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

Review of Evidence

Based on laboratory and other preliminary evidence available to date, 2 candidate medication regimens, among many others, have been widely discussed for outpatient treatment: remdesivir (Veklury; Gilead Sciences, Inc., Foster City, California), and hydroxychloroquine (HCQ) plus azithromycin (AZ). Remdesivir has been studied extensively in laboratory work and in animals[8] and for other viral diseases and has good biological properties, suggesting utility for the treatment of SARS-CoV-2 infection. In a study of compassionate use of remdesivir in 53 hospitalized patients with severe disease,[9] 13% died, which appears lower than what might have been expected without treatment, though greater than the proportion of deaths in the placebo arm of the Adaptive COVID-19 Treatment Trial (more below). In a randomized, controlled but relatively underpowered trial carried out among nonventilated hospitalized patients with severe disease in China,[10] investigators were not able to demonstrate benefit in either improvement or mortality in comparison with placebo. An appreciable fraction of the remdesivir patients left the trial early because of serious adverse events. The Adaptive COVID-19 Treatment Trial, a study of hospitalized patients with advanced lung disease, has released initial results[11] showing that patients on remdesivir had 31% faster recovery than patients on placebo (medians of 11 days and 15 days, respectively)—a difference which was statistically significant—but these results involved patients who did indeed survive. Mortality in the 2 groups (8.0% and 11.6%, respectively) was better for remdesivir but not significantly so (P = 0.059). More specific for consideration here, outpatient use of remdesivir has not been studied. The "secret" report issued by Scientists to Stop COVID-19 recommends widespread use of remdesivir and "as early in infection as possible" (,[12] p. 7), but no actual evidence as yet shows that it would be helpful for routine outpatient circumstances and disease in humans. The Food and Drug Administration (FDA) recently approved use of remdesivir in the current public-health emergency circumstances, but only for patients with "severe disease defined as SpO2 ≤ 94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)" and "administered in an in-patient hospital setting via intravenous (IV) infusion by a healthcare provider" (,[13] p. 2). This approval seems specifically not to allow outpatient use. Symptomatic outpatient infection is a pathologically and clinically different disease than the life-threatening inpatient acute respiratory distress syndrome caused by SARS-CoV-2; thus, there is little reason to think that the same treatment would be useful for both.[14] In any event, none of 20 currently registered trials is scheduled to provide data on outpatient use of remdesivir, and thus we may not know whether it could be used effectively to prevent hospitalization of symptomatic outpatients unless or until it is actually tried that way.

The other suggestion is the combined regimen of HCQ + AZ (or its variant, HCQ + doxycycline (DOX)). The FDA recently issued guidance to physicians and the general public[15] advising that the combination HCQ + AZ should not generally be used except by critically ill hospital inpatients or in the context of registered clinical trials. The National Institutes of Health (NIH) panel for COVID-19 treatment guidelines says essentially the same thing,[16] and a similar statement has been released by major cardiology societies.[17] Numerous reviews of HCQ efficacy and adverse events have been and continue to be published. To my knowledge, all of these reviews have omitted the 2 critical aspects of reasoning about these drugs: use of HCQ combined with AZ or with DOX and use in the outpatient setting. For example, a study carried out at Veterans' Administration medical centers[18] examined treated hospitalized patients and was fatally flawed.[19] The same point about outpatient use of the combined medications has been raised by a panel of distinguished French physicians[20] in petitioning their national government to allow outpatient use of HCQ + AZ. It appears that the FDA, NIH, and cardiology society positions have been based upon theoretical calculations about potential adverse events and from measured physiological changes rather than on current real-world mortality experience with these medications and that their positions should be revised. In reviewing all available evidence, I will show that HCQ + AZ and HCQ + DOX are generally safe for short-term use in the early treatment of most symptomatic high-risk outpatients, where not contraindicated, and that they are effective in preventing hospitalization for the overwhelming majority of such patients. If these combined medications become the standard of care, they are likely to save an enormous number of lives that would otherwise be lost to this endemic disease.

What is the evidence for these assertions? Similar to remdesivir, 16 clinical trials of HCQ + AZ are listed in the ClinicalTrials.gov database.[21] Of these, only 5 involve treating outpatients with the combined HCQ + AZ regimen (see Web Table 1, available at https://academic.oup.com/aje). For the earliest trial, between now and September, assuming a flat epidemic curve of 10,000 deaths per week, I estimate that approximately 180,000 more deaths will occur in the United States before the trial results are known. The Centers for Disease Control and Prevention has estimated substantially greater numbers of deaths,[22]

In this context, we cannot afford the luxury of perfect knowledge and must evaluate, now and on an ongoing basis, the evidence for the benefit and risk of these medications.[23] Available evidence of efficacy of HCQ + AZ has been repeatedly described in the media as "anecdotal," but it most certainly is not. The evidence is not perfect either. Each piece of evidence, contained in each study, must be carefully considered and not dismissed, because in an ideal world such evidence would fall into a lower part of the evidence-quality triangle. Furthermore, and most critical to the correct understanding of what evidence is available, evidence for single agents cannot be extrapolated to apply to combined agents, evidence for one biochemical form of a drug cannot be extrapolated to another form, and even more importantly, evidence for utility or lack thereof or toxicity in hospitalized patients cannot be extrapolated to apply to outpatient use—outpatient use comprising the sole argument for application that I am making in this review.

Thus, for example, studies of chloroquine or HCQ used alone do not bear upon evidence for efficacy of HCQ + AZ or HCQ + DOX. This point has been argued forcefully by the French physicians.[20] The first study of HCQ + AZ was controlled but not randomized or blinded and involved 42 patients in Marseilles, France.[24] That study showed a 50-fold benefit of HCQ + AZ versus the standard of care (P = 0.0007). In the study, 6 patients progressed, stopped medication use, and left the trial before the day-6 planned outcome measure of swab-sampled nasopharyngeal viral clearance. Reanalysis of the raw study data elsewhere[25] and by myself shows that including these 6 patients does not much change the 50-fold benefit. What does change the magnitude of benefit is presentation with asymptomatic or upper respiratory-tract infection versus lower respiratory-tract infection—the latter cutting the efficacy in half (25-fold vs. standard of care). This shows that the sooner these medications are used, the better their effectiveness, as would be expected for viral early respiratory disease. The average start date of medication use in this study was day 4 of symptoms. The study has been criticized on various grounds that are not germane to the science, but the most salient criticism is the lack of randomization into the control and treatment groups. This is a valid general scientific criticism, but it does not represent epidemiologic experience in this instance. If the study had shown a 2-fold or perhaps 3-fold benefit, that magnitude of result could be postulated to have occurred because of subject-group differences from lack of randomization. However, the 25-fold or 50-fold benefit found in this study is not amenable to lack of randomization as the sole reason for such a huge magnitude of benefit. Further, the study showed a significant, 7-fold benefit of taking HCQ + AZ over HCQ alone (P = 0.035), which cannot be explained by differential characteristics of the controls, since it compares one treatment group with the other, and the treated subjects who received AZ had more progressed pneumonia than the treated subjects receiving HCQ alone, which should otherwise have led to worse outcomes. The study has also been described as "small," but that criticism only applies to studies not finding statistical significance. Once a result has exceeded a plausible chance finding, greater statistical significance does not contribute to evidence for causation.[26] No different conclusion would have resulted had a study with 1,000 patients found the same 50-fold benefit but with a P value of 10−10. Study-size limitation only applies to studies having findings within the play of chance. That is not the case here.

A second study by the Marseilles group involved 1,061 patients who tested positive for SARS-CoV-2 and were treated with HCQ + AZ for at least 3 days and followed for at least 9 days.[27] The authors stated that no cardiac toxicity was observed.[27] A good clinical outcome and virological cure were seen in 973 patients (92%). Five patients died, and the remainder were in various stages of recovery.

The third piece of evidence involves a cohort of 1,450 patients treated by Dr. Vladimir Zelenko of Monroe, New York. Dr. Zelenko has released a 2-page report[28] describing his clinical reasoning and procedures, dosing conditions and regimen, and patient results through April 28. Symptomatic patients presenting to Dr. Zelenko were treated with 5 days of HCQ + AZ + zinc sulfate if they were considered high-risk, as evidenced by 1 or more of the following: age 60 years or older; high-risk comorbidity; body mass index (weight (kg)/height2 (m2)) ≥30; and mild shortness of breath at presentation. Patients were considered to have COVID-19 on the basis of clinical grounds and started treatment as soon as possible following symptom onset, rather than waiting for test results before starting treatment. Of the 1,450 patients, 1,045 were classified as low-risk and sent home to recuperate without active medications. No deaths or hospitalizations occurred among them. Of the remaining 405 who were treated with the combined regimen, 6 were ultimately hospitalized and 2 died. No cardiac arrhythmias were noted in these 405 patients.

The fourth relevant study was a controlled nonrandomized trial of HCQ + AZ in 636 symptomatic high-risk outpatients in São Paulo, Brazil.[29] All consecutive patients were informed about the utility and safety profile of the medications and offered the treatment, and those who declined (n = 224) comprised the control group. Patients were monitored daily by telemedicine. The study outcome was a need for hospitalization, defined as a clinically worsening condition or significant shortness of breath (blood oxygen saturation <90%). Even though the severities of all of the recorded influenza-like signs and symptoms and of important comorbid conditions (diabetes, hypertension, asthma, stroke) were substantially greater in the treated patients than in the controls, the need for hospitalization was significantly lower: 1.2% in patients starting treatment before day 7 of symptoms, 3.2% for patients starting treatment after day 7, and 5.4% for controls (P < 0.0001). No cardiac arrhythmias were reported in the 412 treated patients. The most common side effect of treatment was diarrhea (16.5%), but 12.9% of treated patients presented with diarrhea before treatment began.

Finally, a small study in a long-term-care facility in Long Island, New York, is ongoing.[30] This study has been employing HCQ + DOX rather than HCQ + AZ for treatment of high-risk COVID-19 patients. DOX itself has antiviral activity against SARS-CoV-2 at in vitro concentrations of 5.6 μM (median).[31] Among the first 54 residents treated in the Long Island study, 6 were hospitalized and 3 (5.6%) died.[30] An unofficial update of these data indicates that of about 200 high-risk patients treated with HCQ + DOX, 9 (4.5%) have died.

The 2 nonrandomized but controlled trials provide important evidence, if not "proof," of the major efficacy of early use of HCQ + AZ against SARS-CoV-2 infection in symptomatic high-risk outpatients. What can be said about the uncontrolled large case series of treated patients? Standard published case reports provide clinical evidence of the possibility of an exposure-outcome relationship, but not of the regularity, magnitude, or representativeness of such a relationship. The same can be said of case-series reports, meaning that subject entry into the series is not necessarily well-defined and no denominator information is provided from which to gauge what the series represents. However, a large series in the context of known risks of mortality or adverse events can allow for ballpark estimates of the denominator and thus provide a reasonable frame of reference for whether the outcomes are likely to represent beneficial or harmful results. For example, among Connecticut cases aged 60 years or older, mortality at present is 20%.[32] Thus, it would be ballpark to estimate that some 20% of the 1,466 treated high-risk patients in the Zelenko and Marseilles cohorts would have died without outpatient HCQ + AZ treatment—293 patients, as compared with the 7 who did die. An alternative is to use the 12%–13% mortality of hospitalized patients in the placebo arms of the remdesivir trials.[10,11] This would give about 180 expected deaths.