The Threat of Pandemic Influenza Are We Ready? Workshop Summary (2005) / Chapter Skim
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3 Toward Preparedness: Opportunities and Obstacles
3 Toward Preparedness: Opportunities and Obstacles
Pages 141-221
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From page 141... ...
Even populations wealthy enough to obtain vaccine are unlikely to get enough to prevent significant morbidity and mortality from pandemic influenza unless more rapid vaccine production methods or novel prophylactic vaccines can be introduced before the next pandemic strikes. The circumstances surrounding 2 consecutive years of interpandemic flu vaccine shortages in the United States clearly illustrate this vulnerability.
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From page 142... ...
flu seasons, but as this chapter demonstrates, considerable obstacles currently hinder the production of a vaccine against a pandemic strain of influenza. The critical role of vaccine manufacturers in addressing a pandemic is described, accompanied by a review of methods and logistics for the development and production of a pandemic vaccine.
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From page 143... ...
Europeans will most likely pursue this goal by developing a low-dose adjuvant pandemic vaccine, which differs from the strategy that will be undertaken by the National Institute of Allergy and Infectious Diseases in the United States. He also describes the potential advantages of engineering viral seed strains with reverse genetics and urges a quick resolution to the ongoing dispute regarding ownership of intellectual property for this technology.
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Influenza Pandemic Preparedness and Response, available at: http://www.who.int/gb/ebwha/pdf_files/EB115/ B115_44-en.pdf and (2) Strengthening Pandemic Influenza Preparedness and Response, available at: http://www.who.int/gb/ebwha/pdf_files/EB115/B115_R16-en.pdf.
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This unprecedented situation has significantly increased the risk for the emergence of an influenza pandemic. A pandemic virus capable of efficient human-to-human transmission could arise via two mechanisms: virus reassortment (the swapping of genetic material between viruses)
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To reduce some of this uncertainty, participants based their recommendations on relevant lessons from the recent SARS outbreak, knowledge about the epidemiology of previous influenza pandemics, and clinical data from outbreaks of H5N1 infection in Hong Kong in 1997 and Viet Nam and Thailand in 2004. Modelling of various scenarios for the emergence of a pandemic strain provided an especially useful planning tool.
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For this reason, surveillance systems in countries with outbreaks in animals caused by H5N1 or other influenza viruses of known human pathogenicity should be oriented towards early detection, reporting, and investigation of clusters of human cases, followed by aggressive con
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By including provisions for stopping or adjusting measures in line with clear epidemiological criteria, preparedness plans would help public health authorities withstand this pressure and thus conserve resources for the next objectives: constraining transmission, preventing severe disease, and reducing case fatality. When objectives shift, clear and frank public information and good communications systems would be essential in helping lower expectations and discouraging the continuation of personal protective measures no longer considered effective.
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From page 149... ...
Research on antivirals could determine whether reduced drug dose or shortened treatment course might still have a prophylactic or therapeutic effect, and whether administration later in the course of infection might influence transmission dynamics by reducing virus shedding. As in all public health emergencies caused by an infectious agent, international mechanisms for alert and response can go only a certain way towards mitigating the consequences of an influenza pandemic.
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An influenza pandemic is a public health emergency that rapidly takes on significant political, social, and economic dimensions. A broad
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, limiting the spread of infection by domestic and international travel, and the targeted use of antiviral drugs. Certain measures are recommended for consideration based on a public health perspective, although it is recognized that other factors (such as availability of health resources, political, economic and social considerations)
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7. Increased use of antivirals during the inter-pandemic years, based on better understanding of the medical and economic burden of annual influenza epidemics, is one strategy for augmenting production capacity.
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6. Important constraints to rapid and large-scale production of a pandemic vaccine include intellectual property rights, biosafety requirements for production facilities, and coordination and funding of clinical trials.
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12. Vaccine manufacturers in developing countries should participate in the influenza vaccine supply task force of the International Federation of Pharmaceutical Manufacturers.
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Substantial resources have been allocated to assure and expand influenza vaccine production capacity; increase influenza vaccination use; stockpile influenza antiviral drugs in the Strategic National Stockpile (SNS) ; enhance U.S.
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and global influenza surveillance networks can lead to earlier detection of a pandemic virus or one with pandemic potential. Virus identification and the generation of seed viruses for vaccine production is a critical first step for influenza vaccine development.
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All totaled since September 11, 2001, HHS has invested more than $3.7 billion in strengthening the Nation's public health infrastructure. Preparedness for an influenza pandemic is coordinated in the office of the Assistant Secretary for Health, HHS.
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Progression from a new virus alert to a pandemic alert will be accompanied by response activities that include intensified U.S. and global surveillance; investigation of the virology and epidemiology of the novel influenza strain including collaboration with international partners on containment; vaccine development and clinical testing leading toward licensure of a pandemic vaccine; coordination with health departments and activation of local plans, and implementation of the communications plan which includes education of health care providers and the public.
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· To describe interventions that should be implemented as components of an effective influenza pandemic response. · To guide health departments and the health care system in the development of state and local pandemic influenza preparedness and response plans.
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. · Recent developments that have influenced the influenza pandemic planning process include experience gained through planning for bioterrorist events and other health emergencies such as the international response to SARS and the national responses to anthrax cases and the implementation of a the US smallpox vaccination program.
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From page 161... ...
The amount of pandemic influenza vaccine produced depends on the physical capacity of the manufacturing facilities, the growth character istics of the pandemic virus in embryonated chicken eggs used for vaccine production, and the amount of influenza virus pro tein that is included in each dose to achieve optimal protection. The number of available doses also is limited by manufacturing capacity for filling and labeling vials or syringes.
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From page 162... ...
Given the time required for vaccine development and vaccine production capacity, shortages may exist throughout the first pandemic wave. In recent years when influenza vaccine was delayed or in short supply for annual influenza epidemics, many persons were vac cinated who were not in recommended priority groups, vaccine distribution was inequitable, and a gray market developed in response to increased demand, with high prices being paid for some vaccine doses.
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· Determine the susceptibility of the pandemic strain to existing influenza antiviral drugs and target use of available supplies; avoid inappropriate use to limit the development of antiviral resistance and ensure that this limited resource is used effectively. The objective of antiviral prophylaxis is to prevent influenza illness.
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An influenza pandemic will place a substantial burden on inpa tient and outpatient health care services. Because of the in creased risk of exposure to pandemic virus in health care set tings, illness and absenteeism among health care workers in the context of increased demand will further strain the ability to provide quality care.
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Effective communication with community leaders and the media also is important to maintain public awareness, avoid social disruption, and pro vide information on evolving pandemic response activities. Coordination of a Pandemic Response An influenza pandemic will represent a national health emergency requiring coordination of response activities.
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Preparedness Activities · During the inter-pandemic period many activities can be pursued to assure that the government is as prepared as possible for a pandemic. These include: Expand manufacturing capacity for influenza vaccine, develop surge capacity for a pandemic vaccine production, and assess potential approaches to optimize vaccine dose, and diversify manufacturing.
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In the determination of the optimal vaccine dose, studies should also be performed to assess whether adding an adjuvant -- a substance to enhance the immune response to vac cination -- or alternative vaccine administration approaches will lead to improved protection and/or the ability to protect more people with the available amount of vaccine virus and effec tively expand the vaccine supply. Conduct research to develop new influenza vaccines that are highly efficacious, are easier to administer, or that are directed against a constant portion of the influenza virus and thus side stepping the need to develop a new vaccine every year to match the predominant viral strains that are most likely to cause disease.
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From page 168... ...
Not only do state and local government agencies lack the specific expertise in pandemic influenza that could best guide the planning process, but independent and potentially disparate decisions made at the state and local levels will ultimately result in public confusion and mistrust. For example, if one state established a response to issues posed by a pandemic that differed dramatically from a neighboring state, such as totally dissimilar priority groups for influenza vaccine, chaos would ensue.
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From page 169... ...
Preferably, the general public will be a player in the decision-making and planning process, thus enhancing the public's acceptance of such deliberations as a workable public health tool. By addressing the public's concerns now, in the prepandemic planning stages, the ultimate outcome will be a more realistic approach to dealing effectively with the crisis at hand and to soliciting the cooperation of the public in accepting protective courses of action.
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From page 170... ...
By promoting health care worker acceptance of influenza vaccine, we would also protect the patients those health care workers serve, representing a boost for this cost-effective prevention strategy. Furthermore, improving on the current 34 percent acceptance rate of influenza vaccine among health care workers will also boost demand for the vaccine during the interpandemic years, which will result in an increased number of doses of influenza vaccine produced by manufacturers annually.
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Don't Repeat Swine Flu The response to disease crises from yesterday should assist us in planning for the crises of tomorrow. We need to take seriously lessons learned from recent events such as SARS and smallpox vaccine initiatives and to incorporate those lessons in our pandemic planning efforts.
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From page 172... ...
6365, Copyright 2002, with permission from Elsevier Abstract In the United States, planning for the next influenza pandemic is occurring in parallel at the national, state and local levels. Certain issues, such as conducting surveillance and purchasing pandemic vaccine, require coordination at the national level.
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From page 173... ...
As a result, a piecemeal type of surveillance for influenza exists within the United States with 50 states each having their own surveillance system, some being extensive, and others practically non-existent. National Influenza Pandemic Preparedness In 1993, the National Working Group on influenza pandemic preparedness and emergency response (GrIPPE)
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The group has also recognized that to effectively address the threat of an influenza pandemic, measures to reduce the impact of influenza must be in place and operational at the state and local levels now, during the pre-pandemic period. Because more influenza-related illness and death occur in the aggregate during regularly recurring influenza epidemics than during the pandemics themselves, the GrIPPE has attempted to link its plan to other relevant public health initiatives such as those related to emerging infections and adult immunization.
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The planning guide makes the following recommendations during the pre-pandemic period: · Virologic surveillance capability must be improved by ensuring that at least one laboratory in each state and/or major metropolitan area has the capacity of to isolate and subtype influenza viruses. · Disease-based surveillance capacity must also be improved by defining the existing sentinel physician network, with the aim of establishing a population based system of approximately one sentinel physician per 250,000 population.
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Conclusion National efforts to prepare for the next influenza pandemic require the support and interaction from partners at the state, local and federal levels. A solid influenza surveillance system in place at the state and local levels will assist in proactively planning for the regularly recurring epidemics as well as for the inevitable pandemic.
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The expertise of vaccine manufacturers, particularly those with a track record of influenza vaccine production and distribution, should be utilized at the earliest stage of planning and vaccine development. Manufacturers have access to vaccine production information regarding the timeframes needed to implement specific policy changes.
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Aventis Pasteur's preparations for an influenza pandemic are well underway. The company has entered into an agreement with NIAID to produce influenza vaccine based on a potential pandemic strain.
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Third, we need manufacturing capacity -- including physical facilities, validated equipment and processes, and trained personnel -- dedicated to producing this one vaccine in a short period of time. Three main variables govern the amount of traditional trivalent influenza vaccine that Aventis Pasteur can produce in any season.
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In the United States, 85 percent of influenza vaccine is sold, distributed, and administered in the private market. This approach is working well and should serve as the basis in preparing for a pandemic vaccine.
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As a charter member of the National Influenza Summit's privatepublic partnership and the global leader in influenza vaccine development and production, Aventis Pasteur has recommended a number of steps, described below, to increase influenza immunization. These principles were proposed by the company to the National Vaccine Advisory Committee in Washington, D.C., in February 2004, and reiterated at the Influenza Summit in Atlanta, Ga., in April 2004.
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From page 182... ...
Looking beyond influenza vaccines, stockpiles for all other routine pediatric vaccines must be in place before a pandemic due to the need for manufacturers to focus their efforts on the manufacture, formulation, and filling of 300 to 600 million monovalent doses for a pandemic. During a
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In summary, there are a number of key lessons and principles that the industry, government, and medical community must consider for pandemic influenza planning: · Demand drives supply; industry can optimize and expand influenza production if demand is stable and predictable Sustainable initiatives are needed to drive demand · Manufacturers' expertise should be utilized at the earliest stage of the policy process Companies with a track record of influenza vaccine production should be involved in policy development; pandemic plans conceived without manufacturer involvement run the risk of not being executable · RFP deliverables should realistically reflect pandemic requirements and include appropriate liability protection · The current privatepublic distribution system provides a strong foundation on which to build · Identify high-risk groups and establish priorities for phased immunization · Extend the immunization season · Send influenza vaccine overseas to stem small, virulent outbreaks · Develop shared-risk reserves for unanticipated demand/outbreaks on an annual basis and establish stockpiles of routinely used vaccines
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From page 184... ...
If these effects could be confirmed, they could potentially mitigate the morbidity and mortality of pandemic influenza when there are limited supplies of vaccines and antiviral drugs. Global Distribution of Influenza Vaccine, 20002003 According to a recent report by the Influenza Vaccine Supply (IVS)
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185 In 715 253 4,357 1,540 1,230 sold.
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It should be based on the existing global capacity to produce trivalent influenza vaccines in egg-based production systems. Its goal should be to determine the lowest amount of HA antigen that can be included in an adjuvanted vaccine that will be acceptably immunogenic when given in a two-dose schedule to a population.
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. Unlike registration of influenza vaccines in the United States, EU registration requires demonstration of safety and satisfactory serum anti-HA antibody responses for each company's vaccine (CPMP, 1997; Wood and Lewandowski, 2003)
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The EMEA has not published its own clinical development plan for a "mock-up" pandemic vaccine. However, the EVM Clinical Working Group, which represents all major European vaccine companies, has proposed a step-wise clinical development plan of its own.
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Over a period of 18 months, EMEA staff vaccine experts and European vaccine companies put together an integrated "roadmap" that outlines most of the steps for developing and registering a "mock-up" pandemic vaccine. Once a company obtains a marketing authorization for its core dossier, regulatory approval for a true pandemic vaccine can be quickly obtained.
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. These two dosages comply with FDA requirements for currently licensed influenza vaccines.
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The low-dose, adjuvanted pandemic vaccine strategy is central to the thinking of major influenza vaccine companies located outside the United States. The EMEA Vaccine Expert Group considers it the most promising approach for producing adequate supplies of pandemic vaccines.
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Largely for this reason, no commercially viable H5N1 seed strain for human vaccine production has yet been prepared using genetic reassortment. In the past few years, reference strains suitable for producing human H5N1 influenza vaccines have been prepared in several laboratories using the techniques of reverse genetics (RG)
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All would gain the practical experience needed to prepare them for pandemic vaccine production. However, most vaccine companies won't fund expensive clinical trials of vaccines that won't be marketed.
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Unless the public sector provides a framework for negotiations for RG-IP during interpandemic years, companies will not be prepared to produce pandemic vaccines using RG-engineered seed strains. Moreover, because IP issues are governed by national patent laws, the negotiating framework must be international.
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. Avian H5N1 influenza viruses are potent inducers of proinflammatory cytokines (TNF-alpha and interferon beta)
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For corporate manufacturers considering the commercial sale of pandemic influenza vaccines produced by reverse genetics, MedImmune, Inc., has sent out letters to all such manufacturers offering licenses to its intellectual property under reasonable terms. MedImmune, Inc., has made it clear to its commercial peers that it will waive royalties on its intellectual property for any and all
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From page 197... ...
This intellectual property landscape is relatively simple compared to the typically complex field of biotechnology, where experienced companies like the influenza vaccine manufacturers are used to securing multiple licenses for a single product. Thus, influenza vaccine manufacturers should face little difficulty in obtaining licenses to the relevant intellectual property, and may direct their resources instead toward obtaining regulatory approval for pandemic vaccines.
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From page 198... ...
Markedly increasing the quantity of available antiviral agents through mechanisms such as stockpiling, educating health care providers and the public and developing effective means of rapid distribution to those in need are essential in developing an effective response, but remain currently unresolved problems. Introduction This article provides personal perspectives on selected issues that are relevant to the use of antiviral drugs during the next influenza pandemic.
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From page 199... ...
Efficacy, tolerability, ease of administration and the potential for clinically important drug resistance are all factors that warrant consideration in selecting among the available agents. Data regarding use in pandemic influenza are only available with the M2 inhibitors, but extensive clinical testing of the neuraminidase inhibitors in interpandemic influenza permits reasonable conclusions regarding their efficacy.
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200 Formula Applicable Paediatric/ Liquid Yes Yes Yes Not oseltamivir. and of case Drug Diuretics the Stimulants, in Reported Reported Reported Adverse Interactions CNS Anticholinergics, Antihistamines, Certain Not Not Not interaction drug 70 Years Years Disease 50 65 10 65 30 potential as Dose Adjustments CC Age CC Age Hepatic CC No excretion Influenza renal for inhibits Agents Route Oral Oral Oral Inhalation Probenicid )
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. Such results would predict that the neuraminidase inhibitors would also be effective for prophylaxis of pandemic influenza.
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From page 202... ...
The antiviral and clinical benefits of early antiviral treatment have not been directly compared between an M2 and a neuraminidase inhibitor. Several large placebo-controlled, blinded studies have shown that treatment with either inhaled zanamivir or oral oseltamivir reduces illness duration, the time to resuming normal activities and the likelihood of physiciandiagnosed lower respiratory complications leading to antibiotic use in adults (Monto et al., 1999b; Kaiser et al., 2000; Treanor et al., 2000)
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. No age related adjustments are required for the neuraminidase inhibitors.
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204 Reversible Yes Yes Yes Yes Yes Yes Yes Agents Related Dose Yes Yes Yes Yes Yes No Yes Anti-Influenza During 15%) (5 Uncommon 30% 10% Available Frequency Treatment 10 Uncommon Common < Common Very Common Currently of Severity Mild-moderate Severe Mild Mild-moderate Mild Mild-severe Mild Profiles Reaction Reaction Drug Adverse CNS Gastrointestinal CNS Gastrointestinal Bronchospasm Gastrointestinal Adverse 3-4 TABLE Agent Amantadine Rimantadine Zanamivir Oseltamivir
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From page 205... ...
The clinical pharmacology and adverse drug effect profiles of the antivirals for influenza indicate that the neuraminidase inhibitors and rimantadine are preferable to amantadine with regard to the need for individual prescribing, tolerance monitoring and the seriousness of side-effects. When these findings are considered in the context of the available information about efficacy and antiviral resistance (discussed below)
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From page 206... ...
Primary resistance to the neuraminidase inhibitors has not been described at the enzyme level and these agents are active against all of the nine neuraminidase subtypes recognized in avian influenza viruses (reviewed in Gubareva et al., 2000; Tisdale, 2000)
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207 of 75% is Clinical Person nt to over to varia During Person Transmissibility Yes Unstudied Unstudied adults Recovered elderly in oseltamivir-resistant Animals Viruses Virulence in Wild-type Reduced Reduced 10% one ca.
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From page 208... ...
Such experiences highlight the potential for the emergence of amantadine-resistant influenza A viruses and spread under close contact conditions. Oseltamivir and Zanamivir The neuraminidase inhibitors appear to be associated with a lower frequency of resistance emergence due to neuraminidase mutations (reviewed in McKimm-Breschkin, 2000; Tisdale, 2000)
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. These observations indicate that antiviral resistance due to neuraminidase resistance appears to alter the fitness of influenza viruses and suggests that resistance will be much less likely to be a threat during drug use in epidemic or pandemic influenza.
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(1999) and assumptions regarding drug effectiveness derived from recent therapeutic trials with oseltamivir, preliminary assessment of the economic impact of using antivirals for treatment during an influenza pandemic are possible (Table 3-7)
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211 were years) mathemati- oseltamivir: illnesses (20-64 During with escribedd ,50% Paediatric studies years)
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Health plans and managed care organizations (MCOs) operate at the center of the private medical system.
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Health plans generally find that individual members attend to the topics that are discussed in mailings and in telephone campaigns. Given the proven capability of health plans and MCOs in outreach and education activities, public health agencies should consider them as potential partners in communicating with citizens during an influenza pandemic threat.
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In the past, however, there has been little incentive for health plans to participate in these projects. With the looming threat of an influenza pandemic, this worthwhile concept might well be revisited and meaningful incentives considered.
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From page 215... ...
This issue requires further study and understanding before positing any recommendations. Facilitating Delivery of Medical Services In many circumstances, health plans can most effectively facilitate the delivery of medical services during an influenza pandemic by removing obstacles.
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This precedent to respond quickly and productively in emergency situations will no doubt be replicated during an influenza pandemic. Whether educating their members, promoting immunization, waiving procedures, enhancing surge capacity, or ensuring access to antiviral medications, health plans will play an important role in the day-to-day management of the pandemic.
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From page 217... ...
2004. Chiron to Produce Further Pandemic-Like Influenza Vaccines for National Institutes of Health Clinical Studies.
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Ensuring an adequate global supply of influenza vaccine. Infect Dis News 4:13.
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2000. Resistance of influenza viruses to neuraminidase inhibitors -- a review.
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2000. Influenza vaccine -- a possible trigger of rhabdomyolysis induced acute renal failure due to the combined use of cerivastatin and bezafibrate.
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2004. Responsiveness to a pandemic alert: Use of reverse genetics for rapid development of influenza vaccines.
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