9 Feb 2021 Ep 108 part 3 Colchicine and Ivermectin

Tue, 02/09/2021 - 14:52

Dear colleagues,

The daily saga on vaccines and variants:

  1. A comment in Science about the poor performance of the Astra Zeneca (Chimp Adeno) vaccine against the “South-African variant”: it showed only 22 % protection against mild-to-moderate COVID, while the efficiency against the ‘WT” viruses was 75 %.  As you may remember J§J (Adeno 26) claims 57 % and Novavax (S protein) 49 % efficacy against mild disease in South-Africa, while the protection against severe disease for the latter two vaccines was much higher and not yet known for A-Z.
  • Clearly, these data have to be interpreted with caution, as they are all based on press communications only.  It is, for instance, not clear how the distribution of WT and “variant viruses” was in all these trials

 

  1. Another press release from China, stating the “Chinese” Adenovector (Ad5) vaccine  offers a protection in phase 3 in Pakistan in a very similar range than Astra-Zeneca and J§J, obviously in a country where most probably the new variants were not yet circulating during the trial.    

 

  1. A nice slide show by Abdool Karim on all the recent data about vaccines and the South-African variants.  All of these data have been discussed in previous episodes and, again, most are based on “preprints” or press releases.  It is really not possible to make final statements for instance on which vaccine would protect best against the South-African (or other)  variant, since in the trials of the mRNA (Pfizer and Moderna) and the Russian Sputnik V (Ad26-Ad5) the variants were not yet circulating in the trial populations. The invitro date on neutralization are also not comparable, because different assays were used.
  • Anyhow and unfortunately, it is likely that none of the present generation of vaccines will fully protect against the South-African and Brazilian variants, but the partial protection they offer might be sufficient to protect against severe disease.  To what extent this statement is true, will become clear in the next weeks.
  • It is also likely that we will need a booster by the next generation, which will include these variants

Please note again that all the above is based on non-peer reviewed data and press releases. Interpret with caution !!!

 

Part 3 is last episode on immune modulators for now.  Partly based on hints by colleagues, I will discuss three topics: colchicine, ivermectin and NIH Guidelines as a conclusion

See

  1. Colchicine: is a well-known anti-inflammatory drug that acts by inhibiting the inflammasome and is in clinical use for gout, rheumatoid disease and pericarditis.
  • A recent review of 3 observational and 3 RCT by Leonard Chiu et al (Ep 108-28) concludes that a clearly reduced risk on mortality has been seen in the observational studies Odds ratio 0.36 (95% CI: 0.17, 0.76), while this effect was less pronounced in the RCT OR 0.49 (95% CI: 0.20, 1.24), hence not really statistically significant in none of the RCT (slide 2-3)….
  • Since this drug could be easily given to non-hospitalized patients the RCT by Tardif (Ep 108-29) on over 4400 PCR diagnosed subjects is specifically interesting.  The primary endpoint (death or hospitalization) occurred in 4.7% of the patients in the colchicine group and 5.8% of those in the placebo group (odds ratio, 0.79; 95.1% confidence interval (CI), 0.61 to 1.03; P=0.08) (slide 4).  There was a clear protection against pneumonia: 2.9% colchicine and 4.1% of placebo patients (P=0.02). Diarrhea was reported in 13.7% and 7.3% in the colchicine and placebo groups (P<0.0001), as an expected side effect.
  • The small study by Lopes (Ep 108-32) on hospitalized patients shows nice results, with regard to need for mechanical ventilation (Fig 2); discharge from hospital (Fig 3) and decrease of CRP (Fig 4), without apparent side effects (Table2), all on slide 5.
  • The similarly small GRECCO trial (Ep 109-31) also shows clinical benefit in hospitalized patients (slide 6), but there was no real laboratory correlate.  Diarrhea and abdominal pain were side effects , as expected. 

 

  1. Ivermectin:  there have been many studies with ivermectin, but the field has been “spoiled” by three elements:
  • Claims about antiviral activity are based on in vitro observations with doses that are orders of magnitude higher than the maximum tolerated non-toxic concentrations in humans
  • Claims about anti-inflammatory activity are equally questionable as they rely on in vitro data with cell lines and a single paper on partial prevention of LPS-induced toxicity in mice, also with a dose that is quite higher than what is achievable in humans
  • There have been a number of small uncontrolled studies, mainly in South-America and the Middle East that made big claims in the early days.

More recently, however, there have been several (in)formal reviews about the effectiveness of IVM in various settings (preventive, early treatment, late treatment, post-exposure prophylaxis), which almost all show clear positive effects (see Ep 108-32,33,34).  Especially the latter paper contains a very long list of references.  It is obvious that some proper RCT have already been performed and a number of large RCT is still underway. 

At present, I can only repeat that I don’t see a mechanism to explain how a low dose (often even single dose) of IVM could have such a broad and clear effect on primary and secondary prevention as well as on early and late treatment of COVID.  

I feel incapable of judging the value of all these studies on IVM  by a variety of centers in many countries, mostly not in peer-reviewed journals. 

On the other hand we cannot deny that, superficially, the combined evidence on IVM seems at least equally strong than for instance the previously discussed corticosteroids, “simple” colchicine or the “high tech” cytokine antagonist, which have the “conceptual advantage” of offering a clear rationale and a “track record” of success in inflammatory diseases, therefore being published in good journals, showing promise, but clearly not offering “the magic bullet” either.

 

  1. NIH Guidelines
  • The guideline on corticosteroids (CS) (Ep 108-35) contains a thorough analysis of a number od RCT and has clear conclusions: mainly based on RECOVERY,
    • Dexamethasone seems primarily indicated in patients who were mechanically ventilated or required supplemental oxygen.  There was no clear benefit in patients who did not require oxygen.
    • Although there is a good rationale to combine CS with antivirals, there is no data.
    • One has to be careful about side effects (see text)

 

  • On Tocilizumab (TCZ) (Ep 108-36) the panel was looking mainly at the REMA-CAP study, but the conclusion is not unisono:
    • No definitive  recommendation
    • A single dose of 8mg/kg in addition to corticosteroids could be administered to  “patients who are within 24 hours of admission to the ICU and who require invasive or noninvasive mechanical ventilation or high-flow oxygen (>0.4 FiO /30 L/min)”

 

  • On Baricitinib (the JAK antagonist – Ep 108-37) the panel has no clear positive recommendation for or against, but makes two remarks:
    • If using baricitinib, it has to be combined with Remdesivir
    • Not enough data on the combination with corticosteroids, but be careful, since both are immune-suppressive.

 

  • On Ivermectin (Ep 108-38), the panel is not impressed with the accumulated evidence and states that there are “insufficient data to recommend either for or against

 

My personal interpretation

Obviously, all the fuzz in the early days about repurposing drugs such as CCQ, Azithromycin, HIV protease inhibitors etc, with first “promising” results, which were ultimately not confirmed has made us all skeptical about this principle, unless there is

(1) a good rationale on a clear potential mechanism;

(2) a number of solid RCT, performed by collaborating centers who have experience;

(3) proper peer review. 

If I were a clinician today , I would certainly be tempted to use a drug like colchicine in an outpatient setting and steroids in a hospital setting for critically ill patients, because we know how to use these drugs and we can be confident about their anti-inflammatory effects.  As a researcher, I would be interested in experimental treatments, such as nebulization with type 1 IFN and/or IV monoclonal anti-Spike antibodies in the early phase as well as the anti-cytokine antibodies in late stage. 

However, as I already explained, it is now time to make sure we collect more detailed epidemiological, clinical, laboratory and immunological data (including transcriptomics) in large very well standardized trials, because that will allow us to analyze “a posteriori” which patient profiles can be chosen to take maximum advantage of regimen A or B.         

Where in this scheme will Ivermectin fit? I do not know, but, of course, if it can be shown that it is of benefit, we should use it.  

 

For the coming days, I will be busy with other tasks, but afterwards, I will devote an episode to T cells…..

 

Best wishes,

 

Guido