covid: molnupiravir prob works for new variants

 A recent lab study found that the antiviral agent molnupiravir seems to be effective against the newest omicron subvariants (BQ.1.1 and XBB): see covid omicron molnupravir effective NEJM2022 in dropbox, or DOI: 10.1056/NEJMc2214302

Background:

-- there have been 3 sublineages of the initial omicron variant (B.1.1.529): BA.1, BA.2, and BA.5 (see second graph below)

    -- the current ones that are the circulating the most in the US (and much of the world): BQ.1.1 (a subvariant of BA.5) and XBB (a BA.2 subvariant) and now on its ascendency

    -- in fact, a recent article indicates XBB is becoming the dominant variant (and is already so in the Northeast), along with its own subsubvariants XBB.1 and XBB.1.5: https://edition.pagesuite.com/popovers/dynamic_article_popover.aspx?artguid=458fe1fe-e157-4442-aa54-105c127b7904 from the Boston Globe

-- these variants have large numbers of important substitutions in the receptor-binding domain (RBD) of the spike protein

    -- the BQ.1.1 isolates in this study had 3 more substitutions in the RBD than the BA.5

    -- the XBB isolate had 9 more mutations to the RBD than the BA.2

-- and there is reasonable concern that as a result of the increasing RBD mutations: the RBD is the specific target of the available vaccines and therapeutic monoclonal antibodies, therefore these agents might no longer be so effective

Details:

-- BA.1.1 and XBB strains were harvested from patients in Japan

-- they determined the 50% focus reduction neutralization test (FRNT₅₀) titer of an array of monoclonal antibodies by using a live-virus neutralization assay

-- they also assessed  the anti-viral agents remdesivir (inhibits the RNA-dependent RNA polymerase RdRp of the virus), molnupiravir (an RdRp inhibitor), and nirmatrelvir (inhibitor of the main protease of the virus, given to patients as paxlovid, which also includes ritonavir to slow nirmatrelvir metabolism)

    -- as mentioned above, there have been fewer mutations in the non-RBD regions where these antivirals work, as opposed to the RBD region where the monoclonal antibodies and vaccines work

Results:

-- monoclonal antibodies: 

    -- casirivimab, tixagevimab, cilgavimab and sotrovimab did not neutralize the BQ.1.1 or XBB, even at the highest FRNT₅₀ value

    -- bebtelovimab effectively neutralized omicron BA.1, BA.2, BA.4, BA.5 but had no efficacy against  BQ.1.1 or XBB 

    -- and the combos indevimab-casirivimab and tixagevimag-cilgavimab did not neutralize BQ.1.1 or XBB 

        -- ie, not a pretty picture for the future of these monoclonals

-- antivirals (they assessed the in vitro 50% inhibitory concentration (IC₅₀) against these variants):

    -- the susceptibilities of the BQ.1.1 and XBB strains to all 3 antivirals was similar to that of the ancestral strain

    -- comparing the antivirals:

        --BQ.1.1:

            -- remdesivir: IC50 was lower by factor of 0.6

            -- molnupiravir: higher by factor of 1.1

            -- nirmatrelvir: higher by factor of 1.2

        -- XBB:

            -- remdesivir: IC50 was lower by factor of 0.8

            -- molnupiravir: lower by factor of 0.5

            -- nirmatrelvir: higher by factor of 1.3

        -- these results suggest that all 3 seem to be effective against both strains, with minor differences

[these graphs are easier for me to interpret than the numbers: basically not much difference between any of the antivirals and any of the many SARS-CoV-2 variants tested]

Commentary:

-- this lab study found that the monoclonals did pretty much nothing and the antivirals seemed quite good

Limitations :

-- this is a lab study. Unfortunately, given the speed that the SARS-CoV-2 mutates, we cannot wait for clinical trials: too long to recruit people, enroll them, follow them, report results (a cycle so long that we will then be a few new variants beyond the ones tested)

-- as per the Boston Globe article above, there are 2 new subsubvariants of XBB: XBB.1 and XBB.1.5, and which are evading vaccines and monoclonal antibodies.  at this point, we do not know now how the antivirals will fare...

-- neutralizaing antibody testing seems to be the best lab test to predict clinical efficacy

so, first the apology: it is becoming increasingly difficult to keep track of the subsubsubvariants of the subsubvariants of the subvariants of the variants, what with the increasingly obtuse initials (??XBB). but it seems that we are moving into a new increasingly complex realm (and the names of the monoclonal antibodies and antivirals do not flow easily off the lips either):

-- this miserable SARS-CoV-2 virus seems to be increasingly proficient in mutating to increasingly proficient strains

-- vaccines that target a single area (eg RBD) are likely to be increasingly ineffective, as viral mutations targeting a specific area will more easily develop resistance

    -- and, though mRNA vaccines are a game-changer, their rapid development and upscaling really can't keep pace

    -- and, and, and there seems to be less popular enthusiasm to getting booster after booster after booster

-- so the best alternatives seem to be: a different type of vaccine with broader targets (eg, perhaps a T-cell vaccine: see http://gmodestmedblogs.blogspot.com/2022/01/covid-new-t-cell-vaccine-in-works.html , or broad-targeting antiviral drugs)

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here is the SARS-CoV-2 mutation tree, from (thanks to Paul Susman), from https://yourlocalepidemiologist.substack.com/p/covid-in-china-the-us-and-everything?utm_medium=email .

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-- there was a provocative Hong Kong study on molnupiravir that evaluated SARS-CoV-2 viral rebound, also including results for patients on nirmatrelvir-ritonavir (paxlovid) and those not on any meds (see covid viral rebound after molnupiravir and paxlovid JAMA2022 in dropbox, or doi:10.1001/jamanetworkopen.2022.45086).  They compared 12,629 patients (mean age 65, 53% male, 11,688 not on antivirals, 746 on molnupiravir, 195 on nirmatrelvir/ritonavir), and followed their SARS-CoV-2 PCR cycle thresholds (effectively the inverse of viral loads), from Jan to April 2022 (omicron being prevalent in Hong Kong at that time):

    -- in Hong Kong, even patients with mild to moderate covid were hospitalized (that was the standard of care: all known SARS-CoV-2 positive patients were admitted into the hospital and put in negative pressure rooms), but near the end of this study the hospitals were overwhelmed so there were more nonhospitalized patients and therefore more cases not included in this analysis

    -- patients followed up to 30 days, a total of 4 PCRs done

    -- viral rebound was defined as a Ct >40 (cycle threshold value, where >40 is considered a negative PCR for SARS-CoV-2) but then decreased to <40 on subsequent testing

    -- most viral rebonds occurred 2-5 days after completion of antivirals

    -- viral rebound findings:

        -- nonusers of antivirals: 68 people, 0.6%

        -- molnupiravir: 6 users, 0.6%

        -- nirmatrelvir/ritonavir: 2 users, 1.0%

    -- viral rebound findings using the Ct cutpoint of 36 (a more specific reflection of SARS-CoV-2 infection): no real difference. 4.5% of all groups had this fluctuation

    -- deaths from Covid:

        -- nonusers of antivirals: 12 of the 68 people

        -- molnupiravir: 1 of the 6 users

        -- nirmatrelvir/ritonavir: none of the 2 users

    -- but there were substantial limitations to this study:

        -- there were pretty large differences between the above groups of patients: for example, those on antivirals were older and had more comorbidities, and those on molnupiravir were the sickest overall (being the oldest, and having the most cardiovascular disease, diabetes respiratory disease, kidney disease). pretty strong adverse selection here. And likely reinforces the assessment of the potency of molnupiravir 

        -- small numbers of patients on antivirals, especially for nirmatrelvir/ritonavir

        -- not sure how this study based on PCR would translate to using rapid antigen testing as we do now (PCR also picks up dead viral remnants, and can be positive >3 months after a cleared infection)

        -- no granular data on the individual patient-level baselines and subsequent outcomes. no info on symptoms or correlation between symptoms and rebound (and no collection of data on asymptomatics)

    -- so, this study, within the limitations mentioned, found that viral rebound was actually no different in those not receiving these antivirals as in those getting them. and the overall incidence of rebound by their definition was pretty small despite the rather large cohort of patients. if the study findings were replicated in a more rigorous study (eg with viral culture or at least viral antigen testing), this would suggest that viral rebound is a natural consequence of a SARS-CoV-2 infections, and perhaps not related to the antivirals....

geoff

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