Hydroxychloroquine is ineffective and unsafe in the treatment of COVID-19: This is the belief held by millions of Americans and many healthcare professionals. After months of randomized clinical trials yielding findings that were not statistically significant, and others reporting side effects, no one could be blamed for reaching this conclusion.
But an important slice of the hydroxychloroquine data tells a different story.
Because of the medication’s politicization, and the pernicious tendency for dissenting perspectives to be silenced during the pandemic, data supporting hydroxychloroquine’s effectiveness have been almost inaudible. But a recent analysis pooling together results of randomized clinical trials testing hydroxychloroquine’s use in early COVID-19 infection should substantially raise the volume.
The hydroxychloroquine saga cannot be fully appreciated without first considering the unusual circumstances under which it arose. While the medical profession has always sustained debate over which treatments are best, the tenor of the hydroxychloroquine controversy is unique. Physicians who have advocated for its effectiveness have remained steadfast in their support of the medication, despite unsupportive clinical trials enrolling hospitalized patients, social media blackouts of their opinions, and a chorus of politicians and health officials telling them — and the country — that they’re not only wrong but reckless.
While physicians who hold marginalized or unpopular positions about treatments are often considered by peers to be motivated by profit or other self-serving interests, these physicians were unnoteworthy in that regard, and would largely have been considered “mainstream” prior to the pandemic. Their clinical experiences were dismissed as anecdotal, but consistently achieving patient outcomes that were markedly better than those reported around the country fueled their confidence and tenacity. The nation and the world may now benefit from their steadfastness.
The key data come from randomized trials testing hydroxychloroquine’s effectiveness when used to prevent or treat COVID-19 infection in the early stages of disease, while patients are still home and not hospitalized with severe pneumonia. Because they minimize bias, well-performed randomized trials yield weighty clinical evidence. And unlike many of the clinical trials enrolling hospitalized patients, the hydroxychloroquine doses used in outpatient studies have been lower and not in the toxic range.
These lower doses are more aligned with the reputation for safety that hydroxychloroquine has accrued over decades of use in patients with lupus or needing malaria prophylaxis. Studies generally used a dose ranging from 400 mg one day per week for prevention to 600 mg daily for up to one week for treatment, safe for most older adults with comorbidities. Additionally, early treatment is consistent with what we know about the benefits of earlier antiviral therapy for other viral infections, such as oseltamivir (Tamiflu) in influenza, acyclovir in herpes encephalitis, zanamivir for influenza prophylaxis, and HIV antiviral therapy for pre-exposure or post-exposure prophylaxis.
Five of these outpatient randomized trials were published in time to be included in a new analysis, and each reported a benefit for prevention of death, hospitalization or COVID-19 infection that favored hydroxychloroquine use, although no individual study found this benefit to be statistically significant. We used a popular method in health sciences called meta-analysis to pool the results of these randomized trials for the purpose of obtaining a more statistically definitive result. We prioritized analyzing the most meaningful clinical outcomes — death and hospitalization — and analyzed COVID-19 infection rates when these were unavailable.
Our meta-analysis shows that the statistically insignificant results from each of the randomized COVID-19 trials of outpatient hydroxychloroquine translates into a statistically significant 24% risk reduction. In other words, it is evidence from randomized trials that hydroxychloroquine reduces the risk of death, hospitalization or infection from COVID-19 when used for prevention or early treatment.
Even before this meta-analysis, benefits averaging around a 50% risk reduction had already been reported by several non-randomized studies using standard statistical methods to compare health outcomes among people with COVID-19 treated with hydroxychloroquine versus usual care. A site tracking hydroxychloroquine research lists them, which most readers will be surprised to see is replete with outpatient studies reporting reductions in hospitalization and death.
President Trump’s recent brush with COVID-19 — and the sharp contrast between his treatment and the quarantine-and-wait guidance provided to regular Americans — illustrates how valuable early outpatient therapy could be for millions of vulnerable adults in this country and around the world. Hydroxychloroquine may also play a role in reducing the risk faced by adults who are unwilling or unable to receive a COVID-19 vaccine. The societal benefits of reducing fear due to availability of effective home treatment would be almost immeasurable.
The randomized trials of early outpatient use of hydroxychloroquine, in combination with results from nonrandomized studies, provide very strong evidence of hydroxychloroquine’s benefit in the prevention and treatment of COVID-19. While this inexpensive and old medication may not arouse the same intrigue — or avarice — as experimental antibodies or novel antiviral agents, its outpatient use is likely to prevent avoidable deaths. People in the United States and around the world should have access to it, and physicians should feel empowered to prescribe hydroxychloroquine to their vulnerable patients.
Ladapo, M.D., Ph.D., is associate professor of medicine at David Geffen School of Medicine at UCLA. Risch, M.D., Ph.D., is professor of epidemiology at Yale School of Public Health. The views expressed are not necessarily those of their institutions.
