11 Nov 2021 Episode 187 : News and some critical reflections on antivirals and vaccine risk/benefit

Thu, 11/11/2021 - 19:20

Dear colleagues,

News on drugs

The big news was the clinical success of the protease inhibitor from Pfizer PF-07321332 or Paxlovid

 

Ep 187-1: Jennifer Couzin-Frankel in Science Insider Health, based on the press release by Pfizer, stating that the drug when orally taken within 3-5 days after symptom onset prevented hospitalizations in subjects with underlying risk by 6-8 times.  The orally available protease inhibitor is combined with Ritonavir to decrease breakdown in the liver, hence prolonging its action.   Not clear from different documents what the exact dosage was. 

Clearly, as is the case in HIV and hepatitis C treatment, it is logical to think about a combination with Molnupiravir, the Merck polymerase inhibitor.  

https://www.science.org/content/article/pfizer-antiviral-slashes-covid-19-hospitalizations?utm_campaign=news_daily_2021-11-05&et_rid=17279631&et_cid=3986069

 

https://clinicaltrials.gov/ct2/show/NCT04960202?term=PF-07321332&draw=2&rank=4

 

Ep 187-2: Owen in Science 2 Nov describes how the product was selected (Table 1). It is active at nanomolar conc. against SARS-CoV-1, SARS-CoV-2 and MERS as well as other human CoV (Fig 3).  Rather high dose (1000 mg/kg) is needed to strongly suppress viral load and improve histopathology in a mouse model.

 

Ep 187-3:  Abdelnabi in bioRxiv 5 Nov on results of PF-332 in vitro and in hamster model

  • Equipotent in vitro activity against the alpha, beta, gamma and delta SARS-CoV-2 VOC: IC50 between 100 and 300 nM.
  • Completely arrest replication of the alpha variant in primary human airway epithelial cells grown at the air-liquid interface.
  • Treatment of Syrian Golden hamsters with PF-332 (250 mg/kg, twice daily) completely protected the animals  against intranasal infection with the beta (B.1.351) and delta (B.1.617.2) SARS-CoV-2 variants.
  • Treatment of SARS-CoV-2 (B.1.617.2) infected animals with PF-332 completely prevented transmission to untreated co-housed sentinel animals

 

More concerns about Molnupiravir

 

In Ep 183, I already discussed the mechanism of action of this novel polymerase inhibitor: not chain termination, but induction of “catastrophic” mutations in the virus.  The concern, mainly illustrated in Ep 183-11, was that it could also be incorporated in host DNA of dividing cells and inactivate genes, potentially leading to cancer or birth defects.  This suggestion was based only on experiments in cell lines.

 

Ep 187-4:  the well-known HIV researcher William Haseltine expresses the concern that suboptimal treatment could lead to novel SARS-CoV-2 variants, which could be resistant to the drug, but might also have altered transmission and virulence characteristics.  

The drug developers replied that they have no indication for this scenario and suggest drug combination (with protease inhibitors) to lower the risks.

 

An unexpected effect of the anti-depressive Fluvoxamine

 

Ep 187-5:  Fluvoxamine, a well-known serotonin-reuptake inhibitor, mainly used for psychiatric indications was shown to reduced risk for hospitalization and death.  Finally an example of successful “drug repurposing”? 

 

Ep 187-6: Reis in Lancet Global Health (27 Oct 2021):  it is part of the TOGETHER trial network and was done in Brazil (Jan-August 2021, hence the “gamma and delta period”).

They focused on non-vaccinated patients with confirmed SARS-CoV-2 of max 7 days and at least one risk factor (including hypertension, diabetes, overweight, but also transplant or immune suppression).  About 750 in treatment (2 X 100 mg Fluvoxamine) and in placebo arm.   The study was stopped because of clear superiority of the active arm.  

Risk of hospitalization was

  • Intention to treat: 11 % in active vs 16 % in placebo (Relative risk = 0.68)
  • Per protocol: RR 0.34

Risk on death:

  • Intention to treat: 17 vs 25 (Odd’s ratio = 0.68)
  • Per protocol: 1 vs 12 (OR = 0.09)

The mechanism is unclear.  No viral load measurements or other lab parameters are reported, but in the discussion it is supposed that various “anti-inflammatory” mechanisms may be the reason.  This is worked out in the next review.

 

Ep 187-7:  Sukhatme in Front Pharmacol (April 2021) suggest severalpotential mechanisms (Fig 1):

  • Potential anti-thrombotic effect via decreased platelet aggregation
  • Potential anti-inflammatory effects via decreased mast cell degranulation, sigma-1 receptor activity, inositol requiring enzyme 1 and melatonin.
  • Potential antiviral effects via lysosomotropism and inhibtion of acid sphingomyelinase.

 

Obviously, the clinical effect of fluvoxamine is clear, but the plethora of possible mechanisms is, unfortunately, very much reminiscent of what was proposed for chloroquine, azithromycin, ivermectin etc.  Therefore, independent confirmation of these results in a context where viral and inflammatory parameters can be carefully monitored is absolutely needed. 

This type of study could also clarify if/how Fluvox could be complementary to either genuine antivirals (entry-, polymerase and protease inhibitors) or to anti-inflammatory agents (dexamethasone, anti-IL6).   Moreover, in this study, Fluvox was administered in the non-hospitalized patients and therefore the question whether it has also a role in the later phases, when the inflammation is already established.   

 

Worrying news on vaccines  

 

Ep 187-8: Cohn in Science 4 Nov illustrates the decline of vaccine effectiveness in the well-controled cohort of US military veterans,  being 2.7 % of the US population (hence over 800,000 people).

It is very evident that vaccine effectiveness against infection  decreases from March to Sept

  • For Moderna from 89 % to less than 58%
  • For Pfizer from about 87 to 43
  • For Janssen from 86 to 13 only !!

Also protection against death for + 65 yrs old declined: Moderna 75 %, Pfizer 70 % and Janssen 52 %

So clearly, a third jab is highly indicated!

 

Ep 187-9: A worrying study from the Netherlands on onwards transmission within households, comparing index and secondary cases, who were either vaccinated or not. Effectiveness of full vaccination of the index case against transmission to unvaccinated and fully vaccinated household contacts, respectively, was 63% (95% confidence interval (CI): 46–75) and 40%

(95% CI: 20–54), in addition to the direct protection of vaccination of contacts against infection.

Hence: Possible decreasing vaccine effectiveness against infection and against

onward transmission could result in increased SARS CoV-2 circulation among populations with high vaccine coverage.

 

187-10: Hoeg medRxiv Sept 2021:   Preprint on myocarditis following 2nd dose of Pfizer: For boys 12-17 without medical comorbidities, the likelihood of post vaccination dose two Cardiac Adverse Event is 162.2 and 94.0/million respectively. This incidence exceeds their expected 120-day COVID-19 hospitalization rate at both moderate (August 21, 2021 rates) and high COVID-19 hospitalization incidence. Quantification of the benefits of the second vaccination dose and vaccination in addition to natural immunity in this demographic may be indicated to minimize harm.  

 

Clearly, this type of information becomes more difficult to explain to a lay audience.

 

I have to stop here, because we have to prepare for a family travel….

 

Best wishes,

 

Guido