-risk persons except in very high-incidence settings.
Background
Detection of acute HIV infection (AHI) with pooled nucleic acid amplification testing (NAAT) following HIV testing is feasible. However, cost-effectiveness analyses to guide policy around AHI screening are lacking; particularly after more sensitive third-generation antibody screening and rapid testing.
Methods and Findings
We conducted a cost-effectiveness analysis of pooled NAAT screening that assessed the prevention benefits of identification and notification of persons with AHI and cases averted compared with repeat antibody testing at different intervals. Effectiveness data were derived from a Centers for Disease Control and Prevention AHI study conducted in three settings: municipal sexually transmitted disease (STD) clinics, a community clinic serving a population of men who have sex with men, and HIV counseling and testing sites. Our analysis included a micro-costing study of NAAT and a mathematical model of HIV transmission. Cost-effectiveness ratios are reported as costs per quality-adjusted life year (QALY) gained in US dollars from the societal perspective. Sensitivity analyses were conducted on key variables, including AHI positivity rates, antibody testing frequency, symptomatic detection of AHI, and costs. Pooled NAAT for AHI screening following annual antibody testing had cost-effectiveness ratios exceeding US$200,000 per QALY gained for the municipal STD clinics and HIV counseling and testing sites and was cost saving for the community clinic. Cost-effectiveness ratios increased substantially if the antibody testing interval decreased to every 6 months and decreased to cost-saving if the testing interval increased to every 5 years. NAAT was cost saving in the community clinic in all situations. Results were particularly sensitive to AHI screening yield.
Conclusions
Pooled NAAT screening for AHI following negative third-generation antibody or rapid tests is not cost-effective at recommended antibody testing intervals for high-risk persons except in very high-incidence settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since 1981, acquired immunodeficiency syndrome (AIDS) has killed about 25 million people and about 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV, which is most often transmitted through unprotected sex with an infected partner or injection drug use, infects and kills immune system cells, leaving infected individuals susceptible to other infectious diseases. The first, often undiagnosed stage of HIV infection—acute HIV infection (AHI)—lasts a few weeks and sometimes involves a flu-like illness. During AHI, the immune system responds to HIV by beginning to make antibodies that recognize the virus but seroconversion—the appearance of detectable amounts of antibody in the blood—takes 6–12 weeks. During the second, symptom-free stage of HIV infection, which can last many years, the virus gradually destroys the immune system so that by the third stage of infection unusual infections (for example, persistent yeast infections) begin to occur. The final stage of infection (AIDS) is characterized by multiple severe infections and by the development of unusual cancers.
Why Was This Study Done?
Antiretroviral drugs control HIV infections but don't cure them. It is very important, therefore, to prevent HIV transmission by avoiding HIV risk behaviors that increase the risk of HIV infection such as having sex without a condom or with many partners. Individuals with AHI in particular need to avoid high-risk behaviors because these people are extremely infectious. However, routine tests for HIV infection that measure antibodies in the blood often give false-negative results in people with AHI because of the time lag between infection and seroconversion. Nucleic acid amplification testing (NAAT), which detects HIV genetic material in the blood, is a more accurate way to diagnose AHI but is expensive. In this study, the researchers investigate whether pooled NAAT screening (specimens are pooled before testing to reduce costs) for AHI in clinic settings after third-generation antibody testing is a cost-effective HIV prevention strategy. That is, does the gain in quality-adjusted life years (QALY, a measure of the quantity and quality of life generated by healthcare interventions) achieved by averting new HIV infections outweigh the costs of pooled NAAT screening?
What Did the Researchers Do and Find?
The researchers combined effectiveness data from a US study in which AHI was detected using pooled NAAT in three settings (sexually transmitted disease [STD] clinics, a community clinic serving men who have sex with men [MSM], and HIV counseling/testing sites) with a “micro-costing” study of NAAT and a mathematical model of HIV transmission. They then calculated the costs per QALY gained (the cost-effectiveness ratio) as a result of HIV prevention by identification and notification of people with AHI through pooled NAAT screening compared with repeat antibody testing. Pooled NAAT for AHI screening following annual antibody testing (the recommended testing interval for high-risk individuals), they estimate, would cost US$372,300 and US$484,400 per QALY gained for the counseling/testing sites and STD clinics, respectively, whereas pooled NAAT for AHI screening was cost-saving for the community clinic serving MSM. The cost-effectiveness ratio increased for the counseling/testing sites and STD clinics when the antibody testing interval was decreased to 6 months but remained cost-saving for the community clinic. With an antibody testing interval of 5 years, pooled NAAT was cost-saving in all three settings.
What Do These Findings Mean?
Cost-effectiveness ratios of US$100,000–US$200,000 are considered acceptable in the US. These results suggest therefore, that the cost of pooled NAAT screening for AHI following negative third-generation antibody testing is not acceptable at the recommended testing interval for high-risk individuals except in settings where HIV infection is very common such as clinics serving MSM. The researchers reach a similar conclusion in a separate cost-effectiveness analysis of pooled NAAT screening following a negative rapid HIV test. Although the accuracy of these results depends on numerous assumptions made in the cost-effectiveness analyses (for example, the degree to which awareness of HIV status affects the behavior of people with AHI), sensitivity analyses (investigations of the effect of altering key assumptions) show that these findings are not greatly affected by changes in many of these assumptions. Thus, the researchers conclude, NAAT screening should be reserved for settings that serve populations in which there are very high levels of new HIV infection.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000342.
The US Centers for Disease Control and Prevention provides information on HIV infection and AIDS and on HIV testing and diagnosis
HIV InSite has information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS nonprofit organization on many aspects of HIV/AIDS, including HIV testing (in English and Spanish)
MedlinePlus has links to further resources on AIDS (in English and Spanish)
The UK National Institute of Health and Clinical Excellence has a page on measuring effectiveness and cost-effectiveness
doi:10.1371/journal.pmed.1000342
PMCID: PMC2946951  PMID: 20927354
20.  Omalizumab, an anti-immunoglobulin E antibody: state of the art 
A large number of trials show that the anti-immunoglobulin (Ig) E antibody omalizumab is very effective in patients with severe allergic asthma. This is acknowledged in consensus documents. The drug also has a good safety profile and a pharmacoeconomic advantage due to a reduction in the number of hospitalizations for asthma attacks. In recent years, some studies have shown that omalizumab is effective also in nonallergic asthma. Effects on the complex signaling mechanisms leading to activation of effector cells and to mediator release may account for this outcome. Indeed, omalizumab has been reported to be effective in a number of IgE-mediated and non-IgE-mediated disorders. Concerning the former, clinical efficacy has been observed in rhinitis, allergic bronchopulmonary aspergillosis, latex allergy, atopic dermatitis, allergic urticaria, and anaphylaxis. In addition, omalizumab has been demonstrated to be able to prevent systemic reactions to allergen immunotherapy, thus enabling completion of treatment in patients who otherwise would have to stop it. Concerning non-IgE-mediated disorders, omalizumab has been reported to be effective in nasal polyposis, autoimmune urticaria, chronic idiopathic urticaria, physical urticaria, idiopathic angioedema, and mastocytosis. Current indications for treatment with omalizumab are confined to severe allergic asthma. Consequently, any other prescription can only be off-label. However, it is reasonable to expect that the use of omalizumab will be approved for particularly important indications, such as anaphylaxis, in the near future.
doi:10.2147/DDDT.S49409
PMCID: PMC3923619  PMID: 24532966
hypersensitivity; immunoglobulin E; anti-IgE; omalizumab; asthma; atopic dermatitis; anaphylaxis; urticaria; mastocytosis
21.  Immunologic Effects of Omalizumab in Children with Severe Refractory Atopic Dermatitis: A Randomized, Placebo-Controlled Clinical Trial 
Background
Severe refractory atopic dermatitis (AD) is a chronic, debilitating condition that is associated with elevated serum immunoglobulin E (IgE) levels. Thymic stromal lymphopoietin (TSLP), thymus and activation-regulated chemokine (TARC) and OX40 ligand (OX40L) are important immunologic factors involved in the pathogenesis of AD. Omalizumab, an anti-IgE antibody indicated for use in allergic asthma, is implicated in regulating allergen presentation by dendritic cells and the T cell response during the effector phases of allergic disease. We investigated if anti-IgE therapy modulates the allergen-specific responses mediated by the TSLP pathway in young patients with severe refractory AD.
Methods
This was a randomized, double-blind, placebo-controlled study of 8 patients between the ages of 4 and 22 years (mean = 11.6 years) with severe refractory AD (clinical trials.gov NCT01678092). Serum IgE ranged from 218 to 1,890 (mean = 1,068 IU/ml). Subjects received omalizumab (n = 4) or placebo (n = 4) every 2–4 weeks over 24 weeks using a regimen extrapolated from the package insert. TSLP, TARC, OX40L and other cytokines involved in AD were measured by using cytometric bead arrays.
Results
All patients receiving omalizumab had strikingly decreased levels of TSLP, OX40L, TARC (involved in Th2 polarization) and interleukin (IL)-9 compared to placebo. In addition, there was a marked increase in IL-10, a tolerogenic cytokine, in the omalizumab-treated group. Patients on anti-IgE therapy had an improvement in clinical outcomes as measured by the SCORAD system; however, these effects were comparable to improvements in the control group.
Conclusions
Anti-IgE therapy with omalizumab decreases levels of cytokines that are involved in Th2 polarization and allergic inflammation, including TSLP, TARC and OX40L.
doi:10.1159/000350486
PMCID: PMC4161454  PMID: 23816920
Atopic dermatitis; Immunoglobulin E; Omalizumab; Cytokine expression
22.  Effectiveness and Cost Effectiveness of Expanding Harm Reduction and Antiretroviral Therapy in a Mixed HIV Epidemic: A Modeling Analysis for Ukraine 
PLoS Medicine  2011;8(3):e1000423.
A cost-effectiveness study by Sabina Alistar and colleagues evaluates the effectiveness and cost effectiveness of different levels of investment in methadone, ART, or both, in the mixed HIV epidemic in Ukraine.
Background
Injection drug use (IDU) and heterosexual virus transmission both contribute to the growing mixed HIV epidemics in Eastern Europe and Central Asia. In Ukraine—chosen in this study as a representative country—IDU-related risk behaviors cause half of new infections, but few injection drug users (IDUs) receive methadone substitution therapy. Only 10% of eligible individuals receive antiretroviral therapy (ART). The appropriate resource allocation between these programs has not been studied. We estimated the effectiveness and cost-effectiveness of strategies for expanding methadone substitution therapy programs and ART in mixed HIV epidemics, using Ukraine as a case study.
Methods and Findings
We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs using opiates, and IDUs on methadone substitution therapy, stratified by HIV status, and populated it with data from the Ukraine. We considered interventions expanding methadone substitution therapy, increasing access to ART, or both. We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost-effectiveness. Without incremental interventions, HIV prevalence reached 67.2% (IDUs) and 0.88% (non-IDUs) after 20 years. Offering methadone substitution therapy to 25% of IDUs reduced prevalence most effectively (to 53.1% IDUs, 0.80% non-IDUs), and was most cost-effective, averting 4,700 infections and adding 76,000 QALYs compared with no intervention at US$530/QALY gained. Expanding both ART (80% coverage of those eligible for ART according to WHO criteria) and methadone substitution therapy (25% coverage) was the next most cost-effective strategy, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy and averting 8,300 infections versus no intervention. Expanding only ART (80% coverage) added 38,000 QALYs at US$2,240/QALY gained versus the methadone substitution therapy-only strategy, and averted 4,080 infections versus no intervention. Offering ART to 80% of non-IDUs eligible for treatment by WHO criteria, but only 10% of IDUs, averted only 1,800 infections versus no intervention and was not cost effective.
Conclusions
Methadone substitution therapy is a highly cost-effective option for the growing mixed HIV epidemic in Ukraine. A strategy that expands both methadone substitution therapy and ART to high levels is the most effective intervention, and is very cost effective by WHO criteria. When expanding ART, access to methadone substitution therapy provides additional benefit in infections averted. Our findings are potentially relevant to other settings with mixed HIV epidemics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
HIV epidemics in Eastern Europe and Central Asia are mainly driven by increasing use of injection drugs combined with heterosexual transmission. In the Ukraine, in 2007, there were 82,000 officially registered people living with HIV—three times the number registered in 1999—and an estimated 395,000 HIV infected adults. The epidemic in Ukraine, like other countries in the region, is concentrated in at-risk populations, particularly people who inject drugs: in 2007, an estimated 390,000 Ukrainians were injecting drugs, an increase in drug use over the previous decade, not only in Ukraine, but in other former USSR states, owing to the easy availability of precursors for injection drugs in a climate of economic collapse.
The common practices of people who inject drugs in Ukraine and in other countries in the region, such as social injecting, syringe sharing, and using common containers, increase the risk of transmitting HIV. Public health interventions such as needle exchange can limit these risk factors and have been gradually implemented in these countries. In 2007, Ukraine approved the use of methadone substitution therapy and the current target is for 11,000 people who inject drugs to be enrolled in substitution therapy by 2011. Furthermore, since treatment for HIV-infected individuals is also necessary, national HIV control plans included a target of 90% antiretroviral therapy (ART) coverage by 2010 but in 2007 less than 10% of the 91,000 eligible people received treatment. Although the number of people who inject drugs and who receive ART is unknown, physicians are often reluctant to treat people who inject drugs using ART owing to alleged poor compliance.
Why Was This Study Done?
As resources for HIV interventions in the region are limited, it is important to investigate the appropriate balance between investments in methadone substitution therapy and ART in order to maximize benefits to public health. Several studies have analyzed the cost effectiveness of methadone substitution therapy in similar settings but have not considered tradeoffs between ART and methadone substitution therapy. Therefore, to provide insights into the appropriate public health investment in methadone substitution therapy and ART in Ukraine, the researchers evaluated the public health effectiveness and cost effectiveness of different strategies for scaling up methadone substitution therapy and/or expanding ART.
What Did the Researchers Do and Find?
The researchers developed a model to accommodate different population groups: people who inject drugs on substitution therapy with methadone; people who inject opiates and do not take any substitution therapy; and people who do not inject any drugs, hence do not need substitution therapy. The researchers inputted Ukraine country-level data into this model and used current HIV trends in Ukraine to make rational assumptions on possible future trends and scenarios. They considered scenarios expanding methadone substitution therapy availability, increasing acces to ART, or both. Then, the researchers measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, infections averted, and incremental cost effectiveness for the different scenarios. They found that after 20 years, HIV prevalence reached 67.2% in people who inject drugs and 0.88% in people who do not inject drugs without further interventions. Offering methadone substitution therapy to 25% of people who inject drugs was the most effective strategy in reducing prevalence of HIV and was also the most cost effective, averting 4,700 infections and adding 75,700 QALYs versus the status quo at $530/QALY gained. Expanding both methadone substitution therapy and ART was also a highly cost effective option, adding 105,000 QALYs at US$1,120/QALY gained versus the methadone substitution therapy-only strategy. Offering ART to 80% of eligible people who did not inject drugs, and 10% of people who injected drugs averted only 1,800 infections, and added 76,400 QALYs at $1,330/QALY gained.
What Do These Findings Mean?
The results show that methadone substitution-focused therapeutic scenarios are the most cost effective, and that benefits increase with the scale of the project, even among people who do not inject drugs. This makes a methadone substitution strategy a highly cost-effective option for addressing the growing HIV epidemic in Ukraine. Therefore, if it is not feasible to invest in large-scale methadone substitution programs for any reason, political circumstances for example, providing as much methadone substitution as is acceptable is still desirable. While substitution therapy appears to avert the most HIV infections, expanded ART provides the largest total increase in QALYs. Thus, methadone substitution therapy and ART offer complementary benefits. Because the HIV epidemic in Ukraine is representative of the HIV epidemic in Eastern Europe and Central Asia, the cost-effective strategies that the researchers have identified may help inform all decision makers faced with a mixed HIV epidemic.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000423.
Alliance provides information on its work supporting community action on AIDS in Ukraine
USAID provides an HIV/AIDS Health Profile for Ukraine
UNICEF provides information about its activities to help Ukraine fight rising HIV/AIDS infection rates
International Harm Reduction Association provides information about the status of harm reduction interventions such as methadone substitution therapy around the world
doi:10.1371/journal.pmed.1000423
PMCID: PMC3046988  PMID: 21390264
23.  155 Omalizumab Improves Asthma but not Nasal Symptoms in Japanese Patients With Severe Allergic Asthma and Rhinitis 
Background
There is evidence that humanized monoclonal antibody against IgE (Omalizumab) is effective in severe allergic asthma. In this study, we examined the effectiveness of omalizumab on asthma and nasal symptoms in Japanese patients with severe allergic asthma and rhinitis.
Methods
An open-label study that enrolled 7 patients with both severe allergic asthma and rhinitis who visited Allergy Center, Saitama Medical University was performed. All patients presented uncontrolled asthma despite medication including high-dose inhalational corticosteroids, long-acting beta2-agonist, leukotriene receptor antagonist, theophylline, and oral predonisolone. Omalizumab was added on their treatments and symptoms score using Asthma Contol Test (ACT), peak expiratory flow rate (PEFR), exhaled nitric oxide (eNO), sputum eosinophils and nasal symptoms were evaluated before and 12 to 16 weeks after omalizumab.
Results
Omalizumab significantly improved ACT scores especially dose of rescue use of short-acting beta2-agonist (P < 0.05) and PEFR (P < 0.05). Furthermore, omalizumab significantly decreased exhaled both eNO (P < 0.05) and the percentage of eosinophils in induced sputum. On the other hand, nasal symptoms were not change following induction of omalizumab.
Conclusions
Clinical effectiveness of omalizumab was confirmed in Japanese population of severe allergic asthma, but not rhinitis. The therapeutic potency of omalizumab on asthma likely involves anti-inflammatory properties such as decreasing eNO or airway eosinophilia.
doi:10.1097/01.WOX.0000411912.27708.d6
PMCID: PMC3513114
24.  A cost-utility analysis of transcatheter aortic valve implantation in Belgium: focusing on a well-defined and identifiable population 
BMJ Open  2012;2(3):e001032.
Background
Patients with severe aortic stenosis and coexisting non-cardiac conditions may be at high risk for surgical replacement of the aortic valve or even be no candidates for surgery. In these patients, transcatheter aortic valve implantation (TAVI) is suggested as an alternative. Results of the PARTNER (Placement of AoRTic TraNscathetER Valve) trial comparing the clinical effectiveness of TAVI with surgical valve replacement and standard therapy were published. The authors assessed the cost-effectiveness of TAVI in Belgium.
Methods
A Markov model of incremental costs, effects (survival and quality of life) and incremental cost-effectiveness of TAVI was developed. The impact on survival, number of events and quality of life was based on the PARTNER trial. Costs per event were context specific.
Results
In high-risk operable patients, even if the minor differences in 30-day and 1-year mortality are taken into account, the incremental cost-effectiveness ratio (ICER) remains on average above €750 000 per quality-adjusted life-year (QALY) gained (incremental cost: €20 400; incremental effect: 0.03 QALYs). In inoperable patients, an ICER of €44 900 per QALY (incremental cost: €33 200; incremental effect: 0.74 QALYs) is calculated, including a life-long extrapolation of the mortality benefit. This result was sensitive to the assumed time horizon. The subgroup of anatomically inoperable patients had better outcomes than medically inoperable patients, with ICERs decreasing more than €10 000/QALY.
Conclusions
It is inappropriate to consider reimbursement of TAVI for high-risk operable patients. Reimbursing TAVI in inoperable patients in essence is a political decision. From an economic perspective, it would be prudent to first target patients that are inoperable because of anatomical prohibitive conditions. In the search for evidence, the authors identified non-published negative results from a randomised controlled TAVI trial. The study sponsor should be more willing to share this information to allow balanced evaluations and policy recommendations. Payers should require these data before taking reimbursement decisions.
Article summary
Article focus
To assess the cost-effectiveness of transcatheter aortic valve implantation (TAVI) for Belgian patients.
Key messages
In high-risk operable patients, surgical aortic valve replacement and TAVI are associated with similar mortality rates at 1 year. However, there is a twice as high rate of stroke after TAVI. From an economic point of view, the less invasive nature of the TAVI procedure does not weigh against the extra costs of about €20 000 per patient.
In inoperable patients, TAVI significantly reduces the rate of death from any cause as compared with a non-surgical approach. The ICER is about €45 000 per QALY gained. Nevertheless, a distinction should be made between inoperability for anatomic versus medical reasons. TAVI offers more value for money in the former patient group with ICERs decreasing more than €10 000 per QALY.
If policy makers are willing/able to pay the relative high price for TAVI, it is advised to focus in the first place on the anatomic inoperable patients.
Strengths and limitations of this study
Hospital billing data of 183 Belgian patients treated with the Edwards SAPIEN valve were at our disposal for cost calculations.
Next to the published pivotal PARTNER (Placement of AoRTic TraNscathetER Valve) trial, a non-published randomised controlled trial (RCT) with TAVI was identified. This Continued Access trial was performed according to the same study protocol of the pivotal PARTNER trial. The mortality outcomes of this Continued Access RCT, disfavouring TAVI, were included in our analysis.
An unbalance in patient characteristics was observed in the inoperable patients of the PARTNER trial, favouring the TAVI group. A subgroup analysis showed a greater improvement for anatomic inoperable patients versus those inoperable for medical reasons.
The most important limitation of our analysis is the non-availability of all relevant study outcomes, especially for the negative non-published Continued Access RCT. The study sponsor should be willing to reveal this information in due time. Payers should require access to these non-published data before deciding on reimbursement.
doi:10.1136/bmjopen-2012-001032
PMCID: PMC3358616  PMID: 22561354
25.  Cost-Effectiveness of Recombinant Tissue Plasminogen Activator 3–4.5 Hours after Onset of Acute Ischemic Stroke in Patient Subgroups 
Annals of emergency medicine  2012;61(1):46-55.
Background
The ECASS III study showed that recombinant tissue plasminogen activator (rtPA) given 3–4.5 hours after acute ischemic stroke (AIS) led to improvement in patient disability versus placebo.
Objective
To evaluate the long-term incremental cost-effectiveness of rtPA given 3–4.5 hours after AIS onset versus no treatment based on patient clinical and demographic factors.
Methods
We developed a disease-based decision analytic model to project lifetime outcomes of patients post-AIS from the payer perspective. Clinical data were derived from the ECASS III trial, longitudinal cohort studies, and health state preference studies. Cost data were based on Medicare reimbursement and other published sources. We performed probabilistic sensitivity analyses to evaluate uncertainty in the analysis.
Results
rtPA in a hypothetical cohort of 100 patients resulted in a gain of 7 years of life (95% credible range [CR], 0.05–17) and 24 quality-adjusted life-years (QALYs) (95% CR, 1–60), and a difference in cost of $149,500 (95% CR, −$463,700 – $610,000) compared with placebo. The incremental cost-effectiveness ratio for all patients was $6,300 per QALY gained; for patients <65 years old, cost saving; ≥ 65 years old, $35,800/QALY; for patients with baseline NIHSS 0–9, $16,300/QALY; 10–19, $37,500/QALY; ≥ 20, $2,400/QALY. The majority of other subgroups such as gender, history of stroke, and history of hypertension were cost-saving to cost-effective with the exceptions of diabetes and atrial fibrillation.
Conclusion
The results indicate that rtPA in the 3- to 4.5-hour therapeutic window provides improvement in long-term patient outcomes in most patient subgroups and is a good economic value versus no treatment.
doi:10.1016/j.annemergmed.2012.04.020
PMCID: PMC3598015  PMID: 22633340
Cerebrovascular disorders; Stroke; Cost effectiveness; Outcome studies; Quality of life; Thrombolytic therapy

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