2 April 2022 Episode 253 Treatment and omicron

Episode 253 : Treatment and omicron

Dear colleagues,

Today’s episode focuses on the questions how active the established specific anti-SARS-CoV-2 treatments are against omicron BA.1 and BA.2.  In addition, I looked for evidence of resistance development against Remdesivir, Molnupiravir or Nirmatrelvir.  And there is a final (??) negative judgment about Ivermectin.

First a table with all the (sometimes very confusing) names (see first pdf in attachment) 

Ep 253-1: Rajal J Med Virol Genetic differences between variants

As can be seen, Omicron has a number of mutations, not only in Spike, but also in ORF1 (encoding thevarious components of polymerase and protease).  Moreover, some of these mutations are common to BA.1 and BA.2, while other are different.  Hence, it is not immediately clear which anti-virals will remain active against which sub-variant.  

Ep 253-2: Ohashi bioRxiv 28 Feb 2022 comparison of activity in several variants including omicron BA.1 and BA.2

Molnupiravir (EIDD-1931) and Nirmatrelvir keep good activity against both BA.1 and BA.2

Sotrovimab (S309) loses about 10 fold activity against both sublineages

Casivirimab and Imdevimab also pporly active against both sublineages

Ep 253-3: Takashita NEJM Feb 2022 focus on BA.2

Etesevimab and Bamlanivimab essentially inactive against BA.2

REGN combination and Sotrovimab lose a lot (50- 60 X)

Evusheld still active, but based on Cilgavimab only

Remdesivir (GS-441524), Molunipiravir (EIDD-1931) and Nirmatrelvir (PF-07321332)  fully active

Ep 253-4: Bruel medRxiv 12 March comparison BA.1 vs BA.2 v

Confirmation that

• The Eli Lilly cocktail (Bam-Ete) and the REGN cocktail (Casi-Imde) no longer useful for omicron
• Sotrovimab loses most activity against BA.2, but keeps activity against BA.1
• Evusheld keeps some activity against BA.2, less against BA.1 but fully dependent on Cilgavimab  

ALL THE FOLLOWING PAPERS FOCUS ON “OMICRON” , BUT IT IS IN FACT BA.1, since the work was carried out before BA.2 was prevalent.

Ep 253-5:  Vangeel Antiv Res Feb 2022

Remdesivir, Molnupiravir and Nirmatrelvir are equally active against omicron (BA.1) as against other variants

Ep 253-6:  Pengfei Li Cell Res Jan 2022 : Omicron (BA.1) is sensitive to nirmatrelvir molnupiravir and the combination

The antiviral effects of combining molnupiravir and nirmatrelvir in WT SARS-CoV-2-infected Calu-3 cells based on intracellular viral RNA levels (n =3–4) shows evidence of synergy

Ep 253-7: Pitss bioRxiv Feb 2022 confirmation of activity Remdesivir against severel variants, including omicron BA.1

Ep 253-8: Rosales Jan 2022 Nirmatrelvir, Molnupiravir, and Remdesivir maintain potent in vitro activity against the

SARS-CoV-2 Omicron variant (BA.1)

CONCLUSIONS :

1. Remdesivir, Molnupiravir and Nirmatrelvir maintain full activity against omicron BA.1 and BA.2
2. The Regeneron and Eli Lilly mAb cocktails no longer useful against omicron BA.1 and BA.2
3. Sotrovimab loses all activity against BA.2 and has weak activity against BA.1: probably 10-fold higher doses needed
4. Evusheld: Tixagevimab compound inactive against both BA.1 and BA.2; Cilgavimab good activity against BA.2, but is very weak against BA.1.   

Obviously, in subjects with immunocompromise and chronic SARS-CoV-2 infection, the use of partly active mAb could result in induction of resistance-associated mutations.

Is there evidence of resistance development towards Remdesivir, Molnupiravir or Nirmatrelvir?

1. Remdesivir: 2 papers found

Ep 253-9: Szmiel PLoS Pathogens Sept 2021: in vitro selection of resistance towards Remdesivir.

After serial passage a single mutation E802D in the RNA-dependent RNA polymerase NSP12. 

• Conferred only 2-2.5 fold resistance
• Associated with reduced fitness
• Associated with “spontaneous” mutations in Spike H69, E484, N501, H655, without immune pressure
• Is very rare in untreated subjects: 36 E802 mutations in > 800,000 sequenced cases (of which 24 E802D)

Ep 253-10:  Shiv Gandhi  Nat Comm March 2023: the same E802D mutation identified in an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection in 2020 (ancestral COVID strain).   This mutation was indeed associated with a moderate 6-fold resistance and reduced fitness of the virus.    

The Remdesivir treatment was followed by Casivirimab + Imdevimab with reduction of viral load and improvement of clinical symptoms.

2. Molnupiravir: no evidence found in published studies.  The mode of action of Molnupiravir is to induce hypermutations in SARS-CoV-2.  Therefore, it is possible that Molnupiravir could facilitate development of resistance towards co-administered drugs.  

3. Nirmatrelvir: no evidence found

The end of the Ivermectin saga?

As you remember, the worm-killer Ivermectin has been proposed as a cheap and effective COVID drug, based on in vitro activity against SARS-CoV-2 at very high concentrations and a presumed anti-inflammatory activity.  Many small poorly controlled studies claimed a beneficial effect of Ivermectin, but there has always been a lot of scepticism.  

Ep 253-11: Reis on behalf of TOGETHER consortium in NEJM 30 March

Double blind randomized controlled study in 3515 patients with at least one risk factor and within 7 days of diagnosis were treated with either Ivermectin 400 µg/kg or placebo once a day for 3 days

→ No difference in outcome = hospitalization due to COVID within 28 days.