key: cord-1011105-8f83k2ce
authors: Prodromos, Chadwick; Rumschlag, Tobias
title: Hydroxychloroquine is effective, and consistently so used early, for Covid-19: A systematic review
date: 2020-10-05
journal: New Microbes New Infect
DOI: 10.1016/j.nmni.2020.100776
sha: ea2803a99a811f946a49affc77883c3a6638bc78
doc_id: 1011105
cord_uid: 8f83k2ce

Introduction Hydroxychloroquine (HCQ) has shown efficacy against COVID-19 in some but not all studies. We hypothesized that systematic review would show HCQ to be: effective against COVID-19, more effective when used earlier, not associated with worsening, and safe. Methods We searched PubMed, Cochrane, EmBase, Google Scholar, and Google for all reports on hydroxychloroquine as a treatment for COVID-19 patients. This included pre-prints and preliminary reports on larger COVID-19 studies. We examined the studies for efficacy, time of administration and safety. Results HCQ was found consistently effective against COVID-19 when used early, in the outpatient setting. It was found overall effective also including inpatient studies. No unbiased study found worse outcomes with HCQ use. No mortality or serious safety adverse event was found Conclusions HCQ is consistently effective against COVID-19 when used early in the outpatient setting, it is overall effective against COVID-19, it has not produced worsening, it is safe.

There is a need for effective treatment for COVID-19 infection. Hydroxychloroquine (HCQ), with or 26 without azithromycin, has been found to have efficacy as a treatment for COVID-19 in some studies [1, 27 2] , while other studies have not shown efficacy [3, 4] . While we do not prescribe HCQ to typical patients, 28

we do treat various forms of inflammatory arthritis in patients taking HCQ prescribed from outside 29 providers. Some physicians have stated that HCQ has greater efficacy if given earlier in the course of the 30 disease [5, 6] . Several studies showing negative efficacy have been withdrawn due to methodological 31 improprieties [7] . We hypothesized that HCQ clinical studies would show significant efficacy more often 32 than not for COVID-19; and that efficacy would be greater if HCQ were used earlier in the course of the 33 disease. We also hypothesized that some studies that failed to show efficacy would be biased against 34 positive efficacy and that no unbiased studies would show worsening. We also hypothesized that HCQ 35 would be found to be safe. 36

We searched PubMed, Cochrane, EmBase, Google Scholar, and Google for all reports on 38 hydroxychloroquine as a treatment for COVID-19 patients. This included pre-prints and preliminary 39 reports on larger COVID-19 studies. We included papers with HCQ alone as well as in combination with 40

Azithromycin and/or Zinc. We excluded papers that studied Chloroquine. While Chloroquine has 41

shown efficacy it has a higher side effects profile than HCQ. For this reason, and because HCQ is 42 inexpensive and widely available we believe that future treatment will and should focus on HCQ. It was 43 thus our priority to examine HCQ as fully as possible. We excluded papers that only examined 44 hydroxychloroquine as a means to decrease transmission of coronavirus since our focus was on 45 demonstrated clinical efficacy. Reports were analyzed for efficacy, type of study, time of intervention 46 with HCQ during the COVID-19 disease course, and for adverse events. Our final search was performed 47 This study has four important findings. The first is that HCQ appears to be consistently effective for the 83 treatment of COVID-19 when used early in the course of disease in the outpatient setting, and is 84 generally more effective the earlier it is used. The second is that overall HCQ has had efficacy against 85 COVID-19 in a majority of studies. The third is that there are no unbiased studies showing a negative 86 effect of HCQ treatment of COVID-19. The fourth is that HCQ appears to be safe for the treatment of 87 COVID-19 when used responsibly. 88 TIMING OF HCQ USE: It was striking that 100% of the 11 studies which used HCQ early in the disease on 89 an outpatient basis showed positive results. In two of the studies [9, 10] the benefit was only a trend. 90

However the effects were clinically important: in Mitja's study resolution of symptoms was decreased 91 from 12 to 10 days; In Skipper's study the rate of hospitalization was decreased by 60%. It is likely that 92 with higher powering statistical significance would have been reached. In the 32 other studies HCQ was 93

given on an inpatient basis with more advanced disease. The studies were divided into early, late and 94 ICU administration times. The early use, within 48 hours of admission showed 6 of 9 or 67% of the 95 studies to have positive efficacy. The two later groups, after 48 hours admission and in the ICU showed 96 2 of 5 or 40% to have positive efficacy. Thus, from 100% for early outpatient, to 67% for early hospital, 97 to 40% for later hospital use, there appears to be a relationship with time of initiation of treatment, and 98 better results the earlier HCQ is used. strength is the critical methodological study analysis heretofore not attempted to our knowledge for 157 these studies. One weakness is the heterogeneity of study designs which rendered comparison of study 158 results challenging. Another perceived weakness of the study could be that these include reports made 159 outside of peer-reviewed literature. Multiple papers reporting both improvement and no efficacy using 160 hydroxychloroquine that have been included in the study are either pre-prints or preliminary results of 161 larger trials. Because of the unprecedented and time sensitive nature of the SARS-COV2 pandemic the 162 scientific community has shared data and studies on a level unseen prior to this emergency. We believe 163 that these reports hold valuable information and decided to include them regardless of the way in which 164 they were published. In addition we found that both the peer-reviewed and non-peer reviewed papers 165 showed a similar breakdown between studies showing efficacy vs not so that bias was not introduced. 166 SIGNIFICANCE: We believe our findings have substantial societal global importance since there have 167 been numerous edicts either preventing HCQ use for COVID-19 or limiting it to the inpatient setting, 168 which we believe have unintentionally resulted in many unnecessary deaths. Our findings showing 169 efficacy and safety of HCQ against COVID-19 indicate that HCQ should be freely available to patients and 170 physicians who choose to use it. And it should especially be freely available to be used on an outpatient 171 basis before hospitalization where it appears to be more effective and where early fears of fatal heart 172 arrhythmias have been shown to be unfounded [45] . This is particularly important because of the other 173 drugs to show efficacy, Remdesivir, has shown no significant benefit in a recent study [46] . It is also 174 expensive and not widely available. And dexamethasone has only been shown effective in critically ill 175 J o u r n a l P r e -p r o o f hospitalized patients [47] . Convalescent plasma has shown benefit [48] but even this is not well 176 validated and plasma is not available in large numbers of doses. Thus HCQ with proven efficacy and 177 safety, a cost of 37 cents per pill and thus a total treatment cost of under 20 dollars[49], versus 3,100 178 dollars for Remdesivir[50], as well as wide supply chain availability, would appear to be the best COVID-179 19 treatment option available and needs to be widely promoted as such. Unfortunately the 180 controversies surrounding HCQ have resulted in physicians being afraid to prescribe it for reasons which 181 have nothing to do with medicine, and in patients being afraid to take it due to spurious reports of 182 danger, or fears that it is not effective. It is hoped that this study will disabuse the medical community 183 of these misapprehensions about efficacy and validate that it is both efficacious and safe, and needs to 184 be freely prescribable. 185

We also do not believe that randomized controlled studies are necessary before HCQ is authorized for 186 general use because the efficacy seen in studies already done indicates that control patients in such 187 studies might die unnecessarily; and because the time delay to do any such study would cause yet more 188 deaths by preventing HCQ use when it is most needed -which is immediately. Our study has shown 189 that good evidence of efficacy exists; and there is no safety, cost, or supply reason to not treat now. 190

Unnecessary death from delayed treatment is too high a price to pay for greater certainty of knowledge. 191

Many may have already died unnecessarily due to inaccurate HCQ information, and it is imperative that 192 we do not further add to the toll. 193

Hydroxychloroquine has been shown to have consistent clinical efficacy for COVID-19 when it is used 195 early in the outpatient setting, and in general would appear to work better the earlier it is used. Overall 196

Effectiveness of Hydroxychloroquine 204 in COVID-19 disease: A done and dusted situation?

Azithromycin and hydroxychloroquine accelerate recovery of outpatients with mild/moderate COVID-207 19

Hydroxychloroquine is associated with slower viral clearance in clinical COVID-19 patients with mild to 210 moderate disease: A retrospective study, medRxiv

Hydroxychloroquine alone or in combination with azithromycin to 213 prevent major clinical events in hospitalised patients with coronavirus infection (COVID-19): rationale 214 and design of a randomised

Early treatment of COVID-19 patients with hydroxychloroquine and 218 azithromycin: A retrospective analysis of 1061 cases in Marseille, France

Two Coronavirus studies retracted after questions emerge about data

Empirical treatment with 223 hydroxychloroquine and azithromycin for suspected cases of COVID-19 followed-up by telemedicine

Hydroxychloroquine for Early Treatment of

Adults with Mild Covid-19: A Randomized-Controlled Trial

Hydroxychloroquine in nonhospitalized adults with early COVID-19: a 234 randomized trial

Efficacy of 236 hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Treatment with hydroxychloroquine, azithromycin, and combination in 239 patients hospitalized with COVID-19

Barbot, nImpact of medical care including anti-infective agents use on the prognosis of

COVID-19 hospitalized patients over time

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Compassionate use of hydroxychloroquine in clinical practice for patients with 248 mild to severe Covid-19 in a French university hospital

No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for

COVID-19 infection with oxygen requirement: results of a study using routinely collected data to 252 emulate a target trial

Observational study of hydroxychloroquine in hospitalized patients with Covid-19

Association of treatment with hydroxychloroquine or azithromycin with 258 in-hospital mortality in patients with COVID-19 in New York state

Beneficial effects exerted by hydroxychloroquine in 260 treating COVID-19 patients via protecting multiple organs

Low dose of hydroxychloroquine 262 reduces fatality of critically ill patients with COVID-19

Treatment Response to Hydroxychloroquine and Antibiotics for mild to moderate COVID-19: a 265 retrospective cohort study from South Korea, medRxiv

Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary 268 results from a multi-centre, randomized, controlled trial, medRxiv

Effects of Hydroxychloroquine on Covid-19 in Intensive Care Unit Patients: Preliminary Results, 271

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Outcomes of Hydroxychloroquine Treatment Among 276

Hospitalized COVID-19 Patients in the United States-Real-World Evidence From a Federated Electronic 277

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Utilization of COVID-19 treatments and clinical outcomes among 282 patients with cancer: A COVID-19 and Cancer Consortium (CCC19) cohort study

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COVID-19 in Iran, a comprehensive investigation from exposure to 289 treatment outcomes, medRxiv

Observational Study 291 of the Efficiency of Treatments in Patients Hospitalized with Covid-19 in Madrid, medRxiv

Hydroxychloroquine and 293 azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-294 19 patients, medRxiv

Early hydroxychloroquine is associated with an increase of 297 survival in COVID-19 patients: an observational study

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an 300 open-label non-randomized clinical trial

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Hydroxychloroquine Prices, Coupons, and Patient Assitance Programs

Remdesivir Priced At More Than $3,100 For A Course Of Treatment

treated group. As described above both studies had clinically important trends toward positive results, 106 although were underpowered and did not reach statistical significance. The other five RCTs were in 107 hospitalized patients later in disease where efficacy seems to be less. There was 1 positive [11], 3 no-108 effect [4, 43, 44] , and 1 negative effect [22] studies. The negative effect study, however, was biased, as 109 described below ("negative effect studies"), such that any negative or no-effect result would not be The third study showing worse results with HCQ was a highly powered non-peer reviewed study whose 130 primary outcome of 28 day mortality actually showed no difference between the HCQ treated group and 131 the usual treatment group. Two of the secondary results did just barely reach significance negatively. 132 [22] . However the reporting of results was flawed as follows. 8% of the treatment group patients did 133 not receive HCQ at all; and the median number of days of treatment for all treated patients was only 6 134 out of a prescribed 9. These facts mean that less than half of patients received the full treatment 135 regimen or even two thirds of the full treatment regimen, with 1 in 12 receiving no treatment at all. 136These untreated and undertreated patient outcomes were however grouped with the fully treated 137 patient outcomes. If HCQ has any positive effect which we believe is well established, this 138 undertreatment would invalidate their borderline negative secondary results. In addition treatment was 139 initiated more than 48 hours after admission when our aggregate data has shown a high incidence of 140 no-effect results. The study was not blinded introducing a potential undertreatment bias toward 141 patients who were known by the staff to be treated with HCQ. This study most reasonably is actually a 142 no effects study, which is common in already hospitalized patients such as these treated more than 48 143 hours after admission. 144 ADVERSE EVENTS: There have been fears among some that the increased QTc seen in some patients 145 treated with HCQ or azithromycin would predispose to Torsades de Pointes (TDP) and then death from 146 ventricular fibrillation. We found no such deaths, or death from any cause related to HCQ treatment, 147 and indeed only 1 case of TDP at all -which resolved spontaneously without treatment and without 148 sequelae. This is consistent with our prior study showing an absence of TDP mortality with HCQ use 149[45]. All of the adverse events which seemed attributable to HCQ treatment in the 43 studies were side 150 effects known to occur with HCQ. These included nausea, vomiting, diarrhea, stomach pain, headache, 151