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Influenza remains global threat with limited treatment options
Influenza virus is a highly transmittable infectious disease. Its history reaches back as far as the 16th century, where it was first described in Italy in 1580. Since then, significant pandemics have plagued the world in the 19th, 20th and even 21st centuries. The “Spanish” influenza pandemic of 1918 claimed 20 million lives, including 500,000 in the United States within a 1-year period. This pandemic claimed more lives in a shorter period of time than any war or famine in the world. It was in 1936 that the influenza virus was first grown in embryonated hen eggs, leading to the development of influenza vaccine. It was not until the 1950s that the protective efficacy of inactivated influenza vaccine was seen in the public.
Public health continues to battle seasonal influenza and most recently had one of the most notable influenza pandemics. The 2009-2010 influenza season proved to be one of the most significant threats to public health caused by a new novel virus strain — influenza A(H1N1). It spread rapidly across the United States and the world. Novel H1N1 was first reported in mid-April, and by June, 18,000 cases had been reported in the United States; overall, 74 countries were affected. It was declared a public health emergency and pandemic.
Kimberly D.
Boeser
The H1N1 influenza pandemic resulted in more than 60 million infections among Americans, leading to 270,000 hospitalizations and 12,500 deaths. The 2012-2103 season also was noted to be one of the most severe. Deaths attributed to influenza and pneumonia exceeded the epidemic thresholds for 13 consecutive weeks of the viral season. From Dec. 30, 2012, to March 30, 2013 (weeks 1-13), the percentage of deaths peaked at 9.9% during week 3. This was an increase from the previous three influenza seasons, 2008-2011, which ranged from 7.9% to 9.1%. In general, influenza epidemics are associated with increased morbidity and mortality. It was estimated in a recent study that influenza epidemics contribute to 610,660 life-years lost, 3.1 million days of hospitalizations and 31.4 million outpatient visits.
Influenza treatments
The treatment mainstay for influenza continues to be neuraminidase inhibitors (NAIs). NAIs work by inhibiting the neuraminidase enzymes, which affects the release of viral particles, thereby reducing the circulating virus in the system. NAIs work against both influenza A and B strains. The two marketed products are oseltamivir (Tamiflu, Genentech) and zanamivir (Relenza, GlaxoSmithKline).
Rare cases of oseltamivir-resistant virus infection associated with the H275Y mutations have been reported, including in the United States. These agents also only cover influenza A strain. All four marketed agents are administered orally or by inhalation, often making this difficult in severely ill patients. The reliability of these agents has been questioned, such as the limited pulmonary absorption of inhaled zanamivir in an immunocompromised host; the unreliable bioavailability of oseltamivir via nasogastric tube; and when critically ill patients have decreased gastrointestinal motility.
M2 inhibitors (amantadine and rimantadine) are the other antiviral agents marketed to treat influenza infections, although resistance is notable in this class.
Investigational drug shows promise
Intravenous peramivir (BioCryst Pharmaceuticals), an NAI, is another agent in this class that is not yet widely available for treatment. Peramivir is an investigational antiviral agent that is intended for the treatment of influenza A and B in critically ill patients. It is approved in Japan and Korea but has yet to receive widespread approval. In 2006, BioCryst received US FDA fast track designation for peramivir. Additionally, BioCryst established agreements with partners to have stockpiling opportunities for countries outside of the United States; Merck Serono for Europe, Russia, Canada and Singapore, and Neopharm Group for Israel.
IV peramivir was used during the influenza A(H1N1) pandemic in 2009-2010, at which time the FDA issued an emergency use authorization (EUA) for peramivir for the treatment of certain hospitalized and critically ill adult patients with suspected or confirmed pandemic H1N1. The EUA for IV peramivir expired in June 2010.
Ison and colleagues reported in Clinical Infectious Diseases that approximately 1,274 patients received IV peramivir during the 2009-2010 pandemic. It was limited to use in those patients who had lack of response to other antivirals and could not receive oral or inhaled treatment. It was not recommended for use in patients with suspected oseltamivir-resistant influenza because of potential cross resistance.
The emergency investigational new drug application case series noted that IV peramivir’s use was primarily in the critically ill, and the pretreatment population did not receive treatment until late in the disease course. Although worse outcomes would be expected, given the circumstances for which IV peramivir was used during the EUA, further randomized controlled trials are needed to establish safety and efficacy. Peramivir is currently in phase 3 trials.
This digitally-colorized negative-stained transmission electron micograph
(TEM) depicted a number of influenza A virions.
Image: CDC
Before the EUA, approximately 1,891 clinical trial participants had received peramivir IV or intramuscularly. Phase 2 and 3 safety and efficacy data show significant effect of a single 300-mg or 600-mg IV dose of peramivir compared with placebo in adult patients with acute, uncomplicated influenza. Additionally, three phase 2 trials and one phase 3 trial demonstrated no statistically significant difference between peramivir IV and placebo or oseltamivir. One of these trials includes hospitalized patients.
IV peramivir would add to the arsenal for the treatment of epidemic or pandemic influenza, particularly in those patients in which oral access is not available or reliable or failure of other first-line treatments. Additionally, since the EUA, several reports have evaluated the safety and efficacy of IV peramivir for the treatment of influenza, although there were no formal mechanisms to collect outcomes data.
Future of influenza
Influenza has been in our communities for centuries. It continues to be a highly transmittable infectious disease with significant increase in morbidity and mortality. Although this infectious disease is preventable, we continue to face epidemics and pandemics in the 21st century. The two primary reasons include overall low vaccination rates and that the variability from year to year in the circulating viral strains will make this infectious disease difficult or impossible to be 100% preventable.
Arguably, the best way to face influenza is to increase our vaccination rates globally. Inevitably, influenza virus will continue to plague the global health and cause widespread disease with varying severity. Although our current treatment options (oseltamivir and zanamivir) are still effective, they both have their limitations. We have yet to have an IV product widely available for use. IV peramivir may be a potential option in the future.
References:
CDC. Influenza. Available at: www.cdc.gov/vaccines/pubs/pinkbook/flu.html. Accessed Oct. 15, 2013.
CDC. MMWR. 2013;62(RR-07):1-43.
Crosby AW Jr. Epidemic and Peace, 1918. Westport, Conn.: Greenwood Press; 1976:311.
FDA. Peramivir IV questions and answers for health care providers. Available at: www.
fda.gov/Drugs/DrugSafety/PostmarketDrug
SafetyInformationforPatientsandProviders
/ucm187980.htm. Last updated Aug. 27, 2013; Accessed Nov. 1, 2013.
Flu.gov. Pandemic flu history. Available at: www.flu.gov/pandemic/history. Accessed Oct. 15, 2013.
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Disclosure: Boeser reports no relevant financial disclosures.