Safety of treatment with chloroquine and hydroxychloroquine: A ten-year systematic review and meta-analysis
Introduction
Previously known as SN7618, chloroquine has been used since the early 1940s for the treatment of malaria [1]. In 1946 Loeb F. et al., in a statement approved by the board for coordination of malarial studies, highlighted the efficacy and safety profile of the drug – “with minor side effects as mild and transient headache, visual disturbances, pruritus, and gastrointestinal complaints”. The authors also noted that none of the adverse symptoms was serious and all of them were readily reversible [2]. In 1953, Hoenkenga M.T. et al. reported encouraging results for the treatment of malaria with 7-chloro-4-[4-(N-ethyl-N-β-hydroxyethylamino)-1-methylbutylamino], later known as hydroxychloroquine. Besides its efficacy, the authors did not find any side effects during its first clinical study [3].
Since its discovery, other diseases besides malaria – like lupus [4], rheumatoid arthritis (RA) [5], hand osteoarthritis [6], and antiphospholipid syndrome [7], – have been successfully treated with chloroquine and hydroxychloroquine. In general, both drugs have been considered safe for nearly 60 years, even for long term use. Gastrointestinal complaints are the most frequent side effects, although retinopathy has been the most feared one. Dermatological, neurological, musculoskeletal, and cardiovascular side effects are also reported, though less frequently [8].
In 2018, Chatre C. et al. systematically reviewed the cardiac toxicity attributed to chloroquine and hydroxychloroquine and concluded that both drugs were safe and well-tolerated, but cardiotoxicity could be a rare, severe, and overlooked complication of such therapy [9].
In 2020, the world spread of the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) – the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), has demanded innovative treatment options to halt the disease progression and the already high, death toll. Wang M. et al. suggested, in February of that same year, that chloroquine was highly effective in the control of SARS-Cov-2 infection in vitro [10]. With the potential use of chloroquine and hydroxychloroquine for the treatment of COVID-19, the debate on its safety have reemerged, and studies with conflicting results have been published [11], [12], [13].
Considering that both drugs have been in the market for a long time, the extensive body of evidence supporting them, and the recent doubts on its safety, we decided to conduct a systematic review to assess the safety of hydroxychloroquine and chloroquine for the treatment of lupus, RA, malaria, and COVID-19.
Section snippets
Objectives
We systematically reviewed randomized controlled trials (RCTs) reporting adverse events (AE) in users of chloroquine or hydroxychloroquine - for the treatment of lupus, RA, malaria and COVID-19 - in comparison to non-users, to estimate the incidence rate ratio (IRR) of developing AE, in general and categorized by system.
Methods
This systematic review with meta-analysis was conceived according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) [14], its checklist is provided as a supplementary file and its protocol is available online at the PROSPERO database (identifier CRD42020197938).
Study selection
Our research generated 938 records for evaluation. After excluding duplicates, a total of 925 titles and abstracts were screened. As we did not find any information about AE in 787 studies, they were considered irrelevant and excluded from our analysis. We retrieved 138 articles for full-text appreciation. 42 studies met our eligibility criteria and were included in our systematic review and meta-analysis.
As we found only 2 RCTs evaluating the use of hydroxychloroquine in patients with lupus,
Publication bias
The visual inspection of the funnel plot suggested some asymmetry, later confirmed in a weighted linear regression of the treatment effect on its standard error (P-value = 0.003229) (fig.S30).
Considering the asymmetry observed in our funnel plot, we performed Duval S. and Tweedie R.'s “Trim and fill” procedure [24] to estimate potentially missing studies and adjust the overall effect estimate. This analysis revealed an IRR of 1.41(CI 95% 1.25 - 1.59) suggesting that we may have underestimated
Sensitivity analysis
We performed a sensitivity analysis to assess the robustness of our results. Firstly, we repeated our main analysis excluding outliers as described by Viechtbauer and Cheung [25]. This procedure significantly reduced the heterogeneity of our analysis (I2 from 89% to 35%) (fig.S31) and the pooled IRR still suggested a statistically significant higher risk of developing any AE in hydroxychloroquine and chloroquine users (IRR 1.11 [CI 95% 1.04 – 1.18]).
We conducted the same analysis for
Discussion
We found a higher IRR of total AE in hydroxychloroquine or chloroquine users. This risk was 83% higher in patients infected with COVID-19 in comparison with non-users.
A higher IRR of gastrointestinal AE was observed in patients treated with either antimalarials, after exclusion of outliers (IRR 1.14 [CI 95% 1.01 – 1.29]). This risk was significantly higher in COVID-19 patients (IRR 2.65[CI 95% 1.60– 4.39]). Gastrointestinal complaints are the most reported AE in hydroxychloroquine and
Conclusions
We found that chloroquine and hydroxychloroquine have in general a good safety profile, as most of their side effects were mild and not fatal. COVID-19 patients seem to have a higher risk of general and gastrointestinal AE during their use. These AE may be related to an interaction between virus, host and polypharmacy, not the antimalarial use itself. Although our analysis did not suggest a significantly higher IRR of cardiovascular AE in antimalarial users when compared to non-users,
Declarations: funding
M.B.S. has received a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The government funding agency had no role in study design, manuscript elaboration, authors decisions, or manuscript approval for publication.
Availability of data and materials
The authors declare that this systematic review is an original work and all the data will be available from the corresponding author on request.
Ethics approval and consent to participate
As all the data used in this systematic review is available for public access, there is no need of ethics committee approval.
Consent
Not applicable.
Author's contribution
FLBE conceptualized, drafted and is the guarantor of this manuscript. FLBE and SG developed the selection criteria, the risk of bias assessment strategy and data extraction criteria. MBS and SG reviewed the manuscript. All authors read, provided feedback and approved this systematic review.
Declaration of Competing Interest
The authors declare that they have no competing interest.
Acknowledgments
The authors would like to thank Evidence Partners for providing us free access to their systematic review software – Distiller SR – through COVID-19 initiative.
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