Antiviral drugs for the control of pandemic influenza virus

Peramivir efficacy is based on clinical trials versus placebo in which the predominant influenza virus type was influenza A; in one trial, a very limited number of subjects infected with influenza B virus were enrolled. On November 23, , FDA approved baloxavir for post-exposure prophylaxis of influenza in persons aged 12 years and older. The safety and efficacy of baloxavir for the treatment of influenza have been established in pediatric patients 12 years and older weighing at least 40 kg..

Baloxavir efficacy for initial FDA approval in October was based on clinical trials in previously healthy outpatients 12 to 64 years old Hayden, external icon. Single-dose baloxavir treatment was superior to placebo and had similar clinical efficacy in time to alleviation of symptoms to a 5-day treatment course of oseltamivir.

In October , FDA approved an indication for baloxavir treatment of acute uncomplicated influenza within 2 days of illness onset in people 12 years and older at high risk of developing influenza-related complications, based upon the findings of a clinical trial Ison, external icon ; Baloxavir marboxil Xofluza pdf icon [package insert] external icon. Food and Drug Administration website; In this clinical trial of early initiation of antiviral treatment for uncomplicated influenza in high-risk patients, baloxavir was superior to placebo and had similar overall efficacy to oseltamivir in the time to alleviation of symptoms.

For patients with influenza B virus infection, baloxavir significantly reduced the median time to improvement of symptoms compared with oseltamivir by more than 24 hours. However, there are no available data for baloxavir treatment of influenza in pregnant women, immunocompromised people, or in people with severe influenza. There are no available data from clinical trials for baloxavir treatment of hospitalized patients with influenza. Figure: Guide for considering influenza testing and treatment when influenza viruses are circulating in the community regardless of influenza vaccination history 1.

Complete footnotes for this algorithm are available. Because many children with mild febrile respiratory illness might have other viral infections e.

Treatment of patients with severe influenza e. The effect of specific antiviral strategies in serious or life-threatening influenza is not established from clinical trials conducted to support licensure of oral oseltamivir, inhaled zanamivir, intravenous peramivir, or oral baloxavir, as those studies were conducted primarily among previously healthy outpatients with uncomplicated illness.

No randomized, placebo-controlled clinical trials have been conducted of neuraminidase inhibitors for treatment of influenza in hospitalized patients.

However, a number of observational studies in hospitalized influenza patients have shown clinical benefit of neuraminidase inhibitor antiviral treatment compared with no treatment, particularly when started within two days of influenza illness, including reducing the duration of hospitalization or risk of death Hiba, external icon ; Coffin, external icon ; Hsu, external icon ; Louie, external icon ; Muthuri, external icon ; Muthuri, external icon ; Miyakawa, external icon ; Lytras, external icon ; Katzen, ; external icon Reacher, external icon.

In addition, some observational studies have reported that oral oseltamivir treatment started 4 and 5 days after illness onset in patients hospitalized with suspected or confirmed influenza was associated with lower risk for severe outcomes EH Lee, external icon ; N Lee, external icon ; N Lee, external icon ; Louie, external icon ; McGeer, external icon ; Siston, external icon , although one report found this benefit only in hospitalized adult patients in the ICU Muthuri, external icon.

A small number of observational studies and one meta-analysis of observational studies of hospitalized influenza patients reported that neuraminidase inhibitor treatment did not have survival benefit Choi, external icon ; Wolkewitz, external icon ; Heneghan, external icon.

The following recommendations do not necessarily represent FDA-approved uses of antiviral products but are based on published observational studies and expert opinion and are subject to change as the developmental status of investigational products and the epidemiologic and virologic features of influenza change over time. Although not part of the FDA-approved indications, use of oral oseltamivir for treatment of influenza in infants less than 14 days old, and for chemoprophylaxis in infants 3 months to 1 year of age, is recommended by the CDC and the American Academy of Pediatrics Committee on Infectious Diseases, external icon.

The American Academy of Pediatrics has recommended an oseltamivir treatment dose of 3. It is unknown whether this higher dose will improve efficacy or prevent the development of antiviral resistance. However, there is no evidence that the 3. Premature infants might have slower clearance of oral oseltamivir because of immature renal function, and doses recommended for full-term infants might lead to very high drug concentrations in this age group.

Daily dosing for a minimum of 5 days was used in clinical trials of hospitalized patients with influenza de Jong, external icon , Ison, external icon. Baloxavir marboxil Xofluza pdf icon [package insert] external icon. Baloxavir marboxil should not be administered with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids or oral supplements e.

There are no available published data from clinical trials for baloxavir treatment of influenza in patients who are pregnant, immunocompromised, have severe disease, or in hospitalized patients. A randomized clinical trial external icon of baloxavir treatment of influenza in hospitalized patients 12 years and older is in-progress. Oseltamivir is not recommended for patients with ESRD not undergoing dialysis.

The recommended doses are detailed in Table 3; duration of treatment and chemoprophylaxis is the same as recommended for patients with normal renal function. No dose adjustment is recommended for inhaled zanamivir for a 5-day course of treatment for patients with renal impairment.

The effects of severe renal impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite, baloxavir, have not been evaluated. Treatment can be initiated immediately if influenza symptoms develop during the 48 hours between hemodialysis sessions; however, the post-hemodialysis dose should still be administered independently of time of administration of the initial dose.

Clinicians should contact their local or state health department for information about current local influenza activity. To receive weekly email updates about Seasonal Flu, enter your email address:. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Influenza Flu. Section Navigation. Facebook Twitter LinkedIn Syndicate. Influenza Antiviral Medications: Summary for Clinicians.

Minus Related Pages. Priority Groups for Antiviral Treatment of Influenza Antiviral treatment is recommended as soon as possible for any patient with suspected or confirmed influenza who: is hospitalized ; has severe, complicated, or progressive illness; or is at higher risk for influenza complications.

Antiviral Drug Options For hospitalized patients with suspected or confirmed influenza, initiation of antiviral treatment with oral or enterically-administered oseltamivir is recommended as soon as possible. For outpatients with complications or progressive disease and suspected or confirmed influenza e. For outpatients with suspected or confirmed uncomplicated influenza, oral oseltamivir, inhaled zanamivir, intravenous peramivir, or oral baloxavir may be used for treatment, depending upon approved age groups and contraindications.

In one randomized controlled trial, baloxavir had greater efficacy than oseltamivir in adolescents and adults with influenza B virus infection Ison, external icon. Co-circulation of Influenza Viruses and SARS-CoV-2 During periods of community co-circulation of influenza viruses and SARS-CoV-2, empiric antiviral treatment of influenza is recommended as soon as possible for the following priority groups: a hospitalized patients with respiratory illness; b outpatients with severe, complicated, or progressive respiratory illness; and c outpatients at higher risk for influenza complications who present with any acute respiratory illness symptoms with or without fever.

Forgot your password? Get help. Create an account. Review Article Vol. V37N6p 15 June View Citing Articles. Antiviral drugs do not eliminate the risk of complications. Some complications can be life-threatening. There have been reports of people with other types of infections that got worse because they were treated only for influenza and not for the other infections. Influenza viruses can become resistant to specific anti-influenza antiviral drugs, and all of these drugs have side effects.

If you experience new symptoms during treatment or your symptoms persist or get worse during treatment, see your health care professional. For more information and public health recommendations about circulating influenza virus, including resistance patterns for specific drugs, go to Flu.

There are four FDA-approved influenza antiviral drugs recommended by CDC for use against recently circulating influenza viruses.

Two older drugs, amantadine generic and rimantadine Flumadine and generic historically have been approved for treatment and prevention of influenza A virus infection. But many strains of influenza virus, including the H1N1 influenza virus, are now resistant to these drugs.

CDC has not recommended the use of amantadine and rimantadine for recently circulating influenza viruses, although recommendations could change if there were future re-emergence of specific virus strains with susceptibility patterns favoring such use. If these drugs, used prophylactically or for treatment, are effective in reducing transmission of the next pandemic strain, they should provide benefits by reducing the number of infected patients and delaying transmission, even if resistant strains ultimately become widespread.

Note that table entries are inflated by a factor of 10 9 for readability. We thank C. Mills, I. Longini, A. Demma, and R. Hatchett for helpful comments on a previous draft. ML and BRL designed the study and analyzed the data, following conversations involving all four authors.

All authors contributed to writing the paper. Abstract Background The response to the next influenza pandemic will likely include extensive use of antiviral drugs mainly oseltamivir , combined with other transmission-reducing measures.

Methods and Findings We designed and analyzed a deterministic compartmental model of the transmission of oseltamivir-sensitive and -resistant influenza infections during a pandemic.

Conclusions The benefits of antiviral drug use to control an influenza pandemic may be reduced, although not completely offset, by drug resistance in the virus. Abbreviations: NI, neuraminidase inhibitor. Editors' Summary Background. Why Was This Study Done? What Did the Researchers Do and Find? What Do These Findings Mean? Additional Information. Introduction Antiviral drugs, especially the neuraminidase inhibitor NI oseltamivir, play a major role in plans to mitigate the next influenza pandemic [ 1 , 2 ].

Methods Here we describe a homogeneous population model of pandemic influenza and its control by prophylaxis and treatment. Download: PPT. Modeling Low Probabilities of Resistance Emergence Because we are using a continuous model to evaluate scenarios with a very low probability that resistance will emerge c p and c T , it is important to ensure that we do not generate artifacts by creating a fraction of a resistant case and then allowing that fraction of a case to transmit.

This is readily accommodated by incorporating an indicator variable Model equations are: Baseline parameter values used, and their justifications, are given in Table 1. Age-Structured Model The extent to which individual humans transmit influenza is related to a variety of factors, many of which depend on age.

Treatment and Prophylaxis We initially considered the effects of treatment and prophylaxis separately and together; these results are shown in Figure 2. Figure 2. Results Effects of Treatment and Prophylaxis on Resistance We initially assumed that resistant strains emerge de novo in 0. Effects of Antiviral Use on the Size of the Epidemic In what follows, we considered the effect of treating a specified fraction of infectious cases while also prophylaxing the same fraction of contacts of infectious cases see Methods.

Figure 3. Figure 4. Effects of Nondrug Interventions The four curves in each graph of Figure 3 can represent either different basic reproductive numbers for the sensitive strain reflecting viral properties and population contact patterns or, equivalently, varying levels of nondrug interventions lower R E corresponding to more-effective nondrug interventions. Effects of Resistance on Epidemic Size Significant spread of a resistant strain partially compromises the benefits of antiviral use Figure 3 A.

Dependence of Outcomes on Fitness Cost and Intensity of Control Overall, the benefit of antiviral use in the model depends strongly on the fitness of the resistant strain and on the intensity of control measures. Discussion In the absence of a resistant strain, our model, like others before it, predicts that use of an effective antiviral drug combined with other effective measures to reduce transmission could reduce the size of a pandemic and delay its onset, buying valuable time for vaccine production.

Supporting Information. Protocol S1. Table S1. Acknowledgments We thank C. Author Contributions ML and BRL designed the study and analyzed the data, following conversations involving all four authors. References 1. Washington D. Accessed 7 December Am J Epidemiol — View Article Google Scholar 4. Nature — View Article Google Scholar 5. View Article Google Scholar 6. Yang Y, Longini IM, Halloran ME Design and evaluation of prophylactic interventions using infectious disease incidence data from close contact groups.

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