Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study

Jennifer C.E Lane; James Weaver; Kristin Kostka; Talita Duarte-Salles; Maria Tereza F. Abrahao; Heba Alghoul; Osaid Alser; Thamir M Alshammari; Patricia Biedermann; Edward Burn; Paula Casajust; Mitch Conover; Aedin C. Culhane; Alexander Davydov; Scott L. DuVall; Dmitry Dymshyts; Sergio Fernández Bertolín; Kristina Fišter; Jill Hardin; Laura Hester; George Hripcsak; Seamus Kent; Sajan Khosla; Spyros Kolovos; Christophe G. Lambert; Johan ver der Lei; Ajit A. Londhe; Kristine E. Lynch; Rupa Makadia; Andrea V. Margulis; Michael E. Matheny; Paras Mehta; Daniel R. Morales; Henry Morgan-Stewart; Mees Mosseveld; Danielle Newby; Fredrik Nyberg; Anna Ostropolets; Rae Woong Park; Albert Prats-Uribe; Gowtham A. Rao; Christian Reich; Jenna Reps; Peter Rijnbeek; Selva Muthu Kumaran Sathappan; Martijn Schuemie; Sarah Seager; Anthony Sena; Azza Shoaibi; Matthew Spotnitz; Marc A. Suchard; Joel Swerdel; Carmen Olga Torre; David Vizcaya; Haini Wen; Marcel de Wilde; Seng Chan You; Lin Zhang; Oleg Zhuk; Patrick Ryan; Daniel Prieto-Alhambra

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic exerts an unprecedented pressure on health care systems worldwide, there remains a paucity of evidence surrounding the safety and effectiveness of potential treatments. 1 Several existing drugs have been postulated to be effective against SARS-CoV-2. These include conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), which are most commonly used as the first line treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systematic lupus erythematosus (SLE). 2, 3 Hydroxychloroquine (HCQ) has been proposed as potential treatment options for COVID-19 based on its mechanism of action. Accumulating in the acid vesicles (endosome, Golgi vesicles, lysosomes), HCQ causes alkalinisation, leading to enzyme dysfunction and preventing endosome mediated viral entry to the cell. [3] [4] [5] [6] It is also suggested in vitro that HCQ can prevent glycosylation of virus cell proteins including the ACE2 receptor, inhibiting virus entry and replication, and that similar compounds like chloroquine can specifically inhibit SARS-Cov-2. 5, [7] [8] [9] In clinical studies, the addition of HCQ has shown increased early virological response to treatment for chronic hepatitis C, and reduced viral load in patients with HIV infection, compared to placebo. 10, 11 Treatment with HCQ also lowered IL-6 level in HIV patients, suggesting the agent may have immunosuppressive properties helpful in the prevention or treatment of cytokine storm associated with severe COVID-19 disease. 12, 13 As of 28 th March 2020, there are over 21 registered ongoing clinical trials and 3 prophylactic studies assessing the efficacy of hydroxychloroquine HCQ for the treatment of SARS-Cov-2. 14-20 Early results from randomised controlled trials conducted in China have shown reduced severity and course of the disease with hydroxychloroquine HCQ, compared with placebo, without detecting serious adverse effects, although others have suggested no difference in outcome from conventional treatment. 21, 22 Of those studies that have reported more detailed results and received significant media attention, HCQ . CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.