What are the benefits of baloxavir (Xofluza) over oseltamivir (Tamiflu)?

Comment by InpharmD Researcher

Recent meta-analyses and pharmacoeconomics studies have found baloxavir to be more effective and less costly than oseltamivir. Baloxavir showed superiority over oseltamivir in reducing influenza viral titers and viral RNA loads (p<0.001) and similar safety profiles, although baloxavir had a lower incidence of nausea (p= 0.03). Baloxavir led to shorter hospitalization periods in the inpatient setting (p= 0.01), though mortality outcomes were comparable. However, benefits seem to be isolated to high-risk patients, with little to no benefit of neuraminadase inhibitors seen in low-risk patients.

Background

In a 2024 systematic review and meta analysis, efficacy and safety of baloxavir was compared against oseltamivir in patients with influenza virus. Two randomized trials (N= 1,624 outpatients) and two retrospective trials (N= 874 inpatients) were assessed for mortality, hospital length of stay, illness duration and viral load, and treatment adverse events. In outpatients, no deaths occurred with either baloxavir or oseltamivir, and illness duration was comparable between groups; however, baloxavir was superior in influenza virus titer reduction (p<0.001), viral RNA load reduction (p<0.001), and was more tolerable (p= 0.03) compared to oseltamivir. In inpatients, baloxavir patients had a lower hospitalization period (p= 0.01), though mortality outcomes were similar. Based on these findings, baloxavir use may be safer and more efficacious than oseltamivir for treatment of influenza, though more data is required to confirm these findings. [1]

A 2024 systematic review and network meta-analysis of 33 randomized trials evaluated the efficacy and safety of six antiviral agents, including zanamivir, oseltamivir, laninamivir, baloxavir, amantadine, and rimantadine for post-exposure prophylaxis of influenza. A total of 19,096 individuals, with a mean age ranging from 6.75 to 81.15 years, were included. The analysis incorporated trials comparing antivirals to placebo or standard care, with primary outcomes including symptomatic influenza, asymptomatic infection, hospital admission, all-cause mortality, and adverse events. Zanamivir, oseltamivir, laninamivir, and baloxavir probably reduce the risk of symptomatic seasonal influenza in high-risk individuals when administered within 48 hours of exposure, with relative risk reductions ranging from 0.35 to 0.43. However, these agents likely provide little to no benefit in low-risk populations. No trial directly assessed post-exposure prophylaxis against zoonotic influenza; however, indirect evidence suggested that neuraminidase inhibitors and baloxavir might reduce symptomatic zoonotic influenza following exposure to novel influenza A viruses. No significant effect was observed on hospital admissions (moderate certainty) or all-cause mortality (high to moderate certainty). Adverse events and serious adverse events did not significantly increase with any antiviral, though certainty varied. The findings underscore the potential clinical utility of these antivirals in targeted high-risk populations while highlighting the need for further data in vulnerable groups, including pregnant individuals and those with comorbidities. [2]

A 2021 systematic review and meta-analysis of randomized trials evaluated the clinical efficacy and safety of baloxavir marboxil in comparison to oseltamivir and placebo for the treatment of influenza. The analysis included data from three phase 3 randomized trials, encompassing 3,771 patients (baloxavir, n= 1,451; oseltamivir, n= 1,288; placebo, n= 1,032). In comparison to placebo, baloxavir significantly reduced the time to symptom alleviation by an average of 26.32 hours (95% confidence interval [CI] -33.78 to -18.86) with no observed heterogeneity (I²= 0%). The virological response was superior with baloxavir, demonstrating a greater reduction in influenza virus titers and viral RNA load by day 2 compared to both oseltamivir and placebo. Although the time to symptom resolution was similar between baloxavir and oseltamivir (mean difference -1.29 hours; 95% CI -6.80 to 4.21; I²= 0%), baloxavir was associated with fewer overall adverse events than oseltamivir (odds ratio [OR] 0.82; 95% CI 0.69 to 0.98; I²= 0%), particularly for nausea. These findings support baloxavir as a clinically effective and relatively safe antiviral option, with a distinct virological advantage over oseltamivir. [3]

A 2021 Bayesian network meta-analysis assessed the efficacy and safety of baloxavir marboxil compared to neuraminidase inhibitors, including oseltamivir, zanamivir, laninamivir, and peramivir, in the treatment of influenza among high-risk and uncomplicated patients. A systematic literature review identified 32 relevant randomized controlled trials, comprising 7 studies involving high-risk patients, 13 trials focused on otherwise healthy individuals, and 14 studies that included both populations. The primary outcome evaluated was the time to alleviation of all influenza symptoms, while secondary measures included the time to resolution of fever, changes in viral titer at 24 and 48 hours post-treatment, and adverse event profiles. The analysis demonstrated that baloxavir significantly reduced the time to symptom resolution compared to placebo in high-risk individuals, with comparable efficacy to neuraminidase inhibitors. Notably, baloxavir was associated with a significantly greater decline in viral titer at 24 and 48 hours post-treatment when compared to oseltamivir and peramivir. In terms of safety, baloxavir exhibited a similar adverse event profile to other antiviral agents and was associated with a lower incidence of drug-related adverse events than oseltamivir and laninamivir. The findings remained consistent when pooling data from all uncomplicated influenza patients, reinforcing baloxavir’s superior antiviral activity and comparable clinical efficacy and safety to neuraminidase inhibitors. [4]

A 2024 cost-effectiveness analysis evaluated baloxavir marboxil compared with oseltamivir or no antiviral treatment for influenza management in the United States. A decision tree cost-effectiveness model was developed utilizing a lifetime time horizon with a 3.0% discount rate for costs and quality-adjusted life-years (QALYs). The model incorporated patient data from the Merative™ MarketScan® Research Databases, which included US commercial claims, Medicare, and Medicaid Supplemental databases from the 2018-2020 influenza seasons. Complication rates, healthcare resource utilization, and costs were extrapolated from real-world administrative claims data. Outcomes were reported in terms of total QALYs, incremental cost-effectiveness ratios (ICERs), and net monetary benefit (NMB) based on a willingness-to-pay threshold of $100,000 per QALY. Findings demonstrated that baloxavir was cost-effective compared with oseltamivir ($6,813/QALY gained) and no antiviral treatment ($669/QALY gained). The NMB of baloxavir was projected at $1,180 compared with oseltamivir and $6,208 compared with no treatment, with greater cost savings observed in high-risk individuals. Sensitivity analyses confirmed the robustness of these results, with probabilistic modeling indicating that baloxavir remained cost-effective in 69.3% of simulations versus oseltamivir and 95.2% versus no treatment. Scenario analysis assessing the impact of viral transmission reduction revealed that a 5% reduction increased the NMB of baloxavir to $2,592 over oseltamivir and $7,621 over no treatment, with baloxavir becoming dominant (more effective and less costly) at viral transmission reductions of 12.0% and 6.0%, respectively. These findings emphasize the economic and potential public health benefits of baloxavir in influenza management, particularly when considering its effect on viral transmission. [5]

References:

[1] Shiraishi C, Kato H, Hagihara M, Asai N, Iwamoto T, Mikamo H. Comparison of clinical efficacy and safety of baloxavir marboxil versus oseltamivir as the treatment for influenza virus infections: A systematic review and meta-analysis. J Infect Chemother. 2024;30(3):242-249. doi:10.1016/j.jiac.2023.10.017
[2] Zhao Y, Gao Y, Guyatt G, et al. Antivirals for post-exposure prophylaxis of influenza: a systematic review and network meta-analysis. Lancet. 2024;404(10454):764-772. doi:10.1016/S0140-6736(24)01357-6
[3] Kuo YC, Lai CC, Wang YH, Chen CH, Wang CY. Clinical efficacy and safety of baloxavir marboxil in the treatment of influenza: A systematic review and meta-analysis of randomized controlled trials. J Microbiol Immunol Infect. 2021;54(5):865-875. doi:10.1016/j.jmii.2021.04.002
[4] Taieb V, Ikeoka H, Wojciechowski P, et al. Efficacy and safety of baloxavir marboxil versus neuraminidase inhibitors in the treatment of influenza virus infection in high-risk and uncomplicated patients - a Bayesian network meta-analysis. Curr Med Res Opin. 2021;37(2):225-244. doi:10.1080/03007995.2020.1839400
[5] Kommandantvold SA, Chang SC, Surinach A, et al. Cost-Effectiveness of Baloxavir Marboxil Versus Oseltamivir or no Treatment for the Management of Influenza in the United States. Infect Dis Ther. 2024;13(9):2071-2087. doi:10.1007/s40121-024-01027-9

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What are the benefits of baloxavir (Xofluza) over oseltamivir (Tamiflu)?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Table 1 for your response.


Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents

Design

Two randomized, double-blind, controlled trials

Phase 2 trial; N= 400

Phase 3 trial (CAPSTONE-1; N= 1,064

Objective

To report the results of single-dose baloxavir treatment in otherwise healthy persons with acute influenza from phase 2 and 3 randomized, controlled trials.

Study Groups

Phase 2 trial:

Baloxavir 10 mg (n= 100)

Baloxavir 20 mg (n= 100)

Baloxavir 40 mg (n= 100)

Placebo (n= 100)

Phase 3 trial:

Baloxavir (n= 376)

Oseltamivir (n= 377)

Placebo (n= 231)

Methods

Phase 2 trial inclusion: Japanese adults age 20 to 64 years with positive rapid antigen tested acute influenza were randomized to receive a single dose of baloxavir 10, 20, 40 mg, or placebo.

Phase 3 trial inclusion: Age 12 to 64 years with suspected influenza-like illness in the United States and Japan were included. Patients age 20 to 64 years were randomized 2:2:1 to receive a single dose of baloxavir (40 mg for patients weighing <80 kg or 80 mg for those weighing ≥80 kg), oseltamivir 75 mg BID for 5 days, or placebo. Patients age 12 to 19 were randomized 2:1 to receive single-dose baloxavir or placebo. 

Exclusion criteria: Underlying conditions, pregnancy, weight < 40 kg, illness requiring hospitalization. Only acetaminophen was allowed for symptomatic therapy.

Duration

Phase 2 trial: December 2015 to December 2016

Phase 3 trial: December 2016 to March 2017

Outcome Measures

Primary endpoint: Time to alleviate symptoms based on seven influenza-related symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue).

Secondary endpoint: Time to resolution of fever, time to return to usual health, newly occurring complications leading to antibiotic use.

Baseline Characteristics

No significant differences between baselines were observed between groups in either trial.

Results

Phase 2 Trial Endpoint

Baloxavir 10 mg

(n=100)

Baloxavir 20 mg

(n=100)

Baloxavir 30 mg

(n=100)

Placebo

Median time to alleviation of symptoms, hours

p-value versus placebo

54.2

p= 0.009

51.0

p= 0.02

49.5

p= 0.005

77.7

-

Any adverse events

Serious adverse events

Adverse events leading to withdrawal

27

0

0

23

0

0

26

0

0

29

5

2

Phase 3 Trial Endpoint

Baloxavir

(n= 456)

Placebo

(n= 231)

Oseltamivir

(n= 377)

 

Presence of A(H3N2)

393 (86.2%) 196 (84.8%) 332 (88.1%)  

Median time to alleviate symptoms, hours

Difference versus placebo (95% confidence interval [CI])

p-value versus placebo

53.7

26.5 (17.8 to 35.8)

p< 0.001

80.2

-

-

53.8

-

-

 

Median time to resolution of fever, hours

p-value versus placebo

24.5

p< 0.001

42.0

-

   

Median time to return to usual health

p-value versus placebo

129.2

p= 0.06

168.8

-

   

Newly occurring complications leading to antibiotic use

3.5%

4.3%

2.4%  

Phase 3 Trial Safety Analysis

Baloxavir

n= 610 

Placebo

n= 309

Oseltamivir

n= 513

 

Any adverse event

126

76

127

 

Adverse events > 1% in any group

Diarrhea

Bronchitis

Nausea

Headache

Dizziness

Vomiting

Leukopenia

Constipation

 

18 (3.0%)

16 (2.6%)

8 (1.3%)

5 (0.8%)

3 (0.5%)

5 (0.8%)

0

0

 

14 (4.5%)

17 (5.5%)

4 (1.3%)

3 (1.0%)

4 (1.3%)

2 (0.6%)

3 (1.0%)

3 (1.0%)

 

11 (2.1%)

18 (3.5%)

16 (3.1%)

4 (0.8%)

1 (0.2%)

6 (1.2%)

1 (0.2%)

0

 

Phase 3 trial: Only those with confirmed influenza diagnoses were included in the intent-to-treat efficacy endpoint analysis. All patients that received trial drugs were included in the intent-to-treat safety analysis.

Study Author Conclusions

Single-dose oral baloxavir in these modest-size trials did not result in apparent safety concerns and was associated with clinical benefit and antiviral activity in patients with uncomplicated influenza. Because this treatment is inhibitory for influenza virus strains resistant to neuraminidase inhibitors or M2 ion-channel inhibitors, it could provide an option for patients with infections caused by such viruses.

InpharmD Researcher Critique

The results can only be extrapolated to patients with uncomplicated influenza without other explicit underlying conditions. Adverse events were overall greater in those taking antivirals and two serious events (incarcerated inguinal hernia and aseptic meningitis) were not considered related to the trial drugs. 

 

 
References:

Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med. 2018;379(10):913-923. doi: 10.1056/NEJMoa1716197