Sat, 01/28/2023 - 20:49
Episode 311: Will the variant CH.1.1 (or CA.3.1) beat XBB.1.5? Are Remdesivir and Molnupiravir out?
Dear colleagues,
The news about COVID is mixed: hospitalizations and deaths decrease, but the virus keeps circulating, now more under the radar, and evolves further, as does our insight in treatment options. Unfortunately, from both those ‘fronts” the news is probably not so bright….
Par 1 CH.1.1 and CA.3.1
As we have seen in previous episodes, ECDC was expecting that the recombinant XBB.1.5 will take over the epidemic in Europe, but as you can see below, in Belgium, there is another competitor: the BA.2.75 derived CH.1.1 which seems on the rise. It has acquired the L452R mutation, which is typical for the Delta virus.
Note: also CA.3.1 has L452R, but derives from another branch than CH.1.1
Delta: key mutations
Ep 311-1: Erin Frater Fortune 27 Jan: nick name “Orthus” = a mythical two-headed cattle dog killed by Hercules.
Ep 311-2: Anne Xaillé Top Santé 24 Jan
Ep 311-3 : GISAID on CH.1.1
CH.1.1 hash 39 mutations in Spike; 20 in ORF1 (polymerase and protease complex); 12 in other genes
The variant is spreading mainly in South-East Asia, Hong-Kong, Ireland, parts of UK, New Zealand, coming up in the Netherlands; but not (yet ?) in US or France. The date in GISAID are compiled over the last 60 days
Ep 311-4: Outbreak report on CA.3.1
It has a similarly high number of mutations, but, at present, a clearly much lower global distribution.
WHAT IS THE Possible SIGNIFICANCE of these new variants?
Ep 311-5: Panke Qu medRxiv 17 Jan 2023: Comparison of new variants XBB.1.5, CH.1.1 and CA.3.1 for neutralization sensitivity and fusion capacity
Neutralization of Omicron XBB.1.5, CH.1.1, and CA.3.1 subvariants by sera of bivalent or monovalent mRNA vaccinated health care workers (HCWs) and BA.4/5 wave infection.
Bivalent HCW: basic vaccination + monovalent RNA + bivalent (WT/BA.5) vaccine
3 dose HCW = basic vaccination + monovalent RNA
BA.4/5 infection: 20 subjects tested positive during the BA.4/5 wave of infection, of whom 17 unvaccinated and 3 with 3 doses of vaccine
Clearly, CH.1.1 and CA.3.1 are most “neutralization-resistant”, but either infection with BA.5 or bivalent vaccination increases the level of neutralization as compared to 3 doses of vaccine.
Fusogenic capacity of CH.1.1 and CA.3.2 is higher than BA.2, but lower than D614G ( = Wuhan strain with 1 mutation, that “conquered Europe” in 2020à
IMPORTANCE OF L452R MUTATION
Ep 311-6: Veronika Tchesnokova J Clin Microbiol Nov 2021: Acquisition of the L452R Mutation Triggers Recent Massive Expansion of SARSCoV-2 Variants.
Global analysis revealed that L452R is nearly omnipresent in a dozen independently emerged lineages, including
the most recent variants of concern/interest delta, kappa, epsilon and iota
It was reported that the L452R mutation is associated with immune escape and could result in a stronger cell attachment of the virus, with both factors likely increasing viral transmissibility, infectivity and pathogenicity.
Ep 311-7: Chihiro Motozono Cell Host Microbes July 2021 SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity
Escape of two naturally occurring SARS-CoV-2 mutations (L452R and from S RBM-specific CD8+ T cells
Increase in the binding affinity to ACE2, viral infectivity, fusogenicity, and replication capacity by the L452 mutation
Par 2 Are Remdesivir and Molnupiravir out?
Ep 311-8: Cochrane Review on Remdesivir (sorry I have only access to the summary)
Nine RCT with almost 6000 pt on Remdesivir compared to standard of care + placebo
- In hospitalized patients:
Mortality: little or no difference day 28 (risk ratio (RR) 0.93, 0.81 to 1.06. and day 60 (RR 0.85, 95% CI 0.69 to 1.05); or in‐hospital mortality at up to day 150 (RR 0.93, 95% CI 0.84 to 1.03;
Clinical improvement: decreases risk of clinical worsening within 28 days (hazard ratio (HR) 0.67, 95% CI 0.54 to 0.82)
No difference in adverse effects
- In non-hospitalized patients: only 1 RCT
probably decreases the risk of clinical worsening (hospitalisation) at up to day 28 (RR 0.28, 95% CI 0.11 to 0.75;
BUT: very low‐certainty evidence!
Ep 311-9: Butler PANORAMIC trial Molnupiravir in high-risk community members
Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]
However, participants in the molnupiravir plus usual care group recovered faster than those in the usual care group, had a higher rate of early sustained recovery, and had fewer general practitioner consultations.
This faster patient-reported recovery was consistent with a reduction in detectable virus and viral load in participants who received molnupiravir compared with those who received usual care only.
CONCLUSIONS
- The complex omicron variants CH.1.1 and CA.3.1 are very neutralization-resistant, probably because of L452R mutation (= example of “convergent evolution”). CH.1.1 is spreading extensively in some countries and is coming up also in the Netherlands and Belgium. No data on pathogenicity yet.
- While there is clear in vitro and also some in vivo evidence that the polymerase inhibitors Remdesivir and Molnupiravir can lower SARS-CoV-2 replication, the clinical benefit now seems less convincing than we had hoped, based on early phase 3 and “real world” data (see Episode 295). A possible explanation is that when treatment is started several days after symptoms onset, the “inflammatory” phase has already started in the most vulnerable patients and reduction of viral load offers little benefit to stop that “self-perpetuating” process?
Best wishes,
Guido
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