Early Outpatient Treatment of Symptomatic, High-risk COVID-19 Patients That Should Be Ramped Up Immediately as Key to the Pandemic Crisis

Harvey A. Risch


Am J Epidemiol. 2020;189(11):1218-1226. 

In This Article


Given that a detailed and dispassionate review of all of the available relevant evidence leads to conclusions about outpatient HCQ + AZ use that are different from those of the FDA and NIH panels (which comprise wider expertise than the cardiology societies), I address how different underlying scientific worldviews might be involved. This is particularly reflected in the Scientists to Stop COVID-19 position about remdesivir use "as early as possible" (,[12] p. 5)—that is, early outpatient use being implied. All but 1 of the scientists on the Scientists to Stop COVID-19 panel are laboratory or clinical scientists; only 1 is an epidemiologist. Their recommendation for remdesivir use as early as possible was made without either FDA approval or randomized controlled trial (RCT) evidence of efficacy in the outpatient context. This recommendation therefore appears to be an extrapolation from animal and laboratory data and from use in severely ill hospitalized patients. However, a history of epidemiology shows numerous instances of failed extrapolation from animals to humans. As Bracken noted, "Animal research on almost any topic of epidemiologic interest is so heterogeneous and inadequately synthesized that it is possible to selectively assemble a body of evidence from the animal and in-vitro studies that support almost any epidemiologic result" (,[43] p. 221). For example, some carcinogens have been affirmed in animal studies but carcinogenicity has not been shown in human studies (acrylamide, alar, cyclamate, red dye #2, saccharin).[43] This is partly why the FDA has an approval system of phased RCTs leading to safety and efficacy of use in humans, in the specific contexts in which the drug is intended. It is not a question of off-label use, but of who are the patients for whom to use the medication. For COVID-19, inpatient acute respiratory distress syndrome is typically a florid immune-system overreaction, whereas initial outpatient illness is a viral multiplication problem involving the beginnings of immune response. These are different diseases. Thus, how well remdesivir might perform in outpatients will not be known until it is tried in typical outpatient circumstances, whether in RCTs or in any other unbiased systematic study of such use. Further, to the degree that remdesivir is similar in temporal characteristics to an antiviral agent like oseltamivir, it would be used in general societal contexts where patients must first recognize that they might have symptoms of the disease (and not something else) and go to their physicians or clinics for care and either be rapidly tested as positive with an assay that has negligible false-negative results or be symptomatic enough for the disease to be clinically distinguished and diagnosed, but definably positive in this way not more than 2 days after symptoms start. This is a very narrow temporal window in which to be definitive and to obtain full antiviral effectiveness, and it could be difficult to achieve in general in the mass-treatment circumstances that we are facing. So regardless of the strength of the implied evidence of outpatient efficacy when given shortly after the start of symptoms, remdesivir efficacy might be substantially lower in the context of actual population outpatient usage. This is another reason why empirical studies of medication use in the full context of application are needed.

The extrapolation from laboratory theory to empirical use also seems to underlie resistance to the idea that combined HCQ regimens could work for early outpatient use. HCQ is known to interfere with toll-like receptor signaling, reducing dendritic cell activation and immune response. This would seem to be counterproductive for suppressing SARS-CoV-2 multiplication in early treatment. Again, in extrapolation from physiological theory to human data, the epidemiologic data are definitive. The fact that epidemiologic data to date show strong evidence for efficacy of combined HCQ + AZ in early outpatient treatment, even if there is not "proof" yet at the level of several successful RCTs, is evidence that this medication regimen works in that context. The clash in scientific worldviews is that basic and clinical scientists seem to feel that biological and drug-development evidence for medication use in nonhuman and nonoutpatient contexts can be extrapolated to recommendations for outpatient use without benefit of RCT evidence but do not accept epidemiologic evidence without RCTs, whereas epidemiologists have had career experience with laboratory and animal evidence that did not hold up under epidemiologic study but do reason by including all types of epidemiologic study designs and derive causal conclusions in the standard way following Hill's aspects[26] on the basis of strong totality of evidence, sometimes even without RCT evidence. There are contexts in which each approach is valid. However, it is not my point to say that remdesivir has little evidence to support its potential outpatient utility, only efficacy considerations that have not been addressed and that could lead to lack of efficacy under general use, but that HCQ + AZ has been directly studied in actual early high-risk outpatient use with all of its temporal considerations and found empirically to have sufficient epidemiologic evidence for its effective and safe employment that way, and that requiring delay of such general use until availability of additional RCT evidence is untenable because of the ongoing and projected continuing mortality. No studies of COVID-19 outpatient HCQ + AZ use have shown higher mortality with such use than without, cardiac arrhythmias included; thus, there is no empirical downside to use of this combined medication.

Some of my medical colleagues still prefer to wait until more studies are done and stronger evidence such as that from RCTs becomes available and government and professional advisory panels reevaluate the evidence. I strongly urge these panels to reconsider the data and arguments discussed above. Substantial fractions of physicians treating COVID-19 patients in Europe and elsewhere report use of HCQ + AZ: 72% in Spain, 49% in Italy, 41% in Brazil, 39% in Mexico, 28% in France, 23% in the United States, 17% in Germany, 16% in Canada, and 13% in the United Kingdom[44]—much of the non-US use in outpatients. HCQ + AZ has been standard-of-care treatment at the 4 New York University hospitals, where a recent study showed that adding zinc sulfate to this regimen significantly cut both intubation and mortality risks by almost half.[45] The French physicians are insistent that with careful clinical judgment and supervision, these medications are safe and should be used as early as possible for outpatients, and they provide a detailed clinical guide to their use.[20] Until we have quantitative evidence for the utility and safety of other medications for preventing hospitalization and mortality in high-risk COVID-19 outpatients, the urgency of current mass mortality requires an immediate application of the best treatment that we have available, even if knowledge is imperfect and even if efficacy is yet unproven to the standards of double-blinded RCTs. This problem will get even worse as US states and cities yield to the acute pressure at this moment to begin lifting stay-at-home restrictions and even more people become infected. Some people will have contraindications and will need other agents for treatment or will need to remain in isolation. However, I conclude that for the great majority, HCQ + AZ and HCQ + DOX, preferably with zinc,[46] can be this outpatient treatment, at least until we find or add something better, whether that be remdesivir or something else.

It is our ethical and professional obligation not to just stand by "carefully watching" as the old, the infirm, and inner-city residents are killed by this disease and our economy is destroyed by it and offer nothing except high-mortality hospital treatment. We have a solution, albeit imperfect, to attempt to deal with this disease. We have to let physicians employing good clinical judgment use it and informed patients choose it. There is a small chance that it may not work, but the urgency of the circumstances demands that we at least start to take that risk and evaluate what happens. If the situation does not improve, we can stop it, but we will know that we did everything we could instead of sitting by and letting hundreds of thousands of people die because we did not have the courage to act according to rational calculations.