key: cord-0759070-8gl323hs authors: Risch, Harvey A title: Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis date: 2020-05-27 journal: Am J Epidemiol DOI: 10.1093/aje/kwaa093 sha: 3bc8d46a6cd029274302dc3df15701338e0c4f66 doc_id: 759070 cord_uid: 8gl323hs More than 1.6 million Americans have been infected with SARS-CoV-2 and >10 times that number carry antibodies to it. High-risk patients presenting with progressing symptomatic disease have only hospitalization treatment with its high mortality. An outpatient treatment that prevents hospitalization is desperately needed. Two candidate medications have been widely discussed: remdesivir, and hydroxychloroquine+azithromycin. Remdesivir has shown mild effectiveness in hospitalized inpatients, but no trials have been registered in outpatients. Hydroxychloroquine+azithromycin has been widely misrepresented in both clinical reports and public media, and outpatient trials results are not expected until September. Early outpatient illness is very different than later hospitalized florid disease and the treatments differ. Evidence about use of hydroxychloroquine alone, or of hydroxychloroquine+azithromycin in inpatients, is irrelevant concerning efficacy of the pair in early high-risk outpatient disease. Five studies, including two controlled clinical trials, have demonstrated significant major outpatient treatment efficacy. Hydroxychloroquine+azithromycin has been used as standard-of-care in more than 300,000 older adults with multicomorbidities, with estimated proportion diagnosed with cardiac arrhythmias attributable to the medications 47/100,000 users, of which estimated mortality is <20%, 9/100,000 users, compared to the 10,000 Americans now dying each week. These medications need to be widely available and promoted immediately for physicians to prescribe. Aside from the now more than 1.6 million Americans found through testing and publichealth reporting to be infected with SARS-CoV-2, seropositivity studies in California (1, 2), Colorado (3) and New York City and State (4) suggest that some 10-50-fold larger numbers of people carry antibodies to the virus. The workforce and effort required to carry out contacttracing on these tens of millions of Americans is not practical. While these studies have generated some media criticism, recent similar studies of blood donor samples in the Netherlands found 3% with SARS-CoV-2 antibodies (5) , and 5% among household volunteers in Spain (6) . Even allowing for some degree of false-positivity of these antibody tests, they still indicate that appreciably larger fractions of the population have been infected than have been characterized by identified reported cases. "Flattening the curve," by social distancing, mask wearing and staying at home, serves to reduce hospital loads and spread them out over time, but to-date has pushed infection reproduction numbers R t down only to about 1.0 (7), thus even if maintained, over time very large numbers of people in the US may eventually get the infection. The great majority of infected people are at low risk for progression or will manifest the infection asymptomatically. For the rest, outpatient treatment is required that prevents disease progression and hospitalization. Exposures will occur as isolation policies are lifted and people begin to mix, All treatments have costs and benefits. In an ideal world, randomized double-blinded controlled clinical trials establish evidence for the relative degree of benefit, and if large enough, for estimates of the frequencies of adverse events. These trials take time to conduct: to get formal approval, to get funding, to enroll enough eligible patients, to wait for the outcomes to occur, and to analyze the data. In the context of the Covid-19 pandemic, we are presently averaging about 10,000 deaths per week in the US, under moderately strong isolation policies that have put more than 36 million people out of work. Results of currently ongoing or planned randomized trials for use of a number of outpatient medications are many weeks or months off, and there are no guarantees that the results for these agents, even if statistically significant, will show sufficient magnitudes of effectiveness to be useful clinically. We are rapidly reaching a breaking point in the ability to maintain the status quo; states have begun the process of lifting their restrictions, and we thus need to evaluate what evidence we do have for promising outpatient treatments. Based on laboratory and other preliminary evidence to-date, among many others, two candidate medication regimens have been widely discussed for outpatient treatment: remdesivir (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 SARS- recommends widespread use of remdesivir, and "as early in infection as possible," but no actual evidence as yet shows in humans that it would be helpful for routine outpatient circumstances and disease. The FDA recently approved use of remdesivir in the current public-health emergency circumstances (13) , 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." 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, 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 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 physiologic changes rather than from 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+doxycycline 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 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 five involve treating outpatients with the combined HCQ+AZ regimen (Web Table 1 ). 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 US before the trial results are known. The CDC 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 benefit and risk of these medications (23) . Available evidence of efficacy of HCQ+AZ has been repeatedly described in the media as "anecdotal," but most certainly is not. does change the magnitude of benefit is presentation with asymptomatic or upper respiratorytract infection, vs 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. This 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 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-value=.035, which cannot be explained by differential characteristics of the controls, since it compares one treatment group to 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 plausible chance finding, greater statistical significance does not contribute to evidence for causation (26) . mortality of hospitalized patients in the placebo arms of the remdesivir trials (10, 11) . This would give about 180 expected deaths. Both proposed drug regimens have shown side effects. Remdesivir, in its phase-3 trial of 10-day vs 5-day therapeutic courses in hospitalized patients, produced a range of adverse events in more than 70% of patients in both treatment arms (33) . Adverse events requiring medication discontinuation were many fewer, 5% in the 5-day group and 10% in the 10-day group. In the Chinese trial, 12% of remdesivir patients stopped the medication before the end of the 10-day treatment because of drug-related adverse events (10) . Further evidence of the real-world unimportance of arrhythmia and other cardiovascular adverse event endpoints of HCQ+AZ use is given in the large Oxford-based record-linkage study (41, 42 Second, the stated concern of the FDA and NIH advisories and the cardiology society opinion restricting use of HCQ+AZ was for fatal Torsades de Pointes and long QT-interval syndrome, two rare types of cardiac arrhythmias, as well as for cardiac arrhythmias in general. The Oxford study (41, 42) examined cardiac arrhythmia outcomes and obtained for its random effects meta-analysis result, RR=1.08, P-value=. 36 for HCQ+AZ use vs HCQ+amoxicillin use. The fixed-effects meta-analysis RR=1.04, P-value=. 41 . This study clearly demonstrates that cardiac arrhythmia adverse events are not appreciably increased by combining HCQ with AZ. The same study compared HCQ use to sulfasalazine use and again found no difference in cardiac arrhythmia risk: for HCQ, a slightly lower RR=0.89, P-value=. 13 . The subjects analyzed in the Oxford study were largely older adults with multiple comorbidities in addition to rheumatoid arthritis. Finally, the Oxford study allows for a direct estimate of the number of arrhythmia events attributable to HCQ+AZ use (41, 42) . Among 306,106 people taking sulfasalazine (which is known not to produce QT prolongation), 877 with cardiac arrhythmias were identified, 0.287%. In 320,589 people taking HCQ+AZ, 1,068 had arrhythmias, 0.333%. The difference, 0.047% or 47/100,000 older multicomorbidity patients taking HCQ+AZ, is attributable to the HCQ+AZ use. These are events, not fatalities. As noted above, fatalities according to FAERS comprise warnings about the use given during that time. I note that since doxycycline is believed to cause even fewer cardiac arrhythmias than AZ, in patients where that is a concern (43), the long-term care-facility evidence suggests that HCQ+doxycycline likely will work about as well. Given that a detailed and dispassionate review of all of the available relevant evidence leads to conclusions about outpatient HCQ+AZ use different than 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 human studies (acrylamide, alar, cyclamate, red dye #2, saccharin) (44) . This is in part 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 which 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 won't 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 like Tamiflu, 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 positive with an assay that has negligible false negatives, or be symptomatic enough for the disease to be clinically distinguished and diagnosed, but definably positive in this way not more than two days after symptoms start. This is a very narrow temporal window to be definitive and to obtain full antiviral effectiveness, and 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 less 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 in Mexico, 28% in France, 23% in the US, 17% in Germany, 16% in Canada, 13% in the UK (45) , much of the non-US use in outpatients. HCQ+AZ has been standard-of-care treatment at the four 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 (46) . The French physicians are insistent that with careful clinical judgement 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 that we have available, even if knowledge is imperfect and even if yet unproven to the standards of doubleblinded RCTs. This problem will get even worse as 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 to remain in isolation. But for the great majority, I conclude that HCQ+AZ and HCQ+doxycycline, preferably with zinc (47) can be this outpatient treatment, at least until we find or add something better, whether that could be remdesivir or something else. It is our obligation not to stand by, just "carefully watching," as the old and infirm and inner city of us are killed by this disease and There is a small chance that it may not work. But the urgency demands that we at least start to take that risk and evaluate what happens, and if our situation does not improve we can stop it, but we will know that we did everything that we could instead of sitting by and letting hundreds of thousands die because we did not have the courage to act according to our rational calculations. 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