Yale School of Public Health professor Harvey Risch has been a vocal supporter of the use of hydroxychloroquine to treat COVID-19, despite a lack of scientific evidence that it works. 

In a July 23 opinion piece in Newsweek, Risch argued for the use of hydroxychloroquine, in combination with the antibiotic azithromycin, to treat high-risk COVID-19 patients without waiting for further testing on the effectiveness of the treatment. He published this piece after his May 27 paper in the American Journal of Epidemiology was widely criticized due to a lack of evidence from randomized trials. Both articles argued this combination of drugs can effectively prevent hospitalization for most symptomatic high-risk outpatients and that it is safe for short-term use early in the course of infection. This claim is now widely disputed. 

Prior to the COVID-19 pandemic, hydroxychloroquine was used to treat other diseases, such as rheumatoid arthritis, malaria and lupus. In vitro experiments from early in the outbreak showed that hydroxychloroquine was able to stop the replication of SARS-CoV-2 within cells, according to Albert Ko, Department Chair and Professor of Epidemiology at the Yale School of Public Health. 

In April, President Trump endorsed hydroxychloroquine. The FDA provided an Emergency Use Authorization for the drug allowing it to be used to treat COVID-19 in the United States and the WHO and NIH started running clinical trials to test its effectiveness. As of early July, however, both organizations have stopped their investigations, and the FDA has revoked the Emergency Use Authorization due to concerns over the effectiveness and safety of the treatment. 

These changes have been in response to new evidence of the inefficacy of hydroxychloroquine for treating COVID-19 and have caused many members of the scientific community to shift their attention away from this drug. But Risch has expressed different views on the subject, which have caused some backlash from his colleagues at Yale and beyond.

In a statement released on Medium on Aug. 4, members of the Yale scientific and medical community voiced concern over Risch’s ardent advocacy of hydroxychloroquine. It is signed by more than 20 Yale faculty members. 

“As his colleagues, we defend the right of Dr. Risch, a respected cancer epidemiologist, to voice his opinions,” the letter states. “But he is not an expert in infectious disease epidemiology and he has not been swayed by the body of scientific evidence from rigorously conducted clinical trials, which refute the plausibility of his belief and arguments.”

The statement also expresses concern about the safety of patients and “the coherence of our national COVID-19 emergency response,” in the midst of misinformation being disseminated by people like Risch when there exists clear contrary evidence.

Risch did not respond to the News’ requests for comment.

According to Naftali Kaminski, Chief of Pulmonary, Critical Care and Sleep Medicine at the School of Medicine, hydroxychloroquine and the antibiotic azithromycin were a part of the treatment protocol at YNHH at the beginning of the pandemic, and doctors there were widely prescribing it to COVID-19 patients. There were historical suggestions that this drug might work, and with such limited knowledge about the virus at the time, it was viewed as a viable potential treatment option, according to Kaminski

However, with the mounting evidence against the drug, it is no longer a part of the protocol. Ko said he does not personally know of any doctors continuing to prescribe it at Yale.

The May 27 paper — of which Risch is the only author — was in line with many assumptions about the drug combination early in the pandemic. However, of the five studies Risch cites, none of them are randomized and some are on the smaller side for clinical trials (including Gautret et al. 2020, Million et al. 2020, Zelenko 2020, Esper et al. 2020). He acknowledges this in the paper, but rationalizes that a benefit as large as the one found in one of the studies cannot be invalidated by the lack of randomization. He also states that the concerns about the sample size are only relevant when statistical significance is not found.

“This is a valid general scientific criticism, but does not represent epidemiologic experience in this instance,” Risch wrote in the paper.

This lack of randomization has received some criticism from other scientists at Yale and beyond. Akiko Iwasaki — professor of molecular, cellular and developmental biology — wrote in an email to the News that randomized controlled trials are the only way to know the efficacy of a given treatment. 

Other scientists have pointed out that our understanding of the treatment of infectious diseases is not  founded on only randomized clinical trials.

Caleb Skipper — infectious disease fellow at the University of Minnesota — said that the data builds on itself over time. Starting with in vitro and animal models, scientists are able to develop a hypothesis to test in a clinical trial.

“When we look at COVID-19, there are more data than just [randomized control trials, [RCTs]  but RCTs should indeed be held in high regard, because they attempt to study an intervention while removing as much bias as possible,” Skipper said.

Yale faculty have raised other problems with the manuscript submitted by Risch. Ko, for example, said that it makes him question whether the American Journal of Epidemiology actually carried out the peer review process. 

After having received backlash on the paper, Risch published his July 23 opinion piece in Newsweek

In this piece, he urges doctors to begin prescribing hydroxychloroquine and azithromycin to high-risk patients right away, without waiting for test results, and praises doctors that have already been doing this. 

“I am fighting for a treatment that the data fully support but which, for reasons having nothing to do with a correct understanding of the science, has been pushed to the sidelines,” Risch wrote. “Nobody needs me to remind them that this is not how medicine should proceed. We must judge this medication strictly on the science… Lives must come first.”

Although they go unacknowledged in Risch’s paper and Newsweek piece, there have been a number of randomized control trials conducted to evaluate the efficacy of hydroxychloroquine (alone and with drugs like azithromycin), which have not found promising results (Cavalcanti et al. 2020, Maisonnasse et al. 2020, Mitja et al. 2020, Tang et al. 2020).

“The evidence from randomized clinical trials is very clear and it shows without a doubt that this drug has no effect,” said Carlos delRio, a professor at the Emory School of Medicine. “So we need to move on and think about something else.”

David Boulware — an infectious disease physician-scientist at the University of Minnesota — published a paper that showed that post-exposure prophylactic, or preventative, use of hydroxychloroquine or hydroxychloroquine and zinc did not prevent symptomatic infection after being exposed to a COVID-19 infected individual. 

Skipper is the lead author of a study which found that treating patients with hydroxychloroquine early in their course of infection did not lead to a statistically significant reduction of symptom severity compared to the placebo, and that it also failed to reduce hospitalizations by a significant amount.

“Our study does not conclude that hydroxychloroquine cannot be effective against COVID-19 in a different setting, population, dose, or drug combination,” Skipper said. “I would advocate that our study is seen as one piece of evidence in the whole puzzle of finding an effective therapy against COVID-19.”

Another concern with using hydroxychloroquine as treatment is that it has been shown to be linked to an increased risk of heart problems such as cardiac arrhythmias, according to Ko. 

Risch expressed in his paper that these risks are outweighed by the lives that are being lost daily to this disease.

He has also argued that conducting a randomized, double-blind control clinical trial to test the effectiveness of hydroxychloroquine and azithromycin would be able to take place right away in “an ideal world.” Iwasaki countered, however, that even during a pandemic, treatment choices must be guided by rigorous science.

“While it is easy to criticize Prof. Risch, perhaps a better question is why has there not been a randomized trial conducted testing hydroxychloroquine, azithromycin, and zinc?” Boulware wrote in an email to the News. “If Yale University supports Prof. Risch, why doesn’t Yale University or the Yale School of Public Health fund the double blind, randomized placebo-controlled clinical trial to prove the world wrong that hydroxychloroquine + azithromycin + zinc works as COVID-19 therapy?”

The Yale School of Public Health released a statement at the end of July — written by Dean Stephen Vermund — to address Risch’s paper and the debate surrounding hydroxychloroquine.

“I have championed maintaining open academic discourse, including what some may view as unpopular voices. The tradition of academia is that faculty may do research, interpret their work, and disseminate their findings,” Vermund wrote. “My role as Dean is not to suppress the work of the faculty, but rather, to support the academic freedom of our faculty, whether it is in the mainstream of thinking or is contrarian.”

As the pandemic rages on, the debate over the use of hydroxychloroquine highlights the complexity of responding to a novel virus.  

“The bottom line is that there needs to be mechanisms to safeguard both the academic independence and the freedom of faculty and students,” Ko said. “But on the other hand, we have to also be sure of the safety of the public. We have to ensure the safety of ideas in society… This certainly raises that issue.”

As of Aug.13, there have been more than 5.2 million COVID-19 cases in the United States.

Charlotte Zimmer | charlotte.zimmer@yale.edu