Studies reporting lack of benefit from hydroxychloroquine to treat COVID-19
14 May 2020. Related: COVID-19: investigational drugs, COVID-19.
Several studies have recently reported a lack of benefit from using hydroxychloroquine (HCQ) to treat COVID-19, with or without use of azithromycin (AZ).
These results challenge a controversial French study reported that an initial benefit that led to more than 100 new studies investigating this potential treatment, including some based in the UK, and despite higher risk of serious side effects.
The first observational study, published in the NEJM, reported no association between HCQ and intubation or death in 1446 consecutive patients at a single centre in New York from 7 March to 8 April 2020, 70 were excluded due to intubation, death, or discharged within 24 hours.
In the remaining 1376 patients, 811 (58.9%) received HCQ (600 mg twice on day 1, then 400 mg daily for a median of 5 days) during a median follow-up of 22.5 days.
Just under half (45%) were treated within 24 hours of admission to ER and 86% within 48 hours. Participants receiving HCQ were more severely ill at baseline. Overall, 346 patients (25.1%) had a primary end-point event (180 patients were intubated, of whom 66 subsequently died, and 166 died without intubation). In the main analysis, there was no significant association between HCQ use and intubation or death (HR: 1.04, 95%CI: 0.82 to 1.32). A small percentage of patients also used tocilizumab or remdesivir. Results were similar in multiple sensitivity analyses.
Given the observational design and the relatively wide confidence interval, the researchers concluded that their findings did not rule out either benefit or harm of HCQ treatment, but that they also did not support use of HCW outside of a research setting.
The second report is a retrospective analysis of 368 patients hospitalised with COVID-19 in the US Veterans Affairs hospitals (n=97 HCQ; n=113 HCQ+AZ, n=113; n=158 no HCQ) and published ahead of peer review. 
The two primary outcomes were death and the need for mechanical ventilation and results used propensity scores to calculate adjusted hazard ratios (adj HR) for clinical characteristics.
Baseline characteristics included median age 70 years (youngest 59), 100% male and 66% black.
Rates of death were 27.8%, 22.1%, 11.4% and ventilation were 13.3%, 6.9%, 14.1% in the HCQ, HCQ+AZ, and no HC groups, respectively.
Compared to the no HCQ group, the risk of death from any cause was higher in participants using HCQ (adj. hazard ratio, 2.61; 95% CI: 1.10 to 6.17; p=0.03) but not in the HCQ+AZ group (adj. HR 1.14; 95% CI: 0.56 to 2.32; p=0.72).
Also compared to the no HC group, the risk of ventilation was similar in participants using either HCQ (adj. HR, 1.43; 95% CI: 0.53 to 3.79; p=0.48) and HCQ+AZ group (ad. HR, 0.43; 95% CI: 0.16 to 1.12; p=0.09),
These researchers emphasised the importance of results of prospective, randomised, controlled studies before general use of these drugs.
A third study, ahead of review for Nature Research reported lack of effect from HCQ in vitro and also in macaques. 
The abstract reports that HCQ showed antiviral activity in African green monkey kidney (VeroE6) cells but not in a model of reconstituted human airway epithelium. Also that in macaques, neither HCQ nor HCQ + azithromycin compared to placebo, showed a significant effect on the viral load levels in any of the tested compartments, including before and after peak viral load.
No benefit was seen when HCQ was tested as a pre-exposure prophylaxis (PrEP).
Of note, none of these studies commented on the use of zinc supplement that is hypothesised to increase likelihood of benefit.
Many comments posted online about the pre-peer review paper from Geleris et al emphasise the higher rate of hospitalisation in the HCQ group and the limited characteristics for many patients.
The independent publication Prescrire also failed to find evidence of efficacy in its review of new data on HCQ, following several earlier articles cautioning positive data. 
The FDA have issued a cautioned against the use of HCQ outside of clinical studies due to the risk of cardiovascular toxicity and that strongly recommends close supervision. 
- Geleris J et al. Observational study of hydroxychloroquine in hospitalized patients with Covid-19. DOI: 10.1056/NEJMoa2012410. (7 May 2020).
- MagagnoliJ et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. DOI: 10.1101/2020.04.16.20065920. (23 April 2020).
Maisonnasse P et al. Hydroxychloroquine in the treatment and prophylaxis of SARS-CoV-2 infection in non- human primates. Nature Research. In Review. (6 May 2020).
Prescrire. Covid-19 and hydroxychloroquine (Plaquenil): new data show no evidence of efficacy.
FDA press releases. FDA cautions against use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. (24 April 2020).