Hydroxychloroquine Ineffective for COVID-19,
VA Study Suggests

Marcia Frellick

April 23, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's  Coronavirus Resource Center.

Hydroxychloroquine (HCQ) with or without azithromycin (AZ) is not associated with a lower risk of requiring mechanical ventilation, according to a retrospective study of Veterans Affairs (VA) patients hospitalized with

The study, which was posted on a preprint server April 21 and has not been peer reviewed, also showed an increased risk of death associated with
COVID-19 patients treated with HCQ alone.

"These findings highlight the importance of awaiting the results of ongoing prospective, randomized controlled studies before widespread adoption of these drugs," write Joseph Magagnoli, MS, with Dorn Research Institute at the Columbia VA Health Care System, Columbia, South Carolina, and the Department of Clinical Pharmacy & Outcomes Sciences, University of South Carolina, and colleagues.

A spokesperson with University of Virginia School of Medicine, where several of coauthors practice, told Medscape Medical News the authors declined to comment for this article before peer review is completed.

The new data are not the first to suggest no benefit with HCQ among patients with COVID-19. A randomized trial showed no benefit and more side effects among 75 patients in China treated with HCQ compared with 75 who received standard of care alone, according to a preprint posted online April 14.

No Benefit in Ventilation, Death Rates

The current analysis included data from all 368 male patients hospitalized with confirmed COVID-19 and treated at Veterans Health Administration (VA) medical centers in the United States through April 11.

Patients were categorized into three groups: those treated with HCQ in addition to standard of care (n = 97); those treated with HCQ and the antibiotic azithromycin plus standard of care (n = 113); and those who received standard supportive care only (n = 158).

Table. Outcomes for Three Study Groups

Group Rates of Ventilation (%) Rates of Death (%)
HCQ 13.3   27.8
HCQ+AZ   6.9   22.1
No HCQ 14.1   11.4


Compared with the no HCQ group, the risk of death from any cause was higher in the HCQ group (adjusted hazard ratio [aHR], 2.61; 95% confidence interval (CI), 1.10 - 6.17; P = .03) but not in the HCQ+AZ group (aHR, 1.14; 95% CI, 0.56 - 2.32; P = .72).

The risk of ventilation was similar in the HCQ group (aHR, 1.43; 95% CI, 0.53 - 3.79; P = .48) and in the HCQ+AZ group (aHR, 0.43; 95% CI, 0.16 - 1.12; P= .09), compared with the no HCQ group.

This study provides another counterbalance to claims of HCQ efficacy, David R. Wessner, PhD, professor of biology and chair of the Department of Health and Human Values at Davidson College in Davidson, North Carolina, told Medscape Medical News.

Interest in HCQ spiked after an open-label, nonrandomized, single-center study of COVID-19 patients in France suggested that hydroxychloroquine helped clear the virus and had a potential enhanced effect when combined with azithromycin.

But as Medscape and Retraction Watch previously reported, the 36-patient trial has since been called into question.

Wait for Convincing Data

Wessner, whose research focuses on viral pathogenesis, says that although the current data don't definitively answer the question of whether HCQ is effective in treating COVID-19, taking a "let's try it and see" approach is not reasonable.

"Until we have good, prospective randomized trials, it's hard to know what to make of this. But this is more evidence that there's not a good reason to use [HCQ]," Wessner said.

He points out that the small randomized trial from China shows that HCQ comes with potential harms.

Anecdotal evidence is often cited by those who promote HCQ as a potential treatment, but "those are one-off examples," Wessner continued. "That doesn't really tell us anything."

Some HCQ proponents have said that trials finding no benefit are flawed in that the drug is given too late. However, Wessner says, there's no way to prove or disprove that claim without randomized controlled trials.

Conflicting Messages

Despite lack of clear evidence of benefit for patients with COVID-19, HCQ is recommended off-label by the Chinese National guideline, and the US Food and Drug Administration has issued an emergency-use authorization for the treatment of adult patients with COVID-19.

Conversely, the Infectious Diseases Society of America and a guideline panel convened by the National Institutes of Health each concluded recently that because of insufficient data, they could not recommend any specific treatments for patients with COVID-19.

The VA data for the current study came from the Veterans Affairs Informatics and Computing Infrastructure (VINCI), which includes inpatient, outpatient and laboratory data and pharmacy claims.

The authors acknowledge some limitations, "including those inherent to all retrospective analyses such as non-randomization of treatments."

However, they note that they did adjust for potential confounders, including comorbidities, medications, and clinical and laboratory factors.

A coauthor, Jayakrishna Ambati, MD, is a cofounder of iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics, and has received consultancy fees from Allergan, Biogen, Boehringer Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences, all unrelated to this work. Ambati is named as an inventor on a patent application filed by the University of Virginia relating to COVID-19 but unrelated to this work. Another coauthor has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics, all unrelated to this work. The other authors and Wessner have disclosed no relevant financial relationships.

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