key: cord-0687152-tydnalmb authors: Chi, Gerald; Memar Montazerin, Sahar; Lee, Jane J.; Kazmi, Syed Hassan A.; Shojaei, Fahimehalsadat; Fitzgerald, Clara; Gibson, C. Michael title: Effect of azithromycin and hydroxychloroquine in patients hospitalized with COVID‐19: Network meta‐analysis of randomized controlled trials date: 2021-08-17 journal: J Med Virol DOI: 10.1002/jmv.27259 sha: 5e77d3a709fb0078084081dd965641ec8625975b doc_id: 687152 cord_uid: tydnalmb Chloroquine or its derivative hydroxychloroquine (HCQ) combined with or without azithromycin (AZ) have been widely investigated in observational studies as a treatment option for coronavirus 2019 (COVID‐19) infection. The network meta‐analysis aims to summarize evidence from randomized controlled trials (RCTs) to determine if AZ or HCQ is associated with improved clinical outcomes. PubMed and Embase were searched from inception to March 7, 2021. We included published RCTs that investigated the efficacy of AZ, HCQ, or its combination among hospitalized patients with COVID‐19 infection. The outcomes of interest were all‐cause mortality and the use of mechanical ventilation. The pooled odds ratio was calculated using a random‐effect model. A total of 10 RCTs were analyzed. Participant's mean age ranged from 40.4 to 66.5 years. There was no significant effect on mortality associated with AZ plus HCQ (odds ratio [OR] = 0.562 [95% confidence interval {CI}: 0.168–1.887]), AZ alone (OR = 0.965 [95% CI: 0.865–1.077]), or HCQ alone (OR = 1.122 [95% CI: 0.995–1.266]; p = 0.06). Similarly, based on pooled effect sizes derived from direct and indirect evidence, none of the treatments had a significant benefit in decreasing the use of mechanical ventilation. No heterogeneity was identified (Cochran's Q = 1.68; p = 0.95; τ (2) = 0; I (2) = 0% [95% CI: 0%–0%]). Evidence from RCTs suggests that AZ with or without HCQ was not associated with a significant effect on the mortality or mechanical ventilation rates in hospitalized patients with COVID‐19. More research is needed to explore therapeutics agents that can effectively reduce the mortality or severity of COVID‐19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 , is an enveloped virus with a positive-sense single-stranded ribonucleic acid (RNA) genome. This virus was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China. On March 12, 2020 this local epidemic was escalated to a pandemic by the World Health Organization (WHO) due to its rapid rate of global spread. Ever since its emergence, has devastated the healthcare, socioeconomic and educational sectors of society through a ripple effect. Infected patients can have a wide range of presentations ranging from asymptomatic infection to acute respiratory distress syndrome and death. 1 Worldwide case fatality rate ranges between 2% and 3%. 2, 3 In addition to affecting the respiratory tract, SARS-CoV-2 infection has been shown to establish an proinflammatory milieu capable of promoting various complications such as thrombosis, cardiac arrhythmias, exacerbations of heart failure, acute kidney injury, stroke and encephalitis. [4] [5] [6] [7] [8] [9] [10] [11] [12] The medical, economical and psychological impact of social distancing, quarantining and isolation may have lingering effects in the community. [13] [14] [15] These challenges have driven the scientific community to seek therapies aiming at treatment and prevention of COVID-19 in a race against time to curtail the morbidity and mortality associated with this rapidly spreading disease. [16] [17] [18] Various pharmacological agents have been studied over the course of the pandemic for their effectiveness on COVID-19. Azithromycin (AZ) and hydroxychloroquine (HCQ) were extensively investigated in a series of observational studies and randomized controlled trials for their real-world efficacy against COVID-19, due to their availability, prior success in the treatment of inflammatory airway disease, in vitro antiviral activity, cost, and publicity. Previous meta-analyses and systematic reviews have analyzed the evidence based on mostly observational studies and noted heterogeneous results. To validate the potential efficacy of AZ and HCQ, a network meta-analysis including only randomized clinical trials was undertaken to estimate the treatment effect of these agents based on higher-quality data. Detailed queries are provided in Table S1 . In this analysis, the outcomes of interest are (1) all-cause mortality and (2) the use of mechanical ventilation. Randomized trials that involve any of the following treatment comparisons were analyzed: (1) AZ plus HCQ (AZ + HCQ); (2) AZ; (3) HCQ; and (4) usual standard of care or placebo (control group). Data extracted from each study included study design, patient characteristics, and the number of events (all-cause mortality and use of mechanical ventilation). Database search, article screening, and study selection were performed independently by two investigators using a standardized approach. Disagreement in extracted data was adjudicated by a third investigator. A flow diagram depicting the process of literature search and screening is provided in Figure 1 . Two independent investigators assessed the quality of included studies with the revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Disagreement in the quality assessment was resolved by discussion and consensus. A network meta-analysis using the netmeta package was performed to compare the treatment effect. The measure of treatment effect was expressed as odds ratio (OR) with 95% confidence interval (CI). A fixed-effect or random-effect model was fitted to estimate the treatment effect based on the presence of heterogeneity. Heterogeneity across the studies was evaluated using Cochran's Q test (with the threshold of p > 0.10) and Higgins's I 2 statistic (with the values of 0.25, 0.50, and 0.75 indicating a low, moderate, and a high degree of heterogeneity, respectively). Analysis was performed using R software (Version 3.5.2; The R Foundation for Statistical Computing). A total of 10 randomized controlled trials were included in the final analysis ( Figure 1 ). [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] The study design and patient characteristics of included studies were summarized in Table 1 . Results of risk of bias assessment were presented in Figure S1 . Three studies were considered to be at a high risk of bias. The network graph was provided in Figure S2 . The network graph was provided in Figure designs (Q = 0.00; p = 0.95). Additionally, there was no significant inconsistency between direct and indirect evidence ( Figure 5 ). comes Score). 26 The ORCHID study found no benefit of HCQ use. The HAHPS trial compared HCQ with AZ in 85 patients, and showed no benefit of HCQ over AZT; moreover, patients treated with HCQ had a higher rate of acute kidney injury. 20 In the open-label DIS-COVERY trial, 11 330 patients were randomly assigned to HCQ, remdesivir, lopinavir, interferon, or control. 24 In this trial conducted across 30 countries, none of the treatments were successful in reducing in-hospital mortality, initiation of ventilation, and hospitalization duration. Of these, 947 were randomized to receive HCQ and 906 patients were included in the control group. HCQ was not associated with a significant difference in mortality compared to the control group. Previously reported data indicating the efficacy of chloroquine or HCQ against coronavirus infection were mostly observational or from in vitro experiments. 30, 31 This led to its testing in randomized clinical trials. HCQ is an aminoquinoline derivative primarily used as an antimalarial and immunomodulatory agent. 32 The compound also has antiautophagic activity, which has driven widespread testing of its antiviral activity. As a lysosomotropic agent, HCQ alkalizes in- Another report also demonstrated that a combination of HCQ and AZ were able to inhibit the replication of SARS-CoV-1 and 2 viruses. 37 Interestingly, a study showed that the combination of these two antimicrobial agents possesses synergistic interactions that not only neutralize the viral shedding but also inhibit host lysosomal enzyme activity and cease viral entry to other cells. 38, 39 This study explained that both AZ and HCQ are weak bases and are more prone to accumulate in the endosomal vesicles and lysosomes, increasing their pH and making them dysfunctional. This property was believed to block viral shedding from lysosomes and uncoating of enveloped viruses. 40 However, in vitro activity does not necessarily confer clinical efficacy. Another important point to consider is the avoidance of adding harm to the patients while using unnecessary treatments based on low-quality evidence. A recent meta-analysis with 11 932 participants showed that the combination of AZ and HCQ can increase mortality among patients with COVID-19 infection. 36 One possible mechanism for this observation is that this combination was associated with an increase in life-threatening cardiovascular events. Both HCQ and AZ are associated with prolongation of QT interval and provide a substrate for abnormal arrhythmogenic activity. 41, 42 Furthermore, the combination of these two agents has been observed to prolong the QT interval to a greater extent than each agent alone. 43, 44 In line with this finding, another systematic review of 14 studies reported a higher rate of mortality in patients receiving both HCQ and AZ. 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