Let me start by saying that I still think that Paxlovid is a very useful medication against Covid and I prescribe it often, but I don’t think it’s a miracle drug. Here’s why—

You may have heard about Paxlovid rebound—When Covid sometimes comes roaring back when the drug is stopped at 5 days.

“The 7-day and 30-day COVID-19 rebound rates after Paxlovid treatment were 3.53% and 5.40% for COVID-19 infection, 2.31% and 5.87% for COVID-19 symptoms, and 0.44% and 0.77% for hospitalizations.”

In that same study, Molnupiravir rebound occurred as well, but it’s a moot point for me at least, because I won’t prescribe that drug due to its lackluster efficacy and potential for significant toxicity.

An Ounce of Prevention

When there’s a considerable risk for something serious to occur, like a recurrence of Covid, it’s prudent to have a plan in place to prevent that from happening. So is it possible to lessen the frequency or severity of a Paxlovid rebound?

Dr. Paul Auwaerter, head of Infectious Diseases at Johns Hopkins said:

“I think when you're using drugs such as Paxlovid for only 5 days with one specific protease inhibitor, the nirmatrelvir component of the drug, it may be that that is not sufficient.”

So in my mind, rather than relying on Paxlovid as a single agent drug, it makes sense to use a multi-agent approach. The synergistic potential of multiple therapeutics against Covid means that the effect of 1 + 1 can equal more than 2. Taking advantage of synergism is well-known in the use of both antibiotics and antivirals, and a mix of therapies has been published to have excellent efficacy against Covid:

“Subjects with early COVID-19 treated with two-to-four drug combinations showed overwhelming improvements compared to untreated patients.”

And others are thinking along these same lines in regard to potentially synergistic combinations of agents with antiviral activity, like Michael Lin, MD, PhD, associate professor of Neurobiology & bioengineering at Stanford University:

Michael Lin, MD PhD 🧬 @michaelzlin

President @JoeBiden @POTUS is likely to be getting Paxlovid. If so, then to avoid rebound, his doctors should consider two other things that are usually not discussed: remdesivir and the experimental BA.5 booster

Remdesivir failed to reduce mortality in a meta-analysis of 4 large randomized controlled trials of hospitalized Covid patients. It also has the potential for significant toxicity when used in that capacity, which is typically for a duration of 5-10 days. This lack of efficacy combined with the potential for toxicity prompted WHO to recommend against its use for hospitalized patients.

Yet despite all of these negatives when used in late illness, it appears that remdesivir may be potentially safe and effective in early Covid when used for a short course, no more than 3 days, reducing the combined outcome of hospitalization or death from any cause by 87%:

“Covid-19–related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P=0.008).”

But a multi-drug/herbal/supplement cocktail along with Paxlovid can be daunting due to potentially serious drug interactions. Ritonavir, a component of Paxlovid, slows down the metabolism of certain enzymes in the liver. This can cause alterations in blood levels of some drugs, often going way up, but sometimes, paradoxically going down. On the flip side, other drugs and supplements can likewise change the blood levels of Paxlovid, also via actions on liver enzymes.

When considering a multi-agent regimen that includes Paxlovid, a thorough review of every medication and supplement is necessary, along with a plan of action for medications and supplements that interact—But some supplements, especially herbals, can’t be safely cleared for use with Paxlovid because not all are included in drug interaction checkers. And the possibility for drug antagonism cannot be ruled out. Although uncommon, it’s been documented with some combinations of agents studied for Covid.

It’s complex, and it takes time, but I’ve been able to safely orchestrate effective multi-agent Covid protocols that include Paxlovid. In fact, I’ve never relied on Paxlovid as a single-agent and have no plans to do so. I can’t put my faith in any one drug or supplement for this nasty infection. And I think that my regimens have been effective, because thus far I’m seeing a much lower rate of Paxlovid rebound than what’s being seen in clinical studies.

Cash Cow

According to Pfizer, they appear to think that the answer to Paxlovid rebound is to just take more of it, even though that’s not included in its Emergency Use Authorization (EUA). But they’re not exactly unbiased—They want to sell more drug.

“Pfizer Inc. executives said patients who suffer a relapse in Covid-19 symptoms after taking a full course of Paxlovid should take more of the treatment, though current U.S. guidelines limit use to five consecutive days.”

Pfizer is profiting immensely from Covid. In 2021, its revenue was 81.3 billion, roughly double its revenue in 2020. On a recent investor call, Mikael Dolsten, M.D., Ph.D., chief scientific officer and president of worldwide research, referring to immunocompromised patients, said:

“may carry this virus for a very, very long time…And we see that area as a real new opportunity growth area for Paxlovid to do very well, where you may need to take multiple courses.”

The harsh truth is that I can’t think of a strong financial motivation for Pfizer to prevent or reduce Paxlovid rebound that doesn’t involve selling more of their products.

Viral Persistence

Even though Dr. Dolsten refers to the immunosuppressed harboring the virus for a “very, very long time” (I can’t help but point out here that pharmaceutical companies sell immunosuppressants), there’s robust evidence, to the tune of hundreds of medical journal and scientific articles, documenting that both the immunocompetent and immunosuppressed can carry the virus long term.

Alexandre Freitas @FreitasABR

COVID-19: Reactivation – Recurrence / Viral Persistence Evidences - Articles Compilation (in chronological order; from February 27, 2020)

drive.google.comCOVID-19. Reactivation – Recurrence / Viral Persistence: Articles Compilation.pdf

Paxlovid Safety & Potential Concerns

Although at the time of this writing, liver injury from Paxlovid has not been officially reported within the limitations of the 5-day EUA, it may be difficult to tease out if mild-to-moderate liver injuries are actually occurring from Paxlovid within that 5-day window because Covid itself frequently causes elevation of liver enzymes which can last for months.

We know that Paxlovid is not without its risks because both liver and pancreas injury can occur with the use of the Paxlovid component ritonavir. Ritonavir has been FDA-approved now for many years, and in that time, there have been reports of organ damage resulting in fatalities:

“Hepatotoxicity: Fatalities have occurred. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate”

Risk-Benefit Decisions Handicapped by EUA

I’m not taking the position that the safety and efficacy of longer and repeated courses of Paxlovid shouldn’t be studied—I think that they should be. I am taking the position that Pfizer CEO Albert Bourla should not be making recommendations to physicians to use it outside of its EUA. And I guess Hell must have at least partly frozen over, because in this instance, the FDA agrees with me.

In order to make a fully informed risk-benefit decision—This is going to sound so dumb because it’s self-evident, even as I’m writing it, it sounds dumb in my head—We need to know the full risks and benefits which can’t be known with EUA drugs. The simple truth is that we don’t know if a second course of Paxlovid for rebound would be safe and effective because it’s not been studied. But we do know that ritonavir can have serious side effects. And what do we know of the safety of longer term or repeated courses of nirmatrelvir?—It’s a brand new drug that’s not FDA-approved. In a nutshell, we have no way to make judicious risk-benefit decisions for the prescription of EUA drugs outside of their labeling—And doctors couldn’t legally prescribe Paxlovid outside it’s EUA restrictions even if they threw caution to the wind.

Fully FDA-approved drugs provide physicians with far more flexibility as to how they can be prescribed vs EUA medications. For example, FDA-approved drugs are commonly used off-label:

“Off-label prescribing is when a physician gives you a drug that the U.S. Food and Drug Administration (FDA) has approved to treat a condition different than your condition. This practice is legal and common. In fact, one in five prescriptions written today are for off-label use.”

But EUA drugs aren’t going through the normal scientific channels for approval—Appropriately, they’re subject to more stringent limitations of use:

“COVID-19 interventions that remain available exclusively through EUAs, such as the antiviral pill paxlovid (nirmatrelvir/ritonavir)…are more tightly controlled by the terms of their authorizations, which precisely specify the number of authorized doses, dosing schedule, and eligible population. Unauthorized use outside these EUA parameters may violate the FDCA as provision of an unapproved—rather than off-label—product.”

I put that last bit in bold myself because it’s so important—To repeat and clarify—Prescribing an EUA medication outside of its labeling may equate with prescribing an unapproved drug. It’s like prescribing an experimental drug without a clinical trial.

CDC’s opinion on the use of a second course of Paxlovid for rebound is as follows:

“There is currently no evidence that additional treatment is needed with Paxlovid or other anti-SARS-CoV-2 therapies in cases where COVID-19 rebound is suspected.”

Yet none of this stopped Dr. Anthony Fauci, the highest paid federal employee in our government, who claims to represent science, from taking a 2nd course of Paxlovid during his rebound, when science provided no strong justification for its use. Where is the randomized controlled trial demonstrating that a 2nd course of Paxlovid is safe and effective for Paxlovid rebound? There is none.

Is it OK that Fauci can openly flaunt that he took an EUA-drug outside of its prescribing limitations for Covid—Which as outlined above equates to taking an unapproved drug—While physicians have been persecuted merely for off-label prescribing of the fully FDA-approved, cheap, safe drug ivermectin for Covid? The practice of medicine has been strangled by regulatory authorities claiming that diverse medical views constitute “misinformation,” just as freedom of speech has been eroded on a broader scale over these past 2 years.

A recent prospective observational study of 88,012 subjects from Brazil demonstrated phenomenal outcomes when healthy people took ivermectin regularly on a prophylactic basis, which was defined as taking 2 consecutive daily doses every 15 days:

“Hospitalization rate was reduced by 100% in regular users compared to both irregular users and non-users (p<0.0001 for both), and by 29% among irregular users compared to non-users (RR, 0.781; 95%CI, 0.49–1.05; p=0.099). Mortality rate was 92% lower in regular users than non-users (RR, 0.08; 95%CI, 0.02–0.35; p=0.0008) and 84% lower than irregular users (RR, 0.16; 95%CI, 0.04–0.71; p=0.016), while irregular users had a 37% lower mortality rate reduction than non-users (RR, 0.67; 95%CI, 0.40–0.99; p=0.049)…Conclusion: Non-use of ivermectin was associated with a 12.5-fold increase in mortality rate…compared to the regular use of ivermectin in a PSM [propensity score matching] comparison of a strictly controlled population.

I’d like to call your attention to 4 critically important outcomes from this study.

Hospitalizations were completely prevented (100%) in those who were compliant with their prophylactic ivermectin use, compared to both those who didn’t take any ivermectin, and those who took it non-compliantly, with an extremely low P-value. This is a very big deal.
Mortality was markedly reduced in those who took ivermectin compliantly—By 92% compared to those who didn’t take ivermectin, and by 84% compared to those who took it non-compliantly, again with very low P-values. This is also a very big deal.
The 29% “reduction” in hospitalizations for those who took ivermectin non-compliantly vs those who did not take it was not truly a reduction because it didn’t achieve statistical significance. The 100% reduction in hospitalizations among those taking ivermectin regularly vs those taking it non-compliantly, is further evidence of a lack of treatment effect for preventing hospitalizations when ivermectin was taken less frequently than as outlined in study.
The 37% reduction in mortality for those who took ivermectin non-compliantly vs those who did not take it barely met statistical significance. Since taking ivermectin compliantly reduced mortality by 84% compared to taking it non-compliantly, it’s likely that there was a true reduction in taking ivermectin non-compliantly vs not taking it at all, but that it was only modest.

This is nuanced and complex. But there is great value here, none of which is reflected in a scathing, and in my opinion biased, piece on Brazil’s ivermectin experience in Business Insider:

“Dr. Ana Carolina Antonio, who works at a government hospital in Porto Alegre, Brazil, told Insider many of her ICU patients took ivermectin in the spring — some trying to prevent COVID-19, others "to early treat their first symptoms."
Their strategy didn't work.”

How long did they take ivermectin? At what dose? If they were taking ivermectin prophylactically, were they taking it within the above study parameters?

In the above-referenced ivermectin prophylactic use study, hospitalizations were not reduced for those who took ivermectin non-compliantly. Mortality was only reduced by 37% for the con-compliant group (perhaps a bit less from my interpretation of the statistics), so of course physicians would encounter patients who were hospitalized and died despite having taken some ivermectin.

Does it demonstrate journalistic integrity to write an article without evaluating and presenting the entirety of the issue? Ivermectin hit pieces are a dime a dozen—If a journalist wrote a story chronicling cancer deaths in patients who’ve failed chemo and other cancer therapies, without weighing in the benefits many patients get from these treatments, that person might be predictably besieged by the medical and patient communities. But when it comes to cheap, generic drugs that work for Covid, it’s open season for pot shots.

But my article today isn’t about ivermectin. It’s not about any one drug—It’s about Paxlovid rebound and potential strategies for its mitigation. Would fluvoxamine be a reasonable choice?—I don’t know because this type of study hasn’t been done. But there are two randomized controlled studies showing comparable efficacy to Paxlovid for Covid, plus it’s fully FDA-approved for long term use.

A deep dive comparing fluvoxamine and Paxlovid led me to an unsettling conclusion: Medical science alone is not sufficient to dictate healthcare policy. And I think this is so because we have a decades-long history of infiltration of corporate interests into government regulatory authorities. Fluvoxamine is a cheap, generic drug, which is effective against Covid, but still not endorsed by NIH for its use:

“A 10-day treatment costs only $4 and appears to greatly reduce symptoms, hospitalization and death.”

My 2 cents: I think that a repeat course of Paxlovid for rebound should be studied to see if it’s safe and effective. We also need studies of multi-agent Covid protocols with a goal of mitigating Paxlovid rebound and preventing the development of Long Covid. Until we get good data, sound medical judgement is the best course of action.

And I predict that cheap, generic, effective medications for Covid will continue to be ignored or demonized in favor of corporate profits. Big pharma has enormous influence over FDA—They fund 45% of their budget.

In the fullness of time, several shameful periods in medicine will be looked back upon in disgrace. I think this is probably the biggest to date.

Thank you for taking the time to consider my thoughts. I so appreciate your subscription to this newsletter (and am extraordinarily appreciative of those generously opting for the paid subscriptions!!). If you like what you’ve read here today, please opt for a full-access subscription and share ZeroSpin with people you care about.

Disclaimer: None of my posts, articles, podcasts, or any public communications contain medical advice. These are intended for purely informational purposes only. Please check with your doctor before undertaking any course of treatment.

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Paxlovid Rebound--Seeking Solutions