A tale of two drugs: Hydroxychloroquine (HCQ) and Remdesivir. Remdesivir lowers death rates, but HCQ is associated with higher death rates.
2020-05-25
photo by Petra Goeschel courtesy of pixabay.com
Hydroxychloroquine (HCQ) has been relentlessly touted by a certain political figure, who even claimed to be taking the drug himself. He also claims that there is support from doctors and that some studies show it is good. This is unfortunately not true. A VA study with 368 patients published on April 21 found an elevated death rate in the HCQ group as opposed to no drug or combined HCQ (HC) and azithromycin (AZ): “Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively.” A large multicenter study published in Lancet on May 22 had similar results:
96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality. Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.
These findings are discouraging for proponents of HCQ. The results for remdesivir are much better. Gilead’s scientists released their most recent study details in the New England Journal of Medicine (NEJM) on May 22:
Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).
It is important to note that the study was prematurely terminated because the time to recovery was significantly shorter for remdesivir, although the difference in mortality did not reach statistical significance. The death rate was strikingly less with remdesivir: 7.1% versus 11.9% for placebo, a hazard ratio of 0.70– even though that result did not reach statistical significance because the study was stopped early.
There is strong data for the efficacy of remdesivir and the toxicity of HCQ based on these studies. The mechanisms of action for these two drugs supports these conclusions. With remdesivir, the drug is incorporated into the growing RNA chain as it is built and terminates it, (Wikipedia) damaging the virus’s genetic code. HCQ only increases the pH of the vesicle (bag) (Wikipedia) that the virus creates when it fuses with the cell membrane; although this might help, it is not dispositive. The side effects of HCQ overwhelm this mechanism and result in a higher death rate.
Remdesivir probably works better when it is given very early in the course of COVID-19, when there is active and uncontrolled virus replication. It is less likely to help during the late phase of severe illness, when “cytokine storm” causes inflammatory reactions all over the body. This hypothesis has not been confirmed by experiment, but is highly reasonable given experience with other viral infections. For example, treating the shingles (varicella, or chickenpox) virus effectively requires starting acyclovir or valacyclovir early on (Mayo clinic webpage for shingles.)
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Conrad Theodore Seitz 