Covid-19 : What is the standard of care treatment ? Does it include hydroxychloroquine ?

Everyday new scientific research brings further information and a path to a possible standard of care treatment for Covid-19.  This in general fails to make it to mainstream media.  This is the status of the treatment for Covid-19 to date.

"It starts with a viral lung infection, it ends with a generalized infection"

A closer look reveals that:

• Deeper understanding of the disease, which is multi-factors, multi-stages and multi-organs, drags us away from the simplistic initial option of testing one product against another.
• The sooner we treat, the more likely we are to avoid a rapid spread of the virus on all organs in the light of the complexity and "damage" that evolves over time into "exponential  danger"; including the severe consequences on asymptomatic cases.
• The role of the active treating doctor/physician on a day-to-day basis is key as the treatment is probably multi-product and requires adaptation according to the patient and the clinical condition of the day.

(Editor's note: this article is updated in real time with the additions of various scientific studies that provide important clarifications, the last one dated August 1, 2020 is that of Julien Andrani et al. including Professor Raoult)

Intervene before the virus has penetrated the cell and/or is activated

The first analysis relates to the most interesting phase of the disease, namely before the virus entered the cell and/or was activated. It is known that the virus enters through the cell via the ACE2 protein receptor and that antivirals, such as hydroxychloroquine, can be effective "virus hook blockers"

A recent study shows a second step,namely the activation of the virus by cleavage of the S protein spike of the virus in S1 and S2. This cleavage is activated by one of the proteases in the organ attacked by the virus.  And this protease is different depending on the attacked organ (lungs, kidneys, heart).

In the event of an attack by the virus on the kidneys, hydroxychloroquine (HCQ) is found to be active, in addition to its antiviral action, against the S protein activation protease.

However, one of the latest studies shows that for lung cells, the virus uses TMPRSS2 protease for cleavage activation.  And it appears that "TMPRSS2 plays against hydroxychloroquine» which not only does not act against the activation role but also that TMPRSS2 decreases the antiviral activity of HCQ on the ACE2 cell (Source 6).

This decrease in HCQ efficacy may explain the results of conflicting studies and the discrepancy with initial in vitro tests of hydroxychloroquine and others that have often been done on macaque kidney cells on which the virus does not use TMPRSS2 but another protease present.

As mentioned below, it is possible to observe that for the area of use of hydroxychloroquine (1uM to 12uM) , for lung cells, the effectiveness of HCQ is greatly reduced for people with a high level of TMPRSS2 and moderately reduced for people with a reduced level of TMPRSS2.

The study reveals that "not everyone» has the same TMPRSS2 level." It appears that people with certain comorbidities (and elderly) have a higher rate.

The best prophylaxis is to quickly decrease the NASAL viral load (by HCQ + TMPRSS2 inhibitor) as demonstrated by a new referenced study (Source 7). A very early decrease in nasal viral load decreases the transmission rate; this action protects the infected patient and the uncontaminated population (Source 9).

COVID-19 is "very SELECTIVE but very FAST" on the most people with a fragile immunity.

Thus the study shows that the inhibition of TMPRSS2 not only acts against the cleavage of the Spike cell but also allows hydroxychloroquine to regain its complete antiviral efficacy against the penetration of the virus in ACE2.

And several "TMPRSS2 inhibitors" exist, many of which are well-know "old molecules» such as bromhexine chloride, a mucolytic cough suppressant.

Combining hydroxychloroquine with a TMPRSS2 inhibitor potentially achieves maximum multi-organ efficacy (lungs, kidneys, heart) against the entry and activation of the virus into cells.

Hydroxychloroquine and TMPRSS2 inhibitor are then complementary. This is also shown by a recent randomized study (Source 8):  significant reduction in intensive care admissions (2 out of 39 vs. 11 out of 39, p -0.006) and significant reduction in deaths (0 vs. 5, p - 0.027).

Thus, by combining the effect of the TMPRSS2 inhibitor giving back to hydroxychloroquine its total early viral effectiveness, combined with the effect of azithromycin (see section 2) it is now possible to anticipate in vivo effects on lung cells in invitro results (Source 8) especially with the goal of reducing as quickly as possible the nasal viral load where TMPRSS2 is very present. (Source 10) (this sentence is added on August 1st following the publication of the named study).

It is important to note, without judging their effectiveness, that the "other solutions" studied in the various clinical trials occur after the COVID19 virus has already penetrated the cells and been activated.  So:

• The lopinavir/ritonavir combination is designed to block the virus's replication protease.
• The remdesivir, favipiravir, ribavirin aims to block the synthesis of viral RNA
• Some interferons may act as antivirals.

Moreover, according to various studies, the combination of lopinavir/ritonavir does not appear to have worked and that interferons are cytokines, which for COVID19 characterized in the critical phase by  "cytokine storms",  poses a definite problem.

Also, favipiravir does not appear to have worked in vivo and remdesivir, if it eventually works on lung cells, would appear to "become dangerous" for other organs such as the kidneys.

A significant modification of the microbiota with a bacterial imbalance

The second study reports that in the evolution of the disease, the generalized infection becomes multi-organ and  "corresponds"  to a significant modification of the  microbiota  especially with an important imbalance of bacterial variety. (Source 2 and 3)

In other words (cause or effects) during this phase of disease evolution, some "harmful bacteria take over" and take advantage of the patient's immune weakness.

If this imbalance is confirmed, it would then appear that antibacterial agents, such as azithromycin, are necessary, and even more if they are able to act as "anti-cytokines" also the latest Italian study shows a mortality rate for the hydroxychloroquine + azithromycin group of 23% vs. 51% for the control group (Source 7).

In any case it appears then that the prophylactic and therapeutic solution is unlikely to be in a single product but in a combination of different molecules.

The virus is responsible for heart problems, not hydroxychloroquine

A third study shows that "hydroxychloroquine is not the cause of heart problems» but the person responsible is directly the virus."  (Source 4 and 5).  Put another way, the reality is that:

"It starts with a viral infection, and ends with a generalized multi-organ inflammation-infection"

In conclusion, first of all, the understanding of the disease "takes us away from the over simplistic initial option to test one product against another one " because the disease is multi-factors, multi-step and multi-organ.

Furthermore, the earlier we intervene the more likely we are to prevent the virus from spreading rapidly (from nasal cells and throat) to all organs as the complexity and "damage" evolves over time into "exponential  danger" especially with severe consequences on asymptomatic.

Finally, the active day-to-day role of the treating physician is a key factor, as an effective treatment is likely to be multi-product (including corticosteroids), adapted according to the patient and its clinical condition of the day.

Read also:

Covid-19: medicine biased by statistics

Source:

1. COVID-19: pathophysiology of a multi-faceted disease
2. Potential contribution of beneficial microbes to the COVID-19 pandemic
3. Time dynamics of human respiratory and intestinal microbiomes during COVID-19 in adults
4. Cardiovascular magnetic resonance imaging results in patients newly cured of coronavirus disease 2019 (COVID-19)
5. Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases
6. Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2
7. Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial
8. Hydroxychloroquine effectiveness for COVID-19: a clarified situation?
9. How does SARS-CoV-2 cause COVID-19??
10. In vitro tests of the combination of hydroxychloroquine and azithromycin on SARS-CoV-2 show a synergistic effect

Thanks to the researchers and authors of the articles cited in the links of this article.