Safety of Short-Term Treatments with Oral Chloroquine and Hydroxychloroquine in Patients with and without COVID-19: A Systematic Review

Abstract

Chloroquine (CQ) and hydroxychloroquine (HCQ) have recently become the focus of global attention as possible treatments for Coronavirus Disease 2019 (COVID-19). The current systematic review aims to assess their safety in short treatments (≤14 days), whether used alone or in combination with other drugs. Following the PRISMA and SWiM recommendations, a search was conducted using four health databases for all relevant English-, Chinese-, and Spanish-language studies from inception through 30 July 2021. Patients treated for any condition and with any comparator were included. The outcomes of interest were early drug adverse effects and their frequency. A total of 254 articles met the inclusion criteria, including case and case-control reports as well as cross-sectional, cohort, and randomised studies. The results were summarised either qualitatively in table or narrative form or, when possible (99 studies), quantitatively in terms of adverse event frequencies. Quality evaluation was conducted using the CARE, STROBE, and JADAD tools. This systematic review showed that safety depended on drug indication. In COVID-19 patients, cardiac adverse effects, such as corrected QT interval prolongation, were relatively frequent (0–27.3% and up to 33% if combined with azithromycin), though the risk of torsade de pointes was low. Compared to non-COVID-19 patients, COVID-19 patients experienced a higher frequency of cardiac adverse effects regardless of the regimen used. Dermatological adverse effects affected 0–10% of patients with autoimmune diseases and COVID-19. A broad spectrum of neuropsychiatric adverse effects affected patients treated with CQ for malaria with variable frequencies and some cases were reported in COVID-19 patients. Gastrointestinal adverse effects occurred regardless of drug indication affecting 0–50% of patients. In conclusion, CQ and HCQ are two safe drugs widely used in the treatment of malaria and autoimmune diseases. However, recent findings on their cardiac and neuropsychiatric adverse effects should be considered if these drugs were to be proposed as antivirals again.

Review of Hydroxychloroquine Cardiotoxicity: Lessons From the COVID-19 Pandemic

“…A systematic review published in April 2021 concluded that the combined odds ratio (OR) of all-cause mortality for the use of HCQ in COVID-19 was 1.11 (95% CI 1.02-1.20) [68]. A systematic review from 2022 additionally found that cardiac adverse events were frequent (0-27.3% and up to 33% if concurrent usage of azithromycin) [69]. Given this overwhelming lack of evidence (despite some of the initial trials) (Table 2), the interest and usage of HCQ/CQ seem to be declining.…”

“…•, 67•], its usage is not recommended for the treatment of COVID-19. Multiple subsequent large systematic reviews support this recommendation[68,69]. Although, there may be utility for further studies in outpatient COVID-19, or specific sub-groups, at this time, the literature is limited.…”

Repurposed antimicrobial and antiviral drugs for COVID-19 treatment: safety and side effects in real clinical practice (scientific review)

“…Первый систематический анализ сообщений случаев кардиотоксичности гидроксихлорохина и хлорохина опубликован уже в сентябре 2020 г. [8] Недавно опубликован новый самый обширный систематический обзор 99 исследований (серии случаев, «случайконтроль», перекрестные, когортные и РКИ) по оценке безопасности гидроксихлорохина и хлорохина при краткосрочном лечении (≤14 дней) COVID-19 при использовании отдельно или в комбинации с другими препаратами [11]. У пациентов с COVID-19 побочные эффекты со стороны сердца, такие как удлинение интервала QT и аритмии, оказались относительно частыми (до 25 и 16,2% соответственно; до 33 и 20,4% в сочетании с азитромицином), но частота развития тахикардии типа «пируэт» низкая (3,4%).…”

“…В данный систематический обзор для сравнения характеристики и частоты побочных эффектов гидроксихлорохина и хлорохина включена также группа пациентов с малярией и аутоиммунными воспалительными заболеваниями; сравнение не выявило большую частоту побочных эффектов у пациентов с COVID-19. Однако случаи кардиотоксичности на фоне применения коротких курсов гидроксихлорохина и хлорохина у пациентов с COVID-19 более частые и ранние, что можно объяснить электрофизиологическими эффектами препаратов (блокирование натриевых, кальциевых и калиевых каналов), частой комбинацией с азитромицином и влиянием самого заболевания COVID-19 [11].…”

Hydroxychloroquine for treatment of non‐hospitalized adults with COVID‐19: A meta‐analysis of individual participant data of randomized trials

“…Some of these trials raised concerns regarding treatment safety in patients with COVID‐19, particularly cardiovascular adverse events (e.g., conduction disorders), but also dermatological (e.g., hyperpigmentation of the skin), neuromuscular (e.g., weakness), and ophthalmological (e.g., retinopathy) 8 . However, cumulative experience with HCQ showed no increased risk of adverse events in patients with COVID‐19 compared with the use of this drug in approved indications, thus supporting the safe use of this drug 9,10 . Regarding efficacy, trials focusing on hospital‐admitted patients were completed first, consistently demonstrating no clinical effect on the outcome of death 11–13 .…”