The outburst of the novel COVID-19 has caused unprecedented stress in the healthcare systems and global economy since its outbreak in December 2019. Effective treatment for severely ill patients still needs to be identified, and many countries are still pushed by daily increases in case numbers and deaths. Furthermore, before a vaccine is made available or drugs eventually capable of preventing the infection are identified, exit strategies in those countries that have managed to bend the transmission curve are inevitably governed by trial and error. The alarm remains high also because COVID-19 flare-ups are increasingly likely and a second wave in fall is seen as a real risk.
The effects of hydroxychloroquine (HCQ) on COVID-19 remain at the centre of intense debate. In the laboratory setting, HCQ has initially shown promise by interfering with the attachment, internalisation and replication of SARS-CoV-2,1 2 the causative agent of COVID-19. Additional benefits have been inferred from the capacity of HCQ to modulate inflammatory responses via toll-like receptor inhibition,3 possibly hindering the cytokine storm leading to acute respiratory distress syndrome,4 and to exert anticoagulatory activities5 capable of ameliorating COVID-19-related systemic thrombosis.6 Very recently, however, results from in vitro assays have not been confirmed in vivo in non-human primates.7 In parallel, the early enthusiasm on the clinical efficacy of HCQ on COVID-19 coming on top of small case series and open-label non-randomised trials8 9 has rapidly deflated following the dissemination of the results from large randomised clinical trials (RCTs). Three studies ceased enrolment early because of lack of efficacy of HCQ versus control arm in preliminary analyses.10–12 Similarly, according to rigorous RCTs recently published on high-impact medical journals, the use of HCQ did not result in higher probability of negative conversion13 or neither improved clinical status14 as compared with standard care in hospitalised patients with mild-to-moderate COVID-19. HCQ has also been proven ineffective in reducing symptoms severity in outpatients with early, mild SARS-CoV-2 infection.15 Together with these discouraging clinical results, safety concerns raised on the use of high-dose antimalarials in hospitalised patients have further dimmed the initial hopes that HCQ could represent a treatment option for COVID-19. An interim analysis of a randomised, double-blinded, phase IIb study indeed reported a trend towards excessively high cardiovascular mortality in patients receiving high-dose chloroquine diphosphate (1.2 g every day for 10 days),16 and, despite its retraction, the Lancet paper by Mehra and co-authors17 leaves many questions still open. As a matter of fact, most of the ongoing clinical trials have now stopped their track, and the US Food and Drug Administration (FDA) revoked its emergency use authorisation for HCQ for the treatment of COVID-19.18 In parallel, society guidelines have soon revised their recommendations. On 20 August, the Infectious Diseases Society of America strongly recommended against the use of HCQ among hospitalised patients with COVID-19.19 The Treatment Guidelines Panel of the National Institutes of Health delivered a similar recommendation on 27 August and also discouraged the use of the drug in non-hospitalised patients with the exception of clinical trials.20
While the therapeutic use of antimalarials increasingly appears at its sunset, the eventual role of HCQ in the prophylaxis for COVID-19 remains to be ascertained. In the published RCT so far, it is shown that administration of HCQ in asymptomatic subjects who reported household or occupational exposure to confirmed COVID-19 cases did not reduce the incidence of illness.21 Apart from methodological issues acknowledged by the investigators themselves, a major obstacle in the interpretation of the results in this study remains the relatively long delay in the initiation of HCQ after SARS-CoV-2 exposure, raising the possibility that the explored outcome was in fact progression of early disease rather than prevention of infection.22 Animal models and in vitro experiments have however recently suggested that the prophylactic effects of HCQ are maximised when the drug is administered before SARS-CoV-2 exposure.23 24 While we are still waiting for more responses in vivo, and the possible beneficial role of antimalarials in the initial phases of SARS-CoV-2 infection remains at present only a suggestion, some countries continue to recommend HCQ for the preexposure and postexposure prophylaxis in at-risk individuals.25 Such empirical use is also fuelled by new data on the reassuring safety profile of the drug in outpatient clinical trial participants for COVID-19,26 which adds on those already known from the long-time experience in the use of HCQ as a chronic treatment for many rheumatic diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).3 27 However, HCQ can be still associated with potentially serious harmful side effects, including severe hypoglycaemia, neuropsychiatric effects, hypersensitivity reactions and arrhythmias.28 While the known benefits of HCQ in rheumatic diseases fully overwhelm its side effects, indiscriminate use in healthy subjects who cannot be screened for coexisting conditions that increase the risk of HCQ-related toxicity cannot be justified. Equally important, a new wave of enthusiasm for HCQ now in the setting of COVID-19 prevention may recreate shortage for those patients in whom regular supply of the drug is essential to keep the disease optimally controlled. In this scenario of uncertainty, we urgently need solid clinical data supporting the role—if any—of HCQ in the prevention of SARS-CoV-2 infection. Although both RCTs and observational studies will soon provide valuable information, some possible limitations should be kept in mind in order to balance expectations with reality.
