COVID: Caution with Molnupiravir (Especially Dangerous for Those with Weak Immune Systems)

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COVID: Caution with Molnupiravir (Especially Dangerous for Those with Weak Immune Systems)

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COVID: Caution with Molnupiravir (Especially Dangerous for Those with Weak Immune Systems)

Reports at the onset of the COVID pandemic indicated the presence of long-term health issues post-infection, including fatigue, autonomic dysfunction (or postural orthostatic tachycardia syndrome), post-exertional malaise, and cognitive difficulties (commonly known as “brain fog”), affecting almost all organs/systems, also referred to as Long COVID.

Despite vaccines, breakthrough infections, and the resulting hybrid immunity, COVID has not “disappeared,” with the latest variant being called JN.1 (derived from BA.2.86).

A study published in The Lancet Infectious Diseases reports that compared to other variants (including previously prevalent strains such as XBB.1.5, EG.5.1, etc.), BA.2.86 and JN.1 show higher viral shedding rates, including in individuals before symptoms appear and in those who have been vaccinated. This may be related to JN.1 having stronger transmissibility and immune evasion capabilities, partly explaining the increase in wastewater viral load.

JN.1’s stronger affinity to ACE2 means that increased receptor binding leads to enhanced viral entry, associated with resistance to type I interferon (IFN-I), triggering innate affinity escape, thus prolonging viral replication—enhanced transmissibility and immune evasion.

Moreover, JN.1 (including BA.2.86/87) can infect cells in a manner that does not depend on ACE2. Two COVID proteins, NSP14 and ORF6, play opposing roles to promote virus expansion at different stages of infection. Early in infection, NSP14 promotes IκK phosphorylation to enhance NF-κB signaling for replication, while ORF6, translated later in infection, inhibits NF-κB signal transduction.

Infection not dependent on ACE2 disrupts the translation of ORF6 and other viral structural proteins, but NSP14 can be translated directly from the genomic RNA, leading to excessive activation of the NF-κB pathway, increasing the production of pro-inflammatory cytokines.

COVID proteins, including E/M proteins (targets for antigen testing), interacting with pattern recognition receptors, can directly activate inflammatory responses, such as the interaction of TLR1 with E and M proteins and activation of TLR4 (associated with myocarditis).

Prolonged inflammation/cytokines can cause many discomforts. Compared to infections with other COVID variants, individuals infected with JN.1 commonly experience symptoms such as body aches, cough, loss of appetite, chills, diarrhea, sore throat, and nausea—highly associated with cytokine release (excess).

Viral replication often grows geometrically, and delayed clearance often signifies higher intensity immune activation—cytokine release syndrome can cause devastating tissue damage, leading to multi-organ failure.

Even with restricted clearance delays, the continuous increase in cytokine levels can lead to chronic inflammation, such as activating inflammatory macrophages in the vascular immunological organ. (Through upregulation of interferon signaling).

To prevent/reduce adverse outcomes of COVID, several antiviral drugs for treating COVID infections have been approved by regulatory authorities.

High-risk individuals, including those with obesity, comorbidities, and immunodeficiency, are often associated with adverse clinical outcomes of COVID and were the initial target population for antiviral drugs.

Molnupiravir, an oral small molecule antiviral prodrug, when taken, is activated by cellular kinases into its triphosphate form (NHC triphosphate), which mimics triphosphate cytidine or uridine and incorporates into the viral nucleic acid chain, ultimately causing G to A and/or C to U base substitutions (mutations) and accumulation, which is generally considered detrimental to viral replication, thus exerting antiviral effects. (Lethal mutation)

Tip: This mutagenesis mechanism is not only useful against COVID but also affects other viruses that replicate using RNA-dependent RNA polymerase (RdRp), giving it a “broad-spectrum antiviral effect,” similar to the host’s natural infection-restrictive factor, the ApobEC3 family.

In the early stages of the pandemic, basic immunity to COVID (vaccines and/or natural infection) was far less prevalent than it is now. In the MOVE-OUT study, early use of molnupiravir in the treatment of COVID infection reduced the risk of hospitalization or death in high-risk adults not vaccinated.

With the establishment of basic immunity to COVID, subsequent studies (PANORAMIC study) found that molnupiravir did not reduce the already low rates of hospitalization and death in vaccinated high-risk (but not necessarily highest risk) adults in the community. (It seems to shorten the duration of symptoms and reduce their severity)

Viral clearance almost entirely relies on the immune system, regardless of the use of antiviral drugs,

The introduction of super mutations can inhibit viral replication, but on the other hand, it can increase viral mutations. The risk is related to the time of viral clearance and the level of replication. When there is a delay in viral clearance, we should consider the adverse effects of molnupiravir-related viral mutations.

Especially in immunocompromised individuals, it is worth noting that COVID can already evade cell immune surveillance by downregulating MHC molecules, and the peaks of multiple rounds of variant infections have long heralded the limitations of humoral immunity.

Previously, some researchers on the X platform had discussed the adverse effects of molnupiravir on mutations. This month, an observational study has also been published in the prestigious journal The Lancet Microbe.

Perhaps psychologically, many people believe that COVID has already “ended,” and previous protective measures such as masks, hand hygiene, and vaccines seem to have been rejected for symbolic reasons. The increased transmissibility and immune evasion capabilities of JN.1 clearly pose a challenge to this, especially for immunocompromised individuals. It is worth noting that many media outlets have irresponsibly referred to COVID as “little AIDS”—the ability to downregulate MHC molecules is similar to HIV Nef.

This month, many studies related to COVID have been published in prestigious journals. It seems that we should also set aside our prejudices and preconceived notions, and follow reason and emotion to learn and consider. Literature provides some simple facts, simple views, and some common sense, greatly expanding our horizons while also enabling us to avoid harm and live better lives.

COVID: Caution with Molnupiravir (Especially Dangerous for Those with Weak Immune Systems)

References:

Harris E. COVID-19 Infection Tied to Slight Cognitive Deficits. JAMA. Published online March 22, 2024. doi:10.1001/jama.2024.2087

Al-Aly Z, Rosen CJ. Long Covid and Impaired Cognition – More Evidence and More Work to Do. N Engl J Med. 2024 Feb 29;390(9):858-860. doi: 10.1056/NEJMe2400189. PMID: 38416434.

https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(24)00155-5

https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(23)00393-2

https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(23)00393-2

Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, Martín-Quirós A, Caraco Y, Williams-Diaz A, Brown ML, Du J, Pedley A, Assaid C, Strizki J, Grobler JA, Shamsuddin HH, Tipping R, Wan H, Paschke A, Butterton JR, Johnson MG, De Anda C; MOVe-OUT Study Group. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022 Feb 10;386(6):509-520. doi: 10.1056/NEJMoa2116044. Epub 2021 Dec 16. PMID: 34914868; PMCID: PMC8693688.

Kidd MR, Kelly PM. PANORAMIC: important insights into molnupiravir use in COVID-19. Lancet. 2023 Jan 28;401(10373):250-251. doi: 10.1016/S0140-6736(22)02593-4. Epub 2022 Dec 22. PMID: 36566762; PMCID: PMC9779907.

(source:internet, reference only)

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