Introduction

H5N1 is a looming threat, making regular headlines. The CDC has identified 66 U.S. human cases as of January 4, 2024. Scott Alexander has a recent post outlining the situation.

There are several FDA-approved prescription antiviral flu drugs. The newest, using a novel mechanism of action called "cap-snatching," is baloxavir marboxil (BXM, brand name Xofluza). It is on-patent and substantially more expensive than oseltamivir (OST, brand name Tamiflu, now available as a generic).

I built a Guesstimate model to model the impact of using Xofluza at various stages of illness. A few facts about it:.

• It is primarily based on data from the largest-to-date published clinical trials for BXM, as well as CDC flu modeling and some other flu-related academic literature.
• In Guesstimate, users can simulate different flu and patient characteristics, substituting their assumptions for mine.
• It models two flu types: normal-risk and higher-risk. Normal-risk flu is modeled on clinical trial results and CDC/academic flu modeling. Higher-risk flu traits are multipliers of those modeled for normal-risk flu and are based on case fatality rates for H5 and H7 flu. This is speculative, likely not very accurate for if a pandemic happened.
• It is not medical advice, I am not a medical doctor.
• I leave out financial cost and focus on patient health. Xofluza costs about $180 out of pocket according to Goodrx, which says it's covered by "some Medicare and insurance plans".
• Elizabeth Van Nostrand offers a bounty for substantive bugs ($50/bug, up to $250 total, at her discretion).

Quantified example

Assumptions (the defaults you'll find if you click the link above):

• 85-year-old US male (10.5% chance of death in that year, 5.65 year life expectancy by the actuarial table) considering taking prophylactic BXM after his wife tests positive for influenza
• He has comorbidities giving a 7x hospitalization risk if he becomes ill and a 2x disease duration multiplier
• The chance his wife has higher-risk flu is about 1 in 500,000
• Higher-risk flu lasts 5-24x longer, has a 200-4000x hospitalization and mortality risk, and is 1% as infectious as normal-risk flu

The model estimates the following benefits of taking prophylactic BXM over no prophylactic anti-flu drug and OST-only if hospitalized:

• His chance of getting sick is only 24% of what it would be without medication (reduced by 76%)
• His chance of hospitalization is only 20% of what it would be without medication (reduced by 80%)
• His chance of death from influenza is only 10% of what it would be without medication (reduced by 90%)
• He can expect to spend 38 fewer hours hospitalized with severe influenza
• He can expect to spend 96 fewer hours sick with influenza (mild or severe)
• Taking prophylactic BXM increases his life expectancy by 15-25 days

My opinion

My takeaway after building the model:

• Based on clinical trial results, BXM seems broadly useful at least as a prophylactic and for acute mild influenza. Currently the CDC recommends against giving BXM to "pregnant people, breastfeeding people, outpatients with complicated or progressive illness, severely immunosuppressed people, or hospitalized patients." The reasons given range from "limited evidence" to concerns about drug resistance (see below).
• BXM is expensive out of pocket, won't work against anything except flu, and is more effective the earlier you take it. It seems useful to learn to distinguish likely flu from other colds on the basis of symptoms, to invest in some at-home flu tests, and to promote a culture of prompt testing and sharing results so that exposed people can react in a timely fashion.
• BXM has not been tested in humans against H5N1, but there are preclinical results suggesting BXM may be effective against H5 and H7 flu strains.
• BXM is best taken early. You're less likely to get sick, the duration is shorter if you do, and the hospitalization and death risk is smaller as well. We also know from headline results from the recently completed CENTERSTONE phase III trial that BXM reduces onward transmission.

A major caveat with flu drugs generally, including BXM, is the risk of the emergence of resistant strains.

• Flu has developed resistance to BXM in some patients during trials (9.7% of patients in one BXM trial).
• OST (Tamiflu) resistant flu seems to have waxed and waned over time.^[1]
• Development of resistant flu seems to happen most often in immunocompromised patients who receive anti-flu drugs.

Navigating the model

• Top-left: simulated patient health characteristics (you can substitute your own assumptions)

• Top-center: modeled higher-risk influenza characteristics (you can substitute your own assumptions)

• Top-right: simulated health outcomes +/- BXM over standard of care (this probably does not need any user-adjustments)

• Bottom-left: selected results from BXM clinical trials, CDC flu modeling, and other academic literature (this probably does not need any user-adjustments)

• Bottom-right: intermediate computations (this probably does not need any user adjustments)

You can find my reasoning by hovering over the cells.

Funding and disclosures

• I was funded by Elizabeth Van Nostrand via an unrestricted grant by Timothy Telleen-Lawton to estimate the impact of BXM on personal health, both in the context of normal and higher-risk influenza.
• I am not a medical doctor or infectious disease expert (I'm a PhD student in biomedical engineering studying epigenetics primarily in the context of cancer and development).
• This model is not intended to diagnose any disease or prescribe any drug.
• A few people looked at this pre-publication but no one found any substantive errors except me. If you find any, please report back.
• No conflicts of interest to declare.

1. ^{^}

   I found a source that said >90% of H1N1 was OST-resistant in the US, Canada, UK, and Australia in 2008-2009, and that resistant H1N1 pdm09 has been increasing since 2010-2011. "Preliminary data from the 2008-2009 influenza season identified resistance to oseltamivir among 264 of 268 influenza A(H1N1) viruses (98.5%) tested." source

   Unfortunately, the root of the citation tree is a 2009 CDC weekly influenza surveillance report prepared by the Influenza Division of the CDC, which is no longer online at the cited URL. The CDC has a bunch of notes on flu drug resistance. It says "as of September 2014, no evidence existed of ongoing transmission of oseltamivir-resistant 2009 H1N1 virus strains worldwide." 

   Overall I just do not have clarity on the state of OST resistance trends over time, and I don't know if a formal comprehensive treatment on this subject is even available.