Key findings:

Key findings from this meta-analysis on the efficacy of hydroxychloroquine (HCQ) in treating COVID-19 include: HCQ did not reduce mortality (OR=0.920, 95% CI 0.6402-1.367), time to clinical recovery, length of hospital stay, or need for mechanical ventilation; HCQ also lacked benefits for pre- and post-exposure prophylaxis

What is known and what is new?

The known aspect in this abstract is the global health emergency declared for COVID-19 in 2020, prompting the search for therapeutic measures. The new contribution is the focus on repurposing existing drugs like hydroxychloroquine for COVID-19 treatment, with this study aiming to elucidate its efficacy and safety through a meta-analysis of available research.

What is the implication, and what should change now?

The implication of this meta-analysis is that hydroxychloroquine should not be used for treating COVID-19 patients or as prophylaxis, as it lacks benefits and may expose patients to unnecessary risks. Changes needed include discontinuing the use of hydroxychloroquine for COVID-19 and focusing research efforts on more promising therapeutic options with proven efficacy and safety.

INTRODUCTION

Since December 2019, the disastrous outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infection has contributed to a massive adverse impact internationally. The origin of the outbreak was traced to Wuhan, Hubei Province, China. The World Health Organization (WHO) declared the flare-up as a public health emergency of global concern on January 30, 2020 and thereafter declared it as a pandemic. [1]

Infection by COVID-19 can result in a scale of clinical outcomes, from asymptomatic or showing mild symptoms to severe life-threatening events or even death. Understanding of the epidemiological, clinical patterns and its association with co morbid features are vital for the development of effective therapeutic strategies. [2]

The pandemic has claimed lakhs to millions of human lives and has caused enormous economic imbalance. Alongside the constant efforts of the scientific community to develop an effective vaccine, repurposing of the existing drugs remains the most suitable treatment approach in the current scenario. [3]

Way back since the discovery of the antiviral actions of antimalarials- chloroquine (CQ) and hydroxychloroquine (HCQ) more than 50 years ago, it has always interested the researchers in exploring their therapeutic efficacy against various viral infections. They have been tested against a number of viruses such as influenza, dengue, Ebola, HIV-1, Zika, Chikungunya, MERS-CoV and SARS CoV [4,5,6,7,8,9,10,11]. On account of their long-standing known in-vitro antiviral properties, chloroquine and hydroxychloroquine were among the first drugs that were repurposed in the management of COVID-19 disease. 

The aim of this study is to explore the role of hydroxychloroquine in hospitalized patients with COVID-19, its efficacy when used as pre-exposure prophylaxis and the part of hydroxychloroquine in mortality reduction among COVID-19 patients. 

This systematic review was performed befitting the Preferred Reporting Items of the Systematic review and Meta-Analysis (PRISMA) checklist. All steps were conducted as specified by the Cochrane Handbook of Systematic Review and Meta-Analysis.

Search Strategy

A systematic search of databases like PubMed, Google scholar, Elsevier, Lancet, Medline was carried out. The following search terms were used: ‘Hydroxychloroquine’ ‘Drug trials’ ‘Pharmacotherapy’ ‘randomized control trials’. The search also included reference searching, website tracking and citation following.

Inclusion criteria

• Studies on COVID-19 led between April 2020 and July 2021 

• Studies with sample size greater than 100

• Studies with well-grounded methodologies

• Studies delineating the mechanism of action of HCQ and its adverse effects

Exclusion criteria

• Studies on COVID conducted before 2020

• In-vitro model studies showing the efficacy of HCQ

• Articles with no full text citations

• Guidelines/protocol only articles

• Articles that were not in English

Data Extraction 

Articles that contoured the eligibility criteria were identified and data were extracted from them meticulously. The reliability of the data was ensured by identifying the same article in various systematic reviews of other authors. The odds ratios (ORs) or the proportions of patients for primary outcome variables with 95% confidence intervals (CIs) were estimated using a generic inverse variance method (random-effects model). ‘Selection bias’ was eliminated by taking results after adjustments and propensity score matching.

Statistical analysis 

The odds ratio with 95% confidence intervals of the individual studies were collected. The data were analysed using the Statistical Package for the Social Sciences (SPSS) software version 20.0.

Study selection 

A total of 2528 articles were identified via database searches, website searching and reference chaining. After eliminating duplicate studies (354), articles that were inappropriate to the study topic (436) and articles that did not fit the eligibility criteria (1701), 37 articles were eligible. After quality assessment, 10 articles were taken for the meta-analysis, of which 5 were Randomized control trials, 4 were Cohort studies and 1 observational study (Fig.1).

Fig.1: Prisma flow chart showing study selection

Study characteristics

The studies were chosen based on the following features: date of publication, study design, sample size, country where the study was conducted, number of patients in the intervention group - treated with hydroxychloroquine, combination of drugs if given, comorbidities, number of deaths, number of ICU admissions, need for invasive mechanical ventilation, viral clearance time, length of hospital stay and number of patients in the control group who received standard care of treatment/placebo.

Synthesis of Results

In our meta-analysis, the following parameters were evaluated:

1. Time taken for clinical improvement

2. Length of hospital stay

3. Need for mechanical ventilation

4. Mortality

5. Pre exposure prophylaxis

6. Post exposure prophylaxis

Data of 15822 patients collected from 10 studies conducted in different parts of the world are shown in Table 1. 

Table 1: Summary of studies analysed in the meta-analysis

Out of the 10 studies selected, the results of 9 studies were against the efficacy of hydroxychloroquine, while 1 study favoured the use of hydroxychloroquine. The result of our statistical analysis was that the odds ratio (Fig.2) for mortality reduction of hydroxychloroquine in COVID 19 patients is 0.920 (95% CI; 0.6402 to 1.367).

Fig.2: Risk ratio of mortality reduction of HCQ as per the data of analysed studies

Risk of bias assessment 

We assessed the risk of bias (‘low risk’, ‘unclear’, or ‘high risk’) for the studies included in the meta-analysis using the Cochrane Risk of Bias Assessment Tool version 2 for randomised control trials (Fig.3) and The NewCastle Ottawa scale for non-randomised controlled trials (Table 2). Disagreements aroused during this process were resolved through discussion. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was utilised to assess the quality of the evidence obtained from various studies. See Table.

Fig.3: The Cochrane risk of bias assessment for randomised control trial studies analysed

Table 2: The New Castle Ottawa scale for non-randomised controlled trial studies analysed

The idea of using hydroxychloroquine as a potential therapy for COVID-19 evolved from the results of in vitro studies which showcased the antiviral actions of HCQ. Though the exact mechanism is not known, the various mechanisms postulated are: One, HCQ restricted the entry of SARS-CoV-2 into human cells by inhibiting the glycosylation of angiotensin-converting enzyme 2 (ACE2) receptor and associated gangliosides targeted by coronaviruses [22,23]. Two, HCQ increases the endosomal pH, thereby attenuating the endosome mediated viral entry into the host cells [24, 25, 26]. Three, hydroxychloroquine lowered the production of several proinflammatory cytokines involved in the development of acute respiratory distress syndrome in the course of COVID-19. [27, 28, 29]

COVID-19 patients exhibited obvious immune abnormalities, showing marked lowering of lymphocyte levels in peripheral blood and lymphatic tissues, but erratic lymphocyte infiltration in lungs [30]. Few studies suggested that hydroxychloroquine mimics the effect of anti-IL-6 antibody as decreased levels of Il-6 was observed after hydroxychloroquine administration in the critically ill COVID-19 patients. In addition, modulation of inflammatory macrophage polarization was seen on hydroxychloroquine intake, via downregulation of M1 and upregulation of M2 macrophages [31,32]. There are also studies showing that hydroxychloroquine through inhibition of lysosomal-autophagy pathways [32] and form double membrane vesicles, thereby inhibiting the proinflammatory cytokines [33,34]. Thus, a combination of anti-inflammatory and antiviral action has been observed with hydroxychloroquine. 

Time taken for clinical improvement

In a study conducted by Wesley H.Self et al [16] including 479 patients from the United States, 241 patients received HCQ and 23 patients received placebo. At 14 days after randomization, there was no significant difference in the COVID outcomes scale score between the hydroxychloroquine group and the placebo group. The adjusted odds ratio was 1.02 (95% CI, 0.73-1.42). The 14 day follow up results of the study conducted by Oriol Mitja et al [17] involving 2314 patients from Spain also showed similar results. The risk ratio was 0.86 (95% CI; 0.52 to 1.42) between the hydroxychloroquine group and the usual-care group.

Length of hospital stay

In a study conducted by Joseph Magagnoli et al [15] involving 807 patients from the United States, 214 patients received HCQ + azithromycin, 198 patients received HCQ only and 395 patients received no HCQ. After propensity score adjustment, the length of hospital stay was 33% (95% CI, 6%–67%; p = 0.01) longer in the hydroxychloroquine group and 38% (95% CI, 11%–72%; p = 0.004) longer in the hydroxychloroquine + azithromycin group when compared to the no hydroxychloroquine group. In a study conducted by Peter Horby et al [20] including 4716 patients from the United Kingdom, 1561 patients received HCQ and 3155 patients received usual care. Patients in the HCQ group were found to have a longer time until discharge than those who received usual care. The rate ratio was 0.92 (95% CI; 0.85 to 0.99).

Need for mechanical ventilation 

According to the study conducted by Joseph Magagnoli et al [15], the propensity-score-adjusted risk of mechanical ventilation was not significantly different in the hydroxychloroquine group (adjusted hazard ratio, 1.19; 95% CI, 0.78–1.82; p = 0.42) or in the hydroxychloroquine + azithromycin group (adjusted hazard ratio, 1.09; 95% CI, 0.72–1.66; p = 0.69), compared to the no hydroxychloroquine group. Peter Horby’s [20] study conducted in the United Kingdom involving 4716 patients also showed similar results. Among those who were not on invasive mechanical ventilation initially, the number of patients progressing to the stage invasive mechanical ventilation or death was higher among those who received hydroxychloroquine (risk ratio 1.12, 95% CI 1.01 to 1.25). In a study conducted by Shailendra singh et al [21] including 1820 patients from the United States, the relative risk was 0.81 (95% CI: 0.55,1.18, p= 0.26) for mechanical ventilation in those who received HCQ when compared to those who were not on HCQ.

Mortality

In the study conducted by Eli S. Rosenberg et al including 1438 patients from New York [12], there was no significant differences in mortality rates between the patients receiving hydroxychloroquine + azithromycin (adjusted HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (adjusted HR, 1.08 [95%CI,0.63-1.85]), or azithromycin alone (adjusted HR, 0.56 [95%CI,0.26-1.21], compared with neither drug. In a study conducted by Joshua Geleris et al [13] including 1376 patients from New York, after propensity matching, the hazard ratio for death was 0.97 (95% CI: 0.74-1.28) for HCQ and no HCQ group. In the study by Bo Yu et al [14] involving 568 patients from China, the use of hydroxychloroquine was associated with a significantly decreased mortality risk. The adjusted HR was 0.32 (95% CI: 0.16-0.62; p<0.001). In the Joseph Magagnoli’s study [15], after propensity score adjustment, the risk of death was higher in the HCQ group (adjusted hazard ratio, 1.83; 95% confidence interval [CI], 1.16–2.89; p = 0.009), when compared to the no HCQ group. Similar results were seen in Wesley H.Self’s study [16] wherein there was no difference in the mortality between the HCQ and the no HCQ group. The adjusted odds ratio was 1.07 (95% CI, 0.54-2.09). Peter Horby’s study [20] also showed that there was no significant difference in the 28 days mortality rate between patients in the HCQ and the usual care group. The results of Shailendra singh’s study [21] was also consistent with those of the above studies. The relative risk for 30-days mortality between the 2 groups was 0.95 (95% CI: 0.74-1.23, p=0.72).

Pre exposure prophylaxis

Radha Rajasingham et al [18] studied about the efficacy of hydroxychloroquine when used as pre-exposure prophylaxis. He involved 1483 patients from US and Canada and classified them into 2 arms. One group had subjects who received once-weekly and twice-weekly hydroxychloroquine prophylaxis while the other was comparator group. The hazard ratio was 0.66 (95% CI, .37–1.17; P = 0.16) for the once weekly group and 0.68 (95% CI, .37–1.22; P = 0.19) for the twice weekly group.

Post exposure prophylaxis

David R. Bowlware et al [19] studied about the efficacy of hydroxychloroquine when used as post-exposure prophylaxis. He included 821 patients from US and parts of Canada.The relative risk was 0.024 for the incidence of COVID-19 in patients receiving HCQ when compared to those receiving placebo. In this study, the postexposure prophylaxis of HCQ within 4 days after exposure did not prevent COVID-19 illness. 

Adverse events

The most common reported side effect was gastrointestinal disturbance, nausea and diarrhea [18]. The next commonly observed adverse event was abnormalities in ECG findings, particularly arrhythmias and torsade de pointes [35, 36, 37]. The short-term high dose of 4-aminoquinoline regimens were found to have very high cardiovascular toxicity. Cardiac arrest was more likely seen in patients who received hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95%CI, 1.12-4.05]; E-value = 1.31), than in patients who received hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]. [12] 

Limitations

One limitation in our study is that many studies conducted had administered combinations of drugs along with HCQ to the patients. Hence the isolated efficacy of HCQ could not be strongly commented on. 

The role of hydroxychloroquine in the management of COVID 19 was studied under various parameters. It was found that hydroxychloroquine administration did not reduce the time taken for clinical improvement in the hospitalized COVID 19 patients. The length of hospital stay did not differ and the need for mechanical ventilation was also similar between the hydroxychloroquine and the no hydroxychloroquine groups. In addition, hydroxychloroquine was not proven to show any mortality reduction. Prophylactic intake of hydroxychloroquine either prior to the exposure or after exposure also did not prevent the incidence of the illness.

Acknowledgements

We thank Ms. Sumithra.P, Department of Statistics from Manonmaniam Sundaranar University, Tirunelveli for plotting us the statistical analysis of our results. We also thank David Sam Selva Jeyam, medical scholar from Tirunelveli Medical College for offering technical assistance. 

Funding: No funding sources.

Conflict of interest: None declared.

Ethical approval: The study was approved by the Institutional Ethics Committee of Tirunelveli Medical College.

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