Cell: Baloxavir Marboxil Use for Critical Human Infection of Avian Influenza A H5N6 Virus


In addition to the HPAI H5N1 clade virus which has spread globally since 2021 - we are also watching an older H5N1 clade virus in Cambodia which has infected 6 people (3 fatally) in 2023 - and an HPAI H5N6 virus in China (see map above) which has infected nearly 90 people in the past decade, killing roughly half.

Cambodia's H5N1 and China's H5N6 virus both appear to have a roughly 50% fatality rate - at least among those sick enough to be hospitalized - even when patients get treatment.

Until five years ago, the only antiviral available to treat influenza infections were neuraminidase inhibitors like zanamivir and oseltamivir (Tamiflu ®) and peramivir.
While they could be lifesaving, they are most effective if administered relatively early in the infection (i.e. first 48 hours).

In late 2018, the FDA Approved Xofluza : A New Class Of Influenza Antiviral, but with the drop in human avian flu infections over the past few years, very little is known about its ability to treat severe avian flu infection.

Today we've a case report from China on 5 critically ill H5N6 patients - published last week in the Journal Cell - which finds that XoFluza (Baloxivir Marboxil) can be effective even if given outside of that 48 hour window.

This report also provides valuable insights into the progression and severity of H5N6 infection, which in these 5 cases included the relatively rare diagnosis of `viral sepsis' (see Epidemiology and Immune Pathogenesis of Viral Sepsis).

I've only included the Abstract, Highlights, and background. Follow the link to read the report in its entirety. I'll have a brief postscript after the break.


• After symptom onset, five H5N6 patients developed viral sepsis within 1 week
Delayed baloxavir rapidly decreased viral load and respiratory and serum cytokines
Two patients survived; three died from comorbidity and secondary bacterial infection

Context and significance

Human infection with avian influenza A (H5N6) virus poses a significant threat to public health. The H5N6 virus typically induces fulminant pneumonia and multi-organ failure, driven by high viral loads and an intense inflammatory response, necessitating the development of effective antiviral agents.

In seasonal influenza cases, baloxavir is more effective than the standard first-line treatment, oseltamivir. Guan et al. report on five critically ill patients with H5N6 infection who received baloxavir when delayed administration of oseltamivir (beyond 48 h post onset) was not effective against high viral load. Delayed baloxavir administration demonstrated a potent antiviral effect with decreased inflammation, suggesting the potential value of baloxavir as first-line treatment against avian influenza viruses.

Recent outbreaks of avian influenza and ongoing virus reassortment have drawn focus on spill-over infections. The increase in human infections with highly pathogenic avian influenza H5N6 virus and its high fatality rate posed a potential threat, necessitating the search for a more effective treatment.

Longitudinal clinical data and specimens were collected from five H5N6 patients after admission. All patients received antiviral treatment of either sequential monotherapy of oseltamivir and baloxavir or the two drugs in combination. Severity of illness; viral load in sputum, urine, and blood; and cytokine levels in serum and sputum were serially analyzed.


All patients developed acute respiratory distress syndrome (ARDS) and viral sepsis within 1 week after disease onset. When delayed oseltamivir showed poor effects, baloxavir was administered and rapidly decreased viral load. In addition, levels of IL-18, M-CSF, IL-6, and HGF in sputum and Mig and IL-18 in serum that reflected ARDS and sepsis deterioration, respectively, were also reduced with baloxavir usage. However, three patients eventually died from exacerbation of underlying disease and secondary bacterial infection. Nonsurvivors had more severe extrapulmonary organ dysfunction and insufficient H5N6 virus-specific antibody response.
For critical human cases of H5N6 infection, baloxavir demonstrated effects on viral load and pulmonary/extrapulmonary cytokines, even though treatment was delayed. Baloxavir could be regarded as a first-line treatment to limit continued viral propagation, with potential future application in avian influenza human infections and poultry workers exhibiting influenza-like illness.

(Continue . . . )

While we often see a `50% case fatality rate (CFR)' attached to HPAI H5 infection, in truth, that is among those patients who are hospitalized. Since we don't have a good handle on the denominator - the total number of people infected - we can't reliably calculate the CFR.

Just as with H7N9 (30% CFR) and MERS-CoV (35% CFR), there are presumably mild-to-moderate H5N6 cases that are never diagnosed, and are therefore not factored into the CFR.

I go into considerable depth into this topic in Revisiting the H5N1 CFR (Case Fatality Rate) Debate, where we look at seropositivity studies, and other estimates, that suggest that a lot of cases are never identified.

That said, even a 20-fold reduction in CFR (to 2.5%) would put us in 1918 pandemic territory, so these High CFR pathogens could easily surpass anything we've seen in living memory.

17,813 In addition to the HPAI H5N1 clade virus which has spread globally since 2021 - we are also watching an older H5N1 clade 2....