But last word not yet spoken

Hydroxychloroquine is back in the news as another study, just published in the New England Journal of Medicine, again found that it comes up short as a therapy for Covid-19. This time, researchers explored its use as a prophylactic therapy in individuals exposed to the coronavirus.

“In this trial, high doses of hydroxychloroquine did not prevent illness compatible with Covid-19 when initiated within 4 days after a high-risk or moderate-risk exposure,” David R. Boulware, MD, MPH, from the University of Minnesota, and colleagues reported.

The malaria drug has been touted by President Donald Trump for use as a post-exposure prophylactic, and he admitted that he took a 14-day course following possible exposure at the White House.

Boulware and colleagues’ randomized, double-blind, placebo-controlled trial, with patients enrolled in the U.S. and Canada, was a “pragmatic design,” in that participants were recruited and followed-up through internet-based self-referral with surveys for follow-up — A point which Myron S. Cohen, MD, from the Institute for Global Health and Infectious Diseases, University of North Carolina Chapel Hill, sees as one of the limitations of the study.

However, he noted that a groundswell of research, likely driven by “media and social forces — rather than medical evidence — are driving clinical decisions and the global Covid-19 research agenda.” In his editorial commenting on Boulware et al’s research, he pointed to 203 Covid-19 trials of hydroxychloroquine listed on ClinicalTrial.gov, with 60 focused on prophylaxis use.

“An important question is to what extent the article by Boulware et al, should affect planned or ongoing hydroxychloroquine trials,” Cohen wrote. Should these trials continue if post-exposure prophylaxis does not prevent the virus? Should the participants be informed?

“Do these trial results with respect to postexposure prophylaxis affect trials of preexposure prophylaxis with hydroxychloroquine, some of which are very large (e.g., the Healthcare Worker Exposure Response and Outcomes of Hydroxychloroquine [HERO-HCQ] trial, involving 15,000 health care workers…)?,” he asked.

Cohen called the results of the current trial “more provocative than definitive, suggesting that the potential prevention benefits of hydroxychloroquine remain to be determined.”

So, perhaps it is not yet time to sound the death knell for the drug’s use in Covid-19.

In their study, using the pragmatic design, patients who were exposed to someone with confirmed Covid-19 either at work or at home, at a distance “of less than 6 feet for more than 10 minutes,” without any PPE — face mask, eye shield, etc. (considered high-risk exposure), and those who were exposed but were wear wearing a face mask, or eye shield (moderate-risk exposure) were recruited and randomized.

Of the 821 adult participants (87.6% reported high risk exposure) who were exposed but asymptomatic, 414 were assigned to the hydroxychloroquine arm and 407 to the placebo arm. Those in the hydroxychloroquine arm were given the study drug within 4 days of initial exposure with an initial 800 mg dose, followed by 600 mg in 6-9 hours, then 600 mg daily for 4 additional days.

The researchers were looking at either laboratory-confirmed Covid-19 or overt illness within 14 days. Follow-up was done through online surveys.

“Overall, new Covid-19 (either PCR-confirmed or symptomatically compatible) developed in 107 of 821 participants (13.0%) during the 14 days of follow-up,” Boulware and colleagues reported. “The incidence of new illness compatible with Covid-19 did not differ significantly between those receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]) (P = 0.35). The absolute difference was −2.4 percentage points (95% confidence interval, −7.0 to 2.2). Two hospitalizations were reported (one in each group).

There were 113 participants who developed symptoms, of whom 16 had PCR-confirmed Covid-19, and 74 were diagnosed as “probable” covid-19.

They noted that adherence to the regimen was moderate with 75.4% full adherence in the hydroxychloroquine group and 82.6% in the placebo group. the main reason participants stopped taking the drug were side effects, which were more frequent in the study drug group than the placebo group — 40.1% versus 16.8% respectively.

“Nausea, loose stools, and abdominal discomfort were the most common side effects,” Boulware and colleagues reported. “There were no serious intervention-related adverse reactions or cardiac arrhythmias.” There were no deaths during the trial.

The median age of the participants was 40, and more than half of the participants were women. Just over a quarter (27.4%) reported chronic health conditions, with hypertension being the most common in 12% of the participants. Most of the participants were health care workers (66.4%), and their exposure was mostly from contact with patients. More than half, (60%) reported not wearing any PPE during exposure to the coronavirus.

The study authors admitted limitations of the study, including its design, which relied on participant reports. They also noted that lack of the availability of diagnostic testing as most participants could not access tests, “thus, an a priori symptomatic case definition was used…”

  1. High doses of hydroxychloroquine did not prevent illness compatible with Covid-19 when initiated within 4 days after a high-risk or moderate-risk exposure.

  2. Be aware that while this was a randomized, double-blind, placebo-controlled trial, it was conducted online with a “pragmatic design” with participant reporting.

Candace Hoffmann, Managing Editor, BreakingMED™

Boulware reported grants from Jan and David Barcuski, grants from Alliance of Minnesota Chinese Organizations, grants from Minnesota Chinese Chamber of Commerce, grants from University of Minnesota Foundation, non-financial support from Rising Pharmaceuticals, during the conduct of the study.

Cohen reported non-financial support and other from Gilead, and non-financial support and other from Merck outside the submitted work.

Cat ID: 190

Topic ID: 79,190,254,930,838,914,190,926,192,927,151,590,928,925,934