|REVIEW ARTICLE - COVID-19 SERIES
|Year : 2020 | Volume
| Issue : 3 | Page : 265-272
Effect of chloroquine and hydroxychloroquine on COVID-19 virological outcomes: An updated meta-analysis
Rashmi Ranjan Das1, Bijayini Behera1, Baijayantimala Mishra1, Sushree Samiksha Naik2
1 Department of Pediatrics and Microbiology, AIIMS, Bhubaneswar, Odisha, India
2 Department of Obstetrics and Gynecology, Capital Hospital, Bhubaneswar, Odisha, India
|Date of Submission||15-Jun-2020|
|Date of Decision||18-Jul-2020|
|Date of Acceptance||27-Jul-2020|
|Date of Web Publication||4-Nov-2020|
Dr. Rashmi Ranjan Das
Department of Pediatrics, AIIMS, Bhubaneswar - 751 019, Odisha
Source of Support: None, Conflict of Interest: None
As anti-malarial drugs have been found to inhibit Corona viruses in vitro, studies have evaluated the effect of these drugs inCOVID-19 infection. We conducted an updated meta-analysis of clinical trials and observational studies published till June 2020. Patients with reverse transcription polymerase chain reaction (RT-PCR) confirmed Severe Acute Respiratory Syndrome Coronavirus 2 (COVID-19) infection were included. The drugs used in the intervention group are Chloroquine (CQ)/Hydroxychloroquine (HCQ) with or without Azithromycin. The primary outcome is time to achieve virological cure. Of 1040 citations, 11 studies provided data of 1215 patients. Compared to control, CQ/HCQ has no significant effect on the time to negative COVID-19 RT-PCR results, neither in clinical trials (mean difference [MD] 1.55; 95% confidence interval [CI] - 0.7 to 3.79; P = 0.18; n = 180), nor in observational studies (MD 1.14; 95%CI - 11.98 to 14.26; P = 0.86, n = 407). CQ/HCQ did not affect the virological cure after day 3, 7, 10, 14, 21 and 28; except after day 5, as shown by a single small non-randomised trial (odds ratio [OR] 9.33; 95% CI 1.51 to 57.65; P = 0.02, n = 30). Pooled data from 2 observational studies showed a significant effect of CQ/HCQ on virological cure by after day 10 (OR 7.86; 95% CI 4.4 to 14.04, P < 0.001, n = 373) and day 14 (OR 6.37; 95% CI 3.01 to 13.48, P < 0.001, n = 407). The GRADE evidence generated was of “very low-quality/certainty”. To conclude, CQ/HCQ does not affect the time to virological cure compared to usual/standard of care in COVID-19 infection. Recurrent infection in a smaller number of patients was noted in the CQ/HCQ group. As the evidence generated was of “very low-quality/certainty)”, large good quality studies are needed to confirm the present findings.
Keywords: Aminoquinoline, azithromycin, COVID-19, evidence-based medicine, hydroxychloroquine, severe acute respiratory syndrome coronavirus 2
|How to cite this article:|
Das RR, Behera B, Mishra B, Naik SS. Effect of chloroquine and hydroxychloroquine on COVID-19 virological outcomes: An updated meta-analysis. Indian J Med Microbiol 2020;38:265-72
|How to cite this URL:|
Das RR, Behera B, Mishra B, Naik SS. Effect of chloroquine and hydroxychloroquine on COVID-19 virological outcomes: An updated meta-analysis. Indian J Med Microbiol [serial online] 2020 [cited 2020 Nov 24];38:265-72. Available from: https://www.ijmm.org/text.asp?2020/38/3/265/299836
| ~ Introduction|| |
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or COVID-19, a highly contagious disease emerged in Wuhan, China, in late 2019. Till date, it has infected millions of patients globally. India has a rising number of cases but the mortality is low. As there is no specific anti-viral drugs, pharmaceutical agents (antiviral agents, antibiotics, immune-modulators and convalescent plasma) are being tried with variable success.
Two aminoquinoline anti-malarial drugs (chloroquine [CQ] and hydroxychloroquine [HCQ]) were in the news for treatment of COVID-19 infection, after publication of one study from France. Subsequently, large studies (mainly observational) have been published. Both the drugs have been found to inhibit other corona viruses, such as SARS-CoV-1., The mechanisms of action include – inhibition of angiotensin converting enzyme 2 (ACE-2) used by the virus for entry into the cell,, inhibition of release of viral particles into intra-cellular space,, and a non-specific anti-inflammatory action (inhibition of interleukin-6 [IL-6], tumour necrosis factor, aberrant interferon and other pro-inflammatory cytokines that cause lung injury leading to acute respiratory distress syndrome)., Both the drugs are cheap, and considered safe, as per their approved indications. Compared to CQ, HCQ is more soluble and less toxic and is considered safer.,
There have been published studies evaluating the safety and/or efficacy of these agents (alone or in combination) compared to a control arm or parallel intervention, to treat patients with COVID-19.,,,,,,,,,, However, the results have been contradictory. A published rapid systematic review including data from three studies found no role of anti-malarial drugs on the virological outcomes in patients with COVID-19 infection. After publication of this review, many studies (both observational studies and clinical trials) with larger sample sizes have been published. The present updated meta-analysis has included these larger studies to evaluate the effect of the anti-malarial drugs (CQ and HCQ) to inform clinical practice, and guide the international agencies to formulate recommendation.
| ~ Materials and Methods|| |
Types of studies
Both clinical trials and observational studies comparing anti-malarial drugs (CQ and HCQ) alone or in combination with other drugs versus control (standard of care) or other treatment were included.
Types of participants
Children (age >12 years) and adults with reverse transcription-polymerase chain reaction (RT-PCR) confirmed SARS CoV-2 (COVID-19) cases treated in the hospital were included. Exclusion criteria were allergy to these anti-malarial drugs, hearing loss, retinopathy and severe neuro-psychiatric diseases.
Types of interventions
Anti-malarial drugs (CQ and HCQ) administered (with or without Azithormycin) in various dose schedules to patients with SARS-CoV-2 (COVID-19) infection. Control group patients received usual/standard of care as per the hospital/institute policy or government guideline. Studies comparing different doses (high-dose versus low-dose of anti-malarial drugs) were also included.
Types of outcome measures
- Time to virological cure (days).
- Proportion of patients with virological cure after days 3, 5, 7, 10, 14, 21 and 28
- Proportion of patients with recurrence of infection.
Definition of outcome measures: Virological cure is defined as non-detection (negative report) of COVID-19 by RT-PCR in two consecutive respiratory specimens (naso-pharyngeal swabs, throat swabs, nasal swab, broncho-alveolar lavage fluid and tracheal aspirate) taken 24 h apart. Recurrence of infection is defined as detection (positive report) of COVID-19 by RT-PCR in any of the above specimens collected from a patient at any time point after documentation of virological cure.
Major databases (PubMed/MEDLINE, Cochrane Central Register of Controlled Trials [CENTRAL], EMBASE, Google Scholar and Pre-print servers [medRxiv, bioRxiv, OSF preprints, preprints.org]) were searched systematically from 1970 to 5th June 2020 [Appendix 1]. No language restrictions were applied. Two reviewers (SSN, BB) reviewed the search results to identify relevant studies.
Data extraction was done using a data extraction form that was designed and pilot tested a priori. Two authors (BB and BM) independently extracted the following information from each study: author year, country, study design, setting (hospital or community), method of recruitment, inclusion criteria, risk of bias, participants (age, sex, sample size, disease severity), intervention (dosage, duration, frequency, and co-intervention if any), outcomes (outcome definition, valid unit of measurement, time points of collection, and reporting), loss to follow-up and key conclusions. Any disagreements between the two review authors were resolved through discussion with the third author (RRD).
Assessment of risk of bias in the included studies
Two review authors independently (BB, SSN) assessed the methodological quality of the selected trials by using Cochrane Handbook, and of observational studies by Newcastle Ottawa Scale. Quality assessment was undertaken using the ROBINS-I tool for non-randomised trials. Any disagreements between the two review authors were resolved through discussion with the third author (RRD).
Data were analysed using Review Manager (RevMan) V.5.1. Data were pooled and expressed as mean difference (MD) with 95% confidence interval (CI), if continuous; odds ratio (OR) with 95% CI, if categorical. All the analyses were by Generic Inverse Variance method using random effects weighting, where the log RRs for cohort studies or log ORs for case–control studies were weighted by the inverse of the variance to obtain a pooled RR estimate. A P < 0.05 was considered statistically significant. Inter-study heterogeneity was assessed by Cochrane's Q (Chi-square P < 0.10) and quantified by I2. An I2 ≥50% indicated 'substantial' heterogeneity and ≥75% indicated 'considerable' heterogeneity.
Grade of evidence
To assess the quality of evidence, we used GRADE Profiler software (V.3.2) (Hamilton, Canada)., The software uses five parameters for rating the quality of evidence (risk of bias, inconsistency of results, indirectness of evidence, imprecision of results and publication bias), and does rating as-no, serious and very serious limitation.
| ~ Results|| |
Description of studies
Of 1040 total citations retrieved, the full text of 15 papers was assessed for eligibility, and 4 studies were excluded [Figure 1]. Of the remaining 11 eligible studies (n = 1215), 6 were published in peer-reviewed journals,,,,,, and 5 in pre-print servers (not peer-reviewed).,,,, We contacted the authors of these 5 studies to provide us the permission to use their data in the meta-analysis, but only one study author responded. Hence, we included the data of this study along with other published studies (in peer-reviewed journals) in the present meta-analysis [Table 1], and described the characteristics of rest 4 studies,,, [Table 2]. Of the 7 included studies (n = 726), 5 clinical trials provide data of 319 patients, and the 2 observational studies provided data of 407 patients.,,,,,, A total of 415 patients received HCQ or CQ (clinical trials = 195, observational studies = 220), and 6 received a combination of HCQ plus Azithromycin (in one non-RCT [non-randomised controlled trials]). The studies were conducted in the following countries: Chin (n = 4, 575 patients), Brazil (n = 1, 81 patients), France (n = 1, 36 patients) and UAE (n = 1, 34 patients). One trial compared high versus low-dose of Chloroquine. Of the 5 clinical trials, 2 were double-blind and 1 was a non-RCT.
|Table 2: Characteristics of studies published in pre-print server (not peer-reviewed)|
Click here to view
As shown in [Table 1], the age of included participants, severity of illness, dose schedule and timing of the administration of intervention (HCQ/CQ) varied widely among the studies. Contrary to CQ, the dose schedule of HCQ varied widely. No study was able to start the intervention (HCQ/CQ) in the early phase of illness (within 48 h of symptom onset), which is regarded as the golden window for antiviral treatment (e.g. in influenza).
Risk of bias in included studies
The details have been provided in Supplemental file [Appendix 2]. Except one trial, others had low to high-risk of bias in different domains. One non-RCT had serious risk of biases in all the domains. All the observational studies were at a high risk of bias for selection of controls, and a low risk of bias for the exposure parameters.
Effect of interventions
- Time to virological cure (days): The pooled result from 2 RCTs showed no significant difference between the HCQ group and control group [MD 1.55 (95% CI - 0.7 to 3.79), P = 0.18) [Figure 2]. The pooled result from two observational studies also showed no significant difference between the HCQ group and control group [MD 1.14 (95% CI - 11.98 to 14.26), P = 0.86) [Figure 3].
|Figure 2: Time to virological cure (hydroxychloroquine vs. control; result from randomised controlled trials)|
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|Figure 3: Time to virological cure (hydroxychloroquine vs. control; result from observational studies)|
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- Proportion of patients with virological cure after days 3, 5, 7, 10, 14, 21 and 28: Compared to control, CQ/HCQ did not affect the virological cure after days 3, 7, 21 and 28 [Table 3]. However, the pooled data from 2 observational studies showed a significant effect of CQ/HCQ on virological cure after 10 and 14 days [Table 4].
- Proportion of patients with recurrence of infection: Two studies reported this outcome., In one study, 1 of 20 patients (5%) in the HCQ group tested positive on day 8 (was negative on day 6). In the other study, 3 of 197 patients (1.5%) in the CQ group tested positive (from faecal sample, not from naso-pharyngeal samples) within 7 days following hospital discharge.
|Table 3: Outcome measures from clinical trials (randomised, quazi-randomised and nonrandomised)|
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Grade of evidence
The evidence generated was of 'very low-quality' for all the outcomes (primary and secondary). A detailed analysis of the summary of evidence is provided in [Table 5].
|Table 5: GRADE evidence (Effect of Chloroquine/Hydroxy-chloroquine±Azithromycin vs. Standard of care on COVID-19 virological outcomes)|
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| ~ Discussion|| |
Summary of evidence
After an extensive search of the literature we could find 11 studies (n = 1215) eligible for inclusion in the review. Compared to control, CQ/HCQ has no significant effect on the time to negative COVID-19 RT-PCR results. CQ/HCQ des not affect the virological cure after days 3, 7, 10, 14, 21 and 28 (except after day 5 as shown by a single, small non-RCT). However, pooled data from 2 observational studies showed a significant effect of CQ/HCQ on virological cure after 10 and 14 days. Two studies reported repeat COVID-19 positive with all the patients belonging to the CQ/HCQ group. The GRADE evidence generated for all outcomes was of 'very low-quality'.
It has to be kept in mind that, the anti-viral action of anti-malarial drugs against COVID-19 is still largely unknown. The dose schedule of CQ was nearly uniform, however, the dose of schedule of HCQ varied widely among the included studies (except one large study, the cumulative dose in remaining of the studies was equal to or higher than the recommended). The median time from onset of symptom to admission or treatment initiation was nearly ≤8 days in all but 2 studies. Except one study, others used CQ/HCQ within 48 h of admission/hospitalization. This might be due to the fact that starting anti-viral drugs (including HCQ/CQ) after 48 h of symptom onset might not be beneficial as the golden window for antiviral treatment (e.g. in influenza) is lost. However, this is difficult in a hospitalised setting (may be possible in outpatient or community setting). Another important point is that, the patients included in the present study were having comorbidities, and were on multiple drugs. The interactions between these drugs, and CQ/HCQ in affecting the action of the later on COVID-19 are unknown at present. Moreover, as none of the studies measured the blood level of these drugs, it is difficult to conclude this (at least to some extent). In two studies, recurrent COVID-19 infection was noted (from faecal samples in one study). The authors could not explain the reason for the same as none of the patients in the control group was positive. Future studies with larger samples might provide insight into the causation.
The studies were variable in many aspects (blinding of participants and outcome assessors, patient selection, severity of illness, dose schedule of the anti-malarial drugs, timing of administration, etc). Due to lack of paediatric data, the results of present review cannot be extrapolated to this population.
| ~ Conclusions|| |
CQ/HCQ does not affect the time to virological cure compared to usual/standard of care used in the treatment of COVID-19 infection at present. Recurrent infection in a smaller number of patients was noted in the CQ/HCQ group. Good quality and multi-centric RCTs are required for any firm conclusion to be drawn or recommendation to be made during the on-going pandemic.
We would like to thank Dr NishantPJaiswal, Evidence based health informatics unit, Department of Telemedicine, PGIMER, Chandigarh, for the help in the database search.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]