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Introduction

In the last two decades, the public health community in the United States and internationally began to plan for the possibility of a severe influenza pandemic like that of 1918. The history of influenza viruses shows their potential to mutate or exchange genes with other influenza viruses (for example, a human or mammalian influenza virus and an avian influenza virus that are co-infecting a human or mammalian host). Such genetic reassortment could result in a novel viral strain of great virulence that is capable of efficient human-to-human transmission.

The use of antiviral medications is one of several strategies for mitigating an influenza pandemic that may extend for many months and through multiple waves. Although a well-matched vaccine would be the ideal way to prevent the spread of a pandemic strain, vaccine will likely not be available for several months after the beginning of the pandemic. To attempt to contain the pandemic and decrease mortality until a vaccine is available, the federal government, most states, and some localities plan to use antiviral medications for treatment, and if supplies permit, prophylaxis. The federal government strategy calls for the use of antiviral medications in conjunction with non-pharmaceutical interventions such as social distancing and curtailing or modifying school activities (depending on pandemic level of severity, as described in the Community Mitigation Strategy) (CDC, 2007a).

Two classes of antivirals are available to treat influenza: adamantanes,



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1 Introduction I n the last two decades, the public health community in the United States and internationally began to plan for the possibility of a severe influenza pandemic like that of 1918. The history of influenza viruses shows their potential to mutate or exchange genes with other influenza viruses (for example, a human or mammalian influenza virus and an avian influenza virus that are co-infecting a human or mammalian host). Such genetic reassortment could result in a novel viral strain of great viru- lence that is capable of efficient human-to-human transmission. The use of antiviral medications is one of several strategies for miti- gating an influenza pandemic that may extend for many months and through multiple waves. Although a well-matched vaccine would be the ideal way to prevent the spread of a pandemic strain, vaccine will likely not be available for several months after the beginning of the pandemic. To attempt to contain the pandemic and decrease mortality until a vac- cine is available, the federal government, most states, and some localities plan to use antiviral medications for treatment, and if supplies permit, prophylaxis. The federal government strategy calls for the use of antiviral medications in conjunction with non-pharmaceutical interventions such as social distancing and curtailing or modifying school activities (depend- ing on pandemic level of severity, as described in the Community Mitiga- tion Strategy) (CDC, 2007a). Two classes of antivirals are available to treat influenza: adamantanes, 

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 ANTIVIRALS FOR PANDEMIC INFLUENZA also known as M2 inhibitors, and neuraminidase inhibitors.1 The use of adamantanes is limited due both to their toxicity and the rapid develop- ment of viral resistance to this class of drugs. The neuraminidase inhibi- tors include oseltamivir and zanamivir. These were first approved by the Food and Drug Administration in 1999 for treatment of influenza in adults and oseltamivir also was approved for prevention in individuals 12 years of age and older. In 2005, oseltamivir was approved for preven- tion of influenza in children under age 12 but no younger than 1 year. In 2006, zanamivir was approved for prophylaxis in adults and children age 7 and older. Antiviral medications consisting largely of neuraminidase inhibitors are currently stockpiled by government at the federal, state, and local levels, and to a limited extent by the private sector, including some employers, health care organizations, and individuals. Public health agencies began thinking about and planning for mass dispensing of medications and administration of vaccine for a variety of public health emergencies in the 1990s, and with added intensity in late 2001. The public health community has considerable experience with plans and exercises focusing on the distribution and dispensing of antibiotics such as ciprofloxacin and doxycycline in response to deliberate dispersal of a pathogen such as the anthrax bacillus, cause of a non-transmissible disease. Until recently, somewhat less attention has been paid to antiviral dispensing for pandemic influenza, a public health emergency that would pose some different challenges. Single-point chemoprophylaxis after the deliberate dispersal of a pathogen would be fairly straightforward. The spread of pandemic influenza would require ongoing dispensing for dif- ferent purposes (i.e., treatment, post-exposure prophylaxis, or prophy- laxis for the duration of the outbreak), but supplies are unlikely to be adequate for all potential uses. Finally, unlike some types of pathogens (anthrax, brucellosis, tularemia), influenza is transmissible from person to person, and this has implications for the setting and mechanism used to dispense drugs. AREAS OF UNCERTAINTY AND EXISTING ASSUMPTIONS There are many unknowns about an influenza pandemic, including when and where a new pandemic strain will emerge, the pattern of its spread, the attack rate and the case-fatality rate, the segments of the popu- lation most affected by it, and so on. Furthermore, although neuramini- dase inhibitors have been proven to be effective in treating and preventing 1Although no other drugs are approved to treat or prevent influenza at the present time, ongoing research is supported by the Department of Health and Human Services on other antivirals (e.g., peramivir).

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 INTRODUCTION the spread of seasonal influenza, their effectiveness against a pandemic strain is unknown. It is also not known what potential the virus will have to develop resistance to the antivirals over the course of a pandemic. In the absence of clear answers to these and other questions, public health agencies at all levels have been making a number of assumptions in their pandemic planning. Some assumptions are based on a complete lack of information, while others are based on incomplete or inconclu- sive evidence; all will need to be revisited as more information and data become available. The Department of Health and Human Services (DHHS) Pandemic Influenza Plan (2005) assumes that: the pandemic will be moderate, treat- ment with neuraminidase inhibitors will decrease hospitalization by about half and will decrease mortality, resistance to M2 inhibitors may limit their use, the primary source of antivirals will be federal and state stockpiles, treatment will be most effective in the first 48 hours after disease onset, 35 percent of persons in priority groups (see Box 2-1) will have influenza-like illness and 75 percent of them will present in the first 48 hours, and 80 percent of those admitted to the hospital will be treated (relaxing the 48-hour limit in more ill patients). The DHHS draft Proposed Guidance on Antiviral Drug Use Strategies for an Influenza Pandemic,2 and the summary of that guidance3 (which slightly modifies the earlier document) describe some different and additional assumptions including the following: • The pandemic will be severe (level similar to the 1918 pandemic), with a 30 percent attack rate and 2 percent or greater mortality. • Community mitigation strategies (when used alone) will halve the attack rate and result in reduced hospitalization and mortality. • Antiviral effectiveness will be similar to that for seasonal influ- enza viruses. • Regimens of antiviral drug treatment and prophylaxis will be the same as those used for seasonal influenza. • An accurate point-of-care diagnostic test will not be available. • The positive predictive value of clinical diagnosis (in the absence of accurate point-of-care tests) will be approximately 35 percent.4 • Outbreak duration will be 12 weeks. 2 Dated November 20, 2007. 3 Dated November 6, 2007. 4 This means that 35 percent of cases clinically diagnosed as having influenza actually have the pandemic strain as opposed to seasonal influenza or a condition caused by one of several respiratory viruses.

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 ANTIVIRALS FOR PANDEMIC INFLUENZA • There will be no vaccine effect (due to uncertain timing and amount of vaccine). • Sixty percent of cases of influenza will be treated (within the first 48 hours after onset), and their household contacts will be pro- vided prophylaxis. The following assumptions concerning the pandemic and antiviral drugs set the context for the committee’s discussion of what is needed to effectively implement an antiviral drug program. 1. A severe pandemic (more so than one that is milder) will require a pre-existing ethical framework to guide decision making about prioritization, so that individual and societal interests and goals are effectively, efficiently, and fairly pursued. 2. Antivirals will be used in conjunction with non-pharmaceutical interventions for which the evidence of effectiveness currently is limited or unclear. 3. Resistance to neuraminidase inhibitors may weaken pandemic influenza response. 4. An increase in dosage and/or length of treatment and prophy- laxis (WHO, 2008) may be needed to ensure effectiveness (in the face of resistance and new epidemiologic information), and this will affect the supply of antivirals. 5. Public–private collaboration on a large scale (e.g., private employer antiviral stockpiling for dispensing to large enough groups to enhance flexibility in use of public-sector stockpiles) is unlikely, due to administrative constraints, fiscal limits, and other private-sector concerns about stockpiling. 6. Interjurisdictional coordination in regard to antiviral dispensing (and other aspects of pandemic response) is likely to be chal- lenged by known and unforeseen differences in local circum- stances and expectations. 7. Budget challenges, opportunity costs, and other cost–benefit con- siderations at the state level may affect some jurisdictions’ pur- chasing capability and willingness to stockpile antivirals at levels recommended by federal authorities (ASTHO, 2008). CHARGE TO THE COMMITTEE The Department of Health and Human Services has embarked on a process of stockpiling antivirals for distribution and dispensing as part of a larger and multi-dimensional process of planning for pandemic influ- enza. The committee was asked to advise DHHS on best practices and

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 INTRODUCTION BOX 1-1 Statement of Task An Institute of Medicine committee would plan and convene a workshop of state and local pandemic influenza planners, as well as national and relevant international influenza experts, to consider best practices and policies for imple- menting a pandemic influenza antiviral drug program. Components of the program to be addressed include treatment of cases, post-exposure prophylaxis for their household contacts, and prophylaxis of “front-line” health care workers and emer- gency services personnel. With respect to treatment of cases and post-exposure prophylaxis of their household contacts, key planning issues include, but are not limited to, determining where drugs are dispensed; allocation and distribution of drugs to those sites; diagnostic approach for cases; strategy to enumerate house- hold contacts and assess appropriateness of dispensing drugs for them; potential regulatory barriers to dispensing; and monitoring antiviral drug use and safety. With respect to prophylaxis for targeted health care and emergency services personnel, key issues include, but are not limited to, determining where drugs are dispensed; potential regulatory barriers to dispensing; labor issues that may arise from target- ing some workers, but not others; and monitoring antiviral drug use and safety. The committee will review current state plans and lessons learned from drills and exercises, and will explore the challenges and barriers to rapid and efficient distri- bution of the drugs for treatment and prophylaxis in the general population and in targeted occupationally defined groups. The committee will issue a brief report with conclusions and recommendations regarding components of an effective antiviral program for patients and their household contacts and for prophylaxis of health care and emergency services personnel. policies for implementing an antiviral drug program, focusing on three key components (see Box 1-1): • Treatment of cases • Post-exposure prophylaxis for their household contacts • Prophylaxis of “front-line” health care workers and emergency services personnel Accordingly, this report does not discuss issues related to the admin- istration of vaccines or other components of pandemic planning. The report also does not comment in detail on the organization or movement of antiviral supplies at the proximal end of the distribution chain, namely, the Strategic National Stockpile and state stockpiles. Rather the report focuses on the distal end of the distribution chain, i.e., where antivirals are

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 ANTIVIRALS FOR PANDEMIC INFLUENZA placed in the hands of individuals for treatment or for prophylaxis.5 In this report, the word antivirals refers to (unless otherwise stated) oseltamivir and zanamivir, the main antiviral medications in the federal government stockpile. The report does not comment on the reasoning for stockpiling a certain ratio of one drug to the other, or examine the research on devel- opment of new neuraminidase inhibitors or other classes of antivirals, or on the use of antivirals and/or other drugs in combination to treat or prevent influenza. Further, the committee has not been asked to and does not address what the potential need for prophylaxis for key deci- sion makers and critical infrastructure workers such as those responsible for supporting or maintaining various components of public utilities (see DHHS, 2005); additional antiviral supplies would be needed for those groups if there are prophylaxis goals that include them. Finally, although the committee acknowledges the global effect of an influenza pandemic and the need for antiviral medications outside the United States, these important and challenging issues are beyond the committee’s charge and require separate and in-depth treatment elsewhere. In the second chapter of this report, the committee reviews informa- tion related to the effectiveness and safety of antivirals, and some issues pertaining to the available and projected supply of antivirals. In the third chapter, the committee discusses and makes recommendations about three interrelated topics including (1) the ethical principles and goals to be considered for prioritizing scarce resources, (2) a mechanism for deci- sion making that includes real-time input of data and information needed to assess and change the course of pandemic response, including antiviral dispensing strategies, and (3) several areas of communication related to antivirals that will require attention before and during the pandemic. Study Process During the course of this 4-month study, the committee gathered information to address its charge through a variety of means (commit- tee biographies can be found in Appendix E). It held two information- gathering meetings that were open to the public. The first meeting included a presentation from the sponsor and presentations on influenza antiviral effectiveness and resistance, stockpiling and distribution planning from the Centers for Disease Control and Prevention, related legal issues, and 5 The committee notes that the terms distribution (referring to the movement of drugs, e.g., from a central location to another site) and dispensing (referring to the delivery of drugs to the patient or family member of patient) are sometimes used interchangeably outside certain circles. Strict use of the terms could lead to more confusion. Although the commit- tee generally refers to the act of giving out medication as dispensing, the term distribution is used sometimes.

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 INTRODUCTION diagnosis of influenza. The second meeting focused on learning more about influenza antivirals and their use (effectiveness, resistance, surveil- lance), modeling of antiviral resistance, and distribution and dispensing planning from the perspective of state public health agencies. At that meeting the committee received information on the following topics: les- sons from experience with large-scale distribution/dispensing of drugs or administration of vaccine; decision analysis for antiviral distribution; telephone and web-based decision support and triage; antiviral stockpile planning from the perspectives of the private and public sectors, and in a publicly funded and a private health care system; and ethical principles in planning for the distribution and dispensing of antiviral medication. The complete agendas for both meetings can be found in Appendixes C and D. The committee met in executive sessions for deliberative discus- sions following both information-gathering meetings. Additionally, the committee held weekly conference calls to discuss report findings and to formulate recommendations. A website (http://www.iom.edu/antivirals/) and listserv were cre- ated to provide information to the public about the committee’s work and to facilitate communication with the committee. Many of the slide presentations and audio files from both information-gathering meetings are available in electronic format on the website. The committee also received public submissions of material for its consideration at meetings and by mail and e-mail throughout the course of the study. These may be viewed in the project public access file.6 6A listof materials reviewed by the committee (in the form in which they were reviewed) including all submissions of information from the public and many items not cited in this report, can be found in the study’s public access file, obtained from the National Academies Public Access Records Office at (202) 334-3543 or http://www8.nationalacademies.org/cp/ ManageRequest.aspx?key=48872.

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