Systematic review and meta-analysis of the safety of chloroquine and hydroxychloroquine from randomized controlled trials on malarial and non-malarial conditions

Abstract

Background Despite the expectations regarding the effectiveness of chloroquine (CQ) and hydroxychloroquine (HCQ) for coronavirus disease (COVID-19) management, concerns about their adverse events have remained. Objectives The objective of this systematic review was to evaluate the safety of CQ and HCQ from malarial and non-malarial randomized clinical trials (RCTs). Methods The primary outcomes were the frequencies of serious adverse events (SAEs), retinopathy, and cardiac complications. Search strategies were applied to MEDLINE, EMBASE, LILACS, CENTRAL, Scopus, and Trip databases. We used a random-effects model to pool results across studies and Peto’s one-step odds ratio (OR) for event rates below 1%. Both-armed zero-event studies were excluded from the meta-analyses. We used the Grading of Recommendations Assessment, Development, and Evaluation system to evaluate the certainty of evidence. Results One hundred and six RCTs were included. We found no significant difference between CQ/HCQ and control (placebo or non-CQ/HCQ) in the frequency of SAEs (OR: 0.98, 95% confidence interval [CI]: 0.76–1.26, 33 trials, 15,942 participants, moderate certainty of evidence). However, there was a moderate certainty of evidence that CQ/HCQ increases the incidence of cardiac complications (RR: 1.62, 95% CI: 1.10–2.38, 16 trials, 9908 participants). No clear relationship was observed between CQ/HCQ and retinopathy (OR: 1.63, 95% CI: − 0.4–6.57, 5 trials, 344 participants, very low certainty of evidence). Conclusions CQ and HCQ probably do not increase SAEs, with low frequency of these adverse events on malarial and non-malarial conditions. However, they may increase cardiac complications especially in patients with COVID-19. No clear effect of their use on the incidence of retinopathy was observed. Systematic review registration PROSPERO CRD42020177818

Adverse events in rheumatoid arthritis patients under antimalarial treatment—Is there cardiovascular compromise?

“…On the other hand, the cardioprotective effect of antimalarials in inflammatory diseases that increase cardiovascular risk, such as rheumatic diseases, is well known. Thus, a meta-analysis involving patients with RA and SLE showed that using CQ/HCQ reduced the risk of cardiovascular disease in patients with rheumatic diseases (RR 0.72, 95% CI: 0.56-0.94, p = 0.013) (Liu et al, 2018) (Souza Botelho et al, 2021. Furthermore, studies after this meta-analysis have corroborated the results in patients with SLE (Lo et al, 2021b;Rúa-Figueroa et al, 2022).…”

“…Additionally, another systematic review evaluated the frequencies of serious adverse events such as retinopathy, and cardiac complications through randomized clinical trials of patients with malaria and nonmalarial conditions. It was found that CQ and HCQ are unlikely to increase serious adverse events and such events are low in frequency in both malarial and non-malarial conditions (Souza Botelho et al, 2021).…”

Systemic lupus erythematosus

“…On all scales measuring SLE disease activity, HCQ decreases symptoms. [14][15][16][17] The mechanisms by which HCQ acts to decrease symptoms of lupus are not entirely understood. However, it is known that HCQ accumulates in lysosomes, which contain hydrolytic enzymes activated by the highly acidic pH of the lysosomes.…”

Potential of nanoformulations in malaria treatment

“…The most evident disadvantage of conventional antimalarial drugs is Plasmodium sp resistance due to genetic polymorphisms ( Bree and levy, 2018 ; Wicht et al, 2020 ). However, other disadvantages that influence malaria treatment with conventional antimalarial drugs include low water solubility, low bioavailability, side effects, and relatively short half-life ( Alven and Aderibigbe, 2020 ; Rashidzadeh et al, 2021 ; Souza Botelho et al, 2021 ). Side effects frequently related to conventional antimalarial drugs include abdominal pain and gastrointestinal symptoms such as vomiting, jaundice, itching, hypoglycemia, anemia, dizziness, coma, and altered consciousness ( Novitt-Moreno et al, 2021 ; Rashidzadeh et al, 2021 ).…”