Of three new studies on the effectiveness of antivirals in preventing and treating influenza, two find that the drugs may shorten hospital stays and decrease the risk of infection in those at high risk for severe illness, and one concludes that timely initiation reduces the risk of death from flu-related pneumonia.
Effect on hospital stay, risk of infection
For the first of two World Health Organization (WHO)-funded studies published last week in The Lancet, a Lanzhou University (China)-led research team conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) on the treatment of hospitalized patients with seasonal flu or zoonotic flu (spread between people and animals) published up to September 20, 2023. The trials compared the effects of the direct-acting flu antivirals on death rates and length of hospital stay with placebo, standard care, or other antivirals.
These findings primarily highlight the uncertainty regarding effects of antivirals for treatment of patients with severe influenza but do provide some justification for their use.
The eight trials included in the systematic review involved 1,424 participants with an average age of 36 to 60 years, 79% to 100% of whom had confirmed flu. Six of the trials were included in the meta-analysis. The studied drugs were oseltamivir (brand name, Tamiflu), peramivir (Rapivab), zanamivir (Relenza), rimantadine (Flumadine), zanamivir plus rimantadine, and baloxavir (Xofluza) plus neuraminidase inhibitors (oseltamivir, zanamivir, or peramivir).
"Hospitalised patients with seasonal influenza can develop complications, including severe pneumonia, respiratory failure, multi-organ failure, and secondary bacterial infections, that can lead to death," the researchers wrote. "Therefore, identifying effective therapies for severe influenza is of global public health importance."
The effects of the use of oseltamivir, peramivir, or zanamivir relative to placebo or standard care for the treatment of seasonal and zoonotic flu on death were very uncertain. Similarly, the strength of evidence that oseltamivir or peramivir shortened hospital stays for seasonal flu was low (average difference, –1.63 and –1.73 days, respectively).
Compared with standard care, there was little or no difference in time to symptom relief with oseltamivir (0.34 days) or peramivir (–0.05 day), both with low-certainty evidence. The rate of adverse events or serious adverse events with oseltamivir, peramivir, and zanamivir were comparable (very low certainty).
The researchers said that oseltamivir or peramivir may shorten hospital stays but that uncertainty is high regarding the effects of oseltamivir, peramivir, or zanamivir on admission to an intensive care unit (ICU) and death from severe seasonal or zoonotic flu.
"The effects of all antivirals on mortality and other important patient outcomes are very uncertain due to scarce data from randomised controlled trials," the authors wrote. "These findings primarily highlight the uncertainty regarding effects of antivirals for treatment of patients with severe influenza but do provide some justification for their use. More clinical trials of antivirals are needed to inform the clinical benefit, safety, and effects on antiviral resistance in patients with severe influenza."
The systematic review provided the evidence base for updated WHO clinical recommendations on the use of antivirals to treat severe flu.
Role in preventing seasonal, zoonotic flu
The second systematic review and meta-analysis, conducted by the same research team to support updated WHO flu guidelines, assessed the use of neuraminidase inhibitors for post-exposure prophylaxis, or prevention (PEP) for seasonal and zoonotic flu in RCTs published up to September 20, 2023.
The study included 33 trials of the antivirals zanamivir, oseltamivir, laninamivir (Inavir), baloxavir, amantadine (Symmetrel), and rimantadine that enrolled 19,096 participants total with an average age of 7 to 81 years.
"Although previous systematic reviews have found that antivirals (oseltamivir or zanamivir) are effective in preventing symptomatic influenza, these reviews assessed selected antivirals and did not rate the quality of evidence or consider the importance of effects in their interpretation," the study authors noted. "Additionally, a randomised controlled trial of baloxavir for influenza post-exposure prophylaxis was not included in previous reviews."
The researchers concluded that post-exposure use of zanamivir, oseltamivir, laninamivir, and baloxavir probably reduces symptomatic flu rates in patients at high risk for severe illness (zanamivir risk ratio, 0.35; oseltamivir, 0.40; laninamivir, 0.43; baloxavir, 0·43; moderate certainty) when given within 48 hours after exposure to seasonal flu.
These antivirals, however, probably don't appreciably reduce rates of symptomatic flu in patients at low risk of severe flu when given soon after exposure (moderate certainty), they said. Prompt administration of zanamivir, oseltamivir, laninamivir, or baloxavir may lessen symptomatic zoonotic flu in people exposed to novel influenza A viruses tied to severe infection (low certainty).
Oseltamivir, laninamivir, baloxavir, and amantadine likely lower the risk of symptomatic and asymptomatic infection (moderate certainty), but zanamivir, oseltamivir, laninamivir, and baloxavir probably don't do much—if anything—to prevent asymptomatic flu or reduce all-cause death rates (high or moderate certainty).
Oseltamivir likely has little or no effect on hospitalization rates (moderate certainty), and none of the studied antivirals significantly raise the incidence of drug-related adverse events or serious adverse events (varied strength of evidence).
The findings "support use of zanamivir, oseltamivir, laninamivir, or baloxavir for post-exposure prophylaxis of seasonal influenza in individuals at high risk of severe influenza, and also provide some support for the use of these antivirals for post-exposure prophylaxis of zoonotic influenza," but "do not support using these antivirals among low-risk populations for post-exposure prophylaxis of seasonal influenza and do not support the use of amantadine or rimantadine for preventing symptomatic influenza A virus infection," the researchers concluded.
Ongoing trials may soon provide answers
In a related commentary on both Lancet studies, David Hui, MBBS, MD, of the Chinese University of Hong Kong, said many knowledge gaps remain on the role of antivirals in the prevention and treatment of flu.
"More randomised controlled trial data are needed on antiviral treatment of patients with non-severe or severe zoonotic disease, the role of combination antiviral treatment and immunomodulators for severe seasonal or zoonotic influenza, and post-exposure prophylaxis dosing of different neuraminidase inhibitors or baloxavir against zoonotic influenza," he wrote.
"Ongoing and large-scale multicentre randomised controlled trials such as the REMAP-CAP12 and the RECOVERY trial platforms might provide answers to some of these gaps in the near future."
Delayed antiviral therapy tied to poor pneumonia outcomes
For the third study, published last week in Clinical Infectious Diseases, a US Centers for Disease Control and Prevention (CDC)-led research team assessed the risk of death among 26,233 hospitalized adult flu patients in the CDC's multistate Influenza Hospitalization Surveillance Network (FluSurv-NET) and a diagnosis of pneumonia at hospital release over the 2012 through 2019 flu seasons. Nearly all patients (99.7%) were given oseltamivir.
The team assessed the three treatment groups based on the initiation of antivirals after admission (day 0 [60.9%], day 1 [29.5%], and days 2 to 5 [9.7%]) and used logistic regression models to evaluate the link between delayed treatment and all-cause death at 30 days. Median age was 71 years, and 92.2% had a chronic condition that didn't affect their immune system.
"While most U.S. adults hospitalized with laboratory-confirmed influenza receive antiviral treatment, timing of initiation may vary based on when a patient seeks care after illness onset, availability of influenza test results, and clinical suspicion for influenza, among other factors," the investigators wrote.
In total, 29.1% of patients were admitted to an ICU, 13.1% required invasive mechanical ventilation (IMV), and 8.0% died within 30 days. The percentage of patients who experienced each severe outcome rose with each additional day from admission to treatment initiation.
Delayed initiation of antiviral treatment in patients hospitalized with influenza-associated pneumonia was associated with higher risk of death, highlighting the importance of timely initiation of antiviral treatment at admission.
Relative to those who started an antiviral on day 0, those starting on day 5 were much more likely to be admitted to an ICU (58.5% vs 26.6%), receive IMV (40.2% vs 11.7%), or die within 30 days (19.5% vs 7.5%).
Death by 30 days occurred in 7.5%, 8.5%, and 10.2% of patients who began taking antivirals on days 0, 1, and 2 to 5, respectively. Compared to those treated on day 0, the adjusted odds ratio for those who started antivirals on day 1 and on days 2 to 5 were 1.14 and 1.40, respectively.
"Delayed initiation of antiviral treatment in patients hospitalized with influenza-associated pneumonia was associated with higher risk of death, highlighting the importance of timely initiation of antiviral treatment at admission," the authors wrote.
