Pharmaceutical interventions for mitigating an influenza pandemic: modeling the risks and health-economic impacts

Model-based analyses built on burden-of-disease and cost–effectiveness theory predict that pharmaceutical interventions may efficiently mitigate both the epidemiologic and economic impact of an influenza pandemic. Pharmaceutical interventions typically encompass the application of (pre)pandemic influenza vaccines, other vaccines (notably pneumococcal), antiviral treatments and other drug treatment (e.g., antibiotics to target potential complications of influenza). However, these models may be too limited to capture the full macro-economic impact of pandemic influenza. The aim of this article is to summarize current health-economic modeling approaches to recognize the strengths and weaknesses of these approaches, and to compare these with more recently proposed alternative methods. We conclude that it is useful, particularly for policy and planning purposes, to extend modeling concepts through the application of alternative approaches, including insurers’ risk theories, human capital approaches and sectoral and full macro-economic modeling. This article builds on a roundtable meeting of the Pandemic Influenza Economic Impact Group that was held in Boston, MA, USA, in December 2008.     

Antiviral therapy in seasonal influenza and 2009 H1N1 pandemic influenza: Korean experiences and perspectives

Influenza is a major cause of substantial morbidity and mortality in humans every year. Vaccination is the main strategy to prevent influenza infection, but antiviral agents also play an important role in the control of both seasonal and pandemic influenza. During the influenza A/H1N1 pandemic in 2009, early prompt antiviral therapy may have reduced the severity of the influenza outcomes including pneumonia, hospitalization and mortality in the Republic of Korea. Since the 2009 H1N1 pandemic, there have been increasing usages of antiviral agents for the treatment of patients with seasonal influenza. Although currently rare, antiviral resistance among influenza viruses may emerge and increase with increased use of neuraminidase inhibitors. New agents with different modes of action are under investigation, including favipiravir, DAS181, nitazoxanide and broad-spectrum neutralizing monoclonal antibodies. Data are limited with respect to high-dose and combination antiviral therapies. So, clinical trials are warranted to evaluate diverse antiviral combinations that may be synergistic and less likely to induce breakthrough resistance.     

Pandemic influenza A (H1N1) in pregnant women: impact of early diagnosis and antiviral treatment

Evaluation of: Siston AM, Rasmussen SA, Honein MA et al. Pandemic 2009 influenza A (H1N1) virus illness among pregnant women in the United States. JAMA 303(15), 1517–1525 (2010).

Pregnant women are at increased risk for severe illness from influenza infection, particularly pandemics, including the current flu pandemic. Early antiviral therapy using oseltamivir or zanamivir may be beneficial, but limited information is available regarding their safety and effectiveness during pregnancy. The article by Siston et al. assessed the findings of a recently published paper describing the severity of illness due to 2009 influenza A (H1N1) infection among 788 pregnant women reported to the CDC, stratified by timing of antiviral therapy and pregnancy trimester at symptom onset. The authors’ findings highlight the potential for severe illness and high risk of mortality due to influenza A (H1N1) infection among pregnant women and suggest the benefit of early antiviral treatment in reducing intensive care unit admissions and mortality rate. The WHO and CDC recommendations including 2009 influenza A (H1N1) vaccination and early antiviral therapy in case of influenza-like illness for all pregnant women are discussed regarding the key findings of this paper and other published data on influenza A (H1N1) infection in pregnant women.     

How would Australian hospital staff react to an avian influenza admission,or an influenza pandemic?

Objective: To estimate the expected staff absentee rates and work attitudes in an Australian tertiary hospital workforce in two hypothetical scenarios: (i) a single admission of avian influenza; and (ii) multiple admissions of human pandemic influenza. Methods: A survey conducted at hospital staff meetings between May and August 2006. Results: Out of 570 questionnaires distributed, 560 were completed. For scenario one, 72 (13%) indicated that they would not attend work, and an additional 136 (25%) would only work provided that immunizations and/or antiviral medications were immediately available, so that up to 208 (38%) would not attend work. For scenario two, 196 (36%) would not attend work, and an additional 95 (17%) would work only if immunizations and/or antiviral medications were immediately available, so that up to 291 (53%) staff would not attend work. Staff whose work required them to be in the ED (odds ratios 2.2 and 1.6 for each scenario respectively) or on acute medical wards (odds ratios 2.2 and 2.0 respectively) were more likely to work. Conclusion: High absenteeism among hospital staff should be anticipated if patients are admitted with either avian or pandemic influenza, particularly if specific antiviral preventative measures are not immediately available. Measures to maximize the safety of staff and their families would be important incentives to attend work. Education on realistic level of risk from avian and pandemic influenza, as well as the effectiveness of basic infection control procedures and personal protective equipment, would be useful in improving willingness to work.     

Production of adenovirus vectors and their use as a delivery system for influenza vaccines

Importance of the field: With the emergence of highly pathogenic avian influenza H5N1 viruses that have crossed species barriers and are responsible for lethal infections in humans in many countries, there is an urgent need for the development of effective vaccines which can be produced in large quantities at a short notice and confer broad protection against these H5N1 variants. In order to meet the potential global vaccine demand in a pandemic scenario, new vaccine-production strategies must be explored in addition to the currently used egg-based technology for seasonal influenza.

Areas covered in this review: Adenovirus (Ad) based influenza vaccines represent an attractive alternative/supplement to the currently licensed egg-based influenza vaccines. Ad-based vaccines are relatively inexpensive to manufacture, and their production process does not require either chicken eggs or labor-intensive and time-consuming processes necessitating enhanced biosafety facilities. Most importantly, in a pandemic situation, this vaccine strategy could offer a stockpiling option to reduce the response time before a strain-matched vaccine could be developed.

What the reader will gain: This review discusses Ad-vector technology and the current progress in the development of Ad-based influenza vaccines.

Take home message: Ad vector-based influenza vaccines for pandemic preparedness are under development to meet global vaccine demand.     

Oseltamivir in seasonal,pandemic, and avian influenza: a comprehensive review of 10-years clinical experience

Oseltamivir (Tamiflu®; F. Hoffmann-La Roche Ltd, Basel, Switzerland) is an orally administered antiviral for the treatment and prevention of influenza A and B infections that is registered in more than 100 countries worldwide. More than 83 million patients have been exposed to the product since its introduction. Oseltamivir is recommended by the World Health Organization (WHO) for use in the clinical management of pandemic and seasonal influenza of varying severity, and as the primary antiviral agent for treatment of avian H5N1 influenza infection in humans. This article is a nonsystematic review of the experience gained from the first 10 years of using oseltamivir for influenza infections since its launch in early 2000, emphasizing recent advances in our understanding of the product and its clinical utility in five main areas. The article reviews the pharmacokinetics of oseltamivir and its active metabolite, oseltamivir carboxylate, including information on special populations such as children and elderly adults, and the co-administration of oseltamivir with other agents. This is followed by a summary of data on the effectiveness of oseltamivir treatment and prophylaxis in patients with all types of influenza, including pandemic (H1N1) 2009 and avian H5N1 influenza. The implications of changes in susceptibility of circulating influenza viruses to oseltamivir and other antiviral agents are also described, as is the emergence of antiviral resistance during and after the 2009 pandemic. The fourth main section deals with the safety profile of oseltamivir in standard and special patient populations, and reviews spontaneously reported adverse event data from the pandemic and pre-pandemic periods and the topical issue of neuropsychiatric adverse events. Finally, the article considers the pharmacoeconomics of oseltamivir in comparison with vaccination and usual care regimens, and as a component of pandemic influenza mitigation strategies.     

Influenza in the nursing home.

Although influenza affects persons of all ages, the Centers for Disease Control and Prevention has identified several groups who are at increased risk for complications. One such group is residents of nursing homes or other long-term care facilities. During influenza epidemics, mortality rates among nursing home residents often exceed 5 percent. To lessen the impact of this infection, the influenza vaccine is recommended as the primary way of preventing the illness and its complications. Many studies have shown that vaccination of nursing home residents and staff can significantly decrease rates of hospitalization, pneumonia, and related mortality. When an influenza outbreak occurs in a nursing home, several measures can be implemented by the treating physician. Treatment and prophylaxis can be accomplished using antiviral medications such as amantadine, rimantadine, and oseltamivir. The antiviral medication zanamivir can be used in the treatment of influenza, but not for prophylaxis. Once an outbreak has been established, control measures, including vaccination of unvaccinated residents and employees, and limitations on resident movement and visits, can be implemented.     

Pharmaceutical interventions for mitigating an influenza pandemic: modeling the risks and health-economic impacts

Model-based analyses built on burden-of-disease and cost-effectiveness theory predict that pharmaceutical interventions may efficiently mitigate both the epidemiologic and economic impact of an influenza pandemic. Pharmaceutical interventions typically encompass the application of (pre)pandemic influenza vaccines, other vaccines (notably pneumococcal), antiviral treatments and other drug treatment (e.g., antibiotics to target potential complications of influenza). However, these models may be too limited to capture the full macro-economic impact of pandemic influenza. The aim of this article is to summarize current health-economic modeling approaches to recognize the strengths and weaknesses of these approaches, and to compare these with more recently proposed alternative methods. We conclude that it is useful, particularly for policy and planning purposes, to extend modeling concepts through the application of alternative approaches, including insurers' risk theories, human capital approaches and sectoral and full macro-economic modeling. This article builds on a roundtable meeting of the Pandemic Influenza Economic Impact Group that was held in Boston, MA, USA, in December 2008.     

A Collaborative Approach to Meeting the Psychosocial Needs of Children During an Influenza Pandemic

PURPOSE. The purpose of this article is to address how those caring for children during an influenza pandemic can best respond to their psychosocial needs. CONCLUSION. Throughout 2009, the United States grappled with an influenza pandemic, including how to care for children during outbreak of illness. As disease spread, children were identified as being highly susceptible to infection. It is not known how severe future influenza outbreaks will be. PRACTICE IMPLICATIONS. Pediatric healthcare professionals must be prepared to collaboratively address the psychosocial needs of children before, during, and after a pandemic in order to avoid fear and panic.     

Peramivir for the treatment of influenza

Peramivir (BioCryst Pharmaceuticals) is a novel investigational intravenous neuraminidase inhibitor that exhibits potent antiviral activity against influenza A and B viruses. Peramivir is created by a structure-based drug design and consists of a cyclopentane backbone with a positively charged guanidinyl group and lipophilic side chains. Peramivir was made available in the USA through the Emergency Investigational New Drug regulations and under an Emergency Use Authorization for hospitalized patients with known or suspected influenza during the 2009 H1N1 influenza pandemic. In trials involving ambulatory adult subjects, intravenous peramivir is safe and has a pharmacokinetic profile that supports once-daily dosing. The drug is licensed in Japan and South Korea and is currently undergoing Phase III trials in the USA. Viral resistance mechanisms to peramivir have not been fully delineated and ongoing surveillance is important. Given the serious health threat of influenza at all ages and limitations in vaccine delivery, peramivir is a promising addition to the currently limited treatment options for the treatment of severe influenza infection.     

Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic

Recent cross species transmission of avian influenza has highlighted the threat of pandemic influenza. Oseltamivir (Tamiflu) has been shown to be effective in the treatment and prevention of epidemic influenza infection in adults, adolescents and children (> or = 1 year). Although oseltamivir has not been approved for prophylactic use in children, it has been shown to be effective. Oseltamivir is also active against avian influenza virus strains. Evidence suggests that lower doses or shorter durations of treatment/chemoprophylaxis other than those approved may not be effective and may contribute to emergence of viral resistance. Safety data from dose ranging studies show that 5 day courses of 150 mg twice daily for treatment and 6 week courses of 75 mg twice daily for prophylaxis were as well tolerated as the approved dose regimens. The use of oseltamivir in a pandemic is influenced by the goals of the pandemic plan developed by the responsible Government and Health Authority. To optimize use of antiviral medications, processes will be needed to collect, collate and report outcome data from treated patients and/or from use for chemoprophylaxis of pandemic influenza during the first-wave outbreaks. If oseltamivir is included in a national or regional pandemic plan, stockpiling of the material, either in the form of capsules or the bulk active pharmaceutical ingredient will be necessary. In the absence of a stockpile, there is no guarantee that an adequate supply of oseltamivir will be available.     

Use of molecular assays for the diagnosis of influenza

Respiratory infections are the third highest cause of death worldwide and influenza has the highest mortality rate among lower respiratory tract infections (LRTIs). Diagnosis of LRTIs relies mostly on clinical symptoms and is not fully satisfactory. Influenza laboratory diagnosis improves the efficiency of prophylaxis or treatment of influenza by antiviral molecules and has a strong impact on the cost–effectiveness of curative treatment. Inappropriate treatment of patients may result in spreading of resistant strains. Molecular diagnostics play a central role in the surveillance and response of pandemic influenza due to highly pathogenic strains. Real-time assays can be used for diagnosis or surveillance purposes in humans and animals, and microarrays can be used to identify and monitor the spread of dangerous variants. Molecular assays are also useful to identify and distinguish influenza, other respiratory viruses and bacteria, although their cost–effectiveness must be proven on a large scale. As new antiviral options will be available to clinicians, a better treatment choice will benefit the patient and community. Recent progress in molecular techniques will be reviewed. Examples of real-time assays for the detection of influenza viruses, including the highly pathogenic influenza A strains H5N1 and H7N7, will be discussed. Promising new techniques that allow detailed genotyping of viruses or multiplex detection of several respiratory pathogens from a unique specimen will also be discussed. These techniques will, in the near future, significantly improve the quality of diagnosis and surveillance of respiratory pathogens.     

Preparedness for Influenza Pandemic in Hong Kong Nursing Units

BACKGROUND: To present preparedness planning for an influenza pandemic for two nursing subunits: nursing services in hospitals and schools of nursing in universities. DISCUSSION: The preparedness plan is modeled on a modified Haddon matrix, a logical approach to identify measures appropriate for the pre-event, event, and postevent phases of an influenza pandemic. For the pre-event phase, the objective is to ensure preparedness for the potential pandemic outbreak through training, communication, surveillance, infection control, and vaccination. Once the pandemic outbreak is declared, the aim is to implement effective measures to ensure a rapid and appropriate response. For the postevent phase, the plan is focused on the restoration of core functions, vigilance for a second or possibly more waves of the pandemic, and psychosocial support to staff and students. CONCLUSION: Measures required to prepare for, respond to, and manage the consequences of influenza pandemic are identified. This planning indicates the need to balance a logical approach with contextual perspectives and the importance for nursing leaders to develop plans for subunits of larger entities.     

Avian influenza: a new pandemic threat?

In December 2003, the largest outbreak of highly pathogenic avian influenza H5N1 occurred among poultry in 8 Asian countries. A limited number of human H5N1 infections have been reported from Vietnam and Thailand, with a mortality rate approaching 70%. Deaths have occurred in otherwise healthy young individuals, which is reminiscent of the 1918 Spanish influenza pandemic. The main presenting features were fever, pneumonitis, lymphopenia, and diarrhea. Notably, sore throat, conjunctivitis, and coryza were absent. The H5N1 strains are resistant to amantadine and rimantadine but are susceptible to neuraminidase inhibitors, which can be used for treatment and prophylaxis. The widespread epidemic of avian influenza in domestic birds increases the likelihood for mutational events and genetic reassortment. The threat of a future pandemic from avian influenza is real. Adequate surveillance, development of vaccines, outbreak preparedness, and pandemic influenza planning are important. This article summarizes the current knowledge on avian influenza, including the virology, epidemiology, diagnosis, and management of this emerging disease.     

2009年湖北省咸宁市甲型H1N1流感样病例流行特征分析

目的揭示新出现的甲型H1N1流感在湖北省咸宁市的流行病学特征。方法分别收集国家"疾病监测信息报告管理系统"、"甲型H1N1流感信息管理系统"、"中国流感监测信息系统"中,咸宁市2009年报告的甲型H1N1流感、流行性感冒(流感)、流感样病例(ILI)的流行病学监测数据(以发病日期统计),用Excel 2000软件建立数据库进行统计分析。结果 2009年咸宁市共报告甲型H1N1流感41例,其中危重病例2例,无死亡病例。所有病例均为境内感染的本土病例。疫情发病高峰与当年普通季节性流感发病相当。发病集中于市区,暴发主要出现在学校,发病人群以学生为主,绝大多数病例属于轻症病例。流感网络实验室监测结果提示,随着疫情的进展,甲型H1N1流感病毒逐渐成为流感大流行的优势毒株。结论咸宁市甲型H1N1流感疫情流行特点与当地普通季节性流感不尽相同。由于防控得力,未造成疫情大面积传播,为进一步调整防控措施提供有力依据。     

一起由输入病例引起的学校甲型H1N1流感暴发调查

该起学校暴发为新加坡输入病例引起,疫情持续8 d,共发生流感样病例12例,皆为甲型H1N1流感病例,罹患率为2.61%(12/460)。对所有流感样病例采集咽拭子标本检测甲型H1N1流感病毒核酸阳性。传播一代的时间平均65.2 h(32~96 h)。     

Emerging Antiviral Strategies to Interfere with Influenza Virus Entry

Influenza A and B viruses are highly contagious respiratory pathogens with a considerable medical and socioeconomical burden and known pandemic potential. Current influenza vaccines require annual updating and provide only partial protection in some risk groups. Due to the global spread of viruses with resistance to the M2 proton channel inhibitor amantadine or the neuraminidase inhibitor oseltamivir, novel antiviral agents with an original mode of action are urgently needed. We here focus on emerging options to interfere with the influenza virus entry process, which consists of the following steps: attachment of the viral hemagglutinin to the sialylated host cell receptors, endocytosis, M2‐mediated uncoating, low pH‐induced membrane fusion, and, finally, import of the viral ribonucleoprotein into the nucleus. We review the current functional and structural insights in the viral and cellular components of this entry process, and the diverse antiviral strategies that are being explored. This encompasses small molecule inhibitors as well as macromolecules such as therapeutic antibodies. There is optimism that at least some of these innovative concepts to block influenza virus entry will proceed from the proof of concept to a more advanced stage. Special attention is therefore given to the challenging issues of influenza virus (sub)type‐dependent activity or potential drug resistance.     

Avian influenza pandemic threat and health systems response

Avian influenza is a panzootic and recurring human epidemic with pandemic potential. Pandemic requirements for a viral pathogen are: a novel virus must emerge against which the general population has little or no immunity; the new virus must be able to replicate in humans and cause serious illness; and the new virus must be efficiently transmitted from person to person. At present, only the first two conditions have been met. Nonetheless, influenza pandemics are considered inevitable. Expected worldwide human mortality from a moderate pandemic scenario is 45 million people or more than 75% of the current annual global death burden. Although mathematical models have predicted that an emerging pandemic could be contained at its source, this conclusion remains controversial among public health experts. The Terrestrial Animal Health Code and International Health Regulations are enforceable legal instruments integral to pandemic preparedness. Donor support in financial, material and technical assistance remains critical to disease control efforts - particularly in developing countries where avian influenza predominately occurs at present. Personal protective equipment kits, decontamination kits and specimen collection kits in lightweight, portable packages are becoming standardized. Air transport border control measures purporting to delay importation and spread of human avian influenza are scientifically controversial. National pandemic plans prioritize beneficiary access to antiviral drugs and vaccines for some countries. Other medical commodities including ventilators, hospital beds and intensive care units remain less well prioritized in national plans. These resources will play virtually no role in care of the overwhelming majority of patients worldwide in a pandemic. Prehospital care, triage and acute care all require additional professional standardization for the high patient volumes anticipated in a pandemic.     

A case of pandemic 2009 influenza A (H1N1) in a patient with HIV infection

Little is known about pandemic 2009 influenza A (H1N1) among patients with human immunodeficiency virus (HIV) infection. We report a case of 2009 influenza A (H1N1) in a patient who was newly diagnosed as having HIV. His general condition was good, and he was successfully treated in an outpatient setting. The literature was reviewed for the diagnosis, treatment, prevention, and infection control of pandemic 2009 influenza A (H1N1) among those who have HIV infection.     

Influenza infection in human host: challenges in making a better influenza vaccine

Influenza is a ubiquitous infection with a spectrum ranging from mild to severe. The mystery regarding such variability in the clinical spectrum has not been fully unravelled, although a role for the complex interplay among virus characteristics, host immune response and environmental factors has been suggested. Antivirals and current vaccines have a limited role in prophylaxis and treatment because they primarily target surface glycoproteins which undergo antigenic/genetic changes under host immune pressure. Targeting conserved internal proteins could lead the way to a universal vaccine which can be used against various types/subtypes. However, this is on the distant horizon, so in the meantime, developing improved vaccines should be given high priority. In this review, we discuss where the current influenza research stands in terms of vaccines, adjuvants, and how we can better predict the vaccine strains for upcoming influenza seasons by understanding complex phenomena which drive the continuous antigenic evolution.