As the life-science research engine roared into action in response to the novel coronavirus pandemic, intriguing early data from the generic anti-malarial drug hydroxychloroquine drew an unusual amount of attention, due in part to advocacy from President Donald Trump and television doctors.
Now as small studies have started generating additional data, the case to use hydroxychloroquine to combat severe cases of COVID-19 has weakened. This week, an expert U.S. panel specifically recommended against one regimen thought to have promise, citing potential cardiac side effects.
Hydroxychloroquine was proposed as a treatment because it may block the fusing of SARS-CoV-2 — the virus causing coronavirus disease — with host cells in which it can reproduce and spread. The drug, typically used to treat lupus and rheumatoid arthritis, also has an immunosuppressive effect that was speculated to be helpful in cases of severe COVID-19.
Small studies in China and France raised hopes of a possible benefit, helping use of the drug gain traction in several countries, including the U.S.
Data from a small retrospective analysis of 368 COVID-19 patients hospitalized at U.S. Department of Veterans Affairs published online Tuesday, however, suggested neither hydroxychloroquine or a combination with the antibiotic azithromycin prevented patients from dying or needing mechanical ventilation.
The results are not conclusive, as they comes from a retrospective study rather than a clinical trial. Moreover, the data was published online as a pre-print, meaning the study has not yet been peer reviewed for potential errors or other sources of bias that might affect the authors’ conclusions. Pre-print studies are early in the process of scientific publishing, and can be withdrawn or otherwise retracted.
If the study’s conclusions hold, however, they will add to mounting signs that the case of prescribing the antimalarial is not nearly as clear-cut as some, including the president, have indicated. A Chinese study, for example, found that hydroxychloroquine does not significantly increase the rate of patients testing negative for coronavirus infection following 30 days of treatment when compared to patients who didn’t take the pill.
That study was among the data cited by a National Institutes of Health expert panel tasked with developing guidelines on treating COVID-19. Based on the results, the guidelines, issued for the first time Tuesday, state that there are “insufficient clinical data” to recommend either for or against use of hydroxychloroquine.
Novartis, one manufacturer of hydroxychloroquine pills, is among multiple groups testing its use in COVID-19 in broader clinical trials that will attempt to establish a clearer case for or against the drug.
Larger, randomized studies of hydroxychloroquine (HCQ) as a treatment for COVID-19
| Study sponsor | Treatment setting | Target enrollment | Control group? | Details |
|---|---|---|---|---|
| INSERM | Hospitalized adults | 3,100 | Yes | Tests four treatments, including HCQ, in parallel |
| Columbia Univ. | Post-exposure prophylaxis (PEP) | 1,600 | Yes | Tests HCQ PEP among household contacts of COVID-19 patients |
| Univ. of Minnesota | Pre-exposure prophylaxis | 3,500 | Yes | Tests once-weekly and twice-weekly dosing against placebo |
| Univ. of Washington | Post-exposure prophylaxis | 2,000 | Yes | Tests HCQ sulfate among close contacts of COVID-19 patients |
| Mass General, NIH | Hospitalized adults | 510 | Yes | Tests HCQ in adults hospitalized with COVID-19 |
| Henry Ford Health System | Healthcare workers | 3,000 | Yes | Tests HCQ in healthcare workers and first responders in Detroit |
| Cambridge Univ. Hospitals, NHS | Healthcare workers | 1,000 | Yes | Tests HCQ in National Health Service workers |
SOURCE: Clinicaltrials.gov
The NIH guidelines are characterized as a “living document” that will be subject to change as clinical studies generate fresh data. Larger tests, like those listed above, could still show a benefit to hydroxychloroquine.
In patients taking the pill either as part of a clinical trial or emergency use from the Strategic National Stockpile, physicians need to monitor for a cardiac side effect called a QT prolongation, which is a sign of potential heart rhythm disruptions, according to the guidelines.
For that same reason, the NIH guidelines recommend against the use of the hydroxychloroquine-azithromycin combination outside of a clinical trial.
The guidelines also warned against the use of the HIV drug Kaletra and other, similar HIV medicines known as protease inhibitors “because of unfavorable pharmacodynamics and negative clinical trial data.” A study of 199 COVID-19 patients in China previously found little benefit to taking Kaletra.
The guidelines say there is “insufficient clinical data to recommend either for or against” Gilead Sciences’ closely watched antiviral remdesivir, which has been used in both clinical trials and compassionate use settings.
Likewise, the panel made an “insufficient data” recommendation about immune modulators like Actemra and Kevzara. These treatments are being tested by drugmakers to see if they can suppress the fierce inflammatory responses that can lead to patients’ respiratory complications and deaths.
Outside of clinical trials, the guidelines caution against the use of interferons and Janus kinase inhibitors like Jakafi, the former for a lack of effectiveness battling related viral infections SARS and MERS, and the latter for weakening patients’ immune systems.
