Abstract

This work aimed to evaluate the effects of drug therapies for coronavirus infections. Rapid systematic review with search in the MEDLINE, EMBASE, Cochrane, BVS, Global Index Medicus, Medrix, bioRxiv, Clinicaltrials.gov and International Clinical Trials Registry Platform databases. Thirty-six studies evaluating alternative drugs against SARS, SARS-CoV-2 and MERS were included. Most of the included studies were conducted in China with an observational design for the treatment of COVID-19. The most studied treatments were with antimalarials and antivirals. In antimalarial, the meta-analysis of two studies with 180 participants did not identify the benefit of hydroxychloroquine concerning the negative viral load via real-time polymerase chain reaction, and the use of antivirals compared to standard care was similar regarding outcomes. The available scientific evidence is preliminary and of low methodological quality, which suggests caution when interpreting its results. Research that evaluates comparative efficacy in randomized, controlled clinical trials, with adequate follow-up time and with the methods properly disclosed and subject to scientific peer review is required. A periodic update of this review is recommended.

Key words
Coronavirus; Coronavirus Infections; Severe Acute Respiratory Syndrome; Therapeutics; Systematic Review

Introduction

The outbreak of pneumonia cases, which initially occurred in Hubei, China, evolved into the 2019 Coronavirus Disease pandemic (COVID-19)¹1 Ren LL, Wang YM, Wu ZQ, Xiang ZC, Guo L, Xu T, Jiang YZ, Xiong Y, Li YJ, Li H, Fan GH, Gu XY, Xiao Y, Gao H, Xu JY, Yang F, Wang XM, Wu C, Chen L, Liu YW, Liu B, Yang J, Wang XR, Dong J, Li L, Huang CH, Zhao JP, Hu Y, Cheng ZS, Liu LL, Qian ZH, Qin C, Jin Q, Cao B, Wang JW. Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study. Chin Med J (Engl) 2020; 133(9):1015-1024.. The disease is caused by the Coronavirus-2 of severe acute respiratory syndrome (SARS-CoV-2)²2 World Health Organization (WHO). Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020 [Internet]. [acessado 2020 Fev 19]. Disponível em: https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020
https://www.who.int/dg/speeches/detail/w... . The World Health Organization (WHO) has declared strategic objectives on the pandemic, among them responding to critical knowledge gaps about the therapeutic options²2 World Health Organization (WHO). Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020 [Internet]. [acessado 2020 Fev 19]. Disponível em: https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020
https://www.who.int/dg/speeches/detail/w... available for coronavirus infections.

Understanding the complete natural history of COVID-19 is evolving. The WHO³3 World Health Organization (WHO). Novel Coronavirus (2019-nCoV) technical guidance [Internet]. [acessado 2020 Fev 18]. Disponível em: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance
https://www.who.int/emergencies/diseases... published the provisional guidelines. In the clinical presentation, pneumonia seems to be the most severe frequent manifestation of the infection, characterized mainly by fever, dry cough, dyspnea, and bilateral infiltrates in chest imaging tests⁴4 Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, Liu L, Shan H, Lei C, Hui DSC, Du B, Li L, Zeng G, Yuen K, Chen R, Tang C, Wang T, Chen P, Xiang J, Li S, Wang J, Liang Z, Peng Y, Wei L, Liu Y, Hu Y, Peng P, Wang J, Liu J, Chen Z, Li G, Zheng Z, Qiu S, Luo J, Ye C, Zhu S, Zhong N, China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020; 382(18):1708-1720.

5 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223):497-506.

6 Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395(10223):507-513.^-77 Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020 323(11):1061-1069.. As of April 2020, there no vaccines or specific treatments were available for human coronavirus infections.

Given the developing coronavirus situation, policymakers urgently require a synthesis of evidence to make decisions and guide the population. Rapid evidence synthesis is recommended by WHO⁸8 World Health Organization (WHO). Alliance for Health Policy and Systems Research. Rapid reviews to strengthen health policy and systems: a practical guide. Geneva: WHO; 2017. in circumstances like these. Thus, this study aims to evaluate the effects of drug therapies for coronavirus infections.

Methods

Design and protocol registration

A quick, systematic review of the literature was carried out, a secondary study that gathers the available evidence on a topic, carried out swiftly, to meet the decision-makers’ demand in a timely fashion⁹9 Higgins JPT, Thomas J, Li T, Page M, Welch V, Cumpston M, Chandler J, Mellor L, editores. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019) [Internet]. Cochrane; 2019. [acessado 2020 Mar 18]. Disponível em: https://training.cochrane.org/handbook
https://training.cochrane.org/handbook... . The study was conducted to scientifically and impartially inform the decision-making in the health of managers of the Brazilian Ministry of Health in the context of the public health emergency of national importance, COVID-19. The study protocol was submitted to the International Prospective Register of Systematic Reviews (PROSPERO) platform. The report of this review is in line with the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Eligibility criteria

Studies of systematic reviews, randomized clinical trials, cohorts, case-controls, and case series that evaluated the effects of alternative drug therapies for infection by any type of human coronavirus were included. We excluded studies that contained data that could not be extracted completely, overlapping data between studies, book chapters, letters to the editor, posters, editorials, modeling, guidelines or country guides, studies carried out on animals, or in silico.

Information sources and search strategies

A bibliographic search was performed in the sources of Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Cochrane Library, and Virtual Health Library (BVS). The lists of bibliographic references of the relevant studies were examined to identify possible eligible studies. A search was also conducted on the Global Index Medicus, Medrix, and bioRxiv, as well as free search on the websites of the governments of countries with confirmed cases and clinical trial, records through the Clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP) databases. There were no restrictions on the participants’ age, language, status, and year of publication.

The search was updated until April 21, 2020. The search strategy was developed by one researcher and independently reviewed by another researcher. The following search strategy was used to search in Medline, being adapted for the other databases: ((“coronavirus”[mesh] or “cov”[all fields] or “coronavirus infections”[mesh] or “wuhan coronavirus”[all fields] or “human coronavirus”[all fields] or “coronavirus nl63, human”[mesh] or “coronavirus oc43, human”[mesh] or “coronavirus 229e, human”[mesh] or covid-19[all fields] or “new coronavirus” [all fields] or 2019-ncov[all fields] or “novel coronavirus” [all fields] or betacoronavirus[all fields]) and (“antiviral agents”[mesh] or “therapeutics”[mesh] or drug[all fields] or “emergency treatment”[mesh])) and “treatment outcome”[mesh terms] ((“coronavirus”[mesh] or “cov”[all fields] or “coronavirus infections”[mesh] or “wuhan coronavirus”[all fields] or “human coronavirus”[all fields] or “coronavirus nl63, human”[mesh] or “coronavirus oc43, human”[mesh] or “coronavirus 229e, human”[mesh] or covid-19[all fields] or “new coronavirus” [all fields] or 2019-ncov[all fields] or “novel coronavirus” [all fields] or betacoronavirus[all fields]) and (“antiviral agents”[mesh] or “therapeutics”[mesh] or drug[all fields] or “emergency treatment”[mesh])) and “treatment outcome”[mesh terms].

Data collection process

The Rayyan system¹⁰10 Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev 2016; 5(1):210. was adopted for the selection of studies and data extraction. After removing duplicate records, two reviewers independently selected paper by title and abstract, as per pre-defined eligibility criteria. The selected works were independently read in full by two authors. In both stages, any case disagreement was resolved by a third reviewer. The following data were extracted: author, year of publication, country, study design, age (mean years), type of coronavirus, sample size, proportion of men (%), funding sources, intervention, comparator, and (clinical, laboratory) outcomes.

Methodological quality assessment

The evaluation of the methodological quality and the risk of bias of the included studies was carried out independently by six researchers, using appropriate tools for each study design, as follows: a) systematic reviews: A MeaSurement Tool to Assess Reviews (AMSTAR 2)¹¹11 Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E, A Henry DA. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017; 358:j4008.; b) randomized clinical trial: Cochrane bias risk assessment⁹9 Higgins JPT, Thomas J, Li T, Page M, Welch V, Cumpston M, Chandler J, Mellor L, editores. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019) [Internet]. Cochrane; 2019. [acessado 2020 Mar 18]. Disponível em: https://training.cochrane.org/handbook
https://training.cochrane.org/handbook... ; c) cohort and case series: Joanna Briggs Institute tools¹²12 Moola S, Munn Z, Tufanaru C, Aromataris E, Sears K, Sfetcu R, Currie M, Lisy K, Qureshi R, Mattis P, Mu P. Chapter 7: Systematic reviews of etiology and risk. In: Aromataris E, Munn Z, editores. Joanna Briggs Institute Reviewer's Manual. The Joanna Briggs Institute [Internet]. 2017 [acessado 2020 Mar 18]. Disponível em: https://reviewersmanual.joannabriggs.org/
https://reviewersmanual.joannabriggs.org... .

Summary of results and statistical analysis

The outcomes assessed in this review were mortality rate, clinical outcomes (length of hospital stay, length of ICU stay, need for non-invasive mechanical ventilation, need for oxygen therapy, adverse events, body temperature), and detection of viral RNA (RT-PCR). The results of the included studies were presented descriptively. Data on outcomes evaluated by the included studies were reported considering the size of effect estimates (relative risk, absolute risk difference, odds ratio, the number required to treat, and others) and their respective confidence and variance measures (a measure of dispersion, confidence intervals, and p-values).

Due to the limited number of studies reporting similar results for infections, the meta-analysis was conducted only for two studies on hydroxychloroquine against SARS-CoV-2. A meta-analysis using the Mantel-Hazel method for dichotomous data with the random-effects model was chosen a priori. Risk ratio (RR) was used for timely estimation together with the 95% confidence interval. The chi-square test was applied to measure heterogeneity between studies with a significance level of p < 0.05. The magnitude of the inconsistency was measured using the I-square (I²2 World Health Organization (WHO). Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020 [Internet]. [acessado 2020 Fev 19]. Disponível em: https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020
https://www.who.int/dg/speeches/detail/w... ) statistics. High heterogeneity was considered when I²2 World Health Organization (WHO). Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020 [Internet]. [acessado 2020 Fev 19]. Disponível em: https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020
https://www.who.int/dg/speeches/detail/w... was above 75%, moderate when it was between 55% and 75%, and low when I²2 World Health Organization (WHO). Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020 [Internet]. [acessado 2020 Fev 19]. Disponível em: https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020
https://www.who.int/dg/speeches/detail/w... was below 25%. RevMan version 5.3 was used for the analysis.

Results

Selection of studies

We identified 2,259 records, of which 91 were duplicated. After screening titles and abstracts, 68 records were selected for full-text reading. Of these, 36 met the eligibility criteria and were included in this review. The details of the selection process are illustrated in Figure 1.

Main characteristics of the included studies

The main characteristics of the included studies are shown in Chart 1. Most of the 36 included studies were retrospective cohorts and conducted in China, and published between 2018 and 2020. The mean age of patients was 48 years, and most of these people were diagnosed with SARS-CoV-2 infection or severe acute coronavirus syndrome (SARS-CoV) through real-time polymerase chain reaction (RT-PCR). Studies with patients with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) were also included. The effects of coronavirus drug therapies are described in Chart 2.

Antimalarials

Four randomized controlled trials (RCTs)¹³13 Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, Ling Y, Huang D, Song S, Zhang D, Qian Z, Li T, Shen Y, Lu H. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci) 2020; 49(2):215-219.

14 Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, Zhuang R, Hu B, Zhang Z. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020 [preprint].

15 Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo AGC, Brito M, Mourão MPG, Brito-Sousa JD, Baía-da-Silva D, Guerra MVF, Hajjar LA, Pinto RC, Balieiro AAS, Pacheco AGF, Santos Jr JDO, Naveca FG, Xavier MS, Siqueira AM, Schwarzbold A, Croda J, Nogueira ML, Romero GAS, Bassat Q, Fontes CJ, Albuquerque BC, Daniel-Ribeiro CT, Monteiro WM, Lacerda MVG, CloroCovid-19 Team. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. A Randomized Clinical Trial. JAMA 2020; 3(4):e208857.^-1616 Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, Wu Y, Xiao W, Liu S, Chen E, Chen W, Wang X, Yang J, Lin J, Zhao Q, Yan Y, Xie Z, Li D, Yang Y, Liu L, Qu J, Ning G, Shi G, Xie Q. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. medRxiv 2020 [preprint]., two retrospective cohorts¹⁷17 Mahévas M, Tran V, Roumier M, Chabrol A, Paule R, Guillaud C, Gallien S, Lepeule R, Szwebel TA, Lescure X, Schlemmer F, Matignon M, Khellaf M, Crickx E, Terrier B, Morbieu C, Legendre P, Dang J, Schoindre Y, Pawlotski JM, Michel M, Perrodeau E, Carlier N, Roche N, De Lastours V, Mouthon L, Audureau E, Ravaud P, Godeau B, Costedoat N. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial. medRxiv 2020 [preprint].^,1818 Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, Ambati J. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Med 2020; 1:1-4., a prospective cohort¹⁹19 Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 105949., and three case series²⁰20 Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, Castro N. No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection. Med Mal Infect 2020; 50(4):384.

21 Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Sevestre J, Mailhe M, Doudier B, Aubry C, Amrane S, Seng P, Hocquart M, Eldin C, Finance J, Vieira VE, Tissot-Dupont HT, Honoré S, Stein A, Million M, Colson P, La Scola B, Veit V, Jacquier A, Deharo JC, Drancourt M, Fournier PE, Rolain JM, Brouqui P, Raoult D. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis 2020; 34:101663.^-2222 Chorin E, Dai M, Shulman E, Wadhwani L, Cohen RB, Barbhaiya C, Aizer A, Holmes D, Bernstein S, Soinelli M, Park DS, Chinitz L, Jankelosn L. The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin. medRxiv 2020 [preprint]. evaluated the use of hydroxychloroquine (HCQ) or chloroquine (CQ) for SARS-CoV-2. Four studies compared HCQ with standard treatment¹³13 Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, Ling Y, Huang D, Song S, Zhang D, Qian Z, Li T, Shen Y, Lu H. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci) 2020; 49(2):215-219.^,1414 Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, Zhuang R, Hu B, Zhang Z. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020 [preprint].^,1616 Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, Wu Y, Xiao W, Liu S, Chen E, Chen W, Wang X, Yang J, Lin J, Zhao Q, Yan Y, Xie Z, Li D, Yang Y, Liu L, Qu J, Ning G, Shi G, Xie Q. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. medRxiv 2020 [preprint].^,1919 Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 105949.. Three studies evaluated the time to clinical improvement¹³13 Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, Ling Y, Huang D, Song S, Zhang D, Qian Z, Li T, Shen Y, Lu H. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci) 2020; 49(2):215-219.^,1414 Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, Zhuang R, Hu B, Zhang Z. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020 [preprint].^,1616 Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, Wu Y, Xiao W, Liu S, Chen E, Chen W, Wang X, Yang J, Lin J, Zhao Q, Yan Y, Xie Z, Li D, Yang Y, Liu L, Qu J, Ning G, Shi G, Xie Q. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. medRxiv 2020 [preprint].. In one RCT¹³13 Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, Ling Y, Huang D, Song S, Zhang D, Qian Z, Li T, Shen Y, Lu H. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci) 2020; 49(2):215-219., the time to normalize body temperature was similar between the groups, while treatment with HCQ resulted in less time in two other RCTs¹⁴14 Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, Zhuang R, Hu B, Zhang Z. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020 [preprint].^,1616 Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, Wu Y, Xiao W, Liu S, Chen E, Chen W, Wang X, Yang J, Lin J, Zhao Q, Yan Y, Xie Z, Li D, Yang Y, Liu L, Qu J, Ning G, Shi G, Xie Q. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. medRxiv 2020 [preprint].. In a single study¹⁴14 Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, Zhuang R, Hu B, Zhang Z. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020 [preprint]., the number of days of cough was significantly less in the HCQ group. Two RCTs¹⁴14 Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, Zhuang R, Hu B, Zhang Z. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020 [preprint].^,1616 Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, Wu Y, Xiao W, Liu S, Chen E, Chen W, Wang X, Yang J, Lin J, Zhao Q, Yan Y, Xie Z, Li D, Yang Y, Liu L, Qu J, Ning G, Shi G, Xie Q. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. medRxiv 2020 [preprint]. evaluated the negative viral load by RT-PCR on the seventh day after starting therapy. The meta-analysis found no significant difference in the probability of negative viral load by RT-PCR between the HCQ group and the group that received conventional treatment (RR = 0.94; 95%CI: 0.78-1.13; 180 participants; I² = 0%) (Figure 2).

Moreover, a cohort¹⁹19 Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 105949. had a significantly lower proportion of patients with negative RT-PCR in the HCQ group. A cohort¹⁸18 Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, Ambati J. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Med 2020; 1:1-4. showed that the HCQ group has a higher risk of death from any cause when compared to the group without HCQ. However, another cohort¹⁷17 Mahévas M, Tran V, Roumier M, Chabrol A, Paule R, Guillaud C, Gallien S, Lepeule R, Szwebel TA, Lescure X, Schlemmer F, Matignon M, Khellaf M, Crickx E, Terrier B, Morbieu C, Legendre P, Dang J, Schoindre Y, Pawlotski JM, Michel M, Perrodeau E, Carlier N, Roche N, De Lastours V, Mouthon L, Audureau E, Ravaud P, Godeau B, Costedoat N. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial. medRxiv 2020 [preprint]. found no difference between the groups.

Five studies investigated the effects of HCQ associated with azithromycin (AZT) compared to standard treatment¹⁷17 Mahévas M, Tran V, Roumier M, Chabrol A, Paule R, Guillaud C, Gallien S, Lepeule R, Szwebel TA, Lescure X, Schlemmer F, Matignon M, Khellaf M, Crickx E, Terrier B, Morbieu C, Legendre P, Dang J, Schoindre Y, Pawlotski JM, Michel M, Perrodeau E, Carlier N, Roche N, De Lastours V, Mouthon L, Audureau E, Ravaud P, Godeau B, Costedoat N. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial. medRxiv 2020 [preprint].

18 Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, Ambati J. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Med 2020; 1:1-4.

19 Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 105949.

20 Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, Castro N. No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection. Med Mal Infect 2020; 50(4):384.^-2121 Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Sevestre J, Mailhe M, Doudier B, Aubry C, Amrane S, Seng P, Hocquart M, Eldin C, Finance J, Vieira VE, Tissot-Dupont HT, Honoré S, Stein A, Million M, Colson P, La Scola B, Veit V, Jacquier A, Deharo JC, Drancourt M, Fournier PE, Rolain JM, Brouqui P, Raoult D. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis 2020; 34:101663.. In a cohort¹⁹19 Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 105949., the proportion of patients with negative RT-PCR was significantly lower in the HCQ group. On the other hand, the therapeutic combination had no significant effect in case series²⁰20 Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, Castro N. No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection. Med Mal Infect 2020; 50(4):384.. Another case series²¹21 Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Sevestre J, Mailhe M, Doudier B, Aubry C, Amrane S, Seng P, Hocquart M, Eldin C, Finance J, Vieira VE, Tissot-Dupont HT, Honoré S, Stein A, Million M, Colson P, La Scola B, Veit V, Jacquier A, Deharo JC, Drancourt M, Fournier PE, Rolain JM, Brouqui P, Raoult D. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis 2020; 34:101663. with 80 participants evidenced a negative virological result in 83% of patients who used HCQ on day 7 of follow-up, and in 93% on day 8. The mortality rate was assessed in two cohorts. In the first one¹⁸18 Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, Ambati J. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Med 2020; 1:1-4., it was worse in the group treated with HCQ and AZT, and in the other¹⁷17 Mahévas M, Tran V, Roumier M, Chabrol A, Paule R, Guillaud C, Gallien S, Lepeule R, Szwebel TA, Lescure X, Schlemmer F, Matignon M, Khellaf M, Crickx E, Terrier B, Morbieu C, Legendre P, Dang J, Schoindre Y, Pawlotski JM, Michel M, Perrodeau E, Carlier N, Roche N, De Lastours V, Mouthon L, Audureau E, Ravaud P, Godeau B, Costedoat N. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial. medRxiv 2020 [preprint]., no differences were observed between groups. In one of the case series²¹21 Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Sevestre J, Mailhe M, Doudier B, Aubry C, Amrane S, Seng P, Hocquart M, Eldin C, Finance J, Vieira VE, Tissot-Dupont HT, Honoré S, Stein A, Million M, Colson P, La Scola B, Veit V, Jacquier A, Deharo JC, Drancourt M, Fournier PE, Rolain JM, Brouqui P, Raoult D. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis 2020; 34:101663., patients had nausea, vomiting, diarrhea, and blurred vision. In two other case series²⁰20 Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, Castro N. No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection. Med Mal Infect 2020; 50(4):384.^,2222 Chorin E, Dai M, Shulman E, Wadhwani L, Cohen RB, Barbhaiya C, Aizer A, Holmes D, Bernstein S, Soinelli M, Park DS, Chinitz L, Jankelosn L. The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin. medRxiv 2020 [preprint]., patients had persistent QT interval prolongation.

An RCT¹⁵15 Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo AGC, Brito M, Mourão MPG, Brito-Sousa JD, Baía-da-Silva D, Guerra MVF, Hajjar LA, Pinto RC, Balieiro AAS, Pacheco AGF, Santos Jr JDO, Naveca FG, Xavier MS, Siqueira AM, Schwarzbold A, Croda J, Nogueira ML, Romero GAS, Bassat Q, Fontes CJ, Albuquerque BC, Daniel-Ribeiro CT, Monteiro WM, Lacerda MVG, CloroCovid-19 Team. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. A Randomized Clinical Trial. JAMA 2020; 3(4):e208857. compared the use of CQ administered at different dosages. Preliminary results suggest that the high-dose QC regimen (12g administered over 10 days) was not safe. The authors canceled the tests when they found that one quarter of the patients tested with a high-dose of QC showed persistent QT prolongation above 500ms and higher lethality.

Antivirals and Antiretrovirals

Two clinical trials²³23 Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, Mo X, Wang J, Wang Y, Peng P, Chen X, Hong W, Xiao G, Liu J, Zhang L, Hu F, Li F, Li F, Zhang F, Deng X, Li L. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv 2020 [preprint].^,2424 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 2020; 382:1787-1799. and one case series²⁵25 Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, Ng OT, Marimuthu K, Ang LW, Mak TM, Lau SK, Anderson DE, Chan KS, Tan TY, Ng TY, Cui L, Said Z, Kurupatham L, Chen MIC, Chan M, Vasoo S, Wang LF, Tan BH, Lin RTP, Lee VJM, Leo YS, Lye DC, Singapore 2019 Novel Coronavirus Outbreak Research Team. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA 2020; 323(15):1488-1494. that reported treatments with lopinavir/ritonavir, arbidol (umifenovir), and interferon-α2b, were included. Most of the studies were conducted in China (n = 2), and all targeted SARS-CoV-2. One of the studies compared the use of lopinavir (associated with ritonavir) with arbidol (umifenovir) and standard treatment without antivirals²³23 Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, Mo X, Wang J, Wang Y, Peng P, Chen X, Hong W, Xiao G, Liu J, Zhang L, Hu F, Li F, Li F, Zhang F, Deng X, Li L. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv 2020 [preprint].. The rate of negative SARS-CoV-2 viral load after seven days was 35.3% for the group that took lopinavir/ritonavir, 37.1% for the group that received arbidol, and 41.2% for the group that did not receive antiviral therapy²³23 Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, Mo X, Wang J, Wang Y, Peng P, Chen X, Hong W, Xiao G, Liu J, Zhang L, Hu F, Li F, Li F, Zhang F, Deng X, Li L. An exploratory randomized, controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI). medRxiv 2020 [preprint].. Patients who received lopinavir/ritonavir associated with standard treatment had fewer days of hospitalization (6 days) than the group that received only standard treatment (11 days)²⁴24 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 2020; 382:1787-1799.. Adverse events were also lower among the group that received the intervention (19 events in the intervention group versus 32 events in the control group)²⁴24 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 2020; 382:1787-1799..

Immunomodulators

In a retrospective cohort²⁶26 Zhou Q, Wei XS, Xiang X, Wang X, Wang ZH, Chen V, Shannon CP, Tebbutt SJ, Kollmann TR, Fish EN. Interferon-a2b treatment for COVID-19. medRxiv 2020 [preprint]. conducted in China, viral clearance took about eight days (IQR: 5.5-15.5) between the group that received nebulized interferon-α2b and 6.5 days (IQR: 3.0-10.0) for the group that received interferon associated with arbidol²⁶26 Zhou Q, Wei XS, Xiang X, Wang X, Wang ZH, Chen V, Shannon CP, Tebbutt SJ, Kollmann TR, Fish EN. Interferon-a2b treatment for COVID-19. medRxiv 2020 [preprint].. The group that received only arbidol took about 10 days (IQR: 4.5-19.5) for viral clearance²⁶26 Zhou Q, Wei XS, Xiang X, Wang X, Wang ZH, Chen V, Shannon CP, Tebbutt SJ, Kollmann TR, Fish EN. Interferon-a2b treatment for COVID-19. medRxiv 2020 [preprint]..

Anticoagulants

Negri et al²⁷27 Negri EM, Piloto B, Morinaga LK, Jardim CVP, Lamy SAED, Ferreira MA, D'Amico EA, Deheinzelin D. Heparin therapy improving hypoxia in COVID-19 patients - a case series. medRxiv 2020 [preprint]. evaluated the use of heparin for the treatment of COVID-19 in a hospital in São Paulo, Brazil. The PaO2/FiO2 oxygenation index was evaluated before and after 72 hours of treatment, besides the duration of hospitalization and mechanical ventilation. The PaO2/FiO2 ratio improved from 254 to 325 (p=0.013), the mean hospital stay was 7.3, and the mean duration of mechanical ventilation was 10.3²⁷27 Negri EM, Piloto B, Morinaga LK, Jardim CVP, Lamy SAED, Ferreira MA, D'Amico EA, Deheinzelin D. Heparin therapy improving hypoxia in COVID-19 patients - a case series. medRxiv 2020 [preprint].. Another study²⁸28 Shi C, Wang C, Wang H, Yang C, Cai F, Zeng F, Cheng F, Liu Y, Zhou T, Deng B, Vlodavsky I, Li J, Zhang Y. The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID-19 patients: a retrospective clinical study. medRxiv 2020 [preprint]. evaluated heparin use in the treatment of COVID-19 through negative viral outcomes, coagulation parameters, the concentration of C-reactive protein and inflammatory cytokines, number of lymphocytes before and after treatment. There was no significant difference between the two groups, except for an increase in IL-6 and in lymphocytes in the intervention group. The authors pointed out that heparin improves coagulation dysfunction, has anti-inflammatory effects, and can be used as a treatment for COVID-19²⁸28 Shi C, Wang C, Wang H, Yang C, Cai F, Zeng F, Cheng F, Liu Y, Zhou T, Deng B, Vlodavsky I, Li J, Zhang Y. The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID-19 patients: a retrospective clinical study. medRxiv 2020 [preprint]..

Corticoids

Four retrospective cohorts²⁹29 Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, Jose J, Pinto R, Al-Omari A, Kharaba A, Almotairi A, Al Khatib K, Alraddadi B, Shalhoub S, Abdulmomen A, Qushmaq I, Mady A, Solaiman O, Al-Aithan AM, Al-Raddadi R, Ragab A, Balkhy HH, Harthy A, Deeb AM, Mutairi HA, Al-Dawood A, Merson L, Hayden FG, Fowler RA, Saudi Critical Care Trial Group. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome. Am J RespirCrit Care Med 2018; 197(6):757-767.

30 Wang Y, Jiang W, He Q, Wang C, Wang B, Zhou P, Dong N, Tong Q. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. medRxiv 2020 [preprint].

31 Lu X, Chen T, Wang Y, Wang J, Zhang B, Li Y, Yan F. Adjuvant corticosteroid therapy for critically ill patients with COVID-19. medRxiv 2020 [preprint].^-3232 Auyeung TW, Lee JS, Lai WK, Choi CH, Lee HK, Lee JS, Li PC, Lok KH, Ng YY, Wong WM, Yeung YM. The use of corticosteroid as treatment in SARS was associated with adverse outcomes: A retrospective cohort study. J Infect 2005; 51(2):98-102. reported corticosteroid therapies. Two were performed in China, focusing on the SARS-CoV-2³⁰30 Wang Y, Jiang W, He Q, Wang C, Wang B, Zhou P, Dong N, Tong Q. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. medRxiv 2020 [preprint].^,3131 Lu X, Chen T, Wang Y, Wang J, Zhang B, Li Y, Yan F. Adjuvant corticosteroid therapy for critically ill patients with COVID-19. medRxiv 2020 [preprint]. coronavirus. The time to symptom improvement was assessed and was shorter in the group that received methylprednisolone (2.06 days) than in the group that did not receive treatment (5.29 days)³⁰30 Wang Y, Jiang W, He Q, Wang C, Wang B, Zhou P, Dong N, Tong Q. Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: single-center experience from Wuhan, China. medRxiv 2020 [preprint].. One study showed a higher mortality rate for patients with COVID-19 who received corticosteroids (39%) than in the group of patients who did not receive them (16%; p = 0.09)³¹31 Lu X, Chen T, Wang Y, Wang J, Zhang B, Li Y, Yan F. Adjuvant corticosteroid therapy for critically ill patients with COVID-19. medRxiv 2020 [preprint].. In patients with MERS-CoV, the mortality rate (74.2% versus 57.6%) and the need for invasive mechanical ventilation (93.4% versus 76.6%) were higher in the group receiving corticosteroids than in the group control group²⁹29 Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, Jose J, Pinto R, Al-Omari A, Kharaba A, Almotairi A, Al Khatib K, Alraddadi B, Shalhoub S, Abdulmomen A, Qushmaq I, Mady A, Solaiman O, Al-Aithan AM, Al-Raddadi R, Ragab A, Balkhy HH, Harthy A, Deeb AM, Mutairi HA, Al-Dawood A, Merson L, Hayden FG, Fowler RA, Saudi Critical Care Trial Group. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome. Am J RespirCrit Care Med 2018; 197(6):757-767.. SARS-CoV patients who received corticosteroids were 20.7 times more likely (OR = 20.7; 95% CI: 1.3-338) to be admitted to the ICU or die than those who did not use corticosteroids³²32 Auyeung TW, Lee JS, Lai WK, Choi CH, Lee HK, Lee JS, Li PC, Lok KH, Ng YY, Wong WM, Yeung YM. The use of corticosteroid as treatment in SARS was associated with adverse outcomes: A retrospective cohort study. J Infect 2005; 51(2):98-102..

Combined therapies

Bian et al.³³33 Bian H, Zheng Z, Wei D, Zhang Z, Kang W, Hao C, Dong K, Kang W, Xia J, Miao J, Xie R, Wang B, Sun X, Yang X, Lin P, Geng J, Wang K, Cui H, Zhang K, Chen X, Tang H, Du H, Yao N, Liu S, Liu L, Zhang Z, Gao Z, Nan G, Wang Q, Lian J, Chen Z, Zhu P. Meplazumab treats COVID-19 pneumonia: an controlled add-on clinical trial open-labelled, concurrent. medRxiv 2020 [preprint]. evaluated the efficacy of meplazumab, an anti-CD147 antibody, as a complementary therapy in patients with COVID-19 in China. Other associated treatments were antiretroviral (lopinavir/ritonavir), immunomodulator (recombinant interferon α-2b), glucocorticoid, and antibiotic (not specified) drugs. The control group did not receive meplazumab. In the intervention group, 94% of patients (p = 0.006) were discharged from the hospital, and the median for the negative viral load was three days, with an increased C-reactive protein in 82.4% of cases. The reported adverse effects were only 2 cases that had elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and the condition was reversed after seven days. The researchers reported that this increase in transaminases was not associated with the use of meplazumab, as the same effect was observed in the control group³³33 Bian H, Zheng Z, Wei D, Zhang Z, Kang W, Hao C, Dong K, Kang W, Xia J, Miao J, Xie R, Wang B, Sun X, Yang X, Lin P, Geng J, Wang K, Cui H, Zhang K, Chen X, Tang H, Du H, Yao N, Liu S, Liu L, Zhang Z, Gao Z, Nan G, Wang Q, Lian J, Chen Z, Zhu P. Meplazumab treats COVID-19 pneumonia: an controlled add-on clinical trial open-labelled, concurrent. medRxiv 2020 [preprint]..

In another study³¹31 Lu X, Chen T, Wang Y, Wang J, Zhang B, Li Y, Yan F. Adjuvant corticosteroid therapy for critically ill patients with COVID-19. medRxiv 2020 [preprint]., treatment with corticosteroids (methylprednisolone, dexamethasone, and hydrocortisone) associated with antivirals (oseltamivir, arbidol, ganciclovir, interferon-α) and antiretrovirals (lopinavir/ritonavir) was compared with a group that received the same treatment, without corticosteroids. No difference was observed between the groups (adjusted OR = 1.05; 95% CI: -1.92 to 2.01, p > 0.3)³¹31 Lu X, Chen T, Wang Y, Wang J, Zhang B, Li Y, Yan F. Adjuvant corticosteroid therapy for critically ill patients with COVID-19. medRxiv 2020 [preprint]. in the mortality outcome after 28 days of hospitalization.

In yet another study³⁴34 Morra ME, Van Thanh L, Kamel MG, Ghazy AA, Altibi AMA, Dat LM, Thy TNX, Vuong NL, Mostafa MR, Ahmed SI, Elabd SS, Fathima S, Vu TLH, Omrani AS, Memish ZA, Hirayama K, Huy NT. Clinical outcomes of current medical approaches for Middle East respiratory syndrome: A systematic review and meta-analysis. Rev Med Virol 2018; 28(3):e1977., treatment with interferon associated with ribavirin was evaluated, compared with the use of a support measure for the treatment of MERS. There was a need for mechanical ventilation in 76% of patients in the intervention group compared with 90% in the control group. The adverse effects reported in the intervention group were elevation of pancreatic enzymes and hemolysis, present in 3 patients³⁴34 Morra ME, Van Thanh L, Kamel MG, Ghazy AA, Altibi AMA, Dat LM, Thy TNX, Vuong NL, Mostafa MR, Ahmed SI, Elabd SS, Fathima S, Vu TLH, Omrani AS, Memish ZA, Hirayama K, Huy NT. Clinical outcomes of current medical approaches for Middle East respiratory syndrome: A systematic review and meta-analysis. Rev Med Virol 2018; 28(3):e1977..

Chiou et al.³⁵35 Chiou HE, Liu CL, Buttrey MJ, Kuo HP, Liu HW, Kuo HT, Lu YT. Adverse effects of ribavirin and outcome in severe acute respiratory syndrome: Experience in two medical centers. Chest 2005; 128(1):263-272. evaluated a therapy with an antiviral (ribavirin) associated with corticosteroids (methylprednisolone, prednisone) for the treatment of COVID-19 compared with a regimen without ribavirin. An improvement in the chest image’s infiltrations was reported by 71% of the patients who received ribavirin compared to the control group (67%, p = 0.05)³⁵35 Chiou HE, Liu CL, Buttrey MJ, Kuo HP, Liu HW, Kuo HT, Lu YT. Adverse effects of ribavirin and outcome in severe acute respiratory syndrome: Experience in two medical centers. Chest 2005; 128(1):263-272..

A study³⁶36 Yan D, Liu XY, Zhu YN, Huang L, Dan BT, Zhang GJ, Gao YH. Factors associated with prolonged viral shedding and impact of Lopinavir/Ritonavir treatment in patients with SARS-CoV-2 infection. medRxiv 2020 [preprint]. compared the use of antiretrovirals (lopinavir/ritonavir), corticosteroids, antibiotics, and supportive treatment vis-à-vis a similar treatment, but without lopinavir/ritonavir. The time to viral clearance had a median of 22 days compared to 28.5 in the control group. Moreover, the median hospital stay was 23 days compared to 18.5 in the control group³⁶36 Yan D, Liu XY, Zhu YN, Huang L, Dan BT, Zhang GJ, Gao YH. Factors associated with prolonged viral shedding and impact of Lopinavir/Ritonavir treatment in patients with SARS-CoV-2 infection. medRxiv 2020 [preprint]..

Methodological quality assessment

In general, the methodological quality of the included studies was moderate. The main limitations of the included randomized clinical trials were lack of allocation secrecy, blinding, and sample size of fewer than 100 participants. The primary limitations observed in the systematic reviews were related to the authors’ clarity regarding the process of assessing the risk of bias in the included studies, lack of description of eligibility criteria, and discussion about the heterogeneity in the findings. The included cohort studies were unclear as to the information about the control of confounding variables, length of follow-up, and patient eligibility criteria, besides the lack of comparable groups. Case series did not adequately describe patient eligibility criteria, demographic characteristics, and clinical data. No study was excluded because of its methodological quality. The critical assessment of the individual quality of each study is found in Charts 3-6.

Discussion

This review identified three systematic reviews, eight randomized clinical trials, 18 cohorts, and seven case series, evaluating different drug alternatives to human coronavirus, who reported mortality in 14 days, a progression of lung lesions on computed tomography, clinical improvement, absence of viral detection in RT-PCR and adverse events. Antivirals and antimalarials were among the most studied therapies.

When there are no clinically proven treatments during epidemics, the tendency is to use drugs based on in vitro activity or observational studies. However, effective drugs based on in vitro studies and observational studies for other diseases were later proven to be ineffective in clinical trials³⁷37 Kalil AC. Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA 2020; 323(19):1897-1898..

CQ and HCQ showed in vitro inhibitory effects on coronavirus infections³⁸38 Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, Li Y, Hu Z, Zhong W, Wang M. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020; 6:16.^,3939 Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020; 14(1):72-73.. As a known antimalarial and anti-autoimmune agent, HCQ appears to block infection by the SARS-CoV virus, increasing the endosomal pH required for membrane fusion between the virus and the host cell⁴⁰40 Paton NI, Lee L, Xu Y, Ooi EE, Cheung YB, Archuleta S, Wong G, Wilder-Smith A. Chloroquine for influenza prevention:a randomised, double-blind, placebo controlled trial. Lancet Infect Dis 2011; 11(9):677-683.^,4141 Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: Anold drug against today's diseases. Lancet Infect Dis 2003; 3(11):722-727..

Furthermore, it has been shown to specifically inhibit SARS-CoV-2 replication by interfering with the glycosylation of the angiotensin-converting enzyme 2 (ACE2)⁴²42 Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020; ciaa237.. In vitro tests have revealed its ability to reduce the number of viral copies of SARS-CoV-2⁴³43 Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin P, Ksiazek TG, Seidah NG, Nichol ST. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J 2005; 2:69. effectively.

Considering the low costs of CQ, good safety profile, in vitro activity against other viruses⁴⁴44 Rolain JM, Colson P, Raoult D. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century. Int J Antimicrob Agents 2007; 30(4):297-308.^,4545 Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun 2004; 323(1):264-268., pre-existing supply chain with potential for increased public and private production, and knowledge about specificity and management of accumulated side effects of use in malaria, some countries have recommended the use of CQ in the treatment of COVID-19. In China, CQ was added to the COVID-19 guideline for prevention, control, diagnosis, and management on February 18, 2020⁴⁶46 National Health Commission of the People's Republic of China. Interpretation of the Sixth Edition of the Guidance for COVID-19: Prevention, Control, Diagnosis, and Management [Internet]. 2020 [acessado 2020 Abr 2]. Disponível em: http://www.nhc.gov.cn/xcs/fkdt/202002/54e1ad5c2aac45c19eb541799bf637e9.shtml
http://www.nhc.gov.cn/xcs/fkdt/202002/54... . In the U.S., the Food and Drug Administration issued an emergency use authorization for CQ/HCQ to treat this disease on March 28, 2020⁴⁷47 Lenzer J. Covid-19: US gives emergency approval tohydroxychloroquine despite lack of evidence. BMJ 2020; 369:m1335.. The European Drug Agency claimed that the two drugs should be used in clinical trials or national drug programs of emergency use for the treatment of COVID-19 on April 1st, 2020⁴⁸48 European Medicines Agency. COVID-19: chloroquine and hydroxychloroquine only to be used in clinical trials or emergency use programmes [Internet]. 2020 [acessado 2020 Abr 6]. Disponível em: https://www.ema.europa.eu/en/documents/press-release/covid-19-chloroquine-hydroxychloroquine-only-be-used-clinical-trials-emergency-use-programmes_en.pdf
https://www.ema.europa.eu/en/documents/p... .

Clinical trials are underway in several countries to evaluate the use of chloroquine or hydroxychloroquine for COVID-19. The best available evidence, until April 2020, failed to demonstrate or exclude a beneficial effect of CQ or HCQ on human coronavirus infections or viral negative by RT-PCR¹³13 Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, Ling Y, Huang D, Song S, Zhang D, Qian Z, Li T, Shen Y, Lu H. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci) 2020; 49(2):215-219.

14 Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, Zhuang R, Hu B, Zhang Z. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020 [preprint].

15 Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo AGC, Brito M, Mourão MPG, Brito-Sousa JD, Baía-da-Silva D, Guerra MVF, Hajjar LA, Pinto RC, Balieiro AAS, Pacheco AGF, Santos Jr JDO, Naveca FG, Xavier MS, Siqueira AM, Schwarzbold A, Croda J, Nogueira ML, Romero GAS, Bassat Q, Fontes CJ, Albuquerque BC, Daniel-Ribeiro CT, Monteiro WM, Lacerda MVG, CloroCovid-19 Team. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. A Randomized Clinical Trial. JAMA 2020; 3(4):e208857.

16 Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, Wu Y, Xiao W, Liu S, Chen E, Chen W, Wang X, Yang J, Lin J, Zhao Q, Yan Y, Xie Z, Li D, Yang Y, Liu L, Qu J, Ning G, Shi G, Xie Q. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. medRxiv 2020 [preprint].

17 Mahévas M, Tran V, Roumier M, Chabrol A, Paule R, Guillaud C, Gallien S, Lepeule R, Szwebel TA, Lescure X, Schlemmer F, Matignon M, Khellaf M, Crickx E, Terrier B, Morbieu C, Legendre P, Dang J, Schoindre Y, Pawlotski JM, Michel M, Perrodeau E, Carlier N, Roche N, De Lastours V, Mouthon L, Audureau E, Ravaud P, Godeau B, Costedoat N. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial. medRxiv 2020 [preprint].

18 Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, Ambati J. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. Med 2020; 1:1-4.^-1919 Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 105949.^,2222 Chorin E, Dai M, Shulman E, Wadhwani L, Cohen RB, Barbhaiya C, Aizer A, Holmes D, Bernstein S, Soinelli M, Park DS, Chinitz L, Jankelosn L. The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin. medRxiv 2020 [preprint].. Furthermore, the results presented are limited and should be interpreted with caution since the essential outcomes for patients (e.g., mortality, rate of progression of the severe acute respiratory syndrome, and need for mechanical ventilation) were not reported in most publications.

Patients have been receiving off-label and compassionate therapies³⁷37 Kalil AC. Treating COVID-19-off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA 2020; 323(19):1897-1898., and the association of lopinavir and ritonavir stood out among the treatments tested for COVID-19⁴⁹49 Scavone C, Brusco S, Bertini M, Sportiello L, Rafaniello C, Zoccoli A, Berrino L, Racagni G, Rossi F, Capuano A. Current pharmacological treatments for COVID-19: what's next? Br J Pharmacol 2020; 10.1111/bph.15072.
https://doi.org/10.1111/bph.15072... . These drugs are used in combination to increase plasma half-life by inhibiting cytochrome P450²⁴24 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med 2020; 382:1787-1799.. Some have raised the hypothesis that lopinavir/ritonavir inhibits protease in a similar way to SARS and MERS 3-chymotrypsin and appears to be associated with better clinical outcomes in patients with SARS⁵⁰50 Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 2017; 9(396):eaal3653.. This inhibitor, which was used mainly for HIV infection, has activity in vitro against SARS-CoV⁵¹51 Groneberg DA, Poutanen SM, Low DE, Lode H, Welte T, Zabel P. Treatment and vaccines for severe acute respiratory syndrome. Lancet Infect Dis 2005; 5(3):147-155. and appears to have some activity against MERS-CoV in animal studies⁵²52 Chan JF, Yao Y, Yeung ML, Deng W, Bao L, Jia L, Li F, Xiao C, Gao H, Yu P, Cai J, Chu H, Zhou J, Chen H, Qin C, Yuen K. Treatment With Lopinavir/Ritonavir or Interferon-ß1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis 2015; 212(12):1904-1913.. Evidence for the use of lopinavir/ritonavir is still limited for SARS-CoV-2, and further studies should be conducted to determine the efficacy and safety of these drugs⁴⁹49 Scavone C, Brusco S, Bertini M, Sportiello L, Rafaniello C, Zoccoli A, Berrino L, Racagni G, Rossi F, Capuano A. Current pharmacological treatments for COVID-19: what's next? Br J Pharmacol 2020; 10.1111/bph.15072.
https://doi.org/10.1111/bph.15072... .

The use of corticosteroids for viral pneumonia still has inconclusive effects among studies, and so far, it is difficult to have a position on the use of corticosteroids in patients with SARS-CoV-2²⁶26 Zhou Q, Wei XS, Xiang X, Wang X, Wang ZH, Chen V, Shannon CP, Tebbutt SJ, Kollmann TR, Fish EN. Interferon-a2b treatment for COVID-19. medRxiv 2020 [preprint].. A diagnosis and treatment regimen was published by the National Health Commission of China, where corticosteroid therapy was indicated as adjuvant therapy, as its use was associated with a delayed viral clearance⁵³53 Fang X, Mei Q, Yang T, Li L, Wang Y, Tong F, Geng S, Pan A. Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-19. J Infect 2020; 81(1):147-178.. A meta-analysis identified that patients with severe conditions were more likely to require corticosteroid therapy and to have a higher mortality rate and adverse effects⁵⁴54 Yang Z, Liu J, Zhou Y, Zhao X, Zhao Q, Liu J. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis. J Infect 2020; 81(1):e13-e20.. According to the Centers for Disease Control and Prevention (CDC)⁵⁵55 Centers for Disease Control and Prevention (CDC). Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). Washington: CDC; 2020., the use of corticosteroids cannot be indicated based on observational data. Both the CDC and the WHO believe that the use of corticosteroids should only be indicated when there is septic shock, asthma exacerbation, or chronic obstructive pulmonary disease⁵⁵55 Centers for Disease Control and Prevention (CDC). Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19). Washington: CDC; 2020.^,5656 World Health Organization (WHO). Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: Interim guidance. Geneva: WHO; 2020.. Thus, the use of corticosteroids remains controversial⁵⁷57 Brasil. Ministério da Saúde (MS). Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde. Diretrizes para diagnóstico e tratamento da COVID-19. Brasília: MS; 2020..

In total, 202 studies investigating different alternatives for the treatment of COVID-19 are in progress (Chart 7).

Most of them are being developed in China, are not yet recruiting participants, are expected to end in 2020, and are available on the ClinicalTrials.gov and Chinese Clinical Trial Registry platforms. Ongoing trials vary in the study’s design, the severity of the disease in the target population, the dosage, and the duration of treatment. The WHO⁵⁸58 World Health Organization (WHO). Guidance for managing ethical issues in infectious disease outbreaks. Geneva: WHO; 2016. published guidelines on the ethics of testing amid outbreaks in 2016 and is working to standardize the design of the studies.

The number of studies conducted in parallel suggests that the scientific community is making a great effort to search for safe and effective treatments. However, there is a high likelihood that we are dealing with a virtually untreatable disease, only in need of supportive measures⁵⁹59 Ferner RE, Aronson JK. Chloroquine and hydroxychloroquine in covid-19. BMJ 2020; 369:m1432.. Besides the financial resources involved with unproven therapies, the focus on effective interventions to prevent mortality and other important outcomes for the patient, such as social isolation, advancing testing capacity, and preventive measures, can be reduced in the general population.

A search in different databases and repositories of prepress papers and an evaluation of the methodological quality of the included studies were performed to identify studies on the theme. However, the evidence found has critical methodological weaknesses, such as a limited number of participants and a lack of control or conventional group¹⁷17 Mahévas M, Tran V, Roumier M, Chabrol A, Paule R, Guillaud C, Gallien S, Lepeule R, Szwebel TA, Lescure X, Schlemmer F, Matignon M, Khellaf M, Crickx E, Terrier B, Morbieu C, Legendre P, Dang J, Schoindre Y, Pawlotski JM, Michel M, Perrodeau E, Carlier N, Roche N, De Lastours V, Mouthon L, Audureau E, Ravaud P, Godeau B, Costedoat N. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial. medRxiv 2020 [preprint].^,2121 Gautret P, Lagier J-C, Parola P, Hoang VT, Meddeb L, Sevestre J, Mailhe M, Doudier B, Aubry C, Amrane S, Seng P, Hocquart M, Eldin C, Finance J, Vieira VE, Tissot-Dupont HT, Honoré S, Stein A, Million M, Colson P, La Scola B, Veit V, Jacquier A, Deharo JC, Drancourt M, Fournier PE, Rolain JM, Brouqui P, Raoult D. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis 2020; 34:101663..

In one of the studies, the two arms of the study received HCQ (high-dose and low-dose), which did not allow to evaluate the effect of HCQ in comparison with placebo or standard treatment¹⁵15 Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo AGC, Brito M, Mourão MPG, Brito-Sousa JD, Baía-da-Silva D, Guerra MVF, Hajjar LA, Pinto RC, Balieiro AAS, Pacheco AGF, Santos Jr JDO, Naveca FG, Xavier MS, Siqueira AM, Schwarzbold A, Croda J, Nogueira ML, Romero GAS, Bassat Q, Fontes CJ, Albuquerque BC, Daniel-Ribeiro CT, Monteiro WM, Lacerda MVG, CloroCovid-19 Team. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. A Randomized Clinical Trial. JAMA 2020; 3(4):e208857.. Other limitations are the heterogeneity of the included studies concerning different dosages, routes, and duration of administration. Moreover, we were unable to detail the treatments described as standard in all studies.

There are some restrictions on the synthesis of evidence. In this synthesis, an assessment of the set of evidence generated was not conducted, employing The Grading of Recommendations Assessment, Development, and Evaluation (GRADE)⁶⁰60 Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol 2011; 64(4):380-382. approach, due to the heterogeneity between the studies, which evaluated neither exposures nor similar outcomes. This rapid review evidenced few overlaps between individual studies underlying the systematic reviews. Only nine duplications were identified in the three reviews included, which contained 48 primary studies.

Final considerations

Despite the various drug options identified, scientific evidence is still incipient and of low methodological quality. There is no proven efficacy and safety of any medication for human coronavirus infections. Thus, it is necessary to carry out randomized controlled clinical trials with adequate follow-up time and methods disclosed and subject to scientific peer review. Furthermore, dozens of clinical studies evaluating the efficacy and safety of drugs are underway worldwide. Periodic updating of this review is recommended to monitor scientific evidence as it becomes available.

References

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