Respiratory Syncytial Viral Infection: Treatment With Ziresovir in Infants

The fall and winter months signal an increase in viral infections circulating among children and families, including influenza, COVID-19, and respiratory syncytial virus (RSV). Although RSV is a public health concern for individuals of all ages, infants and toddlers, especially those born prematurely or with compromised immune systems, and older individuals have particular vulnerability to severe complications. Each year, RSV accounts for more than 2.1 million outpatient visits in children younger than 5 years and more than 60,000 hospitalizations, making it the most common cause of hospital admission in children younger than 1 year.¹ In vulnerable groups, RSV can lead to severe conditions such as bronchiolitis, often resulting in emergency department visits and hospitalization.

In an effort to protect these populations with high risk, the US Food and Drug Administration approved nirsevimab-alip (Beyfortus) in July 2023. Nirsevimab-alip is a monoclonal antibody administered as a preventive measure for all infants younger than 8 months whose mothers did not receive an RSV vaccine during pregnancy.² Despite recent advances in RSV prevention, effective antiviral treatments remain unavailable. Current treatment guidelines emphasize supportive care, such as oxygen supplementation, fluid management, and nutritional support when needed. Although aerosolized ribavirin is available, its use is limited by significant drawbacks. Ribavirin requires prolonged administration, is expensive, and raises safety concerns for health care providers due to potential teratogenic effects. Consequently, its role in clinical practice is minimal. These limitations highlight the urgent need for more practical and effective antiviral therapies in RSV management, extending beyond preventive options.

Ziresovir: A Promising Antiviral for RSV

Ziresovir (AK0529) is a potent, selective RSV F protein inhibitor aimed at reducing the severity and duration of respiratory symptoms, leading to shorter hospital stays and fewer complications.³ Ziresovir is dosed based on body weight, with a minimum dose of 2 mg/kg necessary to achieve the suggested trough concentration of at least 130 ng/mL, which has been shown to correlate with improvements in clinical symptom scores and reduced viral loads.⁴ A recent phase 3 trial conducted in China evaluated the efficacy and safety of ziresovir therapy in children hospitalized with RSV infection.

Study Design and Participants

This randomized, double-blind, placebo-controlled trial was conducted across 28 hospitals in China. Participants were children aged 1 to 24 months hospitalized with confirmed RSV infection within 36 hours prior to receiving their first dose of ziresovir or placebo. Infants were excluded if they had positive test results for HIV, were coinfected with influenza or bacterial pneumonia, or had a known or suspected immunodeficiency. Participants were randomly assigned 2:1 to receive either ziresovir (n = 164) or placebo (n = 80), with both treatments administered every 12 hours for 5 days. Doses ranged from 10 to 40 mg, depending on body weight. The primary efficacy end point was assessed using the Wang Bronchiolitis Severity Score, which evaluates symptoms such as wheezing, respiratory rates, and the child’s general condition, from baseline to day 3. Secondary end points included reductions in RSV viral loads, symptom remission, and length of stay in the intensive care unit, if applicable. The trial was divided into 2 parts: The first focused on safety and pharmacokinetics, whereas the second evaluated efficacy. The safety analysis (part 1) included 302 participants, whereas the efficacy portion of the trial (part 2) evaluated 244 participants. Part 2 of the trial was initiated after part 1 was completed. Participants received ziresovir or placebo for 5 days, with a 9-day safety follow-up period.

Key Findings and Limitations

Findings from the phase 3 trial demonstrated that ziresovir had significant efficacy compared with placebo, offering a promising therapeutic option for infants and toddlers hospitalized with RSV (TABLE). The adverse event profile of ziresovir was minimal and comparable to that of placebo, suggesting a favorable safety profile (adverse event occurrences, 61% vs 53%). Additionally, resistanceassociated mutations were identified in the ziresovir treatment group. However, no correlation was observed between these mutations and viral rebound, indicating that the presence of resistance mutations did not affect viral load recurrence in these patients.

There are some limitations to the study worth noting. First, there was a lack of multinational enrollment, with approximately 89% of the intention-to-treat population identifying as Han Chinese. This may warrant further studies across diverse global populations to ensure the broader applicability of the findings. Second, a common end point for assessing treatment response, time to discontinuation of supplemental oxygen, was not included whereas end points such as change in Wang bronchiolitis score and viral load were included. The former is not yet validated for RSV infection, and the latter is not regularly used in clinical practice.

Given these limitations, readers should interpret the findings with caution regarding applicability across diverse patient populations and should consider that an alternative clinical scoring tool might have provided a more optimal measure of treatment response. However, the variables assessed are intuitive and frequently used in clinical practice, lending relevance to the study’s findings. Ultimately, these data contribute promising insights toward the development of more effective RSV treatment options, an area of critical need. Considering that the median time from symptom onset to the first dose was 4 days—when viral load is naturally declining—the timing of intervention is a critical factor in interpreting the efficacy of the antiviral.

Like most antivirals, earlier administration is generally associated with greater effectiveness, as early intervention can actively inhibit viral replication before substantial immune response and viral decline occur. Given the delayed dosing in this study, it raises the question of whether the observed antiviral effect was due to the treatment itself or was partially attributable to the natural course of infection. Therefore, readers should consider that although promising, these results might reflect the antiviral’s potential in later stages rather than its full efficacy if administered earlier, underscoring the need for further studies exploring optimal timing of treatment initiation.

Conclusion

As the use of nirsevimab-alip continues to grow for RSV prevention, the development and approval of an effective antiviral treatment, such as ziresovir, would be a significant advancement in managing severe cases. Although further research is necessary to confirm the efficacy and safety of ziresovir in more diverse populations, findings from this trial highlight its potential as a valuable therapeutic option in the fight against RSV.

References

1.Surveillance of RSV. Centers for Disease Control and Prevention. Accessed October 15, 2024. http://www.cdc.gov/rsv/php/surveillance/index.html
2.Dalton M. Respiratory syncytial virus (RSV). National Foundation for Infectious Diseases. September 14, 2024. Accessed October 15, 2024. http://www.nfid.org/infectious-disease/rsv/
3.Zheng X, Gao L, Wang L, et al. Discovery of ziresovir as a potent, selective, and orally bioavailable respiratory syncytial virus fusion protein inhibitor. J Med Chem. 2019;62(13):6003-6014. doi:10.1021/acs.jmedchem.9b00654
4.Zhao S, Shang Y, Yin Y, et al; AIRFLO Study Group. Ziresovir in hospitalized infants with respiratory syncytial virus infection. N Engl J Med. 2024;391(12):1096-1107. doi:10.1056/nejmoa2313551