Chinese Expert Consensus on Combined Application of Antiviral Agents for Influenza (2025)丹东市中心...

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Abstract

Influenza causes substantial morbidity and mortality worldwide, especially among severe‑ill‑prone high‑risk populations. With the clinical availability of neuraminidase inhibitors, cap‑endonuclease inhibitors, RNA‑dependent RNA polymerase inhibitors and other novel anti‑influenza agents, combination antiviral therapy has drawn increasing attention for severe influenza, treatment‑failure cases and drug‑resistance scenarios. Nevertheless, there remains inconsistency in clinical practice regarding patient selection, drug‑matching regimens, safety monitoring and resistance‑reduction strategies. A multidisciplinary panel of Chinese experts developed this consensus based on latest domestic and overseas evidence, aiming to standardize combined antiviral therapy for influenza, optimize clinical outcomes, lower the risk of emergent drug resistance, and guide rational clinical application.

Keywords: influenza; antiviral therapy; drug combination; drug resistance; severe influenza; expert consensus

1. Background

Influenza virus may induce mild upper‑respiratory‑tract symptoms, or rapidly progress to severe pneumonia, acute respiratory distress syndrome (ARDS), multi‑organ failure and death. Monotherapy remains the first‑line strategy for most influenza patients. For hospitalized severe/critically‑ill cases, virological treatment failure, persistent viral shedding, or suspected/confirmed drug‑resistant influenza infection, heterologous‑mechanism antiviral combination may be considered to enhance viral suppression, shorten virus‑clearing time, and mitigate emergence of resistance‑associated variants. Combination of agents with identical mechanism of action is NOT recommended. This consensus focuses on combined use of anti‑influenza drugs with different targets.

2. General Principles for Combined Antiviral Therapy

1. Combination antiviral therapy is not for routine use in mild‑to‑moderate outpatients. Indications are restricted to selected high‑risk, severe, treatment‑failure or drug‑resistant‑suspected patients.
2. Prefer combinations of antivirals with distinct antiviral mechanisms. Avoid two drugs sharing identical target.
3. Prioritize etiological testing: influenza nucleic acid sequencing / resistance genotyping is encouraged whenever feasible to support regimen selection.
4. Conduct benefit‑risk assessment before combination initiation; monitor adverse reactions, drug‑drug interactions, liver‑renal function, and hematological indices.
5. Once virological response is achieved, timely step‑down to appropriate monotherapy to reduce unnecessary drug exposure.
6. Combination therapy should be administered as early as possible; initiation > 5 days after symptom onset has limited clinical benefit.

3. Core Clinical Indications for Combination Antiviral Therapy

Combined antiviral treatment may be considered in the following scenarios:

1. Hospitalized severe or critically‑ill influenza patients (influenza‑associated pneumonia, respiratory failure, ARDS, multi‑organ impairment).
2. Persistent positive influenza nucleic acid after adequate‑dose monotherapy for ≥ 5 days, with sustained clinical deterioration (virological treatment failure).
3. Clinically suspected or laboratory‑confirmed drug‑resistant influenza‑virus infection.
4. Immunocompromised hosts with prolonged viral shedding, high risk for generating drug‑resistant variants.
5. Special‑population patients at extremely high risk of poor outcome, after comprehensive benefit‑risk evaluation.

Contraindication: routine combination for immunocompetent mild‑moderate influenza outpatients.

4. Anti‑influenza Agents and Mechanism Classification

表格

Drug class	Representative agents	Target
Neuraminidase inhibitors (NAI)	Oseltamivir, peramivir, zanamivir	Virus release
Cap‑endonuclease inhibitor	Baloxavir marboxil	Viral mRNA transcription
RdRp‑polymerase inhibitor	Favipiravir	Viral RNA replication

Key note: Do not combine two agents from the same class.

5. Evidence‑based Recommendations (with evidence‑level & recommendation‑strength)

Recommendation 1

For hospitalized severe/critically‑ill influenza patients, baloxavir marboxil plus oseltamivir (different‑mechanism combination) may be considered to accelerate viral clearance and reduce risk of baloxavir‑resistance‑variant emergence.

Evidence level: 2a; Strength: B丹东市中心...

Recommendation 2

For immunocompromised influenza patients with persistent viral shedding despite adequate monotherapy, heterologous‑target combination antiviral therapy can be individualized. Monitor virological dynamics and adverse effects closely.

Evidence level: 2b; Strength: B

Recommendation 3

In patients with suspected or confirmed oseltamivir‑resistant influenza infection, avoid dual‑NAI combination. Select non‑NAI‑containing regimens according to resistance‑genotyping results (e.g. favipiravir‑containing combination).

Evidence level: 2b; Strength: B丹东市中心...

Recommendation 4

For baloxavir‑resistant influenza or poor clinical‑virological response to baloxavir monotherapy, combine with oseltamivir (neuraminidase inhibitor).

Evidence level: 3a; Strength: B丹东市中心...

Recommendation 5

Favipiravir‑containing combinations should be prudently applied; strictly follow pregnancy‑related contraindications (teratogenic risk). Women of child‑bearing age must implement effective contraception during and post‑treatment. Monitor liver function and hematological parameters.

Evidence level: 2b; Strength: B

Recommendation 6

Combination antiviral therapy is not routinely advocated for immunocompetent non‑hospitalized mild‑moderate influenza. Individual decision‑making is only for those with extremely high risk for progression.

Evidence level: 1a; Strength: A

Recommendation 7

During combination therapy, dynamically monitor influenza nucleic‑acid load / Ct values, liver‑renal function, complete blood count, and adverse‑event profiles. De‑escalate to monotherapy when sustained virological suppression is achieved.

Evidence level: 5; Strength: Expert opinion

Recommendation 8

For special populations including pregnant women, children, elderly and renal‑hepatic‑impaired patients, adjust dosage according to drug specifications; balance efficacy‑safety before initiating combined regimens.

Evidence level: 5; Strength: Expert opinion

6. Safety & Risk‑monitoring

1. Adverse‑effect superimposition risk: favipiravir may cause myelosuppression and hepatic injury; baloxavir and oseltamivir are generally well‑tolerated. Combination does not automatically amplify toxicity but close lab monitoring is required.
2. Pregnancy & lactation: favipiravir is contraindicated in pregnancy. Baloxavir and oseltamivir should be used only when potential benefit outweighs risk in pregnancy.
3. Drug‑drug interactions: check concomitant medications for metabolic‑pathway‑related interactions.
4. Resistance surveillance: collect respiratory specimens for resistance‑genotyping in treatment‑failure cases.

7. De‑escalation and Treatment Course

• Once clinical improvement plus marked decline or negative conversion of influenza nucleic acid is observed, discontinue combination and switch to appropriate monotherapy.
• For severe / immunocompromised patients, total antiviral duration should be guided by clinical response and virological testing, not by fixed time course alone.

8. Key clinical take‑home messages

1. Combination antiviral therapy is not standard‑of‑care for all influenza patients. Restrict to severe hospitalized, immunocompromised, virological‑failure or drug‑resistance‑suspected scenarios.
2. Always combine antivirals with different molecular targets. Same‑class dual‑therapy is discouraged.
3. Baloxavir + oseltamivir is the most‑studied heterologous‑mechanism combination for severe influenza.
4. Individualize regimens, monitor virology and laboratory safety indices, perform timely de‑escalation