Public Health Lessons for Non-Vaccine Influenza Interventions Looking Past COVID-19 (2022) / Chapter Skim
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5 Therapeutics
5 Therapeutics
Pages 125-154
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From page 125... ...
While early treatment of influenza viruses can both prevent the spread of infection to close contacts and shorten symptom duration, pharmacotherapy for respiratory viruses has otherwise largely been unsuccessful (Villamagna et al., 2020)
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From page 126... ...
. This chapter examines the role that therapeutics can play in mitigating the impact of future respiratory virus outbreaks, particularly influenza, drawing on lessons learned during the COVID-19 pandemic in the research, scale up, and use of therapeutic resources.
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FINDINGS, OPPORTUNITIES, AND CHALLENGES IN THE USE OF THERAPEUTIC RESOURCES DURING OUTBREAKS This section explores the landscape of evidence, opportunities, and challenges related to the use of therapeutics during the COVID-19 pandemic and considers their potential applications to seasonal and pandemic influenza outbreaks. For the purposes of this study, the committee has defined therapeutics as the actual medications (both those directed against the virus itself and those needed to address associated symptoms and complications)
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From page 128... ...
During the COVID-19 pandemic, equity issues have been exacerbated as some higher-income countries -- which already had greater access to pharmaceutical products -- have hoarded medical supplies and halted the export of critical medical products to conserve them for domestic use (Burry et al., 2020)
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From page 129... ...
This austere environment and incredible burden on health care workers led to more than a decade of work on crisis standards of care. Institute of Medicine reports from 2012 and 2013 outline a systems framework for crisis standards of care and indicators and triggers to guide health care systems at all levels for use during disasters when needed, grounded in ethical and legal principles (IOM, 2012, 2013)
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From page 130... ...
These strategies warrant difficult decisions about when and why to use scarce therapeutic resources for particular patients. However, alternative approaches may not be as safe, tolerable, or effective.
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. Stockpiling critical medical supplies allowed countries to meet demand on health systems to an extent during the pandemic, from national to facility levels, but most countries still appeared to be inadequately prepared to quickly scale up therapeutic resources during demand surges.
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However, the absence of an assistance mechanism for therapeutic shortages leaves countries unprepared to proactively anticipate and evaluate the efforts required to respond to pandemics rapidly and nimbly. THERAPEUTICS PREVIOUSLY USED FOR INFLUENZA AND THOSE TRIALED IN COVID-19 WITH POTENTIAL APPLICATIONS TO PANDEMIC INFLUENZA The COVID-19 pandemic has highlighted the dearth of knowledge and limited evidence base about treatments for severe viral respiratory infections in general.
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From page 133... ...
outcomes of mono- versus favipiravir (viral RNA-dependent RNA combination therapies on polymerase selective inhibitor) different strains of influenza • Need to further investigate additional broad-spectrum inhibitors of the RNA polymerase enzyme common to both COVID-19 and influenza • Need to explore the impact of host factors on replication of coronaviruses and influenza viruses Monoclonal Used for COVID-19 • Limited evidence of clinical antibody bamlanivimab benefit in COVID-19 patients if (mAb)
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From page 134... ...
in patients with moderate to severe COVID-19 treated with corticosteroids, but limited data on influenza • Need further data to substantiate the potential to reduce host inflammatory response in patients with severe COVID-19 and influenza both with and without cytokine inhibitors Cytokine Tocilizumab • Both agents currently inhibitors Baricitinib recommended by NIH in hospitalized, hypoxic COVID patients with rapid worsening of oxygenation and/or inflammation • Effectiveness data limited for severe COVID cases, particularly patients requiring mechanical ventilation • Case report evidence of effectiveness of tocilizumab in influenza among a small number of patients taking it for other conditions, but otherwise insufficient or no data on use of either medication in influenza Combination Antibiotic agents added to antivirals • Limited to no evidence of treatments for clinical benefit for empirically coinfection treating COVID-19 patients and secondary with antibiotics to prevent infections secondary infections • Studies of the prevalence of risk factors for bacterial coinfections and secondary infections in COVID-19 patients ongoing and would need to be performed for any novel pathogen
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From page 135... ...
Studies during the COVID-19 pandemic explored antiviral agents with activity against SARS-CoV-2 and the impact of combination therapies on clinical outcomes and opportunities for dose sparing; these research efforts could inform therapeutic regimens for influenza. Remdesivir was found to decrease the time to recovery in hospitalized patients with COVID-19 (Beigel et al., 2020)
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Corticosteroid Treatments Systemic corticosteroids have been used to treat patients with severe COVID-19 who develop a systemic inflammatory response; they can also be used for influenza. A prospective meta-analysis of clinical trials investi
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. A different systematic review found that tocilizumab has evidence of moderate certainty that it may reduce the likelihood that hospitalized patients will need mechanical ventilation, although it was not associated with a lower risk of short-term mortality (Tleyjeh et al., 2021)
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From page 138... ...
Potential for Therapeutics to Mitigate Transmission In addition to mitigating the impact of a disease, therapeutics may reduce the risk of transmitting it to close contacts -- particularly if the respiratory pathogen is thought to have a high secondary attack rate, such as SARS-CoV-2. If antiviral drugs are administered early enough after the onset of symptoms, they may reduce viral shedding in the respiratory secretions and thus the risk that contacts may become infected (Mitjà and Clotet, 2020)
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From page 139... ...
. Limited evidence from clinical trials suggests that some of these repurposed therapeutics may have benefit against COVID-19, but their safety and efficacy is not yet well established; phase III clinical trials are ongoing for certain agents, including remdesivir and favipiravir (Pagliano et al., 2021)
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Limitations of Randomized Controlled Trials and Advantages of Adaptive Trial Design The COVID-19 pandemic has exposed fundamental flaws in current clinical trial research systems and incentive structures. Due to the design of RCTs, they can be poorly suited to evaluating complex treatment and subgroup interactions.
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From page 141... ...
For instance, the COVID-19 pandemic has demonstrated the feasibility and value of adaptive platform trials with master protocols used worldwide. An adaptive design approach can contribute to greater efficiency in a clinical trial -- thus accelerating the development process for a therapeutic -- by adjusting an ongoing trial's design and objectives based on interim results (see Box 5-1)
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. Additionally, the lack of coordination in developing innovative research protocols has led to inefficiencies and inadequacies in many of the COVID-19 clinical trials conducted.
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Such partnerships can facilitate international cooperation, boost regulatory agility, and serve as platforms for sharing information on product development, clinical trials, and supply chain issues (Bolislis et al., 2021)
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; • Secure sources that can reliably supply all items needed during an influenza pandemic; and • Assess, and establish where possible, local production capabili ties for all such items. Pandemic Response Conclusion: COVID-19 demonstrated the need for a framework to guide distribution of scarce and/or novel therapeutic resources in the most rational and equitable way.
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From page 145... ...
The frame work should identify: • Who will evaluate guidance from global and national health organizations and from professional societies in order to define evidence-based treatment guidelines; • How guidelines for treatment selection and delivery will be communicated to health agencies in the country's states/prov inces/regions and to frontline health care facilities, with a focus on avoiding the use of non-evidence-based therapeutics outside of clinical trials; • How suitable places to administer care will be selected, with consideration of options that provide alternatives for care deliv ery outside of already overwhelmed health facilities and primary care clinics; • Which populations should be the focus for therapeutic delivery with scarce resource availability (e.g., prevention in those not yet infected, versus treatment of those who are mildly or criti cally ill) , who will make those determinations, and how com munity interests will be incorporated; and • How to distribute a treatment modality equitably throughout the country and among patients including when health systems have moved to crisis standards of care because the available resources have become inadequate to meet the needs of all patients.
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From page 146... ...
Conclusion: Open repositories, which include negative research results, need to be maintained to house these efforts, in order to identify public health measures of prevention and assessment and to ensure resources are effectively used rather than used for repeated assessment studies. Conclusion: COVID-19 has shown the necessity of ongoing research focused on treatment of both existing and novel respiratory viruses, including those that cause seasonal and pandemic influenza, and has highlighted the success of collaborative efforts and innovative part nerships.
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Recommendation 5-4: Intergovernmental organizations, government agencies, foundations, pharmaceutical and biotechnology companies, universities, and research institutes should focus their efforts on re search strategies and platforms that were shown to be particularly effective during the COVID-19 pandemic: screening potential antiviral drugs for safety and efficacy; evaluating therapeutic approaches that target host responses in addition to the viruses themselves; developing and maintaining national and international research collaboratives; and building the capacity for rapid adaptive therapeutic evaluation during a pandemic to inform evidence-based treatment guidelines. REFERENCES Afshinnekoo, E., C
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From page 148... ...
2020. At the epicenter of COVID-19 -- the tragic failure of the global supply chain for medical supplies.
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2021. Randomised controlled trials for COVID-19: Evaluation of optimal randomisation meth odologies -- need for data validation of the completed trials and to improve ongoing and future randomised trial designs.
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2021. Can adaptive clinical trials help to solve the productivity crisis of the pharmaceutical industry?
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2021b. The security of America's medical product supply chain: Considerations for critical drugs and devices: Proceedings of a workshop -- in brief.
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2021. Repurposed antiviral drugs for COVID-19 -- interim WHO Solidarity trial results.
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2021. Repurposed antiviral drugs for COVID-19 -- interim WHO Solidarity trial results.
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