Recently, I sent a letter to the editor for the Journal of American Medical Association regarding their review of ivermectin on COVID-19 outcomes. Hopefully they will print it, but I’m definitely not holding my breath here. I have included it for your perusal:
To the Editor:
I read with interest the article, “Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19, A Randomized Clinical Trial” published October 21, 2022 JAMA online. [1]
While the conclusion supports that from a previous JAMA published study[2] regarding ivermectin and COVID outcomes, both studies failed to control for time from symptom onset to intervention in a way that is common in evaluating efficacy of other antiviral medications. For example, the NEJM study[3] for Nirtravelmir specifically designed for a 3-day symptom onset window in order to be considered for intervention. Interestingly, all outcome data were eliminated from inclusion in the final NEJM study if an intervention started even after 5 days of symptom onset.
Studies on other antiviral medications, including Oseltamivir for flu[4] and Valacyclovir for herpes, were designed to be controlled very tightly for time since symptom onset, as studies show that any signal for benefit becomes indistinguishable after 36-72 hours depending on the medication used. This is a well-known phenomenon in the practicing clinical medical community.[5]
While the two JAMA studies were both designed for intervention at 5 and 7 days respectively, the intervention didn’t start for most participants for at least 7 days and in many cases up to 13 days or more since symptom onset, significantly outside the efficacy window for typical antivirals. After discussing with one of the co-authors of the most recent JAMA study, the statement that “there was no evidence of a differential treatment effect based on the median time of symptom onset to receipt of study drug” is unsupported due to the their exclusive reliance on a non-transparent Bayesian model, and no reliance on actual patient data to make this claim.
This is a critical, confounding error. If we are to compare apples to apples, it is prudent that JAMA should require the authors of each of these papers to resubmit data collected only on those patients who received intervention with no more than 5 days of symptom onset for re-evaluation, or to require re-evaluation of the efficacy of Nirtravelmir, Oseltamivir, and Valacyclovir and other antivirals using the same time window that was afforded ivermectin in order to fully evaluate, compare, and contrast the efficacy of ivermectin in COVID-19 outcomes with other antiviral medications and their respective outcomes.
Sincerely,
Scott Hastings D.O.
Family/internal medicine
[1] Naggie S, Boulware DR, Lindsell CJ, et al. Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2022;328(16):1595–1603.
[2] López-Medina E, López P, Hurtado IC, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA. 2021;325(14):1426–1435.
[3] Hammond J, Leister-Tebbe H, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized adults with COVID-19. NEJM. 2022; 386:1397-1408.
[4] Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and Safety of the Oral Neuraminidase Inhibitor Oseltamivir in Treating Acute Influenza: A Randomized Controlled Trial. JAMA. 2000;283(8):1016–1024.
[5] McQuade B, Blair M, et al. Influenza treatment with oseltamivir outside of labeled recommendations. American Journal of Health-System Pharmacy, Volume 72, Issue 2, 15 January 2015, Pages 112–116.