Comprehensive Update on SARS-CoV-2 and COVID-19

Posted byceopatePosted inUncategorized

This blog post continues a blog series providing a comprehensive update on COVID-19 and the virus that causes it. The last blog post in this series addressed the effectiveness of ivermectin in treating COVID-19. We reviewed well-designed, well-conducted studies that clearly established:

  1. Ivermectin was not effective in shortening the course of illness;
  2. Ivermectin was not effective preventing worse clinical outcomes with SARS-CoV-2 infection; and
  3. The lack of benefit was not only at standard dosing, but at high doses.

As I concluded, while I question the motives of many of the physicians and organizations that pushed ivermectin as a cure-all for COVID-19 beyond 2020 as vaccines became available and clinical trials were already casting doubt on the effectiveness of ivermectin for COVID-19, my objection to those prescribing it were largely based on the following:

  1. The purported benefits were being overhyped and oversold, without informed consent of patients.
  2. Even as data continued to amass from high quality studies that ivermectin simply was not effective against COVID-19, the fact that many of these same doctors continued to promote it that suggests to me that their assessment and promotion of ivermectin was never, or at least no longer, based on science, but either their egos and attempts to preserve their reputations are getting in the way of admitting they were wrong or they are continuing to personally benefit from pushing the use of ivermectin.
  3. My biggest concern was that while promoting ivermectin, they were attacking proven options that people had to protect themselves against severe disease including non-pharmaceutical measures and vaccines as ineffective and dangerous.

As I stated in that blog piece, I hope we can now put a stake through the heart of the notion that ivermectin has a role in the therapeutics for COVID-19. But, could these rogue doctors and anti-vax organizations have been right about hydroxychloroquine, even if wrong about ivermectin? Well, the hydroxychloroquine story is worse. Science has put the nails in this coffin.

No medication is without potential side effects and adverse events (side effects are unpleasant symptoms you might experience such as with Paxlovid when people report an unpleasant after-taste, while adverse events are harms, sometimes minor and temporary such as the potential for anti-inflammatory medications to cause impairment to kidney functioning, but other times, these harms can be more serious or longer-lasting). Early on in the pandemic, in my cautions to persons who told me that they intended to seek out ivermectin and/or hydroxychloroquine from some of these sketchy telemedicine services where you fill out a form, pay a lot of money, and then get a prescription, I would often hear back as the rejoinder – “even if it doesn’t work, what’s the harm?”

I tried, almost always unsuccessfully, to point out what the harms could be and the fallacy of their argument:

  1. All medications have potential side effects and potentially can cause adverse events. When prescribed by a physician, we generally help patients weigh the risks of leaving their disease untreated versus the risks of taking the recommended medication. Even with safe and effective medications, there are risks, but these risks are generally much less than those posed by not treating the patient’s disease. Ivermectin is generally well-tolerated, but it too has risks. When used to treat diseases that we know it is effective against, usually patients and physicians will agree that the risks of ivermectin are greatly outweighed by its benefits in treating the condition.
  2. If a medication has no clinically significant benefit in treating a disease, then the benefit (zero in this case) never outweighs the potential risks of the medication, no matter how minor or rare.
  3. Finally, a tactic that I have used as an attorney in weighing credibility of witnesses, as a CEO in weighing the credibility of different arguments for a decision that needs to be made, and during the pandemic for assessing which physicians were trusted voices on COVID-19 is to examine the totality of their statements and actions for what I refer to as internal inconsistencies. In this case, I would attempt to point out the internal inconsistencies of those wanting to take ivermectin or hydroxychloroquine and asking what the harm in doing so would be, by pointing out their desire to take a medication with no proven benefit while giving no consideration at all to the potential side effects and adverse events, while refusing a vaccine and ignoring all of the documented benefits while obsessing over the relatively minor side effects and rare adverse events, without any weighing of these risks against the risks of getting COVID-19.

Now, lets look at three studies that are well-designed, well-conducted, and like the case of ivermectin, should cause anyone willing to be guided by the science rather than ideology, to agree that hydroxychloroquine was not only ineffective in the treatment of COVID-19, but unlike the case of ivermectin, people were hurt by hydroxychloroquine.

  1. Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19. The RECOVERY Collaborative Group. https://www.nejm.org/doi/full/10.1056/NEJMoa2022926. The RECOVERY TRIAL

This was a randomized, controlled, open-label trial comparing various possible treatments relative to usual care in hospitalized patients with COVID-19. 1,561 patients were randomized to the hydroxychloroquine group and 3,155 to the usual care arm. The primary outcome was 28-day mortality.

The enrollment of patients for the hydroxychloroquine group was closed on June 5, 2020 after early results already established that there was no benefit to treatment with hydroxychloroquine. Let me emphasize this point. We knew from a high-quality trial that hydroxychloroquine did not benefit patients who were hospitalized with COVID-19 as early as June 5, 2020, yet a number of physicians making appearances on cable networks and in their social media continued to push this as a treatment for COVID-19.

Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P=0.15). Further, patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine.

Importantly, the results were consistent across subgroups according to age, sex, race, time since illness onset, level of respiratory support, and baseline-predicted risk, in other words, this was not just the case for the elderly. The same results were obtained in young and middle-aged adults.

The authors concluded that the patients who received hydroxychloroquine had a longer duration of hospitalization and, among those who were not undergoing mechanical ventilation at baseline, there was a higher risk of invasive mechanical ventilation or death than for those who received usual care.

In this study, patients hospitalized for COVID-19 were randomized and assigned to receive one of four repurposed drugs (one was hydroxychloroquine) or assigned to the control group. This study included 11,330 patients hospitalized for COVID-19 at 405 hospitals in 30 countries. 947 patients were assigned to receive hydroxychloroquine. Death occurred in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23). For patients not already receiving mechanical ventilation (on a ventilator to assist with breathing), 75 patients receiving hydroxychloroquine progressed to the need for ventilator support compared to 66 in its control group. Further, there was no evidence to suggest that treatment with hydroxychloroquine reduced the time to recovery.

The authors concluded: “For hydroxychloroquine, the joint rate ratio for death (combining the Solidarity and RECOVERY trials) was 1.10 (95% CI, 0.98 to 1.23), with no apparent benefit whether the patient was receiving ventilation or not. This confidence interval rules out any material benefit from this hydroxychloroquine regimen in hospitalized patients with Covid-19.”

This study was a randomized, controlled, double-blinded trial that unlike the two studies above that examined hydroxychloroquine’s efficacy in treating hospitalized patients, evaluated its effectiveness in treating outpatients with COVID-19 who were not seriously ill. All study participants had at least one risk factor placing them at risk for progression to severe disease. The primary outcome for this study was the need for hospitalization by day 30 following the initiation of treatment.

From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalization between hydroxychloroquine and placebo groups (44/689 [6·4%] and 57/683 [8·3%], RR 0·77 [95% CI 0·52–1·12], respectively, p=0·16).

Of note, I mentioned above that the investigators suspended the RECOVERY trial on June 5, 2020 because of the lack of evidence of benefit from hydroxychloroquine based on the ethical premise that it would be inappropriate to continue to allow study participants to be treated with hydroxychloroquine. Similarly, in the SOLIDARITY study, the World Health Organization suspended the hydroxychloroquine arm of this trial on June 17, 2020 due to lack of benefit and the same ethical principles. Yet, a relatively few doctors with large social media followings, continued to make these claims for years afterwards.

To be clear, if people don’t want to take the COVID-19 vaccines, I support their right to decline them. If people don’t want to take any precautions against getting infected, I support their right to do so, but I do ask that they protect others when they get infected. What I object to is physicians, all the while promoting their faculty positions, their training at prestigious medical schools, their board certifications, etc., purposefully misleading and deceiving the public for their own ideological or financial or whatever other personal gain. I think that our duty as physicians is to inform the public and our patients with facts, the best medical evidence and the best recommendations of our collective professional organizations so that they can make informed decisions as to what is the best course of action for them. As physicians, we should NEVER manipulate the public or our patients into making ill-advised decisions. If patients are provided with good information, but want to decline our advice, that is their choice to make.

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